General and highly efficient synthesis of 2-alkylideneazetidines and β-lactams via copper-catalyzed intramolecular N-vinylation

Article abstract of DOI:10.1021/ol062274i

N-Tosyl-3-halo-3-butenylamines underwent efficient Ullmann-type coupling with the catalysis of Cul/N,N-dimethylethylenediamine to afford 2-alkylideneazetidines, which could be readily converted to the corresponding β-lactams by oxidation with O₃

Full text of DOI:10.1021/ol062274i

ORGANIC
LETTERS
2
006
Vol. 8, No. 23
365-5367
General and Highly Efficient Synthesis
of 2-Alkylideneazetidines and -Lactams
via Copper-Catalyzed Intramolecular
N-Vinylation
5
â
Hongjian Lu and Chaozhong Li*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, PRC
clig@mail.sioc.ac.cn
Received September 15, 2006
ABSTRACT
N-Tosyl-3-halo-3-butenylamines underwent efficient Ullmann-type coupling with the catalysis of CuI/N,N′-dimethylethylenediamine to afford
2
-alkylideneazetidines, which could be readily converted to the corresponding -lactams by oxidation with O .
â
3
4
Small-ring nitrogen heterocycles are of considerable interest
not only because of their wide use as important synthetic
intermediates but also because of their biological activities
such as antibiotic properties. Among them, the four-
membered azetidine series, especially azetidin-2-ones (â-
palladium-catalyzed processes. By the appropriate combina-
tion of copper source, ligand, base, and solvent, these
coupling reactions have been developed to include a wide
5
range of substrates under mild conditions. This methodology
was successfully extended to vinylic C-X bond formation
and found important application in natural product synthesis.
However, to the best of our knowledge, no copper- or even
palladium-catalyzed C-N bond formation via a four-
membered ring closure has been reported. We were moti-
vated to explore this possibility owing to our interest in the
1
lactams), has gained enormous attention. However, the
formation of a four-membered ring system is difficult mainly
because of the Dunitz-Schomaker strain, which is significant
in four-membered rings but does not exist in three-membered
6
2
rings. Despite the significant progress achieved in this field,
7
the development of convenient, general, and synthetically
useful methodologies for azetidines is still highly desirable.
The formation of aryl C-X bonds (X ) O, S, N, etc.) via
copper-catalyzed Ullmann coupling between aryl halides and
heteroatom-centered nucleophiles has received considerable
copper-catalyzed intramolecular vinylation. Herein, we wish
(
3) 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,
400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
48, 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.
4) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
002, 219, 131. (b) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negichi, E.-i., Ed.; Wiley: New York,
002; Vol. 1, p 1051. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
5
2
3
attention in the past few years. The high stability and low
(
cost of the copper catalysts enable these transformations to
be a useful complement to the more extensively investigated
2
2
(
1) For reviews, see: (a) Cromwell, N. H.; Philips, B. Chem. ReV. 1979,
9, 331. (b) Davies, D. E.; Storr, R. C. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
984; Vol. 7, p 237. (c) De Kimpe, N. In ComprehensiVe Heterocyclic
Chemistry II; Padwa, A., Ed.; Elsevier: Oxford, 1996; p 508.
2) Crener, D.; Gauss, J. J. Am. Chem. Soc. 1986, 108, 7467.
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.
7
1
(
1
0.1021/ol062274i CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/18/2006

to report that the copper-catalyzed Ullmann-type coupling
of N-tosyl-3-halo-3-butenamines provides an extremely ef-
ficient entry to 2-alkylideneazetidines and, by subsequent
Table 1. Optimization of the Synthesis of 8a from 5a
entrya
ligandb
base
time (h)
yield (%)c
oxidation with O , to â-lactams.
3
We first chose 3-chloro-3-butenylamines 3, 4, and 5a as
the substrates. These compounds could be readily prepared
from the commercially available 2-chloroallyl chloride 1 by
zinc-mediated condensation with benzaldehyde (to give 2)
followed by Mitsunobu reactions (Scheme 1). We then
1
2
3
4
5
6
7
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
15
15
15
15
15
2
2
2
15
0
35
5
<5
27
99
99
87
9
L-1
L-2
L-3
L-4
L-5
L-5
L-5
L-5
8
9d
Scheme 1. Synthesis of Substrates 3a, 4, and 5
Cs CO
2
3
a
Reaction conditions: 5a (0.3 mmol), CuI (0.06 mmol), ligand (0.12
mmol), base (0.6 mmol), dioxane (10 mL), reflux. b L-1: Me2NCH2CO2H‚
HCl. L-2: L-proline. L-3: 2-aminoethanol. L-4: 1,10-phenanthroline. L-5:
N,N′-dimethylethylenediamine. c Isolated yield based on 5a. The reaction
was run at 80 °C.
d
1
. The choice of ligand proved to be critical to the coupling
(entries 1-6, Table 1). Without the aid of a ligand, no
reaction occurred (entry 1, Table 1). Among the frequently
used ligands screened (L-1-L-5), N,N’-dimethylethylene-
diamine L-5 gave the best performance. The reaction was
clean and fast when L-5 was used as the ligand, and the
product 8a was achieved in almost quantitative yield (entry
subjected them to the treatment of a typical Ullmann coupling
condition: CuI (20 mol %), N,N-dimethylglycine hydro-
chloride (L-1, 40 mol %), and Cs CO (2 equiv) in dioxane,
2 3
respectively. The mixture was refluxed for 15 h. No reaction
was observed for amine 3. For Boc-protected amide 4, only
a trace amount of the desired product 7 could be detected.
To our delight, when sulfonamide 5a was used as the
substrate, the expected product 8a was achieved in 35% yield
6
, Table 1). No intermolecular coupling products could be
detected. Interestingly, no significant difference was observed
when the base was switched from Cs CO to K CO or
PO (entries 6-8, Table 1). Lowering the temperature to
0 °C resulted in a much slower reaction (entry 9, Table 1).
2
3
2
3
K
8
3
4
As a comparison, under the optimized conditions (entry 6,
Table 1), amide 4 afforded the product 7 in 55% yield and
amine 3 remained unchanged. These different reactivities are
in parallel with the acidities of the N-H protons in the
substrates.
(Scheme 2).
Scheme 2. Copper-Catalyzed Cyclization of 3, 4, and 5a
We then prepared a number of N-(3-halo-3-buten-1-yl)-
sulfonamides 5a-k and carried out their cyclization reactions
under the catalysis of CuI. The results are summarized in
Table 2. With the bromo analogue of 5a, vinyl bromide 5b,
as the substrate, the reaction could be performed under much
milder conditions (entry 2, Table 2). The reaction was
complete at a lower temperature within a shorter time (1 h)
with the use of less CuI. With vinyl iodide 5f as the substrate,
the reaction took place even at room temperature. When the
temperature was raised to 40 °C, the reaction was complete
within 2 h and the product 8f was obtained in 94% yield
(entry 6, Table 2). Substrates of various substitution patterns
all underwent cyclization smoothly to afford the expected
We then conducted a brief optimization of reaction
conditions for 5a, and the results are summarized in Table
(5) For the latest selected examples, see: (a) Gorobets, E.; McDonald,
R.; Keay, B. A. Org. Lett. 2006, 8, 1483. (b) Cai, Q.; He, G.; Ma, D. J.
Org. Chem. 2006, 71, 5268. (c) Shafir, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2006, 128, 8742. (d) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006,
2
-alkylideneazetidines in excellent yields. Moreover, the
8
, 2779. (e) Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew.
configuration of the CdC double bond was nicely retained
as evidenced by the reactions of 5j and 5k (entries 10 and
11, Table 2).
Chem., Int. Ed. 2006, 45, 2274. (f) Cai, Q.; Zou, B.; Ma, D. Angew. Chem.,
Int. Ed. 2006, 45, 1276. (g) Taillefer, M.; Ouali, A.; Renard, B.; Spindler,
J. Chem.-Eur. J. 2006, 12, 5301. (h) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.;
Zhao, Y. Chem.-Eur. J. 2006, 12, 3636. (i) Strieter, E. R.; Blackmond, D.
G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120. (j) Trost, B. M.;
Stiles, D. T. Org. Lett. 2005, 7, 2117. (k) Yang, T.; Lin, C.; Fu, H.; Jiang,
Y.; Zhao, Y. Org. Lett. 2005, 7, 4781. (l) Wrona, I. E.; Gabarda, A. E.;
Evano, G.; Panek, J. S. J. Am. Chem. Soc. 2005, 127, 15026. (m) Alcalde,
E.; Dinar e` s, I.; Rodr ´ı guez, S.; Miguel, C. G. Eur. J. Org. Chem. 2005, 8,
(6) Joyeau et al. reported the formation of â-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. However, our attempts in the Cu(I)-
catalyzed coupling reactions of 3-iodo-3-butenamides failed. See ref 7b.
(7) (a) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427. (b) Hu, T.; Li, C.
Org. Lett. 2005, 7, 2035. (c) Fang, Y.; Li, C. Chem. Commun. 2005, 3574.
1
637. (n) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (o)
Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G. T.; Sreedhar,
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Org. Lett., Vol. 8, No. 23, 2006

five-membered ring, could be favorable sterically and
thermodynamically.
Table 2. Synthesis of Azetidines 8
The convenient synthesis of 2-alkylideneazetidines as a
unique class of strained cyclic enamines should have
important applications in organic synthesis, although little
is known of their chemistry because of their difficult
8
preparation. As an example, we show here that these
compounds could be readily converted to the corresponding
â-lactams in high yields by a conventional O
procedure (Scheme 3).
3
oxidation
9
Scheme 3. Synthesis of â-Lactams 10-15
a
Isolated yield based on 5.
Thus, the above Ullmann coupling-oxidation processes
constitute an efficient and general entry to the synthesis of
1
0
â-lactams.
Acknowledgment. This project was supported by the
National NSF of China (Nos. 20325207 and 20472109) and
by the Shanghai Municipal Committee of Science and
Technology (No. 04QMH1418).
Supporting Information Available: Synthesis and char-
acterizations of 2-9. This material is available free of charge
via the Internet at http://pubs.acs.org.
a
1
00 °C and 68 °C refer to the refluxing temperatures of dioxane and
b
THF, respectively. Isolated yield based on 5.
OL062274I
(8) For the synthesis and reactions of 2-methyleneazetidines, see: (a)
Zhao, G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737. (b) Martinez,
I.; Howell, A. R. Tetrahedron Lett. 2000, 41, 5607. (c) Tehrani, K. A.; De
Kimpe, N. Tetrahedron Lett. 2000, 41, 1975. (d) Sulmon, P.; De Kimpe,
N.; Schamp, N. J. Org. Chem. 1988, 53, 4462.
The above results clearly demonstrated the high efficiency
of the four-membered ring closure. Presumably, this might
be rationalized by the possible transition state 9 which, as a
(9) Hon, Y.; Lin, S.; Lu, L.; Chen, Y. Tetrahedron 1995, 51, 5019.
10) For reviews on the synthesis of â-lactams, see: (a) Alcaide, B.;
(
Almendros, P. Synlett 2002, 381. (b) Alcaide, B.; Almendros, P. Chem.
Soc. ReV. 2001, 30, 226. (c) Synthesis of â-Lactam Antibiotics: Chemistry,
Biocatalysis and Process Integration; Bruggink, A., Ed.; Kluwer: Dorfrecht,
2
001. (d) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett
2
001, 1813. (e) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E.,
Ed.; VCH: New York, 1997.
Org. Lett., Vol. 8, No. 23, 2006
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