Synthesis of γ-Lactams by Formal Cycloadditions with Ketenes

Article abstract of DOI:10.1021/acs.orglett.1c00335

The synthesis of γ-lactams is reported by a formal (3+2) cycloaddition between readily available ketenes and aziridines or a one-pot formal (2+1+2) cycloaddition using imines as aziridine precursors. The method is practical, is scalable, and affords high yields. It also offers a high level of regio- and diastereoselectivity on a wide range of substrates as well as a high stereoselectivity in the case of enantiopure aziridines.

Full text of DOI:10.1021/acs.orglett.1c00335

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Letter
Synthesis of γ‑Lactams by Formal Cycloadditions with Ketenes
Audrey Viceriat, Isabelle Marchand, Sébastien Carret,* and Jean-Franco̧ is Poisson*
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ABSTRACT: The synthesis of γ-lactams is reported by a formal (3+2) cycloaddition between readily available ketenes and
aziridines or a one-pot formal (2+1+2) cycloaddition using imines as aziridine precursors. The method is practical, is scalable, and
affords high yields. It also offers a high level of regio- and diastereoselectivity on a wide range of substrates as well as a high
stereoselectivity in the case of enantiopure aziridines.
Scheme 1. Ketene Cycloadditions in the Synthesis of γ-
Lactams
etenes have been extensively used in thermal [2+2]
cycloadditions to afford a unique entry to four-membered
K
ring scaffolds.1 Their original heterocumulenic structure allows
normally forbidden [2+2] thermal cycloadditions.2 The reaction
of ketenes with imines and aldehydes offers particularly
straightforward access to β-lactams and β-lactones, respectively.
The thermal [2+2] cycloaddition of ketenes with alkenes has
also led to a wide diversity of functionalized cyclobutanones
through a highly diastereoselective process with electron rich
chiral enol ethers.3 Due to their high ring strain, cyclobutanones
can in turn undergo ring expansion to diversely substituted five-
membered carbo- and heterocycles such as cyclopentanones
(with diazoalkanes), γ-lactams (through a Beckmann trans-
position), and γ-lactones (via a Baeyer−Villiger oxidation).4 In
the past several decades, our group has been involved in the
synthesis of a variety of γ-butyrolactams using the ketene [2+2]
cycloaddition and ring expansion strategy in the context of the
total synthesis of natural products (Scheme 1a).5 During these
syntheses, we often faced difficulties at the ring expansion step,
particularly with the Beckmann transposition: yields and
selectivities were highly sterically and electronically dependent.
In fact, the normal Beckmann reaction is well-known to be often
hampered by the formation of appreciable amounts of abnormal
Beckmann nitrile derivatives.6 We wondered whether a
cycloaddition between a ketene and a suitable 1,3-dipole
would be possible as it would allow direct access to the
corresponding γ-lactams and thus offer an effective alternative
preparation of these particularly useful pyrrolidine scaffolds.7
Compared to other reactions involving ketenes, only a few
examples of (3+2) cycloadditions have been reported so far,
most often involving nonclassical dipoles.8 To the best of our
knowledge, the only example in the literature that involves an
aziridine is a genuine Huisgen type 1,3-dipolar cycloaddition
giving a mixture of cycloadducts.9 In this study, the 1,3-dipole is
generated by the thermal C−C bond cleavage of an aziridine and
reacted with a ketene to afford a mixture of two cycloaddition
products, namely, the 2-oxopyrrolidine from cycloaddition on
the CC bond of the ketene and an oxazolidine from
cycloaddition on the CO bond. Even though aziridines are
known to react as 1,3-heterodipoles through C−N bond
cleavage, a (3+2) cycloaddition of aziridines with ketenes
through this mode of cleavage has not yet been reported
Received: January 28, 2021
Published: March 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00335
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2449−2454
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(Scheme 1b). The main challenges associated with this reaction
are the selectivity between the two cleavable C−N bonds and
the site selectivity of the addition to the ketene (CC vs C
O).
The investigation started with N-tosyl-2-phenylaziridine 2a
and diphenyl ketene, both readily available.10 The strong
electrophilicity of ketenes prompted us to directly test its ability
to act as the activating agent of the aziridine: mixing aziridine 2a
with diphenyl ketene, however, did not lead to lactam 3a, the
aziridine being quantitatively recovered (Table 1, entry 1). The
enhance the yield of lactam, 76% with 20 mol % lithium iodide
and 45% with 10 mol % [reaction lasting 18 h instead of 2 h
(Table 1, entries 6 and 7)]. Different solvents such as diethyl
ether, dichloromethane, and toluene were also evaluated: minor
variations were observed, tetrahydrofuran and diethyl ether
being the best solvents, for both the yield and the selectivity.10
Ultimately, the best conditions were obtained when the reaction
was performed in tetrahydrofuran at room temperature using 0.8
equiv of lithium iodide, with slow addition of the ketene over 1 h
[83% isolated yield (Table 1, entry 8)].
As N-tosylaziridines are concomitantly generated with lithium
iodide by reacting an N-tosylimine with iodomethyllithium,15
a
Table 1. Influence of Additives on the Formal (3+2)
Cycloaddition
a
one-pot (2+1+2) reaction was an interesting alternative that
would allow the formation of a lactam directly from the
corresponding imines. This would not only provide a more
straightforward route to γ-lactams but also eliminate the
requirement to isolate the sometimes sensitive and potentially
toxic aziridines. To our delight, the addition of methyllithium to
a solution of diiodomethane and N-tosylimine 1a at −78 °C,
followed by a subsequent slow addition of 2 equiv of diphenyl
ketene at room temperature, afforded γ-lactam 3a in 88% yield,
which compared favorably with the 66% combined yield
obtained through the stepwise procedure (Scheme 2).
With these optimal conditions in hand for both the one-pot
(2+1+2) and the stepwise (3+2) formal cycloadditions, the
scope of the reaction was next explored. Interestingly, the two
methods appeared to be very complementary, the one-pot
(2+1+2) cycloaddition conditions being very effective from N-
tosylimines and the (3+2) conditions being essential when
alternative strategies are used to obtain the aziridines (Scheme
2).
The p-fluorophenyl- and p-bromophenyl-substituted azir-
idines 2b and 2c afforded lactams 3b and 3c, respectively, in very
good yields, with equal efficiency for the one-pot and stepwise
processes (Scheme 2). The next example was particularly
striking as it also highlighted the advantage of the one-pot
procedure over the stepwise protocol. Indeed, whereas p-
methoxyphenyl lactam 3d could be isolated in 75% in the one-
pot process, the two-step sequence was unfruitful due to the
inherent instability of aziridine 2d, which could not be isolated
in >25% yield. Another feature of the formal cycloaddition is the
rather limited electronic influence of the substituents at the
aromatic para position on the efficiency of the cycloaddition:
both electron-donating and electron-withdrawing groups
leading to high yields. The p-nitrophenyl group, however, led
to a significant decrease in the yield of lactam 3e (47%). This low
yield of the one-pot process is essentially due to the rather
inefficient formation of aziridine 2e, isolated in only 57% yield
from p-nitro imine 1e, the subsequent (3+2) cycloaddition
being very effective affording lactam 3e in 94% yield. The m-
fluoro-, m-bromo-, and m-methoxy-substituted phenyl deriva-
tives (1f−h) afforded γ-lactams 3f−h, respectively, in yields
ranging from 71% to 87%, with again slightly better yields for the
one-pot procedure. The o-tolyl lactam 3i and 1-naphthyl lactam
3j were obtained with equal efficiency, showing the compati-
bility of the cycloaddition with slightly more sterically
demanding mono ortho-substituted aryl derivatives. Furyl-
derived lactam 3k, however, was isolated in only 15% yield in
the one-pot sequence. This poor yield is again due to the
inefficient formation and instability of aziridine 2k, which in this
case could not be isolated from imine 1k.
b
c
entry
additive
equiv
conversion (%)
3a:4a ratio
1
2
3
4
5
none
LiCl
LiBr
LiI
nBu4NI
LiI
−
1
1
1
0
0
−
−
75:25
>95:5
75:25
>95:5
>95:5
60
98
80
76
45
100
1
d
6
7
0.2
0.1
0.8
d
LiI
LiI
8
>95:5 (88%)
a
Reaction conditions: diphenyl ketene (2.0 equiv, slow addition of
ketene over 1 h), aziridine 2a (1.0 equiv, 0.2 M), additive, THF, rt, 2
b
h. NMR measurement, on the crude mixture, based on the
c
d
transformation of aziridine 2a. Isolated yield in parentheses. In
this cases, the second equivalent of ketene was added after reaction for
8 h; the total reaction time was 18 h.
Lewis acid activation of aziridines into 1,3-heterodipoles by
selective cleavage of the C−N bond is well documented.11 We
thus tested a wide variety of Lewis acids such as boron
trifluoride,11a scandium triflate,11b copper triflate,11c zinc
bromide,11d and nickel iodide,11e but in combination with
ketene, all failed to produce any detectable amounts of lactam,
affording only ketene dimers and aziridine ring-opened and
unidentified side products.10 The ring opening of the aziridine in
the presence of carbon dioxide has also been reported to be
triggered by first-row metal-halide.12 We thus decided to test
lithium halides as the co-activator, which turned out to be much
more rewarding. While the addition of lithium chloride left the
starting aziridine untouched (Table 1, entry 2), the use of
lithium bromide led, for the first time, to the formation of two
cycloaddition products: desired lactam 3a, resulting from the
ring opening at C-2, and oxazolidine 4a, resulting from the
opening of the aziridine at the less hindered C-3 (Table 1, entry
3).16 Eventually, lithium iodide rewardingly afforded γ-lactam 3a
with complete conversion of the aziridine and only traces of
oxazolidine 4a (Table 1, entry 4).14 Changing lithium to
tetrabutylammonium led to incomplete conversion, and less
repeatable reactions, producing the lactam and the oxazolidine
in a 75/25 ratio (Table 1, entry 5). A substoichiometric amount
of lithium iodide was also sufficient to effectively promote the
reaction (Table 1, entries 6 and 7). However, at 20 mol %, the
reaction became much slower, most probably favoring ketene
dimerization, thus decreasing the level of formation of the
lactam; introducing the ketene in two portions allowed to
To further test the scope of the reaction, non-aryl-substituted
aziridines were next engaged. Hence, cinnamyl lactam 3l was
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a
Scheme 2. Scope of the (2+1+2) and (3+2) Cycloaddition
a
Reaction conditions A for the (2+1+2) reaction: imine 1 (1 equiv, 0.2 M), CH2I2 (2 equiv), MeLi (2 equiv), THF, −78 °C for 1 h and then rt for
30 min, then ketene (2.0 equiv, added over 1 h), rt, 3 h. Reaction conditions B for the (3+2) reaction: ketene (2.0 equiv, added over 1 h), aziridine
2 (1.0 equiv, 0.2 M), LiI (0.8 equiv), THF, rt, 3 h. All reactions performed on a 0.2−0.3 mmol scale. See the experimental section in the Supporting
Information for full details. Yields are those of isolated products of the one-pot process; yields in parentheses, when present, refer to the combined
b
yields of the two-step procedure. Yields for the (3+2) cycloaddition step.
obtained through both the one-pot and stepwise processes from
cinnamyl imine 1l in 88% and 65% yields, respectively. Lactam
3m was obtained in 43% yield starting from isopropenyl
aziridine 2m.16 To further evaluate the scope of the reaction,
cyclohexyl-substituted imine 1n was engaged in the formal
cycloaddition and interestingly also proved to be compatible:
the corresponding lactam 3n was obtained in 68% yield. Finally,
we also evaluated the necessity of having an electron-
withdrawing group on the nitrogen atom by performing the
reaction with N-ethyl aziridine 2o. The latter, prepared from
dimethylsulfurane ylide and ethylamine,17 provided the
corresponding N-ethyl lactam 3o in a decent 60% yield, thus
showcasing the wide scope of the method.
addition conditions (Scheme 2). Interestingly, cycloheptyl
ketene led to the corresponding lactams with the same efficiency
as diphenyl ketene from imines 1a and 1c under the one-pot
conditions. With m-substituted aromatic imines 1h and 1f,
similar results were observed affording lactams 3r and 3s in 88%
and 81% yields, respectively. Lactam 3t, bearing an o-tolyl
substituent, was also efficiently formed (81% yield). The next
question to address was the potential control of the
diastereoselectivity using unsymmetrical ketenes. Interestingly,
ethyl phenyl ketene and imine 1a led to the corresponding
lactam 3u in 83% yield as a single diastereoisomer, hence with
full control of the quaternary stereogenic center. The same result
was obtained starting from p-fluorophenyl imine 1b and m-
bromophenyl imine 1g, which both afforded the corresponding
lactams 3v and 3w as single diastereoisomers. Finally, 1-
naphthyl-derived lactam 3x was also obtained with complete
After exploring various structural variations on both the
aziridine and the imine, we next focused on the ketene. Both the
cycloheptyl ketene18 and the ethyl phenyl ketene19 were
subjected to the optimized one-pot (2+1+2) formal cyclo-
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control of the diastereoselectivity. The cis orientation of the
phenyl groups in lactam 3u was determined by X-ray analysis.13
To further demonstrate the synthetic utility of the method,
the reaction was run on a gram scale with diphenyl ketene and
imine 2a: 1.5 g of lactam 3a was obtained in 83% yield,
comparable to the result obtained on a smaller scale [88% (see
Schemes 2 and 3a)].
Considering the observed selectivities and reactivity, in
combination with previous DFT studies of aziridine ring
opening,23 we can propose a mechanism for the formal
aziridine/ketene cycloaddition in the presence of lithium iodide.
No reaction occurs when the aziridine and lithium iodide are
mixed at room temperature, which is in agreement with the fast
formation of the aziridine from the imine and iodomethyl
lithium.15 An initial reversible complexation of the aziridine by
the ketene is necessary to weaken the C−N bond,24 followed by
an SN2-like ring opening of the aziridine at the most substituted
side of the aziridine25 by the iodide to produce an enolate type
intermediate that subsequently cyclizes (Scheme 4). The
Scheme 3. Additional Scope of the Ketene (3+2)
Cycloaddition
Scheme 4. Proposed Mechanism Involving Two SN2-like
Pathways
a
Under reaction conditions B with imine 1a (1.0 g, 3.9 mmol).
b
c
Using conditions B on a 0.2 mmol scale. Using conditions A on a
d
e
0.2 mmol scale. Yield of 3y and cis-2p (76:24). Yield of 3z and cis-
2p (65:32).
selective ring opening can be attributed to the stabilization of
a developing positive charge by a neighboring aryl and even
more strikingly alkyl substituent, even though in the latter case
the yield is slightly lower. The observed retention of the
configuration starting from the enantioenriched aziridine comes
from a double inversion. The formation of a single
diastereoisomer with unsymmetrical ketenes would come from
a geometrically defined enolate,19 followed by an intramolecular
SN2 cyclization minimizing gauche interactions (B being more
favorable than A) (Scheme 4). Finally, the apparent absence of
reactivity of cis-aziridine can be attributed to a more difficult
initial complexation of this cis isomer with ketene, due to
unfavorable steric interactions. Considering the different
conformers of the sp3-hybridized nitrogen on the aziridines,26
in conformer C, the ketene should approach through the most
hindered side (two steric interactions with methyl and phenyl),
whereas for D and E, a single unfavorable steric interaction
would be present.
In summary, we have developed an unprecedented direct
synthesis of γ-lactams starting from imines, through a formal
(2+1+2) cycloaddition process that involves iodoalkyllithium
species and isolable ketenes, and a (3+2) formal cycloaddition
starting from aziridines. These formal cycloadditions show a
great diversity, remarkable selectivities, and, notably, conserva-
tion of the chiral information with an enantioenriched aziridine.
Additional studies are ongoing to broaden the scope and add
further insights into the mechanism and observed diastereose-
lectivities of this unusual reaction.
Considering the diastereoselectivity obtained with unsym-
metrical ketenes, it was appealing to test the reaction with
unsymmetrical ketene and a 2,3-disubstituted aziridine. Upon
addition of iodoethyllithium to imine 1a, a cis/trans mixture of
N-tosyl-2-phenyl-3-methyl aziridine 2p was obtained (27:73,
cis/trans mixture).20 The latter was subsequently reacted with
diphenylketene to afford trisubstituted lactam 3y as a single trans
diastereoisomer, isolated as a mixture with unreacted cis-2p
[76%, 76:24 3y:cis-2p (Scheme 3b)]. Surprisingly, only the trans
aziridine reacted to form the corresponding lactam 3y. In fact,
pure cis-2p, prepared by nitrene aziridination of cis-β-
methylstyrene,21 did not lead to any detectable amount of
lactam. Even more striking was the result obtained with the
unsymmetrical ethyl phenyl ketene, which afforded 3,4,5-
substituted lactam 3z as a single diastereoisomer along with
unreacted aziridine cis-2p [57%, 65:35 3z/cis-2p (Scheme 3b)].
The relative stereochemistry of lactams 3y and 3z was assigned
by NOE experiments.
The final aspect that needed to be evaluated was the
stereospecificity of the (3+2) formal cycloaddition starting
from an enantioenriched aziridine. Aziridine (R)-2a was thus
synthesized from the corresponding enantiopure amino
alcohol11d and engaged with diphenyl ketene under the (3+2)
conditions. To our delight, the resulting lactam (S)-3a was
obtained with an only slight erosion of enantiopurity (Scheme
3c).22
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2] Cycloaddition Reactions? J. Phys. Chem. A 2014, 118, 4288−4300.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00335.
■
̀
(e) Rulliere, P.; Carret, S.; Milet, A.; Poisson, J.-F. Kinetic Resolution in
sı
the [2 + 2] Cycloaddition of Ketenes: An Experimental and Theoretical
Study. Chem. - Eur. J. 2015, 21, 3876−3881.
(3) (a) Darses, B.; Greene, A. E.; Coote, S. C.; Poisson, J.-F. Expedient
Approach to Chiral Cyclobutanones: Asymmetric Synthesis of
Cyclobut-G. Org. Lett. 2008, 10, 821−824. (b) Darses, B.; Greene, A.
E.; Poisson, J.-F. Asymmetric Synthesis of Functionalized, Monocyclic
Chlorocyclobutenes. Org. Lett. 2010, 12, 3994−3997. (c) Darses, B.;
Greene, A. E.; Poisson, J.-F. Asymmetric Synthesis of Cyclobutanones:
Synthesis of Cyclobut-G. J. Org. Chem. 2012, 77, 1710−1721.
Full experimental details, compound characterization, and
1H and 13C NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 1998270−1998271 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
̀
(d) Rulliere, P.; Grisel, J.; Poittevin, C.; Cividino, P.; Carret, S.;
Poisson, J.-F. Thermal [2 + 2]-Cycloaddition of Ketenes with Chiral
Enol Ethers: Route to Densely Substituted Cyclobutanones. Org. Lett.
2016, 18, 2824−2827.
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M. C.; Ghosh, A. K.; Houpis, I. N. Total synthesis of ( )-ginkgolide B.
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AUTHOR INFORMATION
Corresponding Authors
■
Sébastien Carret − Univ. Grenoble Alpes, CNRS, DCM, 38000
Grenoble, France; Email: sebastien.carret@univ-grenoble-
alpes.fr
Jean-Franco̧ is Poisson − Univ. Grenoble Alpes, CNRS, DCM,
38000 Grenoble, France; orcid.org/0000-0002-4982-
7098; Email: jean-francois.poisson@univ-grenoble-alpes.fr
Authors
Audrey Viceriat − Univ. Grenoble Alpes, CNRS, DCM, 38000
Grenoble, France
Isabelle Marchand − Univ. Grenoble Alpes, CNRS, DCM,
38000 Grenoble, France
(5) (a) Ceccon, J.; Poisson, J.-F.; Greene, A. E. Extending the Scope of
the [2 + 2] Cycloaddition of Dichloroketene to Chiral Enol Ethers:
Synthesis of (−)-Detoxinine. Synlett 2005, 1413−1416. (b) Ceccon, J.;
Greene, A. E.; Poisson, J.-F. Asymmetric [2 + 2] Cycloaddition: Total
Synthesis of (−)-Swainsonine and (+)-6-Epicastanospermine. Org.
Lett. 2006, 8, 4739−4742. (c) Ceccon, J.; Danoun, G.; Greene, A. E.;
Poisson, J.-F. Asymmetric synthesis of (+)-castanospermine through
enol ether metathesis−hydroboration/oxidation. Org. Biomol. Chem.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00335
Notes
̀
2009, 7, 2029−2031. (d) Rulliere, P.; Cannillo, A.; Grisel, J.; Cividino,
The authors declare no competing financial interest.
P.; Carret, S.; Poisson, J.-F. Total Synthesis of Proteasome Inhibitor
(−)-Omuralide through Asymmetric Ketene [2 + 2]-Cycloaddition.
Org. Lett. 2018, 20, 4558−4561.
ACKNOWLEDGMENTS
■
(6) For examples of abnormal Beckmann rearrangement from
cyclobutanones, see: (a) Morita, K.; Suzuki, Z. The Beckmann
Rearrangement and Fragmentation of Substituted Bicyclo[2.2.2]-
octan-2-one Oximes. J. Org. Chem. 1966, 31, 233−237. (b) Hutt, O.
E.; Doan, T. L.; Georg, G. I. Synthesis of Skeletally Diverse and
Stereochemically Complex Library Templates Derived from Isosteviol
and Steviol. Org. Lett. 2013, 15, 1602−1605. (c) Shenvi, S.; Rijesh, K.;
Diwakar, L.; Reddy, G. C. Beckmann rearrangement products of methyl
3-oxo-tirucall-8, 24-dien-21-oate from Boswellia serrata gum and their
anti-tumor activity. Phytochem. Lett. 2014, 7, 114−119. (d) Lachia, M.;
Richard, F.; Bigler, R.; Kolleth-Krieger, A.; Dieckmann, M.; Lumbroso,
A.; Karadeniz, U.; Catak, S.; De Mesmaeker, A. An improved procedure
for the Beckmann rearrangement of cyclobutanones. Tetrahedron Lett.
2018, 59, 1896−1901.
The authors gratefully acknowledge the ANR (project ketflo
ANR-18-CE07-0035-01) and EUR-CBH (ANR-11-LABX-
0003-01) for financial support. The authors are also thankful
for support from ICMG FR 2607, Grenoble, through which
NMR, MS, and X-ray analyses have been performed.
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