Base-Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino-Staudinger Synthesis

Article abstract of DOI:10.1002/chem.201702545

Ynamides were used as precursors for the in situ generation of highly reactive ketenimines that could be trapped with imines in a [2+2] cycloaddition. This imino-Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely azetidinimines (2

Full text of DOI:10.1002/chem.201702545

A Journal of
Accepted Article
Title: Base-Mediated Generation of Ketenimines from Ynamides: Direct
Access to Azetidinimines by an Imino Staudinger Synthesis
Authors: Eugénie Romero, Corinne Minard, Mohamed Benchekroun,
Ventre Sandrine, Pascal Retailleau, Robert H. Dodd, and
Kevin Cariou
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To be cited as: Chem. Eur. J. 10.1002/chem.201702545
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Base-Mediated Generation of Ketenimines from Ynamides: Direct
Access to Azetidinimines by an Imino Staudinger Synthesis
Eugénie Romero,† Corinne Minard,† Mohamed Benchekroun,‡ Sandrine Ventre,‡ Pascal Retailleau,
Robert H. Dodd,* Kevin Cariou*
Abstract: Ynamides were used as precursors for the in situ
generation of highly reactive ketenimines which could be trapped with
imines in a [2+2] cycloaddition. This imino Staudinger synthesis led to
a variety of imino-analogs of β-lactams, namely azetidinimines (20
examples), that could be further functionalized through a broad range
of transformations.
In order to further expand the potential of this highly reactive
intermediate (3), we sought to trap it in a [2+2] cycloaddition.6 By
analogy with the well-established Staudinger synthesis of β-
lactams,7 and based on the pioneering studies by Ghosez8 and
Regitz,9 we envisioned that the N-phenylethenimine 3a generated
in situ from ynamide 1a would be sufficiently electrophilic to react
with imine 4 to ultimately give azetidinimine 5 (Scheme 2).10 From
our previous experience, an unsubstituted N,N-Boc-aryl-ynamide
would be the best precursor for the generation of the ketenimine
and we assumed an electron-rich nitrogen atom in the imine
would favor the desired cycloaddition.
Ynamides (1) are versatile nitrogen-containing building blocks
composed of an acetylene moiety directly attached to a nitrogen
atom that generally bears at least one electron-withdrawing group
that stabilizes the molecules.1 The strong inherent polarization of
the triple bond, that can be visualized by drawing the main
mesomeric form 1’, generally drives their reactivity towards
nucleophilic addition on the α position and reactions with
electrophiles at the β position.1 This trend can be further
enhanced by acid activation, since protonation of the substrate
yields keteniminium 2 (Scheme 1).2
Scheme 2. In situ Generation of an Ethenimine and Trapping with an Imine
However, direct application of our previously disclosed reaction
conditions4 – i.e., 1.0 equiv. of ynamide, 1.0 equiv. of t-BuONa as
base, DMF as solvent, with molecular sieves at room temperature
– proved totally ineffective, even after prolonged reaction time
(Table 1, entry 1). We reasoned that the cycloaddition process
required thermal activation and thus, while traditional heating
(entry 2) was unsuccessful, switching to microwave conditions11
allowed the reaction to take place (entry 3). By replacing the
sodium salt by potassium (entry 4) or lithium (entry 5) t-butanolate
the desired azetidinimine 5aa could be isolated with 46% and 47%
yield, respectively. Doubling the amount of both the ynamide and
the base (X = 2) had little effect (entry 6) unless the temperature
was raised to 100 °C (entry 7) which allowed 5aa to be isolated in
50% yield. This 50% threshold could be overcome by using silica
gel as the additive instead of molecular sieves (entry 8, 54%).
These optimized conditions were then applied to p-
chlorobenzaldehyde-derived imine 4b which led to the isolation of
64% of azetidinimine 5ab (entry 9). Improved formation of the
latter was attempted by using a catalytic amount of a Lewis acid
as the additive (entry 10, 50%) or as a co-additive (entry 11, 52%)
but to no avail.
Scheme 1. Ynamides: Inherent Polarization vs Acid and Base Activations
For our part, we have shown that using strongly basic conditions3
an unprecedented nucleophilic addition of various heteroarenes
at the β position could take place.4 Moreover, depending on the
substitution pattern of the nitrogen atom, the same basic
conditions could lead to an α nucleophilic addition, albeit with the
loss of the electron-withdrawing group (EWG). In this latter case,
base activation would trigger the cleavage of the EWG, leading to
an amide that will eventually evolve towards ketenimine 3.4,5
[a]
Dr E. Romero, Dr C. Minard, Dr M. Benchekroun, Dr S.Ventre, Dr P.
Retailleau, Dr R. H. Dodd,* Dr K. Cariou*
Having determined the optimal reaction conditions, we then
explored the scope of this cycloaddition (Table 2). First, the
influence of the substituents on the imine partners was assayed.
Unsubstituted diphenyl aldimine 4c allowed formation of the
corresponding azetidinimine 5ac in only 22% yield (entry 3).
Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
Université Paris-Sud, Université Paris-Saclay
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: kevin.cariou@cnrs.f r
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of the [2+2] Cycloaddition between Ynamide 1a and Imines 4a,b.a
Entry
1
X
1
1
1
1
1
2
2
2
2
2
2
4
Base
Additive
Time
24 h
24 h
1 h
Heating
Yield, 5
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
t-BuONa
t-BuONa
t-BuONa
t-BuOK
t-BuOLi
t-BuOK
M. S.
RT
0%
2
M. S.
60 °C
Traces
3
M. S.
80 °C µW
80 °C µW
80 °C µW
80 °C µW
100 °C µW
100 °C µW
100 °C µW
100 °C µW
100 °C µW
20% conv.
46%, 5aa
47%, 5aa
45%, 5aa
50%, 5aa
54%, 5aa
64%, 5ab
50%, 5ab
52%, 5ab
4
M. S.
M. S.
1 h
5
1 h
6
M. S.
1 h
7
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi[b]
t-BuOLi[b]
M. S.
1 h
8
SiO2 (1 equiv.)
SiO2 (1 equiv.)
ZnOTf (10 mol%)
SiO2 (1 equiv.) + ZnOTf (10 mol%)
1 h
9
1 h
10
11
1 h
1 h
[a] Isolated yields. [b] A 2.2 M solution of t-BuOLi in THF was used.
This result appears consistent with the positive effect of
having an electron-donating group on the nitrogen (entries 1,2)
and an electron-poor aryl group on the carbon of the imine partner
(entry 2). Imines derived from meta- (4d) and ortho-anisidine (4e)
were then reacted with ynamide 1a, providing cycloadducts 5ad
and 5ae in 26% and 37% yields, respectively (entries 4,5).These
yield variations can be accounted for by standard electronic (meta
vs. para/ortho) and steric (ortho vs. para) effects.
Table 2. Scope and limitations of the [2+2] Cycloaddition with Ynamides 1 and Imines 4. [a]
Entry
1
Ar, 1
Ar2, Ar3, 4
Yield, 5a
Ph, 1a
Ph, 4-MeO-C6H4, 4a
54%, 5aa[b] [c]
64%, 5ab[b]
22%, 5ac[d]
26%, 5ad[d]
37%, 5ae[d]
54%, 5af[b]
40%, 5ag[b]
63%, 5ah
61%, 5ai[c]
4%, 5aj + 26%, 5aj’[d]
10%, 5ba[c]
29%, 5bb
2
Ph, 1a
4-Cl-C6H4, 4-MeO-C6H4, 4b
Ph, Ph, 4c
3
Ph, 1a
4
Ph, 1a
4-Cl-C6H4, 3-MeO-C6H4, 4d
4-Cl-C6H4, 2-MeO-C6H4, 4e
Ph, 3,4,5-triMeO-C6H4, 4f
4-MeO-C6H4, 4-MeO-C6H4, 4g
4-Br-C6H4, 4-MeO-C6H4, 4h
4-I-C6H4, 4-MeO-C6H4, 4i
4-MeO2C-C6H4, Ph, 4j
Ph, 4-MeO-C6H4, 4a
5
Ph, 1a
6
Ph, 1a
7
Ph, 1a
8
Ph, 1a
9
Ph, 1a
10
11
12
13
14
15
16
17
18
19
20
Ph, 1a
4-Cl-C6H4, 1b
4-Cl-C6H4, 1b
4-Br-C6H4, 1c
4-Br-C6H4, 1c
4-I-C6H4, 1d
4-I-C6H4, 1d
4-CF3-C6H4, 1e
4-CF3-C6H4, 1e
4-MeO-C6H4, 1f
4-MeO-C6H4, 1f
4-Cl-C6H4, 4-MeO-C6H4, 4b
Ph, 4-MeO-C6H4, 4a
11%, 5ca
4-Cl-C6H4, 4-MeO-C6H4, 4b
Ph, 4-MeO-C6H4, 4a
40%, 5cb
10%, 5da
4-Cl-C6H4, 4-MeO-C6H4, 4b
Ph, 4-MeO-C6H4, 4a
29%, 5db
36%, 5ea
4-Cl-C6H4, 4-MeO-C6H4, 4b
Ph, 4-MeO-C6H4, 4a
36%, 5eb
22%, 5fa[c]
4-Cl-C6H4, 4-MeO-C6H4, 4b
35%, 5fb
[a] Isolated yields, using a 2.2 M solution of t-BuOLi in THF. [b] Solid t-BuOLi was used. [c] An X-ray structure was obtained, see Supporting Information for
details.12 [d] 10 mol% of ZnOTf2 was used as the additive instead of silica gel.
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Strongly electron-enriched 3,4,5-trimethoxylated imine 4f
reacted smoothly with 1a to give 5af in 54% yield (entry 6) while
dianisyl imine 4g led to 5ag in 40% yield (entry 7). In order to allow
further functionalization, p-bromo- and p-iodobenzaldehyde-
derived imines (4h and 4i) were subjected to the reaction
conditions and the desired adducts were obtained in 63% and
61% yields, respectively (entries 8,9). Imine 4j bearing a
methoxycarboxylate was then used, leading to an overall 30%
yield of cycloaddition adduct 5a, most of which had been trans-
esterified to the corresponding t-butoxycarboxylate 5aj’ during the
course of the reaction (entry 10). While various substitution
patterns on the imine partner were well tolerated, this was not the
case for the ketenimine precursor. Indeed, a series of ynamides
was evaluated for which no cycloaddition took place (Table 2, top-
right b). These include: sulfonamides (GP = tosyl, mesyl and p-
nosyl) and N-alkyl (R = benzyl or allyl) as well as C-substituted (R’
= phenyl, n-butyl and triisopropylsilyl) derivatives. The reaction did
take place, however, when functionalized aryl groups such as
para halo- (Cl, Br and I), trifluoromethyl- and methoxy-phenyl
were incorporated on the ynamide partner (1b–f). All of these
reacted with both imines 4a and 4b (entries11–20) providing
yields of cycloadducts ranging from 10–36% with imine 4a (entries
11, 13, 15, 17 and 19) to 29–40% with imine 4b (entries 12, 14,
16, 18 and 20). Compared with ynamide 1a, yields were
systematically lower and this can be attributed to a variety of
factors difficult to unambiguously pinpoint since the substitution of
this aryl presumably has an influence on both the generation of
the active ketenimine and its subsequent stability and reactivity.
A strong Lewis acid such as boron tribromide (Scheme 4, Eq. 1)
could be employed, without any noticeable degradation of the
amidine ring, to selectively cleave the methyl group of 5ab to give
phenolic azetidinimine 8. The latter could in turn be alkylated with
t-butyl bromoacetate to give 9 in 78% yield. Finally, treatment of
carboxylate 5aj’ (Eq. 2) with a strong acid such as trifluoroacetic
acid or a strong reducing agent such as lithium aluminum hydride
gave respectively carboxylic acid 10 (96%) and primary alcohol
11 (82%), leaving the four-member ring untouched. Benzyl
alcohol 11 could furthermore be transformed into the
corresponding chloride 12 in 70% yield, using methanesulfonyl
chloride.
Having a wide panel of azetidinimines at our disposal we then
turned our attention to their use for further functionalization.
Satisfyingly, this unusual four-membered ring proved to be quite
tolerant to a broad range of reaction conditions, obviating the
necessity of extensive optimization. First, Suzuki coupling was
used as a typical Pd-catalyzed cross-coupling reaction. Thus, an
additional p-methoxyphenyl moiety could be added with excellent
yields on both the C-aryl (6) or iminoaryl (7) part of the scaffold,
using either bromo- (5ah & 5ca) or iodo-azetidinimines (5ai &
5da) (Scheme 3).
Scheme 4. Further Functionalization around the Azetidinimine Ring
In conclusion, we have taken advantage a specific mode of
activation of ynamides under basic conditions to generate N-
arylethenimines from Boc-aryl-ynamides and react them with
imines in a [2+2] cycloaddition. This reaction further ascertains
the intermediacy of the ketenimine intermediate and paves the
way for other types of cycloadditions. Moreover, the
azetidinimines resulting from this imino Staudinger synthesis can
undergo a broad array of chemical transformations that leave the
4-membered amidine ring intact. This work should allow for further
exploration around this particular heterocyclic scaffold which can
be viewed as an imino-analog of monocyclic β-lactams.13 Studies
in these directions are currently ongoing in our laboratory and will
be reported in due course.
Experimental Section
Imine 4a (63 mg, 0.3 mmol, 1.0 equiv.), ynamide 1a (130 mg, 0.6 mmol,
2.0 equiv.) and SiO2 (18 mg, 0.3 mmol, 1.0 equiv.) were successively
added in a microwave sealable tube and placed under argon before the
addition of t-BuOLi (48 mg, 0.6 mmol, 2.0 equiv.) followed by extra dry
DMF (900 µL). The sealed tube was placed in a microwave apparatus for
1 h at 100 °C. The crude material was purified by flash chromatography on
silica gel (10% ethyl acetate in heptane as eluent) to provide azetidinimine
5aa with 54 % yield (53 mg, yellow solid).
Scheme 3. Ynamides: Inherent Polarization vs Acid and Base Activations
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Acknowledgements
The authors thank CNRS, ICSN, Labex Lermit (ANR grant ANR-
10-LABX-33 under the program Investissements d’Avenir ANR-
11-IDEX-0003-01) and FCS Campus Saclay for financial support.
E. R., C. M. and S. V thank Labex Lermit and M. B. thanks FCS
Campus Saclay for fellowships.
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K. C. and R. H. D. designed and supervised the experiments and
wrote the manuscript, C. M.† and S. V.‡ optimized the reaction
conditions and initiated the scope study, E. R.† and M. B.‡
expanded the scope and performed the functionalization of the
compounds. P. R. performed the X-ray crystallography
experiments. † These authors contributed equally. ‡ These
authors contributed equally. The authors declare no competing
financial interests.
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Keywords: ynamides • ketenimines • [2+2] cycloaddition •
azetidinimines • Staudinger synthesis
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[11] See Supporting Information for details.
[12] CCDC 1546588–1546592 (5aa, 5ba, 5ai, 5fa, 6 respectively) contain the
crystallographic data for this paper.
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
Dr E. Romero, Dr C. Minard, Dr M.
Benchekroun, Dr S. Ventre, Dr P.
Retailleau, Dr R. H. Dodd,* Dr K. Cariou*
Page No. – Page No.
Base-Mediated
Generation
of
Ketenimines from Ynamides: Direct
Access to Azetidinimines by an Imino
Staudinger Synthesis
Base Jump: Under strong basic conditions ynamides gave highly reactive
ketenimines which could be trapped with imines in a [2+2] cycloaddition. This imino
Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely
azetidinimines (20 examples), that could be further functionalized through a broad
range of transformations.
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