One-pot synthesis of pyridines or pyrimidines by tandem oxidation-heteroannulation of propargylic alcohols

Article abstract of DOI:10.1055/s-2003-40827

Pyridines and pyrimidines are prepared in a single step from propargylic alcohols by in situ oxidation with o-iodoxybenzoic acid or manganese dioxide and reaction with enamines or amidines, respectively, under either thermal or microwave-assisted conditions in a new one-pot tandem oxidation-heteroannulation procedure. The reaction of a β-ketoester, propargylic alcohol and ammonium acetate, with in situ oxidation, constitutes a highly facile three-component reaction for the synthesis of pyridines that accomplishes four distinct synthetic operations in one-pot, good yield and with total regiocontrol.

Full text of DOI:10.1055/s-2003-40827

LETTER
1443
One-Pot Synthesis of Pyridines or Pyrimidines by Tandem Oxidation-
Heteroannulation of Propargylic Alcohols
One-Pot Synthesis of
P
a
yridines or
r
Pyrimid
k
ine
s
C. Bagley,* David D. Hughes, Halima M. Sabo, Paul H. Taylor, Xin Xiong
Department of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Fax +44(29)20874030; E-mail: Bagleymc@cf.ac.uk
Received 5 June 2003
R4
R4
Abstract: Pyridines and pyrimidines are prepared in a single step
NH
NH2
from propargylic alcohols by in situ oxidation with o-iodoxybenzo-
ic acid or manganese dioxide and reaction with enamines or
amidines, respectively, under either thermal or microwave-assisted
conditions in a new one-pot tandem oxidation-heteroannulation
procedure. The reaction of a b-ketoester, propargylic alcohol and
ammonium acetate, with in situ oxidation, constitutes a highly facile
three-component reaction for the synthesis of pyridines that accom-
plishes four distinct synthetic operations in one-pot, good yield and
with total regiocontrol.
R2
HO
N
R6
O
R6
1
3
2
R4
R4
NH2
R3
R2
R3
R2
R2
N
R6
N
R6
Key words: heterocycles, pyridines, pyrimidines
4
5
6
Figure 1
Facile one-pot transformations involving alcohol oxida-
tion followed by in situ trapping of the resulting aldehyde
have attracted considerable attention in recent years. Tay-
lor has reported a number of tandem manganese dioxide
mediated processes,1 particularly in situ oxidation–Wittig
methodology that avoids the need to isolate aldehyde in-
termediates that may be toxic, volatile or highly reactive.
Similar procedures using a range of different oxidants, in-
cluding o-iodoxybenzoic acid (IBX),2 the Dess–Martin
periodinane3 and barium manganate,4 have been shown to
be successful in a number of tandem processes for rapid
access to different synthetic targets. Following on from
our work on the development of new heteroannulation
procedures5 and multiple-component reactions,6 we set
out to establish a whole new type of tandem process that
was appropriate for the rapid synthesis of pyridines 6 and
pyrimidines 4, thus preparing different heteroaromatic
building blocks7 from a single propargylic alcohol subset
1 by in situ oxidation to alkynone 2 and subsequent het-
eroannulation with a bis-nucleophile such as amidine 3 or
enamine 5 in a single preparative step (Figure 1).
failed to generate more than a trace (typically less than
5%) of the oxidized product 1-phenyl-2-propynone (2a)
even after 1 hour irradiation time, making the prospect of
establishing an efficient one-pot microwave-assisted
process unlikely.
In spite of this set back, we decided to try a simple tandem
oxidation–heteroannulation reaction under either conduc-
tive or microwave heating regardless, in order to establish
if difficulties encountered in propargylic alcohol oxida-
tion were reflected in the overall efficiency of the process.
Two different oxidants, manganese dioxide and IBX,
were investigated for the one-pot oxidation–heteroannula-
tion of 1-phenyl-2-propyn-1-ol (1a) with benzamidine or
acetamidine, 3a or 3b respectively (Scheme 1). Surpris-
ingly, when the reaction was carried out in the presence of
amidine 3a or 3b, pyrimidines 4a,b were generated in up
to 84% yield, the reaction under microwave-assisted con-
ditions with manganese dioxide, irradiating at 120 °C
over 40 minutes, proving to be the most efficient
(Table 1).9
In order to examine if the tandem oxidation–heteroannu-
lation of propargylic alcohols was viable as a new one-pot
method for the synthesis of nitrogen-containing heterocy-
cles, the oxidation of 1-phenyl-2-propyn-1-ol (1a) was in-
vestigated under microwave-assisted conditions that were
successful in preliminary studies for the heteroannulation
of alkynones 2 and amidines 3.8 However, irradiating a
mixture of 1-phenyl-2-propyn-1-ol (1a) and manganese
dioxide in wet acetonitrile at 100 °C, 120 °C or 140 °C in
a self-tunable CEM Discover microwave synthesizer
N
3, oxidant, MeCN
R2
N
Ph
∆ (30-69%)
µwave (61-84%)
HO
Ph
4a R2 = Ph
4b R2 = Me
1a
Scheme 1 Tandem oxidation–heteroannulation of 1-phenyl-2-
propyn-1-ol (1a) in the synthesis of pyrimidines 4a,b
A one-pot synthesis of pyrimidines from amidines and
propargylic alcohols by a coupling–isomerization–cyclo-
condensation sequence has been reported by Müller10 but
our new route is quicker, simpler and proceeds under
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1443,1446,ftx,en;D12803ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1444
M. C. Bagley et al.
LETTER
Table 2 Optimizing the Synthesis of Pyridine 6a by Tandem Oxida-
tion–Heteroannulation of 1-Phenyl-2-propyn-1-ol (1a)
Table 1 Effect of Substrate, Oxidant and Heating Method
Entry
Product
4a
Oxidant
IBX
Yielda (%) Yield (%)b
Oxidant
5a:1a:
Oxidant
Conditions
Yield
(%)a
1
2
3
4
30
69
54
56
80
84
61
65
4a
MnO2
IBX
IBX
1:1:1
DMSO–HOAc (5:1), 65 °C
DMSO–HOAc (5:1), 65 °C
DMSO–HOAc (5:1), 55 °C
DMSO–HOAc (5:1), 65 °C
PhMe–HOAc (5:1), 50 °C
CHCl3–HOAc (5:1), reflux
PhMe, ZnBr2 (20 mol%), reflux
54
70
69
24
45
23
64
4b
IBX
1:2:2
1:2:2
4b
MnO2
IBX
a Isolated yield after heating at reflux and purification on silica.
b Isolated yield after microwave irradiation at 120 °C for 40 min and
purification on silica.
IBX
1:2:4
MnO2
MnO2
MnO2
1:2:10
1:2:10
1:2:10
much more facile conditions, representing the first exam-
ple of a tandem oxidation–heteroannulation reaction us-
ing propargylic alcohols to access these heterocyclic
targets.
a Isolated yield after purification on silica.
In order to extend these findings and establish a new one-
pot method for the synthesis of pyridine heterocycles, pro-
pargylic alcohol 1a (R = Ph) was reacted with ethyl b-
aminocrotonate (5a) in the presence of IBX or manganese
dioxide (Scheme 2). Pyridine formation from 1-phenyl-
prop-2-yn-1-one (2a) traditionally requires very high
temperatures11 and so these tandem processes were con-
ducted in the presence of either a Brønsted or Lewis acid
as a catalyst to facilitate cyclodehydration to the target
heterocycle.5a A range of conditions were investigated
(Table 2) and although in situ oxidation with MnO2 and
IBX gave comparable yields, the IBX mediated process
was found to be superior for the synthesis of pyridine 6a.
Optimum conditions involved heating enamine 5a and a
one-fold excess of both the propargylic alcohol 1a and
IBX in DMSO–acetic acid (5:1) at 65 °C overnight to give
pyridine 6a in 70% isolated yield after purification on
silica.12
Table 3 One-Pot Synthesis of Pyridines 6 Mediated by IBX12
Entry
Alcohol 1 Pyridine 6 R
Yield (%)a
1
2
3
4
5
1a
1b
1c
1d
1e
6a
6b
6c
6d
6e
Ph
70
45
20
73
53
Me
Et
4¢-C6H4Cl
4¢-C6H4OMe
a Isolated yield after purification on silica.
ethyl b-aminocrotonate (5a) under the reaction condi-
tions. Thus, generating enamine 5 in situ by the condensa-
tion of a b-ketoester precursor and ammonia should
reduce enamine degradation and furthermore establish a
new and highly facile 3-component cyclocondensation
route to these targets that affects four transformations in a
single preparative step. When a range of propargylic alco-
hols 1, b-ketoesters 7 and ammonium acetate was heated
at reflux in toluene–acetic acid (5:1) in the presence of
manganese dioxide (Scheme 3), pyridines 6b,d–h were
formed directly in up to 96% yield (Table 4) and with total
regiocontrol.
OH
EtO2C
NH2
O
R
1a–e
Me
OEt
Me
N
R
MnO2 or IBX,
cat. (20–73%)
6a–e
5a
Scheme 2 Tandem oxidation–heteroannulation of propargylic
alcohols 1a–e in the synthesis of pyridines 6a–e
7 R2, R3
O
a Me, CO2Et
R3
t
With successful conditions established for the tandem
process, a range of propargylic alcohols 1a-e was submit-
ted to in situ oxidation–heteroannulation with ethyl b-
aminocrotonate (5a) mediated by IBX in DMSO–acetic
acid (5:1) at 65 °C.12 It was found that the efficiency of the
reaction was highly dependent upon the nature of the pro-
pargylic alcohol, pyridines 6a-e generated in between
20% and 73% yield (Table 3). Although the efficiency of
the transformation was quite variable, in most instances it
nonetheless compared quite favourably with traditional
methods involving three separate preparative steps.5a It
was postulated that the moderate yield of the one-pot pro-
cess was a consequence of the oxidative degradation of
b Me, CO2 Bu
R2
c Ph, CO2Et
MnO2, NH4OAc
PhMe-AcOH
reflux (60–96%)
OH
R6
R4
1
R4
R3
R2
N
R6
6b,d–h
Scheme 3 New three-component synthesis of pyridines 6 from
propargylic alcohols 1 and b-keto esters 7
Synlett 2003, No. 10, 1443–1446 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Pyridines or Pyrimidines
1445
Table 4 Variation in Yield Using Different Propargylic Alcohols 1
and b-Ketoesters 7
References
(1) (a) Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K.
Synthesis 2003, 1055. (b) Blackburn, L.; Kanno, H.; Taylor,
R. J. K. Tetrahedron Lett. 2003, 44, 115. (c) Runcie, K. A.;
Taylor, R. J. K. Chem. Commun. 2002, 974. (d) Blackburn,
L.; Pei, C.; Taylor, R. J. K. Synlett 2002, 215.
1
7
6
R2
R3
R4 R6
Yield
(%)a
1b
1d
1e
1f
7a
7a
7a
7b
7b
7c
6b
6d
6e
6f
Me CO2Et
Me CO2Et
Me CO2Et
H
H
H
Me
66
96
85
60
73
63
(e) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637.
(f) Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 617.
(g) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem. Commun.
1999, 1337. (h) Wei, X.; Taylor, R. J. K. Tetrahedron Lett.
1998, 39, 3815.
4′-C6H4Cl
4′-C6H4OMe
Me CO2-t-Bu Et Me
(2) Crich, D.; Mo, X.-S. Synlett 1999, 67.
(3) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem.
1997, 62, 9376.
(4) Shuto, S.; Niizuma, S.; Matsuda, A. J. Org. Chem. 1998, 63,
4489.
1a
1d
6g
6h
Me CO2-t-Bu
Ph CO2Et
H
H
Ph
4′-C6H4Cl
a Isolated yield after purification on silica.
(5) (a) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.;
Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin
Trans. 1 2002, 1663. (b) Bagley, M. C.; Lunn, R.; Xiong, X.
Tetrahedron Lett. 2002, 43, 8331.
(6) Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun. 2002,
1682.
(7) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
(8) Bagley, M. C.; Hughes, D. D.; Taylor, P. H. Synlett 2003,
259.
(9) Typical Procedure for the One-Pot Synthesis of
Pyrimidines 4. A mixture of 1-phenyl-2-propyn-1-ol (1a)
(0.13 g, 1.0 mmol), benzamidine hydrochloride salt
(2a·HCl) (0.19 g, 1.2 mmol), Na2CO3 (0.25 g, 2.4 mmol) and
activated MnO2 (0.87 g, 10 mmol) in acetonitrile (5 mL) was
irradiated for 40 min in a self-tunable CEM microwave
synthesizer at 120 °C (initial power 90 W) and then allowed
to cool. The solution was filtered through Celite® and
evaporated in vacuo. Purification by flash chromatography
on silica gave pure 2,4-diphenylpyrimidine (3a)8 as a pale
yellow solid (0.19 g, 84%).
This highly facile one-pot process13 presumably proceeds
by in situ oxidation of propargylic alcohol 1 and simulta-
neous enamine formation, followed by Michael addition,
double bond isomerization under the acidic reaction con-
ditions and subsequent cyclodehydration (Scheme 4), al-
though the involvement of an alternative mechanistic
pathway that proceeds via Michael addition of the b-ke-
toester 7 and alkynone 2 prior to condensation with am-
monia cannot be discounted.
In conclusion, the in situ oxidation–heteroannulation of
propargylic alcohols with either IBX or manganese diox-
ide provides a new one-pot tandem route to nitrogen-con-
taining heteroaromatic building blocks, affecting up to
four separate synthetic transformations in a single prepar-
ative step. Many of these heteroannulation reactions pro-
ceed in good yield and, for the synthesis of pyridines, with
total regiocontrol from either enamine or b-ketoester pre-
cursors.
(10) Müller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2,
1967.
(11) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(12) Typical Procedure for the One-Pot Synthesis of
Pyridines 6 from Enamines 5. A solution of IBX (0.56 g,
2.0 mmol) in DMSO–HOAc (5:1) (18 mL) was stirred at
65 °C until homogeneous. A solution of 1-phenyl-2-propyn-
1-ol (1a) (0.26 g, 2.0 mmol) and ethyl b-aminocrotonate (5a)
(0.13 g, 1.0 mmol) in DMSO (1 mL) was added and the
resulting solution was stirred at 65 °C overnight. Water (10
mL) was added and the mixture was stirred for 10 min,
allowed to cool, diluted with water (40 mL) and extracted
with EtOAc (2 × 30 mL). The organic extracts were
Acknowledgment
We thank Pfizer Ltd and the BBSRC for their generous support,
and the EPSRC Mass Spectrometry Service, Swansea for high-reso-
lution spectra.
H2N
R2
R3
O
R3
NH3
NH2
R4
R4
R3
R2
R2
acid
cat.
R3
R2
R3
R2
7
5
Michael
addition
-H2O
OH
R6
R4
O
R4
R4
N
N
R6
H
MnO2
R6
6
HO
R6
O
R6
1
2
Scheme 4 Proposed mechanistic course of the one-pot three-component synthesis of pyridines 6 from propargylic alcohols 1 and
b-ketoesters 7
Synlett 2003, No. 10, 1443–1446 © Thieme Stuttgart · New York

1446
M. C. Bagley et al.
LETTER
(0.52 g, 6.0 mmol) in toluene–glacial acetic acid (5:1)
combined, washed sequentially with sat. aq NaHCO3
solution (20 mL) and brine (20 mL), dried (Na2SO4) and
evaporated in vacuo. Purification by flash chromatography
on silica gave pure ethyl 2-methyl-6-phenylpyridine-3-
carboxylate (6a)5a as a pale yellow solid (169 mg, 70%).
(5 mL) was heated at reflux overnight. The mixture was
allowed to cool, filtered through Celite®, partitioned
between sat. aq NaHCO3 solution (30 mL) and EtOAc
(30 mL) and the aqueous layer was further extracted with
EtOAc (20 mL). The combined organic layers were washed
sequentially with sat. aq NaHCO3 solution (20 mL) and
brine (20 mL), dried (Na2SO4) and evaporated in vacuo.
Purification by flash chromatography on silica gave pure
pyridine 6d5a as a pale yellow solid (80 mg, 96%).
(13) Typical Procedure for the One-Pot Synthesis of
Pyridines 6 from b-Ketoesters 7. A solution of ethyl
acetoacetate (7a) (39 mg, 0.3 mmol), 1-(4-chloro-
phenyl)prop-2-yn-1-ol (1d)5a (100 mg, 0.6 mmol),
ammonium acetate (0.46 g, 6.0 mmol)) and activated MnO2
Synlett 2003, No. 10, 1443–1446 © Thieme Stuttgart · New York