A novel combination of (diacetoxyiodo)benzene and tert-butylhydroperoxide for the facile oxidative dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2008.09.045

A clean and efficient oxidative dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones to 1,2-dihydropyrimidines has been achieved through a novel combination of (diacetoxyiodo)benzene and tert-butylhydroperoxide in CH₂Cl₂.

Full text of DOI:10.1016/j.tetlet.2008.09.045

Tetrahedron Letters 49 (2008) 6698–6700
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Tetrahedron Letters
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A novel combination of (diacetoxyiodo)benzene and
tert-butylhydroperoxide for the facile oxidative dehydrogenation
of 3,4-dihydropyrimidin-2(1H)-ones
*
Nandkishor N. Karade , Sumit V. Gampawar, Jeevan M. Kondre, Girdharilal B. Tiwari
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431 606, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2008
Revised 6 September 2008
Accepted 10 September 2008
Available online 13 September 2008
A clean and efficient oxidative dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones to 1,2-dihydropyr-
imidines has been achieved through a novel combination of (diacetoxyiodo)benzene and tert-butylhydro-
peroxide in CH2Cl2.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Dehydrogenation
1,2-Dihydropyrimidine
Hypervalent iodine
(Diacetoxyiodo)benzene
tert-Butylhydroperoxide
Multi-functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
obtained from the Biginelli reaction have been used as potent
calcium channel blockers, antihypertensive agents, and neuropep-
tide Y antagonists.1 The oxidative dehydrogenation of Biginelli
DHPMs provides an efficient access to the corresponding 1,2-dihy-
dropyrimidines. However, despite the fact that pyrimidines are
found in a wide range of biologically active molecules,2 there are
few methods available to convert efficiently Biginelli DHPMs to
1,2-dihydropyrimidines.3 In contrast to 1,4-dihydropyridines
(DHPs) of the Hantzsch type, where aromatization to pyridines is
typically an easy process, the dehydrogenation of Biginelli DHPMs
is more difficult.4 This is mainly due to the sensitivity of the methyl
group at C-6 to oxidizing agents such as SeO2.5 The DHPM ring was
also found to be inert to dehydrogenation using DDQ as an oxidiz-
ing agent.6 The operationally less convenient electrochemical oxi-
dation at a graphite electrode7 and oxidation with CrO3 in the
presence of H2SO4, AcOH, and Ac2O at 0–10 oC can be utilized for
the dehydrogenation of DHPMs.8 Another dehydrogenation meth-
od requires a high temperature of 230 oC involving oxidation with
palladium on charcoal.9 However, this method cannot be applied to
the dehydrogenation of DHPMs with an ester functionality at the
5-position. The dehydrogenation of DHPMs is achieved effectively
using 60% nitric acid10 at 0 oC and using CAN/NaHCO3.11 Recently,
a mild procedure for the oxidative dehydrogenation of DHPMs
with catalytic amounts of a copper salt, K2CO3, and tert-butylhy-
droperoxide was reported.12 A literature survey suggests that
DHPMs have proven to be quite stable toward a variety of oxidizing
agents yielding 1,2-dihydropyrimidines under typical reaction
conditions. Thus, there is a need to develop a more efficient and
practical method for the dehydrogenation of DHPMs.
There has been increasing interest from organic chemists in the
oxidizing properties of hypervalent iodine compounds.13 (Diacet-
oxyiodo)benzene [DIB, PhI(OAc)2] is the parent member of the
hypervalent iodine reagent family and is environmentally benign,
easy to handle, and commercially available, and is similar in reac-
tivity to heavy metal oxidants.14 The oxidizing capacity of this ver-
satile class of hypervalent iodine reagents has been investigated
extensively for the dehydrogenation of Hantzsch 1,4-dihydropyr-
idines,15 2-imidazolines,16 and pyrazolines.17 The reactions of
DHPMs with hypervalent iodine reagents are hitherto unknown
in the literature. In continuation of our work on hypervalent io-
dine,18 herein we report a facile oxidative dehydrogenation of
DHPMs using a combination of DIB with tert-butylhydroperoxide.
Our results demonstrate that DIB alone was unable to induce dehy-
drogenation of DHMP in satisfactory yields due to lower nucleo-
philic nature of the N-3 nitrogen of the ring. However, the
addition of tert-butylhydroperoxide (TBHP) as an additive facili-
tated the dehydrogenation of DHPMs under mild reaction condi-
tions (Scheme 1).
* Corresponding author. Tel.: +91 2462 266999; fax: +91 2462 229245.
E-mail address: nnkarade@gmail.com (N. N. Karade).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.045

N. N. Karade et al. / Tetrahedron Letters 49 (2008) 6698–6700
6699
Table 2
PhI(OAc)2 (1.1 equiv),
t-BuOOH (2 equiv)
O
R
O
R
Dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) with DIB and TBHP
in CH2Cl2
H
O
CH2Cl2, r. t.
EtO
N
EtO
N
Entry
DHPM
R
Producta
Yieldb (%)
N
H
N
H
O
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5–
2a
2b
2c
2d
2e
2f
2g
2h
2i
84
83
79
80
83
84
79
83
79
73
72
4-MeOC6H4–
3-MeOC6H4
3,4-(MeO)2C6H3–
4-MeC6H4–
4-ClC6H4–
1a-k
2a-k
Scheme 1.
3-BrC6H4
3-O2NC6H4–
4-O2NC6H4–
(CH3)2CH–
(CH3)2CHCH2–
The reaction conditions were optimized by investigation of the
model dehydrogenation of 1a (R = C6H5) using DIB in various sol-
vents with or without the use of additives. The results are summa-
rized in Table 1. The reaction of 1a with DIB in CH3CN, MeOH, or
CH2Cl2 did not produce 2a. There is a report in the literature which
describes that the oxidizing properties of hypervalent iodine
reagents change remarkably on addition of certain additives.19
Therefore, we decided to use hypervalent iodine reagents in com-
bination with KBr or I2. In these cases, the in situ-generated acetyl
hypobromite or iodite (CH3COOX, X = Br or I) was expected to be
the active oxidant for bringing about dehydrogenation of the
DHPMs.20 However, we obtained relatively poor yields of the dehy-
drogenation products (Table 1, entries 4–8). Next, we used the
combination of tert-butylhydroperoxide with DIB. To our delight,
we observed facile oxidative dehydrogenation of 1a to give 2a in
84% yield.21 In a blank experiment, tert-butylhydroperoxide alone
did not oxidize 1a to 2a. The highest yield of 2a was obtained in
CH2Cl2 when a 1:2 molar ratio of DIB to tert-butylhydroperoxide
was used.
Following the success in the oxidation of 1a with the DIB/TBHP
system, we extended this method to several DHPMs with aryl and
alkyl substituents at C-4 and the results are summarized in Table 2.
All the reactions were complete in less than 4 h under mild condi-
tions, and high yields of the products were obtained. Both electron-
donating and electron-withdrawing substituents on the precursors
afforded the corresponding 1,2-dihydropyrimidine derivatives in
good to excellent yields. Aliphatic substituents such as iso-propyl
and iso-butyl at C-4 of the DHPMs (Table 2, entries 10 and 11) also
gave clean oxidative dehydrogenation without the formation of
any concomitant dealkylation product. The structures of all the
products were established from IR, NMR, and mass spectral analy-
sis (Supplementary data). The 1H NMR spectra of all the products
10
11
1j
1k
2j
2k
a
The structures of the products were confirmed from IR, NMR, and mass spectral
analysis.
b
Isolated yield.
showed a characteristic broad signal due to the enolizable –OH
or NH(1) protons around d 12–13 ppm and the absence of CH(4)
and NH(3) resonances around d 5.2 and 8.2 ppm, respectively.22
The tautomerization of NH(1) to N(3) in solution is reported in
the literature10,11 and therefore, the identity of C-4, C-6, and substi-
tuted aromatic carbons was difficult to locate in the 13C NMR spec-
tra of the dehydrogenated product.
Mechanistically, the ligand exchange reaction between tert-
butylhydroperoxide and DIB forms intermediate 3, which under-
goes homolytic cleavage of the hypervalent iodine(III)-peroxy bond
to form [9-I-2] iodanyl radical 4 and tert-butylhydroperoxy radical
5 (Scheme 2).23 The dehydrogenation mechanism may involve
abstraction of the hydrogen at C-4 of the DHPM by tert-butylhydr-
operoxy radical 5 to form the resonance stabilized radical 6, which
is further converted by single electron-transfer process to form the
iminium ion 7. Finally, a tert-butylhydroperoxy anion, acting as a
base, can abstract a N–H proton from 7 to form the 1,2-dihydro-
pyrimidine 2.
In conclusion, a transition metal-free protocol for the facile
oxidative dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones is
reported using the novel combination of tert-butylhydroperoxide
and (diacetoxyiodo)benzene. This is the first report describing
the reactions of DHPMs with hypervalent iodine reagents. Mild
reaction conditions, short reaction times, and easy isolation of
the desired product make the present method convenient.
Table 1
Optimization of the reaction conditions
PhI(OAc)2
PhI(OO-tBu)2
2 AcOH
+
+
2 t-BuOOH
3
O
Ph
PhI(OO-tBu)2
+
t-BuOO
Ph-I-OO-tBu
O
Ph
3
4
5
H
O
(1.1 equiv)
PhI(OAc)2
EtO
N
R
EtO
N
OO-tBu
R
H
EtO2C
H
EtO2C
H
O
N
H
2a
O
- t-BuOOH
N
N
H
1a
N
N
O
N
H
1
H
6
Entry
Additive
Solvent
Reaction timea (h)
Yield of 2ab (%)
1
2
3
4
5
6
7
8
9
—
—
—
CH3CN
CH2Cl2
CH3OH
CH3CN
CH3OH
CH3OH
CH3COOH
CH2Cl2
CH2Cl2
24
24
24
24
8
0
0
- PhI Ph-I-OO-tBu
13
24
31
47
28
31
84
R
R
KBr (2 equiv)
KBr (1 equiv)
KBr (2 equiv)
I2 (1 equiv)
I2 (1 equiv)
t-BuOOH (2 equiv)
EtO2C
H
N
EtO2C
OOBu-t
- t-BuOOH
N
5
12
24
4
N
O
N
O
H
7
H
2
a
The reactions were carried out at room temperature.
Isolated yield.
b
Scheme 2.

6700
N. N. Karade et al. / Tetrahedron Letters 49 (2008) 6698–6700
20. (a) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Synlett 2004, 3, 461; (b) Togo,
Acknowledgments
H.; Sakuratani, K. Synlett 2002, 1966.
21. General experimental procedure: To a stirred suspension of appropriate DHPM
(2 mmol) and TBHP (5.0–6.0 M solution in decane, 0.45 mL, 0.360 g) in CH2Cl2
(10 mL) was added DIB (0.708 g, 2.2 mmol) at room temperature. The reaction
mixture soon turned yellow in color and the progress of the reaction was
monitored by TLC. After 3–4 h of stirring, the solution was concentrated under
vacuum and the residue was purified by column chromatography (silical
gel, petroleum ether–ethyl acetate) to give the corresponding 1,2-
dihydropyrimidine in good yield.
The authors are thankful to the Department of Science and
Technology (No. SR/FTP/CS-77/2005) and to the University Grants
Commission, New Delhi, India (No. MRP 32-245/2006 SR) for the
financial support.
Supplementary data
22. Spectral data for new products:
Ethyl 1,2-dihydro-4-(3-methoxyphenyl) 6-methyl-2-oxopyrimidine-5-carboxylate
(2c): Mp 102–104 oC; IR (KBr):
m = 2927, 2859, 1713, 1662, 1540, 1481, 1358,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.045.
1359, 1283, 1109, 1043, 800, 680 cmÀ1.1H NMR (400 MHz, CDCl3): d 0.97 (t, 3H,
J = 7.2 Hz, CH3), 2.58 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 4.07 (q, 2H, J = 7.16 Hz,
OCH2), 7.02 (m, 1H, ArH), 7.10 (d, 1H, J = 6.72 Hz, ArH), 7.16 (s, 1H, ArH), 7.31 (t,
1H, J = 7.92 Hz, ArH), 13.42 (br s, 1H).13C NMR (100 MHz, CDCl3): d 13.24,
29.76, 55.54, 61.78, 100.05, 111.69, 112.90, 117.45, 120.39, 129.50, 138.02,
157.92, 159.69, 166.08. LCMS: m/z = 289 (M+1).
References and notes
1. (a) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med.
Chem. 1990, 33, 2629; (b) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806 and
references cited therein.
2. (a) Itami, K.; Yamazaki, D.; Yoshida, J. J. Am. Chem. Soc. 2004, 126, 15396; (b)
Kang, F.-A.; Kodah, J.; Guan, O.; Li, X.; Murray, W. V. J. Org. Chem. 2005, 70,
1957; (c) Wong, K.; Hung, T. S.; Lin, Y.; Wu, C.; Lee, G.; Peng, S.; Chou, C. H.; Su,
Y. O. Org. Lett. 2002, 4, 513; (d) Rombouts, F. J. R.; Fridkin, G.; Lubell, W. D. J.
Comb. Chem. 2005, 7, 589.
3. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Lavilla, R. J. Chem. Soc., Perkin
Trans. 1 2002, 1142; (c) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291.
4. (a) Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 8, 1283; (b) Han, B.; Liu, Z.; Liu,
Q.; Yang, L.; Liu, Z. L.; Yu, W. Tetrahedron 2006, 62, 2492; (c) Anniyappan, M.;
Muralidharan, D.; Perumal, P. T. Tetrahedron 2002, 58, 5069; (d) Nakamichi, N.;
Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955.
5. Khanina, E. L.; Duburs, G. Khim. Geterotsikl. Soedin 1982, 535.
6. Eynde, J. J. V.; Audiart, N.; Canonne, V.; Michel, S.; Haverbeke, Y. V.; Kappe, C. O.
Heterocycles 1997, 45, 1967.
7. (a) Kadis, V.; Stradins, J.; Khanina, E. L.; Duburs, G.; Muceniece, D. Khim.
Geterofsikl. Soedin 1965, 117; (b) Kadis, V.; Stradins, J.; Khanina, E. L.; Duburs, G.
Electrochim. Acta 1989, 34, 899.
8. Slavinskaya, V. A.; Dubus, G.; Sile, D.; Krerle, D.; Khanrna, E. L. USSR Patent 632,
695, 1978; Chem. Abstr. 1979, 90, 121631y.
9. Kappe, C. O.; Roschger, P. J. Heterocycl. 1989, 26, 55–64.
10. Puchala, A.; Belaj, F.; Bergman, J.; Kappe, C. O. J. Heterocycl. Chem. 2001, 38,
1345.
11. Shanmugam, P.; Perumal, P. T. Tetrahedron 2006, 62, 9726.
12. Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005, 21, 4673.
13. (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656; (b) Moriarty, R. M. J. Org.
Chem. 2005, 70, 2893; (c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523.
Ethyl
1,2-dihydro-4-(3,4-dimethoxyphenyl)
6-methyl-2-oxopyrimidine-5-
carboxylate (2d): Mp 156–158 oC; IR (KBr):
m
= 3028, 2841, 1716, 1670, 1593,
1518, 1437, 1369, 1319, 1271, 1151, 1099, 1022, 875, 792 cmÀ1.1H NMR
(400 MHz, CDCl3): d 1.06 (t, 3H, J = 7.12 Hz), 2.58 (s, 3H), 3.93 (s, 6H), 4.12 (q,
2H, J = 7.12 Hz), 6.89 (d, 1H, J = 8.32 Hz), 7.20 (d, 1H, J = 8.36 Hz), 7.26 (s, 1H),
13.65 (br s, 1H).13C NMR (100 MHz, CDCl3): d 13.82, 29.75, 56.08, 56.13, 61.81,
110.52, 111.36, 111.48, 121.77, 149.03, 151.74, 158.48, 166.75. LCMS: m/z =
319 (M+1).
Ethyl 1,2-dihydro-6-methyl-2-oxo-4-p-tolylpyrimidine-5-carboxylate (2e): Mp
183–185 oC; IR (KBr):
m = 2999, 2981, 1712, 1643, 1600, 1437, 1278, 1207,
1107, 1016, 964, 869, 802 cmÀ1.1H NMR (400 MHz, CDCl3): d 0.99 (t, 3H,
J = 7.08 Hz, CH3), 2.40 (s, 3H, ArCH3), 2.59 (s, 3H, CH3), 4.09 (q, 2H, J = 7.08 Hz,
OCH2), 7.23 (d, 2H, J = 8.04 Hz, ArH), 7.50 (d, 2H, J = 8.04 Hz, ArH), 13.57 (br s,
1H).13C NMR (100 MHz, CDCl3): d 13.60, 21.52, 61.62, 65.89, 111.43, 128.17,
129.14, 141.47, 158.45, 166.43. LCMS: m/z = 273 (M+1).
Ethyl 4-(4-chlorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate
(2f): Mp 181–183 oC; IR (KBr):
m = 3090, 2982, 2904, 1707, 1645, 1597, 1435,
1367, 1282, 1211, 1087, 1014, 840, 798 cmÀ1.1H NMR (400 MHz, CDCl3): d 1.02
(t, 3H, J = 7.08 Hz, CH3), 2.62 (s, 3H), 4.08 (q, 2H, J = 7.08 Hz, OCH2), 7.41 (d, 2H,
J = 8.56 Hz, ArH), 7.55 (d, 2H, J = 8.56 Hz, ArH), 13.73 (br s, 1H).13C NMR
(100 MHz, CDCl3):
d 13.65, 29.75, 61.87, 111.38, 128.70, 129.56, 137.27,
158.34, 165.89. LCMS: m/z = 293 (M+1).
Ethyl 4-(3-bromophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate
(2g): Mp 108–110 oC; IR (KBr):
m = 2926, 1719, 1600, 1560, 1438, 1367, 1278,
1103, 1103, 792, 684 cmÀ1.1H NMR (400 MHz, CDCl3): d 1.07 (t, 3H, J = 7.08 Hz,
CH3), 2.62 (s, 3H, CH3), 4.11 (q, 2H, J = 7.2 Hz, OCH2), 7.31 (t, 1H, J = 7.88 Hz,
ArH), 7.52 (d, 2H, J = 7.72 Hz, ArH), 7.60 (d, 1H, J = 8.76 Hz, ArH), 7.77 (s, 1H,
ArH).13C NMR (100 MHz, CDCl3): d 13.63, 29.74, 54.59, 61.86, 111.25, 122.54,
126.75, 130.03, 131.20, 134.04, 139.52, 158.01, 165.65. LCMS: m/z = 337 (M+1).
Ethyl
4-(3-nitrophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate
(2h): Mp 165–167 oC; IR (KBr):
m
= 3082, 2924, 1683, 1616, 1508, 1267,
1074, 794, 696 cmÀ1.1H NMR (400 MHz, CDCl3): d 1.03 (t, 3H, J = 7.08 Hz, CH3),
2.69 (s, 3H, CH3), 4.13 (q, 2H, J = 7.08 Hz, OCH2), 7.64 (t, 1H, J = 7.96 Hz, ArH),
7.96 (d, 1H, J = 7.66 Hz, ArH), 8.36 (d, 1H, J = 8.16 Hz, ArH), 8.49 (s, 1H, ArH),
13.81 (br s, 1H).13C NMR (100 MHz, CDCl3): d 13.71, 18.89, 54.65, 60.49, 62.06,
111.18, 123.32, 125.28, 129.49, 134.03, 148.06, 158.09, 165.21. LCMS: m/z =
304 (M+1).
14. Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: London,
1997.
15. Varma, R. S.; Kumar, D. J. Chem. Soc., Perkin Trans. 1999, 1, 1755.
16. Ishihara, M.; Togo, H. Synlett 2006, 227.
17. Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Synth. Commun. 1997, 27,
2683.
18. (a) Karade, N. N.; Tiwari, G. B.; Shinde, S. V.; Gampawar, S. V.; Kondre, J. M.
Tetrahedron Lett. 2008, 49, 3441; (b) Karade, N. N.; Gampawar, S. V.; Kondre, J.
M.; Shinde, S. V. Tetrahedron Lett. 2008, 49, 4402; (c) Karade, N. N.; Tiwari, G. B.;
Gampawar, S. V. Synlett 2007, 1921; (d) Karade, N. N.; Tiwari, G. B.; Huple, D. B.
Synlett 2005, 2039; (e) Karade, N. N.; Gampawar, S. V.; Kondre, J. M.; Shinde, S.
V. ARKIVOC 2008, xii, 9.
Ethyl 1,2-dihydro-4-iso-butyl-6-methyl-2-oxopyrimidine-5-carboxylate (2k): Mp
131–132 oC; IR (KBr):
m = 2983, 1708, 1656, 1599, 1452, 1371, 1259, 1134,
1016, 964, 869, 804 cmÀ1.1H NMR (400 MHz, CDCl3): d 0.95 (d, 6H, J = 6.64 Hz,
2CH3), 1.38 (t, 3H, J = 7.2 Hz, CH3), 2.12 (m, 1H, CH), 2.52 (s, 3H, CH3), 2.73 (d,
2H, J = 7.32 Hz, CH2), 4.37 (q, 2H, J = 7.16 Hz, OCH2), 13.31 (br s, 1H).13C NMR
(100 MHz, CDCl3): d 14.22, 22.40, 28.88, 29.76, 31.99, 61.75, 112.02, 158.23,
165.77. LCMS: m/z = 239 (M+1).
19. (a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem., Int. Ed. 2000,
39, 1306; (b) Tohma, H.; Maegawa, T.; Kita, Y. Synlett 2003, 723.
23. Ochiai, M.; Sueda, T. Tetrahedron Lett. 2004, 45, 3557.