Enantioselective Formal (3+3) Cycloadditions of Ketones and Cyclic 1-Azadienes by Cascade Enamine-Enamine Catalysis

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DOI: 10.1002/chem.

201404550 Full Paper

& Organic Synthesis

Enantioselective Formal [3+3] Cycloadditions of Ketones and


Cyclic 1-Azadienes by Cascade Enamine–Enamine Catalysis
Xiao-Long He,[a] You-Cai Xiao,[a] Wei Du,[a] and Ying-Chun Chen*[a, b]

Abstract: An asymmetric formal [3+3] cycloaddition process reaction to afford spirocyclic architectures in excellent dia-
with diversely structured aliphatic ketones and electron-defi- stereo- and enantioselectivity. Importantly, high regioselec-
cient cyclic 1-azadienes was developed by cascade enam- tivity was realized for a number of unsymmetrical aliphatic
ine–enamine catalysis of a cinchona-based primary amine. ketone substrates.
This sequence involved a domino Michael addition–Mannich

Introduction cycloaddition reactions, probably due to relatively lower reac-


tivity and poor control of regioselectivity.
[3+3] Cycloaddition is a powerful method to construct six- Recently, we realized a highly asymmetric formal [5+3] cy-
membered-ring systems, which offers an alternative tool in cloaddition of b-substituted 2-cyclopentenones and 3-styryl-
comparison with extensively studied [4+2] cycloaddition pro- 1,2-benzoisothiazole-1,1-dioxides through cascade dienamine–
cess.[1, 2] In such fields, formal [3+3] cycloaddition through dienamine catalysis.[7] Such cyclic 1-azadienes[8] could serve as
a well-ordered cascade reaction pattern under metal-free con- good biselectrophilic partners in domino Michael addition–
ditions has become an efficient strategy.[3] In particular, amino- Mannich reactions. Inspired by this success, we envisaged that
catalysis has demonstrated to be extremely fruitful in [3+3] cy- an asymmetric formal [3+3] cycloaddition process would be
cloadditions with a,b-unsaturated aldehydes.[4] In fact, a cas- performed among aliphatic ketones and the above-mentioned
cade enamine–enamine catalysis[5] with aliphatic ketone sub- biselectrophiles in a similar domino Michael addition–Mannich
strates and some biselectrophilic reagents has been developed reaction sequence, producing structurally useful sultams incor-
to furnish multifunctional cyclohexanes in a formal [3+3] cyclo- porating a spirocyclohexane skeleton.[9] As unsymmetrical ke-
addition manner. In 2009, Tang and co-workers achieved an tones would generate two different types of enamine inter-
asymmetric formal [3+3] cycloaddition reaction with symmet- mediates,[10] it would be very intriguing if the expected asym-
ric cyclic ketones and (E)-2-nitroallylic acetates catalyzed by metric formal [3+3] cycloaddition could proceed in a highly re-
a bifunctional secondary amine–thiourea substance, affording gioselective pattern (Scheme 1).
bicyclo[3.3.1] adducts.[6a] The same group also reported a com-
plementary process by using b,g-unsaturated a-ketoesters as
dual acceptors.[6b] In addition, the Liu group presented a [3+3]
reaction of a,b-unsaturated trifluoromethyl ketones and ace-
tone albeit with low enantioselectivity.[6c] Nevertheless, the
formal [3+3] cycloaddition reactions of ketone substrates by
enamine–enamine catalysis have been less explored; moreover,
to the best of our knowledge, unsymmetrical linear ketones
have not been successfully applied in amine-catalyzed [3 + 3]

[a] X.-L. He, Y.-C. Xiao, W. Du, Prof.Dr. Y.-C. Chen


Key Laboratory of Drug-Targeting and
Drug Delivery System of the Ministry of Education
West China School of Pharmacy
Sichuan University, Chengdu 610041 (China) Scheme 1. Asymmetric formal [3+3] cycloadditions of ketones by cascade
E-mail: ycchen@scu.edu.cn enamine–enamine catalysis.
[b] Prof.Dr. Y.-C. Chen
College of Pharmacy, Third Military Medical University Results and Discussion
Chongqing 400038 (China)
Supporting information for this article is available on the WWW under Initially, we investigated the reaction of 3-styryl-1,2-benzoiso-
http://dx.doi.org/10.1002/chem.201104550. thiazole-1,1-dioxides 3 a and simple acetone catalyzed by 9-

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amino-9-deoxyepiquinine (1 a) and salicylic acid A1 at room mized the reaction with amine 1 c, and a good ee value could
temperature.[11] To our delight, the desired formal [3+3] cyclo- be obtained at lower temperature, though a modest yield was
addition reaction occurred smoothly to give spirocyclic prod- given even after a longer time (entry 16).
uct 4 a as a single diastereomer in various solvents (Table 1, en- With the optimized catalytic conditions in hand, the sub-
tries 1–6), and excellent results were obtained in THF in consid- strate scope and limitations of the formal [3+3] cycloaddition
reaction were explored (Table 2). At first, an array of aliphatic

Table 1. Condition optimization for asymmetric formal [3+3] cycloaddi-


tion.[a] Table 2. Substrate scope of asymmetric formal [3+3] cycloadditions.[a]

Entry R1, R2, R3, R4 T [8C] t [h] Yield [%][b] ee [%][c]


1 H, H, Ph, H RT 10 4 a, 85 97
2 Me, Me, Ph, H 40 50 4 b, 78 98
3 H, Me, Ph, H RT 24 4 c, 80 97
4 H, Et, Ph, H 40 52 4 d, 82 98
5 H, nBu, Ph, H 40 48 4 e, 79 99
6 H, OTBS, Ph, H RT 12 4 f, 85 96[d]
Entry 1 Solvent Acid t [h] Yield [%][b] ee [%][c]
7[e] H, SBn, Ph, H 40 24 4 g, 72 78
1 1a CH3CN A1 8 60 93 8[f] H, CH2OTBS, Ph, H 40 36 4 h, 62 95
2 1a toluene A1 6 63 97 9[f] H, (CH2)2OTBS, Ph, H 40 60 4 i, 35 98
3 1a DCE A1 12 62 92 10 H, H, 3-MeC6H4, H RT 24 4 j, 85 92
4 1a CHCl3 A1 9 62 91 11 H, H, MeOC6H4, H RT 24 4 k, 82 98[g]
5 1a dioxane A1 6 63 98 12 H, H, 3,4-(MeO)2C6H3, H 40 24 4 l, 94 94
6 1a THF A1 8 83 96 H, H,
7 1b THF A1 10 70 49 13 40 24 4 m, 87 90
8 1c THF A1 20 60 64
9 1d THF A1 12 65 60 14 H, H, 4-ClC6H4, H RT 18 4 n, 80 95
10 1a THF A2 8 50 74 15 H, H, 4-BrC6H4, H RT 48 4 o, 75 95
11 1a THF A3 6 82 94 16 H, H, 2-naphthyl, H 40 48 4 p, 91 90
12 1a THF A4 6 79 95 17 H, H, 2-furyl, H 40 36 4 q, 78 60
13 1a THF A5 6 80 96 18 H, H, 3-thienyl, H 40 36 4 r, 80 89
14 1a acetone A1 10 85 97 19 H, H, 2-styryl, H 40 48 4 s, 60 84
15[d] 1a acetone A1 18 84 88 20 H, H, H, 6-Cl RT 24 4 t, 83 91
16[e] 1c acetone A1 60 62 85 21 H, H, H, 5,7-Me2 RT 24 4 u, 88 96
[a] Unless noted otherwise, the reactions were carried out with acetone 2 a [a] Unless noted otherwise, reactions were conducted with 1-azadiene 3
(0.5 mmol), 3 a (0.1 mmol), catalyst 1 (0.02 mmol), and acid A (0.04 mmol) in (0.1 mmol), catalyst 1 a (0.02 mmol) and acid A1 (0.04 mmol) in ketone 2
1.0 mL of solvent at room temperature. [b] Isolated yield. [c] Determined by (1.0 mL) at RT or 40 8C. [b] Isolated yield. [c] Determined by HPLC analysis
HPLC analysis on a chiral column; d.r. > 19:1 as determined by 1H NMR spec- on a chiral column; d.r. > 19:1 as determined by 1H NMR analysis. [d] The
troscopic analysis. Negative values referred to the opposite enantiomer. absolute configuration of product 4 f was determined by X-ray analysis.
[d] With 0.01 mmol of 1 a and 0.02 mmol of A1. [e] At 5 8C. The other products were assigned by analogy.[14] [e] Ketone (0.2 mmol)
was used in THF (1.0 mL). [f] Ketone (0.4 mmol) was used in THF (1.0 mL).
[g] Determined after converting the carbonyl group of the product to
1,3-dithioketal.
eration of both yield and enantioselectivity (entry 6). A few
chiral primary amine catalysts were further tested. Interestingly,
6’-OH-9-amino-9-deoxyepiquinine 1 b produced cycloadduct ketones were examined in reactions with 1-azadiene 3 a. Com-
4 a with an opposite configuration but with fair enantioselec- pared to simple acetone, 3-pentanone exhibited lower reactivi-
tivity (entry 7). Both 9-amino-9-deoxyepiquinidine 1 c and bi- ty, while a good yield with excellent stereoselectivity could be
functional catalyst[12] 1 d also gave inferior results (entries 8 obtained at higher temperature (40 8C) after 50 h (Table 2,
and 9). Moreover, a series of acidic additives were screened as entry 2). On the other hand, some unsymmetrical ketones, in-
well (entries 10–13). The results demonstrated that benzoic cluding those possessing functional OTBS (tert-butyldimethyl-
acid bearing an ortho-OH group was crucial for the reactivity silyl) and thioether groups, could be successfully utilized (en-
and enantiocontrol, as much inferior data were delivered with tries 3–9). It was noteworthy that all the reactions showed ex-
simple benzoic acid (entry 10).[13] Further study indicated that cellent regioselectivity, whereas the thermally more stable en-
outstanding results were attained by employing acetone as amines I outlined in Scheme 1 initiated the Michael addition
both reactant and solvent (entry 14). The reaction still proceed- step. Moreover, outstanding enantioselectivity was generally
ed smoothly with lower catalyst loadings, but giving slightly achieved except for a ketone with an a-thioether group
decreased enantioselectivity (entry 15). Finally, we further opti- (entry 7), but the yields were decreased when the reactions

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were carried out using larger ketone substrates in THF (en-


tries 8 and 9). Subsequently, a spectrum of 3-vinyl-1,2-benzoi-
sothiazole-1,1-dioxides 3 were investigated in combination
with simple acetone. In general, 1-azadienes bearing diverse
electron-rich and -deficient aryl or heteroaryl groups could be
well tolerated, and the corresponding cycloaddition products
were produced in good yields with excellent enantioselectivity
(entries 10–21). It should be noted that only a moderate ee
value was attained for a 1-azadiene substrate with a 2-furyl
Scheme 3. Formal [3+3] cycloaddition reactions with b,g-unsaturated ke-
substitution (entry 17). Interestingly, a 2-styryl-substituted sub- tones and 1-azadiene 3 a.
strate still afforded the corresponding [3+3] adduct in a good
yield and enantioselectivity though it rendered a more remote
1,6-addition site (entry 19). In addition, cyclic 1-azadienes with
different substitutions on the phenyl ring also furnished good
results in reactions with acetone (entries 20 and 21).
Moreover, we also investigated the potential formal [3+3]
cycloadditions with cyclic ketones and 1-azadiene 3 a. Cyclo-
pentanone 2 j could smoothly afford the desired bridged prod-
uct 4 v in a good yield, but unfortunately with low enantiose- Scheme 4. Exploration with more 1-azadiene substrates.
lectivity. In contrast, an excellent ee value with a moderate
yield was obtained for cycloadduct 4 w when cyclohexanone
2 k was employed under the identical conditions. It should be
pointed out that an ipso,a-regioselective inverse-electron-
demand aza-Diels–Alder cycloadduct 5 was also isolated as
a byproduct in 25 % yield with 95 % ee (Scheme 2).[15]

Scheme 5. Diastereoselective reduction of the carbonyl group of product


4 a.

chiral sultams may find applications in medicinal chemistry[19]


and other synthetic fields.[20]
Scheme 2. Formal [3+3] cycloadditions with cyclic ketones. Based on the X-ray structure of the formal cycloadduct 4 f,
we have proposed a plausible catalytic transition state to ra-
tionalize the generation of the observed chiral product. The
In addition, g-heteroaryl substituted b,g-unsaturated ketones thermodynamic E-enamine intermediate would be formed
2 l–n did not undergo any Diels–Alder cycloaddition pathway from chiral amine 1 a and unsymmetrical ketone 2 f. Salicylic
with 1-azadiene 3 a by extended dienamine or formal triena- acid would react with amine 1 a through multiple hydrogen-
mine species,[16] but also provided the a,a’-regioselective bonding interactions, which acts as a synergistic Brønsted acid
formal [3+3] cycloadducts 4 x–z in good diastereo- and enan- for the activation of N-sulfonyl ketimine 3 a. Then Michael addi-
tioselectivity in acetonitrile albeit with moderate yields tion to 1-azadiene occurs from Re-face attack. Subsequently,
(Scheme 3). the secondary enamine intermediate would be formed and un-
On the other hand, other types of electron-deficient 1-aza- dergo the intramolecular Mannich reaction, finally giving the
dienes were further explored in reactions with acetone. The observed chiral product 4 f (Scheme 6).
analogous cyclic (E)-4-styryl-benzo[e][1,2,3]oxathiazine 2,2-diox-
ide 6 was also a compatible partner though lower reactivity
Conclusions
was observed.[17] The formal [3+3] cycloadduct 7 was pro-
duced in a moderate yield with good enantioselectivity. How- We have investigated the asymmetric formal [3+3] cycloaddi-
ever, the acyclic 1-azadiene[18] 8 failed to participate in reaction tions of aliphatic ketones and electron-deficient cyclic 1-aza-
with acetone 2 a, instead producing the decomposed ketoester dienes bearing a 1,2-benzoisothiazole-1,1-dioxide or 1,2,3-ben-
under the catalytic conditions (Scheme 4). zoxathiazine-2,2-dioxide motif. These reactions proceeded in
The reduction of the carbonyl group of product 4 a with dii- a domino Michael addition–Mannich reaction sequence by cas-
sobutylaluminum hydride (DIBAL-H) under an Ar atmosphere cade enamine–enamine catalysis of a cinchona-based amine. A
proceeded smoothly in dry toluene, giving the alcohol 9 in variety of spirocyclic structures were efficiently constructed in
good yield with excellent diastereoselectivity (Scheme 5). Such high stereoselectivity, and excellent regioselectivity was realiz-

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residue was purified by flash chromatography on silica gel (petrole-


um ether/ethyl acetate = 5:1, and then dichloromethane/acetone =
120:1) to afford the chiral product 4.

(1’S,5’S)-5’-Phenyl-2H-spiro(benzo[d]isothiazole-3,1’-cyclo-
hexan)-3’-one 1,1-dioxide (4 a)
Obtained as a white solid in 85 % yield after flash chromatography
and the enantiomeric excess was determined to be 97 % by HPLC
analysis on Chiralpak OD-H column (40 % 2-propanol/n-hexane,
1 mL min 1), UV: 220 nm, tmajor = 15.74, tminor = 10.24 min; [a]20
D = 1.0
(c = 0.61 in CHCl3); 1H NMR (400 MHz, CDCl3 + [D]DMSO): d = 7.59–
7.57 (m, 2 H), 7.52–7.49 (m, 1 H), 7.42–7.36 (m, 2 H), 7.17–7.15 (m,
4 H), 7.09–7.06 (m, 1 H), 3.46–3.43 (m, 1 H), 2.82–2.78 (m, 1 H), 2.63–
2.53 (m, 3 H), 2.29–2.23 (m, 1 H), 2.13 ppm (d, J = 12 Hz, 1 H);
13
C NMR (100 MHz, CDCl3): d = 205.9, 143.4, 142.5, 135.8, 132.8,
129.1, 128.3, 126.5, 122.6, 120.7, 120.7, 64.7, 50.8, 47.0, 43.4,
38.9 ppm; ESI-HRMS: calcd for C18H17NO3S + Na + : 350.0821; found:
350.0829.

Scheme 6. Proposed catalytic transition state for asymmetric formal [3+3] (1’S,2’S,4’R,5’S)-2’,4’-Dimethyl-5’-phenyl-2H-spiro(benzo[d]i-
cycloaddition. sothiazole-3,1’-cyclohexan)-3’-one 1,1-dioxide (4 b)
Obtained as a white solid in 78 % yield after flash chromatography
and the enantiomeric excess was determined to be 98 % by HPLC
ed for unsymmetrical ketones with diverse substitutions. These analysis on Chiralpak IA column (40 % 2-propanol/n-hexane,
chiral frameworks with high molecular and stereogenic com- 1 mL min 1), UV: 220 nm, tmajor = 30.32, tminor = 23.54 min; [a]20 D =
plexity might find further application in organic synthesis and 8.1 (c = 0.88 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.77 (d, J =
medicinal chemistry. 7.6 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.51 (d,
J = 8.0 Hz, 1 H), 7.35–7.31 (m, 2 H), 7.25–7.22 (m, 3 H), 4.57 (s, 1 H),
3.33 (q, J = 6.8 Hz, 1 H), 3.02 (td, J = 12.0, 3.6 Hz, 1 H), 2.96–2.89 (m,
1 H), 2.50–2.44 (m, 1 H), 2.29 (dd, J = 14.0, 3.6 Hz, 1 H), 0.92 (d, J =
Experimental Section 6.0 Hz, 3 H), 0.86 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3):
General 209.3, 141.6, 141.5, 135.4, 133.7, 129.9, 128.8, 127.4, 127.2, 122.7,
121.7, 70.0, 51.6, 50.3, 49.3, 47.4, 12.2, 8.0 ppm; ESI-HRMS: calcd for
NMR spectra were recorded with tetramethylsilane as the internal C20H21NO3S + Na + : 378.1134; found: 378.1139.
standard. 1H NMR spectra were recorded at 400 or 600 MHz and
13
C NMR spectra were recorded at 100 or 150 MHz. Chemical shifts
(1’S,4’R,5’R)-4’-[(tert-Butyldimethylsilyl)oxy]-5’-phenyl-2H-spi-
are reported in ppm downfield from CDCl3 (d = 7.26 ppm) for
1 ro(benzo[d]isothiazole-3,1’-cyclohexan)-3’-one 1,1-dioxide
H NMR and relative to the central CDCl3 resonance (d = 77.0 ppm)
for 13C NMR spectroscopy. Coupling constants are given in Hz. (4 f)
Enantiomeric excess was determined by HPLC analysis on Daicel Obtained as a white solid in 85 % yield after flash chromatography
Chiralpak AD-H Column (250  4.6 mm) or Chiralpak OD-H Column and the enantiomeric excess was determined to be 96 % by HPLC
(250  4.6 mm), Chiralpak IA Column (250  4.6 mm), Chiralpak IB analysis on Chiralpak AD-H column (40 % 2-propanol/n-hexane,
Column (250  4.6 mm), Chiralpak IC Column (250  4.6 mm). UV de- 1 mL min 1), UV: 220 nm, tmajor = 5.34, tminor = 6.73 min; [a]20D = + 50.7
tection was monitored at 220 or 254 nm. TLC analysis was per- (c = 0.84 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 7.2 Hz,
formed on glass-backed silica plates. UV light and I2 were used to 1 H), 7.70 (t, J = 6.8 Hz, 1 H), 7.59–7.53 (m, 2 H), 7.33–7.22 (m, 5 H),
visualize products. Column chromatography was performed using 4.93 (s, 1 H), 4.44 (d, J = 10.8 Hz, 1 H), 3.40 (td, J = 12.0, 3.6 Hz, 1 H),
silica gel (200–300 mesh) eluting with EtOAc/petroleum ether and 3.24 (d, 14.0 Hz, 1 H), 2.73 (dd, J = 14.0, 3.6 Hz, 1 H), 2.62–2.55 (m,
acetone/dichloromethane). Optical rotations were measured at 1 H), 2.31 (dt, J = 14.0, 3.6 Hz, 1 H), 0.64 (s, 9 H), 0.04 (s, 3 H),
589 nm at 20 8C. Unless otherwise noted, commercial reagents 0.38 ppm (s, 3 H); 13C NMR (150 MHz, CDCl3): 204.5, 142.7, 140.2,
were used as received and all reactions were carried out directly 135.8, 133.6, 130.0, 128.5, 128.1, 127.3, 122.7, 121.6, 81.0, 65.4, 50.6,
under an air atmosphere. 3-Vinyl-1,2-benzoisothiazol-1,1-dioxides 3 49.5, 43.3, 25.4, 18.1, 6.1, 6.2 ppm; ESI-HRMS: calcd for
and 4-styryl-1,2,3-benzoxathiazine-2,2-dioxide 6 were prepared ac- C24H31NO4SSi + Na + : 480.1635; found: 480.1640.
cording to the literature procedures.[8, 17] The primary amines
1 were also synthesized according to the literature procedures.[21]
(1’S,3’S)-3’-(Furan-2-yl)-2H-spiro(benzo[d]isothiazole-3,1’-cy-
clohexan)-5’-one 1,1-dioxide (4 q)
Typical procedure for asymmetric formal [3+3] cycloaddi-
Obtained as a white solid in 78 % yield after flash chromatography
tion
and the enantiomeric excess was determined to be 60 % by HPLC
The reaction was carried out with 1-azadiene 3 (0.1 mmol), catalyst analysis on Chiralpak OD-H column (40 % 2-propanol/n-hexane,
1 a (0.02 mmol), and salicylic acid (0.04 mmol) in corresponding 1 mL min 1), UV: 220 nm, tmajor = 14.36, tminor = 9.72 min; [a]20
D = 4.2
ketone (1.0 mL) at room temperature or 40 8C (unless otherwise (c = 0.29 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 8.0 Hz,
noted). After completion, the solution was concentrated and the 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.49 (d, J =

& & Chem. Eur. J. 2015, 21, 1 – 7 www.chemeurj.org 4  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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7.6 Hz, 1 H), 7.33–7.26 (m, 1 H), 6.29 (br s, 1 H), 6.08 (d, J = 2.8 Hz, 2010, 29, 2126; f) X. Wang, X. Xu, P. Y. Zavalij, M. P. Doyle, J. Am. Chem.
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& & Chem. Eur. J. 2015, 21, 1 – 7 www.chemeurj.org 6  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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FULL PAPER
& Organic Synthesis
X.-L. He, Y.-C. Xiao, W. Du, Y.-C. Chen*
&& – &&

Enantioselective Formal [3+3]


Cascade catalysis: A highly regioselec- dition–Mannich reaction sequence,
Cycloadditions of Ketones and Cyclic
tive and asymmetric formal [3+3] cyclo- giving spirocyclic frameworks with ex-
1-Azadienes by Cascade Enamine–
addition of diversely structured aliphatic cellent diastereo- and enantioselectivity
Enamine Catalysis
ketones and cyclic 1-azadienes was de- (see scheme).
veloped through a domino Michael ad-

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