4.

4
Degradation Reactions
TAKAYUKI SHlOlRl

Nagoya City University, Japan

795
795
798

4.4.1 FROM CARBOXYLIC ACIDS TO AMINES

4.4.1 .I General Aspects

4.4.1.2 Mechanism and Stereoselectivity

800

4.4.2 THE HOFMANN REACTION

800
802

4.4.2.1 Under Basic Conditions

4.4.2.2 Under Acidic Conditions

806
806

4.4.3 THE CURTIUS REACTION

4.43.1
4.4.3.2
4.4.3.3
4.43.4

Via Hydrazides
Via Acyl Chlorides
Via Mired Anhydrides
By Use of Diphenyl Phosphoraridate

807
810
81 1

4.4.4.1 With Carboxylic Acids

4.4.4.2 With Ketones

817
817
820

THE LOSSEN REACTION

4.45.1 Under Basic Conditions
4.4.5.2 Under Neutral Conditions
4.4.5.3 Under Acidic Conditions

82 1
82 1
824
825

4.4.4 THE SCHMIDT REACTION

4.4.5

4.4.6

REFERENCES

4.4.1

4.4.1.1

825

FROM CARBOXYLIC ACIDS TO AMINES

General Aspects

Degradation reactions of carboxylic acids and their derivatives to amines and their derivatives with
one less carbon
involve rearrangements of a carbon to an electron deficient nitrogen atom as key
steps, namely the Hofmann (H),6,7Curtius (C):lg Schmidt (S)lo-l3and Lossen (L)14,15rearrangements, as
shown in Scheme 1.
The overall process of going from carboxylic acids to amines is known as the Hofmann, Curtius,
Schmidt or Lossen reaction, but these are quite often described as rearrangements and sometimes
called degradations. These reactions were all discovered in the late 19th century (Hofmann, 1881; Curtius, 1890; Lossen, 1872) except for the Schmidt reaction (1923). Since these reactions provide a practical procedure for replacing a carboxy group by an amino group, they have been extensively used since
their discoveries. Inspection of Chemical Abstracts between 1967 and 1988 has revealed that the numbers of papers related to these four rearrangement reactions are 233 for the Hofmann reaction, 522 for the
Curtius reaction, 332 for the Schmidt reaction (including the Schmidt reaction of ketones, aldehydes and
others) and 57 for the Lossen reaction.
795

796

Functional Group Interconversion

0

Hofmann

II

Schmidt

Scheme 1

The common initial products of the rearrangements are isocyanates, which readily react with all types
of compounds containing-OH, -NH or - S H functions, giving amines, ureas, urethanes, thiourethanes, amides etc. (Scheme 2).16 Isolation of the isocyanates may be possible under some reaction conditions, especially in the Curtius reaction when the rearrangement is conducted in aprotic solvents, but
usually the solvolytic conversion of isocyanates occurs to give amines or ureas.

H20, H" or O H

R1NH2

R'NH

K NR2R3
0

R'NH

Scheme 2

The Hofmann r e a ~ t i o ninvolves

~.~
the conversion of carboxylic primary amides to primary amines or
their derivatives. Generally, alkaline hypohalites or a combination of halogens and alkaline hydroxides
are used in aqueous solutions. The rearrangement generally occurs by heating. The intermediate isocyanates are easily hydrolyzed to amines under the reaction conditions, as shown in Scheme 3. When sodium methoxide in methanol is used in place of aqueous alkaline hydroxide, the corresponding
methylurethanes are formed and may be hydrolyzed to yield amines.
The Hofmann reaction is applicable to the preparation of a wide variety of aliphatic, aromatic and heterocyclic amines, and is suitable for large-scalepreparative work, since it is safe and relatively inexpensive to cany out, especially when chlorine and sodium hydroxide can be used.
Oxidizing agents such as lead tetraacetate or [IJ-bis(trifluoroacetoxy)iodo]benzene can also be used
for the Hofmann reaction. The usual Hofmann reaction shown in Scheme 3 proceeds under alkaline con-

Degradation Reactions

R
L'

,N=.=o

X,, MeONa
"2'

LR

1-

MeOH

797

H
I

Scheme 3

ditions; hence, it can not be applied to compounds containing alkali labile functions. For these compounds, the alternative Hofmann reaction (equation 1) can be used, since it proceeds under mildly acidic
conditions.
0
R~

Pb(OAc),

NH,

-[

or PhI(OCOCF,),

RNH, orderivatives

The Curtius reactions.9 involves the thermal rearrangement of acyl azides, with expulsion of nitrogen,
to produce isocyanates. Although the rearrangement of acyl azides proceeds by photochemical means at
lower temperatures, photolysis has no advantage over thermolysis from preparative points of view. Preparation of acyl azides is conducted in three ways, shown in Scheme 4. A common classical route to acyl
azides involves the preparation of acyl hydrazides by the action of hydrazine on esters, followed by treatment of hydrazides with nitrous acid or alkyl nitrites. Interaction of acyl chlorides with sodium azide also
gives acyl azides. Mixed anhydrides prepared from carboxylic acids and alkyl chloroformates are useful
alternatives for acyl chlorides, giving acyl azides when reacted with sodium azide. The hydrazide
method requires more steps and is less convenient than the other methods. Although the acyl chloride
method is convenient, it is sometimes difficult to obtain pure acyl chlorides efficiently from acids, since
decomposition or isomerization occurs in the presence of mineral acids. In contrast to these, the mixed
anhydride method proceeds under mild reaction conditions and mostly gives satisfactory results. The
overall process of converting carboxylic acids to amines or their derivatives through the corresponding
acyl azides is commonly referred to as the Curtius reaction. Since the Curtius reaction proceeds under
relatively mild conditions, it is suitable for sensitive compounds and can be carried out on a wide variety
of acids.

1
R'NH2
base

R'
Scheme 4

One of the most useful variants of the Curtius reaction is the reaction of carboxylic acids with diphenyl
phosphorazidate (DPPA; (Ph0)2P(O)N3) in the presence of base, such as triethylamine (equation 2). 1 7 ~ 1 8

Functional Group Interconversion

798

The Schmidt reactionIGi3is the name given to a group of reactions which involve the addition of hydrazoic acid to carboxylic acids, ketones and aldehydes, alcohols and alkenes under strongly acidic conditions. The most common reaction is the reaction with carboxylic acids, which give amines in a single
step (equation 3). Usually, a mixture of sodium azide and sulfuric acid is used to conduct the reaction,
though the use of a solution of free hydrazoic acid together with sulfuric acid sometimes gives better results. The Schmidt reaction often gives higher yields than the other rearrangement reactions since it is a
one-step reaction. However, the strongly acidic conditions preclude the use of carboxylic acids containing strongly acid labile or reactive functions. Advantages and drawbacks of the Hofmann, Curtius and
Schmidt reactions carried out before 1946 have been discussed in ref.8.

Reaction of ketones with hydrazoic acid proceeds similarly to the Beckm,mn rearrangement to give
amides, while aldehydes yield nitriles and formamides under analogous reaction conditions (equations 4
and 5 ) .

1HN,, H+

R-N+

The fourth related rearrangement reaction is the Lossen reaction,I4J5 which generally occurs by base
treatment of 0-substituted hydroxamic acids which possess electron-withdrawing functions at the
oxygen atom (e.g. 0-acylhydroxamic acids), giving amines via isocyanates (equation 6). Preliminary
0-activation (e.g. 0-acylation) of hydroxamic acids is essential for a smooth rearrangement, otherwise it
will not occur. The Lossen reaction is not as useful as the other three rearrangements since hydroxamic
acids are not readily available.

4.4.1.2

Mechanism and Stereoselectivity

The Hofmann, Curtius, Schmidt and Lossen rearrangements generally involve nucleophilic migrations
from a carbon to an electron deficient nitrogen center (Scheme 5 ) , giving isocyanates as the initial products, which undergo further reactions as already shown in Scheme 2.

X = C1 or Br (Hofmann), X = N2 (Curtius), X = OCOR etc. (Lossen)

Scheme 5

799

Degradation Reactions

Mechanistic studies on these four rearrangement^^.^.^ have revealed that: (i) these are concerted intramolecular rearrangements; (ii) stereochemical configurations of the migrating groups are completely retained; (iii) the kinetics are first order; and (iv) neither free carbonium ions nor radical intermediates are
formed during the rearrangements.
The first intermediates of the Hofmann reaction are N-haloamides (eg. l),which are subsequently
converted to alkaline salts (e.g. 2). Both intermediates can be isolated under carefully controlled conditions. Kinetic evidence on both the s~bstituent'~
and isotope20 effects in the Hofmann rearrangement of
various N-halobenzamides (1) in an aqueous sodium hydroxide solution strongly support a concerted
mechanism, involving the bridged anion (3), shown in Scheme 6.

Scheme 6

Practically, the carbon-nitrogen rearrangements occur with almost complete retention of optical and
geometrical configurations. (S)-(+)-2-Phenylpropionic acid (4) and its derivatives undergo the Hofmann,
Curtius, Schmidt and Lossen rearrangements to give (S)-(-)- 1-phenylethylamine (5) with more than 99%
retention of configuration.21.22Strong alkaline conditions used in the Hofmann reaction cause some
racemization (ca. 4%) before the rearrangement (equation 7).
co2H

+H

ih

Hofmann, Curtius,

"2
c

Schmidt or Lossen

+H

(7)
Ph

(4)

(5)

Conversion of (S)-2-cyano-2-methyl-3-phenylpropionic
acid (6) to (S)-a-methylphenylalanine(7)
through the Hofmann and Curtius rearrangements followed by hydrolysis also proceed with nearly complete retention of configuration (equation 8).23
CO2H
CN

2"

Hofmann or Curtius
c

C02H

The four rearrangements may be utilized for the determination of absolute configurations by correlation to compounds of established configurations. Thus, the absolute configurations of two binaphthyl
derivatives (8 and 9 ) have been determined by utilizing the Curtius rearrangement (Scheme 7).24
Perfect retention of the geometrical configurations has been observed in the Curtius rearrangement of
cis- and trans-crotonyl azides (lo), which respectively give cis- and trans-propenyl isocyanates (ll),
characterized as their urea derivatives (12; Scheme 8).25 The cis isomers (lob) and (llb) tend to
isomerize thermally to the trans isomers (loa) and (lla) respectively.
The Curtius rearrangements of some trans-cinnamoyl azides (13), obtained by treatment of the corresponding chlorides with sodium azide, smoothly give trans-P-styryl isocyanates (14), which are efficiently isomerized in an inert solvent at 250 "C to produce I-isoquinolone derivatives (15; equation 9).26
The isomerization proceeds more conveniently at 140 "C in the presence of iodine.

800

Functional Group Interconversion

i, SOCI,; ii, NaN3

c

2"

iii, A, O H

goMe
(8)

i, SOCI,: ii, NaN3

COZH

2"OMe

iii, A, O H

(9)

Scheme 7

NaN3

m-xylene

V C O C I

aq. Me2C0
85%

VCON~
reflux
35%

(loa)

"3

V N C O

V NHCONH,

ether

Ph

Ph

Ph

benzene

reflux
37-81%

49-100%

H
0

R = H, Me, Ph

(13)

(14)

(15)

4.4.2 THE HOFMANN REACTION

4.4.2.1 Under Basic Conditions

The classical and most standard reaction conditions of the Hofmann rearrangement use sodium or
potassium hypobromite (or bromine with sodium or potassium hydroxide) under aqueous conditions.

Degradation Reactions

80 1

Sodium or potassium hypobromite may be replaced with the other alkaline hypohalites such as sodium
hypochlorite, calcium hypochlorite or barium hypobromite. The other alternative reagent used under
aqueous alkaline conditions is sodium bromite (NaBrO2) in the presence of a catalytic amount of sodium
bromide27or a calculated amount of benzyltrimethylammonium bromide (PhCH2N+Me3Br).28
Neopentylglycine (17) is conveniently prepared from neopentylmalonamic acid (16) by the action of
hypobromite (equation
The method using the carbon-nitrogen rearrangements of malonic half-acid
derivatives is one of the classical methods for the preparation of a-amino acids.
-0Br

Buf

yC02H"y
CONH2

C02H

But

NH2

quantitative

The Hofmann reaction under basic conditions is apparently suitable for degradation of acid sensitive
compounds, e.g. acetals, without any change at their acid sensitive functions (equation 1l).30

Br,, aq. NaOH

0 "C,1 h; 80 "C,1 h

OEt

67%

(11)

OEt

' N

Isocyanates, the initial products of the Hofmann rearrangement, usually undergo solvolysis to give
amines, as described earlier (Section 4.4.1.1). However, a two-phase Hofmann reaction using phase
transfer catalysts allows isolation of reactive isocyanates (equation 12).31The phase transfer catalyst is
essential for the formation of primary and secondary isocyanates, while tertiary isocyanates are formed
without the catalyst. Shorter reaction times at room temperature as well as high dilution conditions
minimize the formation of by-products such as dialkylureas or acylalkylureas. Chlorine in place of
bromine considerably decreases the yield of isocyanates.

CONH2

Br,, PTC
D
aq. NaOH-CH2C12
25 "C,15 min
87%

&

NCO

PTC = Bu4N+HS04-, PhCH,N+Et,CI-, or Bu4P+Br-

Although the Hofmann reaction is applicable to various amides under usual aqueous alkaline conditions, it sometimes proceeds sluggishly, especially in the rearrangement of hydrophobic amides such as
aliphatic amides containing a longer carbon chain. However, use of bromine and sodium methoxide
gives better results though the product is a methylurethane, as already shown in Scheme 3. This methoxide method is classified into three approaches according to the order of mixing reagents: (i) addition of
bromine to a methanolic solution of an amide and sodium methoxide (the Jeffreys' method, J);6,7*32
(ii)
use of a methanolic solution of bromine in the Jeffreys' method (the Nagai-Matsuo method, N);7*33.34
and (iii) addition of bromine to sodium methoxide in methanol to produce methyl hypobromite, followed
by addition of amides (the Radlick and Brown method, R),35,36shown in Scheme 9. The last method is
utilized for the amide (201, which is highly susceptible to electrophilic addition reactions.35
The electroorganic method also induces the Hofmann reaction, by use of potassium bromide as a catalytic mediator, giving methyl urethane^.^^ Since the reaction proceeds without heating under neutral conditions, this method can be applied to a base labile epoxyamide (21),which gives unidentified products
with no epoxide function when treated under the usual alkaline conditions of the Hofmann reaction
(equation 13).
An attempted Hofmann reaction of phosphonoacetamides (22) with alkaline sodium hypobromite
shows a dramatic substituent effect (Scheme
The rearrangement occurs when the alkyl residue (R)
is ethyl or phenyl, while only bromination occurs when R is hydrogen or benzyl.

802

But

But
CONI42

J (O%),

N (96%)

But

p-".

But

O H
p N H C O z M e

*
aq. MeOH

But

85.4%

But

Scheme 9
-2e-

CCONHz

O
(21)

NHC02Me
MeOH-KBr
18.4 F mol-'

Scheme 10

Phthalimides undergo the Hofmann reaction by an initial hydrolytic ring-opening, giving the N-haloamides formed from either of the free imides or the N-haloimides, followed by their rearrangement to
give anthranilic acids.39The regioselectivity in the Hofmann rearrangement of N-chloro-4,4-dialkylh~
mophthalimides (23)is governed by the bulkiness of the 4,4-dialkyl groups.4o The imides containing
small substituents give rise to indolinones (24), while isoindolinones (25) are formed from the imides
containing bulky substituents (equation 14).
(S)-N-Carbarnoylalanine (26) also undergoes the Hofmann rearrangement to give (S)-N-aminoalanine
(27), by use of sodium hypochlorite but not hypobromite (equation 15).'"

4.4.2.2

Under Acidic Conditions

The oxidative Hofmann rearrangement of primary carboxamides occurs by use of lead tetraacetate
(LTA) and several hypervalent organoiodine compounds IF5 (28), PhI(OCOCF3)2 (29), PhI(0H)OTs
(30) and Phi0 (31) under mildly acidic conditions.
Although some conflicting results have been presented by B e ~ k w i t hand
~ ~Ba~mgarten?~
LTA is still
an interesting reagent for the oxidative rearrangement. LTA in benzene converts primary amides to acyl-

Degradation Reactions

H2NCONH

$OZH
H

803

i, NaOCI. NaOH
D

ii, HCI
27%

H2NNH

(27)

(26)

amines, together with a small amount of dialkylureas?* The reaction, which may also be conducted in
acetic acid or benzene-acetic acid, is catalyzed by pyridine. Acetic acid may be replaced with other carboxylic acids (equation 16).
P ~ ( O A C )R2C02H
~,

(16)

benzene

With LTA in refluxing t-butyl alcohol, t-butyl carbamates are conveniently produced from various
amides (equation 17).43 Triethylamine, tin(1V) chloride and dibutylstannyl dilaurate are effective catalysts for the reaction of the intermediate isocyanates and t-butyl alcohol. When the reaction is run in dimethylformamide, isocyanates can be isolated and easily converted to ureas with ?-butylamine(equation
1q.43

CONHz

Pb(OAc),, Bu'OH
D

NHCO~BU'
(17)

reflux, 2 h
79%
i, Pb(OAc)4, DMF

'p^hYCONHZ

(18)
ii, Bu'NH2
97%

In addition, both primary and secondary alcohols can be used, alone or together with benzene.42Pyridine also serves as a catalyst. The method is applicable to a wide variety of amides and alcohols, including compounds containing alkenic, ester, aromatic and other reactive: functions, as shown in Scheme

11.
The oxidative rearrangement with LTA also proceeds with retention of configuration about the migrating carbon atom, as shown in equations (19)43and (20).44
Iodine pentafluoride (28) in hot pyridine works like LTA as a Hofmann reagent for aliphatic primary
carboxamides (equation 2 l).45Iodination occurs together with rearrangement when benzamide is treated
under similar reaction conditions.
[IJ-Bis(trifluoroacetoxy)iodo]benzene (PIFA; 29) also brings about the facile oxidative rearrangement
of aliphatic amides to amines in mildly acidic (pH 1-3) 50% aqueous acetonitrile at rmm temperature
within several hours, as shown in equation (22).46947The reagent cannot be applied to the formation of
aromatic amines since the latter are further oxidized. The intermediates of the reaction are isocyanates,
which are rapidly hydrolyzed to amines under mildly acidic conditions. The acidic conditions protect the

804

Functional Group Interconversion

PhKNH2

Pb(OAc),+,benzene, pyridine

HO

W OC, 1 h
35%

PhNHCOp

Cholesterol
Pb(OAc),, cyclohexanol

su

benzene, 1.5 h
75%

%CONH,

&

Scheme 11

Pb(OAc),+,SnC14,Bu'OH
I

C02Me

reflux, 19 h
87%

7CO2Me

Pb(OAc),, pyridine

(20)
95%

IF,, pyridine

product amines from reacting with the intermediate isocyanates and forming ureas. The reaction is catalyzed by pyridine though this is not strictly necessary.
RCONH2 + PhI(OCOCF3)2 + H20

RNH3' + C02 + PhI + 2CF3C02- + H+

(22)

(2%

PIFA easily converts succinic acid derivatives (32)to p-alanine derivatives (33)!7 Limited use of
PIFA (1 equiv.) allows the rearrangement of 3-cyclohexene-1-carboxamide(34)without oxidation of the
double bond, as shown in Scheme 12. Cyclohexanone is obtained by the PIFA oxidation of l-cyclohexenecarboxamide (35). Selective oxidation of the primary amide (36)occurs without effect on secondary
or tertiary amides in the same rn~lecule?~
The rearrangement of the cyclopropane derivative (37)accompanies the ring cleavage to give the p-alanine derivative (38) after treatment with benzyloxycarbonyl
chloride!*
Retention of configuration during the Hofmann reaction promoted with PIFA has been rigorously
demonstrated in the rearrangements of (S)-(+)-2-phenylpropionamide (39)47as well as the peptide derivative (40),49as shown in Scheme 13. The latter reaction can be employed in the sequential degradation of
carboxy terminal peptidesx as well as modifications of peptide^.^'

805

Degradation Reactions

R = H,81%
R = Et, 86%

(32)

PhI(OCOCF3)z

55%

A,-N?coz CONEtz

(33)

NH;

*cy-

c1-

CONEt2

(36)

quantitative
(37)
Scheme 12

PhI(OCOCF&
85%

PhYCONHZ
(39)

PhI(OCOCF3)z

Scheme 13

Hydroxy(tosy1oxy)iodobenzene (HTIB; 30) is another hypervalent organoiodine compound which acts

as a Hofmann reagent?2 converting aliphatic carboxamides to alkylammonium tosylates in refluxing acetonitrile (equation 23).
Ph
I

MeCN
__c

HO I OTs

RNH~+--OTS +

ph~

(23)

nflux

(30)

in contrast to the classical HofHTIB is particularly useful for the degradation of long chain
mann reaction under alkaline conditions (see Section 4.4.2.1). The double bonds remain intact with

806

Functional Group Interconversion

HTIB. In the reaction with malonamide, however, only tosylation at the active methylene carbon occurs
(Scheme 14).52

n = 11,90%; n = 12,81%; n = 13.91%; n = 14,88%; n = 15,91%; n = 16,89.5%; n = 20,94%

PhI(0H)OTs
80%

trans

trans

CONH2

PhI(0H)OTs

CONH2
81%

TsO-(
CONH2

Scheme 14

Iodosylbenzene (31), together with formic acid, can also be used for the oxidative Hofmann reactiod4
in an acetonitrile-water mixture (3: 1) at room temperature (equation 24). The reaction behavior of (31) is
quite similar to that of PIFA.
Ph

4.43

4.43.1

)!,

NH2

HCOZH

PhIO

(31)

aq.MeCN

RNH3' H C O l

PhI

(24)

THE CURTIUS REACTION

Via Hydrazides

As described earlier (Section 4.4.1. l), the intermediates of the Curtius reaction are acyl azides, which
thermally rearrange to isocyanates. One of the classical procedure^*^^ for the preparation of acyl azides
consists of the formation of hydrazides from esters and hydrazine, followed by treatment of the hydrazides with nitrous acid, generated from sodium nitrite and acetic, hydrochloric or sulfuric acid. Acyl
azides are commonly used in the crude state or in solution since they are thermally unstable and potentially explosive.
Conversion of phosphonoacetic esters (41) to aminophosphonic acids (42) is conveniently carried out
by chemoselective reaction of (41) with hydrazine, followed by the Curtius rearrangement without isolation of any intermediates (equation 25).55

R = H, 54%; R = Me, 80%; R = PhCH2, 56%

(42)

807

Degradation Reactions

The pyrazole derivatives (44),prepared from the lactones (43), give the cyclized (45 and 46) or uncyclized products (47) by the Curtius rearrangement, depending on the substrates and reaction solvents
(Scheme 15).56

; J fo
Me
0
(43)

\
n=O

Dh4E or EtOH

(45) 58-72%

n= 1

R'
(46) 6 1 4 7 %

EtOH

(47) 3 9 4 9 %

Scheme 15

The Curtius rearrangement of the acyl azide derived from optically pure a-methoxy-a-(trifluoromethy1)phenylacetic acid (MTPA; 48) also proceeds with retention of configuration, giving a-methoxyw(trifluoromethy1)benzyl isocyanate (49; equation 26).57 The isocyanate (49) is useful for the
determination of the enantiomeric composition of optically active primary and secondary amines.

Alkyl nitritesSEand nitrogen

together with acid are also effective for the formation of
acyl azides from hydrazides under anhydrous conditions. As shown in Scheme 16, the Curtius reaction is
especially suitable for the formation of complex reactive molecules.

4.4.3.2

Via Acyl Chlorides

Formation of acyl azides from acyl chlorides is also a classical p r o c e d ~ r efor

~ ~the
~ Curtius reaction.
Sodium azide is used for the azidation under aqueous and anhydrous conditions, called the wet and dry
methods respectively (equations 2761and 2862).

Functional Group Interconversion

808

&

M12"2*H20

CONHNH2

NHCOzEt

HCI, EtOH

N2O4, NaOAc, CH2C12

NH#l"H*H20

EtOH
r.t. 3 h

-70 O C , 5 min

f i n

rlene. reflux

i, NZO4, CH2CI2, -78 OC

ii, Me3SiCI.Et3N

EtOH

Me0

OSiMe3

OSiMe3

4gN3dNC
benzene, NaOAc

reflux

Me0

BU"~N+F

THF, 20 min

Me0

OMe H
Scheme 16

<

i, S W I 2

CO2H

ii, NaN3, aq. acetone

-20 O C , 30 min

<ECON3
i, PhH, reflux

LNH~
C02H

HO

ii, aq. HCI

reflux, 15 min

(27)

46% overall

i, (COCI)z,PhH, DMF (catalyst), 82%

L

9
%c02H

(28)

ii, NaN,, MeCN, A, 1 h, 84%

Trapping of isocyanates, the intermediates of the Curtius reaction, is usually carried out with methanol, ethanol, r-butyl alcohol or benzyl alcohol. Use of 9-anthrylmethanol (AnOH) gives the correspond-

Degradation Reactions

809

ing urethanes, which can be converted to amines by treatment with sodium ethanethiolate under neutral
conditions (equation 29).63
CO2H
I

NHC02An
I

i, SOCI,; ii, NaN3; iii, A, toluene; iv, AnOH

A useful variant of the Curtius reaction comprises the reaction of acyl chlorides in dichloromethane
with sodium azide under phase transfer conditions, followed by treatment of the dried dichloromethane
solution, which contains acyl azides, with a slight excess of trifluoroacetic acid. The resulting trifluoroacetamides can easily be cleaved with potassium carbonate in aqueous methanol at room temperature,
giving the amines (equation 30).@

Hl

KzC03, aq. MeOH

RNH2

R"'COCF,

In place of sodium azide, which has low solubility in common organic media, use of a mixture of hydrazoic acid and
tetrabutylammonium azideM or tetramethylguanidinium azide6' has been
recommended. One of the most useful and safe alternatives is trimethylsilyl azide (50), which reacts with
various acyl chlorides or anhydrides to give isocyanates directly, under thermal conditions (Scheme
17).68*69
0

p+COCI

/VNC0

Me3SiN3 (50). CCI,

0
Me$iN, (SO)
50
benzene
'C,16 h

- (lo
I

R
R = Me3Si, 15%; R = H, 52%
Scheme 17

When the usual reaction conditions using trimethylsilyl azide (50) are not suitable for the Curtius reaction, addition of catalytic amounts of powdered potassium azide and 18-crown-6 is quite effective in
conducting the reaction (equation 3 l).70
Tributylstannyl azide (51), prepared from tributylstannyl chloride and sodium azide, is also useful for
the direct conversion of acyl chlorides to isocyanates (equation 32).71 In addition, succinic anhydride

810

Functional Group Interconversion

Me3SiN3 (SO), KN3

18trown-6, benzene
reflux, 35 h

88% overall

reacts with (51) to give tributylstannyl 3-isocyanatopropionate (52), which on treatment with benzyl alcohol and then aqueous alkali affords N-benzyloxycarbonyl-f3-alanine(53; equation 33).

Bu$nN3

N=.=O

Bu3SnC1

R'

(32)

(51)

H
Bu3SnN3(51)
*

(Nco

i, PhCHtOH

CO2SnBu3'

ii, O H

c"-a"-"

(33)

COzH

0
(52)

(53) 35% overall

dNJoM

Acyl chlorides may be replaced with imidazolides, which react with sodium azide to give acyl azides.
In the reaction shown in equation (34). 2-trimethylsilylethanolis used for trapping the i ~ o c y a n a t eThe
.~~
resulting 2-trimethylsilylethyl ester is easily cleaved with tetra-n-butylammonium fluoride.
OMe

QJJC02H

i,CO(Im)2

Me0

ii, NaN3
87%

ii, HOCH2CH2SiMe3
90%

CON3

CO(Im), = carbonyl diimidazole

d:ZoMe
NH

(34)

NJV-Dimethylchlorosulfitomethaniminium
chloride (54), prepared from thionyl chloride and dimethylformamide, together with sodium azide is useful for the direct preparation of acyl azides from carboxylic
acids (equation 35).73
0
II

ArAOH

OSOcl
Me2; =/
C1- (54). NaN3
/

Bu4N+Br-, pyridine, CH2C12

9II

(35)

Ar A N3

75-96%

4.43.3

Via Mixed Anhydrides

Mixed carboxylic-carbonic anhydrides, prepared from carboxylic acids and alkyl chloroformates in
the presence of base, are easily converted to acyl azides by the action of sodium azide. Since the reaction
sequence from carboxylic acids to acyl azides proceeds under mild conditions, it has a broad applica-

Degradation Reactions

811

bility. cis-2-Phenylcyclopropanecarboxylicacid (55) is easily converted to cis-2-phenylcyclopropylamine (56), without isomerization to the trans isomer, by consecutive treatment with: (i) ethyl chloroformate in the presence of triethylamine; (ii) sodium azide; (iii) refluxing toluene; and (iv) hydrochloric
acid, without purification of the intermediates (equation 36).74

- XPh

i-iv
77%

'12H

(36)

2"

(55)

(56)

i, ClC02Et,Et3N,aq. Me2C0,0 OC, 30 min; ii, NaN3 in water, 0 OC, 1 h; iii, toluene, reflux;
iv, 20% aq. HCI, reflux, 9 h
Various trans- 1-N-acylamino- 1.3-butadienes (58) are prepared from 2,4-pentadienoic acids (57) by the
mixed anhydride method (equation 37).75 The procedure is reproducible when Nfl-diisopropylethylamine is used in place of triethylamine.
i-iv

R ' O C 0 2 H

44-808

R'm
"COX

(57)

(37)

(58)

i, C1CO2Et,Pr',NEt, 0 OC, 30 min; ii, NaN3 in water, 0 O C , 30 min; iii, toluene;

iv, XH (R20H, R3NHR4 or R'SH), reflux

The mixed anhydride method is analogously and conveniently applied to the preparation of a-amino
acids (60) from malonic acid half-esters (59; equations 38 and 39)?6.77

COzEt

(59b)

4.4.3.4

CO2Et

X=NH.S

(60b)

By Use of Diphenyl Phosphorazidate

Diphenyl phosphorazidate (DPPA; (Ph0)2P(O)N3) is a useful and versatile reagent in organic synthesis,'* and can be conveniently used for the Curtius reaction under mild reaction conditions, using carboxylic acids as a starting material.17J8 Exchange of the azide group occurs from DPPA to carboxylic
acids in the presence of base, e.g. triethylamine, giving acyl azides. When the reaction is conducted
under thermal conditions, the rearrangement occurs in situ to give isocyanates in a single step. Addition
of water, or preferably a mineral acid, to the reaction mixture containing isocyanates gives amines in a
one-pot process, while addition of alcohols yield urethanes. When this modified Curtius reaction is carried out in refluxing t-butyl alcohol, t-butylurethanes are formed in a single process from carboxylic
acids. The modified Curtius reaction using DPPA is similar to the Schmidt reaction in the sense that carboxylic acids yield amines or their derivatives in a one-pot process, but is more like the Curtius reaction

Functional Group Interconversion

812

from a mechanistic point of view.18 Since the reaction proceeds under mild and neutral conditions, it has
a broad applicability.
Acyl azides (61)79and (62)80and isocyanate (63),81the reaction intermediates of the modified Curtius
reaction using DPPA, have been isolated in a pure state, since they are relatively thermally stable, and
further converted to urethanes or ureas by the addition of alcohols or amines respectively.

2"

Pyridine-2-carboxylic acid (M),which is known to fail in the Schmidt reaction, smoothly undergoes
the reaction with DPPA to give the r-butylurethane (65).lsThe potassium salt of penicillin G (66) also
gives the t-butylurethane (67) in a single operation. Although levulinic acid (68)gives the r-butylurethane (69) together with the carbamoyl azide (70) in unsatisfactory yields, the corresponding acetal
derivative (71) smoothly undergoes the rearrangement to give the urethane (72) in good yield, together
with small amounts of the carbamoyl azide (73)and the benzyl ester (74 Scheme 18).18
(PhO)$'(O)N3,
COzH

NHCOzBu'

Bu'OH, reflux, 23 h
73%

(64)

ph7"

Et3N

&N/X

(65)

H H

0 0

ph7'Nzr-

Bu'OH, reflux,28 h
COzK

H H

(PhO)*P(O)N3

0 0

5-

NHCO~BU'

80%

(66)

(67)

A2NHCON3
Bu'OH, reflux, 17 h
(69) 27.5%

(72) 83%

(73) 8%

(70) 14%

(74) 6%

Scheme 18

Reaction procedures affect the products when malonic acid halfesters (75) with an acidic hydrogen at
the a-position are subjected to the modified Curtius r e a c t i ~ n . *The
~*~
usual
~ one-pot procedure, in which
alcohols are present from the beginning, affords esters (76), whereas the two-in-one procedure, in which

813

DegradationReactions

alcohols are added after the formation of isocyanates, conveniently produces urethanes (77; Scheme 19).
Formation of esters can be explained by the generation of ketene intermediates in equilibrium with acyl
azides. The former irreversibly react with alcohols to give esters.83Malonic acid half-esters with no
acidic hydrogen, e.g. (78), do not undergo the esterification but give the rearranged products, e.g. (79).
even in the one-pot procedure since no ketene intermediates can be formed (Scheme 19).
(m0)2P(O)N3, Et$

R'+cozEt
COzEt

-I
(79)

Scheme 19

The one-step modified Curtius reaction of N-benzyloxycarbonyl-L-proline(80) gives the allophanate

(82) as the major product in addition to the expected urethane
However, the use of r-butyl carbamate (83)as an additive changes the reaction course and the desired carbamate (81b),though accompanied by racemization, is obtained in good yield. Similarly, the p-carboline derivative (84) also affords a
mixture of the urethane (85) and the allophanate (sa), with the latter as the major product, by a one-step
pr0cedure.8~The two-step procedure, however, produces more of the urethane (85; Scheme 20).

N H ~ C O ~ B(83)
U'

benzene, reflux

(81b) 66%

wN-z

NHCOZBu'
_-'3N3,Et3N

Bu'OH, reflux

- \

1N \

one-step procedure
two-step procedure

10%
22%

Scheme 20

N ' Z \+

NHCONHCO~BU'

IN

32%

Functional Group Interconversion

814

Within the total synthesis of the antitumor antibiotics streptonigrin and lavendamycin, sterically hindered polyfunctional pyridinecarboxylic acids (87-89) have been conveniently converted to their corresponding amines by treatment with DPPA-triethylamine in refluxing benzene for 1-25 h, followed by a
brief reflux after addition of

0I
N
COpMe

Me02c8c02Me

HOpC
H0pC

P h V

x /

Me0

OMe

(87a) X = H, 60% (ref. 86)

(87b) X = Br, 71% (ref. 87)

OMe
(89) 43% (refs. 89.90)

(88)83% (ref. 88)

Sensitive molecules such as (90)?' (92),92and (94)93smoothly undergo the modified Curtius reaction
with DPPA to give the corresponding carbamates (91), (93) and (93, as shown in Scheme 21.

qCopH
i, (PhO)2P(0)N3,Et3N, toluene, 80 O C

'To*SiMe3

ii, HOCH2CH2SiMe3,80 "C

86%

(90)

GxH

(91)

NHCOpMe

i, (PhO)2P(0)N3,Et3N, benzene, reflux

ii, MeOH. reflux

-ki

(92)

a,X=

(93)

,71%

b,X=

xo

,41%

c,X=

N-Ph

,77%

LOH E x o
i, (PhO),P(O)N,, Et3N

ii, benzene, reflux, high dilution

80%

(95)

(94)

Scheme 21

Analogously, the Curtius rearrangement followed by an intramolecular cyclization easily occurs by the
reaction of DPPA with hydroxycarboxylic acids (96) and (9%).giving cyclic carbamates (97)94and (99;
equations 40 and 41).95
Rearrangement of @-alanineand succinic acid derivatives (100 and 102) gives 1-acyl-2-imidazolidinones (101) and @-alaninederivatives (103) respectively (Scheme 22).96However, the N-methylcarbox-

Degradation Reactions

815

, N 4

HOAPh
benzene, reflux, 30 h

OT0Aph

quantitative

amide function has been found to have a deleterious effect and the compounds (104a) and (104b) afford
a complex mixture of products.

R"

R* = Ph, R2 = H, 74%; R' = PhCHzO, RZ= H, 55%; R' = Ph, R2 = COzMe, 60%

("g"-"
H
I

"zH

i, (Ph0)2P(O)N,, Et3N*
ii, PhCH20H

'COR

COR

(102)

(103)
R = COzMe, 80%;R = CONMe2,60%

RG

(104a) R = H
(104b) R = PhCONH

Scheme 22
1-Aryl-] ,2,4-triazolin-5-ones (106) are conveniently prepared from arylhydrazones of a-keto acids
(105) by the Curtius rearrangement with DPPA, followed by an intramolecular cyclization (equation
42)?7
Ar

Ar""

COzH

lA

(105)

(PhO)$WNj, Et3N
(42)

toluene, reflux, 1 h
5146%

H
(106)

Functional Group Interconversion

816

1-Cyclohexenyl isocyanate (108),produced from 1-cyclohexenecarboxylic acid (107) and DPPA in

situ, reacts with 1-(N-pyrrolidiny1)cyclohexene (109)to give the pyridone derivative (110;equation
43).98 The similar vinyl isocyanate-enamine cyclocondensation presents a general method for the preparation of various pyridone derivatives.

-0

do

[ oNco
1
(109)

C O ~ H (Ph0)2P(0)N3.Et3N_
toluene, reflux

73%

(107)

(108)

(43)

H
(110)

Preparation of a-amino acid amides of aromatic amines (111) is easily conducted as a one-pot procedure by the modified Curtius reaction of aromatic carboxylic acids with DPPA, followed by reaction
with N-protected a-amino acids (equation 44).% By this method, N-t-butoxycarbonyl-L-leucine
p-nitroanilide, which serves as a substrate for leucine aminopeptidase after deblocking of its t-butoxycarbony1 group, has been efficiently prepared from p-nitrobenzoic acid and N-t-butoxycarbonyl-L-leucine.
0

i, (PhO),P(0)N3, Et3N

Ar

Ama-NH Ar

t -Boc-L-

ii, t-BOC-L-Ama-OH, ClCH,CH,L

(44)

(111)
t-BOC = Bu'OCO Ama = amino acid residue

Analogs of DPPA such as diethyl phosphorazidate (112),18di-p-nitrophenyl phosphorazidate (113)lo0

and phenyl N-phenylphosphoramidoazidate(114)lo' can also be used for the Curtius reaction. Di-p-nitrophenyl phosphorazidate (113)has been proposed as a reagent for the determination of the carboxy terminal residue of peptides.Im A simple protected form of diaminomethane (116),an interesting building
block for peptide mimetics, has been prepared from t-butoxycarbonylglycine(115) using di-p-nitrophenyl phosphorazidate (113;Scheme 23). lO2 Phenyl N-phenylphosphoramidoazidate(114)has been utilized
for the preparation of NN-diarylureas (117)from aromatic carboxylic acids and aromatic primary
amines.lO'

(114)
i, (113),Et3N
ii, PhCH,OH, 75 "C, 4.5 h
83%

0
B u t O K NI A N

ii, A?",

"y'A?
0
(117)

Scheme 23

i, (114). Et3N, MeCN

Ar'
Ar'

AOn

Ph

817

Degradation Reactions

THE SCHMIDT REACTION

4.4.4

4.4.4.1

With Carboxylic Acids

The Schmidt r e a ~ t i o n ' ~is' ~

usually carried out using a mixture of sodium azide and sulfuric acid,
which generates hydrazoic acid. Free hydrazoic acid together with sulfuric acid may also be used. Although the Schmidt reaction of carboxylic acids is quite useful for the preparation of amines with one
less carbon unit, it is less flexible than the other rearrangements since it requires hazardous hydrazoic
acid and strongly acidic conditions. Since hydrazoic acid is very poisonous and potentially explosive, the
reaction should be conducted under an efficient hood and precautions should be taken against explosion,
especially in a large-scale preparation. In place of sulfuric acid, polyphosphoric acid and trifluoroacetic
acid-trifluoroacetic anhydride may be used. Usual solvents are chloroform, 1,2-dichloroethaneand benzene.
Aliphatic carboxylic acids, even in the case of a sterically hindered carboxylic acid such as (118), are
usually converted to the corresponding amines, e.g. (119), by the Schmidt reaction (equation 45).Io3
0

Ph

II

FP

"e

..

NaN3, H2SO4, CHCl,

c

Ph'

50-55 OC, 1.5 h

1
I

(45)

L N . 2

Both phenylacetic and 3-phenylpropionic acids (120) easily undergo the Schmidt reaction under the
standard conditions using sulfuric acid, giving the corresponding amines (121).'04 4-Phenylbutyric acid
(122), however, produces the cyclic lactam (123), in addition to the sulfonated amine (124). Replacement of sulfuric acid with polyphosphoric acid again affords the lactam (123) mainly, together with
3-phenylpropylamine (125) as a minor product. In the rearrangement of 5-phenylpentanoic acid (126),
only the sulfonated amine (127) is obtained, as shown in Scheme 24.

ph

wc02H

ph

7040%
n = 1.2

(120)

WNH2

NaN3, conc. H2SO4, CHCl3

Ph

M3C02H

40 "C, 1 h
H

(122)

1
(123)
40%

(123) 50%

(124) 40%

NaN3, PPA
80-85 "C, 2 h

PhwF
(125) 24%
NaN3, conc. H2S04, CHCI,

Ph W C O Z H

40 OC, 1 h

80%

Scheme 24

(127)

Functional Group Interconversion

818

Treatment of 2-phenylhexanoic acid (128) with sodium azide in polyphosphoric acid furnishes the expected amine (129) together with aniline (130) in a nearly equal ratio, as shown in Scheme 25.'05 2-Phenyl-2-methylhexanoic acid (131) gives aniline (130) only and no Schmidt product is obtained. Similar
treatment of diphenylacetic, 2,2-diphenylpropionic and triphenylacetic acids mainly gives the unchanged
starting materials. Except in the case of triphenylacetic acid, a small amount of aniline (130) is formed.
The above anomalous formation of aniline can be explained by the decarboxylation at the initial step to
form a benzyl-type cation (132), which reacts with hydrazoic acid, followed by rearrangement with concomitant expulsion of nitrogen and then hydrolysis.
Bu

NaN3, PPA
c

PhAC02H

50 "C

Ph

(128)

(129) 49%
NaN3, PPA
*
50 "C
58%

Phk;02H
(131)

PhNH2

NH2

(130) 46%
PhNH2

(130)

Scheme 25

(E)-Hex-3-ene-l,6-dioic acid (133) undergoes the Schmidt reaction with 1 equiv. of sodium azide to
give (E)-5-aminopent-3-enoic acid (134) in moderate yield, shown in Scheme 26. The Schmidt reaction
of the corresponding (a-isomer (135) analogously proceeds to give the (a-amino acid (136) though
with much lower efficiency.lMFurthermore, hex-3-yne-1.6-dioic acid (137) gives the Schmidt product
(138) in very low yield, presumably because of competing additions of hydrazoic acid to the triple bond.

The absolute configuration of (+)-trunscyclopentane-l,3-dicarboxylic acid (139) has been determined

to be (lS, 3s) by the correlation with trans-(lS, 3S)-3-aminocyclopentanecarboxylicacid (140) through
the Schmidt reaction (equation 46).lo7
HOZC , , , , 0 C O 2 H

"3,

H2SO4

CHCl,, 60 OC, 4 h
12%

(139)

'YYNH2

(46)

Ho2C

(140)

Degradation Reactions

819

Aromatic carboxylic acids, e.g. (141),*08

also undergo the Schmidt reaction to give amines, e.g. (142),
in a single operation. Although the Schmidt reaction of 2,4,4,6,6-pentanitrobiphenyl-2-carboxylic
acid
(143a)proceeds to give the amine (144a)in 49% yield, the corresponding 2,4,6-trinitro analog (143b)
affords only unchanged starting material (Scheme 27).09 In the latter case, however, conversion to the
amine (144b)has been achieved by the Curtius reaction via the acyl chloride.

(142)

COiH

1,2-dichloroethane
70 C, overnight

(143a,b)

a: X = NO,, b: X = H
Scheme 27

Treatment of phthalic acid (145)with sodium azide under acidic conditions has been reportedii0 to
give various products: anthranilic acid (147)and a trace of o-phenylenediamine (148) in concentrated
sulfuric acid; and anthranilazide (149)and benzimidazol-2-one (150)in 90% sulfuric acid. Analogously,
phthalic anhydride (146)gives the following products: anthranilic acid (147),benzimidazol-2-one (150)
and some 3,l-benzoxazine-2,4(1ti)-dione (isatoic anhydride) (151)in sulfuric acid; and benzimidazol-2one (150)in acetic acid. A recent reportilohas revealed that the Schmidt reaction of phthalic acid (145)
in 90-98% sulfuric acid gives anthranilic acid (147)and anthranilazide (149)(major products) by a process thought to involve 3,l -benzoxazine-2,4(Iw-dione (151)as an intermediate. Benzimidazol-2-one
(150)is produced in this reaction by a secondary process from anthranilazide (149).Photolysis of (149)
also produces (150).
0

Under the Schmidt reaction conditions, the lactol (152)of 4-formyl-5-phenanthroic acid gives 1-azapyren-2( lH)-one (153) and phenathrene-4,5-dicarboxirnide (154).* l o The compound (153) may be
formed by attack of hydrazoic acid at the latent aldehyde site in preference to the carboxy site (see Section 4.4.4.2). Phenanthrene-49-dicarboxylic acid (159,obtained by oxidation of (152),similarly affords

Functional Group Interconversion

820

(153) as the major product. Diphenic acid (156) also undergoes the Schmidt reaction to give 2.2-diaminobiphenyl (157) and phenanthridone (158) in proportions dependent on the sulfuric acid concentration,
as shown in Scheme 28.

NaN3,95-98% HzSO4

1.2-dichloroethane

6
/

+H ; @

W C O Z H

NaN,, 95-98% HzSO4

WozH

1,2-dichloroethane
67%

(155)

95-98% HzSO, :
90%H$04:

43%
5%

6%
56%

Scheme 28

4.4.4.2

With Ketones

In addition to carboxylic acids, hydrazoic acid reacts with ketones, aldehydes, alcohols and alkenes
under strongly acidic conditions. Among them, the Schmidt reaction of ketones1&12has been most studied because of its synthetic possibilities as well as its similarity to the Beckmann rearrangement (Section
4.3.1).A drawback of the Schmidt reaction of unsymmetrical ketones is that which one of its substituents
will migrate depends on the structures and reaction conditions (see equation 4 in Section 4.4.1.1).
Regioselective migration, however, has been observed in many cases. Although the Schmidt reaction with
ketones does not strictly belong with the degradation reactions reviewed in this chapter, it will be discussed here briefly since it is often used and its reaction procedure and mechanism are very similar to
those of the Schmidt reaction with carboxylic acids.
In general, ketones are preferentially attacked by hydrazoic acid when both ketonic and carboxylic
groups are present in the same molecule (cf. conversion of 152 to 153 in Scheme 28). Thus, treatment of
the ketophenolic acid (159) with sodium azide in phosphoric acid chemo- and regio-selectively gives the
lactam-lactone (160) as the sole product (equation 47).
The Schmidt rearrangement of optically active a,a-bisalkylated P-keto esters (161) regioselectively
proceeds to give N-acyl a-alkylated a-amino acid esters (162) with retention of configuration and little
or no racemization.IlZAcid hydrolysis of (162), followed by treatment with propylene oxide, affords
a-alkylated a-amino acids (163) in high yield and optical purity (equation 48).

Degradation Reactions

.&

82 1

HO

C02H
NaN3. 85% H3P04

HO

60C,60h
40%

NaN,, MeS0,H
R

3
R2

g
"/Ri

OEt CHCI,, reflux, 0.5-1 h

71-95%

(161)

d,

i, H+

R3yi$
0 RZ

"'/RI OEt ii, 0

(162)

8&99%

EtOH

(47)

C02H

R~+NH~
R'

(48)

(163)

4-Acetyl-3-arylsydnones (164) undergo the regioselective Schmidt reaction to give 3-arylsydnone-4N-methylcarboxamides (165) in good yields without formation of 4-acetamidosydnones (equation 49). I 3
In contrast to this, the Beckmann rearrangement of the oxime of (164, Ar = phenyl) does not proceed at
all.

An interesting version of the Schmidt or Beckmann rearrangement utilizes thioketals (166), which
generate thionium ions (167) as carbonyl substitutes, giving amides (169) or imino sulfides (170) via
a-azido sulfides (168), as shown in Scheme 29.II4 Thus, amides or lactams can be obtained in good
yields by treatment of thioketals (166) with iodine azide ( I N ) , followed by the rearrangement of the resulting a-azido sulfides (168) with trifluoroacetic acid. This method may be superior to the normal
Schmidt or Beckmann rearrangement. For example, the rearrangement of the oxime (171) leads to the
lactam (174) in very poor yield under Beckmann conditions but the yield is greatly increased by starting
with the thioketal (172) and going via the a-azido sulfide (173). The thioketal (175) is also smoothly
converted to N-t-butylacetamide (177) via the a-azido sulfide (176), while the Schmidt reaction of pinacolone exclusively affords fragmentation products.' l4
Imino sulfides ( e g . 180), regarded as an activated form of amides, can be prepared in a single step
from thioketals (e.g. 179) by the action of sodium or trimethylsilyl azide, tin(1V) chloride and a trace of
iodine (equation 50).ll4
Another version of the Schmidt-type rearrangement starts from silyl enol ethers (181) prepared from
acylbenzenes and does not need any acid catalysts.Ils The silyl enol ethers (181) react with N-chlorosuccinimide (NCS) in the presence of sodium azide and benzyltriethylammonium chloride to give chloro
azido derivatives (182) via siloxycarbinyl cations. Subsequent thermal rearrangement of the azido products (182) leads to anilide derivatives (183; equation 51).

4.4.5

THE LOSSEN REACTION

4.4.5.1 Under Basic Conditions

The Lossen r e a c t i ~ n lis~ ,the

~ ~rearrangement of hydroxamic acids, which are prepared from acids,
acyl chlorides and esters. It is usually conducted under alkaline conditions. Initial attachment of electronwithdrawing groups to the oxygen atom of the hydroxamic acids is essential to conduct the reaction; the

Functional Group Interconversion

822

i, IN3, CH2C12-MeCN, -78 OC, 2 h; ii, CF3C02H, CHC13

Scheme 29
Me3SiN3,SnCI,. I, (10 mol %), CH,CI,
M
MeS

-78 OC, 15 min: 0 "C, 1 h; r.t., 1 h

90%

(179)

-m
o

MeS

(50)

(180)

rate of the Lossen rearrangement is directly proportional to the acidity of these groups, which act as leaving groups, or their conjugate acids, where the leaving groups are basic anions.'16 0-Acylhydroxamic
acids are most often used, though 0-sulfonyl or 0-phosphoryl derivatives may also be employed.
The Lossen reaction of peptide carboxylic acids has been investigated in order to determine the
carboxy terminal amino acid residue of peptides.'I7 The procedure first involves the formation of
0-pivaloylhydroxamic acids (187)by condensation of peptide carboxylic acids (184)with O-pivaloylhydroxylamine (185)using a water soluble carbodimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(186).The Lossen rearrangement of (187)occurs at pH 8.5 and 50 'C to give a mixture of isocyanates
(188)and their reaction products, which, on acidic hydrolysis, afford the aldehydes (189),ammonia and
amino acids, as shown in Scheme 3O.ll7 Identification of aldehydes determines the C-terminal amino
acids of the original peptides.
The bishydroxamate (190)prepared from ethyl succinate partially undergoes the Lossen rearrangement with benzenesulfonyl chloride in pyridine to give the uracil derivative (191)."8Treatment of (191)
with ammonia or various amines yields a mixture of 1,2-bis(ureido)ethanes(193)and l-carboxamido-2imidazolidones (194)via the Lossen product, while a hydroxide ion initiated Lossen rearrangement of
(191)leads to ethylenediamine (195),as shown in Scheme 31. N-Benzenesulfonyloxysuccinimide(196)
also undergoes the Lossen reaction with amines to give p-ureidopropionamides(197).11*

DegradationReactions

823

(187)

(184)

JcL

Pep

NCO

others

6N HCI
110 "C, 22 h

RCHO

NH3

aminoacids

(189)

Scheme 30

c
0

cLp""
0

"ONa

phso2c1

"ONa

pyridine

R'NHRZ

_____)

OH-

Although the Lossen reaction of 0-acylated derivatives of the amide oxime (198)has failed, its mesylate (199) easily gives the Lossen product (200) under alkaline conditions (equation 52).II9

Functional Group Interconversion

824
4.45.2

Under Neutral Conditions

A useful variant of the Lossen reaction proceeds under neutral conditions without any prior treatment
of the hydroxamic acids. This 'amide modification' ofthe Lossen rearrangement involves a short heating
of the hydroxamic acid in formamide to give amines.120-122 Anthranilohydroxamic acid120and pyridinecarbohydroxamic acids121undergo the rearrangement to produce benzimidazol-2-one and aminopyridines respectively. The Lossen rearrangement of the hydroxamic acid (201) derived from quinolinic
acid regioselectively occurs to give 2-minonicotinic acid (204) in good yield via the isocyanate (202)
and then the Leuchs anhydride-type intermediate (203; equation 53).12' The latter intermediate (203) is
also obtained when the disodium salt of (201)is heated with benzenesulfonyl chloride.

"
"OH
OH

130-150
HCONH,
80%
'C,20 min

IdNHOH
- &["
NCO

(202)

(201)

(203)

Short heating of 4quinolinecarbohydroxamic acid (205) with formamide affords 4-aminoquinoline

(207) via the isocyanate (206), while use of a large excess of formamide and increasing the temperature
slowly give N-(4-quinoly1)urea (208) exclusively, as shown in Scheme 32. 122 Intermediacy of O-formates or equivalents has been suggested in the above modification of the Lossen reaction.121
2"

(207) 78%

L
(205)

N
excess

(206)

I HCONH,

(208) 67%
Scheme 32

N,"-Dicyclohexylcarbodiimide (DCC) also mediates the Lossen reaction of hydroxamic acids under
neutral condition^.^^^^^^^ In the conversion of the hydroxamic acid (209) to the tricyclic compound (210),
the Lossen rearrangement is accompanied by an intramolecular cycloaddition (equation 54). 123

Degradation Reactions

825

A combination of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobu reagent)125 is useful for the rapid conversion of aromatic hydroxamic acids (211) to 0-(N-arylcarbamy1)hydroxamate.s
(212), products of the Lossen rearrangement.126In some cases, a spontaneous second Lossen rearrangement occurs to give diarylureas (213). as shown in Scheme 33. The yields of (212) and (213) are
7 0 4 5 % . The intermediacy of the phosphonium salts (214) has been suggested.

0
Ar

Ph,P

,CO,Et

NII

NHOH

THF

-IfAr
+
0

C0,Et

H.

Ar.NAO,N
H

Ph3P0

N
I

,C02Et
<COzEt

AryNxAr

4.4.53

Under Acidic Conditions

Aromatic carboxylic acids can be converted to aromatic amines in a single operation by the action of
polyphosphoric acid and hydroxylaminelZ7or nitromethane.128The intermediates are hydroxamic acids
which are activated by phosphorylation with polyphosphoric acid and undergo the rearrangement (equation 55). When nitromethane is used, hydroxylamine is first formed by the action of polyphosphoric acid.
This one-step Lossen reaction works well with aromatic acids containing electron-donating substituents,
but fails or gives poor yield with aliphatic acids and with aromatic acids containing electron-withdrawing
groups.
0
Ar

,OH

or MeN02

PPA

[Ari

--

NHOJ

(55)

Ar*

Hydroxylamine-0-sulfonic acid can be also used for the Lossen rearrangement. Heating acids with hydroxylamine-0-sulfonic acid in hot mineral
or polyphosphoric acid129affords amines, though the
reaction conditions for this transformation still need to be optimized (equations 56 and 57).
N H2 0S03H

k4C02H
mineral oil

kTH2

(56)

170-180 C,2.5 h
23%

C02H

NH,OSO,H, PPA
(57)
115-120 C, 1 h

4-methoxy, 35%; 2,4-dimethoxy, 25%

4.4.6

REFERENCES

1. F. Miiller, Methoden Org. Chem. (Houben-Weyl), 1957, l l / l , 852.

2. P. A . S . Smith, in Molecular Rearrangements, ed. P. de Mayo, Interscience, New York, 1963, p. 528.
3. D. V. Banthorpe, in The Chemistry of the Amino Group, ed. S. Patai, Interscience, New York, 1968, p. 628.

826

Functional Group Interconversion

4. C. A. Buehler and D. E. Pearson, in Survey of Organic Synthesis, Wiley-Interscience, New York, 1970, vol.
1, p. 494; 1977, vol. 2, pp. 447,452.
5. B. Camerino and G. Cainelli, in Methodicum Chimicum: C-N Compounds, ed. F. Zymalkowski, Academic
Press, New York, 1975, vol. 6, p. 560.
6. E. S. Wallis and J. F. Lane, Org. React. (N.Y.), 1946, 3, 267.
7. M. Matsuo, J . Synth. Org. Chem. Jpn., 1968,26, 563 (Chem.Abstr., 1968,69,66 55%).
8 . P. A. S . Smith, Org. React. (N.Y.), 1946, 3, 337.
9. D. V. Banthorpe, in The Chemistry of the Azido Group, ed. S. Patai, Interscience. New York, 1971, p. 397.
10. H. Wolff, Org. React. (N.Y.), 1946, 3, 307.
11. Ref. 9, p. 405.
12. G. I. Koldobskii, G. F. Tereshchenko, E. S. Gerasimova and L. I. Bagal, Russ. Chem. Rev. (Engl. Trunsl.),
1971,40, 835.
13. G. I. Koldobskii, V. A. Ostrovskii and B. V. Gidaspov, Russ. Chem. Rev. (Engl. Trans.), 1978,47, 1084.
14. H. L, Yale, Chem. Rev., 1943,33, 209.
15. L. Bauer and 0. Exner, Angew. Chem.,Inr. Ed. Engl., 1974, 13, 376.
16. R. Richter and H. Ulrich, in The Chemistry of Cyanates and Their Thio Derivatives, ed. S. Patai, Wiley,
New York, 1977, p. 665.
17. T. Shioiri, K. Ninomiya and S. Yamada, J . Am. Chem. Soc., 1972,94,6203.
18. K. Ninomiya, T. Shioiri and S . Yamada, Tetrahedron, 1974,30,2151.
19. T. Imamoto, Y. Tsuno and Y. Yukawa, Bull. Chem. SOC. Jpn., 1971,44, 1632, 1639 and 1644.
20. T. Imamoto, S.-G. Kim, Y.Tsuno and Y. Yukawa, Bull. Chem. SOC. Jpn., 1971,44,2776.
21. C. L. Arcus and J. Kenyon, J. Chem. SOC., 1939,916.
22. A. Campbell and J. Kenyon, J. Chem. SOC., 1946, 25.
23. K. K. Lee, S. Terashima, K. Achiwa and S . Yamada, Chem. Pharm. Bull., 1969, 17, 2540.
24. J. M. Wilson and D. J. Cram, J . Org. Chem., 1984, 49, 4930.
25. M. B. Hocking, Can. J . Chem., 1968.46, 2275.
26. G . J. Mikol and J. H. Boyer, J . Org. Chem., 1972,37, 724.
27. S. Kajigaeshi, T. Nakagawa, S. Fujisaki, A. Nishida and M. Noguchi, Chem. Lett., 1984, 713.
28. S. Kajigaeshi, K. Asano, S. Fujisaki, T. Kakinami and T. Okamoto, Chem. Lett., 1989,463.
29. J. Pospisek and K. Blaha, in Peptides 1982. Proceedings of the 17th European Peptide Symposium, ed. K.
Blaha and P. Malon, de Gruyter, Berlin, 1983, p. 333.
30. T. Sakamoto, Y. Kondo and H. Yamanaka, Chem. Pharm. Bull., 1986,34,2362.
31. A. 0.Sy and J. W. Raksis, Tetrahedron Lett., 1980,21, 2223.
32. E. Jeffreys, Am. Chem. J., 1899, 22, 14.
33. Y. Nagai. M. Matsuo and T. Matsuda, Kogyo Kagaku Zasshi, 1964, 67, 1248 (Chem. Abstr., 1965, 62, 13
277g).
34. Y. Nagai, M. Sugiura and M. Ochi, Kogyo Kugaku Zasshi, 1969,72,696 (Chem. Abstr., 1969, 71,38 2250.
35. P. Radlick and L. R. Brown, Synthesis, 1974, 290.
36. R. Granados, M. Alvarez, F. L6pez-Calahorra and M. Salas, Synthesis, 1983, 329.
37. T. Shono, Y. Matsumura, S. Yamane and S . Kashimura, Chem. Lett., 1982, 565.
38. M. Soroka and P. Mastalerz, Tetrahedron Lett., 1973, 5201.
39. F. S. Spring and J. C. Woods, J . Chem. SOC., 1945,625.
40. N. A. Jonsson and P. Moses, Acta Chem. Scand. Ser. 8, 1974,28,441.
41. H. Gustafsson, Acta Chem. Scand., Ser. B, 1975,29,93.
42. B. Acott and A. L. J. Beckwith, Chem. Commun., 1965, 161; B. Acott, A. L. J. Beckwith, A. Hassanali and J.
W. Redmond, Tetrahedron Left., 1965, 4039; B. Acott, A. L. J. Beckwith and A. Hassanali, Aust. J. Chem.,
1968, 21, 185; 197.
43. H. E. Baumgarten and A. Staklis, J . Am. Chem. Soc., 1965, 87, 1141; H. E. Baumgarten. H. L. Smith and A.
Staklis, J. Org. Chem., 1975, 40, 3554.
44. S. S. Simons, Jr., J . Org. Chem., 1973,38, 414.
45. T. E. Stevens, J . Org. Chem., 1966,31, 2025.
46. A. S.Radhakrishna, M. E. Parham, R. M. Riggs and G. M. Loudon, J . Org. Chem., 1979.44, 1746.
47. G. M. Loudon, A. S. Radhakrishna, M. R. Almond, J. K. Blodgett and R. H. Boutin, J . Org. Chem., 1984,49,
4272.
48. M. Tamura. J. Jacyno and C. H. Stammer, Tetrahedron Lett., 1986,27, 5435.
49. P. Pallai and M. Goodman, J. Chem. SOC., Chem. Commun., 1982,280.
50. M. E. Parham and G . M. Loudon, Biochem. Biophys. Res. Commun., 1978, 80, 1; G. M. Loudon and M. E.
Parham, Tetrahedron Lett., 1978, 437.
51. A. S. Verdini and G. C. Viscomi, J. Chem. SOC., Perkin Trans. I , 1985,697.
52. I. M. Lazbin and G. F. Koser, J. Org. Chem., 1986.51.2669.
53. A. Vasudevan and G. F. Koser, J. Org. Chem., 1988,53,5158.
54. A. S. Radhakrishna, C. G. Rao, R. K. Varma, B. B. Singh and S. P. Bhatnagar, Synthesis, 1983,538.
55. J. R. Chambers and A. F. Isbell, J . Org. Chem.. 1964, 29, 832.
56. B. Chantegrel and S.Gelin, Synthesis, 1979, 584.
57. A. Nabeya and T. Endo, J . Org. Chem., 1988,53,3358.
58. J. J. Tufariello, H. Meckler and K. Winzenberg, J. Org. Chem., 1986.51, 3556.
Ho, Can. J . Chem., 1977, 55,371.
59. 0. E. Edwards and P.-T.
60. R. Bonjouklian and B. Ganem, Tetrahedron Lett., 1977,2835.
61. M. Milewska and T. PoloAski, Synthesis, 1988,475.
62. R. A. Earl and K. P. C. Vollhardt, J . Am. Chem. Soc.. 1983, 105,6991.
63. P. W. Erhardt, J . Org. Chem., 1979,44, 883.
64. J. R. Pfister and W. E. Wymann, Synthesis, 1983, 38.
65. J. W. van Reijendam and F. Baardman, Synthesis, 1973,413.

Degradation Reactions
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.

827

A. Brandstrom, B. Lamm and I. Palmertz, Acta Chem. Scand., Ser. B, 1974.28, 699.
K. Sakai and J.-P. Anselme, J . Org. Chem., 1971,36,2387.
S.S. Washburne and W. R. Peterson, Jr., Synth. Commun., 1972, 2, 227.
S. S. Washburne, W. R. Peterson, Jr. and D. A. Berman, J . Org. Chem., 1972, 37, 1738.
J. D. Warren and J. B. Press, Synth. Commun., 1980, 10, 107.
H. R. Kricheldorf and E. Leppert, Synthesis, 1976,329.
P. H. Mazzocchi and A. D. Schuda, Heterocycles, 1985,23, 1603.
A. Arrieta, J. M. Aizpurua and C. Palomo, Tetrahedron Lett., 1984, 25, 3365.
J. Weinstock, J . Org. Chem., 1961,26, 3511; see also C. Kaiser and J. Weinstock, Org. Synth., 1971.51.48.
P. J. Jessup, C. B. Petty, J. Roos and L. E. Overman, Org. Synth., 1979, 59, 1.
F. BjBrkling, J. Boutelje, S. Gatenbeck, K. Huh and T. Norin, Tetrahedron Lett., 1985,26,4957.
Y. Morimoto and K. Achiwa, Chem. Pharm. Bull., 1987,35,3845.
T. Shioiri and S. Yamada, Org. Synth., 1984, 62, 187; Y. Hamada and T. Shioiri, Org. Synth., 1984,62, 191.
J. E. Martinelli, M. Chaykovsky, R. L. Kisliuk, Y. Gaumont and M. C. Gittelman, J . Med. Chem., 1979, 22,

869.
80. J. E. Martinelli, M. Chaykovsky, R. L. Kisliuk and Y. Gaumont, J . Med. Chem., 1979,22, 874.
81. P. L. Gendler and H. Rapoport, J. Med. Chem., 1981,24, 33.
82. S. Yamada, K. Ninomiya and T. Shioiri, Tetrahedron Lett., 1973, 2343; K. Ninomiya, T. Shioiri and S.
Yamada, Chem. Pharm. Bull., 1974,22, 1398.
83. K. Ninomiya, T. Shioiri and S . Yamada, Chem. Pharm. Bull., 1974, 22, 1795.
84. K. Murato, T. Shioiri and S. Yamada, Chem. Pharm. Bull., 1975.23, 1738.
85. S. Yamada, K. Murato and T. Shioiri, Tetrahedron Lett., 1976, 1605; K. Murato, T. Shioiri and S. Yamada,
Chem. Pharm. Bull., 1977,25, 1559.
86. J. C. Martin, J . Org. Chem., 1982, 47, 3761.
87. D. L. Boger and J. S.Panek, Tetrahedron Lett., 1984,25,3175.
88. F. Z. Basha, S. Hibino, D. Kim, W. E. Pye, T.-T. Wu and S. M. Weinreb,J. Am. Chem. SOC., 1980. 102, 3962;
S . M. Weinreb, F. Z. Basha, S. Hibino, N. A. Khatri, D. Kim, W. E. Pye and T.-T. Wu, J. Am. Chem. Soc.,
1982, 104, 536.
89. A. S. Kende, D. P. Lorah and R. J. Boatman, J . Am. Chem. SOC.,1981,103, 1271.
90. D. L. Boger and J. S . Panek, J . Org. Chem., 1983,48, 621.
91. T. L. Capson and C. D. Poulter, Tetrahedron Lett., 1984,25,3515.
92. T. Sasaki, K. Kanematsu and K. Iizuka, Tetrahedron, 1975, 31, 1671.
93. N. Tokitoh and R. Okazaki, J. Am. Chem. Soc., 1987, 109, 1856.
94. H. Maeda, M. Suzuki, H. Sugano and K. Matsumoto, Synthesis, 1988, 401.
95. C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn and J. Lampe, J. Org. Chem., 1980,
45, 1066.
96. R. K. Olsen, W. J. Hennen and R. B. Wardle, J . Org. Chem., 1982, 47,4605.
97. J. W. Lyga, Synth. Commun., 1986, 16, 163.
98. J. H. Rigby and N. Balasubramanian, J. Org. Chem., 1984,49, 4569.
99. T. Shioiri, M. Murata and Y. Hamada, Chem. Pharm. Bull., 1987,35,2698.
100. M. E. Parham and G.M. Loudon, Biochem. Biophys. Res. Commun., 1978,80, 7.
101. A. Arrieta and C. Palomo, Tetrahedron Lett.. 1981, 22, 1729.
102. F. E. DeBons and G . M. Loudon, J . Org. Chem., 1980,45, 1703.
103. M. Furukawa, T. Okawara, Y. Noguchi and Y. Terawaki, Chem. Pharm. Bull., 1979,27,2795.
104. S. K. Datta, C. Grundmann and N. K. Bhattacharyya, J . Chem. SOC.(C), 1970, 2058.
105. R. M. Palmere and R. T. Conley, J. Org. Chem., 1970,35,2703.
106. R. D. Allan, H. W. Dickenson, G. A. R. Johnston, R. Kazlauskas and H. W. Tran, Aust. J . Chem., 1985, 38,
1651.
107. R. D. Allan, G.A. R. Johnston and B. Twitchin, Aust. J . Chem., 1979, 32, 2517.
108. Y. Nagao and T. Misono, Bull. Chem. SOC. Jpn., 1979,52, 1723.
109. A. J. Bell and R. W. Read, Aust. J . Chem., 1987,40, 1813.
110. E. H. Ruediger, S. S. Gandhi, M. S. Gibson, D. FBrcasiu, and C. Uncuta, Can. J . Chem., 1986, 64, 577, and

refs. therein.
1 11. S. Kobayashi, T. Tokumoto, T. Koike, K. Iizuka, H. Irie and S. Uyeo, Chem. Pharm. Bull., 1986,34, 2443.
112. G. I. Georg. X. Guan and J. Kant, Tetrahedron Lett., 1988,29,403.
113. M.-Y. Yeh, H.-J. Tien and T. Nonaka, J . Org. Chem., 1983,48, 1382.
114. B. M. Trost, M. Vaultier and M. L. Santiago, J . Am. Chem. SOC.,1980, 102,7929.
115. K. Ohkata, M. Mase, and K.-Y. Akiba, J . Chem. Soc., Chem. Commun., 1987, 1727.
116. J . S. Swenson, A. M. Davies, R. A. Deyo, B. W. Graham, E. P. Jahn and J. D. Mattice, J . Org. Chem., 1973,
38, 3956.
117. M. J. Miller and G.M. Loudon, J. Am. Chem. SOC., 1975, 97, 5295; M. J. Miller, F. E. DeBons, and G. M.
Loudon, J. Org. Chem., 1977.42, 1750 and refs. therein.
118. M. E. VanVerst, C.L. Bell and L. Bauer, J . Heterocycl. Chem., 1979, 16, 1329.
119. H. Ulrich, B. Tucker and R. Richter, J . Org. Chem., 1978, 43, 1544.
120. Z. Eckstein, T. Jadach and E. Lipczyfiska-Kochany, J . Chem. Eng. Data, 1983, 28, 279 (Chem. Abstr., 1983,
98, 143 32%).
121. 2.Eckstein, E. Lipczyfiska-Kochany and J. Krzemihski, Heterocycles, 1983, 20, 1899.
122. Z. Eckstein, E. Lipczyfiska-Kochany and E. Leszczyhska, Liebigs Ann. Chem., 1984, 395.
123. J. Bergman, J.-0. Lindstrom, J. Abrahamsson and E. Hadler, Tetrahedron Lett., 1976, 3615.
124. D. G.Hoare, A. Olson and D. E. Koshland, Jr., J . Am. Chem. Soc., 1968,90, 1638.
125. 0. Mitsunobu, Synthesis, 1981, 1.
126. S. Bittner, S. Grinberg and I. Kartoon, Tetrahedron Letr., 1974, 1965.
127. H. R. Snyder, C. T. Elston and D. B. Kellom, J . Am. Chem. Soc.. 1953.75, 2014.

828

Functional Group Interconversion

128. G.B. Bachmann and J. E. Goldmacher, J . Org. Chem., 1964,29,2576.

129. G. P. Dhareshwar and B. D. Hosangadi, Indian J . Chem., 1973, 11,716.