Regioselective synthesis of pyrimidine-annulated spiro-dihydrofurans by silver-catalyzed 5-endo-dig cyclization

Article abstract of DOI:10.1039/c1nj20121b

A simple and efficient method for the synthesis of some hitherto unreported pyrimidine-annulated spiro-dihydrofurans has been described. In the presence of AgSbF₆ spiro- and furo-pyrimidine (10-hydroxy-4,7,9-substituted-1- oxa-7,9-diazaspiro[4.

Full text of DOI:10.1039/c1nj20121b

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LETTER
Regioselective synthesis of pyrimidine-annulated spiro-dihydrofurans by
silver-catalyzed 5-endo-dig cyclizationw
K. C. Majumdar,* Sintu Ganai and Raj Kumar Nandi
Received (in Montpellier, France) 14th February 2011, Accepted 12th May 2011
DOI: 10.1039/c1nj20121b
A simple and efficient method for the synthesis of some hitherto
unreported pyrimidine-annulated spiro-dihydrofurans has been
described. In the presence of AgSbF6 spiro- and furo-pyrimidine
(10-hydroxy-4,7,9-substituted-1-oxa-7,9-diazaspiro[4.5]dec-3-ene-
6,8-dione) heterocycles are obtained in good yields. The nature
of the alkyne moiety present in substrates dictates the mode of
cyclization to form the furopyrimidine derivatives.
prompted us to study the reaction of propargyloxypyrimidine
substrates with AgSbF6. Herein we report the results of our
investigation.
The required precursors 3a–h for this study were prepared in
excellent yields by the Sonogashira cross coupling reaction of
the substrates 1a, b (1 equiv.), aryl iodides (1.2 equiv.) using
Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%) as co-catalysts in
anhydrous DMF and Et3N (10 : 3) at room temperature
(Scheme 1).
Pyrimidine, being a component of nucleic acids, exhibits
diverse role in biological, pharmaceutical as well as agrochemical
sectors. A number of pyrimidine-based molecules like BVDU
(E)-5-(2-bromovinyl)-20-deoxyuridine, Zidovudine, Stavudine
are well known as therapeutic agents due to their anti-cancer
and anti HIV properties.1 It is well established that furo[2,3-d]-
pyrimidine2 and spiropyrimidine3 derivatives have desirable
pharmacological properties. Among them, the furo[2,3-d]-
pyrimidine derivatives act as sedatives, antiulcer agents, muscle
relaxants, antihistamines and diuretics.4 Moreover some of the
furopyrimidine derivatives are potent and selective anti-VZV
agents.5 Introduction of a functionality at the C-5 and C-6
positions of uracil leads to biologically interesting molecules.
Synthesis of furan fused pyrimidines is important because of
their broad spectrum of biological activities. Comparatively
little efforts have been made for the synthesis of furopyrimidine
derivatives6 and spiro-pyrimidine derivatives.7 Reported
methods involve either multisteps7a or require harsh reaction
conditions.7d Due to these limitations we have planned to
develop a simple and short protocol for the synthesis of
furopyrimidines.
After a series of trials, we observed that 5-propargyloxy-
pyrimidine 3a could undergo
a reaction with AgSbF6
(0.1 equiv.) in HOAc at 80 1C to afford selectively a new
compound in 87% yield (mp 172 1C) (Scheme 2).
The spectral and analytical data of the compound showed
the formation of the product 4a. IR spectroscopy indicated
the presence of a hydroxyl group at 3345 cmꢀ1 which was
confirmed by D2O-exchange NMR spectroscopy. Finally, the
structure of the spiro heterocyclic product 4a was established
from the single crystal X-ray diffraction analysis11a (Fig. 1).
Refinement has been carried out including the hydrogen
atom at calculated positions except H8, H8A, H8B and H9.
These hydrogens have been located and refined isotropically.
From the X-ray analysis it is clear that compound 4a is
In continuation of our work on the pyrimidine-annulated
heterocycles,8 we have recently reported9 a novel method for
the synthesis of pyridopyrimidine derivatives by AgSbF6
catalyzed reaction of 5-(N-propargyl)pyrimidines via a 6-endo-dig
mode of cycloisomerization. To our knowledge, there is no report
on the synthesis of bioactive furo-pyrimidine derivatives by
silver-catalyzed reaction. As shown in recent literature data10
silver-catalyzed reactions have received less attention. This has
Scheme 1 Reagents and conditions: (i) Pd(PPh3)2Cl2, CuI, anhyd.
DMF and Et3N, rt, 1 h.
Department of chemistry, Kalyani University, Kalyani-741235,
West Bengal, India. E-mail: kcm_ku@yahoo.co.in
w Electronic supplementary information (ESI) available. CCDC
reference numbers 808360 (4a). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1nj20121b
Scheme 2 Reagent and conditions: (i) AgSbF6, HOAc at 80 1C, 4 h.
c
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AlCl3 (entries 9 and 12) gave very poor yield of the products
(19–21%), but Cu(I) and Cu(II) gave somewhat better results
(27–40%, entries 6–8). We have obtained a moderate yield
of 4a when the reaction was carried out with AuCl3 (48%,
entry 19). But when AuCl3 was used along with AgSbF6 the
yield of the product 4a increased to 82% (entry 20). However,
when the reaction was carried out with AgBF4 a good yield
(68%, entry 21) of the product was obtained. Other silver
catalysts like AgNO3, AgOTf, AgOAc and AgI also gave the
same product but in moderate yields (28–52%, entries 5 and
22–24,). Polar aprotic solvents like DMSO and acetonitrile,
failed to give any cyclized product. The reaction was also
unsuccessful in toluene (entry 4).
However it is remarkable that only HOAc, among various
solvents used, gave the fruitful result. When the reaction was
carried out in HOAc without any catalyst we obtained the
cyclized product within 9 h in very poor yield (16%, entry 16).
According to Toste et al., the coinage metal catalysts accelerate
the cyclization reaction by producing related Brønsted acids in
the reaction medium.12 We have also carried out the reaction
in the presence of Brønsted acids like HCl, H2SO4, triflic acid
but did not get any product (entries 13–15). Thus here, HOAc
might have a role in facilitating the reaction with a silver
catalyst. Other Lewis acids FeCl3 and NiCl2ꢁ2H2O resulted in
the formation of a complicated reaction mixture (entries 10
and 11). The reaction was also carried out in H2O and
DMSO–H2O mixture (entries 17 and 18, Table 1) but we did
not get any product. After a series of experiments was
performed, the optimized condition developed so far was
treatment of the substrate with 10 mol% AgSbF6 in HOAc
at 80 1C (entry 1,Table 1).
Fig. 1 The ORTEP diagram of the compound 4a.
cis-substituted with respect to the ring substituents i.e. hydroxy
(–OH) group and ether (–O–) linkage.11b
However, to optimize the reaction conditions, in order to
obtain a maximum yield of the cyclized product, a set
of experiments were carried out with the substrate 3a by
changing the parameters (solvent, catalyst), see Table 1.
When the reaction was run in the presence of AgSbF6 in
HOAc, an excellent yield of the compound 4a (87%, entry 1)
was obtained. Among the different catalysts used ZnCl2 and
Table 1 Optimization of spiro cyclization of compound 3a
This optimized reaction condition was used for the other
substrates. Treatment of 3b under the optimized condition
afforded the product 4b in 78% yield. Similarly the compounds
4c, 4d, 4e and 4f were obtained from their corresponding
starting materials 3c, 3d, 3e and 3f in 75%, 84%, 80% and
82% yields respectively. The products 4g and 4h were obtained
from 3g and 3h in 5 h with 69% and 62% yields respectively.
When the substrate 1c was subjected to the optimized condition
for 4.5 h the corresponding spiro-dihydrofuran 4i was
obtained in 59% yield. All the spiro-dihydrofurans are cis
with respect to ether linkage and hydroxy group. The results
are summarised in Table 2.
Entry Catalysta
Solvent
Temp./1C Time/h Yieldb (%)
1
2
3
4
5
6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNO3
CuI
HOAc
DMSO
CH3CN
Toluene
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HCl
80
80
Reflux
Reflux
80
80
80
80
80
80
80
80
80
80
80
80
Reflux
4
87
—
—
—
44
34
40
27
19
cm
cm
21
—
—
—
16
—
—
48
82
68
46
52
28
15
15
15
4
4
4
4
4
4
4
7
8
9
Cu(OAc)2
CuSO4ꢁ5H2O
ZnCl2
NiCl2ꢁ2H2O
FeCl3
AlCl3
—
—
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
When 1,3-dimethyl-5-propargyloxyuracil 1a was treated
under the optimized condition (i.e. 10 mol% AgSbF6 and
HOAc) 1,3,7-trimethylfuro[3,2-d]pyrimidine-2,4(1H,3H)-dione
(4j) was obtained in 85% yield instead of the spiro-dihydrofuran
(Table 2, entry 10).
Kawahara et al. have reported13 the formation of the keto
product 5a from 1,3-dimethyl-5-propargyloxyuracil (1a) in the
presence of acid (Scheme 3). However, neither HOAc nor
H2SO4 gave the corresponding keto product from the
substrate 3a. Therefore the Ag(I) catalyst may be responsible
for this type of cyclization.
4
9
9
9
H2SO4
TfOH
HOAc
H2O
9
17
15
6
4
4
4
4
4
—
AuCl3
DMSO, H2Oc 80
HOAc
AuCl3, AgSbF6 HOAc
80
80
80
80
80
80
d
AgBF4
AgOTf
AgOAc
AgI
HOAc
HOAc
HOAc
HOAc
a
Reactions (entries 1–12) were carried out with 1 equiv. 3a and
0.1 equiv. of catalyst. Reactions (entries 13–6) were carried out in
From the results shown in Table 2, it is observed that in the
case of the nonterminal alkynes the reaction shows high
regioselectivity to give only the spiro-heterocycles. The reaction
proceeds via a 5-endo-dig mode of cyclization (through path a,
Scheme 4). But in the case of a terminal alkyne the reaction
b
the presence of Bronsted acids. Isolated yield. Both solvents were
c
d
used in the same ratio cm = complicated reaction mixture. Both
catalysts were used in the same ratio.
c
1356 New J. Chem., 2011, 35, 1355–1359
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Table 2 AgSbF6 catalyzed synthesis of furopyrimidine derivatives
Yielda
Entry Starting materials (3) Time/h Products (4)
(%)
Scheme 3
1
4
87
2
3
4.5
4.5
78
75
4
4.5
84
Scheme 4 Plausible mechanism for the synthesis of furopyrimidines.
carbocations (C and D) from the p-complex B. When R0 = H,
carbocation D is more stable compared to C, but when
R0 = Me or Aryl, carbocation C is stabilized by the +M
effect of the phenyl ring or the +I effect of the –Me group
present in the terminal part of the alkynes.
5
6
4.5
4.5
80
82
The spiro-dihydrofurans may also be assumed to form
by a 5-endo-dig mode of cyclization of B via formation of
carbocation C. The involvement of a lone pair of the N atom
of the pyrimidine ring may facilitate this mode of cyclization by
formation of a Mannich species10e,f E. Then H2O may attack the
imino bond from the opposite side of the substituent –R0 to
avoid the steric crowding to afford the spiro-dihydrofurans
4a–i (path a). Thus stereoselectivity of the reaction is controlled by
a steric factor. The formation of the furo-fused pyrimidine 4j
can be explained by a 5-exo-dig mode of cyclization of B via D
to F followed by isomerization of G (to gain aromaticity). The
yields of regioselective formation of the spiro-dihydrofurans
may also be rationalized by the nature of the group present on
the alkyne terminal; a more electron donating group which
stabilized the carbocation C gave the better yield compared to
the electron withdrawing substituent (–COCH3).
7
5
5
69
62
8
9
4.5
4.5
59
85
Herein we have developed a new straightforward methodology
for the regioselective as well as stereoselective synthesis of
hitherto unreported pyrimidine annulated spiro-heterocycles
from propargyloxyuracil by the AgSbF6 catalyst in HOAc
medium via a 5-endo-dig mode of cyclization, which was
totally controlled by the nature of the acetylenic moiety of
the ether substrate. Sames et al. have reported15 cyclization of
propargyl ether with different catalysts but failed to obtain any
furano derivative. Generally AgSbF6 is used to activate the
gold-catalyst.10a,16 But this is an example of silver mediated
hetero-1,5-enyne cyclization which is currently a topic of
general interest. The observed 5-endo cyclization mode is
rare17 for such reactions where, the 6-endo mode seems to be
more common.18 To our knowledge this is the first report for
this type of spiro heterocyclization solely by the silver catalyst.
In conclusion, we have developed a novel and efficient method
for the regioselective and stereoselective synthesis of hitherto
10
a
Isolated yield.
proceeds via a 5-exo-dig mode of cyclization (path b,
Scheme 4). According to Baldwin’s rule14 both the modes
(5-endo-dig and 5-exo-dig) are favourable for the formation of
a 5-membered ring. The results show that the mode of
cyclization was controlled by the nature of the alkyne moiety
of the enyne part of the substrates. On the basis of the above
results, the formation of the products may be rationalized.
Initially a p-complex B may be formed between an alkyne
segment of the substrate A and a silver ion (Scheme 4). The
formation of products can be explained via the formation of
c
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unreported 4,7,9-substituted-10-hydroxy-1-oxa-7,9-diazaspiro[4.5]-
dec-3-ene-6,8-dione derivatives from various O-propargylated
uracil derivatives by a silver-catalyzed 5-endo-dig mode of
cyclization which is controlled by the nature of the substituents
at the terminal alkyne moiety of the substrates.
2 E. De Clercq, Med. Res. Rev., 2003, 23, 253–274.
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P. P. Mukhopadhyay, Synthesis, 2004, 1864–1868.
8 (a) K. C. Majumdar, P. K. Basu, P. P. Mukhopadhyay, S. Sarkar,
S. K. Ghosh and P. Biswas, Tetrahedron, 2003, 59, 2151–2157;
(b) K. C. Majumdar and P. P. Mukhopadhyay, Synthesis, 2003,
920–924; (c) K. C. Majumdar, U. Das and N. K. Jana, J. Org.
Chem., 1998, 63, 3550–3553; (d) K. C. Majumdar, P. K. Maji,
K. Ray and P. Debnath, Tetrahedron Lett., 2007, 48, 9124–9127;
(e) K. C. Majumdar, B. Sinha, B. Chattopadhyay and K. Ray,
Tetrahedron Lett., 2008, 49, 4405–4408; (f) K. C. Majumdar and
B. Chattopadhyay, Synlett, 2008, 979–982; (g) K. C. Majumdar,
B. Sinha, P. K. Maji and S. K. Chattopadhyay, Tetrahedron, 2009,
65, 2751–2756; (h) K. C. Majumdar, S. Mondal and D. Ghosh,
Synthesis, 2010, 1176–1180; (i) K. C. Majumdar, S. Mondal and
D. Ghosh, Tetrahedron Lett., 2010, 51, 5273–5276.
General procedure for the preparation of compound
3a–h and 1c
A mixture of the compounds 1a (500 mg, 2.74 mmol),
p-chloroiodobenzene (786 mg, 3.29 mmol), Pd(PPh3)2Cl2
(0.13 mmol) and CuI (0.27 mmol) in dry DMF (5 mL) and
dry Et3N (1.5 mL) was stirred at room temperature for 1 h.
After completion of the reaction (as monitored by TLC), the
reaction mixture was poured in water. This was extracted with
dichloromethane (3 ꢂ 15 mL). The combined organic extract
was washed with brine (1 ꢂ 15 mL) and dried over Na2SO4.
The solvent was distilled off. The resulting crude product was
purified by column chromatography over silica gel (60–120 mesh)
using a petroleum ether–ethyl acetate mixture (4 : 1) as an
eluent to give the product 3a. Similarly precursors 3b–h were
prepared from the corresponding iodobenzene derivatives.
The compound 1c was prepared by refluxing 1,3-diethyl-5-
hydroxypyrimidine-2,4(1H,3H)-dione (1 g, 5.4 mmol) with
1-bromobut-2-yne (0.85 g, 6.4 mmol) and anhydrous K2CO3
(1.5 g, 10.8 mmol) in acetone (75 mL) for 5 h and purified by
column chromatography using a petroleum ether–ethyl acetate
mixture (3 : 2) as an eluent.
General procedure for the preparation of compounds
4a–j
9 K. C. Majumdar, R. K. Nandi, S. Ganai and A. Taher, Synlett,
2011, 116–120.
To a stirred solution of AgSbF6 (9 mg, 0.026 mmol) in HOAc
(5 mL), 5-(3-(4-chlorophenyl) prop-2-ynyloxy)-1,3-dimethyl-
pyrimidine-2,4(1H, 3H)-dione 3a (100 mg, 0.26 mmol) was
added at room temperature and stirred at 80 1C for 4 h. After
completion of the reaction (as monitored by TLC), the
reaction mixture was cooled and neutralized with saturated
NaHCO3 solution. This was extracted with dichloromethane
(3 ꢂ 10 mL). The combined organic extract was washed with
brine (1 ꢂ 10 mL) and dried over Na2SO4. The solvent was
distilled off. The resulting crude product was purified by
column chromatography over silica gel (60–120 mesh) using
a petroleum ether–ethyl acetate mixture (2 : 3) as an eluent to
give the product 4a. Similarly compounds 4b–j were obtained
from the corresponding precursors.
10 (a) T. Godet, C. Vaxelaire, C. Michel, A. Milet and P. Belmont,
Chem.–Eur. J., 2007, 13, 5632–5641 and references cited therein;
(b) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108,
3395–3442; (c) M. Alvarez-Corral, M. Munoz-Dorado and
I. Rodrıguez-Garcıa, Chem. Rev., 2008, 108, 3174–3198;
(d) M. Marina Naodovic and H. Yamamoto, Chem. Rev., 2008,
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Synlett, 2004, 2406–2408; (f) D. S. Ermolat’ev, V. P. Mehta and
E. V. Van der Eycken, Synlett, 2007, 3117–3122.
11 (a) CCDC 808360 (4a); (b) The supplementary X-ray structure of the
compound 4a, where two asymmetric centres are superimposed.
We thank CSIR (New Delhi) for financial assistance. We
specially thank Professor S. Chattopadhyay of this department
for helping us with the analysis of XRD data of the compound
4a. Two of us (S. G and R. K. N) are grateful to the CSIR
(New Delhi) for their research fellowships. We also thank the
DST (New Delhi) for providing a Bruker NMR (400 MHz),
Perkin-Elmer CHN Analyser, FTIR and UV-Vis spectrometer.
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