Tf2NH-Catalyzed Amide Synthesis from Vinyl Azides and Alcohols

Article abstract of DOI:10.1021/acs.orglett.5b01458

Triflimide (Tf₂NH) specifically catalyzed reactions of alcohols and vinyl azides, enabling efficient construction of amides with C-C bond formation through nucleophilic attack of vinyl azides onto the putative carbocation intermediates derived from alcohols are described.

Full text of DOI:10.1021/acs.orglett.5b01458

Letter
pubs.acs.org/OrgLett
Tf2NH-Catalyzed Amide Synthesis from Vinyl Azides and Alcohols
Feng-Lian Zhang,† Xu Zhu,† and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: Triflimide (Tf2NH) specifically catalyzed re-
actions of alcohols and vinyl azides, enabling efficient
construction of amides with C−C bond formation through
nucleophilic attack of vinyl azides onto the putative
carbocation intermediates derived from alcohols are described.
he amide functionality is ubiquitous in various functional
molecules of biological, pharmaceutical/medicinal, and
As an alternative amide enolate equivalent, we have recently
utilized vinyl azides. Nucleophilic attack of vinyl azides onto
several carbon electrophiles such as N-Ts imines, aldehydes,
and carbocations derived from alcohols in the presence of BF3·
OEt2 forms iminodiazonium ions A with C−C bond formation
(Scheme 2).6,7 Subsequent substituent migration generates
T
materials importance.1 Amides also serve as a versatile synthon
for a variety of molecular transformations, especially for
synthesis of nitrogen-containing molecules. Therefore, installa-
tion of the amide moiety onto organic frameworks is one of the
most valuable processes in synthetic chemistry.2 Nucleophilic
attack of amide enolates onto suitable carbon electrophiles
could be one of the most step-economical ways to introduce an
acetamide unit through C−C bond formation (Scheme 1).
Scheme 2. Amide Synthesis by Nucleophilic Attack of Vinyl
Azides
Scheme 1. Reactions of Amide Enolates
nitrilium ions B, which are finally hydrolyzed to give amides.
However, the process needs to use excess amounts (2 equiv) of
BF3·OEt2, that causes another procedure requirement of a slow
addition of vinyl azides to the solution to prevent
decomposition of vinyl azides.8 Therefore, we have strived to
develop a catalytic process of the acetamide installation using
vinyl azides, that could be implemented under milder reaction
conditions with easy and simple operation. Herein, we report
Recent advancement in this field involves Kobayashi’s direct
aldol/Mannich reactions of (N-Boc)acylanisidides with barium
phenoxide as a catalyst (Scheme 1a)3 as well as direct Mannich
reactions of unactivated tertiary amides catalyzed by trialkylsilyl
triflate (Scheme 1b).4 Scheidt recently reported base-mediated
amide enolate addition to acylsilanes, which subsequently
induces the Brook rearrangement to form the corresponding
carbanions, enabling efficient construction of tertiary β-hydroxy
amides with alkyl halides (Scheme 1c).5
Received: May 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01458
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
b
run
acid catalysts
conditions
time
3aa [%]
4aa [%]
1
2
3
4
5
6
7
TsOH·H2O
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, rt
CH2Cl2, reflux
DCE, 40 °C
0.5 h
0
51
43
28
41
15
trace
0
d
BINOL-P(O)OH
(PhSO2)2NH
CF3SO3H
2 h
0
14 h
4
5 min
20 min
10 min
5 min
44
75
(CF3SO2)2NH
(CF3SO2)2NH
(CF3SO2)2NH
c
80 (78)
c
88 (86)
a
b
c
All the reactions were carried out using 0.3 mmol of 1a in the presence of 10 mol % of acid catalysts in solvent (0.1 M). 1H NMR yields. Isolated
d
yields. ( )-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate.
a b
,
realization of the catalytic acetamide incorporation with vinyl
azides using triflimide (Tf2NH) as the catalyst for the reactions
with a series of alcohols as a carbocation precursor.9
Scheme 3. Substrate Scope
We became interested in construction of 3-indolyloxindole
skeletons via the reaction of 3-hydroxy-3-indolyloxindoles with
vinyl azides, as these scaffolds are prevalent in biologically active
alkaloids.10 The recent seminal reports by Gong, Guo/Peng,
and Ma demonstrated that 3-hydroxy-3-indolyloxindoles could
be activated by Brønsted acid catalysts to generate the
corresponding carbocation equivalents, which are trapped by
ketone enolate-type carbon nucleophiles.11 Inspired by these
findings, we surmised if the direct installation of the acetamide
unit using vinyl azides is enabled by Brønsted acid catalysts. We
commenced our study to screen Brønsted acids in the reactions
of 3-hydroxy-3-indolyloxindole 1a and vinyl azide 2a to target
amide 3aa (Table 1). The reactions with TsOH·H2O, BINOL-
linked phosphoric acid, and (PhSO2)2NH as the catalyst (10
mol %) resulted in the C−C bond formation but afforded
ketone 4aa in moderate yields as the major product (runs 1−
3), in which almost no formation of desired amide 3aa was
observed.12 The results indicated that these acids are incapable
of enabling migration of the phenyl group from the
iminodiazonium intermediate. On the other hand, use of
CF3SO3H rendered the process very rapid, consuming 1a
within 5 min to give a 1:1 mixture of amide 3aa and ketone 4aa
(run 4). We envisaged that strength of the acidity13 might be
the key to enable selective formation of amide 3aa. Further
screening revealed that the reaction with triflimide (Tf2NH)14
(10 mol %) provided much better selectivity to afford amide
3aa in 75% yield and ketone 4aa in 15% yield (run 5). A
slightly higher reaction temperature enhanced the selectivity
further (runs 6 and 7), giving amide 3aa as a sole product (86%
yield) when the reaction was conducted in 1,2-dichloroethane
(DCE) at 40 °C (run 7).
a
Unless otherwise noted, the reactions were conducted using alcohols
1 (0.20−0.34 mmol) with vinyl azides 2 (1.2 equiv) in the presence of
Tf2NH (10 mol %) in DCE (3 mL) under a N2 atmosphere. See the
b
Supporting Information for more details. Isolated yields were
recorded above. Tf2NH was used at 30 mol %. Tf2NH was used
at 20 mol %. Structure of the major isomer was described, which was
determined by X-ray crystallographic analysis. See the Supporting
Information.
With the optimized reaction conditions in hand, we next
investigated the substrate scope (Scheme 3). By varying the
substituent R1 of vinyl azides 2, a series of aryl groups could be
incorporated in the amide formation generally in good yields
(for 3ab−3af), while the reactions with methoxyphenyl-
substituted vinyl azides 2b and 2c needed 30 mol % of
Tf2NH to complete the processes. The reaction with α-alkyl-
substituted vinyl azide 2g also required 30 mol % of Tf2NH to
c
d
e
give amide product 3ag in 54% yield. In this case, the putative
iminodiazonium ion possesses two different secondary alkyl
B
DOI: 10.1021/acs.orglett.5b01458
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Letter
substitutents, while only formation of 3ag via migration of the
phenethyl group was observed probably because the bulkiness
of the 3-indolyloxyindole moiety in another secondary alkyl
group prevents its migration. The reaction with β-methyl
substituted vinyl azide 1h (R1 = Ph, R2 = Me) proceeded in
diastereoselective manner, giving 3ah in 78% yield with 3.3:1
dr.15 As the substituents R3 and R4 on the nitrogens of 3-
hydroxy-3-indolyloxindoles 1, not only benzyl but also phenyl
(for 3ba), hydrogen (for 3ca), and methyl groups (for 3db)
could be installed. Amide 3db is the key intermediate in
synthesis of folicanthine by Gong,11e in which the 4-
methoxyphenylamide moiety was constructed via a stepwise
sequence including: (1) synthesis of the corresponding ketone
by BINOL-linked phosphoric acid−catalyzed reaction of 3-
hydroxy-3-indolyloxindole 1d with enamide; (2) conversion of
the resulting ketone into oxime; (3) the Beckmann rearrange-
ment. The present strategy using vinyl azide 2b provides an
operationally straightforward installation of acetamide unit onto
1d. A variety of substituents could be installed as R5 and R6 on
the framework of 3-hydroxy-3-indolyloxindoles 1 (for 3ea−
3ja).
corresponding amide products 7 of synthetic and medicinal
relevance (Scheme 5). For example, 2-(9H-xanthenyl)-
Scheme 5. Amide Synthesis from Alcohols 6 with Vinyl
a b
,
Azide 2a
Conversion of amides 3 into pyrroloindolinones 5 was
demonstrated by careful treatment of 3 with LiAlH4 in THF
(Scheme 4).16 For synthesis of 5ac having an allyl group on the
nitrogen, exchange from 2-methoxyphenyl to allyl amide was
first conducted (see the Supporting Information), and then
followed by the reductive ring-closure.
a
All the reactions were conducted using alcohols 6 (0.30−0.32 mmol)
with vinyl azide 2a (1.2 equiv) and Tf2NH (10 mol %) in DCE (3
mL) under a N2 atmosphere. See the Supporting Information for more
b
c
details. Isolated yields were recorded above. Alcohol 6e was
recovered in 20% yield.
The present catalytic amide synthesis with vinyl azides could
be successfully applied for other types of benzylic (for 6a−6c),
allylic (for 6d), and propargylic alcohols (for 6e), providing the
acetamide 7c functions as an acyl-CoA cholesterol acyltransfer-
ase (ACAT) inhibitor for treatment of atherosclerosis.17 β-
Alkynylcarboxamide 7e is severed as a useful synthon for
construction of pyrrolidone scaffolds.18
a b
,
Scheme 4. Construction of Pyrroloindolinone Structures
In summary, we have developed Tf2NH-catalyzed reactions
of alcohols with vinyl azides, enabling a straightforward access
of synthetically and medicinally useful amide derivatives.
Further upgrading of this catalytic method to the asymmetric
variant as well as application of Tf2NH to other types of
catalytic transformations is now underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of new compounds,
and CIF data of 3ah. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01458.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shunsuke@ntu.edu.sg.
Author Contributions
†F.-L. Z. and X. Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
a
All the reactions were conducted using 0.08−0.1 mmol of amides 3 in
THF (3 mL) under a N2 atmosphere. See the Supporting Information
ACKNOWLEDGMENTS
b
c
■
for more details. Isolated yields were recorded above. 5ac was
synthesized from 3ac via amide exchange from 2-methoxyphenyl to
allyl via stepwise sequence followed by LiAlH4 reduction. See the
Supporting Information. The reaction was conducted at 30 °C. PMP
= 4-methoxyphenyl.
This work was supported by funding from Nanyang
Technological University and Singapore Ministry of Education
and Singapore Ministry of Education (Academic Research Fund
Tier 1: RG4/13).
d
C
DOI: 10.1021/acs.orglett.5b01458
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Letter
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DOI: 10.1021/acs.orglett.5b01458
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