PdCl2-catalyzed efficient transformation of propargylic amines to (E)-α-chloroalkylidene-β-lactams

Article abstract of DOI:10.1021/jo0480996

(Chemical Equation Presented) The PdCl₂-catalyzed cyclocarbonylation reaction of propargylic amines with CuCl₂ and benzoquinone afforded (E)-α-chloroalkylidene-β-lactams in moderate to good yields. The formation of the corresponding

Full text of DOI:10.1021/jo0480996

PdCl2-Catalyzed Efficient Transformation of Propargylic Amines
to (E)-r-Chloroalkylidene-â-lactams
Shengming Ma,* Bin Wu, and Xuefeng Jiang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P.R. China
masm@mail.sioc.ac.cn
Received October 27, 2004
The PdCl2-catalyzed cyclocarbonylation reaction of propargylic amines with CuCl2 and benzoquinone
afforded (E)-R-chloroalkylidene-â-lactams in moderate to good yields. The formation of the
corresponding Z-isomers or five-membered products was not observed. The reaction of the readily
available optically active propargylic amines provides a convenient synthesis of the corresponding
(E)-R-chloroalkylidene-â-lactams with high ee values. The structure and the stereochemistry of
the products were established by the X-ray single-crystal diffraction study of (E)-6d and (E)-6e,
which indicates that the stereoselectivity in this reaction is different from what was observed with
propargylic alcohols. A rationale for this reaction was proposed.
Introduction
one of the most important skeletons which have attracted
significant interest among synthetic and medicinal chem-
ists over the years mainly because of their occurrence in
some biologically active natural products and their
potential as useful building blocks in organic synthesis.5
Some of the most important methodologies for the
preparation of R-alkylidene-â-lactams are summarized as
follows: (1) the addition of chlorosulfonyl isocyanate with
functionalized allenes;6 (2) lactamization;7 (3) elimination
reaction of â-lactams forming the exocyclic CdC bonds;8
(4) R-olefination reaction of â-lactams;9 (5) Pd(0)-cata-
Due to the biological activity1 and their potentials as
synthetic intermediates,2 â-lactams (2-azetidinones) are
one of the best known and intensely investigated het-
erocyclic ring systems. Since the introduction of penicillin
into therapy, bacteria have developed an incredible and
growing resistance to â-lactam antibiotics, essentially due
to the hydrolytic ability of extremely active â-lactams,
which can be overcome by using more stable â-lactam
derivative.3 Furthermore, the recent discoveries of some
azetidin-2-ones displaying a broad range of enzyme-
inhibitory activity justify a renewed interest in these
compounds.4 In this family, R-alkylidene-â-lactams are
(4) Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002, 6, 245.
(5) (a) Imuta, M.; Ona, H.; Uyeo, S.; Motokawa, K.; Yoshida, T.
Chem. Pharm. Bull. 1985, 33, 4361. (b) Imuta, M.; Uyeo, S.; Nakano,
M.; Yoshida, T. Chem. Pharm. Bull. 1985, 33, 4371. (c) Imuta, M.; Uyeo,
S.; Yoshida, T. Chem. Pharm. Bull. 1991, 39, 658. (d) Ona, H.; Uyeo,
S. Tetrahedron Lett. 1984, 25, 2237. (e) Coulton, S.; Francois, I. J.
Chem. Soc., Perkin Trans. 1 1991, 2699. (f) Copar, A.; Prevec, T.; Anzˇicˇ,
B.; Mesar, T.; Selicˇ, L.; Vilar, M.; Solmajer, T. Bioorg. Med. Chem. 2002,
12, 971. (g) Ona, H.; Uyeo, S.; Motokawa, K.; Yoshida, T. Chem. Pharm.
Bull. 1985, 33, 4346. (h) Kawashima, Y.; Sato, M.; Hatada, Y.; Goto,
J.; Yamane, Y.; Hatayama, K. Chem. Pharm. Bull. 1991, 39, 3202.
(6) (a) Moriconi, E. J.; Kelly, J. F. J. Am. Chem. Soc. 1966, 88, 3657.
(b) Moriconi, E. J.; Kelly, J. F. J. Org. Chem. 1968, 33, 3036. (c) Colvin,
E. W.; Monteith, M. J. Chem. Soc., Chem. Commun. 1990, 1230. (d)
Buynak, J. D.; Mathew, J.; Rao, M. N.; Haley, E.; George, C.;
Siriwardone, U. J. Chem. Soc., Chem. Commun. 1987, 735.
(1) (a) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V. Eds.; Pergamon: New York, 1996;
Chapter 1.18-1.20. (b) The Chemistry of â-lactams; Page, M. I., Ed.;
Blackie Academic & Professional: New York, 1992. (c) Chemistry and
Biology of â-lactam Antibiotics; Morin, R. B., Gorman, M., Eds.;
Academic Press: New York, 1982; Vols. 1-3.
(2) (a) Synthesis of â-lactam Antibiotics: Chemistry, Biocatalysis and
Process Integration; Bruggink, A., Ed.; Kluwer: Dordrecht, The
Netherlands, 2001. (b) Enantioselective Synthesos of â-Amino Acids;
Juaristi, E., Ed.; VCH: New York, 1997. (c) Ojima, I.; Delaloge, F.
Chem. Soc. Rev. 1997, 26, 377. (d) The Organic Chemstry of â-lactams;
Georg, G. I., Ed.; VCH: New York, 1993. (e) Magriotis, P. A. Angew.
Chem., Int. Ed. 2001, 40, 4377. (f) Fu, G. C.; Shintani, R. Angew. Chem.,
Int. Ed. 2003, 42, 4082. (g) Marco-Contelles, J. Angew. Chem., Int. Ed.
2004, 43, 2198.
(7) (a) Adlington, R. M.; Barrett, A. G. M.; Quayle, P.; Walker, A.;
Betts, M. J. J. Chem. Soc., Perkin Trans. 1 1983, 605. (b) Tanaka, K.;
Horiuchi, H.; Yoda, H. J. Org. Chem. 1989, 54, 63. (c) Adam, W.; Groer,
P.; Humpf, H.-U.; Saha-Mo¨ller, C. R. J. Org. Chem. 2000, 65, 4919.
(d) Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213.
(3) (a) Spratt, B. G. Science 1994, 264, 388. (b) Davies, J. Science
1994, 264, 375.
10.1021/jo0480996 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/24/2005
2588
J. Org. Chem. 2005, 70, 2588-2593

(E)-R-Chloroalkylidene-â-lactams
SCHEME 1
lyzed cyclocarbonylative cyclization reaction of 2-bromo-
2-alkenyl amides;10 (6) Rh-catalyzed silylcarbonylation of
propargylamines;11 (7) [2+2] cycloaddition reactions of
R-heteroatom substituted metallocarbenes with imines
followed by hydrolysis;12 and (8) radical stannylcarbon-
ylation of propargylamines.13 However, these known
methods may, in some cases, suffer from lengthy proce-
dures, harsh conditions, or low yields. Thus, new and
efficient methodologies for R-alkylidene-â-lactams are
still desirable. In this paper, we wish to report our recent
results on the PdCl2-catalyzed cyclocarbonylation of
propargylic amines affording (E)-R-chloroalkylidene-â-
lactams highly selectively.
Results and Discussion
Synthesis of Starting Materials. A number of
methods have been used for the synthesis of different
propargylic amines. Propargylic amines 3a-g were pre-
pared through the application of the Mitsunobu reaction
(Scheme 1).14 The optically active propargylic amine (R)-
3f was prepared according to the same procedure using
optically active propargylic alcohol (S)-1f 1 as the starting
point. Propargylic amines 4a-f and (R)-4f were prepared
via the N-benzylation of amines 3 (Scheme 2).16
Propargylic amine 4h was prepared through the ap-
plication of the known amination of propargylic mesylates
(Scheme 3).17 The optically active propargylic amines (R)-
4b, (S)-4b, (R)-4h, and (S)-4h were prepared accordingly
starting from the optically active propargylic alcohols (S)-
1b, (R)-1b, (S)-1h, and (R)-1h, respectively.
Propargylic amine 4l was prepared via the reaction of
the corresponding 1-alkynyllithium with the imine
(Scheme 4).
Synthesis of (E)-r-Alkylidene-â-lactams via PdCl2-
Catalyzed Cyclocarbonylation of Propargylic
Amines. Recently, we have observed that R-chloroal-
SCHEME 2
(8) (a) Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J.
J. J. Am. Chem. Soc. 1988, 110, 6487. (b) Ishida, M.; Minami, T.;
Agawa, T. J. Org. Chem. 1979, 44, 2067. (c) Minami, T.; Ishida, M;
Agawa, T. J. Chem. Soc., Chem. Commun. 1978, 12. (d) Johner, M.;
Rihs, G.; Gu¨rtler, S.; Otto, H.-H. Helv. Chim. Acta 1994, 77, 2147. (e)
Agawa, T.; Ishida, M.; Ohshiro, Y. Synthesis 1980, 933. (f) Harada, S.;
Tsubotani, S.; Shinagawa, S.; Asai, M. Tetrahedron 1983, 39, 75. (g)
Ona, H.; Uyeo, S. Tetrahedron Lett. 1984, 25, 2237. (h) Coulton, S.;
Francois, I. J. Chem. Soc., Perkin Trans. 1 1991, 2699. (i) Alcaide, B.;
Esteban, G.; Mart´ın-Cantalejo, Y.; Plumet, J.; Rodr´ıguez-Lo´pez, J.;
Monge, A.; Pe´rez-Garc´ıa, V. J. Org. Chem. 1994, 59, 7994. (j) Alcaide,
B.; Plumet, J.; Rodr´ıguez-Lo´pez, J.; Sa´nchez-Cantalejo, Y. M. Tetra-
hedron Lett. 1990, 31, 2493.
(9) (a) Okano, K.; Kyotani, K.; Ishihama, H.; Kobayashi, S.; Ohno,
M. J. Am. Chem. Soc. 1983, 105, 7186. (b) Palomo, C.; Aizpurua, J.
M.; Cossio, F. P.; Garcia, J. M.; Lo´pez, M. C.; Oiarbide M. J. Org. Chem.
1990, 55, 2070. (c) Kano, S.; Shibuya, S.; Ebata, T. J. Chem. Soc.,
Perkin Trans.1 1982, 257.
(10) (a) Mori, M.; Chiba, K.; Okita, M.; Ban, Y. J. Chem. Soc., Chem.
Commun. 1979, 698. (b) Mori, M.; Ban, Y. Heterocycles 1985, 317. (c)
Mori, M.; Chiba, M. K.; Okita, M.; KaYo, I.; Ban, Y. Tetrahedron 1985,
41, 375.
(11) Matsuda, I.; Sakakibara, J.; Nagashima, H. Tetrahedron Lett.
1991, 32, 7431.
(12) Barrett, A. G. M.; Sturgess, M. A. Tetrahedron Lett. 1986, 27,
3811.
kylidene-â-lactones can be prepared from PdCl2-catalyed
cyclocarbonylation of 2-alkynols.18 In our first try, the
reaction of propargylic amine 3a failed to afford the
carbonylative cyclization reaction under the same reac-
tion conditions (10 mol % of PdCl2 and 5 equiv of CuCl2)18
(entry 1, Table 1). To our delight, when 2 equiv of
benzoquinone were added to the reaction mixture, 31%
of product (E)-6a was isolated under the action of 5 mol
% of PdCl2 and 1.5 equiv of CuCl2 (entry 2, Table 1).
Further studies showed that 1 equiv of benzoquinone is
enough for the reaction and the reaction time is a key
factor. When the reaction time was 8 h, the yield of
product was improved to 52% (entry 4, Table 1). With a
(13) Ryu, I.; Miyazato, H.; Kuriyama, H.; Matsu, K.; Tojino, M.;
Fukuyama, T.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2003,
125, 5632.
(14) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Roush, W. R.; Straub,
J. A.; Brown, R. J. J. Org. Chem. 1987, 52, 5127.
(15) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806.
(16) Cancho, Y.; Mart´ın, J. M.; Mart´ınez, M.; Llebaria, A.; Moreto´,
J. M.; Delgado, A. Tetrahedron 1998, 54, 1221.
(17) Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238.
(18) Ma, S.; Wu, B.; Zhao, S. Org. Lett. 2003, 5, 4429.
J. Org. Chem, Vol. 70, No. 7, 2005 2589

Ma et al.
SCHEME 3
SCHEME 4
detected in the presence or absence of CuCl2 when we
added H2O, HCl, AcOH, or LiCl (entries 8-11, Table 1),
indicating that the addition of extra H+ is not good for
this transformation, since H+ was generated in this
reaction.
TABLE 1. PdCl2-Catalyzed Cyclocarbonylation of
Propargylic Amine 3a
Further studies showed that in some cases the reaction
temperature was another key factor. The yield of (E)-6c
at 40 °C was much higher than that at 30 °C (entries 1
and 2, Table 2). Both the reaction temperature and time
were key factors for the reaction of N-benzyl propargylic
amines 4c. From entries 3-5 of Table 2, it can be seen
that the best reaction conditions are 5 mol % of PdCl2, 2
equiv of CuCl2, 1 equiv of benzoquinone, and CO (300
psi) in THF at 40 °C for 12 h. Under these reaction
conditions, (E)-6i was isolated in 80% yield (entry 5,
Table 2).
CuCl2
(equiv)
benzoquinone
(equiv)
time
(h)
isolated
yield (%)
entry
1
2
5
-
2
1
1
1
1
2
1
2
2
1
2
4
trace
31
31
52
23
51
a
1.5
1.5
1.5
1.5
2
3
4
The stereochemistry of (E)-6 was established by the
single-crystal X-ray diffraction study of (E)-6d and (E)-
6e.18 The formation of the Z-isomers and the five-
membered lactams was not observed through the 1H
4
8
5
12
8
6
7
0
8
8b
9c
10d
11e
2
8
a
(19) Crystal data for compound (E)-6d: C14H22NOCl, MW ) 255.78,
monoclinic, space group C2/c, Mo KR, final R indices [I > 2σ(I)], R1 )
0.0764, wR2 ) 0.2031, a ) 28.868(13) Å, b ) 7.868(3) Å, c ) 6.302(3)
Å, R ) 90°, â ) 90°, γ ) 90°, V ) 1431.5(11) Å3, T ) 293(2) K, Z ) 4,
reflections collected/unique 7200/2513 (Rint ) 0.0941), no observation
[I > 2σ(I)] 2080, parameters 151. CCDC 247772. Crystal data for
compound (E)-6e: C16H18NOCl, MW ) 275.76, monoclinic, space group
C2/c, Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0512, wR2 ) 0.0928,
a ) 8.6640(16) Å, b ) 9.2920(17) Å, c ) 9.9179(19) Å, R ) 104.905(3)°,
â ) 103.761(3)°, γ ) 101.298(3)°, V ) 720.8(2) Å3, T ) 293(2) K, Z )
2, reflections collected/unique 4341/3136 (Rint ) 0.0620), no observation
[I > 2σ(I)] 1625, parameters 245. CCDC 247771.
(20) Brandsma, L. In Preparative acetylenic Chemistry; Elsevier:
Amsterdam, The Netherlands, 1988.
(21) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393.
(22) Ba¨ckvall, J. E.; Gogoll, A. Tetrahedron Lett. 1998, 29, 2243.
(23) Grennberg, H.; Gogoll, A.; Ba¨ckvall, J. E. Organometallics 1993,
12, 1790.
0
8
a
0
8
a
0
8
a
a No (E)-6a was detected. b 3 equiv of H2O was added. c 2 equiv
of HCl (12 M) was added. d 2 equiv of AcOH was added. e 2 equiv
of LiCl was added instead of CuCl2.
longer reaction time, the yield decreased probably due
to the instability of E-6a (entries 5 and 6, Table 1). The
reaction with 1 equiv of CuCl2 afforded (E)-6a in similar
yield. However, it should be noted that no (E)-6a was
found in the absence of CuCl2 (entry 7, Table 1). Although
it was reported that an acid is required for the oxidation
of a Pd(0) species by benzoquinone,23 no (E)-6a was
2590 J. Org. Chem., Vol. 70, No. 7, 2005

(E)-R-Chloroalkylidene-â-lactams
TABLE 2. PdCl2-Catalyzed Cyclocarbonylation of
SCHEME 5
Propargylic Amine 3c and N-Benzyl Propargylic Amine
4c
temp
(°C)
time
(h)
isolated
yield (%)
entry
R3
product
1
2
3
4
5
H (3c)
30
40
30
40
40
8
8
(E)-6c
(E)-6c
(E)-6i
(E)-6i
(E)-6i
32
53
15
31
80
H (3c)
Bn (4c)
Bn (4c)
Bn (4c)
8
8
12
TABLE 3. PdCl2-Catalyzed Cyclocarbonylation
gylic amines is depicted in Scheme 5. The coordination
of the triple bond in 3 or 4 with PdCl2 gave complex M1,
which was followed by trans-chlorometalation to give M2.
The subsequent coordination and insertion of CO afforded
intermediate M3. Reductive elimination of M3 would
afford (E)-6 and Pd(0), which would be oxidized with
CuCl2 and benzoquinone to generate PdCl2. Benzo-
quinone and CuCl2 are both essential for a high-yielding
reaction: CuCl2 may provide the source of Cl- as well as
serve as an oxidant since no E-6a was formed when LiCl
was used instead of CuCl2 (entry 11, Table 1). Benzo-
quinone is not only helpful for oxidation,22,23 but also
plays a key role in reductive elimination of M3.24 Com-
pared to the stereochemistry of the similar reaction with
propargylic alcohols,18 the trans-chlorometalation of the
C-C triple bond may be due to the relatively stronger
coordination ability of the amine functionality, which led
to the attack of Cl- from the outside of the coordination
sphere of palladium.25
In summary, we have developed a mild and efficient
methodology for the synthesis of (E)-R-chloroalkylidene-
â-lactams in moderate to good yields. Highly optically
active (E)-R-chloroalkylidene-â-lactams can be easily
formed from the readily available optically active prop-
argylic amines without obvious racemization. trans-
Chlorometalation of the carbon-carbon triple bond was
observed in the reaction. Further studies in this area are
being pursued in our laboratory.
Reaction of Various Propargylic Amines in the Presence
of CuCl2 and Benzoquinone
time
isolated
entry
R1
R2
R3
(h) product yield (%)
1
2
3
4
5
6
7
8
9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
Ph
n-C5H11
C2H5
H (3a)
H (3b)
H (3c)
8
8
8
8
(E)-6a
(E)-6b
(E)-6c
(E)-6d
52
48
53
50
32
42
61
78
80
63
70
61
36
NR
i-Pr
cyclohexyl H (3d)
cyclohexyl H (3e) 10.5 (E)-6e
PhCH2CH2 i-Pr
H (3f)
8
(E)-6f
(E)-6g
(E)-6h
(E)-6i
(E)-6j
(E)-6k
(E)-6l
(E)-6m
n-C4H9
n-C4H9
n-C4H9
n-C5H11
C2H5
i-Pr
Bn (4a) 12
Bn (4b) 12
Bn (4c) 12
10 n-C4H9
cyclohexyl Bn (4d) 12
11 PhCH2CH2 i-Pr
Bn (4f) 12
Bn (4h)
Ts (4l) 12
H (3g)
12 n-C4H9
13 n-C4H9
14 tBu
Me
Ph
i-Pr
8
8
NMR and TLC analysis of the crude reaction mixtures.
It is quite interesting to note that the stereochemistry is
opposite to what was observed with propargylic alco-
hols.18
Then we investigated the PdCl2-catalyzed cyclocarbo-
nylation of various propargylic amines in the presence
of CuCl2 and benzoquinone. The typical results were
summarized in Table 3, which led to the following
conclusions: (1) the reaction is very general, R1, R2 can
be alkyl, aryl group and R3 can be hydrogen (entries 1-6,
Table 3), benzyl (entries 7-12, Table 3), and p-toluene-
sulfonyl group (entry 13, Table 3); (2) when R1 was a
Experimental Section
Synthesis of Starting Materials. Compounds 1a-h were
prepared via the reaction of the corresponding 1-alkynyl-
lithium with aldehydes as reported.20 Propargylic amines 3a-g
were prepared by the application of the Mitsunobu reaction.14
Synthesis of N-(Dodec-5-yn-7-yl)amine (3a). Typical
Procedure I. To a solution of 1a (8.19 g, 45 mmol), phthal-
imide (7.296 g, 49.6 mmol), and PPh3 (12.982 g, 49.5 mmol) in
300 mL of dry THF was added 25 mL (40% in toluene, 9.57
g/55 mmol) of diethyl azodicarboxylate. The resulting yellow
solution was stirred under a N2 atmosphere at room temper-
ature for 29 h. The solvent was removed in vacuo to afford a
semisolid, which was extracted with 1:1 ether-petroleum
ether. The resulting precipitate was dissolved with several
portions of 1:1 ether-petroleum ether. After concentration of
t
bulky group such as Bu, the reaction did not proceed
(entry 14, Table 3); and (3) the yields of products ranged
from 32% to 80%.
Next we examined the cyclocarbonylation reaction of
optically active propargylic amines under the standard
reaction conditions. Some typical results are listed in
Table 4. As can be seen from Table 4, both R and S
substrates can smoothly afford the corresponding prod-
ucts. Racemization of the chiral centers in (R)- or (S)-3
or -4 was not obvious.
(24) Albe´niz, A. C.; Espinet, P.; Mart´ın-Ruiz, B. Chem. Eur. J. 2001,
2481.
Mechanistic Considerations. A plausible mecha-
nism for PdCl2-catalyzed cyclocarbonylation of propar-
(25) Ma, S.; Lu, X. J. Org. Chem. 1991, 56, 5120 and the references
therein.
J. Org. Chem, Vol. 70, No. 7, 2005 2591

Ma et al.
TABLE 4. The Synthesis of Optically Active (E)-r-Chloroalkylidene-â-lactams
the filtrate, the residue was purified via flash chromatography
on silica gel with petroleum ether/ether (20:1) to yield 10.962
g (78%) of 2a.
(711 mg, 4.16 mmol) in 10 mL of dry CH3CN. The reaction
was stirred in N2 atmosphere at room temperature for 20 h.
The precipitate was removed by filtration and the residue was
purified via flash chromatography on silica gel (eluent: pe-
troleum ether:ethyl acetate 20:1) to afford 629 mg (59%) of
A solution of the above 2a (10.781 g, 34.7 mmol) and 10 mL
of hydrazine hydrate in 180 mL of absolute EtOH was heated
to reflux for 5.5 h resulting in the formation of a white
precipitate. The reaction mixture was cooled to room temper-
ature followed by the addition of 40 mL of concentrated HCl.
After being stirred for 1 h, the precipitate was removed by
filtration and the filtrate was concentrated to a solid residue,
which was diluted with ether. The mixture was brought to pH
>10 by the addition of aqueous NaOH. The solution was
extracted with 7 × 30 mL of Et2O. The combined extracts were
dried with Na2SO4, filtered, concentrated, and purified via
flash chromatography on silica gel (eluent: petroleum ether:
ethyl acetate 15:1) to afford 3.568 g (57%) of 3a: liquid; 1H
NMR (300 MHz, CDCl3) δ 3.60-3.45 (m, 1 H), 2.18 (dt, J )
2.0 and 6.8 Hz, 2 H), 1.62-1.20 (m, 14 H), 0.91 (t, J ) 7.1 Hz,
3 H), 0.90 (t, J ) 6.8 Hz, 3 H); 13C NMR (75.4 MHz, CDCl3) δ
83.7, 82.3, 43.6, 38.5, 31.4, 30.9, 25.7, 22.5, 21.8, 18.2, 13.9,
13.5; MS (EI) m/z (%) 182 (M+ + 1, 19.60), 110 (100); IR (neat)
2931, 2228, 1593 cm-1; HRMS (EI) calcd for C12H23N 181.1831,
found 181.1821.
1
4a: liquid; H NMR (300 MHz, CDCl3) δ 7.47-7.20 (m, 5 H),
4.01 (d, J ) 12.6 Hz, 1 H), 3.79 (d, J ) 12.6 Hz, 1 H), 3.34 (dt,
J ) 1.9 and 5.6 Hz, 1 H), 2.24 (dt, J ) 1.5 and 6.8 Hz, 2 H),
1.75-1.13 (m, 13 H), 0.93 (t, J ) 7.4 Hz, 3 H), 0.88 (t, J ) 6.8
Hz, 3 H); 13C NMR (75.4 MHz, CDCl3) δ 140.3, 128.3, 128.3,
126.8, 83.9, 81.4, 51.4, 49.6, 36.3, 31.6, 31.1, 25.7, 22.6, 21.9,
18.4, 14.0, 13.6; MS (EI) m/z (%) 272 (M+ + 1, 4.33), 271 (M+,
1.93), 200 (M+ - C5H11, 94.72), 91 (100); IR (neat) 3368, 2221,
1604 cm-1; HRMS (MALDI/DHB) calcd for C19H30N (M+ + 1)
272.2373, found 272.2378.
N-(Oct-3-yn-2-yl)-N-benzylamine (4h). To a solution of
1h (5.565 g, 44.2 mmol) was added Et3N (12.4 mL, 8.928 g,
88.4 mmol) in 90 mL of dry CH2Cl2. After the reaction mixture
was cooled to 0 °C, a solution of MsCl (5.13 mL, 7.594 g, 66.3
mmol) in 15 mL of CH2Cl2 was added dropwise. After being
stirred at 0 °C for 4 h the reaction was extracted with 3 × 15
mL of CH2Cl2. The combined extracts were washed with
saturated aqueous NaHCO3 and NaCl solution, dried over Na2-
SO4, and evaporated to afford 408 mg of 5 (yellow oil). The
reaction of the above obtained 5 and BnNH2 (0.44 mL, 430
mg, 4.0 mmol) in 4 mL of dry CH3CN was stirred at room
Synthesis of N-(Dodec-5-yn-7-yl)-N-benzylamine (4a).
Typical Procedure II. To a solution of 3a (710 mg, 3.92
mmol) and K2CO3 (570 mg, 4.13 mmol) was added PhCH2Br
2592 J. Org. Chem., Vol. 70, No. 7, 2005

(E)-R-Chloroalkylidene-â-lactams
temperature for 24 h. Then the solution was extracted with 3
× 15 mL of Et2O. The combined extracts were washed with
saturated NaCl and dried over Na2SO4. After evaporation, the
residue was purified by flash chromatography on silica gel
(eluent: petroleum ether:ethyl acetate 10:1) to afford 260 mg
(m, 1 H), 1.68-1.51 (m, 3 H), 1.50-1.18 (m, 8 H), 0.93 (t, J )
7.4 Hz, 3 H), 0.90 (t, J ) 6.6 Hz, 3 H); 13C NMR (75.4 MHz,
CDCl3) δ 162.8, 137.7, 136.4, 57.6, 34.5, 31.8, 31.5, 29.1, 24.7,
22.4, 21.5, 13.9, 13.7; MS (EI) m/z (%) 246 (M+ + 1(37Cl), 1.57),
244 (M+ + 1(35Cl), 5.06), 41 (100); IR (neat) 3235, 1748, 1713
cm-1; HRMS calcd for C13H22NO (M+ - Cl) 208.1701, found
208.1715.
Synthesis of ((E)-6i). Typical Procedure IV. In a flame-
dried nitrogen-flushed flask, a solution of 4c (142 mg, 0.58
mmol) and anhydrous CuCl2 (165 mg, 1.22 mmol) in 8 mL of
dry THF was stirred for 5 min at room temperature followed
by the addition of PdCl2 (6 mg, 0.034 mmol) and benzoquinone
(68 mg, 0.63 mmol). Then the flask was transferred to a Parr
pressure reactor. The Parr reactor was charged with 300 psi
of CO gas. After the mixture was stirred for 12 h at 40 °C, the
gas was ventilated, and the residue was diluted with CH2Cl2.
Filtration through a short column of silica gel, evaporation,
and flash chromatography on silica gel (eluent: petroleum
ether:ethyl 20:1) afforded 143 mg (80%) of (E)-6i.
1
(61%, two steps) of 4h: liquid; H NMR (300 MHz, CDCl3) δ
7.60-7.00 (m, 5 H), 3.99 (d, J ) 12.6 Hz, 1 H), 3.79 (d, J )
12.6 Hz, 1 H), 3.60-3.40 (m, 1 H), 2.22 (dt, J ) 1.7 and 7.1
Hz, 2 H), 1.80-1.25 (m, 5 H), 1.34 (d, J ) 6.9 Hz, 3 H), 0.93 (t,
J ) 6.9 Hz, 3 H); 13C NMR (75.4 MHz, CDCl3) δ 140.1, 128.4,
128.3, 126.9, 83.2, 82.2, 51.4, 44.6, 31.0, 22.7, 21.9, 18.3, 13.6;
MS (EI) m/z (%) 215 (M+, 0.69), 200 (M+ - CH3, 36.99), 91
(100); IR (neat) 2932, 2228, 1603 cm-1; HRMS calcd for
C15H21N (M+) 215.1674, found 215.1689.
N-(1-Phenyl-2-heptynyl)-p-toluenesulfonamide (4l).21
In a flame-dried argon-flushed flask, a solution of 1-hexyne
(818 mg, 10 mmol) in 15 mL of dried THF was cooled to -78
°C. Then n-BuLi (6.25 mL, 1.6 M in hexane, 10 mmol) was
added dropwise to the solution via a syringe. After the mixture
was stirred at -78 °C for 30 min, a solution of N-(p-
toluenesulfonyl)benzaldimine (2.593 g, 10 mmol) in 10 mL of
dried THF was added. The reaction mixture was stirred at
-78 °C and warmed to room temperature overnight. Then
saturated aqueous NH4Cl was added to the reaction mixture
to stop the reaction. The mixture was extracted with Et2O,
washed by saturated NaCl solution, and dried over Na2SO4.
After evaporation, the residue was purified via flash chroma-
tography on silica gel with petroleum ether/ethyl acetate (5:
(E)-r-(1-Chloropentylidene)-â-(isopropyl)-N-benzyl-â-
1
lactam ((E)-6i): liquid; H NMR (300 MHz, CDCl3) δ 7.43-
7.21 (m, 5 H), 4.86 (d, J ) 15 Hz, 1 H), 4.09 (d, J ) 15 Hz, 1
H), 4.00 (d, J ) 2.1 Hz, 1 H), 2.99-2.83 (m, 1 H), 2.80-2.65
(m, 1 H), 2.32-2.15 (m, 1 H), 1.70-1.53 (m, 2 H), 1.45-1.31
(m, 2 H), 1.01-0.88 (m, 9 H); 13C NMR (75.4 MHz, CDCl3) δ
162.7, 135.7, 135.5, 135.4, 128.7, 128.2, 127.7, 65.2, 45.6, 34.9,
29.2, 28.0, 21.5, 19.3, 16.6, 13.7; MS (EI) m/z (%) 307 (M+(37Cl),
1.24), 305 (M+(35Cl), 4.07), 264 (M+ - C3H7(37Cl), 35.84), 262
(M+ - C3H7(35Cl), 100); IR (neat) 1748, 1713 cm-1; HRMS
(MALDI/DHB) calcd for C18H2535ClNO (M+ + 1) 306.1619,
found 306.1640.
1
1) to yield 2.968 g (87%) of 4l. H NMR (300 MHz, CDCl3) δ
7.76 (dd, J ) 1.8 and 6.9 Hz, 2 H), 7.52-7.42 (m, 2 H), 7.38-
7.25 (m, 5 H), 5.29 (dt, J ) 2.0 and 9.0 Hz,1 H), 4.99 (d, J )
8.4 Hz, 1 H), 2.43 (s, 3 H), 2.01-1.89 (m, 2 H), 1.38-1.18 (m,
4 H), 0.92-0.79 (m, 3 H); 13C NMR (75.4 MHz, CDCl3) δ 143.2,
138.1, 137.5, 129.3, 128.5, 128.1, 127.4, 127.2, 87.4, 76.5, 49.4,
30.3, 21.8, 21.5, 18.2, 13.5.
(R)-(+)-(E)-r-(1-Chloro-3-phenylpropylidene)-â-(iso-
propyl)-â-lactam ((R)-(+)-(E)-6f): The reaction of (R)-(-)-3f
(154 mg, 0.77 mmol, 98% ee), PdCl2 (7 mg, 0.04 mmol), CuCl2
(217 mg, 1.6 mmol), and benzoquinone (87 mg, 0.8 mmol)
afforded 111 mg (55% yield) of (R)-(+)-(E)-6f with 97% ee as
determined by HPLC analysis (Chiralcel OJ, n-hexane:i-PrOH
90:10, 230 nm), tr ) 7.8 (minor), 9.9 (major); [R]20D +65.7 (c )
1.45, CHCl3).
PdCl2-Catalyzed Cyclocarbonylation Reaction of Vari-
ous Propargylic Amines in the Presence of CuCl2 and
Benzoquinone. Synthesis of (E)-6a. Typical Procedure
III. In a flame-dried nitrogen-flushed flask, a solution of 3a
(165 mg, 0.91 mmol) and anhydrous CuCl2 (188 mg, 1.39 mmol)
in 10 mL of dry THF was stirred for 5 min at room temper-
ature followed by the addition of PdCl2 (8 mg, 0.045 mmol)
and benzoquinone (98 mg, 0.91 mmol). Then the flask was
transferred to a Parr pressure reactor. The Parr reactor was
charged with 300 psi of CO gas. After the mixture was stirred
for 8 h at 40 °C, the gas was ventilated, and the residue was
diluted with CH2Cl2. Filtration through a short column of silica
gel, evaporation, and flash chromatography on silica gel
(eluent: petroleum ether:ethyl acetate 15:1) afforded 116 mg
(52%) of (E)-6a.
Acknowledgment. Financial support from the Ma-
jor State Basic Research Development Program (Grant
No. G200077500), the National Nature Science Founda-
tion of China, and the Shanghai Municipal Committee
of Science and Technology is greatly appreciated.
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products not listed in
the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
(E)-r-(1-Chloropentylidene)-â-(n-pentyl)-â-lactam ((E)-
6a): liquid; 1H NMR (300 MHz, CDCl3) δ 7.04 (br s, 1 H), 4.17
(dd, J ) 3.2 and 8.3 Hz, 1 H), 2.85-2.65 (m, 2 H), 2.05-1.90
JO0480996
J. Org. Chem, Vol. 70, No. 7, 2005 2593