Microwave-assisted Pd-catalyzed synthesis of fused steroidal and non-steroidal pyrimidines from β-halo-α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2013.10.094

A Pd-catalyzed protocol has been developed for the synthesis of fused steroidal and non-steroidal pyrimidines from β-halo-α,β- unsaturated aldehydes under microwave irradiation. The β-halo-α, β-unsaturated aldehydes are synthesized from corresponding keto

Full text of DOI:10.1016/j.tetlet.2013.10.094

Tetrahedron Letters 54 (2013) 7136–7139
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted Pd-catalyzed synthesis of fused steroidal
and non-steroidal pyrimidines from b-halo-
a,b-unsaturated
aldehydes
⇑
⇑
Junali Gogoi, Pranjal Gogoi , Pranjal Bezbaruah, Romesh C. Boruah
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd-catalyzed protocol has been developed for the synthesis of fused steroidal and non-steroidal pyrim-
Received 22 July 2013
Revised 17 October 2013
Accepted 20 October 2013
Available online 28 October 2013
idines from b-halo-a,b-unsaturated aldehydes under microwave irradiation. The b-halo-a,b-unsaturated
aldehydes are synthesized from corresponding ketones using Vilsmeier formylation reaction. This syn-
thetic protocol is utilized to synthesize some more novel steroidal pyrimidine derivatives and are cur-
rently being evaluated for their biological activities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Heterosteroid
Pyrimidine
Unsaturated aldehyde
Palladium
Microwave
The pyrimidine heterocyclic core is an important class of com-
pounds which has wide occurrence in nature as substituted and
ring fused compounds and derivatives.1 A number of synthetic
pyrimidine base pharmacophores exhibit antibacterial, antimicro-
bial, anticancer, antihypertensive, cardiac stimulant, antimalarial,
anti-HBV, anti-HIV-1, and antirubella virus activities.2 Pyrimidine
derivatives are also used as an emulsion stabilizer in photographic
materials3 and versatile ligands. Their coordination compounds
can be considered as model systems for metal–ligand interactions
observed in biological systems.4 Some of the pyrimidine bearing
derivatives, such as chemotherapeutics trimethoprim and sulfadi-
azine, the dihydrofolate reductase inhibitor pyrimethamine, and
prazosin are used to treat high blood pressure and anxiety (Fig. 1).5
Heterosteroids emerge as an important area of research and
enormous efforts have been made for their synthesis because of
inherent biological activities.6 A great deal of attention has been
made to annelate steroidal moiety with pyrazole, pyridine, isoxaz-
ole, pyrrole, tetrazole, isothiazole rings using various synthetic
strategies.7 Due to emerging interests of pyrimidine derivatives
as potential drugs, the synthesis of annelated steroidal pyrimidine
ring system has become a subject of great interest.8 For example,
Clinton and his co-workers have described the preparation of bio-
logically active steroidal[3,2-b]pyrimidines from condensation of
2-hydroxymethylene-3-ketosteroids with acetamidine-hydrochlo-
ride.9 Laitonjam et al. utilized 2-bis(methylthio)methylene-3-
ketosteroid and guanidine nitrate for the synthesis of A-ring fused
steroidal pyrimidine.10 Hong-Min et al. reported the preparation of
steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines and their bio-
logical evaluation as potential anticancer agents.11 However, ade-
quate catalytic methods to steroidal pyrimidines are limited and
effort to accomplish a more general and versatile synthetic method
for rapid library generation is viewed as an interesting task.
Earlier, we have reported the synthesis of pyrimidines and dihy-
dropyrimidines from steroidal b-formylenamides and 2-hydroxy-
NH2
N
MeO
MeO
O
O
N
S
N
N
H
N
NH2
NH2
OMe
Trimethoprim
Sulfadiazine
NH2
Cl
O
O
NH2
Me
Me
N
N
N
N
N
N
NH2
C2H5
O
⇑
O
Corresponding authors. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail addresses: gogoipranj@yahoo.co.uk (P. Gogoi), rc_boruah@yahoo.co.in
Prazosin
Pyrimethamine
(R.C. Boruah).
Figure 1. Some important molecules having pyrimidine molecular unit.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.094

J. Gogoi et al. / Tetrahedron Letters 54 (2013) 7136–7139
7137
Table 1
Optimization studies for the synthesis of steroidal pyrimidine 3aa,b
Ph
N
Br
N
Benzamidine hydrochloride
Catalyst, ligand
CHO
Base, solvent
H
H
AcO
AcO
3a
2a
Entry
Catalyst (mol %)
Ligand
Base
Solvent
Reaction time (min)
Yieldb
1
2
CuI(2)
CuI(2)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMSO
DMF
8
40
45
L
L
-Proline
-Proline
10
3
4
5
6
7
CuI(2)
CuI(2)
Ethylenediamine
1,10-Phenanthroline
1,10-Phenanthroline
Ph3P
DMSO
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
10
8
8
15
8
8
8
8
8
8
41
40
60
70
70
75
65
81
73
74
80
77
nd
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(2)
Pd(OAc)2(5)
Pd(OAc)2(1)
—
tBu3P
Cy3P
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
8
9
10
11
12
13
14
15
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
8
8
10
The bold values signifies the optimized condition for the product 3a.
a
Reaction conditions: compound 2a (1.0 mmol), benzamidine hydrochloride(1.2 mmol), base (4 mmol), catalyst (2 mol %), ligand (4 mol %) in respective solvent (2 mL),
MW 130 W, 8 bar pressure at 140 °C.
b
Isolated yield; nd: product 3a was not detected.
methylene-3-ketosteroids using microwave and ultrasound tech-
tested, and Cs2CO3 was found to be the most efficient among them.
Additionally, we found that DMF was the most suitable reaction
media for the reaction, giving rise to product 3a. However in the
absence of catalyst, the product 3a was not observed (Table 1, en-
try 15). The detailed optimization studies are summarized in
Table 1.
nique.12–14 In continuation of our interest in b-halo-
a,b-unsatu-
rated aldehydes,7h,15 and to extend the scope of this protocol, we
envisage that reacting benzamidine and acetamidine hydrochlo-
ride with b-halo-a,b-unsaturated aldehydes will lead to 2-substi-
tuted pyrimidines under microwave irradiation.
Initially, the reaction of 3b-acetoxy-16-formyl-17-bromo-and-
rost-5,16-diene (1a) with benzamidine hydrochloride was per-
After the optimization process for the catalytic system, various
steroidal and non steroidal pyrimidine derivatives were
synthesized using our optimized conditions. We have performed
the reactions varying the amidines with a wide range of structur-
formed under the standard conditions of CuI,
L-proline, and
Cs2CO3 in DMSO/DMF at 90 °C for 12 h.16 Only trace amounts of
the desired product 3a was observed under these conditions. How-
ever, when the reaction was conducted in microwave irradiation at
140 °C, for 8 min and 8 bar, the desired product 3a was obtained in
40% yield. As a consequence, to improve the yield, the reaction con-
ditions were screened using various ligands and two solvents (DMF
and DMSO) with copper iodide(I) (Table 1, entries 1–4), but no
improvement was observed on the yield of 3a. In an attempt to in-
crease the yield of the reaction further, we proposed a number of
catalytic systems using Pd(OAc)2 with a variety of ligands, bases,
and solvents (Table 1, entries 5–14). As indicated in Table 1, Pd cat-
alyzed systems were found to be better than Cu catalyzed system.
In terms of the ligands which were screened, 1,10-phenanthroline,
ally diverse b-halo-a,b-unsaturated aldehydes and isolated the de-
sired products in good yields.18 In a typical procedure for the
synthesis of D-ring fused pyrimidine, a mixture of 3b-acetoxy-
17-bromo-16-formyl-androst-5,16-diene (2a, 1 mmol), and acet-
amidine hydrochloride (1.2 mmol) was treated with 2 mol %
Pd(OAc)2 as catalyst, 4 mol % BINAP as the ligand, 4 equiv of Cs2CO3
as the base, and DMF as the solvent at 140 °C under microwave
irradiation to afford the desired pyrimidine 3b with 72% yield
(Scheme 1).
The product 3b was characterized and compared with reported
spectral data.18 The synthetic protocol is also applied for the syn-
thesis of steroidal A-ring fused pyrimidine 3c from their corre-
t
Ph3P, Bu3P, Cy3P, and BINAP17 afforded the desired product up to
sponding b-bromo-a,b-unsaturated aldehyde with 75% yield.
81% yield. Three bases, namely K2CO3, K3PO4, and Cs2CO3 were
Under the optimized reaction conditions, the steroidal pyrimidine
Me
Br
N
O
N
CHO
ii
i
H
H
H
AcO
AcO
AcO
3b
2a
1a
Scheme 1. Reagents and conditions: (i) PBr3/DMF/CHCl3, 72%; (ii) Pd(OAc)2/Acetamidine hydrochloride/BINAP/Cs2CO3/DMF, MW at 130 W, 140 °C, and 8 bar for 8 min, 72%.

7138
J. Gogoi et al. / Tetrahedron Letters 54 (2013) 7136–7139
Table 2
Pd-catalyzed synthesis of steroidal and non-steroidal pyrimidine derivatives (3)a,b
Pd(OAc)2, BINAP
Cs2CO3, DMF
CHO
R
N
HN
NH2
HCl
+
N
X
R
2
3
R= Ph, Me
X=Cl or Br
Ph
N
Me
N
N
H
N
N
H
H
H
Ph
N
AcO
H
AcO
X=Cl; 12min, 63%
3b:8 min, 72%
3a:8 min, 81%
3c
75%
X=Br; 8min;
H
H
H
N
N
N
H
H
H
Ph
N
Ph
N
Ph
N
O
O
3f:12 min, 61%
3d:12 min, 63%
3e:12 min, 60%
Ph
Ph
Me
N
N
N
N
N
N
H
H
H
AcO
HO
AcO
3i: 8 min, 82%
3g: 8 min, 75%
3h: 8 min, 85%
Ph
Ph
N
N
N
N
N
N
Ph
N
H
3k: 8 min, 85%
Ph
N
3l: 8 min, 84%
3j: 15 min, 53%
Ph
Ph
N
N
N
N
N
N
Ph
O
MeO
3n: 8 min, 84%
X=Cl; 10 min, 71%
3o: 8 min, 83%
3m
85%
X=Br; 8 min;
a
Reaction conditions: compound 2 (1 mmol), amidine (1.2 mmol), Pd(OAc)2 (2 mol %), BINAP (4 mol %), Cs2CO3 (4 equiv), DMF (2 mL), MW, 130 W, 8 bar.
Isolated yield.
b
derivative 3c was obtained in enantiomeric pure form and not epi-
rated aldehydes. The, chloro-formyl substrate required longer reac-
tion time in comparison to bromo-formyl substrate and the
merized in any stereo center, as the specific rotation of the product
3c was compared with the reported value (found ½a D23
ꢀ
+59 (c = 2,
b-bromo-
yield than the b-chloro-
and 3m). The starting materials b-halo-
were efficiently synthesized using Vilsmeier reaction.18 Steroidal
a
,b-unsaturated aldehyde gave comparatively higher
,b-unsaturated aldehydes (Table 2, 3c,
,b-unsaturated aldehydes
CHCl3); lit.rep. ½a D23
ꢀ
+61 (c = 2, CHCl3).19
a
On the other hand, other A-ring fused pyrimidines 3d, 3e, and 3f
a
were synthesized from their corresponding b-chloro-a,b-unsatu-

J. Gogoi et al. / Tetrahedron Letters 54 (2013) 7136–7139
7139
Pd(OAc)2
NH
Ligand
X
X
HCl
N
N
NH
R
NH
Base
R
Pd
O
L
N
I
R
H
H
L
L
Pd
X
Pd
N
NH
R
N
R
N
II
H
H
III
Base
Scheme 2. Proposed catalytic cycle.
A- and D-ring annelated b-halo-a,b-unsaturated aldehydes were
References and notes
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a,b-unsatu-
a
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hydes (Table 2).
Regarding the mechanism, it is proposed that the b-halo-
a,b-
unsaturated aldehyde forms imine I with acetamidine/benzami-
dine hydrochloride in the presence of base. The in situ generated
‘Pd–L’ species undergoes oxidative addition to form intermediate
II, which forms intermediate III in the presence of base.20 The
intermediate III reductively eliminates Pd–L to give the pyrimidine
(Scheme 2).
In conclusion, we have developed a Pd-catalyzed protocol for
the synthesis of fused steroidal and non-steroidal pyrimidines
from b-halo-a,b-unsaturated aldehydes with amidines under
microwave irradiation. This approach has been successfully ap-
plied to the synthesis of A/D-ring fused pyrimidines. The b-halo-
a,b-unsaturated aldehydes are synthesized from corresponding ke-
tones using Vilsmeier formylation reaction. This synthetic protocol
is utilized to synthesize some more novel steroidal pyrimidine
derivatives and they are currently being evaluated for their biolog-
ical activities.
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Acknowledgements
13. Barthakur, M. G.; Gogoi, S.; Dutta, M.; Boruah, R. C. Steroids 2009, 74, 730.
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ejoc.201300491.
We acknowledge CSIR, New Delhi for their financial support un-
der the project CSC-301 (Affordable Cancer Therapeutics). J.G.
thanks CSIR, New Delhi for the award of Senior Research
Fellowship and P.B. thanks UGC, New Delhi for the award of Senior
Research Fellowship. We are grateful to the Director, CSIR-NEIST,
Jorhat for his keen interests.
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Supplementary data
17. BINAP = 2,20-bis(diphenylphosphino)-1,10-binaphthyl. Both racemic and
nonracemic BINAP gave similar results.
Supplementary data (experimental details, spectroscopic data
and selected copies of 1H and 13C NMR of starting and final
products) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.094.
18. Experimental details and characterization data are in Supplementary data file.
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