Unexpected Direct Synthesis of N-Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

Article abstract of DOI:10.1002/anie.201702727

The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.

Full text of DOI:10.1002/anie.201702727

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702727
German Edition: DOI: 10.1002/ange.201702727
Synthetic Methods
Unexpected Direct Synthesis of N-Vinyl Amides through
Vinyl Azide–Enolate [3+2] Cycloaddition
Hans Choi, Harry J. Shirley, Paul A. Hume, Margaret A. Brimble,* and Daniel P. Furkert*
Abstract: The unexpected synthesis of industrially important
N-vinyl amides directly from aldehydes and a,b-unsaturated
N-vinyl amides from esters is reported. This reaction probably
proceeds through an initial [3+2] azide–enolate cycloaddition
involving a vinyl azide generated in situ. A survey of the
reaction scope and preliminary mechanistic findings supported
by quantum computational analysis are reported, with impli-
cations for the future development of atom-efficient amide
synthesis. Intriguingly, this study suggests that (cautious)
reevaluation of azidoethene as a synthetic reagent may be
warranted.
erable attention as an important and versatile emerging
technology.[7]
Azide–enolate cycloaddition reactions are known, but
have not been well explored. In a series of early publications,
Olsen originally described enolate-mediated reactions of aryl
azides with ketones or aldehydes to afford hydroxytriazolines,
such as 3 (Scheme 2).[8] Aubꢀ and co-workers reported that
N
-Vinyl amides, a subset of the wider class of enamides,[1]
display useful reactivity as synthetic intermediates.[2] They are
also of increasing importance for the synthesis of poly(vinyl
amides) with an array of applications, including drug for-
mulation and tissue engineering.[3] N-Vinyl amide polymer
variants have not yet been widely explored owing to the lack
of convenient general methods to access the monomer
feedstocks (Scheme 1).[4–6] Given the utility of these com-
Scheme 1. Industrially important N-vinyl amides 1 and 2.[3a]
Scheme 2. Azide–enolate [3+2] cycloaddition reactions implicated in
amide and triazoline synthesis. LDA=lithium diisopropylamide,
LHMDS=lithium hexamethyldisilazide.
pounds, it is surprising that methods to access N-vinyl amides
remain relatively scarce. We report herein a novel method
involving the generation of a vinyl azide in situ for the direct
synthesis of N-vinyl amides from a-substituted aldehydes and,
remarkably, a,b-unsaturated N-vinyl amides from a-substi-
tuted esters. The application of substituted vinyl azides to the
synthesis of amides and heterocycles has attracted consid-
the lithium enolate of ketone 4 underwent [3+2] cyclo-
addition with azide 5 to give triazole 6, but a potential
precursor, enol ether 7, was unreactive.[9] In 2016, Ramstrçm,
Yan, and co-workers reported the enolate-mediated reaction
of aldehydes with aryl azides to give N-aryl amides (e.g. 10).[10]
This reaction was proposed to proceed via a 1,2,3-triazoline
intermediate 9 generated by [3+2] cycloaddition of the aryl
azide with the enolate of aldehyde 8.
Our own investigations began as part of synthetic studies
towards N-heterocyclic systems. Alkylation of methyl ester 11
(Scheme 3) with alkyl iodides was investigated as a means to
access a-quaternary esters 13 and 15. Accordingly, the
treatment of ester 11 with LHMDS and addition of the
[*] H. Choi, H. J. Shirley, P. A. Hume, M. A. Brimble, D. P. Furkert
School of Chemical Sciences, University of Auckland
23 Symonds St, Auckland 1010 (New Zealand)
E-mail: m.brimble@auckland.ac.nz
d.furkert@auckland.ac.nz
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702727.
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Table 1: Scope of the direct synthesis of N-vinyl amides.
Entry Substrate
1
Product
Conditions[a] Yield [%]
A
A
A
85
74
68
2
3
Scheme 3. Initial observation of unexpected N-vinylacrylamide forma-
tion.
4
A
54
three-carbon-atom iodo azide 12 delivered the expected
product 13 in high yield. In contrast, in the analogous reaction
of 11 with the two-carbon-atom iodo azide 14,[11] the desired
azido ester 15 was not observed. Instead, the unexpected N-
vinyl amide 16 was isolated in 85% yield. Of particular note
was the new a,b unsaturation present in amide 16.
5
6
A
A
(14)
(24)
This discovery prompted a survey of the reactivity of
further esters with iodo azide 14 (Table 1). Methyl isobutyrate
(17) was converted into the novel N-vinylacrylamide 18
(entry 2), and methyl 2-methylbutanoate (19) into acrylamide
20 (entry 3), both in high yield. The E-alkene geometry of 20
was determined by NOE analysis. 2-Phenylpropionate 21
similarly afforded acrylamide 22 (entry 4). Submission of a-
unsubstituted esters 23 and 25 to the reaction conditions only
returned known Claisen condensation products 24 (entry 5)
and 26 (entry 6), respectively. The analogous reactivity of
aldehydes was also investigated; the treatment of 27 with
LHMDS and addition of 14 returned only unreacted alde-
hyde. Changing the base to KOtBu led to the isolation of N-
vinyl amide 28 (entry 7). Intriguingly, 28 did not possess the
acrylamide a,b unsaturation obtained from the analogous
ester substrate (entry 1 vs. 7). Notably, isobutyraldehyde 29
was transformed into the valuable monomer N-vinylisobutyr-
amide (NVIBA, 2; entry 8). The initially moderate yields
were significantly improved after brief optimization. Sim-
ilarly, aldehydes 30 and 32 afforded the novel N-vinyl amides
31 and 33, respectively (entries 9 and 10). Finally, a second
method to access 31 was demonstrated from 3-pentenone 34
(entry 11).
The work of Olsen/Pedersen, Aubꢀ, and Malmstrçm/Yan
(see Scheme 1) suggested that this process probably proceeds
through a formal azide–enolate [3+2] cycloaddition. In the
aldehyde manifold (Table 1, entries 7–10), this transformation
would be expected to initially give an intermediate triazoline
35 (Scheme 4, path A). The triazole could then undergo either
cyclization to 36[9] or a 1,2-hydride shift with extrusion of
nitrogen to give amide 37. On further consideration, however,
neither 36 nor 37 appeared sufficiently activated to undergo
elimination to form N-vinyl amide 38.[12] Furthermore, the
mechanism shown for path A would not account for the
different reactivity observed between the three-carbon-atom
iodo azide 12 and the two-carbon-atom iodo azide 14. A
control experiment conducted in the absence of an aldehyde
(Scheme 4, path B) showed rapid conversion of 14 into
7
B
72
8
9
B
B
72
87
10
11
B
C
67
29
[a] Method A: 14, LHMDS, THF, ꢀ788C!rt, 16 h; method B: KOtBu
(5 equiv), 14 (2.5 equiv), CH2Cl2, 08C!rt, 16 h; method C: 14, LDA,
Et2O, ꢀ788C.
azidoethene (39) by NMR spectroscopy upon exposure to
potassium tert-butoxide.[13] These conditions are similar to
those originally developed by Hassner and co-workers in
a series of seminal studies on the formation of substituted
vinyl azides.[14] Azidoethene (39) could then undergo rapid
cycloaddition with an enolate to give a triazole intermediate
40, from which nitrogen extrusion and a 1,2-hydride shift
would give N-vinyl amide 38 either through a concerted
process or an asynchronous sequence involving an intermedi-
ate diazonium ion. Although azidoethene (39) was described
as early as 1910,[15] it has been used for little further practical
chemistry;[16] however, it has been the subject of a number of
computational studies.[17]
To investigate the feasibility of our mechanistic hypoth-
esis, as there are no previous reports of the computational
analysis of azide–enolate cycloaddition reactions, we calcu-
2
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calculated to assess the effects of orbital delocalization on
reactivity and facilitate comparison with the literature and
our own observations.
The theoretical calculations displayed excellent agree-
ment with our experimental results and the regiochemistry
observed in previous [3+2] azide–enolate cycloaddition
reactions.[8–10] Transition states for three virtual azides leading
to the experimentally observed regioisomer, exemplified by
TS1b leading to 42b (R = vinyl), were associated with lower
activation energies of 2.0–6.1 kcalmolꢀ1 (phenyl TS1a ꢁ vinyl
TS1b < ethyl TS1c). The activation energy of 6.1 kcalmolꢀ1
estimated for ethyl azide suggests that cycloaddition of the
enolate of 11 and azide 12 (see Scheme 3) could plausibly
proceed at room temperature, but the alkylation pathway to
give 13 is observed to predominate. Conversely, in the
reaction of 11 and 14, facile formation of azidoethene (39)
would lower the required activation energy for cycloaddition,
thus eventually leading to formation of the a,b-unsaturated
N-vinyl amide 16 as the sole product. In contrast to TS1, it was
determined that transition state TS2b for the formation of the
unobserved regioisomer 43 required a significantly larger
energetic barrier of 15.6 kcalmolꢀ1 to be overcome. Interest-
ingly, the cycloaddition reactions proceeding via TS1 dis-
played pronounced asynchronicity, in contrast to TS2. Sub-
sequent rearrangement of the intermediate triazoline 42b was
found to be dependent on protonation of both the alkoxide
and the amide nitrogen atom; direct rearrangement of the
alkoxide 42b, with concomitant nitrogen extrusion, was
calculated to require a prohibitively high activation energy
of > 25 kcalmolꢀ1, but double protonation essentially abol-
ished this energetic barrier. This prediction was borne out
both by our studies, which involved a mildly acidic workup,[18]
and the much earlier finding of Olsen that hindered triazo-
lines obtained by aryl azide–enolate cycloaddition were stable
to isolation and required exposure to a Lewis acid to undergo
an analogous rearrangement.[8a] Our calculations additionally
indicate that the rearrangement–nitrogen-extrusion process is
likely to be an asynchronous process (see the reaction movie
in the Supporting Information); initial protonation leads
immediately to the formation of diazonium ion 44 through
Scheme 4. Mechanistic possibilities for direct N-vinyl amide formation
from aldehydes.
lated the reaction of aldehyde enolate 41 with azidoethene
(39) by using DFT B3LYP/6-31G + (d,p) with a polarizable
continuum model to account for solvent effects (Scheme 5;
see the Supporting Information for details). Analogous
cycloaddition reactions for phenyl and ethyl azide were also
ꢀ
cleavage of the N N bond, and 44 then undergoes slower
reformation of the carbonyl functionality and a 1,2-hydride
shift to afford vinyl amide 2. The fundamental mechanistic
processes proposed herein also appear to be in broad
agreement with a recent computational study on related
azide–enamine cycloaddition reactions to give ring-con-
tracted amidines.[19] The current work does not appear to
rule out the possible intermediacy of an aziridine species in
these processes.
Mechanistically, the original unexpected observation of
the formation of a,b-unsaturated N-vinyl amides from esters
is also consistent with an enolate–azide cycloaddition mech-
anism (Scheme 6). The initially formed triazole intermediate
45, however, lacks a hydride to undergo the 1,2-shift. Instead,
regeneration of the carbonyl group eliminates methoxide,
followed by b-deprotonation under the basic reaction con-
ditions and extrusion of nitrogen. This direct formation of
a,b-unsaturated N-vinyl amides of general structure 46 from
a-substituted esters is a very unusual example of oxidative
Scheme 5. DFT calculations for the regioisomeric transition states TS1
and TS2 (B3LYP/6-31G+ (d,p); values in kcalmolꢀ1) support the
observed selectivity of cycloaddition and the energetic feasibility of
subsequent rearrangement.
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Acknowledgements
We thank The Royal Society of New Zealand for financial
support by the award of Marsden Grant UOA1422.
Conflict of interest
Scheme 6. Proposed mechanism for the direct formation of
a,b-unsaturated N-vinyl amides from esters.
The authors declare no conflict of interest.
Keywords: amides · [3+2] cycloaddition · rearrangement ·
amide formation from an otherwise unactivated carbonyl
component.
transition states · vinyl azides
Finally, as an extension of this work, the vinyl azide–
enolate cycloaddition approach was further explored to
successfully access substituted N-vinyl amide systems 47–49
(Scheme 7), thus suggesting potential for future wider devel-
opment.
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In conclusion, we have reported the remarkable and
unexpected direct synthesis of a,b-unsaturated N-vinyl
amides from esters and N-vinyl amides from aldehydes. The
reaction most likely proceeds through the in situ formation of
an N-vinyl azide, which undergoes facile azide–enolate [3+2]
cycloaddition, followed by rearrangement and nitrogen
extrusion. The proposed mechanism and observed regio-
chemistry are in accordance with quantum calculations
performed to estimate transition-state activation energies
for alkyl, aryl, and vinyl azides. Both experimental data and
calculations indicate that protonation of the initial triazoline
cycloaddition product is required before rearrangement to
a diazonium ion and nitrogen extrusion can occur to form the
final N-vinyl amides. These investigations contribute useful
data to aid the ongoing development of atom-efficient
methods for amide formation and offer new possibilities in
synthesis for drug discovery and the applications of industri-
ally important N-vinyl amide polymeric materials. Finally, this
study suggests that, given recent progress in batch and flow
reaction technology,[20] (cautious) reevaluation of azido-
ethene as a useful synthetic reagent may be warranted.
4
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Manuscript received: March 15, 2017
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
Worth another look: Industrially impor-
tant N-vinyl amides were synthesized
directly from aldehydes/esters and 1-
azido-2-iodoethane. Quantum-chemical
calculations support the proposed
mechanism involving [3+2] cycloaddition
of the enolate derived from the aldehyde
or ester with a vinyl azide generated in
situ (see scheme). The results suggest
that azidoethene itself may be worth
(cautious) reevaluation as an atom-effi-
cient synthetic reagent.
H. Choi, H. J. Shirley, P. A. Hume,
M. A. Brimble,*
D. P. Furkert*
&&&& — &&&&
Unexpected Direct Synthesis of N-Vinyl
Amides through Vinyl Azide–Enolate
[3+2] Cycloaddition
6
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