Copper(II) acetate promoted intramolecular carboamination of alkenes: An efficient synthesis of pentacyclic sultams

Article abstract of DOI:10.1055/s-0029-1219819

Copper(II) acetate promoted intramolecular carboamination reactions of 5-allyl-N-sulfonylated coumarins and quinolones have been described. The hitherto unreported pentacyclic sultams, obtained by the oxidative cyclization in high yields, are potential in

Full text of DOI:10.1055/s-0029-1219819

LETTER
1389
Copper(II) Acetate Promoted Intramolecular Carboamination of Alkenes:
An Efficient Synthesis of Pentacyclic Sultams
S
ynthesis of Penta
.
cyclic Sultam
C
s
. Majumdar,* Abu Taher, Raj Kumar Nandi
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 5 January 2010
From the last decades several methodologies have been
developed for the synthesis of various sultams – such as
Pictet–Spengler cyclization,21 Friedel–Crafts reaction,22
sulfonamide dianion alkylation,23 cyclization of amino-
Abstract: Copper(II) acetate promoted intramolecular carboamina-
tion reactions of 5-allyl-N-sulfonylated coumarins and quinolones
have been described. The hitherto unreported pentacyclic sultams,
obtained by the oxidative cyclization in high yields, are potential in-
termediates in the synthesis of nitrogen-containing heterocyclic sulfonyl chlorides,24 [3+2] cycloadditions,25 and Diels–
Alder reactions.26 Recently, a number of transition-metal-
compounds.
catalyzed approaches for the synthesis of sultams have
come to light, including the use of Pd-27, Au-28, Rh-,29 and
Ru-30catalyzed cyclization. But in all the cases the cata-
lysts used are costly. Chemler et al. have reported the syn-
thesis of sultams using less expensive Cu catalyst.31
Besides, there are little report on the ability of Cu(II) salts
to promote the addition of unfunctionalized nitrogen to
olefins to form sp3-carbon centers.31,32 Therefore, in order
to explore the importance of Chemler’s methodology, we
have used this less expensive copper(II)-promoted in-
tramolecular oxidative cyclization methodology for the
synthesis of coumarin- and quinolone-containing sultams
which may possess potential bioactivity. Herein, we re-
port our results.
Key words: aza-Claisen rearrangement, sultams, copper(II) ace-
tate, oxidative cyclization, intramolecular carboamination
The importance of sulfonamide moiety and its derivatives
is well recognized due to their extensive chemical and bi-
ological profiles in drug discovery.1 Recently, most fa-
mous example of sulfonamide functionality is Sildenafil
(Viagra). Besides, sulfonamides being used for the devel-
opment of novel peptidomimetics,2 glycoprotein IIB/IIA
inhibitors,3 nonpeptidal HIV protease inhibitors,4 and en-
dothelin-A receptor antagonists.5 High interest has also
been directed to their cyclic counterparts, the sultams.
Though sultams are not found in nature6 but show wide
applications in biological chemistry;7 being used as NF-
kB inhibitors,8 anti-inflammatory agent,9 glucokinase ac-
tivator,10 antiviral and anticancer activator.11 Some other
bioactive sultams are brinzolamide12 for the treatment of
glaucoma, antiepileptic agent sulthiame,13 COX-2 inhibi-
tors S-2474,14 selective inhibitors of calpain I,15 ben-
zodithiazine dioxides11 displaying anti-HIV-1 activity,
and most recently pyrrolo[1,2-b][1,2,5]benzothiadiaz-
epines,7a a new class of potential agent for the treatment
against chronic myelogenous leukemia. Besides, from
chemical point of view sultams have been used as effi-
cient chiral auxiliaries16 or reagents.17
The required carboamination precursors 5a–h were pre-
pared by the arylsulfonylation of compounds 4a–c in
pyridine at 80 °C for 2 hours. Substrate 4c failed to give
the corresponding 4-methoxybenzene sulfonyl derivative,
instead the 2,3-dihydropyrrolocoumarin derivative 6 was
obtained. The compounds 4a–c in turn can be prepared by
aza-Claisen rearrangement of compounds 2a–c. The aza-
Claisen precursors 2a–c can in turn be prepared by the re-
action of 6-amino coumarin 1c or 6-amino quinolones
1a,b and allyl bromide in refluxing acetone in the pres-
ence of anhydrous K2CO3 (Scheme 1). We also tried to
synthesize compound 5b by first tosylation of 2a and then
by aza-Claisen rearrangement of the compound 3b. But
the desired product was not obtained. Presence of an addi-
tional alkyl group in the N-allyl aniline greatly increases
the rate of the aromatic aza-Claisen rearrangement.33 That
is the reason why 3b – with strong electron-withdrawing
substituent (tosyl) – failed to undergo aza-Claisen rear-
rangement to give the product 5b. The aza-Claisen rear-
rangements of the substrates 2a–c are better carried out in
a sealed tube with BF3·OEt2 as catalyst in chlorobenzene
for 6 hours.
On the other hand, coumarin and quinolones are subunits
in numerous natural products that exhibit a wide range of
biological activities such as antibacterial, antifungal, anti-
allergic, and DNA-gyrase inhibition.18 In continuation of
our interest in the synthesis of bioactive heterocycles us-
ing Pd-19 and Ru-20catalyzed intramolecular cyclization,
we became interested to synthesize polycyclic sultams
containing a bioactive coumarin or quinolone subunit.
These particular analogues may be interesting to medici-
nal chemists and pharmacologists.
We next turned our attention to the synthesis of tetracyclic
sultams by carboamination reaction of compounds 5a–h.
Substrate 5a, when treated with Cu(OAc)2 (3 equiv) and
Cs2CO3 (1 equiv) in MeCN in a sealed tube for 7 hours,
gave the carboamination product 7a in 82% yield.34 The
SYNLETT 2010, No. 9, pp 1389–1393
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1219819; Art ID: G00210ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1390
K. C. Majumdar et al.
LETTER
N
NH2
NH
(i)
(iii)
Ar
O
X
O
X
O
X
2a X = NEt
2b X = NMe
2c X = O
1a X = NEt
1b X = NMe
1c X = O
3b X = NEt, Ar =Ts
(ii)
(ii)
H
N
Ar
N
NH2
(iii)
(iii)
Ar
O
X
O
X
O
O
4a X = NEt
4b X = NMe
4c X = O
6 Ar = SO2(4-OMe)C6H4
X = O
5a X = NEt, Ar = SO2Ph
5b X = NEt, Ar =Ts
5c X = NEt, Ar = SO2(4-OMe)C6H4
5d X = NMe, Ar = SO2Ph
5e X = NMe, Ar =Ts
5f X = NMe, Ar = SO2(4-OMe)C6H4
5g X = O, Ar = SO2Ph
5h X = O, Ar = Ts
Scheme 1 Reagents and conditions: (i) allyl bromide, acetone, K2CO3, reflux, 3 h (ii) BF3·OEt2, chlorobenzene, sealed tube, 140 °C, 6 h; (iii)
pyridine, ArSO2Cl, 80 °C, 2 h.
optimized conditions for the carboamination reaction has 32% yield of the product was obtained when K2CO3 (2
been achieved through a series of experiments by chang- equiv) was used as a base in place of Cs2CO3 (entry 3). In
ing solvent, base, and temperature (Table 1).
the absence of any base the reaction became very slug-
gish, and only 9% yield of the product 7a was obtained af-
ter 7 hours (entry 4). Addition of DMSO (4 equiv) in the
reaction mixture did not improve the yield of the product
(entry 5). Similarly, change of the solvent did not influ-
ence the yield of the product (entry 6). Only 22% yield
was obtained when DMF was used as a solvent and
K2CO3 (2 equiv) as a base (entry 7). The requirement of
overstoichiometric amounts of Cu(II) salt is perhaps due
to the disproportionation reaction of Cu(II) to Cu(I) and
Cu(III) intermediates. Among the various conditions em-
ployed it had been observed that the reaction in MeCN as
solvent and Cs2CO3 (1 equiv) as base gave the best result
(Table 1).
Treatment of 5a with Cu(OAc)2 (3 equiv) and Cs2CO3 (1
equiv) in MeCN at 90 °C in a sealed tube provided 25%
yield of the desired product 7a after 7 hours (entry 1).
When the same reaction was carried out at 120 °C for 7
hours the product was obtained in 82% yield (entry 2). A
Table 1 Effect of Reaction Conditions on Oxidative Cyclization of
5a
H
N
S
N
O
S
O
O
O
O
N
O
N
Using the optimized conditions, we have examined the
oxidative cyclization (or carboamination) reaction of var-
ious starting materials 7b–h. The results are listed in
Table 2.
Et
Et
7a
5a
Entry Solvent
Base (equiv) Temp (°C) Time (h) Yield (%)
1
2
3
4
5a
6
7
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
Cs2CO3 (1)
Cs2CO3 (1)
K2CO3 (2)
–
90
120
120
120
120
120
120
7
7
7
7
7
7
7
25
82
32
9
Treatment of 5b with Cu(OAc)2 and Cs2CO3 (1 equiv) in
MeCN at 120 °C for 7 hours in a sealed tube gave product
7b in 85% yield. Similarly, compound 5c furnished prod-
uct 7c in 74% yield. When the same reactions were carried
out with 5d and 5e products 7d and 7e were obtained in
79% and 80% yields, respectively. The product 7f was ob-
tained in 68% yield when the reaction was carried out with
5f. Under the similar reaction conditions 5g and 5h afford-
ed products 7g and 7h in 75% and 78% yields, respective-
ly, after 12 hours. The products were characterized from
their elemental analyses and spectroscopic data.
Cs2CO3 (1)
Cs2CO3 (1)
K2CO3 (2)
80
79
22
DMF
a DMSO (4 equiv) was added.
Synlett 2010, No. 9, 1389–1393 © Thieme Stuttgart · New York

LETTER
Synthesis of Pentacyclic Sultams
Yield (%)a
1391
Table 2 Oxidative Cyclization Reaction of 5a–h
Entry
Substrate 5
Product 7
H
N
N
S
O
1b
82
S
O
O
O
O
N
O
N
Et
Et
5a
7a
H
N
2b
85
N
S
S
O
O
O
O
O
N
O
N
Et
Et
5b
7b
OMe
OMe
H
N
3b
4b
5b
74
79
80
N
S
S
O
O
O
O
O
N
O
N
Et
Et
5c
7c
H
N
N
S
O
S
O
O
O
O
N
O
N
Me
Me
5d
7d
H
N
N
S
S
O
O
O
O
O
N
O
N
Me
Me
5e
7e
OMe
OMe
H
N
6b
68
75
N
S
S
O
O
O
O
O
N
O
N
Me
Me
5f
7f
H
7c
N
N
S
O
S
O
O
O
O
O
O
O
5g
7g
Synlett 2010, No. 9, 1389–1393 © Thieme Stuttgart · New York

1392
K. C. Majumdar et al.
Table 2 Oxidative Cyclization Reaction of 5a–h (continued)
Entry Substrate 5
LETTER
Product 7
Yield (%)a
H
8c
78
N
N
S
S
O
O
O
O
O
O
O
O
5h
7h
a Isolated yields.
b All the reactions were carried out for 7 h.
c The reactions were carried out for 12 h.
Based on analogy to Chemler’s mechanistic proposal, it is
likely that these transformations proceed by the way de-
picted in Scheme 2. We failed to isolate the intermediates
but it is reasonable to assume that the first step is the for-
mation of N–Cu bond to give the intermediates 8 which on
migratory insertion give the intermediates 9. The interme-
diates 9 subsequently add to the aromatic ring to give the
radical intermediates 10 which on aromatization give the
final products 7.
Acknowledgment
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. Two of us (A.T. and R.K.N.) are grateful to the
CSIR (New Delhi) for a Senior and a Junior research fellowship,
respectively. We also thank the DST (New Delhi) for providing
Bruker 400 MHz NMR Spectrometer and PerkinElmer CHN Ana-
lyzer under its FIST program.
References and Notes
In conclusion, we have achieved the synthesis of pentacy-
clic sultams containing bioactive coumarin or quinolone
moieties by intramolecular copper(II) acetate promoted
carboamination (oxidative cyclization) reaction. The ex-
tended methodology is simple, mild, and provides high
yield of the products.
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R
(AcO)Cu
migratory
insertion
Cu(OAc)
N
R
Cu(OAc)2
– AcOH
NH
SO2Ar
N
S
O2
SO2Ar
O
X
O
X
O
X
8
9
5
– CuOAc
R
.
H
CuOAc
– Cu(0)
N
N
SO2
SO2
– AcOH
O
X
O
X
10
7 X = NEt, NMe, O
R = H, Me
Scheme 2 Probable mechanism for carboamination reaction
Synlett 2010, No. 9, 1389–1393 © Thieme Stuttgart · New York

LETTER
Synthesis of Pentacyclic Sultams
1393
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(34) Procedure for the Preparation of Compound 7a
A mixture of compound 5a (100 mg, 0.272 mmol),
Cu(OAc)2 (148 mg, 0.815 mmol), and Cs2CO3 (89 mg, 0.272
mmol) in MeCN (7 mL) was heated in a sealed tube for 7 h.
After completion of the reaction, the reaction mixture was
cooled and filtered through Celite. The solvent was distilled
off. The resulting crude product was purified by column
chromatography over silica gel (60–120 mesh) using PE–
EtOAc (50:50) mixture as eluent to give compound 7a.
Yield 82%, colorless solid; mp 276 °C. IR (KBr):
n
max = 1592, 1663, 2923 cm–1. 1H NMR (500 MHz, CDCl3):
d = 1.31 (t, J = 7.1 Hz, 3 H), 3.08–3.16 (m, 2 H), 3.49 (dd,
J = 9.2, 15.9 Hz, 1 H), 3.75 (dd, J = 5.9, 15.7 Hz, 1 H), 4.28
(q, J = 7.1 Hz, 2 H), 5.07–5.13 (m, 1 H), 6.68 (d, J = 9.5 Hz,
1 H), 7.20 (d, J = 9.0 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.36
(t, J = 7.5 Hz, 1 H), 7.46 (d, J = 9.5 Hz, 1 H), 7.48 (t, J = 7.5
Hz, 1 H), 7.76 (d, J = 9.1 Hz, 1 H), 7.83 (d, J = 7.5 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 12.7, 33.1, 34.5,
37.6, 61.7, 114.1, 117.3, 119.6, 122.8, 124.3, 127.6, 127.9,
129.7, 132.8, 134.2, 134.4, 136.3, 137.0, 138.5, 161.2 ppm.
HRMS: m/z calcd for C20H18N2O3S [M + Na]+: 389.0936;
found: 389.0936.
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P. S. J. Med. Chem. 2006, 49, 5840.
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