Construction of dihydropyrimidine skeleton using 1,2,4-trisubstituted-1,3- diaza-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2011.12.111

Construction of a dihydropyrimidine ring was developed that involved the cyclization of 1,3-diaza-1,3-butadienes having an N-protecting group (N-Cbz, N-Boc, N-alkyl, or N-benzyl) with α,β-unsaturated carbonyl compounds such as ethyl acrylate and p-chlorophenyl vinyl ketone. Consequently, 4-dimethylamino-2-phenyl-1,4,5,6-tetrahydropyrimidines were synthesized in good yields. Subsequently, the β-elimination of the dimethylamino group was carried out with MeI or SiO₂ to afford various N-protecting-2,5- disubstituted-1,6-dihydropyrimidines in good yields. Remarkably, the use of 4-chlorophenyl vinyl ketone directly provided the dihydropyrimidine without the tetrahydropyrimidine intermediate in excellent yield.

Full text of DOI:10.1016/j.tetlet.2011.12.111

Tetrahedron Letters 53 (2012) 1177–1179
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of dihydropyrimidine skeleton using
1,2,4-trisubstituted-1,3-diaza-1,3-butadienes
Hidetsura Cho a,b, , Yoshio Nishimura c, Yoshizumi Yasui d, Masahiko Yamaguchi b,d
⇑
a Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
b Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
c Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
d WPI Advanced Institute for Materials Research, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Construction of a dihydropyrimidine ring was developed that involved the cyclization of 1,3-diaza-1,3-but-
Received 24 November 2011
Revised 22 December 2011
Accepted 26 December 2011
Available online 2 January 2012
adienes having an N-protecting group (N-Cbz, N-Boc, N-alkyl, or N-benzyl) with a,b-unsaturated carbonyl
compounds such as ethyl acrylate and p-chlorophenyl vinyl ketone. Consequently, 4-dimethylamino-2-
phenyl-1,4,5,6-tetrahydropyrimidines were synthesized in good yields. Subsequently, the b-elimination
of the dimethylamino group was carried out with MeI or SiO2 to afford various N-protecting-2,5-disubsti-
tuted-1,6-dihydropyrimidines in good yields. Remarkably, the use of 4-chlorophenyl vinyl ketone directly
provided the dihydropyrimidine without the tetrahydropyrimidine intermediate in excellent yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Dihydropyrimidine
Cycloaddition
Heterocycles
Dienes
Cyclization
Dihydropyrimidines in some cases are spontaneously oxidized
during isolation or storage. Therefore, some of them are unstable
and sometimes difficult to handle.1 However, they exhibit remark-
able pharmaceutical activities, such as calcium antagonistic
activity,2 kinesin spindle protein (KSP) inhibitory activity,3 and
anti-mycobacterial activity.4 They also act as the corrosion inhibi-
tors on austenitic stainless steel in acidic media.5 Therefore, it is
crucial to develop new synthetic methods for dihydropyrimidines.
Generally, the construction of a dihydropyrimidine ring is per-
formed by the cyclization of amidine or guanidine derivatives,1,2
or urea derivatives6 with aromatic aldehydes and 1,3-dicarbonyl
compounds. Recently, we have reported the construction of 4,
6-unsubstituted-1,4-dihydropyrimidine via ethyl 2-oxo-1,2,3,
4-tetrahydropyrimidine-5-carboxylate by cyclization.1f,h In addi-
tion, we described the preparation of the linear compound by the
novel ring cleavage of the dihydropyrimidine with amines.1h As
an alternative procedure for constructing a dihydropyrimidine
ring, we designed a novel method of reacting 1,3-diaza-1,3-dienes
A with various olefinic compounds (Scheme 1). A survey of the
literature indicated that 1,3-diaza-1,3-dienes have been generally
applied to the synthesis of pyrimidinone,7a–d heterocyclic fused
pyrimidinone,8 or pyrimidine.9 Sandhu reported the synthesis of
pyrimidin-6-ones by reacting 4-dimethylamino-2-methylthio-1-
phenyl-1,3-diaza-1,3-butadiene 110 with 2-oxazoline-5-ones.
Mahajan described the synthesis of pyrimidinone derivatives of
4-dimethylamino-1,2-diphenyl-1,3-diaza-1,3-butadiene 27d with
various ketenes.7b,7c,8 Muchowski also reported the preparation
of pyrimidines using 1-tert-butoxycarbonyl-4-dimethylamino-2-
phenyl-1,3-diaza-1,3-diene 3 with dimethyl acetylenedicarboxyl-
ate (Fig. 1).9
6
6
1
X
1
EWG
X
EWG
NMe2
X
EWG
N
N
N
5
5
2
2
Ph
N
NMe2
4
Ph
N
Ph
N
4
3
3
A
B
C
Scheme 1. Novel strategy for constructing dihydropyrimidine skeleton.
X
N
Y
N
NMe2
4: X = Cbz, Y = Ph
1: X = Ph, Y = SMe
5
2
: X = CH2Ph, Y = Ph
6: X = n-C4H9, Y = Ph
: X = Ph, Y = Ph
3: X = Boc, Y = Ph
⇑
Corresponding author. Tel.: +81 22 795 5501; fax: +81 22 795 5502.
E-mail address: hcho@mail.pharm.tohoku.ac.jp (H. Cho).
Figure 1. Various 1,3-diaza-1,3-dienes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.111

1178
H. Cho et al. / Tetrahedron Letters 53 (2012) 1177–1179
Table 2
In this Letter, we report a novel method of constructing 1,4,5,
6-tetrahydropyrimidines B and 4,6-unsubstituted-1,6-dihydropyr-
imidines C from ,b-unsaturated esters or phenyl vinyl sulfone
Preparation of 1,6-dihydropyrimidine
tetrahydropyrimidine 7 with MeI or SiO2
8
by the elimination of NMe2 group of
a
and 1,3-diaza-1,3-dienes A, and also describe the direct construc-
tion of the dihydropyrimidine skeleton from A and 4-chlorophenyl
vinyl ketone (Scheme 1).
6
6
X
EWG
X
EWG
MeI or SiO2
N
N
5
1
1
We prepared novel 1,3-diaza-1,3-butadienes 4–6 (Fig. 1), as
well as 3, and studied cyclization reactions of the diazadienes with
Ph
N
NMe2
4
CH2Cl2, rt
Ph
N
7
8
a,b-unsaturated carbonyl compounds (ethyl acrylate, methyl vinyl
ketone, and p-chlorophenyl vinyl ketone), phenyl vinyl sulfone,
and diethyl vinylphosphonate in mesitylene at 100 °C. Thus, the
treatment of N-Cbz-2-phenylamidine with N,N-dimethylformam-
ide dimethyl acetal afforded 1-benzyloxycarbonyl-4-dimethyl-
amino-2-phenyl-1,3-diaza-1,3-butadiene 4. A solution of 4 and
30 equiv of ethyl acrylate in mesitylene was heated at 100 °C for
24 h to furnish 1-benzyl 5-ethyl 4-dimethylamino-2-phenyl-
1,4,5,6-tetrahydropyrimidine-1,5-dicarboxylate 7a in an 81% yield,
accompanied with the dihydropyrimidine 8a (Table 1, entry 1).11
Entry
7
X
EWG
Methoda
8: Yield (%)
1
2
3
4
5
6
7
7a
7b
Cbz
CH2Ph
CO2Et
CO2Et
A
A
B
A
B
A
C
8a:84
8b:32
8b:71
8c:20
8c:84
8d:79
8e:81
7c
n-C4H9
CO2Et
7d
7e
Boc
Boc
CO2Et
SO2Ph
a
Method A: Treated with MeI (10 equiv) for 4 h. Method B: A mixture of 7 and 8
was treated with silica gel (1000 wt %) in the presence of MS 3 Å (50 wt %) for 6 h.
Method C: Treated with MeI (40 equiv) for 15 h.
Similarly, N-protecting compounds
5 6 (X = n-
(X = CH2Ph),12
C4H9), and 3 (X = Boc) were prepared for the cyclization reaction.
Thus, the reactions of 5, 6, or 3 with ethyl acrylate provided the tet-
rahydropyrimidines 7b, 7c, and 7d in good to excellent yield,
respectively (entries 2, 3, and 4). The cyclization of 3 with methyl
vinyl ketone afforded neither 7 nor 8, but gave a decomposed com-
pound with recovery. In addition, the use of diethyl vinylphospho-
nate instead of ethyl acrylate resulted in the recovery of 3. In the
case of phenyl vinyl sulfone, tetrahydropyrimidine 7e and the
dihydropyrimidine 8e were obtained in modest yields (entry 5).
In contrast, the reaction of 3 with 4-cholorophenyl vinyl ketone13
provided the dihydropyrimidine 8f as a sole compound in a 91%
yield without any tetrahydropyrimidine intermediate (entry 6).
respectively [entries 6 (Method A) and 7 (Method C)]. However, this
method did not work out in the case of N-alkyl tetrahydropyrimi-
dines 7b and 7c, because of an unidentified by-product (entries 2
and 4, Method A). Therefore, we tested again weak acidic reaction
conditions as an alternative effective method. Finally, 8b was
obtained in good yield (71%) when 7b was treated with 1000 wt%
SiO2 in the presence of MS 3 Å (50 wt %) in CH2Cl2 (entry 3, Method
B).15 The method also worked out in the reaction with 7c to afford
8c in an 84% yield (Entry 5, Method B).
The deprotection of 8a, 8b, 8d, 8e, and 8f was carried out
(Scheme 2 and Table 3). Namely, 8a was treated with 10% Pd-C
(20 wt %) under hydrogen atmosphere (1 atm) in EtOAc–MeOH at
rt for 18 h to give 9a in an 89% yield (Scheme 2). Compounds 8d,
8e, and 8f were treated with trifluoroacetic acid (TFA) to quantita-
tively afford the desired 4,6-unsubstituted-1,6-dihydropyrimi-
dines 9a, 9e, and 9f, as shown in Table 3. The reduction of 8b in
the presence of 10% Pd-C (20 wt %) under hydrogen atmosphere
(1 atm) in EtOAc–MeOH at rt for 24 h resulted in recovery, and
so the reduction of 8b in the presence of 20% Pd(OH)2-C
(40 wt %) under hydrogen atmosphere (1 atm) was performed in
EtOAc–MeOH at rt for 4 h to furnish N-benzyltetrahydropyrimidine
10 in a 33% yield, the double bond of which between positions 2
and 3 of 8b was reduced (Supplementary data).
The dihydropyrimidines 9a, 9e, and 9f showed independent tau-
tomers1e,1f by 1H NMR in DMSO-d6 and CDCl3. Namely, 9a is a 2.3:1.0
mixture of tautomers, 9e is a 3.5:1.0 mixture, and 9f is a 1.5:1.0 mix-
ture in DMSO-d6 (0.01 M) (major tautomer: 1,4-dihydropyrimidine;
minor tautomer: 1,6-dihydropyrimidine). On the other hand, 9a
shows a single (average) compound, but the tautomeric ratio of 9e
is 2.9:1.0, and that of 9f is 1.9:1.0 in CDCl3 (0.01 M) (major tautomer:
1,4-dihydropyrimidine; minor tautomer: 1,6-dihydropyrimidine).
A novel method of synthesizing 2,5-disubstituted dihydropyrim-
idines was developed. The cyclization of 1,3-diaza-1,3-butadienes
having an N-protecting group (N-Cbz, N-Boc, N-alkyl, or
The direct synthesis of 8f should be due to strong
a hydrogen acid-
ity (at C-5 of 7) affected by the neighboring carbonyl group com-
pared with the ester or sulfonyl moiety. Thus, the reactions (in
Table 1) regioselectively proceeded to afford tetrahydropyrimi-
dines 7a–7e or dihydropyrimidine 8f without any regioisomer.
Subsequently, the b-elimination of a NMe2 group of the tetrahy-
dropyrimidine derivative 7 was undertaken under several reaction
conditions. Since tetrahydropyrimidine was unstable as well as
dihydropyrimidine, usual acidic reaction conditions (TFA, AcOH,
pyridinium p-toluenesulfonate) gave a complex mixture. An effec-
tive means of eliminating the NMe2 group of 7a was achieved using
10 equiv of MeI in CH2Cl2 to furnish 1-benzyl 5-ethyl 2-phenyl-1,
6-dihydropyrimidine-1,5-dicarboxylate 8a in an 84% yield (Table
2, entry 1, Method A).14 Similarly, the treatment of 7d or 7e with
MeI afforded 1-tert-butyl 5-ethyl 2-phenyl-1,6-dihydropyrimi-
dine-1,5-dicarboxylate 8d or tert-butyl 2-phenyl-5-(phenylsulfo-
nyl)-1,6-dihydropyrimidine-1-carboxylate 8e in excellent yields,
Table 1
Synthesis of tetrahydropyrimidine 7 and/or dihydropyrimidine 8
6
EWG
(30 equiv.)
6
X
X
EWG
NMe2
X
EWG
N
N
N
5
1
1
+
Ph
N
NMe2
Ph
N
4
mesitylene
Ph
N
N-benzyl) with electron-deficient olefins such as
a,b-unsaturated
100 °C
3 6
-
7
8
Entry
3À6
EWG
Time (h)
7, 8: Yield (%)
1
4 (X = Cbz)
5 (X = CH2Ph)
6 (X = n-C4H9)
3 (X = Boc)
3 (X = Boc)
3 (X = Boc)
CO2Et
CO2Et
CO2Et
CO2Et
SO2Ph
24
13
13
13
48
13
7a:81
8a: 3
8b: 9
8c: 8
8d: 3
8e: 30
8f: 91
Cbz
Ph
CO2Et
CO2Et
N
2a
3
7b:69
7c:80
7d:78
7e:30
7f:0
N
H2 (1 atm), 10% Pd-C
EtOAc-MeOH, rt, 18 h
Ph
N
H
N
4
5b
6b
8a
9a
2.3:1.0 mixture
89%
COC6H4Cl-p
a
Yield from N-benzyl-2-phenylamidine.
b
5.0 equiv of the olefin was used.
Scheme 2. Deprotection of N-Cbz group of dihydropyrimidine 8a.

H. Cho et al. / Tetrahedron Letters 53 (2012) 1177–1179
5. Caliskan, N.; Akbas, E. Mater. Chem. Phys. 2011, 126, 983–988.
1179
Table 3
6. (a) Cho, H.; Takeuchi, Y.; Ueda, M.; Mizuno, A. Tetrahedron Lett. 1988, 29, 5405–
5408; (b) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (c) Kappe, C. O.;
Stadler, A. Org. React. 2004, 63, 1–116.
7. (a) Sain, B.; Singh, S. P.; Sandhu, J. S. Teterahedron 1992, 48, 4567–4578; (b)
Mazumdar, S. N.; Mukherjee, S.; Sharma, A. K.; Sengupta, D.; Mahajan, M. P.
Tetrahedron 1994, 50, 7579–7588; (c) Jayakumar, S.; Singh, P.; Mahajan, M. P.
Tetrahedron 2004, 60, 4315–4324; (d) Mohan, C.; Singh, P.; Mahajan, M. P.
Tetrahedron 2005, 61, 10774–10780.
Deprotection of N-Boc group of dihydropyrimidines 8d–f
Boc
EWG
EWG
TFA (excess)
CH2Cl2, rt, 3 h
N
N
Ph
N
Ph
N
H
9
8
8. Sharma, A. K.; Mahajan, M. P. Tetrahedron 1997, 53, 13841–13854.
9. Guzman, A.; Romero, M.; Talamas, F.; Villena, R.; Greenhouse, R.; Muchowski, J.
M. J. Org. Chem. 1996, 61, 2470–2483.
Entry
8
EWG
9: Yield (%)
10. Nishi, M.; Tanimoto, S.; Okano, M.; Oda, R. J. Synth. Org. Chem. Jpn. 1969, 27, 754.
Chem. Abstr. 1969, 71, 101438v.
11. General procedure for cyclization reaction of 1,3-diaza-1,3-butadiene with olefinic
1
2
3
8d
8e
8f
CO2Et
SO2Ph
COC6H4Cl-p
9a:97
9e:98
9f:100
compounds:
A solution of 1-benzyloxycarbonyl-4-dimethylamino-2-phenyl-
1,3-diaza-1,3-butadiene 4 (234 mg, 0.756 mmol) and ethyl acrylate (2.50 mL
mmol) in mesitylene (6 mL) was heated at 100 °C for 13 h under an atmosphere
of argon. The reaction mixture was concentrated under reduced pressure and the
residue was purified by flash column chromatography (SiO2) (hexane/EtOAc/i-
Pr2NEt = 150:25:2–150:75:2) to give 7a (252 mg, 0.615 mmol, 81%) as colorless
crystals [mp 73–74 °C (hexane–chloroform)] and 8a (9.3 mg, 0.026 mmol, 3%) as
carbonyl compounds provided 4-dimethylamino-1,4,5,6-tetrahy-
dropyrimidines in good yields. Subsequently, MeI or SiO2 treatment
resulted in the b-elimination of the dimethylamino group to
afford various N-protecting-2,5-disubstituted-1,6-dihydropyrimi-
dines. Remarkably, the use of 4-chlorophenyl vinyl ketone directly
provided the dihydropyrimidine without the tetrahydropyrimidine
intermediate in excellent yield. This report may provide useful infor-
mation for the construction of other dihydropyrimidines or fused
heterocyclic compounds and may extend the use of 1,2,4-trisubsti-
tuted-1,3-diaza-1,3-butadienes.
a
yellow oil. Compound 7a: Colorless crystals; mp 73–74 °C (hexane–
chloroform); IR (KBr) cmÀ1: 2866, 1736, 1620, 1276, 1195; 1H NMR (600 MHz,
CDCl3) d = 1.28 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.40 (s, 6H, NMe2), 2.86 (ddd, J = 6.6,
9.6, 10.8 Hz, 1H, 5-CH), 3.91 (dd, J = 10.8, 12.0 Hz, 1H, 6-CH), 3.93 (dd, J = 6.6,
12.0 Hz, 1H, 6-CH), 4.17–4.28 (m, 2H, OCH2CH3), 4.33 (d, J = 9.6 Hz, 1H, 4-CH),
4.97 (s, 2H, CH2Ph), 6.87 (d, J = 7.8 Hz, 2H, Ar-o-H), 7.21 (t, J = 7.8 Hz, 2H, Ar-m-H),
7.23-7.28 (m, 1H, Ar-p-H), 7.32 (t, J = 7.8 Hz, 2H, Ar-m-H), 7.38 (t, J = 7.8 Hz, 1H,
Ar-p-H), 7.52 (d, J = 7.8 Hz, 2H, Ar-o-H); 13C NMR (150 MHz, CDCl3) d = 14.1, 40.2,
44.7, 45.5, 61.1, 68.3, 77.7, 127.0, 128.0, 128.10, 128.14, 128.3, 129.7, 134.8,
137.2, 153.7, 153.9, 171.3; LRMS (EI) m/z: 409 (M+); HRMS m/z: calcd for
Acknowledgments
C23H27N3O4, 409.2001; found, 409.2002. Compound 8a: Yellow oil; IR (neat)
cmÀ1: 2982, 1725, 1537, 1281, 1230, 1184; 1H NMR (600 MHz, CDCl3) d = 1.34
(t, J = 7.2 Hz, 3H, OCH2CH3), 4.28 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.59 (d, J = 1.2 Hz,
2H, 6-CH2), 4.99 (s, 2H, CH2Ph), 6.83 (d, J = 7.2 Hz, 2H, Ar-o-H), 7.19 (t, J = 7.2 Hz,
2H, Ar-m-H), 7.24 (t, J = 7.8 Hz, 1H, Ar-p-H), 7.37 (t, J = 7.8 Hz, 2H, Ar-m-H), 7.46
(t, J = 7.2 Hz, 1H, Ar-p-H), 7.65 (d, J = 7.8 Hz, 2H, Ar-o-H), 7.70 (d, J = 1.2 Hz, 1H,
4-CH); 13C NMR (150 MHz, CDCl3) d = 14.2, 40.7, 60.8, 68.7, 115.9, 127.9, 128.2,
128.3, 128.4, 128.5, 131.3, 134.4, 135.7, 143.0, 153.4, 157.2, 164.6; LRMS (EI) m/z:
364 (M+); HRMS m/z: calcd for C21H20N2O4, 364.1423; found, 364.1433.
We appreciate the financial support of the Tohoku University
G-COE program ‘IREMC’. This work was also carried out with
the financial support of Japan Tobacco Inc. to H.C. We thank
Mr. Satoshi Kobayashi for technical support.
12. Because the compound
5 (prepared from the reaction of N-benzyl-2-
Supplementary data
phenylamidine with N,N-dimethylformamide dimethyl acetal) was unstable
and partially decomposed during the purification by silica gel column
chromatography, 7b and 8b were synthesized by one-pot successive reactions
from N-benzyl-2-phenylamidine (Table 1, entry 2); see Supplementary data.
13. 4-Cholorophenyl vinyl ketone was prepared from 4-chlorophenacyl bromide in
33% yield (three steps) according to the reported procedure: An, X.-L.; Chen, J.-
R.; Li, C.-F.; Zhang, F.-G.; Zou, Y.-Q.; Guo, Y.-C.; Xiao, W.-J. Chem. Asian J. 2010, 5,
2258–2265.
Supplementary data (synthesis and characterization of com-
pounds, spectroscopic data of IR, NMR, MS) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.12.111.
14. General procedure for the elimination reaction of the dimethylamino group of
tetrahydropyrimidine using MeI: To a solution of 7a (81.4 mg, 0.199 mmol) in
CH2Cl2 (2 mL) was added iodomethane (0.13 mL, 2.09 mmol) dropwise at room
temperature under an atmosphere of argon. The reaction mixture was stirred at
room temperature for 4 h, and triethylamine (1.0 mL), EtOAc (20 mL), water
(10 mL) were added. The organic layer was separated, and the aqueous layer was
extracted with EtOAc (10 mL Â 2). The combined organic layer and extracts were
washed with water, brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatography (SiO2)
(hexane/EtOAc/i-Pr2NEt = 200:33:2.5) to give 8a (60.7 mg, 0.167 mmol, 84%).
15. General procedure for the elimination reaction of the dimethylamino group of
tetrahydropyrimidine using SiO2: To dried silica gel (376 mg, 1000 wt %) and
molecular sieves 3 Å (18.8 mg, 50 wt %) was added a mixture of a mixture of 7b
and 8b (8.6:1, 37.6 mg, 0.104 mmol) in CH2Cl2 (2 mL) under an atmosphere of
argon. The reaction mixture was stirred at room temperature for 6 h, and
triethylamine (2 mL) was added. The mixture was filtered and concentrated
under reduced pressure, and the residue was purified by flash column
chromatography (SiO2) (hexane/EtOAc/i-Pr2NEt = 60:30:1) to give 8b (23.5 mg,
References and notes
1. (a) Traube, W.; Schwarz, R. Chem. Ber. 1899, 32, 3163–3174; (b) Weis, A. L.
Tetrahedron Lett. 1982, 23, 449–452; (c) Cho, H.; Shima, K.; Hayashimatsu, M.;
Ohnaka, Y.; Mizuno, A.; Takeuchi, Y. J. Org. Chem. 1985, 50, 4227–4230; (d) Weis,
A. L.;van der Plas, H. C. Heterocycles 1986, 24, 1433–1455; (e) Cho, H.; Iwashita, T.;
Ueda, M.; Mizuno, A.; Mizukawa, K.; Hamaguchi, M. J. Am. Chem. Soc. 1988, 110,
4832–4834; (f) Cho, H.; Nishimura, Y.; Yasui, Y.; Kobayashi, S.; Yoshida, S.; Kwon,
E.; Yamaguchi, M. Tetrahedron 2011, 67, 2661–2669; (g) Cho, H.; Yasui, Y.;
Kobayashi, S.; Kwon, E.; Arisawa, M.; Yamaguchi, M. Heterocycles 2011, 83, 1807–
1818; (h) Cho, H.; Kwon, E.; Yasui, Y.; Kobayashi, S.; Yoshida, S.; Nishimura, Y.;
Yamaguchi, M. Tetrahedron Lett 2011, 52, 7185–7188.
2. (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.;
Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.;
Ishihara, T.; Funahashi, K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989,
32, 2399–2406; (b) 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, 2629–2635; (c) Rovnyak, G. C.; Atwal, K. S.;
Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254–3263.
0.0734 mmol, 71%) as a yellow oil. Compound 8b: Yellow oil; IR (neat) cmÀ1
:
2979, 1689, 1624, 1512, 1263, 1106; 1H NMR (600 MHz, CDCl3) d = 1.26 (t,
J = 7.2 Hz, 3H, OCH2CH3), 4.17 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.24 (s, 2H, CH2Ph or
6-CH2), 4.42 (s, 2H, CH2Ph or 6-CH2), 7.22 (d, J = 8.4 Hz, 2H, Ar-o-H), 7.28-7.44 (m,
6H, Ar-H), 7.49 (dd, J = 7.4, 1.5 Hz, 2H, Ar-o-H), 7.52 (s, 1H, 4-CH); 13C NMR
(150 MHz, CDCl3) d = 14.3, 45.9, 56.3, 60.0, 105.2, 127.1, 127.7, 128.0, 128.7,
129.0, 130.0, 134.8, 135.3, 145.8, 163.4, 166.1; LRMS (EI) m/z: 320 (M+); HRMS m/
z: calcd for C20H20N2O2, 320.1525; found, 320.1502.
3. (a) Cox, C. D.; Breslin, M. J.; Mariano, B. J.; Coleman, P. J.; Buser, C. A.; Walsh, E.
S.; Hamilton, K.; Huber, H. E.; Kohl, N. E.; Torrent, M.; Yan, Y.; Kuo, L. C.;
Hartman, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 2041–2045; (b) Zhang, Y.; Xu,
W. Anticancer Agents Med. Chem. 2008, 8, 698–704.
4. Ali, M. A.; Manogaran, E.; Govindasamy, J.; Sellappan, V.; Pandian, S. J. Enzyme
Inhib. Med. Chem. 2011, 26, 149–153.