Regioselective synthesis of pyrano[3,2-c]pyrimidine derivatives via a palladium-catalyzed unusual [1,3] aryloxy shift and cycloisomerization: first report of a [1,3] shift of an aryloxy group

Article abstract of DOI:10.1016/j.tetlet.2008.05.019

Uracil-annulated pyrano heterocycles are regioselectively synthesized in excellent yields (92-100%) via a palladium-catalyzed unusual [1,3] aryloxy shift followed by 6-endo dig cyclization and [1,3] prototropic shift.

Full text of DOI:10.1016/j.tetlet.2008.05.019

Tetrahedron Letters 49 (2008) 4405–4408
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Tetrahedron Letters
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Regioselective synthesis of pyrano[3,2-c]pyrimidine derivatives via a
palladium-catalyzed unusual [1,3] aryloxy shift and cycloisomerization:
first report of a [1,3] shift of an aryloxy group
*
K. C. Majumdar , B. Sinha, B. Chattopadhyay, K. Ray
Department of Chemistry, University of Kalyani, Kalyani 741 235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Uracil-annulated pyrano heterocycles are regioselectively synthesized in excellent yields (92–100%) via a
Received 14 March 2008
Revised 29 April 2008
Accepted 3 May 2008
Available online 9 May 2008
palladium-catalyzed unusual [1,3] aryloxy shift followed by 6-endo dig cyclization and [1,3] prototropic
shift.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
[1,3] Aryloxy shift
Uracil
Palladium acetate
6-endo Dig cyclization
[1,3] H+ Shift
The importance of pyrimidine and its derivatives are well-
known1,2 due to their high biological activities. A number of
pyrimidine and uracil-based molecules,3 such as 30-azido-30-deoxy-
thymidine (AZT), 2,3-dideoxycytidine (DDC) and (E)-5-[2-(bromovi-
nyl)-20-deoxyuridine (BVDU) active against cancer and AIDS
viruses,4 have already been synthesized. The introduction of func-
tionality at the C5- and C6-positions of uracils leads to biologically
interesting molecules. The Claisen rearrangement is an important
and powerful method5 for constructing carbon–carbon bonds. On
the other hand, [1,3] O-migration is rare and whilst thermal [1,3]
sigmatropic shifts that relay stereochemical information have been
reported, there is a dearth of examples and the transformation lacks
generality. Recently, Rovis et al. reported6 in their review article
that the [1,3] O-migration to C is very rare in the literature. So far,
to our knowledge, there is no report of the [1,3] aryloxy migration
to C via palladium-catalyzed (or even any transition metal-cata-
lyzed) rearrangement. In 1979, Ferrier reported7 a [1,3] rearrange-
ment of hexose to cyclohexanone using HgCl2 as a catalyst.
Subsequently, Adam8 independently, and Trost et al. reported9
a
similar transformation by electrophilic-Pd activation of a vinyl
ether. Therefore, the above findings prompted us to undertake a
study of the palladium-catalyzed transformation10 of 1,3-di-
methyl-5-(40-aryloxybut-20-ynyloxy)uracils, and herein we report
the results of our investigation.
The requisite starting materials 1,3-dimethyl-5-(1-aryloxybut-
2-ynyloxy)uracils 3a–j were prepared in 80–96% yields by the
O
Cl
O
Me
O
OH
+
Me
O
3f, Ar = 4-ButC6H4, 80%
3a, Ar = Ph, 88%
N
N
i
3g, Ar = 2,4-Cl2C6H3, 84%
3h, Ar = 1-naphthyl, 83%
3i, Ar = 2-naphthyl, 82%
3j, Ar = 2-ClC6H4
3b, Ar = 4-OMeC6H4, 95%
3c, Ar = 4-MeC6H4, 91%
3d, Ar = 2,6-Me2C6H3, 90%
3e, Ar = 3,5-Me2C6H3, 94%
N
O
N
Me
Me
ArO
2a-h
3a-h
OAr
1
Scheme 1. Reagents and conditions: (i) acetone, K2CO3, reflux, 6–8 h.
* Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K. C. Majumdar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.019

4406
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 4405–4408
O
N
O
O
O
Me
O
O
Me
O
O
Me
O
O
Me
O
O
N
N
N
N
i
Ar
or
O
N
N
N
Me Me
Me
3a-j
Me
B
Me
A
OAr
OAr
4a-j
OAr
Unexpected product.
Expected product,
but not found.
Expected product,
but not found.
Scheme 2. Reagents and conditions: (i) Pd(OAc)2, DMF, Et3N, N2-atmosphere.
Table 1
Summarized results of the Claisen rearrangementsa
Entry
Substrates 3
Time (min)
45
Product 4
Yieldb (%)
100
O
O
Me
O
O
N
N
Me
N
O
1
N
Me
O
N
O
O
Me Me
O
O
O
O
O
Me
O
O
Me
O
OMe
Me
N
N
N
2
3
4
35
40
45
100
100
99
N
Me
OMe
Me
N
Me Me
O
O
O
Me
O
O
O
N
N
Me
O
N
Me
N
O
Me Me
O
O
Me
O
O
O
Me
O
Me
O
N
Me
Me
O
N
Me Me
Me
Me
Me
Me
O
O
O
Me
O
O
N
Me
O
N
N
5
6
45
60
99
98
N
Me
N
O
O
Me
tBu
Me Me
O
Me
tBu
O
O
O
Me
O
O
O
N
N
Me
O
N
Me
N
Me Me
O
O
O
Me
O
O
O
Me
O
Cl
N
N
7
8
70
80
92
N
Me
Cl
N
O
O
Me Me
Cl
Cl
O
O
O
Me
O
O
O
O
N
N
N
Me
O
100
N
Me
N
Me Me
O
O
O
O
O
O
Me
O
Me
O
N
N
9
80
65
100
97
N
Me
N
O
O
Me Me
O
Me
O
O
O
Me
O
10
N
Me
N
Me Me
Cl
Cl
a
All reactions were performed at 80 °C.
Isolated yields.
b

K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 4405–4408
4407
O
O
O
N
Me
O
O
Me
O
O
Me
O
O
N
N
N
Pd(OAc)2
OAr
N
[Pd]
N
.
Me
3
[Pd]
Me
5
Me
6
OAr
OAr
6-endo dig
O
N
O
O
Me
O
O
Me
O
Me
O
protonolysis
OAr
+shift
N
[1,3]
N
N
H
[Pd]
OAr
O
N
OAr
O
N
Me
Me Me
Me
7
8
4
Scheme 3. Proposed mechanistic pathway of the reaction.
alkylation of 1,3-dimethyluracil11 1 with different 1-aryloxy-4-
chlorobut-2-ynes 2a–j12 in refluxing acetone in the presence of
anhydrous potassium carbonate for 6–8 h (Scheme 1).
rearrangement pathway was ruled out. It is therefore reasonable
to assume that the reaction followed palladium-catalyzed
unusual [1,3] aryloxy migration pathway followed by 6-endo dig
cyclization and [1,3] prototropic shift.
a
When the reaction of 3a was performed in the presence of
Pd(OAc)2 (2 mol %) as catalyst, Et3N as the base in dry DMF under
a nitrogen atmosphere for 45 min, the cyclized product 4a was ob-
tained in almost quantitative (ꢀ100%) as a white solid by an unu-
sual pathway. From our previous research,13 the expected products
should have been either A or B. However, we did not obtain even a
trace of either A or B. The structure of the cyclized product 4a was
established from its elemental analysis and spectroscopic data. The
1H NMR spectrum showed three, three-proton singlets due to the
three methyl groups in the compound; a two-proton singlets due
to one OCH2 and five protons in the aromatic region due to the
phenyl ring. The DEPT (135) experiment revealed one OCH2 moiety
present in the compound, and finally the structure was further
supported by its HRMS spectrum. Therefore, to test the generality
of the process we conducted the reaction with substrates 3b–j
under the same reaction conditions to give the corresponding
cyclized products 4b–j in 92–100% yields (Scheme 2 and Table 1).
The reaction may occur either via, (i) a thermal [3,3] Claisen
rearrangement followed by a [1,3] migration of the aryloxy group,
or (ii) by a palladium-catalyzed [1,3] migration of the aryloxy
group. To the best of our knowledge, the thermal [1,3] shift is
known, but the palladium-catalyzed [1,3] aryloxy shift is unknown.
In our present case, the reaction involves a palladium-catalyzed
rearrangement as corroborated by the following reactions.
The mechanistic pathway of the palladium-catalyzed rear-
rangement is depicted in Scheme 3. Initially, Pd(OAc)2 may be
reduced by the organic base14 (Et3N) to give the active species
Pd(0), which may then coordinate to the triple bond of substrate
3 lowering the energy of activation of the substrates and giving
the intermediate complexes 5. The intermediate complexes 5
may undergo an unusual [1,3] aryloxy migration to give allenyl
ethers 6. These allenyl ethers 6 may then undergo a 6-endo dig
cyclization 15 to give intermediates 7. Protonolysis16 of intermedi-
ates 7 gives intermediates 8. The desired product 4 may be formed
from the exocyclic product 8 by a simple [1,3] prototropic shift.
The following experiment supported the involvement of an
unusual [1,3] migration of the aryloxy group in the reaction. When
the palladium-catalyzed reaction was performed with substrate 9
containing a 4-nitro group on the aryloxy moiety, the reaction
did not occur at all and this is perhaps due to the unavailability
of the lone pair of electrons of the oxygen atom of the 4-nitro-
phenol moiety. Due to the strong electron-withdrawing tendency
of the nitro group, the lone pair of the oxygen atom is engaged in
extended conjugation with the nitro group, and consequently the
lone pair becomes unavailable resulting in no reaction (Scheme
4). The results are summarized in Table 1. The reaction pathway
from 3 to 4 follows a concerted mechanism which is evidenced
from the following cross-over type experiment. A different phenol
was added to the reaction mixture and no cross-product was
obtained, suggesting the ‘concerted’ nature of the reaction.
In summary, we have developed an efficient high yielding pro-
tocol for the regioselective synthesis of pyrano[3,2-c]pyrimidines.
The protocol involves a palladium-catalyzed unusual [1,3] aryloxy
group migration followed by a 6-endo dig cyclization, protonolysis
and a [1,3] prototropic shift, perhaps in a concerted manner. Our
literature search did not reveal any earlier reports of catalyzed
[1,3] aryloxy shift.
When the substrates were subjected to Claisen rearrangement
either in dry DMF or in dry Et3N at 80 °C, the cyclization did not
occur or all the starting materials remained unreacted. There was
no reaction when the reaction was carried out in DMF in the
presence of Et3N at 80 °C. Therefore, the reaction was performed
separately either in DMF or Et3N in the presence of Pd(OAc)2 at
80 °C. However, the reaction did not proceed at all as evidenced
by TLC monitoring of the reaction. Therefore, the thermal Claisen
O
O
Me
O
O
Me
O
NO2
1. General procedure for the preparation of the compounds
3a–j
N
N
X
N
O
N
O
NO2
A mixture of 1,3-dimethyl-5-hydroxyuracil 1 (500 mg, 3.8
mmol), 1-aryloxy-4-chlorobut-2-yne 2a (688 mg, 3.8 mmol) and
dry K2CO3 (4.0 g) in dry acetone (75 ml) was refluxed for a period
of 6 h. After cooling, the reaction mixture was filtered and the
Me
9
Me Me
10
O
Scheme 4.

4408
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 4405–4408
solvent was removed. The residual mass was extracted with
dichloromethane, washed with water and brine and then dried
(Na2SO4). Removal of dichloromethane afforded a crude product
which was chromatographed over silica gel (60–120 mesh).
Elution of the column with 30% petroleum ether–ethyl acetate
gave compound 3a in 88% yield. Substrates 3b–j were prepared
according to this procedure.
Acknowledgements
We thank the DST (New Delhi) for financial assistance. Three of
us (B.C., B.S. and K.R.) are grateful to the CSIR (New Delhi) for their
fellowships.
References and notes
1. (a) Lunt, E. In Comprehensive Organic Chemistry; Barton, D., Ollis, W. D., Eds.;
Pergamon Press: Oxford, 1974; Vol. 4, p 493; (b) Sasaki, T.; Minamoto, K.;
Sujuki, T.; Yamashita, S. Tetrahedron 1980, 36, 865 and references cited therein;
(c) Bradshaw, T. K.; Hutchinson, D. W. Chem. Soc. Rev. 1977, 6, 43.
2. (a) Marumoto, R.; Furukawa, Y. Chem. Pharm. Bull. 1977, 25, 2974; (b) Cheng, C.
C.; Roth, B. Prog. Med. Chem. 1971, 8, 61; (c) Jones, S. A.; Sayers, J. R.; Walker, R.
T.; Clereq, E. D. J. Med. Chem. 1988, 31, 268.
3. (a) Macllwain, C. Nature 1993, 365, 378; (b) Balzarini, J.; Pauwels, R.;
Hardewijn, P.; Clercq, E. D.; Cooney, D. A.; Kanj, G. J.; Dalai, M.; Jones, D. G.;
Breder, S. Biochem. Biophys. Res. Commun. 1986, 140, 735.
4. (a) Miyasaka, T.; Tanaka, H.; Baba, M.; Hayasaka, H.; Walker, R. T.; Balzarini, J.;
Clereq, E. D. J. Med. Chem. 1989, 32, 2507; (b) Clereq, E. D. J. Med. Chem. 1986, 29,
1561; (c) Clereq, E. D. Anticancer Res. 1986, 6, 549.
5. (a) Lutz, R. P. Chem. Rev. 1984, 84, 205 and references cited therein; (b) Castro,
A. M. M. Chem. Rev. 2004, 104, 2939; (c) Majumdar, K. C.; Ghosh, S.; Ghosh, M.
Tetrahedron 2003, 59, 7251; (d) Hieresemann, M.; Abraham, L. Eur. J. Org. Chem.
2002, 1461; (e) Majumdar, K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2008,
64, 597 and references cited therein.
2. General procedure for the synthesis of the compounds 4a–j
A mixture of compound 3a (100 mg, 0.33 mmol) and Pd(OAc)2
(1.48 mg, 2 mol %) was heated in dry DMF (3 ml) in the presence
of a catalytic amount of dry Et3N under a nitrogen atmosphere at
80 °C for 35–80 min with continuous stirring. After completion of
the reaction (monitored by TLC), the reaction mixture was cooled
and water (3 ml) was added. It was extracted with dichlorometh-
ane (3 ꢁ 25 ml) and washed with water (3 ꢁ 15 ml) followed by
brine (20 ml). The organic layer was dried (Na2SO4). Evaporation
of dichloromethane furnished a crude mass, which was purified
by column chromatography over silica gel. Elution of the column
with 30% petroleum ether–ethyl acetate afforded the product 4a.
Similarly, compounds 4b–j were prepared from substrates 3b–j.
6. Nasveschuk, C. G.; Rovis, T. Org. Biomol. Chem. 2008, 6, 240.
7. (a) Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455; (b) Blattner, R.; Ferrier,
R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1 1985, 2413; (c) Barton, D. H. R.;
Camara, J.; Dalko, P.; Gero, S. D.; Sire, B. Q.; Stutz, P. J. Org. Chem. 1989, 54, 3764;
(d) Barton, D. H. R.; Dorey, S. A.; Camara, J.; Dalko, P.; Delaumeny, J. M.; Gero, S.
D.; Sire, B. Q.; Stutz, P. Tetrahedron 1990, 46, 215.
2.1. Compound 4a
Yield: 100%, white solid, mp 158–160 °C, IR (KBr): mmax = 1668,
1718 cmꢂ1 1H NMR (CDCl3, 400 MHz): dH = 2.45 (s, 3H, CH3),
,
8. Adam, S. Tetrahedron Lett. 1988, 29, 6589.
9. (a) Trost, B. M.; Runge, T. A.; Jungheim, L. N. J. Am. Chem. Soc. 1980, 102, 2840;
(b) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7550; (c) Trost, B. M.;
Runge, T. A. J. Am. Chem. Soc. 1981, 103, 2485.
3.42 (s, 3H, N–CH3), 3.61 (s, 3H, N–CH3), 4.94 (s, 2H, OCH2),
6.94–7.33 (m, 5H, ArH). HRMS calcd [M+] for C16H16N2O4:
300.1101. Found: [M+]: 300.1100. DEPT (135): dC = 13.1; 28.8;
32.2; 60.1 (OCH2), 115.2; 122.5; 130.2. Anal. Calcd for
10. (a) Majumdar, K. C.; Chattopadhyay, B.; Taher, A. Synthesis 2007, 3647; (b)
Majumdar, K. C.; Pal, A. K.; Taher, A.; Debnath, P. Synthesis 2007, 1707; (c)
Majumdar, K. C.; Chattopadhyay, B.; Ray, K. Tetrahedron Lett. 2007, 48, 7633;
(d) Majumdar, K. C.; Chattopadhyay, B.; Sinha, B. Tetrahedron Lett. 2008, 49,
1319; (e) Majumdar, K. C.; Chattopadhyay, B.; Nath, S. Tetrahedron Lett. 2008,
49, 1609; (f) Majumdar, K. C.; Chattopadhyay, B. Synlett 2008, 979; (g)
Majumdar, K. C.; Chattopadhyay, B.; Pal, A. K. Lett. Org. Chem. 2008, in press.
11. Zsindely, J.; Schmid, H. Helv. Chim. Acta 1968, 51, 1510.
C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.89; H, 5.41;
N, 9.53.
3.2. Compound 4b
12. Preparations of 1-aryloxy-4-chlorobut-2-ynes are reported earlier: (a)
Majumdar, K. C.; Thyagarajan, B. S. Int. J. Sulfur Chem. 1972, 2A, 93; (b)
Thyagarajan, B. S.; Majumdar, K. C. J. Heterocylc. Chem. 1973, 12, 43; (c)
Majumdar, K. C.; Thyagarajan, B. S. Int. J. Sulfur Chem. 1972, 2A, 153.
13. Preparations of compounds 3a,b,e, j are reported earlier: (a) Majumdar, K. C.;
Das, U. Synth. Commun. 1997, 27, 4013; (b) Majumdar, K. C.; Das, U. J. Org. Chem.
1998, 63, 9997.
14. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
15. Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636.
16. Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000, 65, 7516.
Yield: 100%, white solid, mp 148–150 °C, IR (KBr): mmax = 1672,
1708 cmꢂ1 1H NMR (CDCl3, 400 MHz): dH = 2.42 (s, 3H, CH3),
;
3.42 (s, 3H, N–CH3), 3.63 (s, 3H, N–CH3), 3.78 (s, 3H, OCH3), 4.89
(s, 2H, OCH2), 6.86–6.87 (m, 4H, ArH). 13C NMR (CDCl3,
100 MHz), dC = 12.6; 28.3; 29.7; 31.8; 55.7; 60.6; 76.7; 107.8;
114.9; 116.1; 129.7; 137.7; 151.4; 152.0; 153.3; 154.8; 159.5.
HRMS calcd [M+Na] for
C17H18N2O5 Na: 353.1113. Found:
[M+Na]: 353.1113. Anal. Calcd for C17H18N2O5: C, 61.81; H, 5.49;
N, 8.48. Found: C, 62.01; H, 5.37; N, 8.29.