An enantioselective organocatalyzed aza-MBH domino process: Application to the facile synthesis of tetrahydropyridines

Article abstract of DOI:10.1016/j.tetlet.2010.11.045

A chiral acid-base organocatalyst was found to promote an aza-MBH domino process between α,β-unsaturated carbonyl compounds and N-tosylimines to afford tetrahydropyridine derivatives with high enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2010.11.045

Tetrahedron Letters 52 (2011) 377–380
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An enantioselective organocatalyzed aza-MBH domino process: application
to the facile synthesis of tetrahydropyridines
⇑
Shinobu Takizawa, Naohito Inoue, Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiral acid–base organocatalyst was found to promote an aza-MBH domino process between a,b-unsat-
urated carbonyl compounds and N-tosylimines to afford tetrahydropyridine derivatives with high
enantioselectivity.
Received 6 October 2010
Revised 27 October 2010
Accepted 4 November 2010
Available online 16 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Acid–base organocatalyst
Domino reaction
Aza-MBH reaction
Tetrahydropyridines
Enantioselective reaction
Simple construction of highly functionalized chiral molecules is
an ongoing substantial challenge in current synthetic chemistry.
Considerable efforts have been directed toward the development
of asymmetric organocatalyzed domino reactions1 that allow a
rapid increase in molecular complexity from readily available
materials under mild reaction conditions. These reactions can save
the time, chemicals, energy, and labor typically required for isola-
tion or purification of synthetic intermediates. In addition, there is
no concern about metal contamination of the products and toxic
metal waste since organocatalysts contain no toxic or expensive
metals.
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is one of
the most useful and atom-economical C–C bond-forming reactions
of activated alkenes with imines catalyzed by Lewis bases (LB).2,3
The aza-MBH adducts are highly functionalized allylic amines that
are valuable building blocks for medicinal chemistry.4 Although
until now a number of attractive systems have been developed
for this asymmetric catalytic process,5 few reports on the enantio-
selective domino reaction of activated alkenes with imines have
been made.6,7 As a recent excellent investigation of aza-MBH
domino cyclizations, Prof. Huang reported achiral organocatalysis
to produce highly functionalized heterocyclic compounds such as
tetrahydropyridines (Scheme 1),8a dihydrobenzofurans,8b and
chromans.8c
and retro-Michael reaction (b-elimination) as shown in Scheme
2. In chiral acid–base organocatalysis of this process, Michael addi-
tion of the LB part of the catalyst to the activated alkene generates
Brønsted acid (BA) stabilized chiral enolate I, which then reacts
with the imine to afford the zwitterionic intermediate II. A proton
shift from the a-carbon atom to the nitrogen anion in the interme-
diary ketone II followed by b-elimination of the LB catalyst yields
the aza-MBH product with regeneration of the catalyst. With a
suitable chiral acid–base organocatalyst, the nitrogen anion of
intermediate II could react with a second equivalent of the activated
alkene via an aza-Michael addition, followed by aldol/dehydration
reactions to produce chiral tetrahydropyridines.9 Herein, we report
the chiral acid–base organocatalyzed domino process based on
aza-MBH reactions of
a,b-unsaturated carbonyl compounds with
N-tosylimines to give highly functionalized tetrahydropyridines
with up to 93% ee.
PPh2
OH
H
CHO
H
CHO
+
CHCl3, rt
Ar
NTs
Ar
N
Ts
The aza-MBH reaction formally involves a sequence of reactions
including a Michael addition, Mannich reaction, proton-transfer,
up to 50% yield
rac.
⇑
Corresponding author.
E-mail address: sasai@sanken.osaka-u.ac.jp (H. Sasai).
Scheme 1. Achiral acid–base organocatalyzed aza-MBH domino reaction reported
by Huang.8a
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.045

378
S. Takizawa et al. / Tetrahedron Letters 52 (2011) 377–380
O
O
H
R1
NHR3
+
R1
activatedalkene
R2
NR3
R2
aza-MBHproduct
imine
LB
Lewis base
chiral
retro-Michael
reaction
Michael
back bone *
reaction
BA
Brφnsted acid
acid-base organocatalyst
BA
BA
LB
O
O
H
O
LB
R1
H
H-transfer
R1
LB
R2
BA
R1
NHR3
Mannich
reaction
N
R2
NR3
R3
R2
II
III
I
activated alkene
aza-Michael reaction
This Work
R1 R1
BA
O
LB
aldol
reaction
R1
O
dehydration
O
R2
N
R3
R2
N
R1
organocatalyst
R3
tetrahydropyridine
Scheme 2. Acid–base organocatalyzed domino process based on the enantioselective aza-MBH reaction.
We first conducted experiments to assess the feasibility of using
in high enantioselectivity (entry 4).10 We then went on to study
the effects of other conditions on the reaction of 1a with 2a. Sol-
vent effects were crucial for accelerating the domino reaction.
THF and cyclopentyl methyl ether (CPME) (entries 5 and 6), along
with toluene (entry 7) gave mainly the normal aza-MBH adduct 3a.
In contrast, halogenated solvents such as chloroform, dichloro-
methane, and dichloroethane afforded 4a as a major product with
chiral acid–base organocatalysts to promote the enantioselective
domino reaction of acrolein (1a) with 4-chlorophenyl N-tosylimine
(2a) as shown in Table 1. Among the catalysts we examined for the
aza-MBH reaction, including the known chiral organocatalysts
(S)-5,5m (S)-65d,f and (S)-75a–c (Table 1, entries 1–3), the acid–base
organocatalyst (S)-85e,k promoted the domino reaction to give 3a
Table 1
Enantioselective synthesis of tetrahydropyridinesa
H
CHO
CHO
H
Catalyst
CHO
1a
+
+
NTs
NHTs
º
25 C, 24h
N
Ts
2a
3a
4a
Cl
Cl
(3 eq)
Catalyst
Cl
Entry
Solvent
Ratio of 3a:4a
Yieldb (%)
Eec,d (%)
1
2
3
4
5
6
7
8
9
(S)-5
(S)-6
(S)-7
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
(S)-8
CHCl3
CHCl3
CHCl3
CHCl3
THF
CPME
Toluene
CH2Cl2
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
100:0
0:100
0:100
0:100
96:4
81
27
27
9e
72
73
82
81
81
80
83
84
85
92
87
35
100
37f
35f
31
18
58
99:1
83:17
0:100
37:63
38:62
98:2
10g
11g,h
12g,i
98
60
0:100
a
b
c
d
e
f
20 mol % of catalyst was used.
Isolated total yield of 3a and 4a.
Ee of major product.
Determined by HPLC (Daicel Chiralpak AS-H, EtOH/hexane = 35/65).
(R)-form.
Unreacted 2a remained.
MS 3A was added.
At 0 °C for 48 h.
g
h
i
At 0 °C for 48 h then 25 °C for 24 h.

S. Takizawa et al. / Tetrahedron Letters 52 (2011) 377–380
379
OH
N
N
N
PPh2
OH
OH
OH
PPh2
OH
OH
O
N
5
(S)-
6
8
(S)-
(S)-
(S)-7
high enantioselectivity (entries 4, 8 and 9). The addition of MS 3A
was beneficial for suppressing the decomposition of the moisture
sensitive N-tosylimine, resulting in an improvement of the product
yield (entry 10). The normal aza-MBH adduct 3a was obtained in
96% yield with 92% ee at 0 °C, since the lower reaction temperature
drastically diminished the reaction rate of the aza-Michael process
between intermediate II and 1a (entry 11). Finally, when the reac-
tion mixture was stirred at 0 °C until the imine 2a was consumed
completely as determined by TLC analysis and then was slowly
warmed up to 25 °C, tetrahydropyridine 4a was obtained in 60%
yield with 87% ee (entry 12).
The substrate scope under the optimized reaction conditions is
summarized in Table 2. Regardless of whether the aromatic substi-
tuent of 2 is electron withdrawing or electron donating, acid–base
organocatalyst (S)-8 promotes the reaction with good to high
Table 2
Scope and limitations of the enantioselective synthesis of tetrahydropyridinesa
enantioselectivities (Table 2, entries 1–7).
a,b-Unsaturated N-
tosylimine (2i) was able to use as a substrate (entry 8).
H
Being encouraged by the results obtained in Table 2, we at-
tempted the cross domino reaction of the two different Michael
acceptors 1a and methyl vinyl ketone (MVK, 1b) with imine 2b
in one-pot (Scheme 3). The reaction of 1b and 2b with catalyst
(S)-8 was allowed to proceed until 2b was consumed and then
1a was added. Although the normal aza-MBH product 3j was
formed in 93% yield and 93% ee, no desired domino product was
obtained. To promote the following aza-Michael/aldol/dehydration
sequence, various kinds of LB were tested. DBU, which can function
as a strong LB11 promoted the sequential reaction while maintain-
ing the optical purity of 3 (Table 3).
To provide mechanistic insight into the present domino reac-
tion, we performed the aza-Michael/aldol/dehydration reaction of
aza-MBH adduct 3h (optical purity 90% ee) with 1a catalyzed by
(S)-8 (Scheme 4). The domino reaction led to 4h in 60% yield with
88% ee, along with the formation of 4-bromobenzaldehyde, tosyl-
amine, and aldehyde 9. These side products derived from the
decomposition of imine 2h via the retro-aza-MBH reaction of 3h.
Judging from these results, the present acid–base organocatalyzed
CHO
H
Organocatalyst (S)-8
(ClCH2)2, MS 3A, 0 to 25ºC
CHO
+
Ar
NTs
Ar
N
Ts
1a
2
4b-i
(3 eq)
Entry
Ar
Time (h) Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
3-Cl–C6H4
2-Cl–C6H4
4-NO2–C6H4
Ph
3,4-(MeO)2–C6H3 2f
4-NC–C6H4
4-Br–C6H4
2b
2c
2d
2e
48
48
24
48
48
48
4b
4c
4d
4e
4f
4g
4h
4i
55
60
40
49
58
45
60
43
80
83
85
75
83
84
88
78
2g
2h 48
2i 48
(E)-PhCH@CH
a
b
c
20 mol % of catalyst was used.
Isolated yield.
Determined by HPLC (Daicel Chiralpak AS-H for 4b,c,e,h, 2-propanol/hexane =
35/65; Daicel Chiralpak AD-H for 4d,g,i, 2-propanol/hexane = 35/65; Daicel Chi-
ralcel OJ-H for 4f, 2-propanol/hexane = 35/65).
Me
Me
H
i) MVK (1b; 1.5 eq), 0 oC
CHO
O
o
1a
ii)
(1.5 eq), 25 C
NTs
+
NHTs
N
Ts
(S)-8 (20 mol%)
MS 3A, (ClCH2)2
One-pot
2b
3j
4j
Cl
none
93%, 93% ee
Cl
Cl
Scheme 3. Attempt at the cross aza-MBH domino reaction of 1a, 1b and 2b.
Table 3
Stepwise synthesis of chiral tetrahydropyridines
Me
1a
Me
(1.5 eq)
1b
(1.2 eq)
CHO
H
(S)-8 (10 mol%)
DBU (10 mol%)
O
(ClCH2)2
(ClCH2)2
MS 3A, 0 C
>90% yield
Ar
NTs
Ar
N
Ts
MS 3A, 0 oC
o
Ar
NHTs
3
2
4
Entry
Ar
Product
Overall yielda (%)
eeb (%)
1
2
3
4-Cl–C6H4
3-Cl–C6H4
Ph
4j
4k
4l
44
52
40
93
91
87
a
Isolated yield.
b
Determined by HPLC (Daicel Chiralpak AS-H for 4j,k, 2-propanol/hexane = 35/65; Daicel Chiralcel OD-H for 4l, 2-propanol/hexane = 35/65).

380
S. Takizawa et al. / Tetrahedron Letters 52 (2011) 377–380
H
CHO
CHO
(S)-8 (0.2 eq)
1a
(1.5 eq)
+
NHTs
(ClCH2)2, MS 3A, 25ºC
N
Ts
3h
4h
60%, 88% ee
Br
90% ee
Br
CHO
OHC
+
TsNH2
13%
Scheme 4. Aza-Michael/aldol/dehydration reaction of 1a with 3h.
+
NHTs
Br
9
20%
5%
4. (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653; (b) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811; (c) Kataoka, T.;
Kinoshita, H. Eur. J. Org. Chem. 2005, 45; (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem.
2007, 2905; (e) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511; (f) Krishna, P. R.;
Sachwani, R.; Reddy, P. S. Synlett 2008, 2897; (g) Declerck, V.; Martinez, J.;
Lamaty, F. Chem. Rev. 2009, 109, 1; (h) Basavaiah, D.; Reddy, B. S.; Badsara, S. S.
Chem. Rev. 2010, 110, 5447.
aza-MBH reaction is likely reversible in halogenated solvents at
25 °C (Scheme 2).12
In conclusion, we have developed the enantioselective aza-
MBH/aza-Michael/aldol/dehydration reaction of
a,b-unsaturated
carbonyl compounds and N-tosylimines promoted by a chiral
acid–base organocatalyst.13,14 The aza-MBH domino system de-
scribed herein was easily accessed to give highly functionalized
tetrahydropyridines in high enantioselectivities (up to 93% ee).
Further investigations to extend the reaction scope and applica-
tions of this process in organic synthesis are underway.
5. (a) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507; (b) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521; (c) Kawahara, S.; Nakano, A.;
Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103; (d) Shi, M.;
Chen, L.-H. Chem. Commun. 2003, 1310; (e) Matsui, K.; Takizawa, S.; Sasai, H. J.
Am. Chem. Soc. 2005, 127, 3680; (f) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790; (g) Shi, M.; Li, C.-Q. Tetrahedron: Asymmetry 2005, 16, 1385;
(h) Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347, 1701; (i) Wurz, R.
P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234; (j) Shi, M.; Xu, Y.-M.; Shi, Y.-L.
Chem. Eur. J. 2005, 11, 1794; (k) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.;
Sasai, H. Tetrahedron: Asymmetry 2006, 17, 578; (l) Liu, Y.-H.; Chen, L.-H.; Shi,
M. Adv. Synth. Catal. 2006, 348, 973; (m) Matsui, K.; Takizawa, S.; Sasai, H.
Synlett 2006, 761; (n) Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.;
Lehmann, C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45,
3689; (o) Ito, K.; Nishida, K.; Gotanda, T. Tetrahedron Lett. 2007, 48, 6147; (p)
Vesely, J.; Dziedzic, P.; Cordova, A. Tetrahedron Lett. 2007, 48, 6900; (q) Utsumi,
N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int. Ed. 2007, 46, 1878;
(r) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129; (s) Fleury-Bregeot, N.;
Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron 2007, 63, 11920; (t) Shi, M.; Ma,
G.-N.; Gao, J. J. Org. Chem. 2007, 72, 9779; (u) Abermil, N.; Masson, G.; Zhu, J. J.
Am. Chem. Soc. 2008, 130, 12596; (v) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S.
Synthesis 2008, 2825; (w) Qi, M.-J.; Ai, T.; Shi, M.; Li, G. Tetrahedron 2008, 64,
1181; (x) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660; (y)
Wang, X.; Chen, Y.-F.; Niu, L.-F.; Xu, P.-F. Org. Lett. 2009, 11, 3310; (z) Garnier, J.-
M.; Anstiss, C.; Liu, F. Adv. Synth. Catal. 2009, 351, 331.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, and The Naito Foundation. We thank the
technical staff of the Comprehensive Analysis Center of ISIR, Osaka
University.
Supplementary data
Supplementary data associated with (experimental procedures
and compound characterization data) this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.045.
6. Till date a number of attractive domino reactions involving achiral aza-MBH
process have been developed. See: Ref. 3g.
7. Recently we have reported the first enantioselective aza-MBH domino reaction
of activated alkenes with imines. Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H.
Angew. Chem., Int. Ed., doi:10.1002/anie.201004547.
8. (a) Meng, X.; Huang, Y.; Chen, R. Chem. Eur. J. 2008, 14, 6852; (b) Meng, X.;
Huang, Y.; Chen, R. Org. Lett. 2009, 11, 137; (c) Meng, X.; Huang, Y.; Zhao, H.;
Xie, P.; Ma, J.; Chen, R. Org. Lett. 2009, 11, 991.
References and notes
1. For recent reviews on organocatalytic enantioselective domino reactions. See:
(a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570;
(b) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477; (c) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167.
9. (a) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47, 5836; (b)
Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47,
2458; (c) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed.
2008, 47, 4012; (d) Ona-Burgos, P.; Fernandez, I.; Roces, L.; Torre-Fernandez, L.;
Garcia-Granada, S.; Lopez-Ortiz, F. Org. Lett. 2008, 10, 3195; (e) Burns, N. Z.;
Krylova, I. N.; Hannoush, R. N.; Baran, P. S. J. Am. Chem. Soc. 2009, 131, 9172; (f)
Pena-Lopez, M.; Martinez, M. M.; Sarandeses, L. A.; Sestelo, J. P. Org. Lett. 2010,
12, 852; (g) Shimada, N.; Ashburn, B. O.; Basak, A. K.; Bow, W. F.; Vicic, D. A.;
Tius, M. A. Chem. Commun. 2010, 46, 3774; (h) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.;
Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu., P.-F. Chem. Eur. J. 2010, 16, 3922.
10. The self-condensation of 1a and the formation of unidentified side-products
were observed.
11. (a) Shi, M.; Xu, Y.-M. Chem. Commun. 2001, 1876; (b) Shi, M.; Xu, Y.-M.; Zhao,
G.-L.; Wu, X.-F. Eur. J. Org. Chem. 2002, 3666.
12. The reversibility of aza-MBH reaction when using acrolein (1a) with chiral
acid–base organocatalyst was reported. See Ref. 5f.
13. Representative procedure for the domino reaction of 1a with 2a: To a solution of
organocatalyst (S)-8 (5.1 mg, 0.012 mmol) and imine (2a, 0.059 mmol) in
2. (a) Morita, K.-I.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815; (b)
Baylis, A. B.; Hillman, M. E. D. German Patent 2155,113, 1972; Chem. Abstr.
1972, 77, 34174q.
3. For recent reports on MBH and aza-MBH reaction. See: (a) Price, K. E.;
Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980; (b)
Buskens, P.; Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2005, 127, 16762; (c)
Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614; (d)
Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007, 129, 15513; (e)
Kwong, C. K.-W.; Huang, R.; Zhang, M.; Shi, M.; Toy, P. H. Chem. Eur. J. 2007, 13,
2369; (f) Santos, L. S. Eur. J. Org. Chem. 2008, 235; (g) Ma, G.-N.; Jiang, J.-J.; Shi,
M.; Wei, Y. Chem. Commun. 2009, 5496; (h) Amarante, G. W.; Benassi, M.;
Milagre, H. M. S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.; Coelho, F. Chem. Eur.
J. 2009, 15, 12460; (i) Roy, D.; Patel, C.; Sunoj, R. B. J. Org. Chem. 2009, 74, 6936;
(j) Mansilla, J.; Saa, J. M. Molecules 2010, 15, 709; (k) Wei, Y.; Shi, M. Acc. Chem.
Res. 2010, 43, 1005; (l) Yukawa, T.; Seelig, B.; Xu, Y.; Morimoto, H.; Matsunaga,
S.; Berkessel, A.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 11988; (m) Shah, J.;
Yacob, Z.; Bunge, A.; Liebscher, J. Synlett 2010, 2079; (n) Anstiss, C.; Garnier, J.-
M.; Liu, F. Org. Biomol. Chem. 2010, 8, 4400; (o) Yuan, K.; Song, H.-L.; Hu, Y.;
Fang, J.-F.; Wu, X.-Y. Tetrahedron: Asymmetry 2010, 21, 903; (p) Anstiss, C.; Liu,
F. Tetrahedron 2010, 66, 5486; (q) Dong, L.; Qin, S.; Su, Z.; Yang, H.; Hu, C. Org.
Biomol. Chem. 2010, 8, 3985; (r) Oh, K.; Li, J.-Y.; Ryu, J. Org. Biomol. Chem. 2010,
8, 3015; (s) Bugarin, A.; Connell, B. T. Chem. Commun. 2010, 46, 2644; (t)
Abermil, N.; Masson, G.; Zhu, J. Adv. Synth. Catal. 2010, 352, 656; (u) Takizawa,
S.; Horii, A.; Sasai, H. Tetrahedron: Asymmetry 2010, 21, 891; (v) Liu, Y.-L.;
Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J. Am. Chem. Soc.
2010, 132, 15176.
(ClCH2)2 (0.20 mL) was added acrolein (1a, 12 lL, 0.18 mmol) at 0 °C. The
solution was stirred until 2a was completely consumed as determined by TLC
analysis and then allowed to slowly warm to 25 °C. The mixture was directly
purified by preparative TLC (SiO2, n-hexane/CH2Cl2 = 1/5 or CH2Cl2 only) to
give the corresponding cyclic products 4a as white solids.
14. We also attempted to utilize an aliphatic N-sulfonated imine (c-C6H11CH@NTs)
for the reaction. However, the corresponding aza-MBH product was not
formed.