γ-Heteroatom directed stereocontrolled Staudinger cycloaddition reaction of vinylketenes and imines

Article abstract of DOI:10.1016/j.tetlet.2006.05.189

Vinylketenes possessing a γ-heteroatom, on Staudinger cycloaddition reaction with imines gave trans-3-vinyl-β-lactams in very good yields. The vinyl side chain stereoselectively adopts the Z-configuration in the transition state to stabilize the vinylkete

Full text of DOI:10.1016/j.tetlet.2006.05.189

Tetrahedron Letters 47 (2006) 5993–5996
c-Heteroatom directed stereocontrolled Staudinger
cycloaddition reaction of vinylketenes and imines
Aarif L. Shaikh,a Vedavati G. Puranikb and A. R. A. S. Deshmukha,*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
bCenter for Materials and Characterization, National Chemical Laboratory, Pune 411 008, India
Received 30 March 2006; revised 12 May 2006; accepted 17 May 2006
Abstract—Vinylketenes possessing a c-heteroatom, on Staudinger cycloaddition reaction with imines gave trans-3-vinyl-b-lactams in
very good yields. The vinyl side chain stereoselectively adopts the Z-configuration in the transition state to stabilize the vinylketene
and produces, exclusively, trans-3-vinyl-b-lactams.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The b-lactam skeleton is recognized as a key structural
unit of the most widely employed class of b-lactam anti-
biotics.1 The constant need for new drugs displaying
broader antibacterial activity and the necessity for new
b-lactam antibiotics to combat microorganisms that
have built up resistance against traditional drugs,2 have
maintained the interest of organic chemists for decades.
As a consequence, a large number of methods are avail-
able for their syntheses and the topic has been exten-
sively reviewed.3 The most convenient procedure for
the synthesis of the b-lactam ring skeleton is the [2+2]
cyclocondensation of ketenes with imines, a procedure
commonly known as the Staudinger reaction.4 In partic-
ular, this method has provided useful and economic en-
tries to b-lactams, mainly due to the ready availability of
both Schiff’s bases and ketenes. In this context, in spite
of the high level of achievement reached in the Stau-
dinger reaction, the subject still continues to be an active
area of research,5 both from synthetic and mechanistic
points of view. We have been using the Staudinger
cycloaddition reaction6 for the diastereoselective synthe-
sis of b-lactams and studied their synthetic utility7 for
the synthesis of various biologically active compounds
for several years. In this letter, we report our work on
the synthesis of trans-3-vinyl-b-lactams employing the
cycloaddition reaction of vinylketenes with imines.
3-Vinyl-b-lactams are important intermediates in the
synthesis of biomedicinally interesting compounds such
as carbapenem,8 asparenomycin9 and thienamycin.10
These b-lactams are prepared by cycloaddition of vinyl-
ketenes with imines. In most of the cases, the vinyl
ketenes are generated from either crotonoyl chloride or
b,b-dimethylacryloyl chloride.11,12 Although normal ket-
enes are extensively used in ketene–imine cycloaddition
reactions, vinylketenes, also referred to as Sheehan’s ket-
enes,11 have not been fully explored. This may be due to
lower yields and variable diastereoselectivities of the
b-lactam formation.13 In general, the stereochemical
outcome of the reaction depends upon the substituents
present on the imine. Imines prepared from aromatic
aldehydes and arylamines give trans-b-lactams, while
imines with alkyl or electron-withdrawing substituents
give either cis or a mixture of cis and trans products.14
Bose et al. have shown that ketenes generated from an
acid chloride with a heteroatom, such as oxygen or
nitrogen at the a-position, in general, give moderate to
good yields of b-lactams with a preference for the cis
product.15 We envisaged that vinylketenes with a hetero-
atom at the c-position would also have some influence
on the diastereoselectivity in the [2+2] cycloaddition
reactions with imines. With this idea in mind we pre-
pared 4-phenoxybut-2-enoyl chloride (4a), a precursor
for phenoxyvinyl ketene, from methyl-4-bromo-2-bute-
noate 1 (Scheme 1).
Keywords: Staudinger reaction; Stereoselective synthesis; Vinylketenes;
Imines.
*
Initially imine 5a was reacted with the ketene, gener-
ated from 4-phenoxybut-2-enoyl chloride (4a) and
Corresponding author. Fax: +91 20 25902624; e-mail: aras.
deshmukh@ncl.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.189

5994
A. L. Shaikh et al. / Tetrahedron Letters 47 (2006) 5993–5996
H
H
H
H
H
OMe
OH
a)
H
H
O
OMe
+
Br
O
O
O
C
O
O
C
O
Ph
O
Ph
OH
O
O
1
O
2
H
H
Ph
A
B
C
c)
b)
Cl
Figure 2. Confirmations of the phenoxyvinyl ketene.
O
O
4a
3
imines 5a–g with various substituents. In all the cases,
irrespective of the substituents on the imine, only
trans-b-lactam formation was observed.
Scheme 1. Reagents and conditions: (a) K2CO3, PTCs, acetone, reflux,
2 h; (b) 1 M NaOH, THF, rt, 15 h; (c) (COCl)2, DCM, reflux 4 h.
We believe that the phenoxyvinyl side chain stereoselec-
tively adopts the Z-configuration to stabilize the ketene
via participation of the oxygen lone pair of electrons
(Fig. 2). In the cycloaddition reaction, the stereochemi-
cal outcome can depend upon the configuration of the
imine.18 The Z-imine can react with the ketene in an
exo-mode to give the zwitterionic transition state TS-1.
Similarly, the E-imine can react only in an endo-mode
to give TS-2 (Fig. 3).
triethylamine, at À40 ꢁC for 30 min and then further
stirred at room temperature for 15 h. A small amount
of trans-vinyl-b-lactam 6a (10%) was isolated from the
reaction mixture. The structure of 6a was established
1
by IR and H NMR spectroscopy. The IR spectrum
showed an absorption at 1756 cmÀ1 for the b-lactam
1
carbonyl group. The H NMR spectrum revealed the
trans stereochemistry for the b-lactam ring (J = 2.5 Hz
for the ring protons) and a Z geometry at the C3 vinyl
side chain (J = 6.0 Hz for the Z-protons of the double
bond). The structure was further confirmed by single
crystal X-ray analysis (Fig. 1).16
TS-1 on conrotatory ring closure would provide a trans-
b-lactam, while TS-2 should give a cis-b-lactam.
Although, the E-imine is more stable compared to the
corresponding Z-imine, it is less reactive due to severe
steric interaction between the phenoxy group and the
aryl group of the imine in the transition state TS-2. This
steric interaction is absent in TS-1, which arises from the
exo attack of the Z-imine to the vinylketene. Therefore,
TS-1 is preferentially formed, which on conrotatory ring
closure gives trans-b-lactams. The rate of the reaction
depends upon the rate of equilibrium of the E and
Z-imines.
An excellent yield of 6a along with a small amount of
the E-isomer 7a (J = 2.5 Hz for the ring protons and
J = 12.0 Hz for the E-protons of the double bond) was
obtained (Z/E = 9/1) when a solution of acid chloride
4a in dichloromethane was added to a solution of imine
5a and triethylamine at 0 ꢁC and then refluxed for 15 h.
Both the isomers (6a and 7a) were separated by flash
1
column chromatography.17 The H NMR spectrum of
the crude product revealed the formation of only the
trans-b-lactam and no trace of the cis-b-lactam was
detected (Scheme 2).
The formation of the trans-b-lactams can also be ex-
plained by the isomerization of TS-2 to the more favor-
able TS-1 followed by conrotatory ring closure.
However, this seems to be less likely as this would pro-
vide, in some cases, depending upon the nature of the
substituents present on the imine,19 a mixture of cis
and trans-b-lactams. In fact, irrespective of the substitu-
ents on the imine, only trans-3-vinyl-b-lactam formation
was observed in the cycloaddition reaction (Table 1).
Several vinyl-b-lactams were prepared in very good
yields from 4-phenoxybut-2-enoyl chloride (4a) and
H
H
Ph Ar
H
Ar
H H
Ar
O
O
Ph
N
PMP
H
N
N
O
PMP
PMP
O
TS-1 (exo)
H
Figure 1. ORTEP diagram of 6a.
H
H
Ar
C
O O
Ph
N
Ph
PMP
H
H
PhO
+
N
5a
H
H
N
H
H
N
H
Ph
Ar
H H
N
Ph
Ph
PMP
Ar
O
Cl
O
Ph
N
PhO
PhO
PMP
H
O
PMP
O
Et3N, DCM,
O
O
PMP
O
PMP
0 oC-reflux, 15 h
4a
6a (major)
7a (minor)
TS-2 (endo)
Figure 3. Plausible mechanism for the formation of a trans-b-lactam.
Scheme 2.

A. L. Shaikh et al. / Tetrahedron Letters 47 (2006) 5993–5996
Table 1. Synthesis of trans-3-vinyl-b-lactams 6a–k and 7a–k
5995
b-Lactams 6 and 7
R
R1
R2
Ratio of 6:7b
Yieldc (%)
Mp of 6 (ꢁC)
Mp of 7 (ꢁC)
a
b
c
d
e
f
OPh
OPh
OPh
OPh
OPh
OPh
OPh
OMe
OMe
Phtha
N3
PMPa
PMP
Ph
Ph
PMP
Ph
PMP
Ph
Ph
CO2Me
Ph
Ph
Ph
Ph
90:10
92:8
91:9
80
77
75
73
78
83
70
75
85
61
66
128–129
125–126
131–132
139–140
112–113
122–123
Oil
88–89
95–96
109–110
Oil
Thick oil
Thick oil
Thick oil
Thick oil
Oil
Oil
—
Oil
Oil
Ph
93:7
4-ClC6H4
4-CH3C6H4
PMP
Ph
PMP
Ph
89:11
90:10
100:0
92:8
90:10
85:15
80:20
g
h
i
j
Oil
Oil
k
Ph
a Phth = phthalimido, PMP = 4-MeOC6H4.
b The ratio of the diastereomers 6 and 7, from 1H NMR.
c Isolated yields of the diastereomeric mixture of 6 and 7.
R2
N
H
H
N
R
R2
R1
R1
H
H
N
R2
R1
Cl
O
5
Cl
+
+
R
R
R
Et3N, DCM,
reflux, 18-48 h
O
O
O
4'b-e (minor)
4b-e (major)
6 (major)
7 (minor)
5b, R1 = PMP, R2 = PMP
5c, R1 = Ph, R2 = Ph
4b, 4'b, R = OMe
4c, 4'c, R = Phth
4d, 4'd, R = N3
4e, 4'e, R = SPh
5d, R1 = Ph, R2 = PMP
5e, R1 = 4-ClC6H4, R2 = Ph
5f, R1 = 4-CH3C6H4, R2 = Ph
5g, R1 = PMP, R2 = CO2Me
Scheme 3.
Similar results were obtained with ketenes having
c-methoxy, azido and phthalimido groups (Scheme 3,
Table 1). In all the cases, irrespective of the substituents
on the imine, only trans 3-vinyl-b-lactams with Z-stereo-
chemistry at the vinyl side chain were formed. A small
amount of the E-isomer possibly arose from thermal
isomerization of the Z-vinyl side chain.
References and notes
1. For reviews on b-lactam antibiotics, see: (a) Durkheimer,
¨
W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H.
Angew. Chem., Int. Ed. Engl. 1985, 24, 180–202; (b)
Chemistry and Biology of b-Lactam Antibiotics; Morin, R.
B., Gorman, M., Eds.; Academic: New York, 1982; Vols.
1–3, (c) Coulton, S.; Hunt, E.. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products; Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p
621; (d) Southgate, R. Contemp. Org. Synth. 1994, 1, 417–
432.
Also, the ketenes generated from 4c and 4d (R = Phth,
N3) gave trans-b-lactams 6j–k and 7j–k. However, the
reaction was slow and gave lower yields of the vinylazeti-
din-2-one. The thiophenoxyketene generated from 4e did
not undergo the cycloaddition reaction with imine 5a.
2. The Chemistry of b-lactams; Page, M. I., Ed.; Chapman
and Hall: London, 1992.
3. For comprehensive general reviews, see: (a) Koppel, G. A.
In Small Ring Heterocycles; Hasner, A., Ed.; Wiley: New
York, 1983; Vol. 42, p 219; (b) Backes, J., In Houben-
Weyl, Methoden der Organischem Chemie, Muller, E.,
Bayer, O., Eds.; Thieme: Stuttgart, 1991; Band E16B, p 31;
(c) de Kimpe, N. In Comprehensive Heterocyclic Chemis-
try II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Padwa, A., Eds.; Pergamon: Oxford, 1996; Vol. 1B, p 507.
4. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
5. (a) Singh, G. S. Tetrahedron 2003, 59, 7631–7649, and
references cited therein; (b) Alcaide, B.; Almendros, P.
Chem. Soc. Rev. 2001, 30, 226–240; (c) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oirabide, M. Eur. J. Org.
Chem. 1999, 8, 3223–3235; (d) Palomo, C.; Aizpurua, J.;
Mielgo, A.; Linden, A. J. Org. Chem. 1996, 61, 9186–9195.
6. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
J. Org. Chem. 1994, 59, 932–934; (b) Srirajan, V.;
In conclusion, we have shown that the c-heteroatom on
a vinylketene directs imine approach in the Staudinger
cycloaddition reaction. Irrespective of the substituents
on the imine, only trans-3-vinyl-b-lactam formation
was observed. Further work on the applications of
trans-3-vinyl-b-lactams as building blocks in organic
synthesis is in progress.
Acknowledgments
The authors thank DST, New Delhi, for financial sup-
port and A.L.S. thanks CSIR, New Delhi, for a research
fellowship.

5996
A. L. Shaikh et al. / Tetrahedron Letters 47 (2006) 5993–5996
Deshmukh, A. R. A. S.; Puranik, V. G.; Bhawal, B. M.
direct methods using SHELXTL. Least squares refinement
of scale, positional and anisotropic thermal parameters for
Tetrahedron: Asymmetry 1996, 7, 2733–2738; (c) Bhawal,
B. M.; Joshi, S. N.; Krishnaswamy, D.; Deshmukh, A. R.
A. S. J. Indian Inst. Sci. 2001, 81, 265–276; (d) Arun, M.;
Joshi, S. N.; Puranik, V. G.; Bhawal, B. M.; Deshmukh,
A. R. A. S. Tetrahedron 2003, 59, 2309–2316; (e) Jayanthi,
A.; Puranik, V. G.; Deshmukh, A. R. A. S. Synlett 2004,
1249–1253; (f) Jayanthi, A.; Thiagrajan, K.; Puranik, V.
G.; Bhawal, B. M.; Deshmukh, A. R. A. S. Synthesis 2004,
18, 2965–2974; (g) Shaikh, A. L.; Puranik, V. G.;
Deshmukh, A. R. A. S. Tetrahedron 2005, 61, 2441–2451.
non hydrogen atoms converged to R = 0.0654. Rw
=
0.1112 for 3476 unique observed reflections. Hydrogen
atoms were geometrically fixed. The refinements were
carried out using SHELXTL-97. Largest diff. peak and hole
0.148 and À0.113eÆAÀ3. Crystallographic data (excluding
˚
structure factors) for the structure 6a in this letter have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
606327.
7. (a) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnas-
wamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A.
Curr. Med. Chem. 2004, 11, 1889–1920, and references
cited therein; (b) Shirode, N. M.; Kulkarni, K. C.;
Gumaste, V. K.; Deshmukh, A. R. A. S. ARKIVOC,
2005; (i), 53–64; (c) Kale, A. S.; Deshmukh, A. R. A. S.
Synlett 2005, 2370–2372; (d) Tiwari, D. K.; Gumaste, V.
K.; Deshmukh, A. R. A. S. Synthesis 2006, 115–122.
8. (a) Banik, B. K.; Manhas, M. S.; Newaz, S. N.; Bose, A.
K. Bioorg. Med. Chem. Lett. 1993, 3, 2363–2368; (b)
Palomo, C. In Recent Progress in the Chemical Synthesis of
Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-Verlag:
Berlin, 1990; p 565.
9. (a) Buynak, J. D.; Rao, M. N.; Pajouhesh, H.; Chandra-
sekaran, R. Y.; Finn, K.; deMeester, P.; Chu, S. C. J. Org.
Chem 1985, 55, 4245; (b) Buynak, J. D.; Mathew, J.;
Narayana Rao, M.; Haley, E.; George, C.; Siriwardane,
U. J. Chem. Soc., Chem. Commun. 1987, 735–737.
10. (a) Fetter, J.; Lempert, K.; Gigur, T.; Nyitrai, J.; Kajtar-
Peredy, M.; Simig, G.; Hornyak, G.; Doleschall, G.
J. Chem. Soc., Perkin Trans. 1 1986, 221–227; (b) Fetter,
J.; Lempert, K.; Kajtar-Peredy, M.; Simig, G.; Hornyak,
G. J. Chem. Soc., Perkin Trans. 1 1986, 1453–1458.
11. Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry
of b-Lactams; VCH: New York, 1993; p 295, and
references cited therein.
12. Manhas, M. S.; Banik, B. K.; Mathur, A.; Vincent, J. E.;
Bose, A. K. Tetrahedron 2000, 56, 5587–5601, and
references cited therein.
13. (a) Bose, A. K.; Spiegelman, G.; Manhas, M. S. Tetra-
hedron Lett. 1971, 34, 3167–3170; (b) Zamboni, R.;
Just, G. Can. J. Chem. 1979, 57, 1945–1948; (c) Bose,
A. K.; Krishnan, L.; Wagle, D. R.; Manhas, M. S.
Tetrahedron Lett. 1986, 27, 5955–5958.
14. Manhas, M. S.; Ghosh, M.; Bose, A. K. J. Org. Chem.
1990, 55, 575–580.
15. Bose, A. K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron
Lett. 1972, 13, 4091–4094.
17. A typical procedure for the synthesis of trans-3-vinyl-b-
lactams 6a and 7a: A solution of 4-phenoxybut-2-enoyl
chloride (4a) (0.280 g, 1.42 mmol) in dry dichloromethane
(20 mL) was added slowly to a mixture of imine 5a
(0.200 g, 0.94 mmol) and triethylamine (0.430 g, 4.26
mmol) in dry dichloromethane (20 mL) at 0 ꢁC. After
addition was complete, the reaction mixture was refluxed
with stirring for 15 h. The reaction mixture was washed
with water (2 · 10 mL), saturated sodium bicarbonate
solution (10 mL) and saturated brine solution (10 mL).
The organic layer was then dried over anhydrous Na2SO4,
and the solvent was removed under reduced pressure to
give a thick brown oil (0.280 g, 80%). 1H NMR of the
crude product showed it to be a mixture of trans-b-lactams
6a and 7a (Z and E isomers 90:10), which were separated
by flash column chromatography (petroleum ether-ethyl
acetate 8:2).
trans-1-(4-Methoxyphenyl)-3-(Z-2-phenoxyvinyl)-4-phenyl-
azetidin-2-one (6a): White needles (MeOH), 0.238 g, 68%;
mp 128–129 ꢁC; IR (CHCl3): 3018, 1741, 1664, 1595, 1512,
1245, 1217 cmÀ1; 1H NMR (200 MHz, CDCl3) d 3.75 (3H,
s, Ph-OCH3), 4.13–4.19 (1H, m, C3H), 4.87 (1H, d,
J = 2.5 Hz, C4H), 5.10 (1H, dd, J = 6.0 Hz, J = 8.0 Hz,
CH@CHOPh), 6.67 (1H, dd, J = 6.0 Hz, J = 1.3 Hz,
CH@CHOPh), 6.77–7.38 (14H, m, Ar–H); 13C NMR
(50 MHz, CDCl3) d 55.4, 55.6, 62.3, 103.9, 114.3, 116.5,
118.3, 123.2, 126.0, 128.4, 128.9, 129.6, 131.4, 137.8, 144.3,
155.9, 156.8, 165.6; MS (m/z): 372 (M+1); Anal. Calcd for
C24H21NO3: C, 77.60; H, 5.69; N, 3.77. Found: C, 77.54;
H, 5.62; N, 3.70%.
trans-1-(4-Methoxyphenyl)-3-(E-2-phenoxyvinyl)-4-phenyl-
azetidin-2-one (7a): Thick oil, 0.042 g, 12%; IR (CHCl3):
3016, 2360, 1743, 1658, 1512, 1240 cmÀ1 1H NMR
;
(200 MHz, CDCl3) d 3.75 (3H, s, Ph-OCH3), 3.68–3.80
(1H, m, C3H), 4.72 (1H, d, J = 2.5 Hz, C4H), 5.53 (1H,
dd, J = 9.3 Hz, J = 12.0 Hz, CH@CHOPh), 6.71–7.38
(15H, m, Ar–H and CH@CHOPh); 13C NMR (75 MHz,
CDCl3) d 55.5, 59.4, 62.7, 104.8, 114.4, 117.1, 118.5, 123.4,
125.9, 128.6, 129.2, 129.7, 137.5, 146.4, 156.2, 156.7, 163.1;
MS (m/z): 372 (M+1); Anal. Calcd for C24H21NO3: C,
77.60; H, 5.69; N, 3.77. Found: C, 77.51; H, 5.60; N, 3.69%.
18. (a) Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.;
Palomo, C. J. Am. Chem. Soc. 1993, 115, 995–1004; (b)
Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad,
D. C. J. Am. Chem. Soc. 1991, 113, 5784–5791.
16. X-ray data for 6a: X-ray structure determination of
C24H21NO3: Colorless needles 0.39 · 0.05 · 0.02 mm
grown from methanol. M = 371.42, Monoclinic, P21/n,
˚
˚
˚
a = 11.3472(2) A, b = 5.9741(8) A, c = 29.163(4) A, b =
3
À3
,
˚
91.397 (2)ꢁ, V = 1976.3(5) A , Z = 4, D = 1.248 mg/cm
l = 0.082 mmÀ1, F(000) = 784, T = 293 K. Data were
collected on a SMART APEX CCD Single Crystal X-ray
˚
diffractometer using Mo-Ka radiation (k = 0.7107 A) to a
19. Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128,
6060–6069.
maximum h range of 25.00ꢁ. The structure was solved by