One-pot, three-step copper-catalyzed five-/four-component reaction constructs polysubstituted oxa(thia)zolidin-2-imines

Article abstract of DOI:10.1055/s-0032-1316606

A novel one-pot synthesis of polysubstituted oxa(thia)zolidin-2-imines has been developed. It employs A³-coupling of aldehyde and amine with alkyne to form propargyl amine, which on (thio)amidation with iso(thio)cyanate produces N-propargyl(thio)urea, and a cyclization reaction. A 5-exo-dig iodocyclization of N-propargylurea constructs 5-iodomethyleneoxazolidin-2-imine, while cycloisomerization of the thio analogue provides 5-methylenethiazolidin- 2-imine. In this process, CuI catalysis has been found to be crucial, and the cyclization occurs through oxygen/sulfur (not nitrogen) nucleophilic attack to alkyne. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316606

LETTER
▌1955
letter
One-Pot, Three-Step Copper-Catalyzed Five-/Four-Component Reaction
Constructs Polysubstituted Oxa(Thia)zolidin-2-imines
Polysubstituted Oxa(Thia)zolidin-2-imines
Chetna Madaan,a Shuddham Saraf,a Garima Priyadarshani,a P. Purushotham Reddy,b Sankar K. Guchhait,*a
A. C. Kunwar,b B. Sridharc
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali)
160062 Punjab, India
Fax +91(172)2214692; E-mail: skguchhait@niper.ac.in
b
NMR Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
c
Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Received: 08.05.2012; Accepted after revision: 05.06.2012
atom-, step-, and pot-economy.7 In this approach, varia-
tion in reactants can also generate a large number of com-
pounds.
Abstract: A novel one-pot synthesis of polysubstituted
oxa(thia)zolidin-2-imines has been developed. It employs A3-cou-
pling of aldehyde and amine with alkyne to form propargyl amine,
which on (thio)amidation with iso(thio)cyanate produces N-propar-
gyl(thio)urea, and a cyclization reaction. A 5-exo-dig iodocycliza-
tion of N-propargylurea constructs 5-iodomethyleneoxazolidin-2-
imine, while cycloisomerization of the thio analogue provides 5-
methylenethiazolidin-2-imine. In this process, CuI catalysis has
been found to be crucial, and the cyclization occurs through oxy-
gen/sulfur (not nitrogen) nucleophilic attack to alkyne.
As part of our research program aimed at realizing new
leads, we became interested in developing a one-pot, mul-
ticomponent reaction that could afford pharmaceutically
significant heterocyclic scaffolds. We speculated that a
sequence of reactions of a multicomponent condensation
of aldehyde, amine, and alkyne (A3-coupling) to form
propargyl amine,8 which on amidation produces N-
propargylurea, whose endo- or exo-dig cycloisomeriza-
tion with alkyne in the terminal step could produce dihy-
dropyrimidinone I or imidazolidinone, respectively
(Scheme 1). The later scaffold via isomerization of the
double bond might possibly form the aromatic compound
imidazolone II. Based on known therapeutic importance
of these scaffolds9,10 and the potential efficiency of the
synthetic approach, we were interested in exploring the
reaction sequence. A one-pot version of this synthesis,
which was our endeavor also, is more challenging, be-
cause the process requires the catalyst and conditions
compatibility and considerably high conversion in each
reaction step. Coinage metal (Cu, Ag, or Au) catalyst
could be crucial for A3-coupling and the cycloisomeriza-
tion with electrophilic activation of alkyne.11 Cu(I) halide
as catalyst was preferentially chosen because of its known
Key words: multicomponent reaction, one-pot, cyclization, cop-
per, heterocycles
The major prescription drugs contain heterocyclic scaf-
folds. The crucial role played by heterocycles in drug-dis-
covery processes has long been known.1 Recent in silico
investigations on drug database toward exploration of po-
tential ‘bioactivity islands’ have revealed the importance
of heterocyclic scaffolds.2 The rapid and molecular-diver-
sity-feasible construction of new and ‘privileged’ hetero-
cyclic scaffolds has gained importance. In this direction,
the amalgamation of a multicomponent reaction3,4 and a
consecutive one-pot process (domino, cascade, or tan-
dem),5 which in many cases gains efficiency under transi-
tion-metal catalysis,6 is a golden nugget for the rapid
construction of polysubstituted molecular scaffolds with
O
R2
R1
R4
R3
N
N
O
R2
R1
R2
R1
R4
R3
E
I
R2 NH2
NH
amidation
R4N=C=O
N
N
A3-coupling
H
cycloisomerization (E = H)
or electrophilic cyclization
O
exo
O
R3
-dig cyclization and
aromatization
R3
R1
R2
R4
H
N
N
E
R1
II R3
Scheme 1 Design of reaction strategy
SYNLETT 2012, 23, 1955–1959
Advanced online publication: 23.07.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316606; Art ID: ST-2012-B0400-L
© Georg Thieme Verlag Stuttgart · New York

1956
C. Madaan et al.
LETTER
efficiency as a π-Lewis acid and less cost. 4-Chlorobenz- while CuI was found to be best for overall process of A3-
aldehyde, benzylamine, phenylacetylene, and benzyl iso- coupling, amidation, and iodocyclization. Optimal
cyanate were used as model substrates. Various amount of catalyst was found to be 30 mol%. Among var-
experiments were carried out on evaluation of Cu catalyst, ious solvents such as toluene, MeCN, DMSO, THF, and
base, π-Lewis acid additive, solvent, and reaction temper- 1,4-dioxane, the later was found to be best. For possible
ature. Optimization was focused on stepwise sequential enhancement of reaction conversion of A3-coupling to-
reactions. In every case, A3-coupling and subsequent ami- wards completion, the additional use of various σ-/π-
dation provided corresponding N-propargylurea in good Lewis acids such as Sc(OTf)3, In(OTf)3, AgOTs, AgOTf,
yield. However, the in situ cycloisomerization towards or RuCl3, and bases such as pyridine, Et3N, or i-Pr2EtNH
formation of product I or II did not materialize. Realizing did not help. Increase in reaction temperature from 80 °C
the inertness of N-propargylurea towards cycloisomeriza- to 100 °C or prolonging the reaction did not improve the
tion, we then investigated its electrophilic cyclization with yields. One-pot reaction of propargylamine with isocya-
iodine and Na2CO3. The scaffold that formed was neither nate underwent with almost quantitative conversion. For
dihydropyrimidinone I nor imidazolone II, rather 5-iodo- iodocyclization, two equivalents of iodine and three
methyleneoxazolidine-2-imine (compound 1, Scheme equivalents of Na2CO3 were found to be optimum. To
2).12 This scaffold structurally resembles the biologically check the efficiency of one-pot process, the products of
active 2-iminoimidazolines13 and 2-imidazolones.14 The the A3-coupling and amidation step were isolated and sub-
compounds containing this scaffold are also known to jected to subsequent reactions. They produced the desired
possess various therapeutic activities.15 These results in- intermediate or final product in similar yields. Various io-
cited us to further explore the one-pot synthesis. In A3- domethyleneoxazolidine-2-imines with four points of di-
coupling, copper(I) halides (I, Br, and Cl) were found to versity were prepared (Scheme 2). Aliphatic aldehydes
be more effective catalysts compared to AgOAc and and aromatic aldehydes with both electron-withdrawing
AuCl3. CuBr was most efficient for the A3-coupling step, and electron-donating groups were compatible. However,
R4
O
R4
O
R2
R1
R2 NH2
O
HN
N
NH
R4N=C=O
R2
R1
CuI (30 mol%)
I2, Na2CO3
R2
N
N
1,4-dioxane, 80 °C
R3
R3
R1
R3
R1
H
R3
I
Cl
N
N
N
N
O
N
N
O
N
O
O
I
N
I
I
I
3 43%
Cl
2 52%
1 51%
4 43%
MeO
MeO
OMe
N
N
MeO
O
N
N
O
O
I
N
N
N
OMe
N
I
O
I
Cl
NC
MeO
MeO
I
5 60%
6 46%
8 60%
7 30%
NO2
MeO
N
MeO
N
N
N
N
N
MeO
O
I
O
O
I
I
9 80%
11 45%
10 50%
Scheme 2 One-pot reactions of A3-coupling, amidation, and iodocyclization – synthesis of iodomethyleneoxazolidine-2-imines.
Reactants (mmol): amine (1 mmol), aldehyde (1 mmol), alkyne (2.2 mmol), isocyanate (1 mmol), iodine (2 mmol), Na2CO3 (3 mmol).
Synlett 2012, 23, 1955–1959
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polysubstituted Oxa(Thia)zolidin-2-imines
1957
aromatic amine and aliphatic alkyne were found to be ppm), and C10/C10′ (δ = 130.46 ppm). The C6H/C6′H
nonfeasible substrates.
protons displayed correlations with C5 (δ = 151.00 ppm)
whereas C7H/C7′H showed correlation with C5
(δ = 151.00 ppm) as well as C8 (δ = 66.11 ppm). For com-
pound 12 (Scheme 3, Figure 1) the olefinic proton C3H
appeared as a doublet at δ = 6.21 ppm and showed a vinyl-
ic coupling (4J C3H–C8H) of 1.4 Hz with C8H. In the HMBC
experiments C3H showed correlations with C1/C1′
(δ = 128.03 ppm), C2 (δ = 133.83 ppm), C4 (δ = 140.28
ppm), and C8 (δ = 70.20 ppm), while C8H depicted corre-
lations with C3 (δ = 122.40 ppm), C4 (δ = 140.28 ppm),
C5 (δ = 155.75 ppm), C9 (δ = 141.38 ppm), and C10/C10′
(δ = 127.51 ppm) whereas C6H/C6H′ showed correlation
with C5 (δ = 155.75 ppm) and C7H/C7H′ depicted corre-
lations with C5 (δ = 155.75 ppm) and C8 (δ = 70.20 ppm).
When isothiocyanate was used in place of isocyanate in
the process, the thioamidation and cycloisomerization re-
actions took place in cascade fashion, yielding 5-methyle-
nethiazolidin-2-imines16
(Scheme
3).
Dihydroisoquinolines as imine equivalents underwent re-
actions with both isocyanate and isothiocyanate in these
processes. The experimental procedures were simple and
straightforward.17
In these one-pot reactions, the 5-exo-dig iodocyclization
of N-propargylurea formed 5-iodomethyleneoxazolidine-
2-imine, and the 5-exo-dig cycloisomerization of N-
propargylthiourea provided 5-methylenethiazolidin-2-im-
ine. This implies that the cyclization took place through
oxygen/sulfur nucleophilic attack to alkyne. The alterna-
tive possible cyclization via nitrogen nucleophilic moiety
did not occur. The cycloisomerization of N-propargylurea
through oxygen, which is less nucleophilic, could not take
The structures of 9 (Scheme 2) and 17 (Scheme 3) were
also deduced from detailed NMR studies (see Supporting
Information), which have been duly confirmed from sin-
gle-crystal X-ray diffraction studies (Figure 2).18
place. It required a more reactive electrophilic cyclization In conclusion, we have developed a novel method of CuI-
pathway such as iodocyclization.
catalyzed four-component, one-pot, three-step reaction
towards construction of 5-iodomethyleneoxazolidin-2-
imines, 5-methylenethiazolidin-2-imines, and their tetra-
hydroisoquinoline-fused analogues. The process employs
the readily available starting materials aldehyde, amine,
alkyne, and iso(thio)cyanate.
The structures of 5-methyleneoxa(thia)zolidin-2-imines
were identified by spectroscopic studies (1H, 13C, HSQC,
HMBC, DQF-COSY NMR, IR, and MS). For compound
1 (Scheme 2, Figure 1) the proton C8H (δ = 5.10 ppm)
showed HMBC correlations with C3 (δ = 74.93 ppm), C4
(δ = 148.27 ppm), C5 (δ = 151.00 ppm), C9 (δ = 134.92
R4
N
R2
R1
R2 NH2
R2
NH
R4-N=C=S
N
S
CuI (30 mol%)
O
1,4-dioxane, 80 °C
R3
R3
R1
R3
R1
H
H
N
N
N
MeO
MeO
N
N
S
S
S
H
N
H
H
MeO
13 50%
14 53%
MeO
OMe
MeO
MeO
MeO
N
S
N
N
MeO
N
N
N
S
H
H
S
H
15 55%
16 40%
17 59%
Me
Scheme 3 One-pot reactions of A3-coupling, thioamidation, and cycloisomerization – synthesis of 5-methylenethiazolidin-2-imines
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1955–1959

1958
C. Madaan et al.
LETTER
(b) Guchhait, S. K.; Madaan, C. Synlett 2009, 628.
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Bharatam, P. V. J. Med. Chem. 2011, 54, 5013.
6 H
6 H
H
N
H
H
7
N
7
H
5
H
10'
N
8
5
H
10'
N
8
H
O
H
S
4
4
1
9
1
9
3
3
(5) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
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Cl
10
2
10
I
2
H
1'
1'
1
12
Figure 1 2D NMR: Deduced Structure of 1 and 12
(7) (a) For atom-economy, see:Trost, B. M. Science 1991, 254,
1471. (b) Step-economy:Wender, P. A.; Verma, V. A.;
Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40.
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(8) (a) Bariwal, J. B.; Ermilat’ev, D. S.; Van der Eycken, E. V.
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Figure 2 ORTEP structures
(9) (a) Brown, L. E.; Dai, P.; Porco, J. A.; Schaus, S. E. Org.
Lett. 2011, 13, 4228. (b) Tale, R. H.; Rodge, A. H.;
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2011, 21, 4648.
Acknowledgment
(10) Gong, X.; Yang, H.; Liu, H.; Jiang, Y.; Zhao, Y.; Fu, H. Org.
Lett. 2010, 12, 3128.
(11) (a) Bruneau, C. Angew. Chem. Int. Ed. 2005, 44, 2328.
(b) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am.
Chem. Soc. 2004, 126, 8654.
We gratefully acknowledge financial support from DST, New Delhi
for this investigation. P.P.R. is thankful to CSIR for senior research
fellowship.
(12) During the progress of this work, a method of amidation of
propargylamine and AgOTf-catalyzed cycloisomerization
towards the synthesis of imidazolone was reported.
See:Peshkov, V. A.; Pereshivko, O. P.; Sharma, S.;
Meganathan, T.; Parmar, V. S.; Ermolat’ev, D. S.; Van der
Eycken, E. V. J. Org. Chem. 2011, 76, 5867.
(13) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.; De
Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew.
Chem. Int. Ed. 2010, 49, 9465.
(14) Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones, E. A.;
Bonner, K.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.;
Fletcher, A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D.
J. Med. Chem. 1999, 42, 2706.
(15) (a) Wollweber, H.; Hiltmann, R.; Stoepel, K.; Kroneberg,
H. G. Eur. J. Med. Chem. 1980, 15, 111. (b) Shibuya, A. US
20040191679 A1 20040930, 2004.
(16) Frost, J. M.; Latshaw, S. P.; Dart, M. J.; Carroll, W. A.;
Perez-Medrano, A.; Kolasa, T.; Patel, M.; Nelson, D. W.; Li,
T.; Peddi, S.; Wang, X.; Lui, B. PCT Int. Appl. WO
2010071783 A1 20100624, 2010.
(17) Representative Experimental Procedure for the
Synthesis of (E,Z)-N,N′-Dibenzyl-4-(4′-chlorophenyl)-5-
(1′,1′-iodophenylmethylene)oxazolidin-2-imine
(Compound 1, Scheme 2)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) (a) Comprehensive Heterocyclic Chemistry; Katritzky, A.;
Rees, C.-W.; Scriven, E.-F.-V., Eds.; Elsevier Science:
Oxford, 1996. (b) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329.
(c) Bon, R. S.; Waldmann, H. Acc. Chem. Res. 2010, 43,
1103. (d) D’Souza, D. M.; Müller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095. (e) Berlinck, R. G. S.; Burtoloso, A. C. B.;
Kossuga, M. H. Nat. Prod. Rep. 2008, 25, 919. (f) Berlinck,
R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22, 516.
(2) (a) Koch, M. A.; Schuffenhauer, A.; Scheck, M.; Wetzel, S.;
Casaulta, M.; Odermatt, A.; Ertl, P.; Waldmann, H. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 17272. (b) Ritchie, T. J.;
Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. Drug
Discovery Today 2011, 16, 164. (c) Reymond, J. L.;
Deursen, R. V.; Blum, L. C.; Ruddigkeit, L. Med. Chem.
Commun. 2010, 1, 30. (d) Ertl, P.; Jelfs, S.; Mühlbacher, J.;
Schuffenhauer, A.; Selzer, P. J. Med. Chem. 2006, 49, 4568.
(e) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39,
2887. (f) Broughton, H. B.; Watson, I. A. J. Mol. Graphics
Modell. 2005, 23, 51.
To a magnetically stirred solution of 4-chlorobenzaldehyde
(140 mg, 1.0 mmol) and benzylamine (107 mg, 1 mmol) in
anhyd 1,4-dioxane (2.5 mL) were added phenylacetylene
(224 mg, 2.2 mmol) and CuI (30 mol%) under nitrogen. The
reaction mixture was heated at 80 °C for 5 h (monitored by
(3) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Dömling, A. Chem. Rev.
2006, 106, 17.
(4) For our publications, see: (a) Guchhait, S. K.; Chandgude,
A. L.; Priyadarshani, G. J. Org. Chem. 2012, 77, 4438.
Synlett 2012, 23, 1955–1959
© Georg Thieme Verlag Stuttgart · New York

LETTER
TLC). To the resultant mixture was added benzyl isocyanate
Polysubstituted Oxa(Thia)zolidin-2-imines
1959
reaction was continued at 80 °C till completion (3 h,
(0.12 mL, 1.0 mmol). The mixture was stirred at 80 °C for
2 h (monitored by TLC). Then I2 (506 mg, 2 mmol) and
Na2CO3 (315 mg, 3 mmol) were added, and the reaction was
continued at 80 °C for further 3 h (monitored by TLC). The
resultant mixture was extracted with EtOAc. The combined
organic solution was washed with H2O, dried over anhyd
Na2SO4, filtered, and concentrated under vacuum. The
column chromatographic purification of crude mass on silica
gel (100–200 mesh) eluting with EtOAc–PE provided (E,Z)-
N,N′-dibenzyl-4-(4′-chlorophenyl)-5-(1′,1′-iodophenyl-
methylene)oxazolidin-2-imine (301 mg, 51% yield); brown
viscous liquid. MS (APCI): m/z = 591 [M(35Cl) + H]+. 1H
NMR (600 MHz, CDCl3): δ = 3.50 (d, J = 15.3 Hz, 1 H),
4.51 (d, J = 14.7 Hz, 1 H), 4.49 (d, J = 14.7 Hz, 1 H), 4.99
(d, J = 15.3 Hz, 1 H), 5.10 (s, 1 H), 7.16–7.37 (m, 17 H) 7.45
(d, J = 7.1 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 46.00, 49.94, 65.97, 74.81, 126.44, 127.40, 127.82,
128.09, 128.21, 128.31, 128.74, 129.13, 129.67, 130.34,
134.43, 134.54, 134.80, 135.63, 137.55, 141.26, 148.15,
150.89 ppm. IR (KBr): νmax = 2932, 2853, 2369, 2335, 1712,
1645, 691 cm–1. HRMS: m/z calcd for C30H24ClIN2O:
591.0702 [M(35Cl) + H]+; found: 591.0685.
monitored by TLC). The resultant mixture was extracted
with EtOAc. The combined organic solution was washed
with H2O, dried over anhyd Na2SO4, filtered, and
concentrated under vacuum. The column chromatographic
purification of crude mass on silica gel (100–200 mesh)
eluting with EtOAc–PE provided (Z,Z)-N,N′-dibenzyl-5-
benzylidene-4-phenylthiazolidin-2-imine (250 mg, 56%
yield); light yellow solid; mp 106–109 °C. MS (APCI):
m/z = 447 [M + H]+. 1H NMR (600 MHz, CDCl3): δ = 3.66
(d, J = 15.1 Hz, 1 H), 4.67 (d, J = 15.2 Hz, 1 H), 4.64 (d,
J = 15.2 Hz, 1 H), 5.23 (d, J = 1.7 Hz, 1 H), 5.42 (d, J = 15.1
Hz, 1 H), 6.21 (d, J = 1.7 Hz, 1 H), 7.17–7.42 (m, 20 H) ppm.
13C NMR (150 MHz, CDCl3): δ = 47.31, 58.18, 70.05,
122.29, 126.50, 127.05, 127.31, 127.34, 127.56, 128.02,
128.26, 128.47, 128.47, 128.48, 128.55, 129.01, 133.82,
136.01, 136.96, 140.27, 141.04, 155.81 ppm. IR (KBr):
νmax = 3032, 2919, 1751, 1645, 1619, 695 cm–1. HRMS: m/z
calcd for C30H26N2S: 447.1897 [M + H]+; found: 447.1902.
All reactions (Scheme 3) were carried out following the
representative procedure: When 3,4-dihydroisoquinoline or
6,7-dimethoxy-3,4-dihydroisoquinoline was used as imine
equivalent (Schemes 2 and 3), the reactions were done by
using 10 mol% of CuI (in place of 30 mol%) keeping all
other conditions the same.
All reactions (Scheme 2) were carried out following the
representative procedure.
Representative Experimental Procedure for the
Synthesis of (Z,Z)-N,N′-Dibenzyl-5-benzylidene-4-
phenylthiazolidin-2-imine (Compound 12, Scheme 3)
To a magnetically stirred solution of benzaldehyde (106 mg,
1.0 mmol) and benzyl amine (107 mg, 1 mmol) in anhyd 1,4-
dioxane (2.5 mL) were added phenylacetylene (224 mg, 2.2
mmol) and CuI (30 mol%) under nitrogen. The mixture was
heated at 80 °C for 5 h (monitored by TLC). Benzyl
isothiocyanate (0.14 mL, 1.0 mmol) was then added. The
(18) Complete crystallographic X-ray data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre (CCDC),
12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336 033; email: deposit@ccdc.cam.ac.uk].
CCDC 879707 contains the supplementary crystallographic
data for Compound 8, Scheme 2. CCDC 857504 contains the
supplementary crystallographic data for Compound 17,
Scheme 3.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1955–1959

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