Kinugasa reaction under click chemistry conditions

Article abstract of DOI:10.1055/s-2007-980383

Various monocyclic P-lactams, both cis and trans, have been successfully prepared via Kinugasa reaction mimicking the click chemistry conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980383

LETTER
1585
Kinugasa Reaction under Click Chemistry Conditions
K
inugasa Reaction
.under
Click
B
C
hemistry Cond
a
itions sak,* K. Chandra, R. Pal, S. C. Ghosh
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: absk@chem.iitkgp.ernet.in
Received 1 March 2007
monocyclic b-lactams in moderate to good yields
mimicking click chemistry conditions. In some cases, the
click chemistry conditions resulted in improved yield.
Abstract: Various monocyclic b-lactams, both cis and trans, have
been successfully prepared via Kinugasa reaction mimicking the
click chemistry conditions.
The Kinugasa reaction is occasionally accompanied by
side products. The main side reaction is the oxidative
dimerization of the terminal acetylene (Glaser coupling)11
and the formation of exomethylene b-lactam with propar-
gyl alcohol.5e The dimerization is due to the presence of
Cu(II) which often contaminates Cu(I) or might have been
generated during the course of the reaction. By carrying
out the reaction in a reductive atmosphere (in the presence
of ascorbic acid), such dimerization can be prevented.
This may also ensure the use of Cu(I) in catalytic amount.
With all these facts in mind, as an initial experiment, the
various alkynes were dissolved in DMF along with Et3N
at 0 °C. The solution was then added to an aqueous solu-
tion of CuSO4 (1 equiv) which was pretreated with sodi-
um ascorbate (2 equiv) for 30 minutes. The various
nitrones12 dissolved in DMF were added to the reaction
mixture. The reaction was complete in about 16–25 hours
after which it was worked up and the cis and trans b-lac-
tams were isolated by silica gel chromatography.13 The re-
action gave almost similar results if CuSO4 was replaced
with Cu(OAc)2. The presence of L-ascorbate is an abso-
lute necessity, as the reaction did not work in its absence,
thus ruling out the involvement of Cu(II) in Kinugasa re-
action. The reaction was free from dimeric acetylenic
products, as was expected. The diastereoselectivity, how-
ever, remained unchanged. The results are shown in
Table 1. Regarding the choice of the solvent, DMF can be
replaced with other solvents like acetonitrile, tert-butanol
or water (Scheme 1). However, amongst the four solvent
systems, acetonitrile–water (2:1) (condition B) gave the
best result in terms of yield. The diastereoselectivity was
almost the same as was observed with other solvent sys-
tems. The click conditions worked really well with prop-
argyl nucleobases; the b-lactam nucleobase chimeric
molecules could be obtained in up to 75% yield (Table 2).
In this case, because of solubility, DMF–water combina-
tion (condition A) had to be employed (Scheme 2).
Key word: Kinugasa reaction, nitrone, b-lactam, click chemistry
Amongst the various heterocyclic ring systems, b-lactams
are possibly one of the best-known and most widely
investigated.1 This is primarily due to their antibacterial
activity, which has so far quite successfully withstood the
onslaught of resistant bacterial infections (e.g. Augmen-
tin) and their ability to act as synthetic intermediates.2
Ever since the discovery of b-lactams, organic chemists
have unraveled various strategies for the synthesis of the
strained 4-membered 2-azetidinone ring. Among these,
Kinugasa reaction,3 involving a Cu(I)-catalyzed cycload-
dition between a nitrone and a terminal acetylene has been
largely neglected. It is only due to recent reports from
Fu’s4 as well as our5 laboratories that this reaction caught
the attention of the scientific community.6 The usual way
of carrying out Kinugasa reaction is to add the solution of
a nitrone in acetonitrile or DMF to an in situ generated
Cu(I) acetylide (acetonitrile or DMF). In the original pa-
per, Kinugasa and Hasimoto3 used pyridine as the solvent.
The mechanism as proposed by Ding and Irwin7 involves
the 1,3-dipolar cycloaddition between the metal acetylide
and the nitrone to form the isoxazoline which then col-
lapses to the b-lactam. The alkyne–nitrone cycloaddition
which would normally occur under refluxing conditions
takes place at room temperature (or even at 0 °C) in the
presence of Cu(I). Recently, a new concept called click
chemistry8 has been developed to generate what are
known as click chemistry products, involving the high-
yielding cyclization of terminal alkyne and azide at room
temperature in the presence of Cu(I). The latter was gen-
erated via reduction of CuSO4 by sodium ascorbate. The
proposed mechanism of click chemistry9 is strikingly sim-
ilar to what has been proposed for Kinugasa reaction. The
logical conclusion that can be immediately drawn is that
perhaps the Kinugasa reaction would work under similar
conditions. Tang et al.10 have earlier reported the use of
Cu(II) perchlorate to carry out the Kinugasa reaction.
These authors used the acetylide to reduce Cu(II) to Cu(I).
The use of ascorbate is simpler and more convenient. In
this paper, we reveal our success in synthesizing various
With water as the only solvent, the reaction worked less
efficiently in terms of yield and duration (usually 30 h)
(see Table 1, entries 12 and 13). The use of organic sol-
vent only led to poor yield (<10%) of the products. The re-
action can also be accomplished with less catalyst [Cu(II)]
loading without sacrificing the yield. The catalyst loading
could be decreased down to 10 mol% (Table 3). Below
this amount, the reaction became sluggish and gave poor
yield.
SYNLETT 2007, No. 10, pp 1585–1588
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Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-980383; Art ID: D05907ST
© Georg Thieme Verlag Stuttgart · New York

1586
A. Basak et al.
LETTER
R
R
HO
H
R
HO
HO
A or B or C or D
+
N
N
+
O
Ph
N
O
Ph
O
Ph
1a
2a–d
3a–d
4a–d
Me
HO
Me
HO
R
R
HO
H
R
A or B or C or D
+
N
+
N
O
Ph
N
O
Ph
O
Ph
1b
2a–d
3e–h
4e–h
OMe
,
2a: R = Ph,
2b: R =
2d: R =
,
2c: R =
S
O
DMF–H2O (1:2)
condition A:
condition C:
condition B:
condition D:
MeCN–H2O (1:2)
H2O
t-BuOH–H2O (1:2)
Scheme 1 Kinugasa reaction under click chemistry conditions
B
B
R
O
H
R
N
N
R
A
N
N
N
H2N
N
O
Ph
O
Ph
Ph
N
1c
2a–d
3i–l
4i–l
B
B
O
R
H
R
R
HN
A
N
O
O
N
N
N
O
Ph
O
Ph
Ph
1d
2a–d
5i–l
6i–l
B
B
R
H
R
O
N
R
A
HN
N
N
N
O
O
O
Ph
O
Ph
Ph
Me
1e
2a–d
7i–l
8i–l
For 2a R = Ph; 2b R = 2-furyl;
2c R = 2-thiophenyl;
For i R = Ph; j R = 2-furyl;
k R = 2-thiophenyl;
2d R = 4-MeOC6H4
l R = 4-MeOC6H4
condition A: DMF–H2O (1:2)
Scheme 2 Synthesis of b-lactam nucleobase chimera under click conditions
In summary we have successfully synthesized various
monocyclic b-lactams as cis and trans forms via Kinugasa
reaction mimicking click chemistry conditions.
Acknowledgment
A.B. thanks CSIR, Government of India for a research grant. K.C.
and R.P. are grateful to CSIR, Government of India for a research
fellowship.
Synlett 2007, No. 10, 1585–1588 © Thieme Stuttgart · New York

LETTER
Kinugasa Reaction under Click Chemistry Conditions
1587
Table 1 Kinugasa Reaction under Click Conditions
Table 3 Effect of Catalyst Loading
Entry
Alkyne
Nitrone
Condition cis/trans Combined
Entry Alkyne Nitrone Catalyst (mol%)
cis/trans Yield
Ratio
2:1
2:1
3:2
2:1
2:1
2:1
3:2
3:2
2:1
3:2
2:1
2:1
2:1
yield (%)
Ratio
(%)
1
2
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1b
2a
2a
2b
2b
2c
2d
2a
2b
2c
2d
2a
2a
2a
A
B
A
B
B
B
B
B
B
B
C
D
D
55
1
2
3
4
5
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
CuSO4·5H2O (50)
CuSO4·5H2O (40)
CuSO4·5H2O (10)
2:1
62
62
60
67
67
64
2:1
3
48
2:1
4
60
Cu(OAc)2·H2O (50) 2:1
Cu(OAc)2·H2O (10) 2:1
5
60
6
62
7
65
References and Notes
8
60
(1) (a) Chemistry and Biology of b-Lactam Antibiotics, Vol. 1;
Morin, R. B.; Gorman, M., Eds.; Academic Press: New
York, 1982. (b) Chemistry and Biology of b-Lactam
Antibiotics, Vol. 2; Morin, R. B.; Gorman, M., Eds.;
Academic Press: New York, 1982. (c) Chemistry and
Biology of b-Lactam Antibiotics, Vol. 3; Morin, R. B.;
Gorman, M., Eds.; Academic Press: New York, 1982.
(d) The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman
& Hall: London, 1992. (e) Antibiotics Containing the b-
Lactam Structure, Part 1; Demain, A. L.; Solomon, N. A.,
Eds.; Springer: Berlin, 1983. (f) Antibiotics Containing the
b-Lactam Structure, Part 2; Demain, A. L.; Solomon, N. A.,
Eds.; Springer: Berlin, 1983.
(2) (a) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30,
226. (b) Alcaide, B.; Almendros, P. Synlett 2002, 381.
(c) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11,
1921. (d) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26,
377. (e) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Curr. Med. Chem. 2004, 11, 1837.
9
61
10
11
12
13
65
55
52
53
Table 2 Preparation of b-Lactam Nucleobase Chimeric Molecules
Entry Alkyne/ Condition cis/trans Total yield Reported
nitrone
1c/2a
1c/2b
1c/2c
1c/2d
1d/2a
1d/2b
1d/2c
1d/2d
1e/2a
1e/2b
1e/2c
1e/2d
Ratio
1:1
1:1
2:1
1:1
2:1
2:1
1:1
1:1
2:1
1:1
2:1
2:1
(%)
71
70
72
75
75
71
73
75
73
70
73
75
yield5e (%)
1
2
A
A
A
A
A
A
A
A
A
A
A
A
64
–
(3) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem.
Commun. 1972, 466.
3
–
(4) (a) Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
4572. (b) Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed.
2003, 42, 4082; Angew. Chem. 2003, 115, 4216.
(5) (a) Basak, A.; Bdour, H. M.; Bhattacharya, G. Tetrahedron
Lett. 1997, 38, 2535. (b) Basak, A.; Bhattacharya, G.;
Bdour, H. M. M. Tetrahedron 1998, 54, 6529. (c) Basak,
A.; Ghosh, S. C.; Bhowmick, T.; Das, A. K.; Bertolasi, V.
Tetrahedron Lett. 2002, 43, 5499. (d) Basak, A.; Ghosh, S.
C. Synlett 2004, 1637. (e) Basak, A.; Pal, R. Bioorg. Med.
Chem. Lett. 2005, 15, 2015.
(6) Contelles, J. M. Angew. Chem. Int. Ed. 2004, 43, 2198.
(7) Ding, L. K.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1
1976, 2382.
(8) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Borman, S. Chem. Eng. News
2002, 80, 29. (c) Demko, Z. P.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2002, 41, 2113. (d) Kolb, H. C.; Sharpless,
K. B. Drug Discovery Today 2003, 8, 1128.
4
–
5
60
–
6
7
–
8
–
9
60
–
10
11
12
–
–
(9) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Rodionov, V.
O.; Fokin, V. V.; Finn, M. G. Angew. Chem. Int. Ed. 2005,
44, 2210.
(10) (a) Ye, M.-C.; Zhou, J.; Huang, Z.-Z.; Tang, Y. Chem.
Commun. 2003, 2554. (b) Ye, M. C.; Zhou, J.; Tang, Y. J.
Org. Chem. 2006, 71, 3576.
(11) (a) Guo, L.; Bradshaw, J. D.; Tessier, C. A.; Youngs, W. J.
J. Chem. Soc., Chem. Commun. 1994, 243. (b) Menger, F.
M.; Chen, X. Y.; Brocchini, S.; Hopkins, H. P.; Hamilton, D.
J. Am. Chem. Soc. 1993, 115, 6600.
Synlett 2007, No. 10, 1585–1588 © Thieme Stuttgart · New York

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A. Basak et al.
LETTER
(12) (a) All the nitrones were prepared according to the procedure
described in: Bhattacharya, G. PhD Thesis; Indian Institute
of Technology: Kharagpur, India, 1997. (b) However, a
general method of preparation is given below along with the
spectroscopic data of some representative compounds:
To a solution of EtOH (30 mL) and H2O (20 mL)
b-Lactam 8j: 1H NMR: d = 1.85 (s, 3 H), 3.90 (dd, J = 7.6,
14.4 Hz, 1 H), 3.98 (dd, J = 7.6, 14.4 Hz, 1 H), 4.14 (m, 1 H),
5.26 (d, J = 5.6 Hz, 1 H), 6.50 (br s, 2 H), 7.08–7.48 (m, 7
H), 8.64 (br s, 1 H). 13C NMR: d = 12.18, 45.51, 50.95,
52.54, 110.41, 111.16, 111.26, 116.77, 124.45, 129.13,
137.09, 140.79, 143.60, 147.73, 150.60, 164.02, 164.29. MS
(ES): m/z = 368 [MH+], 390 [MNa+].
nitrobenzene or p-methoxynitrobenzene (50 mmol),
benzaldehyde (or p-methoxybenzaldehyde or furfural or
thienyl aldehyde; 50 mmol) and Zn dust (5 gm) were placed.
The mixture was stirred at 5 °C. AcOH (30 mL) was slowly
added in a span of 20 min. The reaction mixture was stirred
for an additional 1.5 h at –5 °C. The mixture was filtered and
the residue was washed with EtOAc. The filtrate was
concentrated to 10 mL. H2O was added and the products
were extracted with EtOAc. The organic layer was washed
with NaHCO3, brine and dried over Na2SO4. The solvent
was evaporated under vacuo and the crude mass was
subjected to silica gel column chromatography. The
products were eluted with hexane–EtOAc mixture.
Compound 2a: 1H NMR: d = 7.39–7.52 (m, 6 H), 7.71–7.81
(m, 2 H), 7.90 (s, 1 H), 8.33–8.42 (m, 2 H).
b-Lactam 7j: 1H NMR: d = 1.84 (s, 3 H), 3.76 (m, 1 H), 4.15
(dd, J = 5.6, 14.8 Hz, 1 H), 4.29 (dd, J = 6.6, 14.6 Hz, 1 H),
5.09 (d, J = 2.4 Hz, 1 H), 6.35 (d, J = 2.8 Hz, 1 H), 6.50 (m,
1 H), 7.06–7.48 (m, 7 H), 9.06 (br s, 1 H). 13C NMR: d =
12.23, 45.75, 52.48, 55.86, 110.31, 110.71, 111.32, 116.88,
124.46, 129.10, 137.10, 140.62, 143.43, 148.71, 151.59,
164.08, 164.61. MS (ES): m/z = 368 [MH+], 390 [MNa+].
b-Lactam 8k: 1H NMR: d = 1.82 (s, 3 H), 3.82–3.94 (m, 2
H), 4.13 (m, 1 H), 5.55 (d, J = 5.6 Hz, 1 H), 6.36 (s, 1 H),
6.99–7.40 (m, 8 H), 8.45 (br s, 1 H). 13C NMR: d = 14.13,
24.83, 31.92, 45.64, 52.84, 53.38, 117.16, 124.55, 126.42,
127.18, 127.96, 129.43, 138.51, 140.99, 150.86, 164.31,
164.42. MS (ES): m/z = 384 [MH+], 406 [MNa+].
b-Lactam 7k: 1H NMR: d = 1.90 (s, 3 H), 3.51 (m, 1 H), 4.10
(dd, J = 4.8, 14.8 Hz, 1 H), 4.35 (dd, J = 7.2, 14.8 Hz, 1 H),
Compound 2b: 1H NMR: d = 6.62 (dd, J = 1.3 Hz, 3.2 Hz,
1 H), 7.39–7.44 (m, 3 H), 7.57 (d, J = 3.6 Hz, 1 H), 7.78–7.81
(m, 2 H), 8.0 (d, J = 3.3 Hz, 1 H), 8.14 (s, 1 H).
5.30 (br s, 1 H), 6.92–7.61 (m, 9 H), 8.59 (br s, 1 H). 13
C
NMR: d = 12.31, 22.69, 28.94, 46.01, 55.40, 60.49, 111.59,
117.29, 124.62, 126.09, 127.19, 127.41, 136.82, 140.31,
151.51, 164.32, 164.49. MS (ES): m/z = 384 [MH+], 406
[MNa+].
Compound 2c: 1H NMR: d = 7.15 (dd, J = 4.0, 4.8 Hz, 1 H),
7.39–7.56 (m, 5 H), 7.76–7.81 (m, 2 H), 8.46 (s, 1 H).
(13) General Procedure: To a solution of CuSO4·5H2O (1
mmol) in degassed H2O (10 mL), sodium ascorbate (2
mmol) was added and the mixture was stirred for 30 min at
r.t. (solution X). In another flask, to a solution of propargyl
alcohol–3-butyn-2-ol–propargyl nucleobase (2 mmol) in
DMF–MeCN (3 mL) under argon at 0 °C, Et3N (2 mmol)
was added and the mixture was stirred for 30 min (solution
Y). Solution Y was added dropwise to the solution X at r.t.
after which a 2 mL DMF or MeCN solution of the nitrones12
2a–2d (1 mmol) was added slowly over 10 min. The reaction
was stirred at r.t. for 16–25 h. It was then diluted with H2O
and filtered through celite. The celite bed was washed with
EtOAc. The combined filtrate and washings were extracted
with EtOAc. The organic layer was washed with NH4Cl,
H2O and brine and dried over Na2SO4 and evaporated. The
residue, obtained after evaporation, upon chromatography
afforded a mixture of trans and cis diastereomers.15 These
were easily separated by conventional chromatography over
silica gel using hexane–EtOAc (2:1) as eluent. The various
hydroxymethyl b-lactams [combined mixture of cis (3e–h)
and trans (4e–h) products] could be oxidized to a single
trans ketone by Dess–Martin oxidation14 in quantitative
yield.
b-Lactam 4k: 1H NMR (DMSO-d6): d = 4.18 (dd, J = 8.2,
13.8 Hz, 1 H), 4.35–4.46 (m, 2 H), 5.80 (d, J = 5.2 Hz, 1 H),
7.09–7.60 (m, 9 H), 8.12 (s, 1 H). 13C NMR (DMSO-d6): d =
41.04, 56.27, 58.17, 116.78, 123.87, 125.91, 127.09, 128.37,
128.93, 129.17, 137.03, 137.17, 140.78, 149.49, 152.57,
155.95, 164.08. MS (ES): m/z = 377 [MH+], 399 [MNa+].
b-Lactam 3k: 1H NMR: d = 3.49 (m, 1 H), 4.72 (d, J = 6.0
Hz, 2 H), 5.45 (br s, 1 H), 5.74 (br s, 2 H), 6.91–7.37 (m, 8
H), 7.93 (s, 1 H), 8.44 (s, 1 H). 13C NMR: d = 52.71, 54.49,
60.18, 117.70, 124.12, 126.44, 126.46, 127.74, 127.84,
128.71, 136.91, 137.26, 140.85, 149.55, 152.60, 164.23,
165.00. MS (ES): m/z = 377 [MH+], 399 [MNa+].
b-Lactam 4l: 1H NMR (DMSO-d6): d = 3.75 (s, 3 H), 3.97
(dd, J = 8.0, 14.4 Hz, 1 H), 4.20 (dd, J = 8.0, 14.4 Hz, 1 H),
4.39 (m, 1 H), 5.50 (d, J = 6.0 Hz, 1 H), 7.03–7.37 (m, 10 H),
8.08 (s, 1 H). 13C NMR (DMSO-d6): d = 39.96, 55.23, 58.58,
59.70, 114.57, 119.28, 120.29, 124.92, 128.11, 128.99,
129.43, 136.95, 141.02, 149.71, 153.15, 155.69, 159.84,
164.03. MS (ES): m/z = 401 [MH+], 423 [MNa+].
b-Lactam 3l: 1H NMR: d = 3.52 (m, 1 H), 3.84 (s, 3 H), 4.73
(app d, J = 6.0 Hz, 2 H), 4.97 (br s, 1 H), 6.02 (br s, 2 H),
7.00–7.43 (m, 9 H), 7.95 (s, 1 H), 8.42 (s, 1 H). 13C NMR:
d = 40.99, 52.73, 55.31, 56.88, 114.70, 117.91, 124.28,
126.51, 127.06, 128.11, 129.33, 133.43, 136.95, 140.02,
141.72, 152.72, 160.10, 164.25. MS (ES): m/z = 401 [MH+],
423 [MNa+].
(14) Dess, D. B.; Martin, J. C. J. Am Chem. Soc. 1991, 113, 7277.
(15) The spectral data for all the known compounds have been
reported: (a) Basak, A.; Rudra, K. R.; Ghosh, S. C.;
Bhattacharya, G. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2001, 40, 974. (b) Ghosh, S. C. PhD Thesis;
Indian Institute of Technology: Kharagpur, India, 2005.
(c) For the new compounds, the spectral data are given
below:
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