Base-Mediated Generation of Ketenimines from Ynamides: [3+2] Annulation with Azaallyl Anions

Article abstract of DOI:10.1002/adsc.202100047

Under basic conditions and heat, ynamides can serve as precursors to ketenimines, whose synthetic potential is often hampered by their difficulty of access. Herein, we report that they can undergo a [3+2] cycloaddition with 2-azaallyl anions, obtained from benzylimines under the same reaction conditions. This reaction between two highly reactive intermediates, both generated in situ from bench stable starting materials, gives access to various nitrogen-rich heterocycles. The reaction usually proceeds with excellent diastereoselectivity, in favor of the cis adduct. Deuteration experiments and DFT calculations helped rationalize the regio- and stereoselectivity of the process as well as the formation of side products. (Figure presented.).

Full text of DOI:10.1002/adsc.202100047

UPDATES
DOI: 10.1002/adsc.202100047
Base-Mediated Generation of Ketenimines from Ynamides:
[3+2] Annulation with Azaallyl Anions
Agathe C. A. D’Hollander,a Eugénie Romero,a Kamsana Vijayakumar,a
Camille Le Houérou,a Pascal Retailleau,a Robert H. Dodd,a Bogdan I. Iorga,a and
Kevin Carioua, b,*
a
Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, LabEx LERMIT, UPR 2301, 91198, Gif-sur-
Yvette, France
b
Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic
Chemical Biology, 75005 Paris, France
E-mail: kevin.cariou@cnrs.fr
Manuscript received: January 13, 2021; Revised manuscript received: March 15, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100047
by a [2+2] cycloaddition between a ketene and an
Abstract: Under basic conditions and heat, yna-
imine.[1] This reaction, named the Staudinger synthesis,
mides can serve as precursors to ketenimines, whose
set the template for accessing this particular hetero-
synthetic potential is often hampered by their
cycle and inspired a myriad of synthetic variations.[2]
difficulty of access. Herein, we report that they can
undergo a [3+2] cycloaddition with 2-azaallyl
anions, obtained from benzylimines under the same
reaction conditions. This reaction between two
highly reactive intermediates, both generated in situ
from bench stable starting materials, gives access to
various nitrogen-rich heterocycles. The reaction
Our group developed an imino-variant of this trans-
formation by using an ynamide[3–10] (1a) to generate
in situ[11,12] a highly reactive ketenimine (2a)[13–15]
which can engage in a [2+2] cycloaddition with a
diaryl imine (3a) to give an azetidinimine
(Scheme 1a).[16,17] Exploring this transformation fur-
ther, we found that when the same reaction conditions
usually proceeds with excellent diastereoselectivity,
were applied to the homologous benzylimine 3b, the
in favor of the cis adduct. Deuteration experiments
formation of the expected azetidinimine was not
and DFT calculations helped rationalize the regio-
observed.
and stereoselectivity of the process as well as the
formation of side products.
Instead, 2,5-dihydro-1H-imidazole[18] 6ab was ob-
tained with a 39% yield (Scheme 1b). We hypothesized
that this 5-membered ring arose from a [3+2] cyclo-
addition between the ketenimine and the semi-stabi-
Keywords: Ynamides; azaallyl anion; ketenimines;
cycloaddition
lized 2-azaallyl lithium 5b, which was also formed
in situ under the basic reaction conditions.[19,20] Overall,
reports of 1,3-dipolar cycloaddition with a ketenimine
as the dipolarophile remain rather scarce.[21–25] More-
Long before the discovery of penicillin, Staudinger over, [3+2] cycloadditions with non- or semi-stabi-
devised a straightforward access to the β-lactam ring lized azaallyl anions[26,27] were mostly developed with
Scheme 1. [2+2] and [3+2] annulations involving ketenimines and imines.
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olefins as dipolarophiles.[28–30] This serendipitous dis- base to compensate for the induced hydrolysis (en-
°
covery thus gave us the opportunity to explore some try 10). Lowering the temperature to 80 C did not
unprecedented annulation reactions towards nitrogen- overly affect the yield (entry 11). Finally, to reduce the
rich heterocycles. To optimize this transformation we formation of 8ac, the ynamide to imine ratio was
decided to react ynamide 1a with imine 3c bearing diminished (entry 12 and 13) and better and more
two p-chlorophenyl moieties, which would lead to a consistent results were obtained with a larger excess of
symmetrical 2-azaallyl anion (Table 1). Using micro- base (4.4 equivalents, entry 13). These conditions gave
°
wave heating at 100 C for 1 h in DMF (0.5 M) with the desired adduct 6ac in 66% yield, mostly avoiding
2.0 equivalents of t-BuOLi gave a mixture of 2,5- the formation of side products 7ac and 8ac, and were
dihydro-1H-imidazole 6ac (23%), imidazole 7ac selected to explore the scope of this [3+2] annulation.
(16%) and 4,5-dihydro-1H-imidazole 8ac (12%) that
First, benzylic aldimines 3 leading to symmetrical
incorporates two ketenimine fragments (entry 1). To azaallyl anions 5 having various substituents – H (3d),
minimize the formation of the oxidized derivative 7ac, halogens (3e,f,h), MeO (3g) and electron-withdrawing
a thorough bubbling of argon in the reaction mixture groups (3i,j) on the para positions – were screened.
was performed. When the concentration was decreased 1,5-Dihydro-1H-imidazoles 6 were obtained in moder-
from 0.5 M to 0.2 M, a mixture was still obtained but ate to good yields with good to excellent diastereose-
the overall yield improved by 13% (entry 2). Other lectivities in favor of the cis-isomer (Scheme 2a), as
solvents were tested (see Supplementary Information confirmed by single-crystal X-ray diffraction analysis
for fully detailed optimization) but were found to be for 6ag (Scheme 2b). The reaction was not operative
totally ineffective (THF, entry 3) or did not bring any for imines bearing strong electron-withdrawing groups
improvement (DMA, entry 4). The presence of the such as CF3 or NO2 (3i,j), and the low solubility of
base was found to be essential (entry 5) but alternative diiodo imine 3h was detrimental to the reaction’s
inorganic (Cs2CO3, entry 6) or organic (DBU, entry 7) success. Nevertheless, imines bearing heterocycles
bases did not promote the reaction. Various Lewis such as 2-furanyl (3k), 2-thiophenyl (3l) or 2-
acid-type additives were screened (entries 8–10), Zn- pyridinyl (3m) were well tolerated. Finally, the 1,1-
(II) salts giving the best results (entries 8 and 10). The diphenyl-ketimine 3n was also subjected to the
hygroscopic nature of these salts (in particular zinc reaction conditions, forming 6an as a single re-
triflate) led us to increase the number of equivalents of gioisomer in 72% yield. This is in sharp contrast to the
Table 1. Optimization of the reaction conditions.[a]
Entry
equiv. 1a/
equiv. 3c
Base (equiv.)
Additive[c]
Solvent
(0.2 M)
Temp.
Yield 6ac
Yield 7ac
Yield 8ac
(%)[b]
(%)[b]
(%)[b]
DMF[d]
DMF
THF
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100 C
23 (�3)
45 (�2)
0
16 (�1)
7 (�2)
0
12 (�1)
12 (�1)
0
°
1
2
3
4
5
6
7
8
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
1.5/1.0
1.5/1.0
t-BuOLi (2.0)
t-BuOLi (2.0)
t-BuOLi (2.0)
t-BuOLi (2.0)
none
none
none
none
none
none
none
none
Zn(OAc)2 2H2O
Cu(OAc)2
Zn(OTf)2
°
100 C
°
100 C
°
100 C
16 (�3)
15 (�3)
25 (�3)
°
100 C
0
0
0
0
0
0
0
0
0
°
Cs2CO3 (2.0)
DBU (2.0)
100 C
°
100 C
*
°
t-BuOLi (2.75)
t-BuOLi (2.75)
t-BuOLi (3.3)
t-BuOLi (2.75)
t-BuOLi (2.75)
t-BuOLi (4.4)
100 C
61 (�3)
55 (�1)
63 (�4)
60 (�4)
50
8 (�1)
6 (�1)
8 (�1)
7 (�2)
Traces
Traces
7 (�1)
2 (�2)
8 (�2)
7 (�2)
Traces
Traces
°
9
100 C
°
10
11
12
13
100 C
*
°
Zn(OAc)2 2H2O
Zn(OAc)2 2H2O
Zn(OAc)2 2H2O
80 C
*
°
80 C
*
°
80 C
66 (�1)
[a] All reactions were carried out with 0.20 mmol of 3c, argon was bubbled in the reaction mixture before the addition of the base and
the reaction was performed in a microwave apparatus;
[b] isolated yields, average of two reactions;
[c] 10 mol%;
[d] Reaction run at 0.5 M concentration.
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Scheme 2. Scope of the [3+2] annulation.
reactivity of aldimines bearing two different aryl in Scheme 5c) to give a vinylated 1,5-dihydro-1H-
groups, such as 3b (see Scheme 1), that leads to imidazole, followed by the isomerization of the double
inseparable mixtures of regioisomers. The scope of the bond. For its part, the homologated substrate led to
ynamide partner was then delineated (Scheme 2c). As 6mc with 43% yield. It was also possible to further
with the imino-Staudinger [2+2] cycloaddition,[16] functionalize several adducts (Scheme 3).
only ynamides bearing an aryl group on the nitrogen
For example the p-anisyl derivative cis-6ec could
were suitable for the generation of the ketenimine efficiently be transformed into the corresponding
intermediate and Boc was the best leaving group. N- phenol cis-6nc by treatment with boron tribromide in
Aryl ynamides bearing halogens (Cl and Br, 1b,c), 79% yield and desilylation of cis-6mc using TBAF led
electron-donating (OMe and OEt, 1e,f) or electron to cis-6oc in 78% yield. In both cases, the heterocycle
withdrawing (CF3, 1g) groups gave 1,5-dihydro-1H- was untouched and no isomerization occurred.
imidazoles 6 as the major adducts, generally along
with minor amounts of double addition compound 8.
The difficulty of purification of the p-iodo compound
was responsible for the low yield of 6dc, while the p-
nitro functionality (1h) was incompatible with the
reaction conditions.
The reaction was also successful if the triple bond
was substituted by an alkyl (n-Bu, 6ic), an aryl (Ph,
6jc) or a silyl (TIPS, 6kc), albeit with a low 18% yield
in this case. When an ynamide bearing a silyl-protected
hydroxymethyl group on the triple bond (1l) was
submitted to the reaction conditions, imidazole 9 was
isolated instead of the expected 6lc. The former would
not originate from an oxidation process as for
imidazole 8. Instead, it would more likely result from a
[3+2] annulation with a cumulenimine (see below 2 l’
Scheme 3. Functionalization of the [3+2] adducts.
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In order to gain more insight on the [3+2] addition adduct (8ac, 11%) were also obtained.
annulation process and the formation of side products Interestingly, 8ac did not give back 6ac when it was
7 and 8, we performed several control experiments. subjected to the same reaction conditions (minus the
First, deuterated ynamide 1a-D was synthesized and ynamide). Finally, heating a DMF solution of 6ac at
°
reacted with imine 3c. As could be expected, when the 80 C for 1 h after bubbling air for 10 min only
hydrated zinc salt additive was included, no deutera- marginally led to the formation of 7ac (<5%).
tion was observed. In the absence of the additive,
Considering all these results, a plausible mechanis-
however, all adducts 6ac, 7ac and 8ac were isolated tic proposal was outlined and validated using DFT
as mixtures of non- and mono-deuterated compounds calculations (Scheme 5a). Under the strongly basic
(Scheme 4a), predominantly corresponding to the ini- conditions, and possibly with the assistance of the zinc
tial ynamide deuterium position (C1 as well as C4 for Lewis acid,[31] partial decomposition of the DMF to
8ac). For 6ac–D, other deuterium incorporation sites give lithium dimethylamide would be the trigger to
were identified at the C2 and C3 positions of the five- initiate the cleavage of the Boc protecting group of
membered ring. A complementary experiment was ynamide 1 giving semi-stabilized amide 10 that
performed by reacting ynamide 1a with the bis- protonates to give ketenimine 2. The generation of
deuterated imine 3c–D2 (Scheme 4b). In this setting, dimethylamine in the reaction mixture was confirmed
the adducts were obtained as non-, mono- and di- by the isolation of amidines 15, 15-D6 (when DMF-D7
deuterated compounds, again with several deuterium was used) and 16 (Scheme 5b). These would result
incorporation sites at C1, C2, C3 and/or C4, including from the addition of a lithium amide on ketenimine 2a
a double deuteration at C4 for 8ac–D2. This broad and, in the latter case, on cumulenimine 2 l’. This
distribution pattern seems to indicate that many proton cumulenimine would come from amide 10l, instead of
exchange steps take place during the formation of the giving birth to the expected ketenimine 2l (Sche-
five-membered adducts. However, no deuteration was me 5c). Thus, its reaction with imine 3c would give a
observed when the reaction was performed in deuter- vinyl-1,5-dihydro-1H-imidazole, and eventually ethyl-
ated DMF.
imidazole 9 after isomerization (Scheme 2c). Deproto-
To ascertain whether some elemental steps in our nation of the imine 3 would give the semi-stabilized
manifold are reversible, we resubmitted cis-6ac to the diaryl azaallyl anion 5 that can add onto the ketenimine
reaction conditions with 1.5 equivalents of 1a (Sche- to give enamide 11, followed by cyclization to yield
me 4c). While cis-6ac was mostly recovered (67% imidazolidine 12. Overall, this process is nearly energy
yield), the trans isomer (trans-6ac, 9%), the imidazole neutral (ΔG=1.6 kcal.molÀ 1), the first step being
resulting from an oxidation (7ac, 7%) and the double exergonic by 14.8 kcal.molÀ 1, with a rather low
Scheme 4. Control experiments.
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Scheme 5. Proposed mechanism.
activation barrier (3.1 kcal.molÀ 1) (Figure S1). From
To conclude, we have been able to develop a novel
this intermediate, successive protonations and deproto- [3+2] annulation between ketenimines and azaallyl
nations as well as tautomerization of the enamide and/ anions (both generated in situ from ynamides and
or imine moieties can take place explaining the benzylarylimines, respectively) to access five-mem-
complex deuteration patterns that we observed (Sche- bered heterocycles.
me 4a and 4b). These experiments also indicate that
The reaction mechanism was elucidated by using a
the imine is the major purveyor of protons and that the combination of control experiments and DFT calcula-
ynamide only contributes to a lesser extent, the protons tions, which seem to exclude a concerted process.
being channeled either by direct deprotonation or Taken together, our results open new synthetic oppor-
through the tert-butanol generated from an initial tunities towards nitrogen-containing heterocycles. Pre-
deprotonation with lithium tert-butoxide. By modelling liminary evaluation of these compounds as β-lactamase
the various anions resulting from these events (Fig- inhibitors has been initiated with promising results[32]
ure S2) we were able to identify azaallyl anion 13 as and a more thorough study of the therapeutic potential
being the most favored at À 28.1 kcal.molÀ 1. A final of theses heterocycles is currently underway in our
reversible (as evidenced by the experiment in Sche- laboratory.
me 4c) protonation would give 6. Alternatively, its
reaction with another equivalent of ketenimine would
lead to 8. Calculations indicated that addition at the
Experimental Section
benzylamine position, rather than the aminal position, General Procedure for the [3+2]-Cycloaddition
of 13 to give anion 14 thus leading to the observed
To an oven-dried microwave vessel under argon was added
Zn(OAc)2 2H2O (10 mol%), the ynamide (1.5 equiv.), the imine
(1.0 equiv., 0.20 mmol) and anhydrous DMF (0.2 M). The
*
regioisomer 8, was indeed favored thermodynamically
by 5.6 kcal.molÀ 1 (Figure S3). Although the stereo-
chemistry of 8 could not be unambiguously ascer-
tained, the cis stereoisomer would be obtained as the
activation barrier would only be 3.2 kcal.molÀ 1 vs.
reaction mixture was stirred with argon bubbling for 5–10 min
before t-BuOLi (2.2 M in THF, 4.4 equiv.) was added.1 The
vessel was sealed, vortexed and placed in a Microwave
°
8.4 kcal.molÀ 1 for the trans isomer (Figure S3). More- apparatus for 1 h at 80 C. The reaction mixture was then
1
concentrated in vacuo. H NMR analysis of the crude reaction
over, in the presence of oxygen in the reaction
medium, 13 could be oxidized to 7, presumably
through an intermediate peroxide anion that would
readily aromatize.
1
During the addition of the base a deep dark color develops, if
this color fades an excess base should be added until the color
stays.
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mixture was performed to measure the diastereomeric ratio
before subjecting the crude product to purification by flash
chromatography.
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For full experimental data, see Supporting Information, contain-
ing:
Experimental procedures, characterization data, computed en-
ergies and Cartesian coordinates of all the DFT-optimized
structures, and NMR spectra for all products (PDF)
CCDC-2032327 (6ag) and CCDC-2032328 (7ac) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
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This work was supported by the Laboratory of Excellence in
Research on Medication and Innovative Therapeutics (LERMIT,
grant ANR-10-LABX-33 under the program Investissements
d’Avenir ANR-11-IDEX-0003-01) and the SATT Paris-Saclay
(project CARBAMAT). The authors also thank CNRS, Uni-
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Base-Mediated Generation of Ketenimines from Ynamides:
[3+2] Annulation with Azaallyl Anions
Adv. Synth. Catal. 2021, 363, 1–7
Dr. A. C. A. D’Hollander, Dr. E. Romero, K. Vijayakumar, C.
Le Houérou, Dr. P. Retailleau, Dr. R. H. Dodd, Dr. B. I. Iorga,
Dr. K. Cariou*