Preparation of a series of aryl isonipecotic acids using microwave irradiation

Article abstract of DOI:10.1081/SCC-120021042

Rapid parallel synthesis of arylisonipecotic acids was achieved using microwave irradiation of a palladium catalyzed amination reaction.

Full text of DOI:10.1081/SCC-120021042

This article was downloaded by: [University of California, San Diego]
On: 13 June 2013, At: 02:29
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Preparation of a Series of Aryl Isonipecotic Acids Using
Microwave Irradiation
Schuyler Antane a
a Chemical Sciences, Wyeth Research, Princeton, New Jersey, USA
Published online: 17 Aug 2006.
To cite this article: Schuyler Antane (2003): Preparation of a Series of Aryl Isonipecotic Acids Using Microwave Irradiation,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:12,
2145-2149
To link to this article: http://dx.doi.org/10.1081/SCC-120021042
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,
proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2145–2149, 2003
Preparation of a Series of Aryl Isonipecotic Acids
Using Microwave Irradiation
*
Schuyler Antane
Chemical Sciences, Wyeth Research, Princeton,
New Jersey, USA
ABSTRACT
Rapid parallel synthesis of arylisonipecotic acids was achieved using
microwave irradiation of a palladium catalyzed amination reaction.
Aryl isonipecotic acids (3) are useful intermediates in the preparation
of a wide range of potential drug agents such as anticoagulants,[1] platelet
aggregation inhibitors,[2] fibrinogen receptor antagonists,[3] antimicrobial
agents,[4] neuropeptide Y antagonists,[5] and serotoninergic/dopaminergic
receptor antagonists.[6] These isonipecotic intermediates are generally
prepared by aromaticnucleophilicsubstitution that requires the presence
of an electron withdrawing (NO2, COOR) group on the aromaticring.
Alternatively, displacement of pyridinium salts[6] allows for the presence
*Correspondence: Schuyler Antane, Chemical Sciences, Wyeth Research, CN
8000, Princeton, NJ 08543-8000, USA; E-mail: antanes@wyeth.com.
2145
DOI: 10.1081/SCC-120021042
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2146
Antane
of electron releasing groups, but overall yield is low due to the difficulty
in reducing the pyridinium salts to piperidines. Generation of aryl amines
by coupling of simple amines and variously substituted aryl bromides
using palladium catalysis has been established by Guram et al.[7] and
Louie and Hartwig.[8]
Recently Hallberg and Larhed[9] have utilized a method for micro-
wave assistance in several palladium-catalyzed reactions (Heck, Stille and
Suzuki coupling) for combinatorial synthesis and the production of
chemical libraries. So far, however, there have been no reports on the
Buchwald-Hartwig[10] reactions facilitated by microwave irradiation.
Described below is a palladium catalyzed coupling of an amino ester
(1) with aryl bromides (2a–g) effected in a minimum of solvent using
microwave irradiation.
The reactions are shown in Sch. 1 and results are summarized in
Table 1. Multiple parallel reactions were conveniently assembled using
the 36-position high throughput accessory (CEM Corp.). The number of
vessels used in the microwave carousel did not adversely affect product
yields or reaction time as long as temperature was controlled via a fiber
optic probe. Also scale up of a single reaction is possible by utilizing several
Scheme 1.
Table 1. Preparation of aryl isonipecotic acids.
Compound 3
X
Y
Yield (%)
a
b
c
d
e
f
4-CF3
3-CN
3-F
H
H
50
55
35
53
45
52
45
5-F
3-CF3
2-F
5-CF3
5-CH3
H
2-OCH3
2-CH3
g
H

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Aryl Isonipecotic Acids
2147
vessels with the same reagents. The resultant oily esters were hydrolyzed to
the corresponding acids (3a–g) as solids for characterization.
EXPERIMENTAL
Microwave irradiations were carried out using a CEM MDS 2000
microwave instrument equipped with a fiber optic temperature probe and
a high throughput accessory (carousel of 36 ꢀ 50 mL centrifuge tubes).
1H NMR spectra (400 MHz) were recorded in d6-DMSO using a Varian
Unity plus spectrometer. Mass spectra were recorded on a MAT900 icis
8.2.1. Aryl bromides (2a–g) and isonipecotic acid ethyl ester were
commercially available from Aldrich.
General Procedure
A
mixture of BINAP (100 mg, 3 mol%), NaOtBu (600 mg,
6.06 mmol), Pd2(dba)3 (50 mg, 1 mol%), ethyl isonipecotate (880 mg,
5.60 mmol) and aryl bromide (5.00 mmol) are diluted with toluene to
a total volume of 10 mL in a 50 mL centrifuge tube. Each tube is
agitated and placed into the high throughput carousel and irradiated
at 750 W in three stages of 40 min each (maximum temperature allowed
110ꢁC). The crude mixture was absorbed onto silica gel and subjected
to flash column chromatography (hexane/ethyl acetate). The oily ester
product (2 mmol) was then hydrolyzed in THF (28.8 mL) and methanol
(7.2 mL) with 1 N KOH (2.4 mL). After acidification to pH 5 and
removal of solvents under reduced pressure, the residue was diluted
with water. Final products were isolated by vacuum filtration, rinsed
with water, and dried in vacuo.
1-(4-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3a). M.p.
198ꢁC (dec). 1H NMR (d6-DMSO) ꢀ: 1.53–1.63 (m, 2H), 1.85–1.89
(m, 2H), 2.43–2.48 (m, 1H), 2.87–2.93 (m, 2H), 3.75–3.80 (m, 2H), 7.03
(d, 2H, J ¼ 8.8 Hz), 7.46 (d, 2H, J ¼ 9.0 Hz), 12.23 (br s, 1H). MS
(APCIþ): 315 [100%, M þ CH3CN þ H], 274 [50%, M þ H]þ. Anal.
calcd. for C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.35;
H, 5.17; N, 5.00.
1-(3-Cyano-phenyl)-piperidine-4-carboxylic acid (3b). M.p. 150–152ꢁC.
1H NMR (d6-DMSO) ꢀ: 1.53–1.63 (m, 2H), 1.84–1.89 (m, 2H), 2.39–2.47
(m, 1H), 2.79–2.86 (m, 2H), 3.70–3.76 (m, 2H), 7.10 (d, 1H, J ¼ 7.25 Hz),

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2148
Antane
7.24–7.26 (m, 1H), 7.30–7.37 (m, 2H), 12.23 (br s, 1H). MS (APCIþ): 231
[100%, M þ H]þ. Anal. calcd. for C13H14N2O2: C, 67.81; H, 6.13; N,
12.17. Found: C, 68.07; H, 6.25; N, 11.8.
1-(3,5-Difluoro-phenyl)-piperidine-4-carboxylic acid (3c). M.p.
138–140ꢁC. H NMR (d6-DMSO) ꢀ: 1.53–1.60 (m, 2H), 1.82–1.86 (m,
1
2H), 2.40–2.48 (m, 1H), 2.80–2.87 (m, 2H), 3.66–3.71 (m, 2H),
6.38–6.44(m, 1H), 6.55–6.62 (m, 2H), 12.23 (s, 1H). MS (APCIþ): 242
[100%, M þ H]þ. Anal. calcd. for C12H13F2NO2: C, 59.75; H, 5.43;
N, 5.81. Found: C, 59.87; H, 5.54; N, 5.77.
1-(3,5-bis-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3d).
M.p. 166–168ꢁC. H NMR (d6-DMSO) ꢀ: 1.55–1.65 (m, 2H), 1.88–1.92
1
(m, 2H), 2.43–2.50 (m, 1H), 2.90–2.97 (m, 2H), 3.83–3.88 (m, 2H), 7.25 (s,
1H), 7.44 (s, 2H), 12.25 (br s, 1H). MS (APCIþ): 340 [100%, M ꢂ H]þ.
Anal. calcd. for C14H13F6NO2: C, 49.28; H, 3.84; N, 4.10. Found:
C, 49.40; H, 3.99; N, 4.10.
1-(2-Fluoro-5-methyl-phenyl)-piperidine-4-carboxylic acid (3e). M.p.
108–110ꢁC. 1H NMR (d6-DMSO) ꢀ: 1.62–1.66 (m, 2H), 1.88–1.92
(m, 2H), 2.23 (s, 3H), 2.31–2.39 (m, 1H), 2.65–2.71 (m, 2H), 3.24–3.29
(m, 2H), 6.70–6.74 (m, 1H), 6.80–6.83 (m, 1H), 6.93–6.98 (m, 1H), 12.20
(s, 1H). MS (APCIþ): 238 [100%, M þ H]þ. Anal. calcd. for
C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.63; H, 6.73;
N, 5.77.
1-(2-Methoxy-phenyl)-piperidine-4-carboxylic
acid
(3f ).
M.p.
129–131ꢁC. 1H NMR (d6-DMSO) ꢀ: 1.65–1.72 (m, 2H), 1.85–1.89
(m, 2H), 2.29–2.33 (m, 1H), 2.53–2.60 (m, 2H), 3.25–3.30 (m, 2H), 3.76
(s, 3H), 6.84–6.92 (m, 4H), 12.15 (s, 1H). MS (APCIꢂ): 234 [100%,
M ꢂ H]þ. Anal. calcd. for C15H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.04; H, 7.34; N, 5.81.
1-o-Tolyl-piperidine-4-carboxylic acid (3g). M.p. 156–158ꢁC.
1H NMR (d6-DMSO) ꢀ: 1.65–1.75 (m, 2H), 1.88–1.92 (m, 2H), 2.21 (s,
3H), 2.30–2.37 (m, 1H), 2.57–2.63(m, 2H), 2.98–3.02 (m, 2H), 6.90–6.98
(m, 2H), 7.09–7.14 (m, 2H), 12.19 (br s, 1H). MS (APCIþ): 220 [100%,
M þ H]þ. Anal. calcd. for C15H17NO2: C, 71.21; H, 7.81; N, 6.39. Found:
C, 71.58; H, 7.99; N, 6.30.
NOTE ADDED IN PROOF
Since completion of this work, a report has appeared by Wan, Y.;
Alterman, M.; Hallberg, A. Palladium-catalyzed amination of aryl
bromides using temperature controlled microwave heating. Synthesis,
2002, (11), 1597–1600.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Aryl Isonipecotic Acids
2149
ACKNOWLEDGMENT
Physical analysis provided by Discovery Analytical Chemistry.
REFERENCES
1. Arnaiz, D.O.; Griedel, B.D.; Sakata, S.T.; Shaw, K.J.; Zhao, Z.
Preparation and Formulation of Naphthyl-Substituted
Benzimidazole Derivatives as Anticoagulants. WO 9,721,437, June
19, 1997.
2. Ujiie, S.; Harada, H.; Iyobe, A.; Uchida, M.; Kamata, K.
Preparation of Piperidinoquinoline Derivatives as Blood Platelet
Aggregation Inhibitors. JP 06,298,756, October 25, 1994.
3. Bondinell, W.E.; Ku, T.W. Fibrinogen Receptor Antagonists. WO
9,619,475, June 27, 1996.
4. Yamada, H.; Munesada, K.; Taniguchi, M. Preparation of
(Piperidinophenyl)oxazolidinone Derivatives as Antimicrobial
Agents. WO 9,525,106, September 21, 1995.
5. Fukami, T.; Fukuroda, T.; Kanatani, A.; Ihara, M. Preparation of
Novel Aminopyrazole Derivatives as Neuropeptide Y Antagonists.
WO 9,825,908, June 18, 1998.
6. Kerrigan, F.; Heal, D.J.; Martin, K.F. Preparation of Aromatic
Bicyclic Heterocyclic Compounds as Serotoninergic and
Dopaminergic Receptor Antagonists. WO 9,507,274, March 16,
1995.
7. Guram, A.S.; Rennels, R.A.; Buchwald, S.L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348.
8. Louie, J.; Hartwig, J.F. Tetrahedron Lett. 1995, 36, 3609.
9. Lindeberg, G.; Larhed, M.; Hallberg, A. Method for Organic
Reactions-Transition Metal Catalyzed Organic Reactions. WO
9,743,230, November 20, 1997; Larhed, M.; Hallberg, A. J. Org.
Chem. 1996, 61, 9582.
10. Rossen, K.; Pye, P.J.; Maliakal, A.; Volante, R.P. J. Org. Chem.
1997, 62, 6462; MacNeil, S.L.; Gray, M.; Briggs, L.E.; Li, J.J.;
Snieckus, V. Synlett. 1998, 419.
Received in the USA October 28, 2002

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.