Rhodium-catalyzed oxygenative [2 + 2] cycloaddition of terminal alkynes and imines for the synthesis of β-lactams

Article abstract of DOI:10.1021/ol500856z

A rhodium-catalyzed oxygenative [2 + 2] cycloaddition of terminal alkynes and imines has been developed, which gives β-lactams as products with high trans diastereoselectivity. In the presence of a Rh(I) catalyst and 4-picoline N-oxide, a terminal alkyne is converted to a rhodium ketene species via oxidation of a vinylidene complex and subsequently undergoes a [2 + 2] cycloaddition with an imine to give rise to the 2-azetidinone ring system. Mechanistic studies suggest that the reaction proceeds through a metalloketene rather than free ketene intermediate. The new method taking advantage of catalytic generation of a ketene species directly from a terminal alkyne provides a novel and efficient entry to the Staudinger synthesis of β-lactams under mild conditions.

Full text of DOI:10.1021/ol500856z

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Oxygenative [2 + 2] Cycloaddition of Terminal
Alkynes and Imines for the Synthesis of β‑Lactams
Insu Kim, Sang Weon Roh, Dong Gil Lee, and Chulbom Lee*
Department of Chemistry, Seoul National University, Seoul 151-747, Republic of Korea
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed oxygenative [2 + 2] cyclo-
addition of terminal alkynes and imines has been developed,
which gives β-lactams as products with high trans diastereo-
selectivity. In the presence of a Rh(I) catalyst and 4-picoline
N-oxide, a terminal alkyne is converted to a rhodium ketene
species via oxidation of a vinylidene complex and subsequently undergoes a [2 + 2] cycloaddition with an imine to give rise to the
2-azetidinone ring system. Mechanistic studies suggest that the reaction proceeds through a metalloketene rather than free ketene
intermediate. The new method taking advantage of catalytic generation of a ketene species directly from a terminal alkyne
provides a novel and efficient entry to the Staudinger synthesis of β-lactams under mild conditions.
Scheme 1. Synthesis of β-Lactams via Metalloketene-
Mediated Catalysis
he β-lactams are an important class of heterocycles that
have been intensively investigated across diverse scientific
T
disciplines as well as the pharmaceutical industry because of
their potent antibacterial activity.1 In addition to being the key
pharmacophoric motif of β-lactam antibiotics, the 2-azetidinone
ring system is also used in the development of various non-
antibiotic therapeutic agents as exemplified by the cholesterol-
lowering drug ezetimibe.2 Furthermore, β-lactams have increas-
ingly served as versatile intermediates for the synthesis of a
wide variety of nitrogen-containing compounds,3 rendering the
development of methods for β-lactam synthesis an important
objective.4 Among the different synthetic approaches, the
Staudinger reaction, a formal [2 + 2] cycloaddition of a ketene
with an imine, is a powerful method that provides expeditious
access to β-lactams.5 While numerous applications employing
this process have been reported, the practice of the protocol
typically involves generation of the requisite ketene from acti-
vated carboxylic acid derivatives such as acyl chlorides, thus often
limiting the scope. In this regard, noteworthy is the β-lactam
synthesis using metalloketenes,6 in which the ketene species is
formed via carbene carbonylation, not derived from carbonyl
compounds.7 While this approach has focused mostly on the
stoichiometric use of Fischer carbenes, catalytic examples based
on the carbene carbonylation have been reported making use
of diazo compounds (Scheme 1, metal alkylidene pathway).8 An
attractive alternative is formation of the metalloketene via
oxygenation of a metal vinylidene (Scheme 1, metal vinylidene
pathway). We recently described a rhodium-catalyzed oxygen-
ative addition reaction that furnishes carboxylic acid derivatives
from terminal alkynes and various nucleophiles.9 In continuing
efforts to further develop this process, we questioned if the metal-
vinylidene-to-ketene transformation,10 a crucial event in the
catalytic cycle, could be tapped into for β-lactam synthesis.
Notably, this reaction would enable readily available alkynes
to be employed as substrates for β-lactam synthesis, mirroring
the Kinugasa reaction but with a distinct mechanism.11 Here,
we report a rhodium-catalyzed oxygenative [2 + 2] cycloaddition
of terminal alkynes and imines that affords β-lactam products
with high trans selectivity.
Our studies commenced with applying the conditions of
the oxygenative alkyne addition9 to the reaction of alkyne 1a with
imine 2a (Table 1). Thus, the mixture of 1a and 2a was heated
at 50 °C in the presence of 2.5 mol % [Rh(COD)Cl]2, 10 mol %
P(4−F-C6H4)3, and 1.3 equiv 4-picoline N-oxide for 24 h.
Gratifyingly, a smooth reaction took place to give rise to the
desired β-lactam 3a as a trans isomer exclusively in 90% yield
(entry 1), indicating the metalloketene intermediate involved
in the oxygenative addition to be also viable for cycloaddition with
an imine. While ligand screening experiments revealed triphenyl-
phosphine to be optimal (entries 1−4), the use of Wilkinson’s
catalyst proved equally efficient (entry 5). A brief survey of
ruthenium catalysts established that the reaction could be more
efficiently performed using a rhodium complex as the catalyst
(entries 6−8). Similarly to the results of our previous studies,
Received: March 22, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Rh(PPh3)3Cl, a variety of imines reacted with alkyne 1a to
provide the corresponding β-lactams with high 3,4-trans selec-
tivity. Both aryl and heteroaryl imines with varying substituents
as well as an alkenyl imine (3g) all participated well in the
reaction.13 In terms of N-substitution, methyl, benzyl, allyl, and
isopropyl groups were well tolerated, whereas lower yields were
obtained from the reactions of N-tert-butyl (3j), phenyl (3l),
and tosyl (3m) substrates.
Table 1. Oxygenative [2 + 2] Cycloaddition of Alkyne 1a with
Imine 2a under Various Conditions
a
b
entry
catalyst
yield (%)
Having established a broad scope with regard to imine
substrates, we next turned our attention to probing the alkyne
structure amenable for the [2 + 2] cycloaddition with imine 2a.
As summarized in Table 3, the diversity of suitable alkynes
proved extensive, and a variety of functional groups such as
ether (OMe, OBn, OTBDPS), halide (Br, Cl), ester, and cyanide
did not interfere with the reaction. A broad range of alkynes with
aryl (4−9), heteroaryl (10 and 11), alkenyl (12), and linear alkyl
(13−19) groups were found to be excellent participants of
the reaction, affording the β-lactam products in good yield.
In contrast, the reactions of the alkynes with branched alkyl (20)
and potentially coordinating (21) substituents produced
β-lactams in low yield, suggesting possible involvement of a
metal-bound ketene, rather than free ketene, as an inter-
mediate.14 Interestingly, the reactions of alkyl-substituted
alkynes, in general, were less efficient than those of aryl
and alkenyl substrates under the standard conditions. In these
cases, the addition of ZnCl2 (15 mol %) to the reaction signi-
ficantly accelerated the rate and increased the yield (13−21).
In all cases, these rhodium-catalyzed reactions furnished
β-lactams in trans configuration (dr > 25:1).
1
2
3
[Rh(COD)Cl]2/P(4-F-C6H4)3
[Rh(COD)Cl]2/P(C6H5)3
[Rh(COD)Cl]2/P(4-MeO-C6H4)3
[Rh(COD)Cl]2/dppp
Rh(PPh3)3Cl
90
93
50
4
d
4
c
5
93
0
d
6
TpRu(PPh3)2Cl
d
7
CpRu(PPh3)2Cl
8
d
8
Cp*Ru(PPh3)2Cl
38
a
Alkyne (0.26 mmol), imine (0.2 mmol), and 4-picoline N-oxide
(0.26 mmol) in CH3CN (0.8 mL, 0.25 M), [Rh]/phosphine = 1:2
except for entry 5. Determined by NMR. Isolated yield, 4 h. Alkyne
and imine remained.
b
c
d
4-picoline N-oxide and acetonitrile were found to be the best oxidant
and solvent, respectively.12
With encouraging results from the initial experiment, we
explored the scope of the reaction with respect to the imine
component (Table 2). Under the conditions using 5 mol %
Table 2. Rh-Catalyzed Oxygenative [2 + 2] Cycloaddition of
Alkyne 1a with Various Imines
a
A set of control experiments were performed to gain insight
into the mechanism (Scheme 2). First, whereas the reaction of
Scheme 2. Control Experiments
alkyne 1a with nitrone 22 under Kinugasa conditions gave 3a′
(cis β-lactam) as the major product, no reaction occurred when
RhCl(PPh3)3 was employed instead of CuCl.15 Second, while
3d′ (cis β-lactam) was produced as the major product from the
reaction of acid chloride 23 with imine 2d using a Staudinger
protocol (condition A),16 running the same reaction in the
presence of RhCl(PPh3)3 reoriented the diastereoselectivity to
favor the formation of trans isomer 3d as the major product
(condition B), hinting at the possible intermediacy of a rhodium-
bound ketene rather than free ketene.
a
Alkyne (0.65 mmol), imine (0.5 mmol), and 4-picoline N-oxide
b
c
(0.65 mmol) in CH3CN (2 mL, 0.25 M). dr = 5.8:1. Alkyne
(0.5 mmol), imine (0.55 mmol), 4-picoline N-oxide (0.6 mmol),
Rh(PPh3)3Cl (7.5 mol %), and ZnCl2 (15 mol %) in CH3CN (2.5 mL,
The mechanism of the rhodium-catalyzed oxygenative [2 + 2]
cycloaddition of alkynes and imines is proposed in Scheme 3.
d
e
0.20 M) at 65 °C. Imine recovered. dr = 7.7:1.
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Letter
a
Table 3. Rhodium-Catalyzed [2 + 2] Cycloaddition of Various Alkynes with Imine 2a
a
Alkyne (0.65 mmol), imine (0.5 mmol), 4-picoline N-oxide(0.65 mmol), and Rh(PPh3)3Cl (5 mol %) in CH3CN (2.0 mL, 0.25 M) at 50 °C.
Alkyne (0.5 mmol), imine (0.55 mmol), 4-picoline N-oxide(0.6 mmol), Rh(PPh3)3Cl (7.5 mol %), and ZnCl2 (15 mol %) in CH3CN (2.5 mL,
b
c
d
0.20 M) at 65 °C. dr = 1:1. 3-(Benzyloxy)-N-methylpropanamide was obtained in 46% yield.
Scheme 3. Proposed Mechanism of the Rh-Catalyzed
Oxygenative [2 + 2] Cycloaddition of Alkyne and Imine
The rhodium-catalyzed cycloaddition described here has
several significant features. It demonstrates that an operation-
ally simple Staudinger β-lactam synthesis can be practiced
with readily available and easily handled terminal alkynes as
substrates under mild rhodium catalysis without requiring
activated carboxylic acid derivatives. Taking advantage of a
mechanism based on catalytic oxidation of a metal vinylidene
complex for metalloketene generation, our studies establish
for the first time that a rhodium complexed ketene species
can undergo efficient [2 + 2] cycloaddition with imines.
Further explorations of this reaction, including the develop-
ment of an asymmetric variant, are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Starting with the formation of a rhodium vinylidene from a
terminal alkyne, the catalytic cycle consists of the generation
of a metalloketene and its cycloaddition with an imine. In the
first stage, the oxygen transfer from 4-picoline N-oxide to η1-Rh
vinylidene complex A produces η2- Rh ketene B, which likely
exists in equilibrium with C.17 Subsequently, the nucleophilic
addition of an imine to the metallo-ketene species generates
a rhodium-complexed zwitterionic intermediate (D/E), which
forms the β-lactam product. Given the high preference for trans
product formation, the final step is believed to involve facile
isomerization of iminium D to E prior to the ring closure that
completes the catalytic cycle.18
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chulbom@snu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support was provided by the BRL (Basic Research Laboratory)
program of the National Research Foundation (NRF) funded by
■
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Letter
(15) No oxygen transfer between imines and picoline was observed.
For details of control experiments, see the Supporting Information.
(16) Li, B.; Wang, Y.; Du, D.-M.; Xu, J. J. Org. Chem. 2007, 72, 990.
the Korean government. We thank Heejun Lee for performing
preliminary experiments.
(17) (a) Bleuel, E.; Laubender, M.; Weberndorfer, B.; Werner, H.
̈
REFERENCES
■
Angew. Chem., Int. Ed. 1999, 38, 156. (b) Grotjahn, D. B.; Collins, L. S.
B.; Wolpert, M.; Bikzhanova, G. A.; Lo, H. C.; Combs, D.; Hubbard, J. L.
J. Am. Chem. Soc. 2001, 123, 8260.
(18) For cis−trans imine isomerization, see: Jiao, L.; Liang, Y.; Xu, J. J.
Am. Chem. Soc. 2006, 128, 6060. For cis−trans imine isomerization via a
metallacycle formation, see ref 8b.
(1) For reviews, see: (a) The Organic Chemistry of β-Lactams; Georg,
G. I., Ed.; VCH: New York, 1993. (b) Ojima, I.; Zuniga, E. S.; Seitz, J. D.
Top. Heterocycl. Chem. 2012, 30, 1. (c) Fernandez, I.; Sierra, M. A. Top.
́
Heterocycl. Chem. 2012, 30, 65. (d) Mandal, B.; Basu, B. Top. Heterocycl.
Chem. 2012, 30, 85. (e) Tidwell, T. T. Top. Heterocycl. Chem. 2012, 30,
111. (f) Turos, E. Top. Heterocycl. Chem. 2012, 30, 147. (g) Banik, I.;
Banik, B. K. Top. Heterocycl. Chem. 2012, 30, 183.
(2) For selected examples, see: (a) Han, W. T.; Trehan, A. K.; Kim
Wright, J. J.; Federici, M. E.; Seiler, S. M.; Meanwell, N. A. Biorg. Med.
Chem. 1995, 3, 1123. (b) Rosenblum, S. B.; Huynh, T.; Afonso, A.;
Davis, H. R.; Yumibe, N.; Clader, J. W.; Burnett, D. A. J. Med. Chem.
1998, 41, 973. (c) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.-J.;
Liu, L.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 9276.
(3) (a) Palomo, C.; Arrieta, A.; Cossío, F. P.; Aizpurua, J. M.; Mielgo,
A.; Aurrekoetxea, N. Tetrahedron Lett. 1990, 31, 6429. (b) Ojima, I.;
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377. (c) Deshmukh, A. R. A. S.;
Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.;
Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889. (d) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437.
(4) (a) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem.
Res. 2004, 37, 592. (b) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev.
2008, 108, 3988.
(5) (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51. (b) Palomo,
C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999,
3223.
(6) (a) McGuire, M. A.; Hegedus, L. S. J. Am. Chem. Soc. 1982, 104,
5538. (b) Barrett, A. G. M.; Sturgess, M. A. J. Org. Chem. 1987, 52, 3940.
(c) Hegedus, L. S. Topics Organomet. Chem. 2004, 13, 157.
(d) Fernan
44, 479.
́
dez, I.; Cossío, F. P.; Sierra, M. A. Acc. Chem. Res. 2011,
(7) (a) Alper, H.; Urso, F.; Smith, D. J. H. J. Am. Chem. Soc. 1983, 105,
6737. (b) Padwa, A.; Koehler, K. F.; Rodriguez, A. J. Org. Chem. 1984,
49, 282. (c) Fontana, F.; Tron, G. C.; Barbero, N.; Ferrini, S.; Thomas, S.
P.; Aggarwal, V. K. Chem. Commun. 2010, 46, 267. (d) Li, W.; Liu, C.;
Zhang, H.; Ye, K.; Zhang, G.; Zhang, W.; Duan, Z.; You, S.; Lei, A.
Angew. Chem., Int. Ed. 2014, 53, 2443.
̋ ́ ́ ́ ́
(8) (a) Fordos, E.; Tuba, R.; Parkanyi, L.; Kegl, T.; Ungvary, F. Eur. J.
̈
Org. Chem. 2009, 1994. (b) Zhang, Z.; Liu, Y.; Ling, L.; Li, Y.; Dong, Y.;
Gong, M.; Zhao, X.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133,
4330. (c) Zhang, Z.; Zhang, Y.; Wang, J. ACS Catal. 2011, 1, 1621.
(9) Kim, I.; Lee, C. Angew. Chem., Int. Ed. 2013, 52, 10023.
(10) (a) Madhushaw, R. J.; Lin, M.-Y.; Sohel, S. M. A.; Liu, R.-S. J. Am.
Chem. Soc. 2004, 126, 6895. (b) Ming-Yuan, L.; Madhushaw, R. J.; Liu,
R.-S. J. Org. Chem. 2004, 69, 7700. (c) Lin, M.-Y.; Maddirala, S. J.; Liu,
R.-S. Org. Lett. 2005, 7, 1745. (d) Pati, K.; Liu, R.-S. Chem. Commun.
2009, 5233.
(11) (a) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun.
1972, 466. (b) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4999. (c) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 4572. (d) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 4082.
(12) For details, see Table S2 and S3 in the Supporting Information.
(13) The reaction has been unsuccessful with alkyl imines. For
example, the reaction of 1a with N-methylcyclohexylimine gave a
mixture of intractable products without forming a β-lactam product.
(14) Given the marked difference in reactivity between TBDPS (cf.
19) and Bn (cf. 21) protected substrates, the zwitterionic intermediate
(e.g., D in Scheme 3) leading to 21 is likely to exist as a rhodium enolate
chelated with the OBn group. The formation of a stable enolate may
render the final electrocyclization step sluggish, while the hydrolysis of
the intermediate to an amide byproduct (46%, footnote d of Table 3)
becomes more competitive. Similarly, the reaction of p-nitro-substituted
phenylacetylene with imine 2a did not produce a β-lactam product but
gave an N-methyl amide in 15% yield. See the Supporting Information
for details.
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