Trimethylchlorosilane-promoted aza-Mannich reaction of enecarbamates and aldimines

Article abstract of DOI:10.1016/j.tetlet.2009.09.097

A trimethylchlorosilane-promoted aza-Mannich reaction is reported utilizing enecarbamates as the nucleophile and aromatic N-Boc aldimines as the electrophile. A variety of nucleophiles and electrophiles are tolerated by the reaction conditions, delivering

Full text of DOI:10.1016/j.tetlet.2009.09.097

Tetrahedron Letters 50 (2009) 7249–7251
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Trimethylchlorosilane-promoted aza-Mannich reaction of enecarbamates and
aldimines
*
*
Pengcheng Wu, Deqin Lin, Xiaoxia Lu , Li Zhou, Jian Sun
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A trimethylchlorosilane-promoted aza-Mannich reaction is reported utilizing enecarbamates as the
nucleophile and aromatic N-Boc aldimines as the electrophile. A variety of nucleophiles and electrophiles
are tolerated by the reaction conditions, delivering the adduct products in excellent yields with high E-
stereoselectivities.
Received 8 August 2009
Revised 17 September 2009
Accepted 18 September 2009
Available online 30 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The Mannich reaction is one of the most fundamentally impor-
tant carbon–carbon bond forming reactions in organic synthesis,
which provides an easy access to the versatile b-functionalized
amine products.1 In situ formed or performed enols are known as
classical nucleophilic donors for the Mannich reaction. Enamines
are also effective donors, but mainly as in situ formed transient ac-
tive intermediates in the amine-catalyzed Mannich reaction of ke-
tones or aldehydes.2 Performed enamines, for example, enamides
and enecarbamates, have rarely been utilized as the nucleophilic
donor in the Mannich reactions, the so-called aza-Mannich reac-
tion.3–5 On the one hand, the electron-withdrawing groups on
the nitrogen atom endow these enamines with required stability
for isolation. On the other hand, the electron-withdrawing prop-
erty of these groups causes dramatic decreases in the nucleophilic-
ity of the performed enamines and thus renders them virtually
inactive under normal Mannich reaction conditions.
the allylation conditions when aliphatic N-Boc imine 10 was used
(Scheme 1). We speculated that this self-coupling reaction was
promoted by the Lewis acidic allyltrichlorosilane following an
aza-Mannich reaction pathway. The aliphatic N-carbamoyl imine
is a known typical Mannich acceptor, which tautomerizes into
enecarbamate and thus serves as the Mannich donor. We envi-
sioned that a similar cross-coupling aza-Mannich reaction could
be developed as a high-yielding method for the production of b-
amino enecarbamates 3 if the more-reactive non-tautomerizable
aromatic imines 2 were used as the acceptor (Scheme 1).
Phenylpropionaldehyde-derived enecarbamate 1a and N-Boc
benzaldimine 2a were first utilized as testing substrates and differ-
ent chlorosilanes SiCl4, MeSiCl3, Me2SiCl3, and Me3SiCl as the Lewis
acid promoters. Delightfully, the expected aza-Mannich reaction
went smoothly with all the four Lewis acid promoters in a mixture
solvent of N,N-dimethyl formamide (DMF) and dichloromethane
Recently, Kobayashi4 andTerada5 reportedthattheenamidesand
enecarbamates participated Mannich reaction could be realized
using either Lewis acidic metal complexes or Brønsted acidic organic
phosphoric acids as catalysts. Unlike the typical Mannich reactions
that always give b-oxo amine products, isolable b-imino amines, al-
beit not very stable, are obtained as the products in the aza-Mannich
reactions, which could be either hydrolyzed to give b-oxo amines or
easily converted to 1,3-diamine products upon reduction. Herein,
we report a practical new method for the aza-Mannich reaction of
enecarbamates with N-Boc aryl imines promoted by trimethylchlo-
rosilane, which affords fairly stable b-amino enecarbamates as the
products in high yields and stereoselectivities.
PG
PG
HN
HN
PG
1, AllylSiCl3
R
N
+ R
NHPG
self-coupling reaction
R
R
R
H
1'
3'
4
Boc
Boc
H
PG
HN
N
HN
Me3SiCl
cross-coupling reaction
PG
+
N
H
Ar
During our recent studies on the allylation of N-carbamoyl
imine using allyltrichlorosilane promoted by Lewis base,6 a self-
coupling reaction product 30 was observed as a side product under
Ar
R
3
1
2
PG = Boc, Cbz
R = aryl or alkyl
* Corresponding authors. Tel.: +86 28 85211220; fax: +86 28 85222753 (J.S.).
E-mail addresses: luxx@cib.ac.cn (X. Lu), sunjian@cib.ac.cn (J. Sun).
Scheme 1. The aza-Mannich reaction of enamine with imine. Boc = tert-butoxy-
carbonyl, Cbz = benzyloxycarbonyl.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.097

7250
P. Wu et al. / Tetrahedron Letters 50 (2009) 7249–7251
(DCM) (v/v = 1:1) at ꢀ20 °C, affording the desired b-amino enecar-
bamate product 3a as a mixture of the E and Z stereoisomers in
excellent yield (90–96%) in 24 h (Table 1, entries 1–4).7
To probe the generality of the present aza-Mannich reaction,
various aldehyde-derived enecarbamates 1a–f were reacted with
N-Boc benzaldimine 2a under optimal conditions.8 As shown in Ta-
ble 2, all the reactions proceeded smoothly to give the desired ad-
ducts 3 in high yields (94–96%) with high E selectivities (83:17–
97:3) (entries 1–6). The cyclic enecarbamate 1g derived from 1-tet-
To further optimize the reaction conditions, we selected Me3-
SiCl as the Lewis acid promoter and tested different reaction
parameters. When the reaction temperature was increased from
ꢀ20 to 0 °C, only slightly decreased E/Z selectivity was observed,
whereas the yield was not affected (entries 4 and 5). At room tem-
perature, some decreases in both yield and stereoselectivity were
seen (entry 6). A mixture solvent of DMF and DCM was found to
be favorable to the reaction. High yield and good E/Z selectivity
were obtained with a DMF/DCM ratio of either 1:1 or 1:4 (entries
5 and 7). Without the use of DMF, both the yield and the selectivity
were significantly decreased (entry 8). If only DMF was used as the
solvent, lower yield was achieved with a slightly higher E/Z selec-
tivity (entry 9). Increasing the Me3SiCl amount from 1.0 to
2.0 equiv had little effect on both the high yield and the E/Z selec-
tivity (entry 10), whereas lowering the Me3SiCl amount from 1.0 to
0.5 equiv caused a substantial decrease in the yield, albeit no
change with the E/Z selectivity (entry 11).
The stereoisomers (E)-3a and (Z)-3a were easily separated by
flash chromatography and the E and Z configurations were deter-
mined by NOESY. For the stereoisomer (E)-3a, clear correlations
were observed between H(1) and H(3) and H(4) and between
H(2) and H(5). In contrast, for stereoisomer (Z)-3a, H(1) has no cor-
relation with either H(3) or H(4), but has a clear correlation with
H(2) (Fig. 1).
Table 2
Aza-Mannich reaction of various enecarbamates 1 with N-Boc aryl aldimins 2a
Boc
Boc
H
PG
HN
N
HN
Me3SiCl
PG
+
R
Ar
N
H
Ar
-20 ºC, DMF/DMC
R
3
1
2
Entry
Enecarbamate
Aldimine
Yieldb (%)
E/Zc
1
2
NHBoc
Boc
N
Ph
1
96
92:8
Ph
H
2a
1a
NHBoc
2
3
2a
94
95
97:3
96:4
1b
NHBoc
Table 1
2a
Aza-Mannich reaction of enecarbamate 1a and aldimine 2aa
1c
Boc
Boc
H
HN
Ph
Ph
Boc
NHBoc
N
HN
Boc
Ph
Ph
N
H
+
4
5
2a
2a
95
91
91:9
Ph
Ph
1d
3a
1a
2a
NHCbz
Entry Lewis acid Temp (°C) Solvent (DMF/DCM) Yieldb (%) E/Zc
90:10
1
2
3
4
5
6
7
8
9
SiCl4
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
rt
0
0
0
1:1
1:1
1:1
1:1
1:1
1:1
1:4
0:1
1:0
1:1
1:1
90
92
94
96
92
71
90
56
80
95
57
90:10
94:6
94:6
1e
MeSiCl3
Me2SiCl2
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
NHCbz
94:6
89:11
83:17
88:12
69:31
93:7
6
7
2a
2a
90
86
83:17
1f
NHCbz
10d
11e
ꢀ20
94:6
95:5
ꢀ20
—
a
Unless stated otherwise, reactions were performed on a 0.2 mmol scale with 1a/
1g
2a/silane as 1:1:1 in 1.0 mL of DMF/DCM (v/v 1:1) for 24 h.
b
Isolated yield of 3a as E/Z mixture.
c
The E/Z ratio of 3a was analyzed by 1H NMR and HPLC.
NBoc
H
d
2.0 equiv Me3SiCl was used.
0.5 equiv Me3SiCl was used.
e
8
9
1a
1a
93
93
92:8
91:9
F
2b
(4)
H
(4)(5)
NH HN
Boc
Ph
Boc
Ph
Boc
NBoc
(1)
N
H
H
(3)
H
H
Boc
(1)
H
N
H
(5)
H
H
(2)
H
H3CO
(3)
(2)
2c
Ph
Ph
H
a
All reactions were performed on a 0.2 mmol scale with 1/2/Me3SiCl as 1:1:1 in
(
E
)
(Z)
1.0 mL of DMF/DCM (1:1) at ꢀ20 °C for 24 h.
b
Isolated yield of 3 as E/Z mixture.
Figure 1. Assignment of the stereochemistry of the E and Z stereoisomers of 3a by
c
The E/Z ratio of 3 was analyzed by 1H NMR and HPLC.
NOESY.

P. Wu et al. / Tetrahedron Letters 50 (2009) 7249–7251
7251
Me
Cl
Acknowledgment
Me
Me
Me
Cl
Me
Me
Si
Si
We are grateful for financial support from the National Science
Foundation of China (20672107 and 20732006).
O
O
O
t
PG
PG
Bu O
t
H
R
N
Bu O
NH
N
HN
PG
t
-
Bu O
N
N
References and notes
Ar
2
Ar
Ar
R
R
1. For reviews on Mannich-type reactions, see: Kleinman, E. F.. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Oxford: Pergamon, 1991; Vol. 2,
p 893; (b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069; (c) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045; (d) Taggi, A. E.;
Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10; (e) Martin, S. F. Acc. Chem.
Res. 2002, 35, 895; (f) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929.
2. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (b) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. Am. Chem. Soc. 2002, 124, 827.
3. Merla, B.; Risch, N. Synthesis 2002, 1365.
4
1
O
t
HN
Ar
O Bu
PG
N
H
R
3
4. (a) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43,
1679; (b) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004,
43, 3258; (c) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2006,
45, 3814; (d) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292.
5. (a) Terada, M.; Machioka, K.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336; (b)
Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45, 2254.
6. Wu, P.; Sun, J. Synth. Commun. 2008, 38, 1003.
Scheme 2. Proposed reaction mechanism.
ralone also underwent the aza-Mannich reaction with 2a to afford
product 3g in 86% yield (entry 7). In this case, the E/Z selectivity is
not an issue since the geometry of the C@C double bond is fixed in
the six-membered ring. Other than 2a, N-Boc aryl aldimines 2b and
2c bearing electron-donating and electron-withdrawing groups,
respectively, were also found to react with 1a to give excellent re-
sults (entries 8 and 9).
According to the aza-ene-type pathway that Kobayashi pro-
posed for the Lewis acidic metal complex-catalyzed addition of en-
amines with imines,4 a similar reaction mechanism was proposed
for the present aza-Mannich reaction promoted by chlorosilane
(Scheme 2). Trimethylchlorosilane coordinates with N-Boc benz-
aldimine 2 to facilitate the electrophilic addition to enecarbamate
1 to form the imino adduct 4,9 which subsequently tautomerizes
into the thermodynamically more stable E-isomer of 3.
In summary, a trimethylchlorosilane-promoted aza-Mannich
reaction of enecarbamates with aldimines has been developed as
a highly efficient method for the preparation of b-amino enecarba-
mates in high yields with high E-selectivities. The proposed reac-
tion mechanism follows an aza-ene-type pathway, wherein
trimethylchlorosilane plays a Lewis acid role for the activation of
the aldimine.
7. (E)-3a, white solid, mp 123–125 °C, 1H NMR (600 MHz, CDCl3): d = 1.39 (s, 9H),
1.42 (s, 9H), 3.23 and 3.30 (AB system, 2 ꢁ d, J = 16.5 Hz, 2H), 4.79 (s, 1H), 5.27
(s, 1H), 6.12 (d, J = 10.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 6.8 Hz, 2H),
7.13–7.36 (m, 8H). 13C NMR (150 MHz, CDCl3): d = 28.2, 28.3, 33.5, 58.3, 117.4,
122.8, 126.5, 127.1, 127.4, 128.2, 128.6, 128.8, 137.9, 140.6, 152.7, 154.9. HRMS
(ESI): m/z [M+Na+] calcd for C26H34N2O4: 461.2411, found 461.2407; (Z)-3a, oil
liquid. 1H NMR (300 MHz, CDCl3), d = 1.41 (s, 9H), 1.48 (s, 9H), 3.05 and 3.18 (AB
system, 2 ꢁ d, J = 15.0 Hz, 2H), 4.55 (d, J = 9.1 Hz, 1H), 5.63 (d, J = 10.9 Hz, 1H),
6.57 (d, J = 10.9 Hz, 1H), 7.00 (d, J = 6.9 Hz, 2H), 7.24 (m, 9H). 13C NMR (150 MHz,
CDCl3): d = 28.9, 31.0, 35.3, 59.2, 120.8, 123.3, 125.2, 126.3, 128.1, 128.4, 128.7,
129.2, 129.8, 129.9, 146.1, 150.7. HRMS (ESI): m/z [M+Na+] calcd for C26H34N2O4:
461.2411, found 461.2411.
8. Typical experimental procedure for the aza-Mannich reaction: Enecarbamate 1
(0.2 mmol) and N-Boc imine 2 (0.2 mmol) were dissolved in a 1.0 mL v/v 1/1
mixture of DMF and DCM. Me3SiCl (0.2 mmol) was added dropwise at ꢀ20 °C.
The reaction mixture was stirred at the same temperature for 24 h and then
quenched with a saturated aqueous NaHCO3 solution and extracted with ether.
The organic extracts were combined, washed with water and brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel to give pure product 3.
9. For activation of imine by Me3SiCl, see example: Hou, X. L.; Zheng, X. L.; Dai, L. X.
Tetrahedron Lett. 1998, 39, 6949.