Application of primary allylamine derivatives of Baylis-Hillman adducts to heterocyclic synthesis: Generation of 5-benzyl-4(3H)-pyrimidinones and 2-benzylidene-2,3-dihydropyrrolizin-1-ones

Article abstract of DOI:10.1055/s-2007-990929

The applications of the primary allylamines obtained from the acetyl derivative of Baylis-Hillman adducts of acrylate for the synthesis of heterocycles using robust reactions are described. In the first strategy, a one-pot synthesis of 5-benzyl-4(3H)-pyri

Full text of DOI:10.1055/s-2007-990929

PAPER
101
Application of Primary Allylamine Derivatives of Baylis–Hillman Adducts
to Heterocyclic Synthesis: Generation of 5-Benzyl-4(3H)-pyrimidinones and
2-Benzylidene-2,3-dihydropyrrolizin-1-ones1
Heterocycles
f
o
romPrimary
m
Amines
A
ffordedb
n
ythe Baylis
a
–Hillma
n
A
t
dductsh Nag, Sudharshan Madapa, Sanjay Batra*
Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
Fax +91(522)2623405, 2623938; E-mail: batra_san@yahoo.co.uk
Received 5 September 2007; revised 24 September 2007
antiplatelet,16 antidepressants,17 kinase inhibitors,18 and
Abstract: The applications of the primary allylamines obtained
from the acetyl derivative of Baylis–Hillman adducts of acrylate for
the synthesis of heterocycles using robust reactions are described.
In the first strategy, a one-pot synthesis of 5-benzyl-4(3H)-pyrimi-
dinones have been achieved via N-formylation of the amines in the
presence of neat formamide followed by ammonium formate-medi-
ated cyclization. These pyrimidinones have been demonstrated to
be excellent precursor to the 4-pyridinamine derivatives. In the sec-
ond strategy, the synthesis of 2-benzylidene-2,3-dihydropyrrolizin-
1-ones have been accomplished via treatment of allylamine with
dimethoxyfuran followed by saponification and PPA-mediated in-
tramolecular cyclization.
non-nucleoside reverse transcriptase inhibitors.19 Intrigu-
ingly, the literature survey revealed that the synthesis of
5-benzyl-4(3H)-pyrimidinones remain unreported.
On the other hand, substituted pyrrolizine derivatives
have been reported to possess aromatase and platelet ag-
gregation inhibitory activity.20 The methodology de-
scribed by Braunholtz et al.21 for the synthesis of 2-
benzylidenepyrrolizin-1-one involve sequential alkyla-
tion of potassium salt of pyrrole with acrylonitrile, hydro-
lysis of the nitrile group to acid, intramolecular cyclization
in the presence of AlCl3, and addition of aldehyde to in-
corporate benzylidene group. They reported that the cy-
clization step in the reaction sequence required highly
critical experimental conditions and was unsuccessful
with PPA. Subsequently Dallemagne and co-workers ob-
tained 3-phenyl-2,3-dihydro-1H-pyrrolizin-1-one starting
from 3-amino-3-phenylpropionic acid and finally treating
it with benzaldehyde.20a They accomplished the Vilsmeier
type cyclization of the ester group onto the pyrrole via bo-
ron tribromide in dichloromethane. More recently,
Michael and co-workers realized the formation of 6,7-di-
hydroindolizin-8(5H)-one from 4-(pyrrol-1-yl)butanoic
acid via PPA-mediated cyclization in good yields.22 Tak-
ing a cue from this report, we envisaged that 2-ben-
zylidene-2,3-dihydropyrrolizin-1-ones could be readily
generated from the Baylis–Hillman acetates via SN2¢ ad-
dition of pyrrole followed by intramolecular cyclization.
However, our attempts to add pyrrole to the acetyl deriv-
ative of Baylis–Hillman adduct of acrylate resulted in low
yield of the desired compound. In view of this outcome,
we developed an alternative route to 2-benzylidene-2,3-
dihydropyrrolizin-1-one via the primary allylamines.
These results invoked us to present details of both the syn-
thetic achievements in this paper.
Key words: Baylis–Hillman, formamide, N-formylation, primary
allyl amine, 4(3H)-pyrimidinone, 4-pyridinamine, 2,3-dihydro-1H-
pyrrolizin-1-one
Primary allylamines2–4 serves as important synthetic inter-
mediate in organic chemistry. They have been shown to
be viable precursors for the preparation of a spectrum of
compounds including a- and b-amino acids,5 alkaloids,6
carbohydrates,7 heterocycles,8 and others.9 In our objec-
tive aimed at the generation of heterocycles from deriva-
tives of the Baylis–Hillman chemistry,10 we have
effectively utilized the primary allyl amines,11 obtained
from the Baylis–Hillman acetate, for synthesis of cyclic
ureides10d and 3,4,6,7,8,9-hexahydropyrimido[1,2-a]pyri-
midin-2-ones.10l
Formamide in the presence of acetic acid has been de-
scribed to be a formylating agent for aromatic amines,12
but with the discovery of other efficient formylating
agents,13 formamide is generally employed as a one-car-
bon source for the synthesis of a pyrimidone subunit from
compounds bearing amino and ester group at adjacent car-
bon atoms in an aromatic system.14 Based on these re-
ports, it was reasoned that the primary allylamine afforded
via the Baylis–Hillman adduct of acrylate on treatment
with formamide might furnish the 4(3H)-pyrimidinones.
Similar reaction of the primary allylamine obtained from
the Baylis–Hillman adduct of acrylonitrile would lead to
4-aminopyrimidine. Substituted 4-pyrimdinone and 4-py-
rimidinamine derivatives have been ascribed with a vari-
ety of biological activities. These includes antidiabetic,15
Our study began with the preparation of primary allyl-
amines 3,4 generated from 1 using the reported procedure
(Scheme 1).11 Treatment of the primary allylamines 3a
and 4a with formamide at 110 °C led to completion of the
reaction in approximately 1.5 hours. The workup and sub-
sequent column chromatography led to isolation of com-
pounds which were identified as 5a and 6a, respectively.
This made evident that contrary to earlier report20 acetic
acid was not required during formamide-mediated N-
formylation. However this was not considered to be an un-
usual observation. Bhaskaran et al. too have proposed that
SYNTHESIS 2008, No. 1, pp 0101–0109
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-990929; Art ID: P10507SS
© Georg Thieme Verlag Stuttgart · New York

102
S. Nag et al.
PAPER
formamide generated from the ammonium formate is re- afford the 5-benzyl-4(3H)-pyrimidinones 7b–j as shown
sponsible for the isolation of N-formanilide directly from in Scheme 1.
aryl azides by reaction with Pd/C in the presence of am-
In our efforts to overcome the shortcoming of our strategy
monium formate.13c Earlier they have reported that al-
wherein we failed to generate the 5-benzyl-4-pyrimidin-
though reaction of ammonium formate with aryl amine
and sec-amine yield N-formamides, primary amine failed
amine directly from the primary allylamines, we decided
to employ an alternative route adopting robust strategies.
Hence, the pyrimidinones 7a–j were transformed into the
corresponding 5-benzyl-4-chloropyrimidines 8a–j via re-
to react and only the alkylammonium formate salts were
isolated.13d However, Kotha et al. reported the N-formyla-
tion of the primary amine of amino acid esters in the pres-
action with phosphorous oxychloride. This reaction takes
ence of ammonium formate in anhydrous acetonitrile.13g
place readily and the yields are usually excellent. Treat-
Notably the formamides 5a and 6a were obtained as a
ment of chloro derivatives 8d–g with benzylamine fur-
nished the desired 4-pyrimidinames 9d–g in good yields.
mixture of rotamers in accordance with the literature.23
Once we had the N-formylated derivatives 5a and 6a in Although we have demonstrated the usefulness of the
hand we decided to utilize them for the generation of de- strategy by carrying out reactions with benzylamine only,
sired heterocyclic system. In principle, compound 5 upon we believe that the reaction should be also successful with
treatment with ammonium formate in situ should lead to other amines. Prompted by the facile reaction between the
5-benzyl-4-pyrimidinamine while similar reaction of 6 4-chloropyrimidine and amine, we decided to investigate
should afford 5-benzyl-4(3H)-pyrimidinone. Therefore, the synthesis of pyrimidoquinoline from 8c. In principle,
the reaction of N-formamide 5a and 6a with ammonium reduction of the nitro group in 8c to amino group should
formate was performed. The N-formamide 5a failed to re- trigger an intramolecular cyclization with the 4-chloro
act with ammonium formate even after prolonged reaction substitution of the pyrimidine ring to furnish the envis-
time at elevated temperature. In comparison, the N-form- aged product. Gratifyingly the In/NH4Cl-promoted reduc-
amide 6a reacted with ammonium formate to yield the de- tion of nitro group in compound 8c initiated the
sired 5-benzyl-4(3H)-pyrimidinone (7a) in 54% yield. At intramolecular cyclization to furnish 10 in 55% yield.
this point, it occurred to us that the formamide formation Similar reaction was also successful with Fe/AcOH, and
and the subsequent cyclization with ammonium formate the product was isolated in 49% yield.
could be accomplished in one pot. Consequently com-
pound 4a was treated with formamide for one hour fol-
lowed by addition of ammonium formate in the same
flask. The workup and isolation of the product furnished
the desired pyrimidinone 7a in 59% yield. Thus, the yield
of the final product was found to be better in the one-pot
process as compared to two individual steps. With the ob-
For the synthesis of pyrrolizin-1-ones, initially it was en-
visaged that they could be readily generated from the
Baylis–Hillman acetates via SN2¢ nucleophilic reaction of
pyrrole on the Baylis–Hillman acetate followed by in-
tramolecular cyclization. To investigate the feasibility of
our approach in a representative reaction, compound 2a
was treated with pyrrole in the presence of K2CO3 or
jective to evaluate the generality of the methodology, sev-
DBU. However, under both conditions 1,3-migration of
eral allylamines 4b–j were subjected to similar protocol to
the acetyl unit to yield 12a occurred. Thereafter 2a was re-
NH2
EWG
OH
CN
OAc
R
iv
R
iii
i
ii
R
N
X
EWG
EWG
R
EWG = CN
84–90%
R
84–88%
NH2
NHCHO
N
1a–j
2a–j
3a,d EWG = CN (78–90%)
5a,d
4a–j EWG = CO2Me (39–50%)
iii and iv
EWG = CO2Me
iii
EWG = CO2Me
69%
48–67%
Cl
N
O
Compd
R
Ph
4-MeC6H4
2-O2NC6H4
2-ClC6H4
4-ClC6H4
2-FC6H4
4-FC6H4
a
b
c
d
e
f
g
h
i
CO2Me
R
iv
R
R
NH
v
65–79%
55%
NHCHO
N
N
8a–j
7a-j
6a
vii
55%
vi
81–92%
3-O2NC6H4
3,4-(MeO)2C6H3
thien-2-yl
NHBn
N
H
j
N
N
R
N
N
9d–g
10
Scheme 1 Reagents and conditions: (i) AcCl, pyridine, CH2Cl2, r.t., 3 h; (ii) methanolic NH3, r.t., 30 min–1 h; (iii) formamide, 110–120 °C,
1.0 h; (iv) HCO2NH4, 140 °C, 3.0 h; (v) POCl3, 110 °C, 2.5 h; (vi) BnNH2, i-PrOH, reflux, 3 h; (vii) In, NH4Cl, MeOH, reflux, 6 h.
Synthesis 2008, No. 1, 101–109 © Thieme Stuttgart · New York

PAPER
Heterocycles from Primary Amines Afforded by the Baylis–Hillman Adducts
103
200 FT or Bruker Avance DRX-300 spectrometers, using TMS as
an internal standard (chemical shifts in d values, J in Hz). The
ESMS were recorded on a Micromass LCMS system. Elemental
analyses were performed on Carlo Erba 108 or Elementar Vario EL
III microanalyzer. The solvent system described in each data corre-
sponds to the one used for column chromatography. The data for the
for the known N-formamide derivatives is not provided. The melt-
ing points of the pyrrolizinone derivatives 14a,b,d,e,k,l synthesized
herein were similar to the ones reported in ref. 20b.
acted with the sodium salt of pyrrole prepared via treat-
ment of pyrrole with NaH. This reaction furnished the
desired pyrrole derivative 11a in 20% yield along with
12a as the major product.
Inspired by the work of Michael and co-workers22 we de-
cided to investigate an alternative route via primary allyl-
amines afforded from the Baylis–Hillman acetates of
acrylate to achieve our goal. Treatment of 4a with
dimethoxyfuran in the presence of acetic acid yielded the
substituted pyrrole derivative 11a in 56% yield
(Scheme 2). Saponification with aqueous sodium hydrox-
ide afforded the acid 13a, which in the presence of PPA at
110 °C underwent the intramolecular cyclization to fur-
nish the desired pyrrolizinone 14a in 50% yield
(Scheme 2). The generality of the reaction sequence was
evaluated by preparing different pyrrolizinones
14b,d,e,g,h,k,l.
(Z)-2-Cyano-3-phenylprop-2-enylformamide (5a); Typical Pro-
cedure
A mixture of 3a (2.0 mmol, 0.32 g) and formamide (6.3 mmol, 0.25
mL) was heated at a temperature between 110–120 °C for 1.5 h. The
mixture was cooled and partitioned between EtOAc (30 mL) and
H2O (30 mL). The organic layer was separated and the aqueous lay-
er was further extracted with EtOAc (2 × 15 mL). The organic lay-
ers were combined, dried (Na2SO4) and concentrated on a
rotavapor. The residue was purified via silica gel column chroma-
tography with hexane–EtOAc (1:2) as eluent to yield 5a. The prod-
uct 5a was recrystallized from EtOAc–hexane mixture to yield
0.316 g (84%) of analytically pure 5a; white solid; mp 70–72 °C.
CO2Me
OAc
R
ii
IR (KBr): 1657 (NHCHO), 2219 (C≡N), 3309 cm–1 (NH).
CO2Me
R
NH2
1H NMR (CDCl3, 300 MHz): d = 4.13 (d, J = 6.8 Hz, 2 H, CH2),
4.19 (d, J = 6.2 Hz, 2 H, CH2), 6.52 (br s, 1 H, NH), 6.68 (br s, 1 H,
NH), 7.11 (s, 1 H, =CH), 7.18 (s, 1 H, =CH), 7.36–7.45 (m, 6 H,
2 × 3 ArH), 7.70–7.75 (m, 4 H, 2 × 2 ArH), 8.17 (d, J = 11.7 Hz, 1
H, CHO), 8.29 (s, 1 H, CHO).
13C NMR (CDCl3, 75 MHz): d = 41.9, 45.7, 107.1, 108.0, 117.8,
128.8, 128.9, 129.0, 130.7, 131.0, 132.7, 144.8, 145.7, 161.5, 164.6.
2a,b,d,e,g,h,k,l
4a,b,d,e,g,h,k,l
46–73%
iii
i
CO2H
N
CO2Me
R
R
iv
N
87–96%
MS (ES+): m/z = 209.0 (M+ + 23).
13a,b,d,e,g,h,k,l
42–74%
11a,b,d,e,g,h,k,l
Anal. Calcd for C11H10N2O (186.08): C, 70.95; H, 5.41; N, 15.04.
Found: C, 70.79; H, 5.64; N, 15.21.
+
v
CO2Me
R
O
(Z)-3-(2-Chlorophenyl)-2-cyanoprop-2-enylformamide (5d)
Hexane–EtOAc (1:2); yield: 90%; white solid; mp 96–98 °C.
IR (KBr): 1674 (NHCHO), 2214 (C≡N), 3266 cm–1 (NH).
OAc
R
12a
N
Compd
R
1H NMR (CDCl3, 200 MHz): d = 4.21 (d, J = 6.9 Hz, 2 H, CH2),
4.28 (d, J = 6.3 Hz, 2 H, CH2), 6.17 (br s, 1 H, NH), 7.31–7.54 (m,
8 H, 2 × 3 ArH and 2 × =CH), 7.92–7.97 (m, 2 H, 2 × ArH), 8.21 (d,
J = 11.7 Hz, 1 H, CHO), 8.34 (s, 1 H, CHO).
1H NMR (CDCl3 + D2O, 200 MHz): d = 4.20 (s, 2 H, CH2), 4.27 (s,
2 H, CH2), 7.33–7.54 (m, 8 H, 2 × 3 ArH and 2 × =CH), 7.92–7.96
(m, 2 H, 2 × ArH), 8.20 (s, 1 H, CHO), 8.33 (s, 1 H, CHO).
a
b
d
e
g
h
k
l
Ph
4-MeC6H4
2-ClC6H4
4-ClC6H4
4-FC6H4
3-O2NC6H4
4-MeOC6H4
3,4-Cl2C6H3
14a,b,d,e,g,h,k,l
13C NMR (CDCl3, 75 MHz): d = 41.5, 45.4, 110.7, 116.9, 127.1,
Scheme 2 Reagents and conditions: (i) NaH, pyrrole, r.t., 5 min; (ii)
methanolic NH3, r.t., 1 h; (iii) 2,5-dimethoxyfuran, AcOH–H2O,
60 °C, 2.0 h; (iv) NaOH, r.t., 3.0 h; (v) PPA, 100–110 °C, 2.0 h.
129.1, 129.8, 131.2, 131.5, 131.8, 134.2, 141.4, 141.9, 161.4, 164.5.
MS (ES+): m/z = 243.0 (M+ + 23).
Anal. Calcd for C11H9ClN2O (220.04): C, 59.88; H, 4.11; N, 12.70.
Found: C, 60.11; H, 4.26; N, 12.63.
In summary, we have demonstrated highly practical and
general methods for the syntheses of 5-benzyl-4(3H)-py-
rimidinones and 2-benzylidene-2,3-dihydropyrrolizin-1-
ones from the primary allylamines afforded by Baylis–
Hillman chemistry using some robust reactions. Substi-
tuted 4(3H)-pyrimidinones have been shown to be viable
precursors for the synthesis of 5-benzyl-4(3H)-pyrimidi-
names and 3,4-dihydropyrimido[4,3-b]quinoline.
Methyl (E)-2-[(Formylamino)methyl]-3-phenylprop-2-enoate
(6a)
Hexane–EtOAc (2:3); yield: 69%; white solid; mp 64–65 °C.
IR (KBr): 1648 (NHCHO), 1717 (CO2Me), 3248 cm–1 (NH).
1H NMR (CDCl3, 200 MHz): d = 3.85 (s, 6 H, 2 × CH3), 4.22 (d,
J = 6.3 Hz, 2 H, CH2), 4.39 (d, J = 5.7 Hz, 2 H, CH2), 6.32 (br s, 1
H, NH), 7.40–7.52 (m, 10 H, 2 × 5 ArH), 7.83 (s, 1 H, =CH), 7.87
(s, 1 H, =CH), 8.05 (d, J = 12.0 Hz, 1 H, CHO), 8.18 (s, 1 H, CHO).
13C NMR (CDCl3, 75 MHz): d = 35.7, 38.8, 52.7, 127.7, 129.2,
129.8, 130.0, 134.4, 143.3, 161.1, 165.0, 168.6.
Melting points are uncorrected and were determined in capillary
tubes on an apparatus containing silicon oil. IR spectra were record-
ed using PerkinElmer Spectrum RX I FTIR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded either on a Bruker DPX-
MS (ES+): m/z = 220.0 (M+ + 1).
Synthesis 2008, No. 1, 101–109 © Thieme Stuttgart · New York

104
S. Nag et al.
PAPER
Anal. Calcd for C12H13NO3 (219.09): C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.59; H, 5.76; N, 6.65.
5-(4-Chlorobenzyl)pyrimidin-4(3H)-one (7e)
Hexane–EtOAc (3:2); yield: 67%; white solid; mp 94–96 °C.
IR (KBr): 1687 (NHCO), 3429 cm–1 (NH).
5-Benzylpyrimidin-4(3H)-one (7a); Typical Procedure
1H NMR (CDCl3, 300 MHz): d = 3.76 (s, 2 H, CH2), 7.19 (d, J = 8.4
Hz, 2 H, ArH), 7.23–7.28 (m, 2 H, ArH), 7.79 (s, 1 H, =CH), 8.06
(s, 1 H, =CH).
13C NMR (CDCl3, 75 MHz): d = 32.8, 128.4, 128.7, 130.2, 132.4,
136.6, 147.4, 152.5, 163.3, 163.6.
A mixture of 4a (8.0 mmol, 1.53 g) and formamide (24.0 mmol,
0.96 mL) was heated at 110 °C for 1 h followed by the addition of
NH4OAc (40.0 mmol, 2.52 g). This mixture was further heated at
140 °C for 3 h. Thereafter, the mixture was cooled and neutralized
with aq sat. NaHCO3. The resulting mixture was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with brine (40 mL), dried (Na2SO4), and evaporated on a rotavapor
to yield the crude product, which was purified via silica gel column
chromatography. Elution with hexane–EtOAc (3:2) gave 0.88 g
(59%) of pure 7a; white solid; mp 125–128 °C.
IR (KBr): 1674 (NHCO), 3430 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.81 (s, 2 H, CH2), 7.20–7.34 (m,
5 H, ArH), 7.79 (s, 1 H, =CH), 8.03 (s, 1 H, =CH).
13C NMR (CDCl3, 75 MHz): d = 33.3, 126.6, 128.6, 128.4, 128.9,
138.0, 147.1, 152.7, 168.7.
MS (ES+): m/z = 187.2 (M+ + 1).
MS (ES+): m/z = 221.2 (M+ + 1).
Anal. Calcd for C11H9ClN2O (220.04): C, 59.88; H, 4.11; N, 12.70.
Found: C, 59.56; H, 3.86; N, 12.83.
5-(2-Fluorobenzyl)pyrimidin-4(3H)-one (7f)
Hexane–EtOAc (3:2); yield: 53%; white solid; mp 86–88 °C.
IR (KBr): 1653 (NHCO), 3424 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.86 (s, 2 H, CH2), 7.04–7.13 (m,
2 H, ArH), 7.22–7.33 (m, 2 H, ArH), 7.81 (s, 1 H, =CH), 8.08 (s, 1
H, =CH).
13C NMR (CDCl3, 50 MHz): d = 27.0, 115.7, 116.1, 124.5, 124.6,
125.1, 125.4, 127.8, 129.0, 129.1, 131.6, 131.7, 147.7, 153.1, 159.1,
164.0, 164.3.
Anal. Calcd for C11H10N2O (186.08): C, 70.95; H, 5.41; N, 15.04.
Found: C, 71.16; H, 5.73; N, 15.12.
MS (ES+): m/z = 205.2 (M+ + 1).
5-(4-Methylbenzyl)pyrimidin-4(3H)-one (7b)
Anal. Calcd for C11H9FN2O (204.07): C, 64.70; H, 4.44; N, 13.72.
Found: C, 64.73; H, 4.25; N, 13.53.
Hexane–EtOAc (3:2); yield: 57%; white solid; mp 149–152 °C.
IR (KBr): 1676 (NHCO), 3446 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 2.33 (s, 3 H, CH3), 3.77 (s, 2 H,
CH2), 7.11–7.17 (m, 4 H, ArH), 7.78 (s, 1 H, =CH), 8.04 (s, 1
H, =CH).
13C NMR (CDCl3, 50 MHz): d = 21.4, 33.3, 129.2, 129.5, 129.7,
135.3, 136.6, 147.6, 152.9, 164.0, 164.3.
5-(4-Fluorobenzyl)pyrimidin-4(3H)-one (7g)
Hexane–EtOAc (3:2); yield: 58%; white solid; mp 110–113 °C.
IR (KBr): 1689 (NHCO), 3417 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.77 (s, 2 H, CH2), 6.96–7.02 (m,
2 H, ArH), 7.20–7.25 (m, 2 H, ArH), 7.78 (s, 1 H, =CH), 8.06 (s, 1
H, =CH).
MS (ES+): m/z = 201.2 (M+ + 1).
13C NMR (CDCl3, 75 MHz): d = 32.6, 115.2, 115.5, 128.7, 130.3,
130.4, 133.7, 147.2, 152.5, 160.0, 163.5.
Anal. Calcd for C12H12N2O (200.1): C, 71.98; H, 6.04; N, 13.99.
Found: C, 72.31; H, 6.13; N, 14.06.
MS (ES+): m/z = 205.2 (M+ + 1).
5-(2-Nitrobenzyl)pyrimidin-4(3H)-one (7c)
Anal. Calcd for C11H9FN2O (204.07): C, 64.70; H, 4.44; N, 13.72.
Found: C, 64.92; H, 4.21; N, 13.59.
Hexane–EtOAc (3:2); yield: 48%; white solid; mp 176–178 °C.
IR (KBr): 1655 (NHCO), 3425 cm–1 (NH).
1H NMR (CDCl3, 200 MHz): d = 4.14 (s, 2 H, CH2), 7.39–7.46 (m,
2 H, ArH), 7.53–7.57 (m, 1 H, ArH), 7.75 (s, 1 H, =CH), 7.96–8.01
(m, 1 H, ArH), 8.08 (s, 1 H, =CH).
13C NMR (CDCl3 + DMSO-d6, 75 MHz): d = 29.5, 123.8, 125.8,
126.9, 131.6, 132.2, 132.3, 147.3, 148.3, 150.8, 160.8, 162.7.
5-(3-Nitrobenzyl)pyrimidin-4(3H)-one (7h)
Hexane–EtOAc (1:1); yield: 66%; white solid; mp 175–178 °C.
IR (KBr): 1663 (NHCO), 3461 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.91 (s, 2 H, CH2), 7.45–7.51 (m,
1 H, ArH), 7.62 (d, J = 7.5 Hz, 1 H, ArH), 7.93 (s, 1 H, =CH), 8.09–
8.11 (m, 2 H, ArH), 8.17 (s, 1 H, =CH).
MS (ES+): m/z = 232.2 (M+ + 1).
13C NMR (CDCl3 + DMSO-d6, 75 MHz): d = 32.8, 121.0, 123.0,
126.9, 128.8, 134.7, 140.4, 147.8, 151.4, 161.5.
Anal. Calcd for C11H9N3O3 (231.06): C, 57.14; H, 3.92; N, 18.17.
Found: C, 57.31; H, 4.16; N, 18.38.
MS (ES+): m/z = 232.2 (M+ + 1).
5-(2-Chlorobenzyl)pyrimidin-4(3H)-one (7d)
Anal. Calcd for C11H9N3O3 (231.06): C, 57.14; H, 3.92; N, 18.17.
Found: C, 57.05; H, 4.21; N, 18.35.
Hexane–EtOAc (3:2); yield: 59%; white solid; mp 164–165 °C.
IR (KBr): 1651 (NHCO), 3445 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.94 (s, 2 H, CH2), 7.20–7.25 (m,
2 H, ArH), 7.30–7.33 (m, 1 H, ArH), 7.38–7.41 (m, 1 H, ArH), 7.73
(s, 1 H, =CH), 8.10 (s, 1 H, =CH).
13C NMR (CDCl3, 75 MHz): d = 31.0, 126.9, 128.3, 129.7, 131.2,
134.3, 135.3, 147.1, 153.0, 163.9.
5-(3,4-Dimethoxybenzyl)pyrimidin-4(3H)-one (7i)
Hexane–EtOAc (3:2); yield: 49%; white solid; mp 141–148 °C.
IR (KBr): 1657 (NHCO), 3431 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.77 (s, 2 H, CH2), 3.86 (s, 6 H,
2 × OCH3), 6.78–6.84 (m, 3 H, ArH), 7.80 (s, 1 H, =CH), 8.09 (s, 1
H, =CH).
MS (ES+): m/z = 221.2 (M+ + 1).
13C NMR (CDCl3, 75 MHz): d = 32.8, 55.8, 111.2, 112.1, 120.9,
129.0, 130.3, 147.0, 147.7, 148.9, 152.6, 163.8.
Anal. Calcd for C11H9ClN2O (220.04): C, 59.88; H, 4.11; N, 12.70.
Found: C, 59.76; H, 4.02; N, 12.95.
MS (ES+): m/z = 247.0 (M+ + 1).
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Heterocycles from Primary Amines Afforded by the Baylis–Hillman Adducts
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Anal. Calcd for C13H14N2O3 (246.10): C, 63.40; H, 5.73; N, 11.38.
Found: C, 63.28; H, 5.97; N, 11.46.
(s, 1 H, ArH), 8.88 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 34.0, 127.3, 128.9, 130.0, 131.0,
131.8, 134.2, 134.4, 156.9, 158.1, 161.0.
5-(2-Thienylmethyl)pyrimidin-4(3H)-one (7j)
Hexane–EtOAc (3:2); yield: 53%; white solid; mp 122–124 °C.
MS (ES+): m/z = 239.2 (M+ + 1).
IR (KBr): 1662 (NHCO), 3449 cm–1 (NH).
Anal. Calcd for C11H8Cl2N2 (238.01): C, 55.26; H, 3.37; N, 11.72.
Found: C, 55.01; H, 3.62; N, 11.98.
1H NMR (CDCl3, 300 MHz): d = 4.02 (s, 2 H, CH2), 6.90–6.96 (m,
2 H, ArH), 7.16–7.18 (s, 1 H, ArH), 7.90 (s, 1 H, =CH), 8.09 (s, 1
H, =CH).
13C NMR (CDCl3, 75 MHz): d = 27.4, 124.3, 125.9, 127.0, 128.1,
140.2, 147.4, 152.8, 163.5.
4-Chloro-5-(4-chlorobenzyl)pyrimidine (8e)
Hexane–EtOAc (11:1); yield: 65%; brown oil.
1H NMR (CDCl3, 300 MHz): d = 4.05 (s, 2 H, CH2), 7.12–7.15 (m,
2 H, ArH), 7.29–7.33 (m, 2 H, ArH), 8.45 (s, 1 H, ArH), 8.89 (s, 1
H, ArH).
MS (ES+): m/z = 193.2 (M+ + 1).
Anal. Calcd for C9H8N2OS (192.04): C, 56.23; H, 4.19; N, 14.57.
Found: C, 56.39; H, 4.06; N, 14.85.
13C NMR (CDCl3, 75 MHz): d = 35.5, 129.1, 130.1, 132.8, 133.1,
135.1, 157.1, 158.2, 161.0.
MS (ES+): m/z = 239.5 (M+ + 1).
5-Benzyl-4-chloropyrimidine (8a); Typical Procedure
A mixture of 7a (4.0 mmol, 0.74 g) and POCl3 (18.0 mmol, 1.7 mL)
was refluxed at 110 °C for 2.5 h. After completion of the reaction as
monitored by TLC, the mixture was poured onto crushed ice and
neutralized with solid NaHCO3. This mixture was then extracted
with EtOAc (3 × 25 mL). The combined organic layers were pro-
cessed as usual and the residue was purified via silica gel column
chromatography using hexane–EtOAc (11:1) to yield 0.64 g (79%)
of pure 8a; yellow oil.
Anal. Calcd for C11H8Cl2N2 (238.01): C, 55.26; H, 3.37; N, 11.72.
Found: C, 55.53; H, 3.48; N, 11.91.
4-Chloro-5-(2-fluorobenzyl)pyrimidine (8f)
Hexane–EtOAc (11:1); yield: 70%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 4.11 (s, 2 H, CH2), 7.06–7.14 (m,
2 H, ArH), 7.18–7.23 (m, 1 H, ArH), 7.25–7.32 (m, 1 H, ArH), 8.49
(s, 1 H, ArH), 8.88 (s, 1 H, ArH).
1H NMR (CDCl3, 300 MHz): d = 4.01 (s, 2 H, CH2), 7.18–7.21 (m,
2 H, ArH), 7.27–7.37 (m, 3 H, ArH), 8.44 (s, 1 H, ArH), 8.87 (s, 1
H, ArH).
13C NMR (CDCl3, 75 MHz): d = 29.7, 29.8, 115.6, 115.8, 123.5,
123.7, 124.4, 124.5, 129.2, 129.3, 131.0, 131.1, 156.9, 158.2, 159.4,
160.9, 162.7.
13C NMR (CDCl3, 75 MHz): d = 36.2, 127.1, 128.9, 129.0, 133.4,
MS (ES+): m/z = 223.3 (M+ + 1).
136.6, 156.9, 158.4, 161.0.
Anal. Calcd for C11H8ClFN2 (222.04): C, 59.34; H, 3.62; N, 12.58.
Found: C, 59.06; H, 3.85; N, 12.64.
MS (ES+): m/z = 205.3 (M+ + 1).
Anal. Calcd for C11H9ClN2 (204.05): C, 64.56; H, 4.43; N, 13.69.
Found: C, 64.83; H, 4.42; N, 13.72.
4-Chloro-5-(4-fluorobenzyl)pyrimidine (8g)
Hexane–EtOAc (11:1); yield: 67%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 4.05 (s, 2 H, CH2), 7.00–7.06 (m,
2 H, ArH), 7.14–7.19 (m, 2 H, ArH), 8.44 (s, 1 H, ArH), 8.88 (s, 1
H, ArH).
13C NMR (CDCl3, 75 MHz): d = 35.4, 115.7, 116.0, 130.3, 130.4,
132.2, 132.3, 133.2, 157.0, 158.2, 160.2, 161.0, 163.5.
4-Chloro-5-(4-methylbenzyl)pyrimidine (8b)
Hexane–EtOAc (10:1); yield: 70%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 2.33 (s, 3 H, CH3), 4.03 (s, 2 H,
CH2), 7.08 (d, J = 8.1 Hz, 2 H, ArH), 7.14 (d, J = 8.1 Hz, 2 H, ArH),
8.43 (s, 1 H, ArH), 8.85 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 21.0, 35.8, 128.7, 129.6, 133.5,
MS (ES+): m/z = 223.2 (M+ + 1).
133.6, 136.8, 156.8, 158.3, 161.0.
Anal Calcd (222.04) for C11H8ClFN2: C, 59.34; H, 3.62; N, 12.58.
Found: C, 59.46; H, 3.81; N, 12.32.
MS (ES+): m/z = 219.2 (M+ + 1).
Anal. Calcd for C12H11ClN2 (218.06): C, 65.91; H, 5.07; N, 12.81.
Found: C, 66.19; H, 5.21; N, 12.57.
4-Chloro-5-(3-nitrobenzyl)pyrimidine (8h)
Hexane–EtOAc (4:1); yield: 74%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 4.21 (s, 2 H, CH2), 7.53–7.55 (m,
2 H, ArH), 8.09 (s, 1 H, ArH), 8.16–8.17 (m, 1 H, ArH), 8.55 (s, 1
H, ArH), 8.93 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 35.8, 122.3, 123.7, 129.9, 131.8,
134.8, 138.7, 148.6, 157.5, 158.3, 161.2.
4-Chloro-5-(4-nitrobenzyl)pyrimidine (8c)
Hexane–EtOAc (4:1); yield: 72%; white solid; mp 96–98 °C.
1H NMR (CDCl3, 300 MHz): d = 4.41 (s, 2 H, CH2), 7.25–7.28 (m,
1 H, ArH), 7.48–7.54 (m, 1 H, ArH), 7.59–7.65 (m, 1 H, ArH),
8.08–8.11 (dd, J = 1.4, 8.1 Hz, 1 H, ArH), 8.28 (s, 1 H, ArH), 8.90
(s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 33.7, 125.4, 128.7, 131.5, 131.6,
132.2, 133.7, 149.1, 157.1, 157.8, 161.0.
MS (ES+): m/z = 250.2 (M+ + 1).
MS (ES+): m/z = 250.2 (M+ + 1).
Anal. Calcd for C11H8ClN3O2 (249.03): C, 52.92; H, 3.23; N, 16.83.
Found: C, 52.61; H, 3.41; N, 16.79.
4-Chloro-5-(3,4-dimethoxybenzyl)pyrimidine (8i)
Hexane–EtOAc (11:1); yield: 77%; yellow oil.
Anal. Calcd for C11H8ClN3O2 (249.03): C, 52.92; H, 3.23; N, 16.83.
Found: C, 53.15; H, 3.46; N, 16.76.
1H NMR (CDCl3, 300 MHz): d = 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H,
OCH3), 4.02 (s, 2 H, CH2), 6.72–6.74 (m, 2 H, ArH), 6.84 (d, J = 8.7
Hz, 1 H, ArH), 8.42 (s, 1 H, ArH), 8.87 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 35.8, 55.9, 111.6, 112.1, 121.1,
129.0, 133.6, 148.2, 149.3, 156.8, 158.2, 160.9.
4-Chloro-5-(2-chlorobenzyl)pyrimidine (8d)
Hexane–EtOAc (11:1); yield: 78%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 4.19 (s, 2 H, CH2), 7.16–7.19 (m,
1 H, ArH), 7.25–7.28 (m, 2 H, ArH), 7.42–7.45 (m, 1 H, ArH), 8.31
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S. Nag et al.
PAPER
MS (ES+): m/z = 265.2 (M+ + 1).
N-Benzyl-5-(2-fluorobenzyl)pyrimidin-4-amine (9f)
Hexane–EtOAc (7:3); yield: 87%; white solid; mp 61–63 °C.
IR (KBr): 3449 cm–1 (NH).
Anal. Calcd for C13H13ClN2O2 (264.07): C, 58.99; H, 4.95; N,
10.58. Found: C, 58.73; H, 4.89, N, 10.69.
1H NMR (CDCl3, 300 MHz): d = 3.75 (s, 2 H, CH2), 4.66 (d, J = 5.4
Hz, 2 H, CH2), 5.11 (br s, 1 H, NH), 7.01–7.08 (m, 3 H, ArH), 7.13–
7.16 (m, 2 H, ArH), 7.23–7.30 (m, 4 H, ArH), 8.02 (s, 1 H, ArH),
8.55 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 27.1, 27.2, 44.7, 115.0, 115.4,
115.7, 123.5, 123.7, 124.5, 124.6, 127.3, 128.6, 128.8, 128.9, 130.2,
130.3, 138.3, 154.0, 157.3, 159.1, 159.9, 162.3.
4-Chloro-5-(2-thienylmethyl)pyrimidine (8j)
Hexane–EtOAc (9:1); yield: 69%; yellow oil.
1H NMR (CDCl3, 300 MHz): d = 4.27 (s, 2 H, CH2), 6.87–6.88 (m,
1 H, ArH), 6.96–6.98 (s, 1 H, ArH), 7.21–7.23 (m, 1 H, ArH), 8.52
(s, 1 H, ArH), 8.89 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 30.4, 125.0, 126.5, 127.2, 132.7,
138.6, 157.1, 158.1, 160.6.
MS (ES+): m/z = 211.2 (M+ + 1).
MS (ES+): m/z = 294.3 (M+ + 1).
Anal. Calcd for C18H16FN3 (293.13): C, 73.70; H, 5.50; N, 14.32.
Found: C, 73.81; H, 5.69; N, 14.09.
Anal. Calcd for C9H7ClN2S (210.00): C, 51.31; H, 3.35; N, 13.30.
Found: C, 51.65; H, 3.16; N, 13.49.
5,10-Dihydropyrimido[4,5-b]quinoline (10)
N-Benzyl-5-(4-fluorobenzyl)pyrimidin-4-amine (9g); Typical
Procedure
To a solution of 8c (1.0 mmol, 0.25 g) in MeOH (4.0 mL) was added
sat. aq NH4Cl (2.0 mL) followed by In powder (2.5 mmol, 0.285 g).
The mixture was heated at reflux temperature under N2 for 6 h. The
reaction was cooled and filtered through a moist Celite bed and
washed with EtOAc (2 × 10 mL). The pH of the filtrate was adjust-
ed to 9.0 with aq 4 N NaOH and then it was extracted with EtOAc
(2 × 25 mL). The combined organic layers were processed and the
residue left after concentration was purified via column chromatog-
raphy over silica gel using hexane–EtOAc (3:1) to yield pure 10 as
a yellow solid (0.1 g, 55%); mp 185–187 °C.
To a solution of 8g (1.5 mmol, 0.33g) in i-PrOH (5.0 mL) was added
benzylamine (3.0 mmol, 0.33 mL) and the mixture was refluxed for
3 h. Thereafter, the excess solvent was removed and the residue was
diluted with H2O (25 mL). The mixture was then extracted with
EtOAc (2 × 20 mL). The combined organic layers were processed
as usual to furnish a residue, which was purified via silica gel col-
umn chromatography. Elution with hexane–EtOAc (7:3) gave 0.375
g (86%) of pure 9g; brown oil.
IR (neat): 3443 cm–1 (NH).
IR (KBr): 3247 cm–1 (NH).
1H NMR (CDCl3, 300 MHz): d = 3.74 (s, 2 H, CH2), 4.60 (d, J = 5.4
Hz, 2 H, CH2), 4.76 (br s, 1 H, NH), 6.95–7.12 (m, 6 H, ArH), 7.24–
7.31 (m, 3 H, ArH), 8.02 (s, 1 H, ArH), 8.58 (s, 1 H, ArH).
1H NMR (CDCl3, 300 MHz): d = 4.49 (s, 2 H, CH2), 7.28–7.34 (m,
2 H, ArH), 7.47–7.52 (m, 2 H, ArH), 8.52 (s, 1 H, ArH), 8.87 (s, 1
H, ArH), 9.35 (s, 1 H, NH).
13C NMR (CDCl3, 75 MHz): d = 34.0, 44.7, 115.7, 116.0, 127.2,
127.4, 128.6, 129.7, 129.8, 132.4, 138.3, 154.1, 157.5, 160.1.
13C NMR (CDCl3 + DMSO-d6, 75 MHz): d = 26.7, 111.1, 114.5,
118.2, 121.4, 126.6, 127.7, 136.9, 152.9, 155.8, 156.8.
MS (ES+): m/z = 294.3 (M+ + 1).
MS (ES+): m/z = 184.4 (M+ + 1).
Anal. Calcd for C18H16FN3 (293.13): C, 73.70; H, 5.50; N, 14.32.
Found: C, 73.56; H, 5.28; N, 14.64.
Anal. Calcd for C11H9FN3 (183.08): C, 72.11; H, 4.95; N, 22.94.
Found: C, 71.89; H, 4.76; N 23.12.
N-Benzyl-5-(2-chlorobenzyl)pyrimidin-4-amine (9d)
Hexane–EtOAc (7:3); yield: 81%; white solid; mp 90–93 °C.
Methyl (E)-3-(4-Fluorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-
2-enoate (11g); Typical
Procedure
IR (KBr): 3446 cm–1 (NH).
To a solution of 4g (10.0 mmol, 2.1 g) in CH2Cl2 (25 mL) were add-
ed simultaneously 2,5-dimethoxytetrahydrofuran (12.4 mmol, 1.6
mL), glacial AcOH (4.0 mL), and H2O (5.0 mL). The mixture was
heated at 60 °C for 2 h. Thereafter, H2O was added to the mixture
and the two layers were separated. The aqueous layer was extracted
with CHCl3 (3 × 20 mL), the organic layers were combined and
dried (Na2SO4). Removal of the solvent in vacuum followed by col-
umn chromatography over silica gel using hexane–EtOAc (24:1) as
eluent furnished pure 11g as a yellow oil (1.3 g, 48%).
1H NMR (CDCl3, 300 MHz): d = 3.84 (s, 2 H, CH2), 4.65 (d, J = 5.4
Hz, 2 H, CH2), 5.00 (br s, 1 H, NH), 7.03–7.06 (m, 1 H, ArH), 7.12–
7.14 (m, 1 H, ArH), 7.15–7.31 (m, 7 H, ArH), 7.96 (s, 1 H, ArH),
8.57 (s, 1 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 31.7, 44.7, 115.0, 127.3, 127.4,
128.6, 129.8, 130.0, 134.0, 138.3, 154.3, 157.4, 160.0.
MS (ES+): m/z = 310.3 (M+ + 1).
Anal. Calcd for C18H16ClN3 (309.10): C, 69.79; H, 5.21; N, 13.56.
Found: C, 69.95; H, 5.53; N, 13.68.
IR (neat): 1718 cm–1 (CO2Me).
1H NMR (CDCl3, 200 MHz): d = 3.80 (s, 3 H, CO2CH3), 4.92 (s, 2
H, CH2), 6.14 (t, J = 2.0 Hz, 2 H, ArH), 6.65 (t, J = 2.0 Hz, 2 H,
ArH), 7.05–7.13 (m, 2 H, ArH), 7.29–7.36 (m, 2 H, ArH), 7.96 (s,
1 H, =CH).
13C NMR (CDCl3, 50 MHz): d = 45.2, 52.8, 108.8, 116.2, 116.7,
120.6, 128.3, 130.8, 131.5, 131.7, 143.3, 161.1, 166.1, 167.8.
N-Benzyl-5-(4-chlorobenzyl)pyrimidin-4-amine (9e)
Hexane–EtOAc (7:3); yield: 92%; brown oil.
IR (neat): 3434 cm–1 (NH).
1H NMR (CDCl3, 200 MHz): d = 3.74 (s, 2 H, CH2), 4.60 (d, J = 5.3
Hz, 2 H, CH2), 4.82 (br s, 1 H, NH), 6.99–7.08 (m, 4 H, ArH), 7.24–
7.35 (m, 5 H, ArH), 8.02 (s, 1 H, ArH), 8.58 (s, 1 H, ArH).
MS (ES+): m/z = 260.2 (M+ + 1).
13C NMR (CDCl3, 50 MHz): d = 34.6, 45.1, 115.9, 127.7, 127.9,
128.4, 128.7, 129.1, 129.6, 130.1, 133.5, 135.7, 138.7, 154.7, 158.0,
160.5.
Anal. Calcd for C15H14FNO2 (259.10): C, 69.49; H, 5.44; N, 5.40.
Found: C, 69.62; H, 5.56; N, 5.32.
Methyl (E)-3-Phenyl-2-(1H-pyrrol-1-ylmethyl)prop-2-enoate
(11a)
MS (ES+): m/z = 310.3 (M+ + 1, 100%).
Anal. Calcd for C18H16ClN3 (309.10): C, 69.79; H, 5.21; N, 13.56.
Found: C, 69.42; H, 5.42; N, 13.66.
Hexane–EtOAc (19:1); yield: 56%; yellow oil.
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107
IR (neat): 1717 cm–1 (CO2Me).
13C NMR (CDCl3, 50 MHz): d = 45.4, 53.1, 109.1, 120.7, 124.3,
129.4, 130.3, 131.4, 136.3, 137.2, 141.1, 148.9, 167.2.
1H NMR (CDCl3, 300 MHz): d = 3.80 (s, 3 H, CO2CH3), 4.94 (s, 2
H, CH2), 6.13 (t, J = 2.1 Hz, 2 H, ArH), 6.65 (t, J = 2.1 Hz, 2 H,
ArH), 7.34–7.42 (m, 5 H, ArH), 8.00 (s, 1 H, =CH).
13C NMR (CDCl3, 50 MHz): d = 45.6, 52.8, 108.6, 120.8, 128.5,
128.9, 129. 3, 129.5, 129.8, 134.8, 144.3, 167.9.
MS (ES+): m/z = 287.3 (M+ + 1).
Anal. Calcd for C15H14ClNO2 (286.10): C, 62.93; H, 4.93; N, 9.79.
Found: C, 63.11; H, 5.20; N, 4.81.
Methyl (E)-3-(4-Methoxyphenyl)-2-(1H-pyrrol-1-ylmeth-
yl)prop-2-enoate (11k)
Hexane–EtOAc (19:1); yield: 59%; yellow oil.
IR (neat): 1710 cm–1 (CO2Me).
MS (ES+): m/z = 242.0 (M+ + 1).
Anal. Calcd for C15H15NO2 (241.11): C, 74.67; H, 6.27; N, 5.81.
Found: C, 74.82; H, 6.46; N, 5.72.
Methyl (E)-3-(4-Methylphenyl)-2-(1H-pyrrol-1-ylmethyl)prop-
2-enoate (11b)
Hexane–EtOAc (24:1); yield: 54%; yellow oil.
IR (neat): 1715 cm–1 (CO2Me).
1H NMR (CDCl3, 300 MHz): d = 2.38 (s, 3 H, CH3), 3.79 (s, 3 H,
CO2CH3), 4.95 (s, 2 H, CH2), 6.13 (t, J = 2.1 Hz, 2 H, ArH), 6.66 (t,
J = 2.0 Hz, 2 H, ArH), 7.22–7.28 (m, 4 H, ArH), 7.97 (s, 1 H, =CH).
1H NMR (CDCl3, 300 MHz): d = 3.79 (s, 3 H, OCH3), 3.83 (s, 3 H,
CO2CH3), 4.97 (s, 2 H, CH2), 6.14 (t, J = 2.1 Hz, 2 H, ArH), 6.69 (t,
J = 2.1 Hz, 2 H, ArH), 6.92 (d, J = 8.8 Hz, 2 H, ArH), 7.33 (d,
J = 8.7 Hz, 2 H, ArH), 7.96 (s, 1 H, =CH).
13C NMR (CDCl3, 50 MHz): d = 45.8, 52.7, 55.8, 106.5, 108.6,
114.8, 120.6, 125.8, 127.1, 131.7, 144.4, 161.2, 168.3.
MS (ES+): m/z = 271.9 (M+ + 1).
13C NMR (CDCl3, 50 MHz): d = 22.0, 45.9, 52.9, 108.9, 120.9,
127.7, 129.9, 130.2, 132.1, 140.4, 144.7, 168.3.
Anal. Calcd for C16H17NO3 (271.12): C, 70.83; H, 6.32; N, 5.16.
Found: C, 70.65; H, 6.59; N, 5.02.
MS (ES+): m/z = 256.1 (M+ + 1).
Methyl (E)-3-(3,4-Dichlorophenyl)-2-(1H-pyrrol-1-ylmeth-
yl)prop-2-enoate (11l)
Hexane–EtOAc (29:1); yield: 60%; yellow oil.
Anal. Calcd for C16H17NO2 (255.13): C, 75.27; H, 6.71; N, 5.49.
Found: C, 75.23; H, 6.97; N, 5.32.
IR (neat): 1720 cm–1 (CO2Me).
Methyl (E)-3-(2-Chlorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-
2-enoate (11d)
Hexane–EtOAc (29:1); yield: 58%; yellow oil.
IR (neat): 1720 cm–1 (CO2Me).
1H NMR (CDCl3, 300 MHz): d = 3.84 (s, 3 H, CO2CH3), 4.83 (s, 2
H, CH2), 6.13 (t, J = 2.1 Hz, 2 H, ArH), 6.62 (t, J = 2.0 Hz, 2 H,
ArH), 7.23–7.39 (m, 3 H, ArH), 7.48–7.51 (dd, J = 1.5, 7.9 Hz, 1 H,
ArH), 8.02 (s, 1 H, =CH).
1H NMR (CDCl3, 300 MHz): d = 3.81 (s, 3 H, CO2CH3), 4.88 (s, 2
H, CH2), 6.14 (t, J = 2.1 Hz, 2 H, ArH), 6.62 (t, J = 2.0 Hz, 2 H,
ArH), 7.13–7.16 (dd, J = 1.7, 8.3 Hz, 1 H, ArH), 7.40 (d, J = 1.7 Hz,
1 H, ArH), 7.47 (d, J = 8.3 Hz, 1 H, ArH), 7.86 (s, 1 H, =CH).
13C NMR (CDCl3, 75 MHz): d = 44.9, 52.5, 108.6, 120.2, 128.0,
129.8, 130.8, 130.9, 133.2, 134.2, 141.1, 166.9.
MS (ES+): m/z = 310.0 (M+ + 1), 311.9 (M+ + 3).
13C NMR (CDCl3, 50 MHz): d = 45.7, 52.9, 108.7, 120.9, 127.3,
130.3, 130.4, 130.8, 133.6, 134.3, 141.1, 167.3.
Anal. Calcd for C15H13Cl2NO2 (309.03): C, 58.08; H, 4.22; N, 4.52.
Found: C, 58.23; H, 4.34; N, 4.39.
MS (ES+): m/z = 276.0 (M+ + 1).
(E)-3-(4-Fluorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic
Acid (13g); Typical Procedure
Anal. Calcd for C15H14ClNO2 (275.07): C, 65.34; H, 5.12; N, 5.08.
Found: C, 65.23; H, 5.26; N, 4.93.
To a solution of 11g (4.2 mmol, 1.1 g) in MeOH (15 mL) was added
5% aq NaOH (10 mL) and the mixture was stirred at r.t. for 3 h. The
mixture was neutralized with 10% aq HCl followed by removal of
MeOH under reduced pressure. Then residue was extracted with
EtOAc (3 × 15 mL), the organic layers combined, dried, and con-
centrated in vacuo. The crude product was purified via column
chromatography on silica gel (hexane–EtOAc, 8:1) to afford 1.01g
(97%) pure 13g as a white solid; mp 158–159 °C.
Methyl (E)-3-(4-Chlorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-
2-enoate (11e)
Hexane–EtOAc (24:1); yield: 73%; yellow oil.
IR (neat): 1720 cm–1 (CO2Me).
1H NMR (CDCl3, 200 MHz): d = 3.80 (s, 3 H, CO2CH3), 4.90 (s, 2
H, CH2), 6.14 (t, J = 2.1 Hz, 2 H, ArH), 6.63 (t, J = 2.1 Hz, 2 H,
ArH), 7.24–7.29 (m, 2 H, ArH), 7.37–7.40 (dd, J = 2.1, 6.7 Hz, 2 H,
ArH), 7.93 (s, 1 H, =CH).
13C NMR (CDCl3, 50 MHz) d = 45.5, 52.8, 108.8, 120.6, 128.8,
129.5, 130.3, 130.9, 131.7, 133.1, 136.0, 143.0, 167.7.
IR (KBr): 1683 (CO2H), 2850 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): d = 4.93 (s, 2 H, CH2), 6.16 (t, J = 2.0
Hz, 2 H, ArH), 6.68 (t, J = 2.0 Hz, 2 H, ArH), 7.06–7.15 (m, 2 H,
ArH), 7.34–7.40 (m, 2 H, ArH), 8.09 (s, 1 H, =CH).
13C NMR (CDCl3, 50 MHz): d = 45.2, 109.0, 116.4, 116.8, 120.6,
127.3, 130.4, 130.5, 131.9, 132.0, 145.7, 161.4, 166.4, 173.0.
MS (ES+): m/z = 276.1 (M+ + 1).
Anal. Calcd for C15H14ClNO2 (275.07): C, 65.34; H, 5.12; N, 5.08.
Found: C, 65.21; H, 5.35; N, 5.19.
MS (ES+): m/z = 246.1 (M+ + 1).
Anal. Calcd for C14H12FNO2 (245.09): C, 68.56; H, 4.93; N, 5.71.
Found: C, 68.72; H, 5.21; N, 5.78.
Methyl (E)-3-(3-Nitrophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-
enoate (11h)
Hexane–EtOAc (10:1); yield: 46%; yellow oil.
IR (neat): 1719 cm–1 (CO2Me).
1H NMR (CDCl3, 200 MHz): d = 3.84 (s, 3 H, CO2CH3), 4.91 (s, 2
H, CH2), 6.13 (t, J = 2.0 Hz, 2 H, ArH), 6.61 (t, J = 2.1 Hz, 2 H,
ArH), 7.59–7.62 (m, 2 H, ArH), 7.98 (s, 1 H, =CH), 8.19–8.25 (m,
2 H, ArH).
(E)-3-Phenyl-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic Acid (13a)
Hexane–EtOAc (8:1); yield: 91%; white solid; mp 90–92 °C.
IR (KBr): 1672 (CO2H), 2942 cm–1 (OH).
1H NMR (CDCl3, 300 MHz): d = 4.95 (s, 2 H, CH2), 6.15 (t, J = 2.0
Hz, 2 H, ArH), 6.68 (t, J = 2.0 Hz, 2 H, ArH), 7.37–7.41 (m, 5 H,
ArH), 8.13 (s, 1 H, =CH).
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108
S. Nag et al.
PAPER
13C NMR (CDCl3, 50 MHz): d = 45.3, 108.8, 120.8, 127.6, 129.1,
129.4, 129.8, 130.3, 134.5, 146.7, 173.2.
(E)-3-(4-Methoxyphenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-eno-
ic Acid (13k)
Hexane–EtOAc (8:1); yield: 92%; white solid; mp 172–175 °C.
IR (KBr): 1669 (CO2H), 2934 cm–1 (OH).
1H NMR (CDCl3, 300 MHz): d = 3.84 (s, 3 H, OCH3), 4.98 (s, 2 H,
CH2), 6.17 (t, J = 2.1 Hz, 2 H, ArH), 6.72 (t, J = 2.1 Hz, 2 H, ArH),
6.92 (d, J = 8.8 Hz, 1 H, ArH), 7.38 (d, J = 8.7 Hz, 1 H, ArH), 8.09
(s, 1 H, =CH).
MS (ES+): m/z = 228.2 (M+ + 1).
Anal. Calcd for C14H13NO2 (227.10): C, 73.99; H, 5.77; N, 6.16.
Found: C, 74.22; H, 5.92; N, 6.23.
(E)-3-(4-Methylphenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic
Acid (13b)
Hexane–EtOAc (8:1); yield: 93%; white solid; mp 184–186 °C.
IR (KBr): 1673 (CO2H), 3428 cm–1 (OH).
13C NMR (CDCl3, 50 MHz): d = 45.5, 55.8, 108.8, 114.9, 120.6,
124.7, 126.9, 132.1, 146.7, 161.6, 173.2.
1H NMR (CDCl3, 300 MHz): d = 2.39 (s, 3 H, CH3), 4.97 (s, 2 H,
CH2), 6.15 (t, J = 2.1 Hz, 2 H, ArH), 6.70 (t, J = 2.1 Hz, 2 H, ArH),
7.22 (d, J = 8.1 Hz, 1 H, ArH), 7.31 (d, J = 8.1 Hz, 1 H, ArH), 8.10
(s, 1 H, =CH).
MS (ES+): m/z = 258.1 (M+ + 1).
Anal. Calcd for C15H15NO3 (257.1052): C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.16; H, 6.01; N, 5.53.
13C NMR (CDCl3, 50 MHz): d = 23.3, 46.8, 110.2, 122.2, 128.0,
131.5, 131.6, 133.1, 142.3, 148.4, 174.8.
(E)-3-(3,4-Dichlorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-
enoic Acid (13l)
Hexane–EtOAc (8:1); yield: 95%; white solid; mp 146–148 °C.
IR (KBr): 1685 (CO2H), 2959 cm–1 (OH).
1H NMR (CDCl3, 300 MHz): d = 4.89 (s, 2 H, CH2), 6.15 (t, J = 2.0
Hz, 2 H, ArH), 6.64 (t, J = 2.0 Hz, 2 H, ArH), 7.15–7.18 (dd,
J = 1.9, 8.3 Hz, 1 H, ArH), 7.42 (d, J = 1.8 Hz, 1 H, ArH), 7.48 (d,
J = 8.3 Hz, 1 H, ArH), 7.98 (s, 1 H, =CH).
MS (ES+): m/z = 242.2 (M+ + 1).
Anal. Calcd for C15H15NO2 (241.11): C, 74.67; H, 6.27; N, 5.81.
Found: C, 74.49; H, 6.18; N, 5.93.
(E)-3-(2-Chlorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic
Acid (13d)
Hexane–EtOAc (9:1); yield: 96%; white solid; mp 153–155 °C.
IR (KBr): 1679 (CO2H), 2945 cm–1 (OH).
13C NMR (CDCl3, 75 MHz): d = 44.6, 108.7, 120.2, 128.2, 129.0,
130.9, 131.1, 133.3, 133.8, 134.1, 143.3, 171.9.
1H NMR (CDCl3, 300 MHz): d = 4.81 (s, 2 H, CH2), 6.12 (t, J = 2.1
Hz, 2 H, ArH), 6.61 (t, J = 2.0 Hz, 2 H, ArH), 7.22–7.38 (m, 3 H,
ArH), 7.47–7.49 (dd, J = 1.3, 7.9 Hz, 1 H, ArH), 8.15 (s, 1 H, =CH).
13C NMR (CDCl3, 50 MHz): d = 45.3, 108.8, 120.9, 127.4, 130.0,
130.3, 131.1, 133.2, 134.5, 143.5, 172.4.
MS (ES+): m/z = 296.1 (M+ + 1).
Anal. Calcd for C14H11Cl2NO2 (295.02): C, 56.78; H, 3.74; N, 4.73.
Found: C, 56.62; H, 3.89; N, 4.81.
2-[(E)-(4-Fluorophenyl)methylidene]-2,3-dihydro-1H-pyrroliz-
in-1-one (14g); Typical Procedure
MS (ES+): m/z = 262.2 (M+ + 1).
A mixture of 13g (2.0 mmol, 0.5 g) and PPA (2.0 mL) was heated
at 110 °C for 1 h. To the cooled mixture, ice-water (50 mL) was
added, and the organic part was extracted with CHCl3 (3 × 20 mL).
The combined organic phases were dried (Na2SO4), concentrated,
and the residue was purified on a silica gel column using hexane–
EtOAc (8:1) as eluent to obtain pure 14g (0.3g, 65%); white solid;
mp 177–178 °C.
Anal. Calcd for C14H12ClNO2 (261.06): C, 64.25; H, 4.62; N, 5.35.
Found: C, 64.06; H, 4.54; N, 5.51.
(E)-3-(4-Chlorophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic
Acid (13e)
Hexane–EtOAc (8:1); yield: 93%; white solid; mp 161–162 °C.
IR (KBr): 1687 (CO2H), 2926 cm–1 (OH).
IR (KBr): 1696 cm–1 (C=O).
1H NMR (CDCl3, 200 MHz): d = 4.92 (s, 2 H, CH2), 6.16 (t, J = 2.0
Hz, 2 H, ArH), 6.66 (t, J = 1.9 Hz, 2 H, ArH), 7.30 (d, J = 8.6 Hz, 2
H, ArH), 7.40 (d, J = 8.5 Hz, 2 H, ArH), 8.07 (s, 1 H, =CH), 8.24-
8.29 (m, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 45.2, 109.0, 120.7, 128.0, 129.7,
131.1, 132.8, 136.5, 145.4, 172.6.
1H NMR (CDCl3, 300 MHz): d = 5.17 (d, J = 2.0 Hz, 2 H, CH2),
6.56–6.58 (m, 1 H, ArH), 6.89–6.91 (m, 1 H, ArH), 7.14–7.20 (m,
3 H, ArH), 7.45–7.52 (m, 3 H, ArH and =CH).
13C NMR (CDCl3, 50 MHz): d = 47.9, 109.4, 116.5, 116.9, 117.3,
122.7, 130.7, 131.1, 132.3, 132.5, 134.7, 134.8, 161.2, 166.2, 179.6.
MS (ES+): m/z = 228.2 (M+ + 1).
MS (ES+): m/z = 262.1 (M+ + 1).
Anal. Calcd for C14H10FNO (227.08): C, 74.00; H, 4.44; N, 6.16.
Found: C, 74.18; H, 4.63; N, 6.04.
Anal. Calcd for C14H12ClNO2 (261.06): C, 64.25; H, 4.62; N, 5.35.
Found: C, 65.38; H, 4.87; N, 5.41.
2-[(E)-(3-Nitrophenyl)methylidene]-2,3-dihydro-1H-pyrroliz-
in-1-one (14h)
Hexane–EtOAc (6:1); yield: 42%; white solid; mp 213–215 °C.
IR KBr): 1693 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): d = 5.26 (d, J = 1.7 Hz, 2 H, CH2),
6.58–6.60 (m, 1 H, ArH), 6.92–6.93 (m, 1 H, ArH), 7.19 (s, 1 H,
ArH), 7.56 (s, 1 H, ArH), 7.63–7.68 (m, 1 H, ArH), 7.78–7.80 (m,
1 H, ArH), 8.24 (s, 1 H, =CH), 8.27–8.29 (m, 1 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 47.4, 109.8, 117.4, 122.7, 123.5,
123.9, 128.5, 130.2, 134.2, 136.0, 136.1, 137.7, 148.7, 178.2.
(E)-3-(3-Nitrophenyl)-2-(1H-pyrrol-1-ylmethyl)prop-2-enoic
Acid (13h)
Hexane–EtOAc (8:1); yield: 87%; white solid; mp 157–160 °C.
IR (KBr): 1687 (CO2H), 2927 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): d = 4.93 (s, 2 H, CH2), 6.16 (t, J = 2.0
Hz, 2 H, ArH), 6.65 (t, J = 2.0 Hz, 2 H, ArH), 7.58–7.65 (m, 2 H,
ArH), 8.12 (s, 1 H, =CH), 8.24–8.29 (m, 2 H, ArH).
13C NMR (CDCl3, 50 MHz): d = 45.0, 109.3, 120.7, 124.5, 124.7,
130.5, 135.1, 135.9, 143.4, 148.9, 171.8.
MS (ES+): m/z = 273.4 (M+ + 1).
MS (ES+): m/z = 255.3 (M+ + 1).
Anal. Calcd for C14H12N2O4 (272.08): C, 61.76; H, 4.44; N, 10.29.
Found: C, 61.62; H, 4.76; N, 10.31.
Anal. Calcd for C14H10N2O3 (254.07): C, 66.14; H, 3.96; N, 11.02.
Found: C, 66.02; H, 4.15; N, 10.86.
Synthesis 2008, No. 1, 101–109 © Thieme Stuttgart · New York

PAPER
Heterocycles from Primary Amines Afforded by the Baylis–Hillman Adducts
109
Org. Chem. 2007, 2970. (l) Pathak, R.; Batra, S.
Tetrahedron 2007, 63, 9448.
(11) Pathak, R.; Singh, V.; Nag, S.; Kanojiya, S.; Batra, S.
Synthesis 2006, 813.
Acknowledgment
Two of the authors (S.N. and S.M.) gratefully acknowledge the fi-
nancial support from UGC and CSIR, New Delhi in the form of fel-
lowship. This work was supported by a grant from DST.
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Synthesis 2008, No. 1, 101–109 © Thieme Stuttgart · New York