Efficient and convenient preparation of 3-aryl-2,2-dimethylpropanoates via Negishi coupling

Article abstract of DOI:10.1039/b902779c

An efficient and convenient Negishi coupling protocol was developed for the preparation of 3-aryl-2,2-dimethylpropanoates providing easy access to key pharmaceutical intermediates that often require multi-step synthesis using conventional enolate chemistr

Full text of DOI:10.1039/b902779c

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Efficient and convenient preparation of 3-aryl-2,2-dimethylpropanoates
via Negishi couplingw
Young-Shin Kwak,*a Aaron D. Kanter,a Bing Wangb and Yugang Liuc
Received (in Cambridge, UK) 10th February 2009, Accepted 5th March 2009
First published as an Advance Article on the web 23rd March 2009
DOI: 10.1039/b902779c
An efficient and convenient Negishi coupling protocol was
developed for the preparation of 3-aryl-2,2-dimethylpropanoates
providing easy access to key pharmaceutical intermediates that
often require multi-step synthesis using conventional enolate
chemistry.
2,2-Dimethylpropanoic acids are common structural motifs in
small molecule drug discovery, particularly in targeting nuclear
hormone receptors.1 Their prevalence may be attributed to the
ability of the geminal methyl groups to shield or add steric
bulk to carboxylic acids. Two examples2 of 3-aryl-2,2-
Fig. 2 Conventional syntheses of 3-aryl-2,2-dimethylpropanoates.
dimethylpropanoates in late stage drug development are
shortcomings described above, we envisioned a direct C–C
coupling5 of two commercially or readily available alkyl
halides (Method C in Fig. 3). The zinc-homoenolate 2,6 readily
derived from 1,7 is known as an air-stable white crystalline
material but few examples report the functionalization of its
hindered neopentyl position despite an abundance of known
examples using zinc-homoenolates for Negishi coupling
reactions.8 Herein we report our studies on a Negishi coupling
reaction using 2 as the key reaction intermediate for preparation
of 3-aryl-2,2-dimethylpropanoates.
shown in Fig. 1.
Conventional syntheses of 2,2-dimethyl-3-arylpropanoates
involve ester enolate alkylation approaches as depicted in
Fig. 2, i.e., an exhaustive alkylation approach (Method A)3
or a C2–C3 bond formation strategy (Method B).4 Each
method has inherent limitations. For instance, the exhaustive
alkylation of unsubstituted enolates (Method A) can rarely be
driven to completion and the remaining mono-alkylation
adducts are often very difficult to separate during purification.
Alkylation of tetrasubstituted enolates (Method B),
meanwhile, depends upon the accessibility of the benzylic
halides. Diverse heteroarylmethyl halides, in particular, are
not readily available from commercial sources.
To develop a viable one-step protocol, the zinc-homoenolate
2 was generated in situ by treating 1 with excess Zn–Cu couple
following Yamamoto’s procedure.9 Formation of 2 was
monitored by TLC observing the consumption of 1. 1 was
not detectable by TLC after heating at 110 1C for 3 h and the
heating was continued for an additional 3 h to ensure complete
formation of 2. The reaction mixture was then treated with
2-bromo-4-methylpyridine and 3 mol% Pd(PPh3)4 at 70 1C to
provide the desired Negishi coupling product 3 in 93%
yield (Scheme 1).z We discovered that formation of the zinc-
homoenolate intermediate is more efficient with the iodide 1
Prompted by the need to develop an alternative synthesis
of 2,2-dimethyl-3-arylpropanoates that would address the
Fig. 1 Drug development candidates bearing 3-aryl-2,2-dimethyl-
propanoates.
a Global Discovery Chemistry, Novartis Institutes for BioMedical
Research, 100 Technology Sq., Cambridge, MA 02139, USA.
E-mail: youngshin.kwak@novartis.com; Fax: +1-617-871-7044;
Tel: +1-617-871-7538
b Analytical Sciences, Institutes for BioMedical Research,
100 Technology Sq., Cambridge, MA 02139, USA
c Chemical Development, Novartis Pharmaceutical Corporation,
One Health Plaza, East Hanover, NJ 07936, USA
w Electronic supplementary information (ESI) available: Charac-
terization spectral data for all compounds described. See DOI:
10.1039/b902779c
Fig.
3
The envisioned direct C–C coupling method and the
zinc-homoenolate 2.
ꢀc
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Chem. Commun., 2009, 2145–2147 | 2145

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Scheme 1
Scheme 2
Mukayama aldol reaction followed by a reductive deoxygena-
tion. Negishi coupling with 2-chloro-4-methoxypyridine and 1
afforded 4 in one step in 62% yield (Scheme 2), which
demonstrates the convenience of our coupling strategy.
Investigation of other coupling partners revealed that
this coupling method appears quite general with diverse
Table
methyl esters via Negishi coupling
1
Preparation of 2,2-dimethyl-3-pyridinylpropionic acid
Entry Hetero-ArBra
Product
Yield (%)b
Table 2 Preparation of 2,2-dimethyl-3-heteroarylpropionic acid
methyl esters via Negishi coupling
1
92
2
3
93
72
Entry Hetero-ArCla
Products
Yield (%)b
98
5
6
7
8
9
73
78
61
49
4
(20)c
a
b
0.74 equiv. of the aryl halides were used relative to iodide. Yields
c
are isolated yields. Not isolated. Reaction failed to proceed after
ca. 20% conversion detected by LC-MS.
than the bromide 6 which required two days under the same
reaction conditions.10
Encouraged by this result, we further examined the Negishi
coupling reaction with 2-halopyridines and the results are
summarized in Table 1. The Negishi coupling was efficient
for most substrates examined thus far, suggesting that their
steric or electronic nature was of minimal influence on the
outcome of the reaction. In the case of 4-amino-2-bromo-
pyridine (entry 4), despite several additions of the Pd catalyst,
the reaction stalled at 20% conversion, presumably due to
unproductive binding of amino group to the Pd catalyst.
To illustrate the efficiency of our system, we recognized the
utility of 4 to prepare a set of imidazopyridine derivatives
for the treatment of ulcers.11 This intermediate is prepared in
ca. 47% overall yield via a multi-step synthesis featuring a
10
73
75
11
a
0.74 equiv. of aryl halide was used with respect to the starting
b
iodide. All the yields are isolated yields.
ꢀc
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N. Miyata, Chem. Pharm. Bull., 2007, 55(7), 1053–1059;
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M. Labelle, D. Mcminn, J. Powers, Y. Rew, D. Sun and X. Yan,
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2 MK-886: H. Chang, C. Huang, H. Cheng, T. Lu, J. Wang, K. Lin,
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Res., 2008, 69(2), 49–57. ZD-1611: R. Bradbury, R. Butlin and
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3 M. Gallant, N. Chauret, D. Claveau, S. Day, D. Deschenes,
D. Dube, Z. Huang, P. Lacombe, F. Laliberte, J. F. Levesque,
S. Liu, D. Macdonald, J. Mancini, P. Masson, A. Mastracchio,
D. Nicholson, D. Nicoll-Griffith, H. Perrier, M. Salem, A. Styhler,
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1407–1412.
4 (a) Y. Nishimoto, M. Yasuda and A. Baba, Org. Lett., 2007, 9(24),
4931–4934; (b) R. Mueller, J. Yang, C. Duan, E. Pop, O. Geoffroy,
L. Zhang, T. Huang, S. Denisenko, B. McCosar, D. Oniciu,
C. Bisgaier, M. Pape, C. Freiman, B. Goetz, C. Cramer,
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5 A C–C coupling reaction of dimethylpropanoic acid with
arylboronates via C–H activation: R. Giri, N. Maugel, J. Li,
D. Wang, S. Breazzano, L. Saunders and J. Yu, J. Am. Chem.
Soc., 2007, 129(12), 3510–3511.
Scheme 3
heterocyclic electrophiles (Table 2). The coupling tolerated a
wide range of substituents including electron withdrawing
trifluoromethyl group and electron donating morpholine
group in good yields (49–98%). We observed a regioselective
(97% by 1H-NMR) alkylation on C-4 with 2,4-dichloro-
pyrimidine (entry 8). Finally, the Negishi coupling of 1 and
3-bromobenzaldehyde occurred smoothly to provide 5 in 86%
yield as shown in Scheme 3. This example attests to the utility
of the coupling protocol in synthesizing 2,2-dimethylpropano-
ates that are not readily accessible via enolate chemistry.
In summary, we have developed a convenient Negishi
coupling method using the zinc-homoenolate 2. We anticipate
that this new protocol will provide a very useful synthetic
strategy in medicinal chemistry for synthesis of 2,2-dimethyl-
3-arylpropanoates. Negishi coupling reactions with amides or
diversely substituted analogues of 1 are being investigated and
will be reported in due course.
6 H. Tsurugi, T. Ohno, T. Yamagata and K. Mashima, Organo-
metallics, 2006, 25(13), 3179–3189.
7 (a) E. Bouey, C. Masson and K. Bertrand, Fr. Demande, 2008, FR
2903984; (b) D. A. Claremon and N. Liverton, US Pat., 1995, US
5389631.
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aminoacids: M. Kruppa, G. Imperato and B. Koenig, Tetrahedron,
2006, 62(7), 1360–1364; (b) An example of Negishi coupling for
synthesis of 3-arylpropanoates: T. Sakamoto, S. Nishimura,
Y. Kondo and H. Yamanaka, Synthesis, 1988, 6, 485–486; (c) A
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Notes and references
z General procedure for the Negishi coupling. Preparation of 3: A
suspension of Zn–Cu couple (3.45 g) in toluene–DMA (13 : 1,
30 mL) was degassed by bubbling N2 into the system for 15 min.
Iodide 1 (2.21 g, 9.14 mmol) was added to the suspension, and the
resulting mixture heated at 110 1C for 6 h. The reaction mixture was
allowed to cool to 70 1C and 2-bromo-4-methylpyridine (751 uL,
6.77 mmol) and Pd(PPh3)4 (235 mg, 0.203 mmol) were added. The
reaction mixture was maintained at 70 1C for 22 h. Upon cooling, the
mixture was filtered, and the filter cake rinsed with Et2O. The filtrate
was extracted with 1 M HCl (2 ꢁ 75 mL). The acidic extracts were
basified by addition of NaHCO3, and the resulting solution extracted
with Et2O (2 ꢁ 75 mL). The combined organics were dried over
Na2SO4 and the solvent evaporated to yield 3 (1.31 g, 6.32 mmol,
93%) as an oil which was pure by NMR and HPLC. 1H NMR
(400 MHz, CD2Cl2): d ppm 1.19 (s, 6 H), 2.32 (s, 3 H), 3.00
(s, 2 H), 3.63 (s, 3 H), 6.94 (s, 1 H), 6.99 (d, J = 4.93 Hz, 1 H), 8.32
(d, J = 5.05 Hz, 1 H); 13C NMR (100 MHz, CD2Cl2): d ppm 21.23,
25.51, 43.46, 48.54, 51.99, 122.84, 125.46, 147.51, 149.13, 158.86,
10 Bromozinc-homoenolate formation with Zn–Cu couple:
11 R. Boer, W. R. Ulrich, M. Eltze, D. Marx, U. Graedler and
T. Fuchss, PCT Int. Appl., 2005, WO 2005030768. An example is
shown below:
178.17; FT-IR (CH2Cl2): 1728, 1605 cmꢂ1
C12H18NO2 [M + H]+: 208.1337, found 208.1336.
; HRMS calcd for
1 For examples in PPAR research: (a) S. Usui, H. Fujieda, T. Suzuki,
N. Yoshida, H. Nakagawa, M. Ogura, M. Makishima and
ꢀc
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Chem. Commun., 2009, 2145–2147 | 2147