The versatile conversion of acyclic amides to α-alkylated amines

Article abstract of DOI:10.1039/b201719a

A general and efficient method for the versatile functionalization of acyclic amide via N,O-acetal TMS ether, an excellent precursor for the N-acyliminium ion, has been developed.

Full text of DOI:10.1039/b201719a

The versatile conversion of acyclic amides to a-alkylated amines
Young-Ger Suh,* Dong-Yun Shin, Jae-Kyung Jung and Seok-Ho Kim
College of Pharmacy, Seoul National University, San 56-1, Shinlim-dong, Kwanak-Gu, Seoul, Korea.
E-mail: ygsuh@snu.ac.kr; Tel: 82-2-880-7875
Received (in Cambridge, UK) 18th February 2002, Accepted 25th March 2002
First published as an Advance Article on the web 15th April 2002
Table 1 Optimization of trapping conditions and the effect of an N-
protective group.
A general and efficient method for the versatile functional-
ization of acyclic amide via N,O-acetal TMS ether, an
excellent precursor for the N-acyliminium ion, has been
developed.
The reaction of an N-acyliminium ion with a variety of
nucleophiles is one of the most powerful methods to introduce
various substituents at the a-carbon of an amine.1 Particularly,
this type of inter and intramolecular C–C bond formation can be
effectively applied to the synthesis of the bioactive natural or
unnatural compounds as well as many bioactive peptidomi-
metics. Accordingly, much attention has been devoted to the
practical and efficient methods for the generation of acylimin-
ium ion precursors though there are many important aspects in
the reaction involving N-acyliminium ions.
The use of a-alkoxy carbamates and amides as precursors for
N-acyliminium ions is well reviewed,1 and these versatile
systems arise from the partial reduction of cyclic imides,2
addition of amides or carbamates to aldehydes,3 or oxidation of
the hydrocarbon under electrochemical or transition metal-
mediated conditions.4 Among them, partial reduction of the
carbonyl in imides or acylamides has been considered as the
best procedure in terms of the reaction efficiency and the
substrate diversity. However, this method has a limitation that it
can be applicable only to cyclic systems, and few are reported
for acyclic ones.5
Substrate (2)
RX
Product (3) (% yield)a
2a (R1 = Benzyl)
Ac2O
—
—
MeOTf
TMSOTf
TMSOTf
TMSOTf
3a (92) (R = TMS)
3b (89) (R = TMS)
3c (83) (R = TMS)
2b (R1 = tert-Butyl)
2c (R1 = Methyl)
a Isolated yields.
yield. Other trapping reagents such as Ac2O–pyridine and
MeOTf–pyridine gave no desired alkoxy carbamates.
To study the reaction details of N,O-acetal TMS ether as an
N-acyliminium precursor, we examined various conditions for
the amidoalkylation reaction. Generally, the reaction was
initiated in the presence of suitable Lewis acids to form N-
acyliminium intermediates, which were then reacted with a
nucleophile, to afford a-substituted amines. With the N,O-
acetal TMS ether 3a‡ as a substrate and TMSCN as a good
nucleophile, various aprotic or protic Lewis acids and solvents
were investigated. As illustrated in Table 2, 3a presented
excellent reactivities to the most aprotic or protic Lewis acids
commonly used, to afford the adduct 4a in nearly quantitative
yields. This result implies that N,O-acetal TMS ethers are able
to undergo facile substitution reactions with a variety of
nucleophiles. In the case of TiCl4, known as a strong Lewis
We have been continuously interested in the functionaliza-
tion of cyclic and acyclic amide carbonyls with regard to
syntheses of natural alkaloids. Herein we report a novel and
general method for the preparation of stable N,O-acetal TMS
ethers,3,6 excellent precursors of linear acyliminium ions, and
we also describe their reactivities and reaction scopes.
Table 2 Effect of Lewis acids and solventsa
Our initial concern was searching for suitable reducing agents
for partial reduction of the acyl-protected amides to hemiami-
nals and their trapping reagents. The acylamide substrates (2a–
2c) could be readily prepared by a protective reaction of amides
with the corresponding reagents using n-butyllithium or other
bases in THF as reported.7 Unlike the cyclic imides of which
many reducing agents have been used for the partial reductions,
only DIBAL-H was effective for the acyclic amide. DIBAL-H
of 1.2 eq. was sufficient for the completion of the carbonyl
reduction. Surveying the trapping reagents commonly used, we
found the TMSOTf–pyridine system, to give the most sat-
isfactory results as shown in Table 1.† Thus, treatment of
acylamide with 1.2 eq. of DIBAL-H in CH2Cl2 at 278 °C for 1
h, followed by sequential addition of pyridine and TMSOTf,
afforded the N,O-acetal TMS ether in excellent yield. TMS
N,O-acetal TMS ether, a very stable intermediate neat as well as
in a variety of solvents, could be easily purified by flash column
chromatography and stored for months. Benzyl and tert-butyl
carbamates were superior to the methyl carbamate in terms of
Lewis acid (eq.)
Solvent
Time
Yield of 3 (%)
BF3.OEt2 (0.2)
BF3.OEt2 (1.0)
TMSOTf (0.2)
TiCl4 (1.0)
SnCl4 (0.2)
TfOH (0.2)
BF3.OEt2 (0.2)
BF3.OEt2 (0.2)
BF3.OEt2 (0.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
20 min
20 min
10 min
2 h
20 min
15 min
30 min
30 min
1 h
98
99
99
20b
98
98
99
98
92
PhCH3
a Reactions were carried out with 3a (0.2-0.3 mmol) and TMSCN (1.3 eq.)
at 278 °C and warmed to 230 °C unless otherwise noted. b Stirred at 0
°C
1064
CHEM. COMMUN., 2002, 1064–1065
This journal is © The Royal Society of Chemistry 2002

acid, the yield was unexpectedly very low. Variation of solvents
gave little difference in yields.
N,O-acetal TMS ether and the alkylated products in high
yields.8 The amides derived from simple ethylamine and
sterically hindered isopropylamine also gave such good results
as other amides. It is noticeable that the various functional
groups are tolerant under the conditions for our two step
procedure.
In summary, this communication discloses a novel and
general method for the efficient functionalization of acyclic
amide carbonyl via a stable N,O-acetal TMS ether intermediate.
Particularly, the reactive N,O-acetal TMS ether could be
conveniently prepared in an excellent yield from the acyl
protected amides by sequential partial reduction of amide
carbonyl with DIBAL-H followed by TMSOTf trapping of
resulting hemiaminal. The N,O-acetal TMS ethers proved to be
excellent precursors for in situ generation of N-acyliminium
ions in overall reaction conditions. The representative function-
alities are tolerant during the two step process for the generation
of N,O-acetal TMS ethers and their facile substitutions with a
variety of carbon nucleophiles. Future studies will involve
studies on asymmetric versions and its application to the
synthesis of macrolactam alkaloids.
With BF3.OEt or TMSOTf as the catalyst, reactions of 3a
with various nucleophiles were also investigated (Table 3).
Allyltrimethylsilane, allyltributyltin, silyl enol ether and propa-
rgyltrimethylsilane nucleophiles underwent facile alkylation to
afford the desired adducts in excellent yields. In the case of
allylation, the allyltin reagent provided higher yields than
allylsilane.
Table 3 Reactions of 3a with various nucleophilesa
Nucleophile
Lewis acid
R (4)
Yield (%)b
CH2NCHCH2SiMe3
CH2NCHCH2SnBu3
CH2NC(OTBS)Ph
CH·CCH2TMS
BF3.OEt2
TMSOTf
BF3.OEt2
TMSOTf
BF3.OEt2
TMSOTf
BF3.OEt2
-CH2CHNCH2 (4b)
83
77
89
84
93
81
85
This work was supported by grant CHMP-00-CH-15-0014
from the Korean Ministry of Health & Welfare and in part by
the Research Institute of Pharmaceutical Science, Seoul Na-
tional University.
-CH2C(O)Ph (4c)
-CHNCNCH2 (4d)
a All reactions were carried out with 3a (0.2 mmol), a nucleophile (1.5 eq.),
and Lewis acids (0.2 eq.) in DCM at 278 °C, and warmed to 220 °C.
b Isolated yields.
Notes and references
† Representative procedure for the preparation of N,O-acetal TMS
ether: to a solution of the amide 2a (820 mg, 2.76 mmol) in CH2Cl2 (12 mL)
was added DIBAL-H (1.0 M solution in toluene, 3.4 mL, 3.4 mmol)
dropwise at 278 °C. After 1 h, the reaction mixture was treated with
pyridine (0.67 mL, 8.32 mmol) and then TMSOTf (1.25 mL, 6.91 mmol).
The mixture was stirred at 278 °C for 10 min, quenched with 15% aqueous
sodium potassium tartrate (10 mL), and diluted with Et2O (40 mL). The
resultant mixture was warmed to rt and stirred vigorously until two layers
were completely separated. The mixture was extracted with Et2O and the
combined organic layers were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (10% EtOAc–hexanes) to afford 942 mg (92%) of
N,O-acetal TMS ether 3a as a colorless oil.
Table 4 shows extended examples for various other acyclic
amides. The selected acylamides possessing the common
functionalities were conveniently prepared from the corre-
sponding amides simply by protective reactions (CbzCl, n-BuLi
or LHMDS, THF, 0 °C). The acylamides possessing phenyl,
alkene, silyl ethers, or bromoalkyl substituents afforded the
Table 4 Extended examples for various acyclic amides; generation of N,O-
acetal TMS ethersa and their reactions with TMSCN and allyltributyltinb
‡ Spectral data for 3a; FT-IR (neat) 1703 cm21 (C = O); 1H-NMR (CDCl3,
500 MHz) rotamers d 7.42–7.18 (m, 10H), 5.77 and 5.61 (br s, 1H total),
5.24 and 5.16 (s, 2H total), 4.53 and 4.48 (ABq, J = 16.2 Hz, 2H total), 1.58
(m, 2H), 0.86 and 0.78 (t, J = 7.1 Hz, 3H total), 0.13 and 0.03 (s, 9H total);
13C-NMR (CDCl3, 75 MHz) d 156.0, 139.6, 136.6, 136.4, 129.0, 128.6,
128.4, 128.2, 128.1, 127.9, 127.5, 127.1, 126.9, 126.5, 116.8, 114.3, 105.7,
TMS N,O-acetal
(% yield)
Product (A: R = CN,
B: R = allyl)
Amide
A: 98
(91)
(87)
B: 91
81.6, 67.4, 67.1, 44.5, 44.3, 29.7, 29.4, 9.81, 1.3; LRMS (EI) 372 (M+
H).
+
A: 99
B: 83
1 (a) For excellent reviews on the chemistry of N-acyliminium ions, see H.
Hiemstra and W. N. Speckamp, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, Vol 2, p.1047; (b)
W. N. Speckamp and M. J. Moolenaar, Tetrahedron, 2000, 56, 3817.
2 For a recent example see G. Chuangxing, S. Reich, R. Showalter, E.
Villafranca and L. Dong, Tetrahedron Lett., 2000, 41, 5307.
3 (a) A. Kamatani and L. E. Overmann, Org. Lett., 2001, 3, 1229; (b) S. J.
Veenstra and P. Schmid, Tetrahedron Lett., 1997, 38, 997.
4 (a) R. C. Corcoran and J. M. Green, Tetrahedron Lett., 1990, 31, 6827;
(b) W. Chao and S. M. Weinreb, Tetrahedron Lett., 2000, 41, 9199.
5 M. P. DeNinno and C. Eller, Tetrahedron Lett., 1997, 38, 6545.
6 (a) For examples of the preparation of acyclic N,O-acetal TMS ether not
starting from an amide, see D. Ferraris, B. Young, C. Cox, T. Dudding,
W. J. Drury III, L. Ryzhkov, A. E. Taggi and T. Lectka, J. Am. Chem.
Soc., 2002, 124, 67; (b) G. Blond, T. Billard and B. R. Langlois, J. Org.
Chem., 2001, 66, 4826; (c) A. P. Johnson, R. W. A. Luke and A. N. Boa,
J. Chem. Soc., Perkin Trans. 1, 1996, 895.
A: 98
B: 79
(90)
(93)
A: 97
B: 80
A: 96
B: 84
(86)
(91)
A: 98
B: 82
7 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., Wiley-Interscience, New York, 1999.
8 Satisfactory spectral and analytical data were obtained for all new
compounds.
a Reactions were carried out according to the representative procedure in
footnote †. b Reactions were carried out with TMSCN and allyltributyltin
according to the general procedure.
CHEM. COMMUN., 2002, 1064–1065
1065