Unexpected transfer of tosyl group of ArCH=NTs-catalyzed by N-heterocyclic carbene

Article abstract of DOI:10.1021/jo800569g

(Chemical Equation Presented) Reactions of N-tosylimines with aziridines and electron-deficient unsaturated compounds in the presence of catalytic amount of NHC afforded unexpected tosyl group transfer products in good to high yields, which represent a new reaction pattern for imines as well as for catalysis of NHC.

Full text of DOI:10.1021/jo800569g

SCHEME 1. NHC-Catalyzed Reaction of Imines with
Aziridines
Unexpected Transfer of Tosyl Group of
ArCHdNTs-Catalyzed by N-Heterocyclic
Carbene
Dong-Dong Chen, Xue-Long Hou,* and Li-Xin Dai
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
ReceiVed March 13, 2008
reactions. There have also been reports that a hydrogen-bonded
intermediate was formed between NHC and alcohol in the trans-
esterification reaction.2 In the course of studies on the trans-
formations of imines3 and aziridines,4 we investigated the
reaction of imines and aziridines in the presence of organo-
catalyst. To our surprise, unexpected tosyl-group transfer
products were detected in the reaction of PhCHdNTs and
aziridine in the presence of NHC·HCl.5,6 Here, we disclose our
results on the reaction of N-tosylimines with aziridines and
electron-deficient unsaturated compounds using NHC as catalyst.
We commenced our investigation by heating a solution of
N-tosylaldimine 1a with aziridine 2a in the presence of 10 mol
% of NHC·HCl 3a in THF at 70 °C under argon (Scheme 1).
Unexpectedly, ring-opening products of aziridine attacked by
the O- and S- of the tosyl group were separated in 30% and
27% yields, respectively, accompanied a colorless oil product,
Reactions of N-tosylimines with aziridines and electron-
deficient unsaturated compounds in the presence of catalytic
amount of NHC afforded unexpected tosyl group transfer
products in good to high yields, which represent a new
reaction pattern for imines as well as for catalysis of NHC.
7
1
which was determined as benzonitrile by GC-MS. The H
NMR showed that the stereochemistry of the S-atom in 5a was
racemic. The antistereochemistry of product 5a was confirmed
by coupling constant of two hydrogens of its oxidation product
5a′ (J ) 9 Hz). The structure of 4a and its anti stereochemistry
N-Heterocyclic carbenes (NHCs) are among the most efficient
organocatalysts in organic synthesis.1 Many types of reactions,
such as benzoin condensation,1i the Stetter reaction,1j transes-
terification and acylation reactions,1k,l formation of homo-
enolates,1m ring-opening and ring-expansion reactions,1m–p and
1,2-addition reaction of carbonyls,1q can smoothly proceed using
NHCs as catalyst.1 A variety of chiral NHCs have also been
developed and used in asymmetric catalysis successfully. In most
cases, NHC served as nucleophilic species to initiate the
(2) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453.
(3) (a) Zhang, W. X.; Ding, C. H.; Luo, Z. B.; Hou, X. L.; Dai, L. X.
Tetrahedron Lett. 2006, 47, 8391. (b) Ding, C. H.; Chen, D. D.; Luo, Z. B.;
Dai, L. X.; Hou, X. L. Synlett 2006, 8, 1272. (c) Hou, X. L.; Yang, X. F.; Dai,
L. X.; Chen, X. F. Chem. Commun. 1998, 747. (d) Wang, D. K.; Dai, L. X.;
Hou, X. L. Chem. Commun. 1997, 1231.
(4) (a) Luo, Z. B.; Wu, J. Y.; Hou, X. L.; Dai, L. X. Org. Biomol. Chem.
2007, 5, 3428. (b) Luo, Z. B.; Hou, X. L.; Dai, L. X. Tetrahedron: Asymmetry
2007, 18, 443. (c) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2008, 852.
(d) Hou, X. L.; Wu, J.; Fan, R. H.; Ding, C. H.; Luo, Z. B.; Dai, L. X. Synlett
2006, 181. (e) Fan, R. H.; Hou, X. L. J. Org. Chem. 2003, 68, 726. (f) Fan,
R. H.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2004, 69, 689. (g) Hou, X. L.; Luo,
Y. M.; Yuan, K.; Dai, L. X. J. Chem. Soc., Perkin Trans. 1 2002, 1487.
(5) NHC-catalyzed reactions involving sulfonyl imines: (a) He, M.; Struble,
J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b) He, M.; Bode, J. W.
Org. Lett. 2005, 7, 3131. (c) He, L.; Jian, T. Y.; Ye, S. J. Org. Chem. 2007, 72,
7466.
(1) Some recent reviews: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem.
ReV. 2007, 107, 5606. (b) D´ıez-Gonza`lez, S.; Nolan, S. P. Coord. Chem. ReV.
2007, 251, 874. (c) Marion, N.; D´ıez-Gonza`lez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988. (d) Zeilter, K. Angew. Chem., Int. Ed. 2005, 44, 7506.
(e) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130.
(f) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. (g) Herrmann,
W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (h) Bourissou, D.; Guerret, O.;
Gabba¨ı, F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39. Some examples for the
applications of NHCs: (i) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem.,
Int. Ed. 2006, 45, 1463. (j) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,
2552. (k) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007,
9, 371. (l) Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8, 3785. (m)
Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129,
3520. (n) Zhou, H.; Campbell, E. J.; Nguyen, S. T. Org. Lett. 2001, 3, 2229. (o)
Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021. (p) Li, Q.-Q.;
Li, Y.; You, S.-L.; Dai, L.-X. Org. Lett. 2007, 9, 3519. (q) Fukuda, Y.; Maeda,
Y.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 397.
(6) NHC-catalyzed ring-opening reactions involving aziridines: (a) Liu, Y. K.;
Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding, L. S. Org. Lett. 2006, 8,
1521. (b) Wu, J.; Sun, X. Y.; Ye, S. Q.; Sun, W. Tetrahedron Lett. 2006, 47,
4813. (c) Sun, X. Y.; Ye, S. Q.; Wu, J. Eur. J. Org. Chem. 2006, 4787.
(7) See the Supporting Information. Also see: (a) Davis, F. A.; Friedman,
A. J.; Klunger, E. W. J. Am. Chem. Soc. 1974, 96, 5000. (b) Mukade, T.; Dragoli,
D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5, 590. (c) Tanuwidjaja, J.; Peltier,
H. M.; Lewis, J. C.; Schenkel, L. B.; Ellman, J. A. Synthesis 2007, 21, 3385.
(d) 4-MeOC6H4CN was also obtained when 4-MeOC6H4CHdNTs was used; its
structure was determined by GC and 1H NMR. (e) The presence of PhCN,
PhCHO, and TsNH2 was sometimes also detected, which may derive from the
decomposition of imines.
5578 J. Org. Chem. 2008, 73, 5578–5581
10.1021/jo800569g CCC: $40.75 2008 American Chemical Society
Published on Web 06/17/2008

TABLE 1. Optimization of the Reaction of Imine 1 with Aziridine
TABLE 2. Tosyl-Transfer Reaction from Imine 1a to Aziridines 2
2a Catalyzed by NHC ·HCl 3a/Basea
Catalyzed by NHC ·HCl 3b/DMAPa
entry
2, R1, R2, R3
yield%b
4/5c
n
1
2
3
4
5
6
7
8
e, Bu, H, H
79
68d
72
69
67
51
85
73
2.8/1
2.3/1
4.5/1
2.6/1
3.3/1
1/0
n
e, Bu, H, H
a, -(CH2)4-, H
entry
1, Ar, G
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
base/solvents
yield%b
4/5c
n
f, hexyl, H, H
g, C16H33, H, H
h, H, Ph, H
i, Me, H, Ph
k, H, H, H
1
2
3
4
5
6
7
8
-/THF
-/toluene
DBU/toluene
DBU/NO2Ph
DBU/FPh
57
72
81
67
81
67
86
77
1.1/1
1.3/1
1.7/1
2.7/1
2.2/1
3.4/1
2.6/1
4.4/1
2.2/1
4.5/1
1/0
2.9/1
a Run at 70 °C using 10 mol % of 3b and DMAP on a 0.5 mmol
scale in 2.5 mL of CF3Ph in 24 h. b Isolated yield of 4 and 5.
DBU/MeOPh
DBU/CF3Ph
DMAP/ CF3Ph
iPr2NEt/ CF3Ph
DMAP/ CF3Phd
DMAP/ CF3Phe
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
DBU/toluene
c
Determined by H NMR. d 10 mol % of 3a was used.
1
9
a, Ph, Ts
a, Ph, Ts
a, Ph, Ts
97
10
11
12
13
14
15
16
17
18
19
20
72
base (entry 8). Almost the same selectivity was given when the
NHC·HCl 3b9 was used in DMAP/CF3Ph (entry 10 vs entry
8). Control experiments showed that no tosyl-transfer product
was detected when the reaction proceeded in the absence of
NHC (entry 11).
NRf
20
b, 4-NO2C6H4, Ts
c, 4-MeOC6H4, Ts
d, 4-BrC6H4, Ts
e, 2,4-diClC6H3, Ts
f, 1-Naphthyl, Ts
g, 4-ClC6H4, Ph
h, Ph, S(O)But
i, 4-MeC6H4, P(O)Ph2
j, Ph, SO2CH3
1/0
73
87
73
73
NR
NR
NR
NR
2.3/1
2.0/1
2.0/1
1.6/1
The effect of different aldimines to this tosyl-transfer reaction
was also examined using 3a/DBU as catalyst in toluene (Table
1, entries 11-19). As expected, all N-tosyl aromatic aldimines
reacted with aziridine 2a successfully (entries 12-15) except
1b with nitro group as substituent on the phenyl ring, which
gave only 20% yield of S-attacked product (entry 11). However,
other aldimines with sulfinyl, phosphinoyl, phenyl, and mesyl
as substituent on nitrogen gave no products (entries 16-19).
These results may reflect the importance of electronic effect of
imine in the reaction.
a All reactions were performed on a 0.5 mmol scale in 2.5 mL of
c
solvent at 70 °C in 24 h. b Isolated yield of 4 and 5. Determined by H
NMR. d NHC·HCl 3b was used. e No NHC was added. f NR ) no
reaction.
1
1
were determined by comparison of its H NMR with that of
product obtained from the reaction of 2a with PhSH followed
With the optimized conditions, the scope of the reaction was
investigated and the results were compiled in Table 2. Compared
to the reaction of aziridine 2e using 3a/DMAP as catalyst, that
use of 3b/DMAP provided better results either in yield or
selectivity (entry 1 vs entry 2). Thus, NHC·HCl 3b was used
in all reactions.
All reactions delivered products 4 and 5 in good yields except
that using aziridine 2h derived from styrene, which gave 4h in
51% yield (entry 6). The ratio of 4 and 5 was between 2.6-4.5.
However, aziridines 2h and 2i with Ph as substituent afforded
S-attacked product only (entries 6 and 7). The reactions provided
terminal attacked products when monosubstituted aziridines
were used (entries 1-5) while that of phenyl-substituted
aziridines preferred to produce benzylic attacked products
(entries 6 and 7). Reaction of aziridine 2b derived from
cyclopetene gave only 10% yield of products, while that of 2c,d
derived from cycloheptene and cyclooctene and that of disub-
stituted aziridine 2j derived from oct-2-ene provided no product
(not showed in Table 2).
by oxidation using m-CPBA.8
The influences of bases and solvents on the reaction using
NHC·HCl 3 were investigated (Table 1). The yields of 4a and
5a were 30% and 27%, respectively, when the reaction
proceeded in THF using 10 mol % of NHC ·HCl 3a (entry 1),
which increased to 41% and 31%, respectively, if toluene was
solvent (entry 2). It increased further to 51% and 30% if 10
mol% of DBU was added (entry 3). The yields of both 4a and
5a were unchanged when the reaction was run under aerobic
conditions. An increase of catalyst loading to 20 mol % did
not increase the yields of products but shortened the reaction
time. A screen of common solvents showed that no products
were separated when the reaction proceeded in EtOH, CH2Cl2,
MeCN, and hexane, while complex products were provided
using DMF as solvent (not showed in Table 1); however, the
yield and selectivity were improved using other aromatic
solvents combined with the change of bases (entries 4-9).
Among them, the best yields (97%) of 4a and 5a with a ratio
of 2.2:1 were provided when using iPr2NEt as base and CF3Ph
as solvent (entry 9), while the better selectivity (the ratio of
4.4:1 for 4a and 5a) was realized in CF3Ph using DMAP as
Surprisingly, propargyl ester 7, allenyl ester 9, and R,ꢀ-
unsaturated ester 11 are suitable acceptors of the tosyl group of
imines. Reactions of them with N-tosyl imine 1a afforded tosyl-
(8) (a) Wu, J.; Hou, X. L.; Dai, L. X. J. Chem. Soc., Perkin Trans. 1 2001,
1314. (b) Hou, X. L.; Fan, R. H.; Dai, L. X. J. Org. Chem. 2002, 67, 5295.
(9) (a) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Org. Chem. 2005, 70, 5725.
(b) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418.
J. Org. Chem. Vol. 73, No. 14, 2008 5579

SCHEME 2. Tosyl-Transfer Reactions of Imines with
Unsaturated Substrates
SCHEME 4. Cross-over Reactions of Imine, Aziridine, or
Acrylate and Cyclohexenone in the Presence of NHC
SCHEME 3. Formation of Imine-NHC Adduct and
Tosyl-Transfer Reaction
SCHEME 5. Plausible Mechanism of Tosyl-Transfer
Reaction
transfer products 8, 10, and 12 in moderate to good yields,
respectively (Scheme 2).10 It was worth noting that in these
cases only S-attacked products were detected. It has well been
documented that aza-Morita-Baylis-Hillman products or cy-
cloaddition products are provided in the reaction of electron-
deficient unsaturated esters with imines catalyzed by amines or
organophosphines.11,12 However, no such products were detected
under our reaction conditions.
Bode has reported the formation of the stable N-tosylimine-
NHC adduct, which inhibited the further catalytic process in
the reaction of N-tosylimine and enals in the presence of NHC.5b
Ye recently reported the aza-Morita-Baylis-Hillman reaction
of N-tosylimine with cyclic enones catalyzed by NHC.5c
However, when we treated the aziridine 2a with imine-NHC
adduct 13 prepared from N-tosylimine 1a and IPr ·HCl,5c tosyl-
transfer product 4a was separated in 34% yield (Scheme 3).
Also, in the cross-over reaction of 1a, 2a and cyclohexenone
14 in the presence of IPr ·HCl and base, no aza-
Morita-Baylis-Hillman product was detected; instead, tosyl-
transfer products 4a and 5a in a ratio of 3:1 were obtained in
46% yield. The reaction of 1a, 11, and cyclohexenone 14 using
NHC·HCl as catalyst also gave no aza-Morita-Baylis-Hillman
product, but tosyl-transfer product (Scheme 4). These results
indicated that N-tosylimine-NHC adduct should be an active
intermediate.
attraction of proton from int-C by 4- and 5- affords final
products 4 and 5 and int-D, which deliveres PhCN and NHC
to complete the catalytic cycle.13
In conclusion, an unexpected tosyl-transfer was discovered
from the reaction of N-tosylimines with aziridines and R,ꢀ-
unsaturated esters catalyzed by NHC, which represents a new
reaction patent for imine as well as for catalysis of NHC.
Controlled experiments showed that N-tosylimine-NHC adduct
should be an active species. Further investigations on the detailed
mechanism and extension of the reaction are in progress.
According to the clues we have found, a plausible reaction
path can be proposed (Scheme 5). The reaction of imine 1 with
NHC forms the adduct 14,5 and then proton transfer of which
provides int-A and decomposition of int-A gives int-B and int-
C. Attack of int-B to aziridine 2 gives rise to 4- and 5- and
Experimental Section
(10) Davis reported the addition of arylsulfenic acid to methyl propynoate:
(a) Davis, F. A.; Billmers, R. L. J. Org. Chem. 1985, 50, 2593. (b) Davis, F. A.;
Billmers, R. L. J. Am. Chem. Soc. 1981, 103, 7016. (c) Davis, F. A.; Jenkins,
R. H., Jr.; Rizvi, S. Q. A.; Yocklovich, S. G. J. Org. Chem. 1981, 46, 3467.
(11) For some recent reviews on aza-MBH reactions, see: (a) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614. (b) Basavaiah,
D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811.
Representative Procedure for the Tosyl-Transfer Reaction
of Aziridines and N-Tosylimines. To a solution of N-tosylphe-
nylimine 1a (130 mg, 0.5 mmol) in 2.5 mL of trifluoromethylben-
zene was added aziridine 2a (125 mg, 0.5 mmol) under argon,
followed by addition of NHC salt 3b (12 mg, 0.05 mmol) and
DMAP (6 mg, 0.05 mmol). The resulting solution was allowed to
(12) For some recent reviews involving allenes and N-tosylimines, see: (a)
Ma, S. M. Chem. ReV. 2005, 105, 2829. (b) Methot, J. L.; Roush, W. R. AdV.
Synth. Catal. 2004, 346, 1035. (c) Lu, X.; Zhang, C. G.; Xu, Z. R. Acc. Chem.
Res. 2001, 34, 535.
(13) The transfer of sulfonyl radical to alkene was reported: (a) Nair, V.;
Augustine, A.; Suja, T. D. Synthesis 2002, 2259.
5580 J. Org. Chem. Vol. 73, No. 14, 2008

stir at 70 °C and monitored by TLC. The reaction mixture was
directly onto a silica gel column. The products 4a and 5a were
isolated by flash column chromatography (petroleum ether/ethyl
acetate, 10:1 to 5:1 to 3:1).
(d, J ) 5.2 Hz, 1H), 7.03 (d, J ) 8.4 Hz, 2H), 7.25-7.38 (m, 6H),
7.47 (d, J ) 7.8, 2H), 7.57 (d, J ) 8.1 Hz, 2H), 7.69 (d, J ) 8.1
Hz, 2H), 7.82 (d, J ) 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
21.36, 21.49, 23.56, 23.76, 23.88, 26.59, 32.54, 32.60, 32.90, 32.55,
55.96, 56.26, 75.83, 79.98, 124.93, 125.40, 127.20, 127.46, 136.92,
137.33, 139.93, 141.44, 142.65, 142.90, 143.03, 143.25; ESI-MS
408.2 (M + H+), 430.2 (M + Na+); IR (cm-1) 3248, 2941, 2864,
1598, 1453, 1335, 1164, 1093. Anal. Calcd for C20H25NO4S2: C,
58.94; H, 6.18; N, 3.44. Found: C, 58.74; H, 6.31; N, 3.27.
4-Methyl-N-(2-tosylcyclohexyl)benzenesulfonamide (4a): col-
1
orless oil; H NMR (300 MHz, CDCl3) δ 1.10-1.40 (m, 4H),
1.51-1.62 (m, 1H), 1.67-1.76 (m, 1H), 1.81-1.91 (m, 1H),
2.40-2.46 (m, 1H), 2.46 (s, 6H), 3.01 (td, J ) 3.6 Hz, 10.5 Hz,
1H), 3.28-3.38 (m, 1H), 6.32 (s, 1H), 7.30-7.36 (m, 4H), 7.61
(d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 21.46, 21.55, 22.50, 23.25, 25.29, 51.44, 64.56, 127.25,
128.85, 129.50, 129.73, 133.32, 136.99, 143.37, 145.12; ESI-MS
430.2 (M + Na+); EI-MS m/z 407 (M+, 0.37), 252 (100), 187 (23),
155 (38), 91 (77); IR (cm-1) 3256, 2939, 2865, 1597, 1452, 1335,
1314, 1303, 1288, 1160, 1143. Anal. Calcd for C20H25NO4S2: C,
58.94; H, 6.18; N, 3.44. Found: C, 59.20; H, 6.37; N, 3.15.
2-(4-Methylphenylsulfonamido)cyclohexyl 4-Methylbenzene-
sulfinate (5a). The compound was isolated as an inseparable
mixture of two diastereoisomers (1:1), whose NMR peaks were
Acknowledgment. Financial support from National Natural
Science Foundation of China, the Major Basic Research Develop-
ment Program (2006CB806100), the Chinese Academy of Sciences
and Science, and the Technology Commission of Shanghai Muni-
cipality are acknowledged.
Supporting Information Available: Experimental proce-
dures and characterization data for products 4a,e-i,k, 5a,e-g,k,
5a′,f′, 10, and 12, synthetic procedure and analysis data for NHC
3b. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
hard to distinguish: colorless oil; H NMR (300 MHz, CDCl3) δ
1.00-1.40 (m, 8H), 1.40-1.60 (m, 3H), 1.60-1.80 (m, 2H),
2.08-2.22 (m, 2H), 2.27-2.40 (m, 1H), 2.29 (s, 3H), 2.42 (s, 3H),
2.44 (s, 3H), 2.46 (s, 3H), 2.81-3.00 (m, 2H), 3.70-3.82 (m, 1H),
3.95-4.05 (td, J ) 4.2, 9.9 Hz, 1H), 5.55 (d, J ) 3 Hz, 1H), 5.92
JO800569G
J. Org. Chem. Vol. 73, No. 14, 2008 5581