Amide synthesis by nucleophilic attack of vinyl azides

Article abstract of DOI:10.1002/anie.201400938

A method for the synthesis of amide-containing molecules was developed using vinyl azides as an enamine-type nucleophile towards carbon electrophiles, such as imines, aldehydes, and carbocations that were generated from alcohols in the presence of BF₃OEt₂. After nucleophilic attack of the vinyl azide, a substituent of the resulting iminodiazonium ion intermediate migrates to form a nitrilium ion, which is hydrolyzed to afford the corresponding amide. Nitrilium intermediate: A new method for amide synthesis employs vinyl azides as enamine-type nucleophiles towards carbon electrophiles in the presence of BF₃OEt₂. After nucleophilic attack of the vinyl azide, a substituent of the resulting iminodiazonium ion intermediate A migrates to form nitrilium ion B, which is hydrolyzed to afford the corresponding amide.

Full text of DOI:10.1002/anie.201400938

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Angewandte
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DOI: 10.1002/anie.201400938
Amide Synthesis
Hot Paper
Amide Synthesis by Nucleophilic Attack of Vinyl Azides**
Feng-Lian Zhang, Yi-Feng Wang, Geoffroy Hervꢀ Lonca, Xu Zhu, and Shunsuke Chiba*
Abstract: A method for the synthesis of amide-containing
molecules was developed using vinyl azides as an enamine-
type nucleophile towards carbon electrophiles, such as imines,
aldehydes, and carbocations that were generated from alcohols
in the presence of BF3·OEt2. After nucleophilic attack of the
vinyl azide, a substituent of the resulting iminodiazonium ion
intermediate migrates to form a nitrilium ion, which is
hydrolyzed to afford the corresponding amide.
amide bond using organic azides and phosphinothioesters and
has been successfully applied for the synthesis of biofunc-
tional peptides (Scheme 1a).[3–5] Aubꢀ and co-workers devel-
oped Lewis acid mediated reactions of ketones (mainly cyclic
ketones) with 2-azidoethanols or 3-azidopropanols for the
synthesis of amides (mainly lactams) by the Schmidt reaction
through the in situ formation of hemiketal intermediates
(Scheme 1b).[6–9] Chang et al. developed an amide synthesis
that proceeds through the copper-catalyzed hydrative cou-
pling of terminal alkynes and sulfonyl azides in the presence
of water through an azide–alkyne [3+2] cycloaddition (Sche-
me 1c).[10,11] A dehydrogenative amide synthesis from organic
azides and alcohols that is catalyzed by a ruthenium N-
heterocyclic carbene (NHC) catalyst system was elegantly
designed by Hong and co-workers.[12]
Vinyl azides have served as versatile synthons for the
synthesis of various nitrogen-containing molecules, in partic-
ular azaheterocycles.[13] Our continuous interest in the
potential chemical reactivity of vinyl azides[14] motivated us
to use them as enamine-type nucleophiles. The groups of
Hassner and Moore reported that protonation of vinyl azides
by aqueous acids generates iminodiazonium ion intermedia-
tes A, which further undergo a Schmidt-type 1,2-migration to
form nitrilium ions B with elimination of dinitrogen (N2;
Scheme 2).[15] Hydrolysis of the nitrilium ions produces the
Organic molecules with amide linkages are prevalent not
only in peptides and proteins, but also in pharmaceuticals,
agrochemicals, and functional materials.[1] Therefore, many
chemical approaches have been developed to access amide-
containing molecules in atom- and step-economical man-
ners.[2] Among the various nitrogen sources that are utilized
for amide synthesis, organic azides have shown a wide
spectrum of chemical reactivity with different types of
reaction modes (Scheme 1). For example, the traceless
Staudinger ligation is a powerful method to construct an
Scheme 2. Protonation of vinyl azides for the formation of amides.
Scheme 1. Amide synthesis with organic azides.
corresponding secondary amides.[16] As two isomers of
iminodiazonium ions (the E and Z isomers) might be
+
ꢀ
formed, and the substituent that is anti to the N N2 bond
[*] F.-L. Zhang, Dr. Y.-F. Wang, G. H. Lonca, X. Zhu, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
should undergo 1,2-migration,[17] the reactions could poten-
tially afford two constitutional isomers; their ratio might
depend on the reaction conditions and the migratory aptitude
of the substituents.
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
Therefore, we wondered whether we might be able to use
[**] This work was supported by funding from Nanyang Technological
University and the Singapore Ministry of Education. Y.-F.W. is
thankful for a Lee Kuan Yew postdoctoral fellowship (the LKY PDF).
G.H.L. is grateful for financial support from the Ecole Polytech-
nique.
carbon electrophiles (E+) for the reaction with vinyl azides, in
ꢀ
which a C C bond could be formed by nucleophilic attack of
a vinyl azide to the electrophile to generate an iminodiazo-
nium ion intermediate A (Scheme 3). Subsequent Schmidt-
type rearrangement might form nitrilium ion B, hydrolysis of
which could produce the amide linkage. In this context, we
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400938.
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2a (1.2 equiv) with BF3·OEt2 (3 equiv) in CH2Cl2 at 08C to
room temperature resulted in rapid consumption of 1a within
ten minutes (entry 1); the desired b-amino amide 3aa could
be isolated in 12% yield along with unidentified complex
mixtures that included unreacted imine 2a. When the
reaction was carried out in the presence of hexafluoroisopro-
panol (HFIP, 2 equiv) as an additive at a lower reaction
temperature (ꢀ408C), the yield of 3aa slightly improved to
49% (entry 3). The poor yields of the target product 3aa are
probably due to decomposition of vinyl azide 1a by the
reaction with BF3·OEt2. We thus examined the slow addition
of a solution of vinyl azide 1a (for 4–5 h with a syringe pump)
to a mixture of imine 2a (1.2 equiv), HFIP (2 equiv), and
BF3·OEt2 (2 equiv; entry 4). As expected, the yield of 3aa was
further improved to 68%. Screening of the additive revealed
that AcOH and H2O worked more efficiently, giving 3aa in
81% and 71% yield, respectively (entries 5–7). These addi-
tives probably play a role in trapping the highly reactive
nitrilium ion intermediate immediately after its formation.
The reaction in the presence of MeOH as an additive afforded
imidate 3aa’, which confirms the formation of the nitrilium
ion B (entry 8). We found that the addition of 1.5–2 equiv-
alents of vinyl azide 1a to imine 2a in the presence of H2O or
AcOH (2 equiv) could further improve the yield of 3aa
(entries 9–11).
Scheme 3. Reactions of vinyl azides with carbon electrophiles.
would strive to design a reaction system and chose reaction
conditions that enable the selective formation of a single
amide product with predictable migration selectivity. Herein,
we report the BF3·OEt2 mediated reaction of vinyl azides with
a series of carbon electrophiles, which enables the efficient
synthesis of amide-containing molecules.
Vinyl azides 1 were readily prepared from the corre-
sponding alkenes by following Hassnerꢁs method, which
entails the addition of IN3 followed by elimination of HI in
the presence of tBuOK (Scheme 4; see the Supporting
Information for details).[18]
With the established procedure in hand (Table 1,
entry 11), the generality of this transformation for the syn-
thesis of b-amino amides was next explored using a variety of
N-tosyl-substituted aldimines 2b–2i and vinyl azide 1a
(Scheme 5).[19] Various aromatic aldimines 2b–2g, including
Scheme 4. Preparation of vinyl azides 1.
Based on the hypothesis shown in Scheme 3, we com-
menced our study with vinyl azide 1a and N-tosyl benzaldi-
mine 2a in the presence of BF3·OEt2 as a Lewis acid promoter
(Table 1). Treatment of a mixture of vinyl azide 1a and imine
Table 1: Optimization of the reaction conditions.[a]
Entry
x
y
z
Additive
T [8C]
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1
3
2
2
2
2
2
2
2
2
2
2
–
0!RT
0!RT
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
0.2
0.2
0.2
4[c]
5[c]
5[c]
5[c]
5[c]
5[c]
5[c]
5[c]
12
22
49
68
81
65
71
34[d]
95
95
96
HFIP
HFIP
HFIP
AcOH
TFA
H2O
MeOH
H2O
AcOH
H2O
Scheme 5. Scope of N-tosyl aldimines 2.
9[e]
10[e]
11[e]
1.5
1.5
2
those with indolyl or benzofuranyl moieties, could be utilized
to give the corresponding b-amino amides 3ab–3ag in good to
excellent yields. The reaction with a,b-unsaturated aldimine
2h resulted in the 1,2-addition product 3ah in 53% yield.
Likewise, the aliphatic aldimine 2i was reacted to afford the
desired amide 3ai, albeit in lower yield (36%).
We next examined the use of aldehydes 4 as electrophiles
instead of N-tosyl aldimine 2 for the synthesis of b-hydroxy
amides 5, which turned out to be rather challenging
1
1
[a] Unless otherwise noted, the reactions were carried out with vinyl
azide 1a (0.3 mmol) in CH2Cl2 (0.1m). [b] Yields of isolated products.
[c] A solution of vinyl azide 1a (in 1.5 mL of CH2Cl2) was slowly added
using a syringe pump for the indicated time, and the reactions were
quenched upon completion of the addition. [d] Yield of isolated imidate
3aa’. [e] The yield of 3aa is based on imine 2a (0.3 mmol). TFA=tri-
fluoroacetic acid.
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Scheme 6. Reactions with aldehydes 4a and 4b.
(Scheme 6). The reactions of vinyl azide 1a with benzalde-
hyde (4a) and ethyl glyoxal (4b) gave the corresponding b-
hydroxy amides 5a and 5b in only 30% and 45% yield,
respectively, under the reaction conditions stated above,
although the reaction conditions were re-examined to
improve the yields (see the Supporting Information).
We then turned our attention towards the scope of vinyl
azides 1 in the reaction with N-tosyl benzaldimine 2a
(Scheme 7–9). When varying the aryl group on the a-aryl
vinyl azide 1 (Scheme 7), we found that both electron-rich and
-deficient aryl groups were tolerated by the present method
and delivered the corresponding products in good yields,
whereas the reaction with a sterically hindered 2-methyl-
phenyl group resulted in a lower yield (56%) of amide
product 3ca.
Scheme 8. Reaction with a-alkyl-substituted vinyl azide 1h.
Scheme 7. Scope of a-aryl vinyl azides 1.
Scheme 9. Reactions of cyclic vinyl azides 1i and 1j.
The reaction of a-alkyl-substituted vinyl azide 1h with
imine 2a provided a 1:1 mixture of amide 3ha and dihydroi-
midazole 6ha in a combined yield of 68% (Scheme 8). This
result indicated that the addition of vinyl azide 1h to imine 2a
would generate a 1:1 mixture of the iminodiazonium ions
(Z)-I and (E)-I, which bear two different secondary alkyl
substituents (marked in blue and green). For (Z)-I, migration
of the substituent leads to nitrilium ion II, hydrolysis of which
then delivers amide 3ha. On the other hand, nitrilium ion III,
which is derived from (E)-I, undergoes cyclization to afford
dihydroimidazole 6ha.
Interestingly, the reaction of 1-azido-cycloheptene (1i)
with imine 2a under the standard reaction conditions gave the
ring-expanded eight-membered lactam 3ia in 47% yield
(d.r. = 4.4:1, major isomer shown; Scheme 9a). On the other
hand, when 1-azido-cyclooctene (1j) was reacted with 2a, the
corresponding lactam was not observed, while bicyclic
dihydroimidazole 6ja was obtained in 52% yield (d.r. =
6.3:1, major isomer shown; Scheme 9b). The stereochemistry
of the major isomers of 3ia and 6ja was determined as syn by
X-ray crystallography (see the Supporting Information for
a preliminary discussion on the diastereoselectivity). These
results suggest that the putative iminodiazonium ion inter-
mediate (E)-IV exclusively undergoes 1,2-migration of the
tertiary carbon atom (marked in green) to form nitrilium ion
V; this process is followed either by hydrolysis to yield lactam
3ia or by intramolecular cyclization to afford 6ja. All of these
observations implicate that the E- and Z-configured imino-
diazonium ion intermediates may be in equilibrium under the
present reaction conditions,[20] which enables the selective
rearrangement of the substituent with the higher migratory
aptitude (i.e., aryl > alkyl, tertiary alkyl > secondary alkyl).
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Taking advantage of the present amide synthesis by
nucleophilic attack of vinyl azides 1, which proceeds under
acidic conditions, we finally explored the functionalization of
carbocations that are derived from alcohols (Table 2).[21] As
expected, the reactions of vinyl azide 1a with diarylmethanols
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Amide
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65
[4] For
a pioneering study on the (non-traceless) Staudinger
7a
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7b
8b
83
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7c
7d
8c
8d
60
53
[8] For
a recent report on an intramolecular strategy using
7a and 7b (1.5 equiv) in the presence of BF3·OEt2 (2 equiv)
resulted in the formation of amides 8a and 8b in 65% and
83% yield, respectively. In these processes, BF3 mediated
dissociation of the hydroxide ion from the alcohol first
generates the corresponding carbocation, which is subse-
quently trapped by nucleophilic attack of vinyl azide 1a.
Similarly, triphenylmethanol (7c) and 2,3-diphenyl-2-propen-
1-ol (7d) could be employed as sources for the trityl and p-
allyl cations, respectively, giving the corresponding amides 8c
and 8d in good to moderate yields. These reactions do not
require the addition of H2O.
We anticipate that the present method, which employs
vinyl azides as enamine-type nucleophiles, may be readily
adopted for the synthesis of biologically and medicinally
important amide-containing molecules. Further investigations
to develop catalytic asymmetric variants of this method with
chiral Lewis acids are currently underway.
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2
ꢀ
C(sp ) H amidation using acyl azides as the nitrogen source;
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Received: January 28, 2014
Published online: March 18, 2014
Keywords: amides · nitrilium ions · nucleophilic attack ·
.
rearrangement · vinyl azides
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