Efficient synthesis of 7-benzyl-5,6,7,8-tetrahydropyrido[4′,3′: 4,5]thieno [2,3-d]pyrimidin-4(3H)-ones via aza-Wittig reaction

Article abstract of DOI:10.2174/157017811799304250

7-benzyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d] pyrimidin-4(3H)-ones were synthesized by base catalytic reactions of nucleophilic reagents (aliphatic amines, alcohols or phenols) with carbodiimides 4, which were obtained from the aza-Wittig reaction of iminophosphoranes 3 with aromatic isocyanates.

Full text of DOI:10.2174/157017811799304250

644
Letters in Organic Chemistry, 2011, 8, 644-647
Efficient Synthesis of 7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno
[2,3-d]pyrimidin-4(3H)-Ones Via Aza-Wittig Reaction
Hong Chen, Kai Yan and Ming-Guo Liu*
Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang
443002, P.R. China
Received April 04, 2011: Revised July 30, 2011: Accepted August 22, 2011
Abstract: 7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones were synthesized by base
catalytic reactions of nucleophilic reagents (aliphatic amines, alcohols or phenols) with carbodiimides 4, which were
obtained from the aza-Wittig reaction of iminophosphoranes 3 with aromatic isocyanates.
Keywords: Aza-Wittig reaction, carbodiimide, iminophosphorane, thieno[2,3-d]pyrimidin-4(3H)-one.
INTRODUCTION
conversion of compound 2 to iminophosphorane 3 involves
initial formation of Ph3PCl2 from the reaction of Ph3P, C2Cl6,
The synthesis of thienopyrimidinone derivatives has been
the focus of great interest recently. This is due, in part, to the
broad spectrum of biological properties of these compounds.
For example, some 2-alkoxy or 2-alkyl substituted
thienopyrimidinones show significant antitrichinellosis, anti-
protozoal [1a], antiarrhythmic, antianxiety [1b], antifungal
and antibacterial activities [1c-1f], whereas others exhibited
good anticonvulsant, angiotensin, or melanin-concentrating
hormone receptor-1(MCH-R1) antagonistic activities [2].
The wide biological activities and characteristic chemical
structures have made synthetic studies of thienopyrimidinone
very attractive.
and further reaction with compound
2
to give
iminophosphorane 3 in the presence of Et3N [6].
Iminophosphorane 3 reacted with an equimolar quantity
of the aromatic isocyanates to give carbodiimides 4, which
were allowed to react with aliphatic amine to provide
guanidine intermediates 5. Even in refluxing toluene,
intermediates 5 did not cyclize. However, by treatment with
EtONa in EtOH at room temperature, intermediates 5
undergo intramolecular heterocyclization to give the
expected 2-alkylamino-thieno[2,3-d]pyrimidin-4(3H)-ones
6a-6g in good yields (Scheme 2, Table 1). The reaction of
carbodiimides 4 with alcohols in the presence of a catalytic
amount of sodium alkoxide produces 2-alkyloxy-thieno[2,3-
d]pyrimidin-4-ones 6h-6j in satisfactory yields at room
temperature. The reaction of carbodiimides 4 with phenols in
the presence of a catalytic amount of solid potassium
carbonate produces 2-aryloxy-thieno[2,3-d]pyrimidin-4-ones
6k-6m in excellent yields. The results were listed in Table 1.
Over the past twenty years, the aza-Wittig reactions of
iminophosphoranes have received increasing attention in
view of their utility in the synthesis of N-heterocyclic
compounds [3]. Annelation of ring systems with N-
heterocycles by means of an aza-Wittig reaction has been
widely utilized because of the availability of functionalized
iminophosphoranes. Consequently, the discovery of novel
functionalized iminophosphoranes is important in this
respect. Recently we have become interested in the synthesis
of thienopyrimidinone, quinazolinones, and imidazolinones
by an aza-Wittig reaction, with the aim of evaluating their
fungicidal activities [4, 5]. Here we wish to report an
efficient synthesis of new derivatives of 7-benzyl-5,6,7,8-
tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-
ones under mild conditions.
Owing to the great reactive activity of carbodiimide 4,
the preparation of carbodiimide 4 must be carried out at low
o
temperature (0-5 C) and long reaction time (12h) under dry
condition. Otherwise, hydrolysis or polymeric side reaction
of carbodiimide 4 might take place, which resulted in low
yields of 6. In the preparation of products 6, all reactions
between carbodiimides 4 and nucleophilic reagents (aliphatic
amines or alcohols) proceeded smoothly at room temperature
though the reactivities of carbodiimide 4 varied with the
substituent on the benzene ring. This implies the high
reactivity of carbodiimide 4.
RESULTS AND DISCUSSION
2-Amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine 2 was synthesized by the Gewald
reaction in good yield (85%). Compound 2 was easily
converted to iminophosphorane 3 by treatment with Ph3P,
C2Cl6 and Et3N in dry CH3CN in good yield (Scheme 1). The
The structures of compound 6 were established based on
their IR, NMR and EI-MS. For example, the 1H NMR
spectral data of 6a (R1 = n-Pr, R2 = H) shows the signals of
NH at 4.12 ppm as a broad triplets and NHCH2 at 3.33 ppm
as quartets, which strongly suggest the existence of
1
NHCH2CH2CH3 group in 6a. The H NMR spectral data of
6b (R1 = t-Bu, R2 = H) shows the signals of NH at 3.90 ppm
as singlet and the C(CH3)3 at 1.35 ppm as singlet. The phenyl
signals of 6b appeared at 7.39-7.25 ppm. The MS spectrum
*Address correspondence to this author at the Hubei Key Laboratory of
Natural Products Research and Development, China Three Gorges
University, Yichang 443002, P. R. China; Tel/Fax: +86-717-6395966;
E-mail: mgliu0427@yahoo.com.cn
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Efficient Synthesis of 7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
645
COOEt
COOEt
NH2
O
Ph3P, C2Cl6
NCCH2COOEt
N
N
N
Et3N
N
PPh3
S
S
S
1
3
2
Scheme 1. Synthesis route of iminophosphorane 3.
COOEt
COOEt
Ar-NCO
HY
Ar
NAr
N
N
C
N
PPh3
N
S
S
3
4
O
COOEt
Base
N
N
NHAr
N
Y
N
S
N
S
Y
5
6
Scheme 2. Synthesis route of compound 6.
of 6e shows molecule ion peak (M+) at m/z 470 with 100%
abundance.
The isolated yields of compound 6 were related to the
substituents (Y) of the nucleophilic reagents. Better yields
obtained as Y were alkyloxy or aryloxy groups (6h-6j, 6k-
6m in Table 1); however, lower isolated yields were
obtained when R1 and R2 were long chain alkyl groups (6d,
6g in Table 1) probably due to their better solubility in
recrystallized solvent.
Whenever the primary amine was small (R1 = n-Pr, R2 =
H) or bulky (R1 = t-Bu, R2 = H), the final cyclization could
achieve in satisfactory yields. It is noteworthy that the
isolated yield of 6 was good even when NR1R2 was bulky di-
n-butylamino group. The results were also listed in Table 1.
The solitary formation of 6 could be rationalized in terms of
a base catalytic cyclization of the guanidine intermediate 5 to
give 6 through the arylamino group rather than the
alkylamino one, which might be the reason of the
preferential generation of –N-Ar from more acidic –NHAr.
The same selectivity was also observed in similar cases [7].
CONCLUSIONS
In conclusion, the present study demonstrates that the
aza-Wittig reaction affords a facile efficient one-pot route for
the synthesis of unreported 2-substituted thieno[2,3-
Table 1. Synthesis of Compound 6
Compound
Ar
Y = NR1R2 or (RO)
Yield * (%)
6a
3-Me-C6H4
4-F-C6H4
Ph
NHCH2CH2CH3
NHC(CH3)3
NHCH2CH2CH2CH3
N(CH2CH3)2
1-Piperidinyl
1-Pyrrolidinyl
N(n-Bu)2
87
89
85
83
87
89
71
91
90
92
93
92
90
6b
6c
6d
Ph
6e
3-Me-C6H4
4-F-C6H4
3-Me-C6H4
Ph
6f
6g
6h
MeO
6i
Ph
EtO
6j
4-Cl-C6H4
Ph
MeO
6k
PhO
6l
4-Cl-C6H4
3-Me-C6H4
2-Me-C6H4O
4-tert-Bu-C6H4O
6m
*Isolated yields based on iminophosphorane 3 used.

646 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Chen et al.
d]pyrimidin-4(4H)-ones with various substituents on the
pyrimidine ring. Due to the easily accessible and versatile
starting material, the synthetic approach discussed here has
the potential of synthesizing of many biologically and
pharmaceutically active thienopyrimidinone derivatives.
of the solvent gave carbodiimide 4, which was used directly
without further purification. Aliphatic amine (2 mmol) was
added to the solution of carbodiimide 4 in anhydrous
dichloromethane (10 mL). After the reaction mixture was
left unstirred for 5-6 hours, the solvent was removed and
anhydrous EtOH (10 mL) with several drops of EtONa (in
EtOH) was added to the mixture. The mixture was stirred for
another 6-8 hours at room temperature. The solution was
condensed and the residual was recrystallized from EtOH to
give the expected cyclic compounds 6a-6g in good yields.
EXPERIMENTAL SECTION
General Procedures
Melting points were determined on a Bibby SMP3
apparatus and uncorrected. IR were recorded on a PE-983
infrared spectrometer as KBr pellets with absorption in cm-1.
1H NMR spectra were recorded in CDCl3 on Varian Mercury
600 spectrometer, 13C NMR spectra were recorded in CDCl3
on Bruker vector 22FT-IR 400 spectrometer and resonances
were given in ppm (ꢀ) relative to TMS. EI-MS were
measured on a Finnigan Trace MS spectrometer. The purity
of the compounds was confirmed by thin layer
chromatography on silica gel HF254 (Merck).
General preparation of 2-alkyloxy-thieno[2,3-d]pyrimidin-
4(3H)-ones 6h-6j
RONa (5% w/w in ROH) was added to the solution of
carbodiimides 4 in anhydrous dichloromethane (10 mL). The
reaction mixture was stirred for 4-7 hours at room
temperature. Then the solution was condensed and the
residual was recrystallized from EtOH to give the expected
cyclic compounds 6h-6j in satisfactory yields.
General preparation of 2-aryloxy-thieno[2,3-d]pyrimidin-
4(3H)-ones 6k-6m
Preparation of 2-amino-6-benzyl--3-ethoxycarbonyl-4,5,6,
7-tetrahydrothieno [2,3-c] pyridine 2
Phenols were added to the solution of carbodiimides 4 in
anhydrous CH3CN (10 mL). After the mixture was stirred for
0.5-1 hours at room temperature, solid potassium carbonate
was added to the solution. The mixture was stirred for 6-8
hours at 40-50 oC and filtered, the filtrate was condensed and
the residual was recrystallized from dichloromethane/
petroleum ether to give the expected cyclic compounds 6k-
6m in excellent yields.
According to literature report [8a], a well-stirred mixture
of 1-benzylpiperidin-4-one (18.9 g, 0.1 mol), sulfur (3.2 g,
0.1 mol), ethyl cyanoacetate (11.3 g, 0.1 mol) in EtOH (100
mL) was cooled in an ice bath and treated dropwise with
Et3N (10.1 g, 0.1 mol). When addition was complete, the
reaction mixture was warmed to 60 °C (internal) for 40 min
and then stored in the cold until crystallization occurred. The
product (26.9 g, yield 85%) was recrystallized from EtOH as
colorless needle, Mp: 113-114 °C (112-113 °C in literature
report [8b]).
ACKNOWLEDGEMENTS
Preparation of Iminophosphorane 3
We gratefully acknowledge financial support of this work
by the Science Foundation of Hubei Province Education
Department, China (Project No. D20091301); Excellent
Fund for Scientific Research and Special Projects in China
Three Gorges University, China (Project No. KJ2009B004).
To a mixture of 2-amino-6-benzyl-3-ethoxycarbonyl-
4,5,6,7-tetrahydrothieno[2,3-c]pyridine 2 (2.53 g, 8 mmol),
PPh3 (3.14 g, 12 mmol) and C2Cl6 (2.84 g, 12 mmol) in
anhydrous CH3CN (40 mL), were added dropwise Et3N
(2.42 g, 24 mmol) at room temperature. The color of the
reaction mixture quickly turned yellow. After stirring for 4-6
hours, the solvent was removed under reduced pressure and
the residue was recrystallized from EtOH to give
iminophosphorane 3 in light yellow needle, 3.83 g (83%),
M.p.115-116 °C; IR (KBr) cm-1 1684 (C=O), 1462, 1174,
684, 524; 1H NMR(CDCl3, 400 MHz) ꢀ(ppm): 7.81-7.21 (m,
20H, Ar-H), 4.28 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.61 (s, 2H,
Ar-CH2), 3.26 (s, 2H, NCH2-thiophene), 2.88 (t, J = 5.6 Hz,
2H, NCH2CH2), 2.71 (t, J = 5.6 Hz, 2H, NCH2CH2), 1.33 (t,
J = 7.2 Hz, 3H, OCH2CH3); MS (70 eV) m/z(%): 576(M+,
65), 262 (63), 183 (100), 108 (41), 91 (63).
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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Efficient Synthesis of 7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno
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