Titanium catalyzed one-pot multicomponent coupling reactions for direct access to substituted pyrimidines

Article abstract of DOI:10.1016/j.tet.2010.02.066

A titanium-catalyzed 3-component coupling reaction can be used to generate tautomers of 1,3-diimines. These diimines produced in situ undergo condensation with amidines in a one-pot procedure to provide substituted pyrimidines. Seventeen examples of pyrimidines are provided using this one-pot, 4-component procedure from simple starting materials. In some cases, catalyst architecture can be tuned to control the regioselectivity of the alkyne addition. Finally, the regioselectivity of amidine addition to unsymmetrical 1,3-diimines is discussed.

Full text of DOI:10.1016/j.tet.2010.02.066

Tetrahedron 66 (2010) 3152–3158
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Titanium catalyzed one-pot multicomponent coupling reactions for direct
access to substituted pyrimidines
*
Supriyo Majumder, Aaron L. Odom
Michigan State University, Department of Chemistry, East Lansing, MI 48824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A titanium-catalyzed 3-component coupling reaction can be used to generate tautomers of 1,3-diimines.
These diimines produced in situ undergo condensation with amidines in a one-pot procedure to provide
substituted pyrimidines. Seventeen examples of pyrimidines are provided using this one-pot, 4-com-
ponent procedure from simple starting materials. In some cases, catalyst architecture can be tuned to
control the regioselectivity of the alkyne addition. Finally, the regioselectivity of amidine addition to
unsymmetrical 1,3-diimines is discussed.
Received 4 December 2009
Received in revised form 17 February 2010
Accepted 17 February 2010
Available online 23 February 2010
Keywords:
Heterocycles
Pyrimidines
Ó 2010 Elsevier Ltd. All rights reserved.
Amidines
Multicomponent coupling
Titanium
1. Introduction
synthetic equivalents of unsymmetrical 1,3-dicarbonyl precursors.
Herein we report a new titanium mediated one-pot multicompo-
The pyrimidine core is found in a wide range of natural products
and bioactive molecules.1 Recently, pyrimidyl structural motifs
have appeared in a variety of synthetic pharmacophores having
antibacterial,2 antimicrobial, antifungal,3 and antimycotic4 activi-
ties. Even in the drug zidovudine (RetrovirÒ), the first drug ap-
proved for the treatment of AIDS and HIV infection, is based on the
pyrimidine core.5 Some diaminopyrimidines, such as pyrimeth-
amine (DaraprimÒ) or trimethoprim (ProloprimÒ) are powerful
antimalarial drugs.6
The ubiquity of the pyrimidine substructure in natural products
and pharmaceuticals, has resulted in a plethora of synthetic routes
to this important ring system; most of these synthetic protocols
involve direct condensation of amidines or amidinium salts
with 1,3-dicarbonyl compounds.7 Cross-coupling chemistry has
advanced the synthesis of various substituted pyrimidines from
halogen precursors.8 In these methods the practical disadvantage is
the difficulty in synthesizing unsymmetrical pyrimidine com-
pounds due to the multistep synthesis of the unsymmetrical
diketone precursors or the appropriately substituted halo
pyrimidines.
nent coupling followed by amidine condensation sequence for di-
rect access to substituted pyrimidines.
2. Results and discussion
In previous multicomponent coupling research in our group, we
discovered a novel titanium-catalyzed 3-component (3CC) coupling9
of an alkyne, isonitrile, and primary amine to generate un-
symmetrical 1,3-diimine tautomers.10 In this work in situ generated
1,3-diimine tautomers are reacted with a variety of amidine de-
rivatives as a new one-pot 4-component coupling strategy for direct
access to substituted pyrimidine compounds.
The multicomponent reaction utilized here is a formal addition
of iminyl and amine groups across an alkyne triple bond, iminoa-
mination.8 The proposed catalytic cycle (Scheme 1) for the forma-
tion of the 3CC product is based on the mechanism of catalytic
alkyne hydroamination.11 It is proposed that the titanium pre-
catalyst, bis(dimethylamido)titanium, reacts with a primary amine
to generate a titanium imido species, which undergoes reversible
[2þ2]-cycloaddition with an alkyne to generate an azametallocy-
clobutene intermediate.12 Subsequent, 1,1-insertion of isonitrile into
the Ti–C bond generates a five-membered metallacycle,13 which is
then proteolytically cleaved from the metal for catalyst turnover.
For this study, two pyrrole-based titanium catalysts, Ti(dp-
To this end, transition metal catalyzed multicomponent cou-
pling reactions can be a suitable alternative for direct access to
14
ma)(NMe2)2 (1) and Ti(dpm)(NMe2)215 (2), were employed. Both
* Corresponding author. Tel.: þ1 517 355 9715x171; fax: þ1 517 353 1793.
E-mail address: odom@chemistry.msu.edu (A.L. Odom).
these catalysts can be synthesized in a single step in almost
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.066

S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
3153
quantitative yield by reacting commercially available Ti(NMe2)4
with H2dpma or H2dpm (Scheme 2). The H2dpma ligand is pre-
pared16 in a single step by Mannich condensation of pyrrole,
formaldehyde, and methylamine hydrochloride in ethanol/water;
whereas, H2dpm is synthesized by condensation of pyrrole and
acetone in the presence of trifluoroacetic acid (TFA).17
addition, the iminoamination procedure produces these useful in-
termediates in a one-step 3-component coupling procedure, and
catalyst variations can be used in some cases to control regiose-
lectivity giving different products from the same substrates (vide
infra).
Initial studies focused on the condensation reaction of the iso-
lated 3CC product with benzamidine hydrochloride. In these re-
actions, the pyrimidine compounds were isolated in 60–70% yield
under optimized reaction conditions. With the optimal conditions
in hand, the multicomponent coupling was carried out with phe-
nylacetylene, cyclohexylamine, and tert-butylisonitrile followed by
one-pot condensation with benzamidine hydrochloride. The
resulting 2,5-diphenylpyrimidine was isolated in 51% yield in this
one-pot methodology.
[Ti](NMe2)2
precatalyst
H2NR1 – 2 HNMe2
R4HN
R1
N
R1
N
R2
R3
The general procedure involves the addition of amine (1 mmol),
catalyst (10 mol %), alkyne (1 mmol), isonitrile (1–1.5 mmol), and
2 mL of toluene to a 40 mL pressure tube under nitrogen, which is
sealed and heated at 100 ꢀC with stirring. Once the multicompo-
nent coupling reaction was complete as judged by GC–FID, the
volatiles were removed in vacuo and 2 mL of tert-amyl alcohol
along with amidine or amidine hydrochloride was added to the
crude residue. After additional heating,21 the product pyrimidine
(3) was purified by chromatography or crystallization (Scheme 3).
[Ti]
H2NR1
R2
R3
R1
N
R2
R3
[Ti]
N
R1
R2
R3
R4
N
[Ti]
C
N
R4
R3
R2
R2
Scheme 1. Proposed catalytic cycle for iminoamination.
+
R1
R3
N
10 mol% 1 or 2
R1 NH2
R4HN
toluene, 100 °C
H
H
+
N
N
N
Me
R4
N C
NH
NH
H2dpm
R5
H2dpma
H2N
NH
tert-amyl alcohol
Ti(NMe2)4
Ti(NMe2)4
150 °C
R5
NMe2
N
N
N
N
N
Ti NMe2
N
R2
NMe2
NMe2
Ti
N
R3
3
Me
Ti(NMe2)2(dpma) (1)
Ti(dpm)(NMe2)2 (2)
Scheme 3. One-pot synthesis of pyrimidines (3).
Scheme 2. Generation of titanium catalysts.
Some applications of this one-pot multicomponent coupling
methodology are shown in Tables 1 and 2. Initial studies focused on
the 3CC of a variety of different alkynes followed by cyclo-con-
densation with benzamidine hydrochloride to afford substituted
pyrimidines. Most of the alkynes listed here formed only one 3CC
product except in case of phenylacetylene (entry 3a), where w5% of
an isomer was observed. Moreover, heteroaromatic alkynes (en-
tries 3i and 3j) as well as enynes (entry 3h) can be successfully
converted to the corresponding pyrimidine compounds.
The regioselectivity of the multicomponent reaction is set by
the [2þ2]-cycloaddition reaction in conjunction with the relative
trapping rates by isonitrile. The regioselectivity of the addition is
electronically controlled when an arene is found on the alkyne
triple bond through stabilization of a partial anionic charge adja-
cent to the metal in the azametallacyclobutene intermediate.12b
This results in 5-(aryl)pyrimidine substitution being electroni-
cally favored for aryl substituted alkynes. For 1-hexyne, for ex-
ample, it is possible to control the regioselectivity of the alkyne
addition to get either 4- or 5-substitution with choice of catalyst
(entries 3c and 3d).
The multicomponent coupling reaction is quite effective for
both terminal and internal alkynes with a variety of aliphatic and
aromatic amines. Because the substituent on the isonitrile does not
end up in the final pyrimidine product, tert-butylisonitrile was
employed exclusively here due to its general applicability in this
reaction. Ease of synthesis is an advantage of t-BuNC as well, which
is readily prepared from tert-butylamine and chloroform in the
presence of base.18 Alternatively, the isonitrile is commercially
available. Similarly in the case of the amine, we used inexpensive
and readily available cyclohexylamine or aniline as these sub-
stituents are lost in the cyclo-condensation step of the one-pot
synthesis.
Barluenga and co-workers have published many notable papers
in ‘1-azabutadiene’ chemistry where the intermediates were iso-
lated from reactions of saturated nitriles with Schiff bases in the
presence of AlCl3.19 Gupton and co-workers reported the synthesis
of pyrimidines from vinylogous iminium salts, which were pre-
pared in a few steps starting from
a,b-unsaturated b-amino-
ketones.20 These ‘1-azabutadienes’ and vinylogous iminium salts
are close derivatives of the iminoamination products used here;
however, the available substitution patterns are quite different. In
For the second stage of the study, we chose to look at the
multicomponent coupling product of phenylacetylene, tert-

3154
S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
Table 2
Examples of pyrimidine syntheses (3) using phenylacetylene and a variety of
amidines
Table 1
Alkyne
Amidine
Catalyst
Product
Yielda %(GC)
43 (52)
Examples of pyrimidine (3) syntheses using benzamidine hydrochloride with dif-
ferent alkynes
N
H
Ph
N
10 mol% Ti-Catalyst
toluene, 100 °C
m
1
1)
2)
R2
Ph
HN
NH
N
N
Ph
Bu
N
R1 NH2
t
+
+
C
R3
Ph
R2
Me
R3
N
Me
NH
H2N
NH•HCl
n
o
1a
1
38 (44)
N
tert-amyl alcohol
3
Ph
Ph
HN
HN
150 °C
Ph
Alkyne
Catalyst
Product
Yielda % (GC)
51 (59)
NH2
N
NH2
NH
N
33
N
a
1
Ph
Ph
Ph
N
Ph
SEt
N
N
SEt
NH
b
c
1
2
p-tol
40 (45)
43 (50)
Ph
p
1
35 (45)
N
N
Me
Ph
HN
Ph
N
a
Bun
Reactions carried out with arylamine, alkyne, and tert-butylisonitrile in a 1:1:1.5
ratio with 10 mol % catalyst at 100 ꢀC for 24–48 h. Once the 3CC is complete, product
was heated at 150 ꢀC in tert-amyl alcohol with amidines.
Ph
n
Bu
N
Bun
N
d
e
1
1
51 (61)b
35 (43)b
n
Bu
Ph
butylisonitrile, and cyclohexylamine with a variety of different
amidines (Table 2). All the amidines attempted reacted with similar
efficiency in the second step of the reaction, and a large variety of 2-
heteroatom substituted pyrimidines can likely be prepared in
comparable yields.
N
Me
Me
N
Ph
Ph
Ph
N
Ph
Et
Ph
Et
N
N
N
f
2
2
17 (29)b,c
25 (36)b
Ph
Et
Ph
Ph
Ph
Et
N
N
3q
PhNH2
+
1) 10 mol% Ti(dpma)(NMe2)2
toluene, 100 °C, 48 h
Me
3.5
Ph
Ph
Me
N
N
g
(1)
+
:
+
HN
But
N
C
1
N
2)
N
H
HCl
H2N
N
N
3r
Me
N
N
h
i
2
2
31 (47)
Ph
t-amyl alcohol, 150 °C
24 h
50%
Ph
N
27 (30)b
Ph
S
N
S
N
N
j
2
2
24b
Ph
Ph
In addition, the unsymmetrical 3CC product from 1-phenyl-
propyne, aniline, and tert-butylisonitrile was reacted with 2-ami-
O
O
nobenzimidazole in
a one-pot protocol. Two regioisomeric
N
pyrimidine products (3q and 3r) were obtained in a 3.5:1 ratio (Eq.
1). The two isomers vary in the placement of the aromatic ring of
the benzimidazole relative to the substituents on the pyrimidine
ring. The structure of the major isomer was found by NOESY NMR
experiments and apparently comes from initial attack of the 2-
amino group on the less sterically encumbered site of the 1,3-di-
imine tautomer.
N
k
31
MeO
Ph
MeO
Et2N
N
l
2
38b
Ph
Ph
Et2N
N
3. Conclusion
a
Most reactions carried out with arylamine, alkyne, and tert-butylisonitrile in
a 1:1:1.5 ratio with 10 mol % catalyst at 100 ꢀC for 24–48 h. Once the 3CC is com-
Titanium-catalyzed multicomponent coupling offers a ready
route to 1,3-diimine tautomers, which can then be directly
employed22 in heterocyclic syntheses. This route to pyrimidines
offers a simple, one-pot method to access pyrimidines with a vari-
ety of different substituents.
plete, product was heated at 150 ꢀC in tert-amyl alcohol with amidines.
b
Aniline was used in place of cyclohexylamine.
Used 20 mol % Ti(dpm)(NMe2)2 at 125 ꢀC.
c

S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
3155
4. Experimental section
by column chromatography on silica. The eluent was hexanes/ethyl
acetate 4:1, which afforded the desired compound (500 mg, 40%) as
a white solid. Mp: 150–151 ꢀC. 1H NMR (CDCl3, 500 MHz): 2.42 (3H,
s, CH3), 7.32 (2H, d, J¼8 Hz, Ar-H), 7.49–7.52 (5H, m, Ar-H), 8.47–
8.49 (2H, m, Ar-H), 9.01 (2H, s, 4-CH pyrimidine). 13C{1H} NMR
(CDCl3, 125 MHz): 21.2, 126.6, 128.1, 128.7, 130.1, 130.9, 131.3, 131.7,
136.8, 139.0, 154.9, 162.7. MS (EI): m/z 246 (Mþ). High resolution
MS: m/z Calcd for C17H15N2þ: 247.1235; found: 247.1236.
4.1. General considerations
All manipulations of air sensitive compounds were carried out in
an MBraun dry box under a purified nitrogen atmosphere. Toluene
was purified by sparging with dry N2 and removing water by run-
ning through activated alumina systems purchased from Solv-Tek.
Deuterated solvents were dried over purple sodium benzophe-
none ketyl (C6D6) or phosphoric anhydride (CDCl3) and distilled
under a nitrogen atmosphere. Deuterated toluene was dried by
passing through two columns of activated neutral alumina. 1H and
13C spectra were recorded on VXR-500 spectrometers. Alkynes were
purchased either from Aldrich or from GFS chemicals and dried from
CaO under dry nitrogen. Amines were purchased from Aldrich, dried
over KOH, and distilled under dry nitrogen. 2-Ethynylthiophene23
and 2-ethynylfuran24 were made according to the literature pro-
cedures. Amidines were purchased either from Alfa Aesar or from
TCI; however, 2-aminobenzimidazole was purchased from Aldrich.
tert-Amyl alcohol was purchased from Eastman Chemical Co., was
dried over Mg, and was distilled under dinitrogen.
4.2.3. 5-Butyl-2-phenylpyrimidine 3c. The general procedure was
followed. The reaction was carried out with tert-butylisonitrile
(855
(575
m
L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), 1-hexyne
mL, 5 mmol), and Ti(NMe2)2(dpm) (154 mg, 0.5 mmol) in tolu-
ene (10 mL) and was heated for 24 h at 100 ꢀC. Volatiles were
removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry
tert-amyl alcohol (10 mL) was added. The mixture was heated to
140 ꢀC for 36 h. Purification was accomplished by column chroma-
tography on silica. The eluent was hexanes/ethyl acetate 4:1, which
afforded the desired compound (457 mg, 43%) as a yellow-red liquid.
1H NMR (CDCl3, 500 MHz): 0.95 (3H, t, J¼7.5 Hz, CH2CH2CH2CH3),
1.37–1.42 (2H, m, CH2CH2CH2CH3), 1.61–1.68 (2H, m,
CH2CH2CH2CH3), 2.66 (2H, t, J¼7.5 Hz, CH2CH2CH2CH3), 7.49–7.50
(3H, m, Ar-H), 8.45–8.47 (2H, m, Ar-H), 8.70 (2H, s, 4-CH pyrimidine).
13C{1H} NMR (CDCl3, 125 MHz): 13.7, 22.1, 29.9, 32.8, 127.8, 128.5,
130.3, 132.9, 137.6, 157.0, 162.6. MS (EI): m/z 212 (Mþ). High resolu-
tion MS: m/z Calcd for C14H17Nþ2 : 213.1392; found: 213.1395.
4.2. General procedure for pyrimidine synthesis
In a N2 filled glove box, a 40 mL pressure tube, equipped with
a magnetic stirbar was loaded with amine (5 mmol), catalyst (10–
20 mol %), alkyne (5 mmol), isonitrile (5–7.5 mmol), and 10 mL of
dry toluene. The pressure tube was sealed with a Teflon screw cap,
taken out of the dry box, and heated to the appropriate temperature
for the desired time with vigorous stirring. After completion of the
reaction as judged by GC–FID, the pressure tube was cooled to room
temperature and volatiles were removed under reduced pressure.
Then the same pressure tube was charged with amidine hydro-
chloride (7.5 mmol) in tert-amyl alcohol (10 mL) and heated to
150 ꢀC for 24 h. After completion of the reaction, tert-amyl alcohol
was removed under reduced pressure. The crude product was
dissolved in CH2Cl2 and washed with water. The organic layer was
dried over Na2SO4 and concentrated on a rotary evaporator. The
crude product was purified either by column chromatography or by
crystallization from a suitable solvent.
4.2.4. 4-Butyl-2-phenylpyrimidine 3d. The general procedure was
followed. The reaction was carried out with tert-butylisonitrile
(570 mL, 5 mmol), aniline (460 mL, 5 mmol), 1-hexyne (575 mL,
5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene
(10 mL) and was heated for 24 h at 100 ꢀC. Volatiles were removed
and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl
alcohol (10 mL) was added. The mixture was heated to 140 ꢀC for
24 h. Purification was accomplished by column chromatography on
silica. The eluent was hexanes/ethyl acetate 3:1, which afforded the
desired compound (540 mg, 51%) as a yellow-red liquid (w10% of
the other isomer was also formed in the reaction). 1H NMR (CDCl3,
500 MHz): 0.95 (3H, t, J¼7.5 Hz, CH2CH2CH2CH3), 1.37–1.43 (2H, m,
CH2CH2CH2CH3), 1.74–1.80 (2H, m, CH2CH2CH2CH3), 2.80 (2H, t,
J¼7.5 Hz, CH2CH2CH2CH3), 7.01 (1H, d, J¼5 Hz, 5-CH pyrimidine),
7.45–7.47 (3H, m, Ar-H), 8.42–8.44 (2H, m, Ar-H), 8.64 (1H, d,
J¼5 Hz, 4-CH pyrimidine). 13C{1H} NMR (CDCl3, 125 MHz): 13.9,
22.4, 30.7, 37.7, 117.9, 128.4, 128.5, 130.4, 137.9, 156.8, 164.3, 171.0.
MS (EI): m/z 212 (Mþ). High resolution MS: m/z Calcd for C14H17Nþ2 :
213.1392; found: 213.1388.
4.2.1. 2,5-Diphenylpyrimidine 3a. The general procedure was fol-
lowed. The reaction was carried out with tert-butylisonitrile (855 mL,
7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene
(510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in
toluene (10 mL) and was heated for 24 h at 100 ꢀC. Volatiles were
removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry
tert-amyl alcohol (10 mL) was added. The mixture was heated to 145–
150 ꢀC for 24 h. Purification was accomplished by column chroma-
tography on silica. The eluent was hexanes/ethyl acetate 4:1, which
afforded the desired compound (588 mg, 51%) as a pale yellow solid.
Mp: 179–180 ꢀC (lit.25 mp: 180–182). 1H NMR (CDCl3, 500 MHz):
7.43–7.46 (1H, m, Ar-H), 7.48–7.53 (5H, m, Ar-H), 7.61–7.63 (2H, m,
Ar-H), 8.46–8.48 (2H, m, Ar-H), 9.01 (2H, s, 4-CH pyrimidine).13C{1H}
NMR (CDCl3, 125 MHz): 126.8, 128.1, 128.6, 128.7, 129.4, 130.8, 131.7,
134.5, 137.2, 155.2, 163.4. MS (EI): m/z 232 (Mþ). High resolution MS:
m/z Calcd for C16H13Nþ2 : 233.1079; found: 233.1075.
4.2.5. 4-Methyl-2,5-diphenylpyrimidine 3e. The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
(680
(625
m
L, 5.5 mmol), aniline (460
mL, 5 mmol), 1-phenylpropyne
mL, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in
toluene (10 mL) and was heated for 48 h at 100 ꢀC. Volatiles were
removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry
tert-amyl alcohol (10 mL) was added. The mixture was heated to
145–150 ꢀC for 24 h. Purification was accomplished by column
chromatography on silica. The eluent was hexanes/ethyl acetate
4:1, which afforded the desired compound (428 mg, 35%) as a white
solid. Mp: 83–84 ꢀC. 1H NMR (CDCl3, 500 MHz): 2.57 (3H, s, CH3),
7.35–7.37 (2H, m, Ar-H), 7.40–7.44 (1H, m, Ar-H), 7.46–7.51 (5H, m,
Ar-H), 8.46–8.48 (2H, m, Ar-H), 8.59 (1H, s, 4-CH pyrimidine).
13C{1H} NMR (CDCl3,125 MHz): 23.1,128.1,128.5,128.7,129.0,130.5,
132.3, 136.1, 137.5, 156.6, 162.9, 164.6. MS (EI): m/z 246 (Mþ). High
resolution MS: m/z Calcd for C17H15Nþ2 : 247.1235; found: 247.1238.
4.2.2. 2-Phenyl-5-(p-tolyl)pyrimidine 3b. The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
(855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), p-tolyl
acetylene (580 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg,
0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and benzamidine hydrochloride (1.17 g,
7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture
was heated to 145–150 ꢀC for 24 h. Purification was accomplished
4.2.6. 2,4,5-Triphenylpyrimidine 3f. The general procedure was
followed. The reaction was carried out with tert-butylisonitrile

3156
S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
(513
m
L, 4.5 mmol), aniline (276
m
L, 3 mmol), diphenylacetylene
CH pyrimidine). 13C{1H} NMR (CDCl3, 125 MHz): 124.8, 126.1, 126.8,
128.0, 128.5, 128.6, 130.8, 136.8, 137.0, 153.7, 163.1. MS (EI): m/z 238
(Mþ). High resolution MS: m/z Calcd for C14H11N2Sþ: 239.0643;
found: 239.0642.
(534 mg, 3 mmol), and Ti(NMe2)2(dpm) (186 mg, 0.6 mmol) in
toluene (6 mL) and was heated for 48 h at 125 ꢀC. Volatiles were
removed and benzamidine hydrochloride (0.702 g, 4.5 mmol) in
dry tert-amyl alcohol (6 mL) was added. The mixture was heated to
150 ꢀC for 24 h. Purification was accomplished by column chro-
matography on neutral alumina. The eluent was hexanes/ethyl
acetate 9:1, which afforded the desired compound (156 mg, 17%) as
a yellow-orange solid. Mp: 108–110 ꢀC. 1H NMR (CDCl3, 500 MHz):
7.26–7.28 (2H, m, Ar-H), 7.30–7.33 (2H, m, Ar-H), 7.36–7.39 (4H, m,
Ar-H), 7.51–7.54 (3H, m, Ar-H), 7.57–7.58 (2H, m, Ar-H), 8.58–8.60
(2H, m, Ar-H), 8.81 (1H, s, 4-CH pyrimidine). 13C{1H} NMR (CDCl3,
125 MHz): 127.9, 128.0, 128.2, 128.5, 128.7, 129.3, 130.0, 130.6, 130.8,
136.6, 137.5, 137.9, 158.6, 163.2, 163.3. MS (EI): m/z 308 (Mþ). High
resolution MS: m/z Calcd for C22H17Nþ2 : 309.1392; found: 309.1399.
4.2.10. 5-(Furan-2-yl)-2-phenylpyrimidine 3j. The general pro-
cedure was followed. The reaction was carried out with tert-buty-
lisonitrile (375 mg, 4.5 mmol), aniline (279 mg, 3 mmol),
2-ethynylfuran (276 mg, 3 mmol), and Ti(NMe2)2(dpm) (93 mg,
0.3 mmol) in toluene (6 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and benzamidine hydrochloride (0.515 g,
3.3 mmol) in dry pyridine (6 mL) was added. The mixture was
heated to 150 ꢀC for 24 h. Purification was accomplished by column
chromatography on neutral alumina. The eluent was hexanes/ethyl
acetate 9:1, which afforded the desired compound (160 mg, 24%) as
a yellow solid. Mp: 151–152 ꢀC (lit.26 mp: 153–154). 1H NMR (CDCl3,
500 MHz): 6.56 (1H, dd, J¼3.5 and 1.5 Hz, Ar-H), 6.87 (1H, d,
J¼3.5 Hz, Ar-H), 7.50–7.52 (3H, m, Ar-H), 7.59 (1H, d, J¼1.5 Hz, Ar-
H), 8.49–8.51 (2H, m, Ar-H), 9.11 (2H, s, 4-CH pyrimidine). 13C{1H}
NMR (CDCl3, 125 MHz): 107.3, 112.0, 122.6, 128.1, 128.6, 130.7, 137.2,
143.7,148.6,152.1,162.8. MS (EI): m/z 222 (Mþ). High resolution MS:
m/z Calcd for C14H11N2Oþ: 223.0865; found: 223.0871.
4.2.7. 4,5-Diethyl-2-phenylpyrimidine 3g. The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
(855 mL, 7.5 mmol), aniline (460 mL, 5 mmol), 3-hexyne (410 mg,
5 mmol), and Ti(NMe2)2(dpm) (154 mg, 0.5 mmol) in toluene
(10 mL) and was heated for 24 h at 110 ꢀC. Volatiles were removed
and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl
alcohol (10 mL) was added. The mixture was heated to 140 ꢀC for
24 h. Purification was accomplished by column chromatography on
silica. The eluent was hexanes/ethyl acetate 3:1, which afforded the
desired compound (265 mg, 25%) as a red liquid. 1H NMR (CDCl3,
500 MHz): 1.29 (3H, t, J¼7.5 Hz, 5-CH2CH3), 1.41 (3H, t, J¼7.5 Hz, 4-
CH2CH3), 2.69 (2H, q, J¼7.5 Hz, 5-CH2CH3), 2.88 (2H, q, J¼7.5 Hz, 4-
CH2CH3) 7.46–7.50 (3H, m, Ar-H), 8.46–8.48 (2H, m, Ar-H), 8.51 (1H,
s, 4-CH pyrimidine). 13C{1H} NMR (CDCl3,125 MHz): 12.2,14.4, 22.4,
27.3, 127.8, 128.4, 130.0, 131.6, 138.1, 156.1, 162.1, 169.1. MS (EI): m/z
212 (Mþ). High resolution MS: m/z Calcd for C14H17Nþ2 : 213.1392;
found: 213.1396.
4.2.11. 5-(4-Methoxyphenyl)-2-phenylpyrimidine 3k. The general
procedure was followed. The reaction was carried out with tert-
butylisonitrile (513 mL, 4.5 mmol), cyclohexylamine (297 mg,
3 mmol), p-methoxyphenylacetylene (396 mg, 3 mmol), and Ti(N-
Me2)2(dpm) (93 mg, 0.3 mmol) in toluene (6 mL) and was heated for
24 h at 100 ꢀC. Volatiles were removed and benzamidine hydro-
chloride (0.702 g, 4.5 mmol) in dry tert-amyl alcohol (6 mL) was
added. The mixture was heated to 145–150 ꢀC for 24 h. Purification
was accomplished by column chromatography on neutral alumina.
The eluent was hexanes/ethyl acetate 85:15, which afforded the
desired compound (245 mg, 31%) as a white solid. Mp: 170–172 ꢀC
(lit.27 mp: 174–175). 1H NMR (CDCl3, 500 MHz): 3.86 (3H, s, OCH3),
7.03–7.04 (2H, m, Ar-H), 7.48–7.50 (3H, m, Ar-H), 7.54–7.56 (2H, m,
Ar-H), 8.45–8.47 (2H, m, Ar-H), 8.97 (2H, s, 4-CH pyrimidine). 13C{1H}
NMR (CDCl3, 125 MHz): 55.4, 114.9, 126.8, 127.9, 128.0, 128.6, 130.6,
131.3, 137.3, 154.7, 160.3, 162.8. MS (EI): m/z 262 (Mþ). High resolu-
tion MS: m/z Calcd for C17H15ONþ2 : 263.1184; found: 263.1183.
4.2.8. 5-Cyclohexenyl-2-phenylpyrimidine 3h. The general pro-
cedure was followed. The reaction was carried out with tert-butyl-
isonitrile (855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol),
cyclohexenylacetylene (530 mg, 5 mmol), and Ti(NMe2)2(dpm)
(154 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at
100 ꢀC. Volatiles were removed and benzamidine hydrochloride
(1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The
mixture was heated to 145–150 ꢀC for 24 h. Purification was ac-
complished by column chromatography on silica. The eluent was
hexanes/ethyl acetate 4:1, which afforded the desired compound
(352 mg, 31%) as a pale yellow solid. Mp: 97–98 ꢀC. 1H NMR (CDCl3,
500 MHz): 1.66–1.70 (2H, m, CH2), 1.78–1.83 (2H, m, CH2), 2.23–
2.25 (2H, m, CH2), 2.40–2.41 (2H, m, CH2), 6.25–6.26 (1H, m, CH),
7.45–7.47 (3H, m, Ar-H), 8.41 (2H, d, J¼8 Hz, Ar-H), 8.77 (2H, s, 4-CH
pyrimidine). 13C{1H} NMR (CDCl3, 125 MHz): 21.7, 22.5, 25.9, 26.5,
127.8,127.9,128.6,130.4,131.1,132.6,137.4,153.4,162.6. MS (EI): m/z
236 (Mþ). High resolution MS: m/z Calcd for C16H17Nþ2 : 237.1392;
found: 237.1384.
4.2.12. 3-(2,5-Diphenylpyrimidin-4-yl)-N,N-diethylpropan-1-amine
3l. The general procedure was followed. The reaction was carried
out with tert-butylisonitrile (85 mL, 0.75 mmol), aniline (46 mL,
0.5 mmol), N,N-diethyl-5-phenylpent-4-yn-1-amine (107.5 mg,
0.5 mmol), and Ti(NMe2)2(dpm) (15.4 mg, 0.05 mmol) in toluene
(1 mL) and was heated for 36 h at 125 ꢀC. Volatiles were removed
and benzamidine hydrochloride (118 mg, 0.75 mmol) in dry tert-
amyl alcohol (1 mL) was added. The mixture was heated to 150 ꢀC
for 24 h. Purification was accomplished by column chromatography
on neutral alumina. The eluent was hexanes/ethyl acetate/trie-
thylamine 78:20:2, which afforded the desired compound (66 mg,
38%) as a red oil. 1H NMR (CDCl3, 500 MHz): 0.93 (6H, t, J¼7 Hz,
CH2CH3), 1.91–1.97 (2H, m, CH2CH2CH2NEt2), 2.41–2.47 (6H, m,
CH2CH2CH2NEt2 and CH2CH3), 2.81 (2H, t, J¼8 Hz, CH2CH2CH2NEt2),
7.34–7.50 (8H, m, Ar-H), 8.49–8.51 (2H, m, Ar-H), 8.56 (1H, s, 4-CH
pyrimidine). 13C{1H} NMR (CDCl3, 125 MHz): 11.7, 25.6, 32.9, 46.7,
52.4, 128.0, 128.1, 128.4, 128.6, 129.1, 130.4, 132.2, 136.2, 137.7, 156.8,
162.9, 167.6. MS (EI): m/z 345 (Mþ). High resolution MS: m/z Calcd
for C23H28Nþ3 : 346.2283; found: 346.2278.
4.2.9. 2-Phenyl-5-(thiophen-2-yl)pyrimidine
3i. The
general
procedure was followed. The reaction was carried out with tert-
butylisonitrile (374 mg, 4.5 mmol), aniline (279 mg, 3 mmol), 2-
ethynylthiophene (324 mg, 3 mmol), and Ti(NMe2)2(dpm) (93 mg,
0.3 mmol) in toluene (6 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and benzamidine hydrochloride (0.515 g,
3.3 mmol) in dry tert-amyl alcohol (6 mL) was added. The mixture
was heated to 150 ꢀC for 24 h. Purification was accomplished by
column chromatography on neutral alumina. The eluent was hex-
anes/ethyl acetate 9:1, which afforded the desired compound
(185 mg, 27%) as a yellow solid. Mp: 118–119 ꢀC. 1H NMR (CDCl3,
500 MHz): 7.16 (1H, dd, J¼9 and 5 Hz, Ar-H), 7.42–7.43 (2H, m, Ar-
H), 7.47–7.50 (3H, m, Ar-H), 8.44–8.46 (2H, m, Ar-H), 9.00 (2H, s, 4-
4.2.13. 5-Phenylpyrimidine 3m. The general procedure was fol-
lowed. The reaction was carried out with tert-butylisonitrile (855 mL,
7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene
(510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in
toluene (10 mL) and was heated for 24 h at 100 ꢀC. Volatiles were

S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
3157
removed and formamidine acetate (0.780 g, 7.5 mmol) in dry tert-
tert-butylisonitrile (136
mL, 1.2 mmol), aniline (92
mL, 1 mmol), 1-
amyl alcohol (10 mL) was added. The mixture was heated to 140 ꢀC
for 24 h. Purification was accomplished by column chromatography
on neutral alumina. The eluent was initially hexanes/ethyl acetate
7:3 and increased to 1:19 methanol/ethylacetate, which afforded the
desired compound in 43% (337 mg) yield (5% of the other isomer
could not be separated). Major isomer 1H NMR (CDCl3, 500 MHz):
7.42–7.46 (1H, m, Ar-H), 7.47–7.51 (2H, m, Ar-H), 7.54–7.56 (2H, m,
Ar-H), 8.92 (1H, s, 4-CH pyrimidine), 9.18 (1H, s, 2-CH pyrimidine).
13C{1H} NMR (CDCl3, 125 MHz): 126.9, 129.0, 129.4, 134.2, 134.3,
154.9,157.5. MS (EI): m/z 156 (Mþ). High resolution MS: m/z Calcd for
C10H9Nþ2 : 157.0666; found: 157.0666.
phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpma) (32.3 mg,
0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 ꢀC.
Volatiles were removed and 2-aminobenzimidazole (200 mg,
1.5 mmol) in dry tert-amyl alcohol (3 mL) was added. The mixture
was heated to 145–150 ꢀC for 24 h. Purification was accomplished
by column chromatography on silica. The eluent was Et3N/ethyl
acetate 3:97, which afforded the desired compound (131 mg, 50%)
as a mixture of two isomers in 3.5:1 ratio (the ratio of the two
isomers was confirmed from the crude product mixture before
purification). Major isomer, 1H NMR (CDCl3, 500 MHz): 3.01 (3H, s,
CH3), 7.38–7.39 (3H, m, Ar-H), 7.46–7.48 (1H, m, Ar-H), 7.50–7.53
(2H, m, Ar-H), 7.56–7.59 (1H, m, Ar-H), 8.05 (1H, d, J¼8.5 Hz, Ar-H),
8.10 (1H, d, J¼8.5 Hz, Ar-H), 8.70 (1H, s, 4-CH pyrimidine). The
13C{1H} NMR (CDCl3, 125 MHz) for the mixture of isomers: 18.4,
25.9, 110.4, 115.2, 120.4, 120.6, 121.4, 121.7, 126.0, 126.3, 128.4, 128.6,
128.9, 129.0, 129.6, 130.1, 130.9, 134.7, 145.0, 145.4, 150.9, 156.5. The
1H, 13C, and 2D spectra are supplied in the NMR file of the
Supplementary data. MS (EI): m/z 259 (Mþ). High resolution MS:
m/z Calcd for C17H14Nþ3 : 260.1188; found: 260.1186.
4.2.14. 2-Methyl-5-phenylpyrimidine 3n. The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
(855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenyl-
acetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg,
0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and acetamidine hydrochloride (0.709 g,
7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture
was heated to 140 ꢀC for 24 h. Purification was accomplished by
column chromatography on neutral alumina. The eluent was hex-
anes/ethyl acetate 4:1, which afforded the desired compound
(321 mg, 38%) as a pale yellow solid. Mp: 57–58 ꢀC. 1H NMR (CDCl3,
500 MHz): 2.79 (3H, s, CH3), 7.41–7.45 (1H, m, Ar-H), 7.47–7.51 (2H,
m, Ar-H), 7.53–7.55 (2H, m, Ar-H), 8.85 (2H, s, 4-CH pyrimidine).
13C{1H} NMR (CDCl3, 125 MHz): 25.4, 126.8, 128.7, 129.3, 131.2,
134.2, 154.9, 166.5. MS(EI): m/z 170 (Mþ). High resolution MS: m/z
Calcd for C11H11Nþ2 : 171.0922; found: 171.0918.
Acknowledgements
The authors thank the National Science Foundation for financial
support.
Supplementary data
1H and 13C NMR spectra for all the pyrimidine products can be
found in the online version at doi:10.1016/j.tet.2010.02.066.
4.2.15. 5-Phenylpyrimidin-2-amine 3o. The general procedure was
followed. The reaction was carried out with tert-butylisonitrile
(855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenyl-
References and notes
acetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg,
0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and guanidine hydrochloride (0.528 g,
7.5 mmol) in dry pyridine (10 mL) was added. The mixture was
heated to 140 ꢀC for 24 h. The crude product was purified by
recrystalization from ethanol, which afforded the desired com-
pound (282 mg, 33%) as a pale brown solid. Mp: 158–159 ꢀC (lit.28
mp: 161–163). 1H NMR (CDCl3, 500 MHz): 5.23 (2H, br s, NH2),
7.33–7.36 (1H, m, Ar-H), 7.41–7.47 (4H, m, Ar-H), 8.52 (2H, s, 4-CH
pyrimidine). 13C{1H} NMR (CDCl3, 125 MHz): 125.0, 126.0, 127.6,
129.2, 135.1, 156.4, 161.9. MS (EI): m/z 171 (Mþ). High resolution MS:
m/z Calcd for C10H10Nþ3 : 172.0875; found: 172.0873.
1. Lagoja, I. M. Chem. Biodivers. 2005, 2, 1.
2. Ahluwalia, V. K.; Kaila, N.; Bala, S. Indian J. Chem., Sect. B 1987, 26B, 700.
3. El-Hashash, M. A.; Mahmoud, M. R.; Madboli, S. A. Indian J. Chem., Sect. B 1993,
32B, 449.
4. Keutzberger, A.; Gillessen, J. Arch. Pharm. (Weinheim, Ger.) 1985, 318, 370.
5. Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottlieb, M. S.; Volberding, P. A.;
Laskin, O. L.; Leedom, J. M.; Groopman, J. E.; Mildvan, D.; Schooley, R. T. N. Engl.
J. Med. 1987, 317, 185.
6. Joffe, A. M.; Farley, J. D.; Linden, D.; Goldsand, G. Am. J. Med. 1989, 87, 332.
7. For a review on related enaminones in synthesis see Elassar, A. Z. A.; El-Khair,
A. A. Tetrahedron 2003, 59, 8463.
8. For reviews see: (a) Chinchilla, R.; Na´jera, C.; Yus, M. Chem. Rev. 2004, 104,
´
´
2667; (b) Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
4489.
9. (a) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880; (b) Banerjee, S.;
Shi, Y.; Cao, C.; Odom, A.L. J. Organometallic Chem., 690, 5066. For a recent
study on a potential side reaction to this 3CC that can occur with some sub-
strates see Barnea, E.; Majumder, S.; Staples, R. J.; Odom, A. L. Organometallics
2009, 3876.
10. (a) For a review on azadienes in synthesis see Jayakumar, S.; Ishar, M. P. S.;
Mahajan, M. P. Tetrahedron 2002, 58, 379 See also; (b) Calvo, L. A.; Gonzalez-
Nogal, A. M.; Gonzalez-Ortega, A.; San˜udo, M. C. Tetrahedron Lett. 2001, 42, 8981
for related silyl isoxazole chemistry.
4.2.16. 2-(Ethylthio)-5-phenylpyrimidine 3p. The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
(855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenyl-
acetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg,
0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 ꢀC.
Volatiles were removed and S-ethylisothiourea hydrobromide
(1.39 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The
mixture was heated to 145–150 ꢀC for 24 h. Purification was ac-
complished by column chromatography on neutral alumina. The
eluent was hexanes/ethyl acetate 85:15, which afforded the desired
compound (350 mg, 35%) as white solid. Mp: 70–71 ꢀC. 1H NMR
(CDCl3, 500 MHz): 1.41 (3H, t, J¼7 Hz, CH2CH3), 3.19 (2H, q,
J¼7.5 Hz, CH2CH3), 7.38–7.42 (1H, m, Ar-H), 7.45–7.48 (2H, m, Ar-H),
7.50–7.52 (2H, m, Ar-H), 8.71 (2H, s, 4-CH pyrimidine). 13C{1H} NMR
(CDCl3, 125 MHz): 14.4, 25.3, 126.5, 128.4, 129.3, 134.4, 155.2, 171.1.
MS (EI): m/z 216 (Mþ). High resolution MS: m/z Calcd for
C12H13SNþ2 : 217.0799; found: 217.0802.
11. For a recent review on hydroamination see Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.;
Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
12. (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708;
(b) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753;
(c) McGrane, P. L.; Jenson, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459;
(d) Zi, G.; Blosch, L. L.; Jia, L.; Andersen, R. A. Organometallics 2005, 24, 4602; (e)
Poise, J. L.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1998, 120, 13405; (f)
Duncan, A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431; (g) Severin, R.; Doye, S.
Chem. Soc. Rev. 2007, 36, 1407.
13. Vujkovic, N.; Fillol, J. L.; Ward, B. D.; Wadepohl, H.; Mountford, P.; Gade, L. H.
Organometallics 2008, 27, 2518 For a recently characterized example of the
proposed 5-membered metallacyclic intermediate prepared by isonitrile in-
sertion see.
14. Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40, 1987.
15. (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003,
586; (b) Novak, A.; Blake, A. J.; Wilson, C.; Love, J. B. Chem. Commun. 2002, 2796.
16. Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2002, 41, 6298.
17. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 1391.
4.2.17. 4-Methyl-3-phenylpyrimido[1,2-a]-benzimidazole
3q. The
general procedure was followed. The reaction was carried out with
18. Gokel, G. W.; Widera, R. P.; Weber, W. P. Org. Synth. 1976, 55, 96.

3158
S. Majumder, A.L. Odom / Tetrahedron 66 (2010) 3152–3158
19. (a) For reviews on the extensive work of Barluenga and coworkers on ap-
21. None of the reaction times have been fully optimized. Reactions were generally
run for about 24 h.
´
plications of 1,3-diimines to organic synthesis see Barluenga, J.; Tomas, M.
Adv. Heterocycl. Chem. 1993, 57, 1; (b) For some references related more
specifically to 1,3-diimines reactions related to those here see Barluenga, J.
Bull. Soc. Chim. Belg. 1988, 97, 545; (c) Barluenga, J.; Rubio, E.; Rubio, V.;
Muniz, L.; Iglesias, M. J.; Gotor, V. J. Chem. Res., Synop. 1985, 124; (d) Bar-
luenga, J.; Iglesias, M. J.; Gotor, V. Synthesis 1987, 662; (e) Gotor, V.; Brieva, R.;
Aguirre, A.; Garcia-Granda, S.; Gomez-Beltran, F. Heterocycles 1989, 29, 1695;
22. (a) Majumder, S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. Adv. Synth. Catal. 2009,
351, 2013; (b) Majumder, S.; Gipson, K. R.; Odom, A. L. Org. Lett. 2009, 11, 4720.
23. Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 17, 4044.
24. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919.
25. Ibrahim, Y. B.; Al-Awadi, N. A.; Ibrahim, M. R. Tetrahedron 2004, 60, 9121.
26. Promel, R.; Cardon, A.; Daniel, M.; Jacques, G.; Vandersmissen, A. Tetrahedron
Lett. 1968, 26, 3067.
27. Mosquera, A.; Riveiros, R.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 2008, 10, 3745.
28. Protopopova, T. V.; Klimko, V. T.; Skoldinov, A. P. Khimicheskaya Nauka i Pro-
myshlennost 1959, 4, 805.
´
´
(f) Barluenga, J.; Lopez-Ortiz, J. F.; Tomas, M.; Gotor, V. J. Chem. Soc., Perkin Trans. 1
1981,1891;(g)Barluenga,J.;Jardo´n,J.;Rubio,V.;Gotor, V.J. Org. Chem.1983, 48,1379.
20. Gupton, J. T.; Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.; Vargas, M.; Hosein, K.
N.; Sikorski, J. A. Heterocycles 1998, 47, 689.