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Org. 2563
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Pyrrole Studies. Part XV.l Vilsmeier-Haack Formylation of I-Substi-

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tuted Pyrroles
By C. F. Candy, R. Alan Jones,' and P. H. Wright, School of Chemical Sciences, University of East Anglia,
Norwich, N O R 88C

The ratio of a- to P-formylated products obtained by the Vilsmeier-Haack reactions with 1-alkyl- and 1-aryl-
pyrroles is controlled mainly by steric factors. Electronic effects of 1- (p-substituted aryl) substituents upon the
position of formylation of the pyrrole ring are small and are essentially inductive.

WITHthe possible exception of nitrosation,2 and seleno- and 3-substituted products were isolated9 do not dis-
~ y a n a t i o n ,electrophilic
~ substit).ztion of pyrrole occurs tinguish clearly between steric and electronic factors.
preferentially a t the a-po~itions.~Extensive studies In this paper we describe the Vilsmeier-Haack formyl-
of electrophilic substitution of C-substituted pyrroles ation of a series of l-substituted pyrroles in which the
also indicate that, in general, further substitution of the size and the electronic character of the l-substituent
ring invariably occurs a t a free a-position, although is varied. I n all instances monoformylated products
electron-withdrawing substituents already present do were formed and, although it was often not possible to
appear to have some control over the orientation of isolate the individual isomers, the relative amounts of
the substituted products. Thus, electrophilic attack each isomer were estimated by g.1.c. or by n.m.r. analysis.
upon the pyrrole nucleus having an electron-with- The difference in the conjugation of the pyrrole ring
drawing substituent in the 2-position leads to the with the formyl groups idthe 2- and 3-positions results in
formation of both 4- and 5-substituted products. No the n.m.r. signal of the formyl proton of the 3-isomer
3-substituted product is formed. Little is known, appearing a t a higher field than that of the corresponding
however, of steric effects upon the electrophilic sub- 2-isomer. Corroborative evidence for the presence of the
stitution of the pyrrole ring and relatively few in- 3-isomer was provided by the low-field signal of the ring
vestigations have been undertaken to assess the elec- proton in the 2-position.
tronic 697 and steric effects of substituents attached to Steric Efect of l-Alkyl Substituents.-Formylation
the ring nitrogen atom upon the orientation of electro- of pyrrole and of l-methyl-, l-ethyl-, l-isopropyl-, and
philic attack. Formylation of 3-methylpyrrole * gives l-t-butyl-pyrrole according to the general method de-
2-formyl-3-methyl- and 2-formyl-4-methylpyrrole in the scribed by Silverstein and his co-workers,1° gave good
ratio 4 : 1, indicating that the electron-donating effect of yields of the monoformylated products (Table 1).
the methyl group is more significant than any steric Analysis of the products showed that as the size of the
factor. However, the limited investigations of electro- alkyl group increased, so did the relative proportion
philic substitution of l-benzylpyrrole in which both 2- of the p-isomer, and that for l-t-butylpyrrole the pre-
Part XIV, L. F. Elsom and R. A. Jones, J . Chem. SOC.( B ) ,
dominant product was l-t-butyl-3-formylpyrrole.
1970, 79. The attacking electrophile in the Vilsmeier-Haack
2 H. Fischer and H. Orth, ' Die Chemie des Pyrrols,' vol. 1,
Akad. Verlagsges., Leipzig, 1934. 6 R. A. Jones, T. M. Spotswood, and P. Cheuychit, Tetra-
L-B. Agenas and B. Lindgren, Arkiv Kemi. 1968, 28, 145. hedron, 1967, 23, 4469.
4 For a review of electrophilic substitution of pyrroles see K. 7 Y . Chiang, R. L. Hinman, S. Theodoropulos, and E. B.
Schofield, ' Heteroaromatic Nitrogen Compounds, Pyrroles and Whipple, Tetralzedmn, 1967, 23, 745.
Pyridines,' Butterworths, London, 1967, pp. 63 et seq. 8 R. L. Hinman and S. Theodoropulos, J . Org. Chem., 1963,
5 See for example H. J. Anderson and L. C. Hoplrins, Canad. 28.
_ _ -3052.
,~ ~

J . Chem., 1964, 42, 1279; 1966, 44, 1831; H. J . Anderson, ibid., H. J. Anderson and S. J. Griffiths, Canad. J . Chenz., 1967,
1959, 37, 2063; H.J. Anderson and C. W. Huang, ibid., 1967, 45, 2227.
45, 897; W. A. M. Davies, A. R. Pinder, and I. G. Morris, Tetra- 10 R. M. Silverstein. E. E. Rvskiewicz. C. Willard. and N. C.
hedron. 1962, 18. 405.
, Koehler, J . Org. CJzeun.., 1955, 20, 668. '
 View Article Online
J. Chem. SOC. (C), 1970
reaction is large, and reports of steric hindrance leading transition state (11) resulting from electrophilic sub-
t o f ormylation in electronically unfavourable positions stitution, but subsequent loss of the proton would be
are to be found.ll The pyrrole nucleus, however, is potentially unfavourable owing to the establishment
activated to electrophilic substitution in both a- and of a larger steric interaction between the a-formyl
p-positions although the available electron-density group and the l-substituent. However, as conjugation
calculations do not indicate a clear preference for of the formyl group with the pyrrole nucleus would
either.12 * The electron-donating effects of the l-alkyl lessen the restriction to rotation of the l-substituent,
the two groups would be free to twist out of plane.
TABLE1 Formylation of l-(p-Substituted Aryl)@yrroles.--Al-
Formylation of l-alkyl- and l-aralkyl-pyrroles though dipole moment studies suggest a collinearity
Overall yield of of the axes of the pyrrole and aryl rings with the possi-
formylated products Ratio of bility of interannular conjugation,17 the n.m.r. data
2-Substituent (%) u- to p-isomers
for the l-arylpyrroles have been interpreted in terms of
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Me 89 a
Et 85 11.5: 1 an essentially inductive interaction between the pyrrole
Pri 79 1.9: 1 nucleus and the aryl substituent. Thus, the electronic
But 69 1 : 14
PhCH, 89 6.2 : 1 b effect of the 9-substituent upon the electron distribution
a 100% a-isomer. b Anderson and Griffiths quote 5.3 : 1.
@
within the pyrrole ring would be expected to be in-
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dependent of the dihedral angle between the two rings,

groups are small, as shown by the small variation in the and, with negligible restricted rotation about the
dipole moments of the l-alkylpyrroles over the range (pyrro1e)N-C(ary1) bond, the contribution of steric
1-83-2.26 Debye,l4 and n.m.r. studies indicate that factors t o the orientation of electrophilic substitution
substitution on the nitrogen atom of pyrrole by alkyl of the arylpyrroles would be expected to be uniform
groups leads to only small and almost equivalent in- and minimal throughout the series.
creases in electron density a t both the a- and p-positions. N.m.r. chemical shifts6 of the a- and p-pyrrolyl
As there is no other evidence that the alkyl groups induce protons show that the aryl groups having electron-
any change in the relative susceptibility of the a- and withdrawing substituents produce almost equivalent
p-positions to electrophilic attack, the differences shown changes in the electron densities a t both positions,
in Table 1 result entirely from steric factors. The steric whereas the l-arylpyrroles bearing electron-donating
effect of the l-benzyl substituent appears to be inter- substituents show larger upfield shifts of the signals
mediate between that of the ethyl and isopropyl groups. for the a-protons than for the p-protons relative to the
Electronic and Steric Eflects of Strongly Electyon- corresponding signals for l-phenylpyrrole. However,
withdrawing Substituents.-Formylation of l-acetyl-, there is no correlation between the n.m.r. chemical
l-benzoyl-, and l-ethoxycarbonyl-pyrroleleads to the shifts and the data given in Table 2 for compounds
exclusive formation of the corresponding 2-formyl 1-5, and one can draw little inference regarding the
derivatives in yields of 61, 74, and 54% respectively. effect of the 9-substituents upon the orientation of
substitution in terms of an inductive interaction be-
tween the two rings.t
The relative yields of the a- and p-formylated pro-
ducts from the 2,6-xylyl and the nitro-Z,6-xylyl com-
pounds (Table 2; compounds 6-8) and from the corre-
sponding phenyl compounds indicate that steric factors
(Ial (Ib1 (=I (In1 and the possibility of interannular mesomeric conjugation
R = Me, Ph, or OEt cannot be dismissed entirely. As basicity measure-
+
E+ = Me,N:CH.O*POCl, '
ments have shown that there is little difference in the
electron densities a t the a-positions of l-phenyl- and of
The electron-withdrawing effect of the l-substituent 1-(2,6-~ylyl)pyrrole,the proportions of a-formylation
would be expected to reduce the overall susceptibility products obtained from these compounds suggest that,
of the pyrrole nucleus to electrophilic attack, and the although the aryl rings in both compounds should be
importance of the zwitterionic canonical forms (Ib) l5 6y
free to rotate about the interannular axis, the xylyl
restricts rotation of the substituent about the N-C substituent presents a larger steric hindrance to a-sub-
bond.16 Steric interaction between the l-substituent substitution than does the phenyl group.
and the a-hydrogen atoms of the pyrrole nucleus would
be small and would be eliminated in the formation of the l1 K. Hafner and K-L. Moritz, Annalen, 1962, 656, 40.
l2 R. A. Jones, Adv. Heterocyclic Chem., 1970, 11, 383.
13 E. €3. Whipple, Y . Chiang, and R. L. Hinnian, J . Amev.
* Although the a-protonated salts of pyrrole are the more CTtem. Soc., 1963, 85, 26; Y. Chiang and E. B. Whipple, ibid.,
stable, deuterium exchange a t the /?-position has been shown t o 1963, 85, 2763.
occur a t the greater rate in concentrated sulphuric acid.l3 1 4 C. F. Candy and R. A. Jones, unpublished work.
t Other workers have also noted that although observed l5 R. A. Jones, Austval. J . Chem., 1966, 19, 289.
n.m.r. chemical shifts of the E- and /I-protons correlated well l6 T. Matsuo and H. Shosenji, Chem. Comm., 1969, 501.
with calculated rr-electron densities they bore little relation to l7 H. Kofod, L. E. Sutton, and J. Jackson, J . Chem. SOL,
the electrophilic reactivity. 1952, 1467.
 View Article Online
Org. 2565
A cursory comparison of the effects of the ineta- 4-nitrophenylpyrrole compared with the total yields
and para-nitro groups (Table 2; compounds 7 and 8) of 2- and 3-formyl-l-(P-nitrophenyl)pyrrolesuggests
upon the ratio of a- and p-formylated products supports that, a t least in the case of P-nitroarylpyrroles, meso-
the contention that the electronic interaction between meric interaction between the aryl and pyrrole rings
exists. The tendency towards coplanarity of the two
TABLE2 rings, as a result of the mesomeric interaction, enhances
Formylation of l-arylpyrroles steric hindrance to oc-substitution of the pyrrole ring and
Overall yield of is reflected in the yields of the formyl derivatives.
formylated products Ratio of Conversely, the lack of mesomeric interaction between
l-Substituent (%) a- t o /3-isomers the meta-nitro-group and the pyrrole ring, with conse-
1 p-MeOC,H, 93 7.0: 1
2 $)-&kC,H, 92 11.0: 1 quent free rotation of the two rings and minimal inter-
3 Ph 93 9.0: 1 action, results in a high yield of formylation products.
4 $-BrC,H, 90 5.6: 1 Full spectroscopic and dipole moment data for all
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5 j+-02NC6H4 $8 7.3: 1
G 2,6-Me2C,H3 71 6.3 : 1 compounds will appear in a later paper concerned with
7 2,6-Me,-3-0,N*C,H2 91 4.7 : 1 conformational analysis of the formyl compounds.14~ l8
8 2,6-Me2-4-02N.C,H2 37a 4.0 : 1
a Unchanged starting material (5076) was recovered. EXPERIMENTAL
I-AZkyZ- and 1-A ryZ-pywoZes.-l-Methylpyrrole (Aldrich)
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the aryl and the pyrrole rings is essentially inductive. was distilled before use. Other allrylpyrroles and all
However, the higher overall yields of formylation 1-arylpyrroles were prepared from 2,5-diethoxytetrahydro-
products, together with the higher ratios of or-sub- furan and the appropriate amine.lg?2O

TABLE3
l-Alkyl and 1-aryl-pyrroles
l-Substituent Yield (76) M.p. or b.p. Lit. m.p. or b.p. Ref.
Me 112"/760 mm. 114-1 15'/760 mm. 2
Et 45 131/760 mm. 129-130/760 mm. 2
Pri 57 49-51/21 mm. a
But 60 51-61/24 mm. 74-79/42 mm. d
PhCH, 97 66-69/0.2 mm. 67-69/0.2 mm. e
p-MeO.C,H, 84 112 111-113 20
p-MeC,H, 90 82-83 80-82 20
Ph 96 60 61-62 20
$-BrC,H, 97 94-95 9 1-92 15
~5-02N*C,Hd 94 179 180-181 20
2,6-Me2C,H3 95 46-47 47-48 7
2, 6-Me,-3-02N*C,H2 94 73-73.5 6
2,6-Me2-4-0,NC,H, 90 156.5-157 6
Found: N, 13.0. Calc. for C,Hl1N: N, 12.80/,; cf. F. Martin and G. A. Kaluza, J . Gas Chromatog., 1967, 5, 562. b Found:
C, 66.8; H, 5.5; N, 13.2. CI2H,,N2O2 requires C, 66.6; H, 5.6; N, 13.0%. c Found: C, 66.7; H, 6.0; N, 12.8%. d M. F.
Fegley, N. M. Bortnick, and C. H. McKeever, J. Amer. Chem. SOG.,1957, 79,4144. e C. F. Hobbs, C. K. McMillin, E. P. Papadro-
poulos, and C. A. VauderWert, J . Amev. Chem. SOC.,1962, 84, 43.

stitution products, from the phenyl and xylyl compounds l-A cetyZpyvroZe.-Thallium(I) ethoxide 21 (61.1 g . , 0.31
compared with those from their P-nitro-derivatives mole) in ether (40 ml.) was added dropwise to a well stirred
suggests that canonical structures of type (IVb) should solution of pyrrole (16.7 g., 0.25 mole) in ether (25 ml.).
The ethanol formed was removed with the ether under
vacuum to give pyrrolylthallium, which was immediately
[C
N
J covered with ether (50 ml.). Acetyl chloride (19-6 g.,
0.25 mole) was then added a t 0" during 1 hr. The pre-
cipitated thallium(1) chloride was filtered off and the
solution was washed with aqueous sodium carbonate
(sat. s o h . ; 2 x 50 inl.), dried (MgSO,), and evaporated
under vacuum to give l-acetylpyrrole (23.7 g., 8S%),
b.p. 69'/15 mm. (lit.,2180-181°).
l-BenzoyZ~yrroZe.-Benzoyl chloride (36.5 g . , 0.26 mole)
(ma1 (rYbl in benzene (25 ml.) was added dropwise to pyrrolylthallium
R=HorMe (70 g., 0.26 mole) in benzene (50 ml.) during 30 min. a t 0".
The solution was then stirred a t 80" for 1 hr., and worked
not be ignored. In particular, the decreased overall up as described for the l-acetyl analogue to give l-benzoyl-
yield of the formylation products of 2,B-dimethyl- pyrrole (40 g., 91%), b.p. 140"/15 mm. (lit.,2 276"/715
mm.).
R. A. Jones and P. H. Wright, Tetrahedron Letters, 1968,
5495. 2o H. Gross, Chem. Rer., 196?, 95, 2270.
1s N. Elming and N. Clauson-Kaas, Acta Chem. Scand., 1952, 21 M. Fieser and L. F. Fieser, Reagents for Organic Synthesis,
6, 867. vol. 3,Wiley-Interscience, New York, 1969, p. 407.
 View Article Online
J. Chem. SOC.(C), 1970
1-EthoxycarbonyZpyvroZe.-This compound, b .p. 175- 0.09 mole) was added dropwise with stirring to dimethyl-
178"/760 mm. (lit.,2 180"/770 mm.), was prepared as de- formamide (6.83 g., 0.09 mole) a t 0". Stirring was con-
scribed in ref. 2. tinued a t 0" for 30 min. ; the mixture was then allowed to
FovrnyZation of 1-Alkyl- and l-AryZ-pyrroles.-This re- warm to room temperature and ethylene dichloride (50
action was carried out as described in ref. 10. The method ml.) was added. The solution was cooled to 0" and
of work-up depended upon the physical character and 1-benzoylpyrrole (16 g., 0.09 mole) in ethylene dichloride
stability of the products and upon the relative proportions (25 ml.) was added with stirring during 1 hr. The stirred
of the isomers. solution was refluxed for 20 min., then cooled to room
Method A . If n.m.r. measurements showed only one temperature, and 50% aqueous sodium acetate (100 ml.)
isomer to be present, the crude product was distilled under containing sodium hydroxide (10 g.) was added, slowly
reduced pressure. a t first and then as rapidly as possible. The mixture was
iwethod B. When the forniylation products were liquids then refluxed for 20 min. and cooled, and the organic
or readily volatilized solids, and n.m.r. measurements layer was separated. The aqueous phase was extracted with
indicated one isomer to be in considerable excess, the crude chloroform (3 x 50 ml.) and the extracts were combined
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TABLE4
Physical data for 1-substituted 2-formylpyrroles
Yield Method of Found (%) Required (%)
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1-Substituent (%) purification M.P. or b.p. Lit. m.p. or b.p. Ref. C H N C H N

Me 89 A 76'113 mm. 72-75"/11 mm. 10
Et 77 B, c 91-95/22 mm. 73-75/7 mm. f
Pri 59 B, c 96-98/19 mm.a 69.7 8.1 10.2 70.0 8-1 10.2
But 4.5 B, c 114-116/19 mm. 9.4 9.3
PhCH, 66-5 B 106/0.4 mm.bsc 77.3 5.9 7.6 77.8 6.0 7.6
p-MeO*C,H, 82 B 46d 71.6 5-2 7.1 71.6 5-5 6.7
p-MeC,H, 84 B 55-5 77.8 5.9 7.6 77.8 6.0 7.6
Ph 84 B 106-109/0-2 mm. 90-93/0-1 mm. 19
p-BrC,H, 86 E 94 52.8 2.8 5.5 52.8 3.2 5-6
$-O,N*C,H, 77 D 169 62.1 4.0 12.9 61.1 3.7 13-0
2,6-Me2C,H, 56 B 65 78.4 6-6 6.7 78-4 6.6 7.0
2,6-Me,-3-O,N*C6H2 91 B 160-170/0.2 mm. 64.0 5.0 11.7 63.9 4.95 11.5
2,6-Me,-4-0,N°C,H, 37 E 180-181 64.2 4.7 11.6 63.9 4.95 11-5
a 2,4-Dinitrophenylhydrazone had m.p. 214" (Found: C, 5 2 . 5 ; H, 5.0; N, 22.1. C,,H,,N,O, requires C, 53.0; H, 4.8; N, 22.1%).
b Semicarbazone had m.p. 172-174" (Found: C, 64-7; H, 5-4; N, 23-1. C,,H,,N,O requires C, 64.4; H, 5 . 8 ; N, 23.1%). c Oxime
had m.p. 110" (lit.,S 111-112"). d Oxime had m.p. 121" (Found: C, 66.5; H, 5-65. C,,H,,N,O, requires C, 66.6, H, 5.6%).
8 Unchanged starting material (50%) was recovered. f M. Stoll, M. Winter, F. Gautshi, I. Flament, and B. Willhalm, Helu. Chim.
Acta, 1967, 50, 628.

TABLE5
Physical data for 1-substituted 3-formylpyrroles
Method of Found (yo) Required (yo)
1-Substituent Yield (yo) purification B.p. C H N C H N
Pri 20 B, c 145-148"/19 mm. 70.4 8.25 9.8 70.0 8.1 10.2
But 79 B, c 148/19 mm.a 72.0 8.7 9.4 71.5 8.7 9-3
PhCH, 12.5 B 160/0.3 mm.b 7.5 7.6
Semicarbazone had m.p. 167" (Found: C, 57.4; H, 7-4; N, 26.2. C,,H,,N,O requires C, 57.7; H, 7.7; N, 26.9%). b Oxime
had m.p. 145" (lit.,%m.p. 14&147").

products were fractionally distilled under reduced pressure. with the organic phase, washed with sat. aqueous sodium
The minor product was collected as an impure fraction carbonate, dried (MgSO,), and evaporated to give l-benzoyl-
boiling over a wide range and was isolated in a pure state 2-formylpyrrole (13.6 g., 74%) (plates from hexane), m.p.
by preparative g.1.c. with a Varian Aerograph model 90-P 89-89.5" (lit.,2290").
gas chromatograph fitted with a 100 cm. column packed 1-Acetyl-2-foruny lfiyrrole .-(a) By treatment analogous to
with polypropylene glycol on Celite (20% w/w). Ana- that described for the preparatipn of 1-benzoyl-2-formyl-
lytically pure samples of the major products were also pyrrole, 1-acetylpyrrole (14 g., 0.13 mole) gave l-acetyl-
obtained by g.1.c. 2-forunylpy~roZe (8.4 g., 61%) (plates from hexane), m.p.
Method C. When the products were readily volatilized, 78-78.5" (Found: C, 61.4; H, 5.0; N, 10-5. C,H,N02
the isomers were isolated by preparative g.1.c. as in method requires C, 61.3; H, 5.1; N, 10.2%).
B without prior fractional distillation. (6) Thallium(1) ethoxide (26 g., 0-1 mole) in ether (50
Method D. Formylated products which could not be ml.) was added dropwise to 2-formylpyrrole (9.5 g., 0.1 mole)
satisfactorily separated by g.1.c. owing to their instability, in ether (50 ml.) with stirring a t 0". The ethanol produced
and which were not readily separated by fractional dis- was removed with the ether under reduced pressure and the
tillation or by crystallization, were isolated by preparative thallium salt was immediately covered with ether (100 ml.).
t.1.c. (silica; chloroform). Acetyl chloride (8.4 g., 0.11 mole) in ether (50 ml.) was
Method E . Crystalline formylated products were purified added dropwise a t 0" and the thalIium(1) chloride was
by fractional crystallization.
l-BenzoyZ-2-fovrnyZfiyv~oZe.-Phosphorylchloride (14.3 g., 22 A. Treibs and H . G. Kolm, Aiznaleiz, 1957, 606, 166.
 View Article Online
Org. 2567
filtered off. The ethereal solution was washed with sat. pyrrole (73%), b.p. 147-149"/15 inm. (lit.,23 144'/24
aqueous sodium carbonate, dried (MgSO,), and evaporated mm.) .
to give the 1-acetyl derivative (13.5 g., 92%), m.p. and
mixed m.p. 78-78.5", identical (i.r. and n.m.r. spectra) We thank the S*R.C*for studentships (to c*F*c*and
with the sample obtained by method (a). P.H. W.).
[0/832 Received, May 19th, 19701
l-EthoxycarbolzyE-Z-forwzyZ~y~roZe.-Formylation23 of
1-ethoxycarbonylpyrrole gave l-ethoxycarbonyl-2-formyl- 23 A. Treibs and A. Dietl, Annulen, 1958, 619, 80.
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