An efficient synthesis of 2-alkylpyridines using an alkylation/double decarboxylation strategy

Article abstract of DOI:10.1016/j.tetlet.2012.05.049

We have discovered a novel route for synthesising 2-alkylpyridines by exploiting the decarboxylation of pyridyl malonate esters. Herein we report the synthesis of a number of examples and describe how the reaction was discovered.

Full text of DOI:10.1016/j.tetlet.2012.05.049

Tetrahedron Letters 53 (2012) 3853–3856
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An efficient synthesis of 2-alkylpyridines using an alkylation/double
decarboxylation strategy
⇑
Craig Donald , Scott Boyd
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We have discovered a novel route for synthesising 2-alkylpyridines by exploiting the decarboxylation of
pyridyl malonate esters. Herein we report the synthesis of a number of examples and describe how the
reaction was discovered.
Received 4 April 2012
Revised 27 April 2012
Accepted 10 May 2012
Available online 19 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Decarboxylation
Malonate
Alkylation
Alkyl halide
Pyridine rings are a common feature of many drug treatments
currently on the market and remain an attractive moiety to medic-
inal chemists.1 We were particularly interested in synthesising 2-
alkylpyridines which are often accessed via cross-coupling meth-
odology between alkyl halides and the corresponding pyridine-
metal compound or 2-halopyridine and an alkyl metal.2–4 Other
approaches often used include alkylation of 2-methylpyridine,
however this requires a strong base, for example, butyllithium.5
Some strategies proceed via a pyridine-N-oxide,6 although this re-
quires subsequent reduction prior to product isolation.
O
O
N
O
N
1) 2 M NaOH, MeOH
2) 2 M HCl
O
O
OH
2
1
1) 2 M NaOH, MeOH
2) 2 M HCl
Herein, we report a mild method for synthesising 2-alkylpyri-
dines which potentially allows easier synthesis of compounds con-
taining functional groups sensitive to strongly basic conditions. We
recently had cause to synthesise 2-(2-pyridyl)acetic acid (1), how-
ever, attempts to synthesise this via hydrolysis and subsequent
decarboxylation of dimethyl 2-(2-pyridyl)propanedioate (2)
yielded doubly decarboxylated 2-methylpyridine (3) (Scheme 1).
We discovered that the decarboxylation is a known reaction in
these systems,7–9 however, we felt that this route might offer the
possibility to introduce alkyl substitution by novel methodology
at the 2-position of the pyridine ring, by exploiting the acidic nat-
ure of the proton alpha to the carbonyl groups.
N
3
Scheme 1. Observed decarboxylation of dimethyl 2-(2-pyridyl)propanedioate.
carbonate or caesium carbonate in DMF at room temperature to
furnish products 6a–h, in good yields (Table 1).
Hydrolysis of compounds 6a–h with sodium hydroxide in
MeOH afforded the sodium salts of the monocarboxylic acids
which were not isolated. The second decarboxylation was not ob-
served with either prolonged reaction time or heating using these
basic conditions. To facilitate the second decarboxylation, the pH of
the reaction mixture was critical. When the pH was adjusted to 1
by the addition of HCl no decarboxylation was observed, even after
prolonged heating. Decarboxylation was effected by adjusting the
pH of the reaction mixture to pH 4–5 by the addition of 1 M citric
To further investigate the scope of this methodology, 2-iodopyr-
idine (4) was reacted with diethyl malonate using Kwong’s condi-
tions10 to yield malonate ester 5 (Scheme 2). This was then
alkylated with a range of alkyl bromides using either potassium
⇑
Corresponding author.
E-mail address: craig.donald@astrazeneca.com (C. Donald).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.049

3854
C. Donald, S. Boyd / Tetrahedron Letters 53 (2012) 3853–3856
Table 2
O
O
Hydrolysis and double decarboxylation
CuI,
picolinic acid,
O
O
I
Substrate
Product
Yielda (%)
OEt
EtO
CO2Et
EtO2C
OEt
EtO
O
N
Cs2CO3,
1,4-dioxane, 70 °C, 16 h
N
82%
4
N
96
N
7a
5
6a
CO2Et
EtO2C
O
N
R
73
71
79
N
N
RBr
OEt
EtO
7b
7c
N
K2CO3 or Cs2CO3
DMF, 25 °C
6b
CO2Et
EtO2C
6a-h
N
6c
Scheme 2. General alkylation reaction scheme.
CO2Et
EtO2C
O
N
N
N
Table 1
Alkylation of diethyl 2-(2-pyridyl)propanedioate
O
N
N
7d
6d
Alkyl halide
Product
Yielda (%)
CO2Et
CO2Et
EtO2C
EtO2C
Br
EtO2C
N
81
90b
95
79
N
93b
7e
N
N
N
6e
N
6a
CO2Et
OH
CO2Et
O
Br
Si
EtO2C
EtO2C
EtO2C
N
N
87c
85b
75c
7f
N
6f
N
6b
CO2Et
O
CO2Et
EtO2C
EtO2C
O
Br
Br
7g
N
6g
N
6c
CO2Et
O
CO2Et
O
N
O
N
N
O
N
7h
6h
6d
a
CO2Et
Isolated yield.
Br
b
EtO2C
EtO2C
The silyl protecting group was unstable to the conditions.
N
44c
N
N
N
N
6e
N
acid and warming to 60 °C overnight (Scheme 3). This gave prod-
ucts 7a–h shown in (Table 2).
O
CO2Et
Br
Si
O
Si
61c
35b
61c
A range of products was synthesised containing a number of
different functional groups (Table 2). Olefins 7a and 7b were syn-
thesised in good yields and this approach appears to offer an
advantage over current methods available which tend to employ
strongly basic or forcing conditions.11,12 Phenethyl examples 7d
and 7e could potentially be accessed from vinyl pyridine,13,14 how-
ever starting materials will most likely be in short supply for this
strategy. Alcohol 7f might be synthesised by a number of methods
including palladium chemistry,15 however our approach avoids the
use of heavy metal catalysis so may be more suited to larger scale
routes. Perhaps one of the greatest advantages of this methodology
is the ability to synthesise carbonyl-containing compounds such as
ketone 7h. We believe that it would be extremely challenging to
access these types of compounds using the alternative methodolo-
gies described.
N
6f
O
CO2Et
Br
EtO2C
EtO2C
O
N
6g
O
CO2Et
Br
O
N
6h
a
b
c
Isolated yield.
Cs2CO3 used as base.
K2CO3 used as base.

C. Donald, S. Boyd / Tetrahedron Letters 53 (2012) 3853–3856
3855
O
O
N
O
R
6a-h
O
R
R
OEt
EtO
OH
citric acid
2 M NaOH, MeOH
25 °C, 16 h
60 °C 16 h
N
N
7a-h
Scheme 3. General decarboxylation conditions.
O
H+
H
N
H
N
N
At pH 4-5
R
R
R
H
O
O
R
O
O
R
H
At pH 14
N
N+
At pH 1
Scheme 4. Mechanistic rationale for decarboxylation.
We postulate that the second decarboxylation proceeds at pH
4–5 as follows (Scheme 4). The lone pair on the nitrogen accepts
the proton from the carboxylic acid which facilitates the con-
certed process to liberate carbon dioxide and generate the ob-
served product. At pH 1, the nitrogen is protonated so the lone
pair of electrons is unavailable to initiate this reaction. At pH
14 the acid is deprotonated and cannot therefore decarboxylate
via this mechanism.
In summary we have presented a convenient method for the
preparation of 2-alkylpyridine compounds. We have demonstrated
that the methodology is versatile and tolerates a number of func-
tional groups and so should be of interest to chemists interested
in synthesising these types of compounds.
136.86, 149.01, 153.12, 167.12; HRMS (ESI): MH+, found
238.10727, C12H16O4N requires 238.10738.
Example procedure for the alkylation. Preparation of diethyl 2-
allyl-2-(pyridin-2-yl)malonate (6b)
K2CO3 (583 mg, 4.21 mmol) was added in one portion to a mix-
ture of diethyl 2-(pyridin-2-yl)malonate (5) (500 mg, 2.11 mmol)
and 3-bromoprop-1-ene (510 mg, 4.21 mmol) in DMF (5 mL). The
resulting suspension was stirred at ambient temperature for
16 h. The reaction mixture was evaporated to dryness, then the
residue was partitioned between CH2Cl2 (25 mL) and H2O
(10 mL). The organic phase was dried over MgSO4, filtered and
evaporated to afford a crude product. This was purified by flash sil-
ica chromatography, elution gradient 0–50% EtOAc in heptane to
give diethyl 2-allyl-2-(pyridin-2-yl)malonate (6b) (510 mg, 87%)
as a colourless oil; 1H NMR (CDCl3, 400 MHz): d (ppm) 1.24 (t,
J = 7.1 Hz, 6H), 3.11–3.15 (m, 2H), 4.24 (qd, J = 7.1, 3.8 Hz, 4H),
4.99 (t, J = 1.1 Hz, 1H), 5.01–5.05 (m, 1H), 5.72–5.85 (m, 1H), 7.18
(ddd, J = 6.7, 4.8, 1.7 Hz, 1H), 7.61–7.69 (m, 2H), 8.52–8.56 (m,
1H); 13C NMR (101 MHz, CDCl3, 30 °C) 13.96, 40.20, 61.52, 65.33,
118.58, 122.31, 124.06, 133.27, 135.80, 148.66, 156.67, 169.65;
HRMS (ESI): MH+, found 278.13867, C15H20O4N requires
278.13868.
Preparation of diethyl 2-(pyridin-2-yl)malonate (5)
CuI (0.465 g, 2.44 mmol) was added to 2-iodopyridine (10 g,
48.78 mmol), diethyl malonate (15.63 g, 97.56 mmol), picolinic
acid (0.601 g, 4.88 mmol) and Cs2CO3 (47.7 g, 146.34 mmol) in
1,4-dioxane (60 mL) under an atmosphere of nitrogen. The result-
ing suspension was heated to 70 °C and stirred for 16 h. The reac-
tion mixture was allowed to cool to ambient temperature and was
partitioned between EtOAc (300 mL) and saturated NH4Cl
(100 mL). The aqueous phase was separated and extracted with
EtOAc (200 mL). The organic extracts were combined, dried over
MgSO4 and reduced to give an oil, which was purified by flash silica
chromatography, elution gradient 0–40% EtOAc in heptane to af-
ford diethyl 2-(pyridin-2-yl)malonate (5) (9.53 g, 82%) as an or-
Example procedure for the decarboxylation. Preparation of 3-
(pyridin-2-yl)propan-1-ol (7f)
ange oil; 1H NMR (DMSO-d6, 400 MHz):
d (ppm) 1.17 (t,
2 M NaOH (1.510 mL, 3.02 mmol) was added to diethyl 2-[2-
(tert-butyldimethylsilyloxy)ethyl]-2-(pyridin-2-yl)malonate (6f)
(239 mg, 0.60 mmol), in MeOH (5 mL). The resulting mixture was
stirred at ambient temperature for 16 h. The solution was acidified
J = 7.1 Hz, 6H), 4.16 (qd, J = 7.1, 1.2 Hz, 4H), 5.07 (s, 1H), 7.35
(ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 7.4–7.45 (m, 1H), 7.82 (td, J = 7.7,
1.8 Hz, 1H), 8.51 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H); 13C NMR
(176 MHz, DMSO-d6, 30 °C) 13.82, 59.63, 61.30, 123.04, 123.86,

3856
C. Donald, S. Boyd / Tetrahedron Letters 53 (2012) 3853–3856
to pH 4 by addition of 1 M citric acid. The resulting mixture was
heated to 60 °C and stirred overnight. The solution was allowed
to cool to ambient temperature before MeOH was removed by
evaporation. The residue was basified to pH 14 with 2 M NaOH.
This aqueous mixture was extracted with CH2Cl2 (2 Â 25 mL).
The organic extracts were combined, dried over MgSO4 and evap-
orated to give 3-(pyridin-2-yl)propan-1-ol (7f) (75 mg, 90%) as an
oil; 1H NMR (CDCl3, 400 MHz): d (ppm) 1.95–2.04 (m, 2H), 2.96–
3.01 (m, 2H), 3.72 (t, J = 5.8, 2H), 7.13 (ddd, J = 7.4, 4.9, 1.0 Hz,
1H), 7.19 (d, J = 7.8 Hz, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 8.47–
8.53 (m, 1H), OH not seen; 13C NMR (101 MHz, CDCl3, 30 °C)
31.78, 35.18, 62.12, 121.22, 123.25, 136.92, 148.60, 161.49; HRMS
(ESI): MH+, found 138.09119, C8H12ON requires 138.09134.
References and notes
1. McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348–
1349.
2. Kanemura, S.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Synthesis 2008, 2659–
2664.
3. Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794–1798.
4. Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5079–5082.
5. Kaiser, E. M.; Thomas, W. R.; Synos, T. E.; McClure, J. R.; Mansour, T. S.; Garlich,
J. R.; Chastain, J. E., Jr. J. Organomet. Chem. 1981, 213, 405–417.
6. Sliwa, H.; Randria-Raharimanana, C. J. Heterocycl. Chem. 1989, 26, 1569–1574.
7. Colbon, P. J. J.; Foster, A. C.; Giles, M. E.; Patel, Z.; Singleton, J. T. J. Heterocycl.
Chem. 2008, 45, 1451–1456.
8. Kamogawa, H.; Kasai, T.; Andoh, T.; Nakamura, T. Bull. Chem. Soc. Jpn. 1987, 60,
2905–2909.
9. Leahy, D. K.; Li, J.; Sausker, J. B.; Zhu, J.; Fitzgerald, M. A.; Lai, C.; Buono, F. G.;
Braem, A.; de Mas, N.; Manaloto, Z.; Lo, E.; Merkl, W.; Su, B.; Gao, Q.; Ng, A. T.;
Hartz, R. A. Org. Process Res. Dev. 2010, 14, 1221–1228.
Acknowledgments
10. Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469–3472.
11. Belomestnykh, I. P.; Isaguliants, G. V. Catal. Today 2009, 142, 192–195.
12. Nunez, A.; Abarca, B.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. J. Org. Chem.
2009, 74, 4166–4176.
13. Amengual, R.; Michelet, V.; Genet, J. Tetrahedron Lett. 2002, 43, 5905–5908.
14. Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem.
Soc. 2001, 123, 5358–5359.
We would like to thank Prof. Joe Sweeney for discussions and
helping to plan the scope of this work. We would also like to thank
Peter Barton, Howard Beeley, Paul Davey and Madeleine Vickers for
analytical support.
15. Iglesias, B.; Alvarez, R.; de Lera, A. R. Tetrahedron 2001, 57, 3125–3130.
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.049.