Br?nsted acid-catalyzed Mannich reaction through dual activation of aldehydes and N-Boc-imines

Article abstract of DOI:10.1039/c5cc07290e

In the presence of a Br?nsted acid catalyst, both aldehydes and N-Boc-aminals were converted to enecarbamates and N-Boc-iminium salts as activated nucleophiles and electrophiles, respectively, giving unprecedented Mannich adducts. The asymmetric variant of the present Mannich reaction has also been demonstrated with a chiral phosphoric acid catalyst.

Full text of DOI:10.1039/c5cc07290e

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DOI: 10.1039/C5CC07290E
Chemical Communications
COMMUNICATION
Brønsted acid-catalyzed Mannich reaction through dual activation
of aldehydes and N-Boc-imines
Received 00th January 20xx,
Accepted 00th January 20xx
Taichi Kano, Yusuke Aota, Daisuke Asakawa and Keiji Maruoka*
DOI: 10.1039/x0xx00000x
www.rsc.org/
In the presence of a Brønsted acid catalyst, both aldehydes and N-
Boc-aminals were converted to enecarbamates and N-Boc-
iminium salts as activated nucleophiles and electrophiles,
respectively, giving unprecedented Mannich adducts. The
asymmetric variant of the present Mannich reaction has also been
demonstrated with a chiral phosphoric acid catalyst.
Boc
H
Boc
HN
+
N
Boc
Boc
N
H
NH
O
acid
catalyst
R1
R1
+
Boc
R1
R2
H2O
H2O
O
HN
Enolizable aldehydes have been used as nucleophiles in
synthetic organic chemistry. In general, such aldehydes are
required to be activated by converting to the corresponding
enolates, enamines, enamides or enecarbamates,1 due to
R2
R2
dual activation of
electrophile & nucleophile
Scheme 1 Brønsted acid-catalyzed Mannich reaction through dual activation of
minuscule amounts of nucleophilic enol form in the keto-enol N-Boc-aminals and aldehydes.
equilibrium. Enamine catalysis, in which aldehydes and
imines generated from N-Boc-aminals through dual activation
ketones form reactive enamine intermediates with amine
catalysts in-situ, has been an active area of research for over a
decade.2 For instance, a number of amine-catalyzed Mannich
reactions of in-situ generated enamines with imines have been
developed to date, while applicable imines are somewhat
limited.2–4
of nucleophiles and electrophiles.
We first examined the in-situ generation of an enecarbamate
from an aldehyde and an alkyl carbamate by a Brønsted acid
catalyst. In the presence of a catalytic amount of binaphthol-
derived phosphoric acid, the mixture of 3-phenylpropanal and
tert-butyl carbamate in CH2Cl2 was found to give the desired
enecarbamate and its derivatives (See the Supporting
Information for details). Based on this result, the Mannich
reaction between the in-situ generated N-Boc-imine and
enecarbamate was then examined in the presence of a
Recently we have developed a method for the in-situ
generation of unprecedented N-Boc-imines having C-alkynyl
groups from N-Boc-aminals under acidic conditions;5 however,
attempts to apply our method to the amine-catalyzed Mannich
reaction were not successful probably due to the deactivation
of the acid catalyst to generate imines by the amine catalyst. In
this context, we became interested in the in-situ generation of
enecarbamates instead of enamines to prevent the use of the
amine catalyst under acidic conditions. In the presence of an
acid catalyst, N-Boc-aminal is converted to N-Boc-imine (or N-
Boc-iminium salt) as an activated electrophile along with the
generation of tert-butyl carbamate, which might react with an
aldehyde to give the corresponding enecarbamate as an
Brønsted acid catalyst.6 The reaction of N-Boc-aminal 1a
,
which is known to give the corresponding N-Boc-imine and
tert-butyl carbamate under acidic conditions, with 3-
phenylpropanal in CH2Cl2 did not proceed in the presence of
benzoic acid and its derivatives (Table 1, entries 1–3). With
more acidic catalysts, on the other hand, the desired Mannich
adduct 2a was obtained in low to moderate yields (entries 4–7),
and diphenyl phosphate was found to afford the best result in
terms of yield (entry 4). In the presence of a catalytic amount
of diphenyl phosphate, the reactions of several N-Boc-aminals
activated nucleophile (Scheme 1). Herein, we report
a
Brønsted acid-catalyzed Mannich reaction of aldehydes with
1
with aldehydes afforded the corresponding anti-Mannich
N-Boc-
adducts 2 as major diastereomers (Table 2).
To evaluate the possibility of an asymmetric variant of the
present reaction, binaphthol-derived chiral phosphoric acid
(S)-
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Table 1 Mannich reaction between N-Boc-aminal 1a and 3-phenylpropanala
operative, and found that the reaction involving the
enecarbamate was much faster (Scheme 4). Since the reaction
using the enecarbamate does not
1)
(S)-3 (10 mol%), DHP
DCE-AcOEt or
PhCF3-AcOEt, rt, 96 h
Boc
Boc
HN
O
NH
OH
Boc
+
N
2)
NaBH4, MeOH
H
R1
R2
R1
R2
Entry Cat
Time (h)
Yieldb (%)
n.d.
n.d.
n.d.
67
anti/sync
1
2
1
2
3
4
5
6
7
PhCO2H
24
24
24
7
-
2-NO2-C6H4CO2H
2,6-(HO)2-C6H3CO2H
(PhO)2PO2H
CF3CO2H
-
R1 = Ph, R2 = Bn:
54%, dr = 3.1 (80% ee) : 1 (8% ee)
-
R1 = 4-MeO-C6H4, R2 = Bn: 55%, dr = 3.3 (85% ee) : 1 (7% ee)
R1 = 4-MeO-C6H4, R2 = i-Pr: 43%, dr = 8.1 (88% ee) : 1 (26% ee)
4.0/1
4.3/1
4.8/1
5.6/1
12
4
37
Ph
TsOH
41
TfOH
1.5
26
O
O
P
a The reaction of 1a (0.10 mmol) with 3-phenylpropanal (0.30 mmol) was carried
out in the presence of an acid catalyst (0.010 mmol) in CH2Cl2 (2.0 mL) at room
OH
O
b
c
temperature. Isolated as an inseparable diastereomixture. Determined by 1H
NMR.
Ph
(S)-3
Table 2 Diastereoselective Mannich reaction between N-Boc-aminals 1 and aldehydesa
Scheme 2 Asymmetric Mannich reaction between N-Boc-aminals 1 and aldehydes.
generate water, the reaction product was obtained as the
enecarbamate but not the hydrolyzed product. The
enecarbamate 9, which generates iminium intermediate 6a
under acidic conditions, was hydrolyzed to the Mannich
adduct 7a under the reaction condition (Scheme 5).11 This
result suggests that the stereochemical information of the
Mannich adduct 7a might be lost via interconversion of
Entry R1
R2
Time (h)
Yieldb (%) anti/sync
1
2
3
4
5
6
7
Ph
Bn
i-Pr
Ph
Bn
Bn
Bn
Bn
7
67
62
66
55
49
44
50
4.0/1
2.7/1
3.0/1
3.4/1
1.9/1
18/1
Ph
12
10
12
11
8
iminium salt
6a and enecarbamate 9. However, since the
Ph
4-MeO-C6H4
4-Br-C6H4
pentyl
Me3Si
enantiomeric excesses showed large differences between two
diastereomers obtained in the catalytic asymmetric reactions
as shown in Scheme 2, most of iminium intermediate 6a seems
10
4.7/1
to be hydrolyzed before converting to enecarbamate
9 and the
a The reaction of 1 (0.10 mmol) with an aldehyde (0.30 mmol) was carried out in
stereochemistry formed in the carbon-carbon bond formation
is largely retained.
the presence of diphenyl phosphate (0.010 mmol) in CH2Cl2 (2.0 mL) at room
b
c
temperature. Isolated as an inseparable diastereomixture. Determined by 1H
In the phosphoric acid-catalyzed reaction, both nucleophile
and electrophile are believed to be activated by the catalyst
NMR.
3
was then employed as catalyst.7 In all cases examined, the
Boc
O
HN
enantiomerically enriched Mannich adducts were obtained in
moderate yields (Scheme 2).8 In the absence of 3,4-dihydro-
2H-pyran (DHP), which can capture the generated tert-butyl
carbamate, the yield was slightly decreased probably due to
hydrolysis of N-Boc-aminal coupled with enecarbamate
generation. The absolute configurations of the Mannich
adduct were determined to be (3R,4S) by conversion to the
known compound and comparison of HPLC retention times
with the literature value.9
Boc
N
R2
H
R1
1
H
BocNH2
H2O
Boc
H
Boc
O
OH
HN
N
Mechanistically, we propose that the combination of N-Boc-
R2
R2
H
R2
R1
path B
4
5
aminal
to the formation of the iminium intermediate
enecarbamate (Scheme 3), which gave the coupling product
and then hydrolyzed Mannich adduct (Path A).
Alternatively, the reaction of the iminium intermediate with
enol as nucleophile could occur to give the Mannich adduct
1
and aldehyde in the presence of an acid catalyst led
4
and the
path A
Boc
5
Boc
H
Boc
6
7
NH
O
NH
N
4
7
R1
R2
R1
R2
7
6
(Path B). We then compared 3-phenylpropanal and its
enecarbamate 5a in the reaction with the isolable and
available N-Boc-imine 810 to determine which pathway is
BocNH2
H
H2O
2 | J. Name., 2012, 00, 1-3
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Notes and references
Scheme 3 Plausible reaction mechanism.
1
For reviews on enamides and enecarbamates as
nucleophiles, see: (a) R. Matsubara and S. Kobayashi, Acc.
Chem. Res., 2008, 41, 292; (b) K. Gopalaiah and H. B. Kagan,
Chem. Rev., 2011, 111, 4599; (c) G. Bernadat and G. Masson,
Synlett, 2014, 25, 2842.
2
For reviews, see: (a) M. Marigo and K. A. Jorgensen, Chem.
Commun., 2006, 2001; (b) S. Mukherjee, J. W. Yang, S.
Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (c) P.
Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew.
Chem., Int. Ed., 2008, 47, 6138.
3
4
For reviews on asymmetric Mannich reaction, see: (a) A. Ting
and S. E. Schaus, Eur. J. Org. Chem., 2007, 5797; (b) J. M. M.
Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg and F. P. J.
T. Rutjes, Chem. Soc. Rev., 2008, 37, 29.
Among imines having C-alkynyl groups, only N-aryl protected
imines have been employed in amine-catalyzed Mannich
reactions, see: E. Gómez-Bengoa, J. Jiménez, I. Lapuerta, A.
Mielgo, M. Oiarbide, I. Otazo, I. Velilla, S. Vera and C.
Scheme 4 Comparison of the reactivity of aldehyde and enecarbamate toward N-Boc-
imine 8.
Palomo, Chem. Sci., 2012, 3, 2949.
5
6
(a) T. Kano, T. Yurino, D. Asakawa and K. Maruoka, Angew.
Chem. Int. Ed., 2013, 52, 5532; (b) T. Kano, T. Yurino and K.
Maruoka, Angew. Chem. Int. Ed., 2013, 52, 11509.
Representative Mannich reactions between imines and
enecarbamates, see: (a) R. Matsubara, Y. Nakamura, S.
Kobayashi, Angew. Chem. Int. Ed., 2004, 43, 1679; (b) M.
Terada, K. Machioka and K. Sorimachi, Angew. Chem. Int. Ed.,
2006, 45, 2254; (c) M. Terada, K. Machioka and K. Sorimachi,
J. Am. Chem. Soc., 2007, 129, 10336; (d) M. Terada, K.
Machioka and K. Sorimachi, Angew. Chem., Int. Ed., 2009, 48
,
2553 (e) G. Dagousset, J. Zhu and G. Masson, J. Am. Chem.
Soc., 2011, 133, 14804.
Scheme 5 Hydrolysis of enecarbamate 9 through iminium salt 6a.
7
8
9
Pioneering reports and a representative review on chiral
phosphoric acid catalysts, see: (a) T. Akiyama, J. Itoh, K.
OAr
Yokota and K. Fuchibe, Angew. Chem. Int. Ed., 2004, 43
,
ArO
P
1566; (b) D. Uraguchi and M. Terada, J. Am. Chem. Soc.,
2004, 126, 5356; (c) M. Terada, Synthesis, 2010, 1929.
Lower enantioselectivities were observed in the reactions
using several other binaphthol-derived chiral phosphoric
acids having modified phenyl groups, such as 4-t-
butylphenyl, 3,5-diphenylphenyl and 2,4,6-trimethylphenyl,
at 3,3’-positions of binaphthyl.
O
Boc
N
O
H
Boc
H
N
R2
R1
Fig. 1 Proposed transition state model.
T. Urushima, H. Ishikawa and Y. Hayashi, Chem. Eur. J., 2011,
17, 8273.
10 N-Boc-imines having
isolated to date probably due to their lower stability
compared to
11 Mannich adduct 7a was isolated after reduction to 2a by
NaBH4.
a C-alkynyl group have not been
through two hydrogen bonds.7c Additionally, since anti-
Mannich adducts were obtained as major diastereomers, N-
Boc-imines might react with (E)-enecarbamates more
favorably than (Z)-isomers as shown in the plausible transition
state model (Fig. 1). In the asymmetric reaction catalyzed by
8.
(S)-3, enecarbamate is seemed to approach the Re-face of
imine based on the observed stereochemistry.
In summary, we have developed the Mannich-type reactions
of aldehydes with N-Boc-aminals catalyzed by phosphoric acids,
in which both substrates are activated as enecarbamates and
N-Boc-imines (or N-Boc-iminium salts). In the present reaction,
hitherto less accessible Mannich adducts having various
alkynyl substituents could be obtained and the possibility of an
asymmetric reaction was also demonstrated by using a chiral
phosphoric acid. We believe that the propargylamine motif in
the product can serve as a useful synthetic handle for further
elaboration into valuable compounds.
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