Carbamoyl Anion Addition to Azirines

Article abstract of DOI:10.1021/acs.orglett.1c01334

The addition of carbamoyl anions to azirines affords synthetically useful 2-aziridinyl amide building blocks. The reaction scope was explored with respect to both formamide and azirine, and the addition was found to be highly diastereoselective. A one-pot conversion of a ketoxime to an aziridinyl amide was demonstrated. The method was employed to incorporate an aziridine residue into a dipeptide segment.

Full text of DOI:10.1021/acs.orglett.1c01334

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Letter
Carbamoyl Anion Addition to Azirines
Michael J. Kerner, Christian A. Kuttruff, Maxim Chevliakov, Frederic G. Buono, Donghong A. Gao,
Mariusz Krawiec, Carl A. Busacca, Chris H. Senanayake, Peter Wipf, and Jonathan T. Reeves*
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ABSTRACT: The addition of carbamoyl anions to azirines affords
synthetically useful 2-aziridinyl amide building blocks. The reaction
scope was explored with respect to both formamide and azirine, and the
addition was found to be highly diastereoselective. A one-pot conversion
of a ketoxime to an aziridinyl amide was demonstrated. The method was
employed to incorporate an aziridine residue into a dipeptide segment.
mong the carbonyl anions, carbamoyl anions have
demonstrated considerable practical utility due to their
relatively high stability and ease of generation from readily
A
available N,N-disubstituted formamides and strong bases such
1
as LDA or t-BuLi. Since the first report of these anions by
Schollkopf in 1967, they have been added to electrophiles
̈
including aldehydes, ketones, esters, alkyl halides, Bu SnCl,
3
2
and trialkylsilyl chlorides. Enders subsequently reported the
addition of chiral prolinol-derived carbamoyl anions to ketones
3
in diastereomeric excess of up to 30%. In 2013, we reported
the first reaction of carbamoyl anions with imine electrophiles,
using the diastereoselective addition to N-sulfinyl imines to
4
obtain α-amino amides (Figure 1A). Subsequently we
reported the addition of these anions to nitrones to provide
5
α-(N-hydroxy)amino amides (Figure 1B). Li and co-workers
further extended the reactivity of carbamoyl anions to a
diastereoselective reaction with chiral N-phosphinyl aldimines
6
(
Figure 1C). The addition of nucleophiles to the CN
double bond of azirines serves as a convenient entry to C-
substituted N−H aziridines. A plethora of nucleophiles have
been reported to add to azirines, including organolithiums,
Grignard reagents, N−H compounds,
thiols, TMSCF3, TMSCN,
7
8
9
9c,10
11
phosphites,
1
2
13
13,14
15
Figure 1. Previously reported reactions of carbamoyl anions with N-
sulfinyl imines (A), nitrones (B), and N-phosphonyl imines (C), and
the extension to azirines (D) reported herein.
and hydride. Given this
excellent demonstrated reactivity of azirines, we reasoned that
carbamoyl anions should also add readily to the strained
heterocycles to provide 2-aziridinyl amides (Figure 1D).
Aziridines are present in natural products and pharmaceuticals,
previously reported that addition of LDA to a solution of an N-
sulfinyl imine and an N,N-disubstituted formamide proved
16
and can serve as useful precursors to diverse functionalities.
Aziridinyl carboxylates and their derivatives are valuable
4
optimal. This protocol minimizes carbamoyl anion decom-
17
position since the electrophile is present in the reaction
mixture and able to immediately react with the anion. We
precursors to unnatural amino acids. When incorporated
into peptides, they provide a convenient handle for site-
18
selective ligation with thiol containing molecules. Thus, new
routes to these valuable building blocks are desirable. Herein,
we report the scope of the addition of carbamoyl anions to
azirines and its application to the synthesis of an aziridinyl
peptide.
Received: April 18, 2021
Published: May 14, 2021
Initial feasibility studies were performed using 2,3-diphenyl-
H-azirine 1 and N,N-diisopropylformamide (Scheme 1). We
2
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01334
4
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Scheme 1. Reaction Optimization of Addition to 2H-Azirine
Table 1. Formamide Scope in the Reaction with Azirine 1
1
reasoned that potential competitive deprotonation of the
azirine 1 by LDA should be disfavored since the resulting
19
anion would be antiaromatic. Thus, addition of LDA (2.0
equiv) to a cold (−78 °C) THF solution of 1 and N,N-
diisopropylformamide (2.1 equiv) gave full conversion to
1
adduct 2 after 10 min. H NMR analysis of the crude product
after workup showed the presence of a single diastereomer,
with the expected trans relationship of the carboxamide and
adjacent phenyl group. The aziridinyl amide 2 was isolated in
9
3% yield after chromatographic purification.
With the reaction conditions defined, the scope of the
addition with respect to formamides was explored (Table 1).
The reaction worked well for sterically demanding (entries 1
and 2) as well as smaller (entries 3 and 4) N,N-
dialkylformamides. The addition of a thioformamide was
possible (entry 5). For generation of small carbamoyl and
thiocarbamoyl anions (entries 4 and 5) as well as N-aryl
carbamoyl anions (entry 6), the bulkier base LiTMP was
employed instead of LDA to avoid transformylation from the
5
formamides to LDA. Cyclic formamides were compatible with
the reaction conditions (entries 7 and 8). Finally, the use of
formamides bearing silyl ether (entry 9) or aminal (entry 10)
moieties was feasible.
The reaction scope for a set of structurally diverse azirines
was examined next (Table 2). The incorporation of a pyridyl
group into the azirine was tolerated (entry 1), and the
corresponding aziridine 13 was obtained in good yield. Vinyl
azirine 14 reacted smoothly, providing the adduct 15 in high
yield (entry 2). Notably, vinyl aziridines have been
demonstrated to be versatile substrates for derivatization to a
wide array of acyclic and heterocyclic compounds. Azirines
possessing geminal disubstitution on the 3-carbon were also
compatible and gave tetrasubstituted aziridine products in
good yields (entries 3−5). The azirines bearing gem-
disubstitution in the form of a spirocycle, as in entries 4 and
20
a
Typical reaction conditions: 1 (1.0 equiv), formamide (2.1 equiv),
b
THF, −78 °C; add LDA solution (2.0 equiv, 2.0 M). The
1
diastereoselectivity as measured by H NMR of the crude product
c
was >97:3 in all cases. Lithium 2,2,6,6-tetramethylpiperidide (3.0
equiv) and formamide (3.1 equiv) used for these examples.
5
, furnished novel spirocyclic aziridinyl amides. Notably, the
highly strained spirocyclopropane in azirine 18 remained intact
and the azaspirocyclopentane 19 was obtained in good yield
lower stability can make their isolation and purification
challenging. Furthermore, these compounds are generally
prepared by thermal or photochemical decomposition of
(
entry 4). Azirines bearing alkyl groups at the 2-position were
amenable to the reaction (entries 6−8), although in these cases
the carbamoyl anion was generated prior to introduction of the
azirine. This protocol, which we originally employed for
additions of carbamoyl anions to enolizable N-sulfinyl imines,
avoided side reactions due to deprotonation of the α-protons
of the alkyl group by LDA. The cyclooctane fused azirine 26
reacted smoothly to give the bicyclic aziridine product 27 in
high yield (entry 8). Finally, the incorporation of a
trifluoromethyl group in azirine 28 provided the corresponding
aziridine 29 in good yield (entry 9).
22
high energy vinyl azides. To avoid the safety concerns of
vinyl azides and to bypass isolation, we developed an in situ O-
tosylation, Neber-type azirine formation, and subsequent
carbamoyl anion addition, all in the same pot (Scheme 2).
Treatment of acetophenone oxime 30 with NaH followed by
TsCl resulted in formation of O-tosyl oxime 31. Addition of
N,N-diisopropylformamide followed by LDA to the reaction
mixture at −78 °C provided the aziridine 33 in 54% isolated
yield. The reaction presumably occurs via deprotonation of the
4
21
23
Azirines lacking substituents in the 2-position are generally
O-tosyl oxime 31 and subsequent cyclization to azirine 32,
7
less stable than their more substituted counterparts. This
which reacted with the concurrently generated carbamoyl-
4
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Letter
Table 2. Scope of Azirine in Carbamoyl Anion Addition
the formation of azirine 32 and the need to isolate and purify
an unstable azirine.
The methodology was applied to the synthesis of an
24
aziridinyl peptide (Scheme 3). We previously reported the
Scheme 3. Synthesis of a Peptidyl Aziridine
synthesis of formamide 34 by the addition of N,N-diisopropyl
carbamoyllithium to an N-sulfinyl imine, and subsequent
4
sulfinyl deprotection, N-formylation, and N-methylation.
Treatment of 34 with LDA in the presence of enantiopure
25
azirine S-1 resulted in the formation of the aziridinyl peptide
5 with >97:3 diastereoselectivity and a 69% yield after
3
isolation by crystallization. Acylation of 35 with 4-bromoben-
zoyl chloride gave the dipeptidyl aziridine 36 in 82% yield.
Single crystal X-ray structure analysis confirmed the stereo-
chemistry at the newly formed quaternary aziridine carbon.
In summary, azirines have been shown to be competent
electrophiles for the addition of carbamoyl anions. The
reaction is amenable to a wide variety of formamides as well
as significant structural diversity of the azirine. The product
aziridines are formed with high trans diastereoselectivity from
2
,3-disubstituted azirines. A one-pot conversion of a ketoxime
to a 2,2-disubstituted aziridinyl amide was demonstrated. The
reaction could be employed for the synthesis of an aziridine
containing peptide.
a
Typical reaction conditions: azirine (1.0 equiv), formamide (2.1
b
equiv), THF, −78 °C; add LDA solution (2.0 equiv, 2.0 M). The
ASSOCIATED CONTENT
sı Supporting Information
1
■
diastereoselectivity for entries 1−2 and 6−9 as measured by H NMR
c
*
of the crude product was >97:3 in all cases. The carbamoyl anion was
generated first and the azirine added immediately thereafter.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01334.
Scheme 2. One-Pot Azirine Formation/Carbamoyl Anion
Addition
Experimental procedures, spectroscopic data, and NMR
spectra (PDF)
Accession Codes
CCDC 2077072 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Jonathan T. Reeves − Chemical Development, Boehringer
Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
06877, United States; orcid.org/0000-0002-3051-3304;
Email: jonathan.reeves@boehringer-ingelheim.com
lithium reagent to give the aziridine 33. This one-pot process
conveniently avoids potentially dangerous azide chemistry for
4
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Authors
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Mr. Scott Pennino (Material and Analytical
Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridge-
field, Connecticut 06877, United States) for HRMS analysis.
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