Preference of β-lactam formation in Cu(I)-catalyzed intramolecular coupling of amides with vinyl bromides

Article abstract of DOI:10.1021/ol801545a

(Chemical Equation Presented) A general and highly efficient synthesis of 4-alkylidene-2-azetidinones was achieved by the Cu(I)-catalyzed intramolecular C-N coupling of amides with vinyl bromides. This 4-exo ring closure was found to be fundamentally preferred over other modes (5-exo, 6-exo, and 6-endo) of cyclization under copper catalysis. Tandem C-N bond formation was then successfully developed to allow the convenient generation of medium-sized lactams.

Full text of DOI:10.1021/ol801545a

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4037-4040
Preference of ꢀ-Lactam Formation in
Cu(I)-Catalyzed Intramolecular Coupling
of Amides with Vinyl Bromides
Qiwu Zhao‡ and Chaozhong Li*,†,‡
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. China, and Department of Chemistry, UniVersity of
Science and Technology of China, Hefei, Anhui 230026, P. R. China
clig@mail.sioc.ac.cn
Received July 9, 2008
ABSTRACT
A general and highly efficient synthesis of 4-alkylidene-2-azetidinones was achieved by the Cu(I)-catalyzed intramolecular C-N coupling of
amides with vinyl bromides. This 4-exo ring closure was found to be fundamentally preferred over other modes (5-exo, 6-exo, and 6-endo) of
cyclization under copper catalysis. Tandem C-N bond formation was then successfully developed to allow the convenient generation of
medium-sized lactams.
ꢀ-Lactams are an intensively studied family of heterocycles
primarily because of their biological activity.1 For example,
ꢀ-lactam antibiotics such as penicillins and cephalosporins have
occupied a central role in the fight against pathogenic bacteria.1
In the meantime, ꢀ-lactams serve as versatile building blocks
in synthetic organic chemistry.2 As a consequence, the synthesis
of ꢀ-lactams has received enormous attention, and considerable
progress has been achieved.1,2
increased inhibition of human leukocyte elastase, a very
potent degradative weapon released by inflammatory cells.3
Some 4-alkylidene-ꢀ-lactams showed promising antibiotic
activity against resistant bacteria.3a Furthermore, they were
the first ꢀ-lactams shown to be active at micromolar
concentrations against two matrix metalloproteases instru-
mental in cancer invasion and metastasis, MMP-2 and MMP-
9.3c In addition to their biological activity, 4-alkylidene-2-
azetidinones, as cyclic enamides, are also useful synthetic
intermediates due to their unique combination of functional
groups. However, there is a scarcity of methods for their
preparation. Bachi et al. reported the synthesis of 4-alky-
lidene-2-azetidinones via rhodium-catalyzed reactions of
4-thioxo-2-azetidinones with diazo compounds.4 Cainelli and
4-Alkylidene-2-azetidinones are a group of ꢀ-lactams with
important biological interest.3 As compared to other ꢀ-lactam
inhibitors, this novel structure was responsible for an
† Chinese Academy of Sciences.
‡ University of Science and Technology of China.
(1) For selected reviews, see: (a) Synthesis of ꢀ-Lactam Antibiotics;
Bruggink, A., Ed.; Kluwer: Dordrecht, Netherlands, 2001. (b) Setti, E. L.;
Micetich, R. G. Curr. Med. Chem. 1998, 5, 101. (c) ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon: New York, 1996; Vol. 1B, Chapters 1.18-1.20. (d) The
Organic Chemistry of ꢀ-Lactams; Georg, G. I., Ed.; VCH: New York, 1993.
(2) For a comprehensive review, see: Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. ReV. 2007, 107, 4437.
(3) (a) Broccolo, F.; Cainelli, G.; Caltabiano, G.; Cocuzza, C. E. A.;
Fortuna, C. G.; Galletti, P.; Giacomini, D.; Musumarra, G.; Musumeci, R.;
Quintavalla, A. J. Med. Chem. 2006, 49, 2804. (b) Cainelli, G.; Galletti,
P.; Garbisa, S.; Giacomini, D.; Sartor, L.; Quintavalla, A. Bioorg. Med.
Chem. 2005, 13, 6120. (c) Cainelli, G.; Galletti, P.; Garbisa, S.; Giacomini,
D.; Sartor, L.; Quintavalla, A. Bioorg. Med. Chem. 2003, 11, 5391.
10.1021/ol801545a CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society

co-workers found that the Lewis acid mediated reactions of
4-acetoxy-2-azetidinones with acyldiazo compounds led to
the generation of 4-(2-oxoethylidene)-ꢀ-lactams.5 Fustero et
al. showed that palladium-catalyzed intramolecular hy-
droamination of difluoropropargyl amides afforded fluori-
nated ꢀ-lactams.6 However, both Z- and E-isomers were
obtained, and the method is limited to R,R-difluoro-
substituted amides. It is therefore of interest to develop
general and efficient methods for the synthesis of 4-alky-
lidene-ꢀ-lactams. Herein we report a highly efficient and
convenient approach to these molecules via Cu(I)-catalyzed
intramolecular N-vinylation of amides.
enamides underwent cyclization in refluxing dioxane, leading
to the formation of five-, six-, and even seven-membered
lactams.10b It is certainly highly desirable to extend this
method to the synthesis of 4-alkylidene-ꢀ-lactams.11 How-
ever, our initial trial with 3-iodobut-3-enamide under the
abovementioned conditions failed to give the desired ꢀ-lac-
tam product.10b The reaction was rather complicated while
all the starting material was consumed.
To explore the possible ꢀ-lactam formation under Cu(I)
catalysis, we then chose N-phenyl-3-bromobut-3-enamide
(1a) as the model substrate and carried out the optimization
of reaction conditions (Table 1). Substrate 1a was first
The formation of aryl C-N bonds via copper-catalyzed
Ullmann coupling between aryl halides and N-centered
nucleophiles has received considerable attention in the past
few years.7 The high stability and low cost of the copper
catalysts enable these transformations to be a useful comple-
ment to the more extensively investigated Pd(0)-catalyzed
processes.8 By the appropriate choice of copper source,
ligand, base, and reaction temperature, these coupling
reactions have been developed to include a wide range of
substrates under mild conditions. This method was success-
fully extended to vinylic C-N bond formation and found
important application in natural product synthesis.9 During
our investigation on Cu(I)-catalyzed intramolecular vinylation
reactions,10 we found that, with CuI as the catalyst and N,N′-
dimethylethylenediamine as the ligand, a number of iodoalk-
Table 1. Optimization of the Synthesis of 2a from 1a
yield (%)c
entry
liganda
base
solvent/timeb
2a
3
4
1
2
3
4
5
6
7
8
A
A
A
A
A
B
C
D
E
Cs2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane (3 h)
dioxane (3 h)
THF (12 h)
THF (12 h)
THF (12 h)
THF (16 h)
THF (16 h)
THF (16 h)
THF (16 h)
THF (17 h)
THF (17 h)
THF (16 h)
13
38
70
10
16
0
69
25
91
94
94
17
25
40
25
20
21
0
6
23
0
0
0
0
0
0
86
9
30
6
4
0
(4) Bachi, M. D.; Goldberg, O.; Grass, A.; Vaya, J. J. Org. Chem. 1980,
45, 1481.
(5) (a) Cainelli, G.; Giacomini, D.; Galletti, P.; Quintavalla, A. Eur. J.
Org. Chem. 2003, 1765. (b) Cainelli, G.; Galletti, P.; Gazzano, M.;
Giacomini, D.; Quintavalla, A. Tetrahedron Lett. 2002, 43, 233. (c)
Battaglia, A.; Cainelli, G.; Giacomini, D.; Martelli, G.; Panunzio, M.
Tetrahedron Lett. 1987, 28, 4347.
9
10d
11e
12
E
E
none
0
0
63
(6) Fustero, S.; Fernandez, B.; Bello, P.; del Pozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251.
16
a A: N,N′-dimethylethylenediamine. B: 1,10-phenanthroline. C: 2-isobu-
tyrylcyclohexanone. D: L-proline. E: Me2NCH2CO2H·HCl. b Reaction
conditions: 1a (0.3 mmol), CuI (0.06 mmol), ligand (0.12 mmol), base (0.6
mmol), solvent (10 mL), reflux. c Isolated yield based on 1a. d 10 mol %
of CuI and 20 mol % of E were used. e 5 mol % of CuI and 10 mol % of
E were used.
(7) For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337. (d) Deng, W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004,
24, 150. (e) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(f) Chemler, S. R.; Fuller, P. H. Chem. Soc. ReV. 2007, 36, 1153.
(8) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (b) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negichi, E.-i. Ed.; Wiley: New York,
2002; Vol. 1, p 1051. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176. (d) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041. (e) Yang, B. Y.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (f) Wolfe, J. P.; Wagaw, S.; Marcoux, J. -F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (g) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (h) Hartwig, J. F. Acc. Chem. Res. 1998,
31, 852.
subjected to the following typical Ullmann coupling condi-
tions: CuI (20 mol%), N,N′-dimethylethylenediamine (A, 40
mol%), Cs2CO3 (2 equiv) in refluxing dioxane. The reaction
was complete within 3 h, and the expected ꢀ-lactam 2a was
isolated in only 13% yield along with the formation of
ꢀ-ketoamide 3 (25%) (entry 1, Table 1). Switching the base
to K2CO3 increased the yields of both 2a and 3 (entry 2,
Table 1). Thinking that 3 might result from the decomposi-
tion of 2a, we lowered the reaction temperature. To our
delight, 2a was achieved in 70% yield when the reaction
was conducted in refluxing THF. K2CO3 was again proven
to be superior over Cs2CO3 and K3PO4 (entries 3-5, Table
1). We next screened the ligands.12 Changing the ligand A
to 1,10-phenanthroline (B) resulted in the generation of allene
(9) For the latest examples of copper-catalyzed N-vinylation, see:(a)
Jiang, B.; Tian, H.; Huang, Z.-G.; Xu, M. Org. Lett. 2008, 10, 2737. (b)
Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008,
130, 1820. (c) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47,
2109. (d) Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521.
(e) Cesati, R. R., III; Dwyer, G.; Jones, R. C.; Hayes, M. P.; Yalamanchili,
P.; Casebier, D. S. Org. Lett. 2007, 9, 5617. (f) Martin, R.; Larsen, C. H.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (g) He, G.; Wang,
J.; Ma, D. Org. Lett. 2007, 9, 1367. (h) Yang, L.; Deng, G.; Wang, D.-X.;
Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9, 1387. (i) Rivero,
M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (j) Toumi, M.; Couty, F.;
Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572. (k) Yuan, X.; Xu, X.;
Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72, 1510.
(10) (a) Fang, Y.; Li, C. Chem. Commun. 2005, 3574. (b) Hu, T.; Li,
C. Org. Lett. 2005, 7, 2035. (c) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (d)
Fang, Y.; Li, C. J. Am. Chem. Soc. 2007, 129, 8092. (e) Pan, Y.; Lu, H.;
Fang, Y.; Fang, X.; Chen, L.; Qian, J.; Wang, J.; Li, C. Synthesis 2007,
1242.
(11) Joyeau et al. reported the formation of ꢀ-lactams via the treatment
of 3-bromo-3-butenamides with copper metal (5 equiv) in DMF at 130-135
°C. See: Joyeau, R.; Kobaiter, R.; Sadet, J.; Wakselman, M. Tetrahedron
Lett. 1989, 30, 337.
4038
Org. Lett., Vol. 10, No. 18, 2008

4 rather than 2a (entry 6, Table 1). On the other hand, N,N-
dimethylglycine hydrochloride (E) turned out to be the best
ligand (entries 5-9, Table 1). The cyclization of 1a
proceeded smoothly to afford 2a in an excellent yield even
when the amount of CuI was reduced to 5 mol % (entry 11,
Table 1).
were well tolerated. The N-alkyl-substituted amides showed
similar behavior as the N-aryl ones, although bulkier N-alkyl
groups might slow down the coupling (entry 13, Table 2).
The above results clearly illustrated the ease of C-N
coupling via a 4-exo ring closure under copper catalysis. As
a comparison, N-phenyl-4-bromopent-4-enamide (5g) was
prepared and subjected to the same conditions in Table 2.
After 24 h reflux in THF, only a trace amount of the expected
product via a 5-exo ring closure could be detected, while
most of the starting material remained unchanged (see also
Table 3). This strongly implied that 4-exo cyclization is more
Table 2. Synthesis of 4-Alkylidene-2-azetidinones 2
Table 3. Preference of 4-exo Ring Closure
a Reaction conditions: 5 (0.3 mmol), CuI (2.9 mg, 0.015 mmol), E (4.2
mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmol), THF (3 mL), reflux. b Isolated
yield based on 5.
favorable than 5-exo cyclization. To have a direct competition
among different modes of cyclization, substrates 5a-f, each
having two possible modes of cyclization, were synthesized
and their reactions under the above optimized conditions
were performed. In each case, only the 4-exo cyclization
product was obtained in almost quantitative yield, while the
competing 5-exo (entries 1 and 2), 6-exo (entries 3 and 4),
or 6-endo (entries 5 and 6) cyclization product was not
observed at all (Table 3). The results in Table 3 unambigu-
ously demonstrated the preference of ꢀ-lactam formation in
the intramolecular C-N coupling processes. This observa-
tion, along with our previous finding in the intramolecular
C-O coupling of alcohols with vinyl bromides,10d strongly
a Reaction conditions: 1 (0.3 mmol), CuI (2.9 mg, 0.015 mmol), E (4.2
mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmol), THF (3 mL), reflux. b Isolated
yield based on 1. c The reaction was conducted in refluxing acetonitrile.
With the optimized conditions in hand (5 mol % of CuI,
10 mol % of E, 200 mol % of K2CO3 in refluxing THF), we
then examined the generality of this method. The results are
summarized in Table 2. Substrates with various substitution
patterns all gave the expected ꢀ-lactams in almost quantita-
tive yield. The configuration of the CdC double bond was
nicely retained, as evidenced by the reactions of 1e and 1f.
Functional groups such as CO2Me (in 1d) and OMe (in 1i)
(12) N,N′-Dimethylethylenediamine: Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421. 1,10-Phenanthroline: Wolter,
M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. 2-Isobutyryl-
cyclohexanone: Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8762. L-Proline: Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. N,N-
Dimethylglycine hydrochloride: Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
Org. Lett., Vol. 10, No. 18, 2008
4039

implies that the preference of the uncommon 4-exo cycliza-
tion is in fact a common phenomenon in Cu(I)-catalyzed
coupling processes. Although the reason for such a preference
remains unclear, it could be possible that the transition state
for 4-exo cyclization as a Cu-containing five-membered ring
is kinetically and thermodynamically more favorable. Theo-
retical analyses on this assumption are currently underway
in our laboratory and will be reported in due course.
The above reactions dealt with N-aryl- or N-alkyl-
substituted amides. We then turned our attention to the
behavior of primary amides. Interestingly, the treatment of
substrate 7 under the optimized conditions afforded ꢀ-lactam
8 in 81% yield (eq 1), which apparently resulted from double
N-vinylation (intramolecularly and intermolecularly). No
monovinylation product could be detected, implying that the
intermolecular coupling is of comparable rate to the intramo-
lecular coupling. This double C-N bond formation13 could
then be extended to the bimolecular cases exemplified by
the reaction of 7 with 2 equiv of iodobenzene (eq 2). The
desired coupling product 2c was generated in 67% yield
along with the formation of 8 in 28% yield.
synthesis of 8-membered lactam 11 (Scheme 1). Presumably
the amide 9 underwent 4-exo cyclization followed by the
intramolecular N-arylation to give the unstable tricyclic
intermediate 10. The hydrolytic cleavage of the enamide
C-N bond afforded the ring expansion product 11. As an
extension of this method, the 9-membered lactam 13 was
achieved from amide 12 in almost quantitative yield.
Scheme 1. Synthesis of Medium-Sized Lactams via
Copper-Catalyzed Tandem C-N Bond Formation
In conclusion, we have developed a general and highly
efficient method for the synthesis of 4-alkyliden-2-azetidi-
nones via copper-catalyzed intramolecular C-N coupling of
3-bromobut-3-enamides. More importantly, this 4-exo ring
closure is fundamentally preferred over other modes of
cyclization, illustrating the unique property of Cu(I)-catalysis.
This method also allows the convenient synthesis of medium-
sized lactams via tandem C-N bond formation.
The ease of 4-exo cyclization and double C-N bond
Acknowledgment. This project was supported by the
National NSF of China (Grant 20672136, 20702060 and
20772142) and by the Shanghai Municipal Committee of
Science and Technology (Grant 07XD14038).
formation shown above should find important application in
organic synthesis. As an example, the copper-catalyzed
reaction of primary amide 9 followed by the subsequent
hydrolysis with aqueous hydrochloric acid led to the efficient
Supporting Information Available: Characterizations of
1-13. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) For examples of copper-catalyzed double C-N bond formation,
see: (a) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 7079. (b) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8,
653. (c) References 9f and 9i.
OL801545A
4040
Org. Lett., Vol. 10, No. 18, 2008