Preparation of tertiary benzylic nitriles from aryl fluorides [1]

Full text of DOI:10.1021/ja9933846

712
J. Am. Chem. Soc. 2000, 122, 712-713
Communications to the Editor
Preparation of Tertiary Benzylic Nitriles from Aryl
Fluorides
Table 1. Nucleophilic Aromatic Substitution of 1a with 2a
St e´ phane Caron,* Enrique Vazquez, and Jill M. Wojcik
Process Research and DeVelopment, Central Research
DiVision, Pfizer Inc., 8156-084 Eastern Point Road
Groton, Connecticut 06340
a
entry base (1.5 equiv) solvent T (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
Cs
LDA
t-BuOK
LiHMDS
NaHMDS
KHMDS
2
CO
3
THF
THF
THF
THF
THF
THF
75
RT
70
60
60
60
70
60
75
75
75
24
<1
24
23
23
23
45
18
24
24
24
no reaction
decomp
decomp
ReceiVed September 20, 1999
3
49
95
82
N
Nucleophilic aromatic substitution (S Ar) of aryl halides has
been used extensively for the elaboration of complex molecules
from simple starting materials.1 Fluoride ion has received much
,2
KHMDS/18-C-6 THF
attention as a leaving group and is generally accepted as the best
KHMDS
KHMDS
KHMDS
KHMDS
toluene
DMSO
95
,4
halide in the S
N
Ar reaction.3 While sulfur, nitrogen, and oxygen
no reaction
nucleophiles have been studied in great detail, there are fewer
reports on the use of carbon nucleophiles, such as nitrile anions,
in this reaction. For instance, it has been reported that the anion
of diphenylacetonitrile reacts with 4-fluoronitrobenzene under
10
11
i-Pr O
3
1
2
NMP
a
Yields < 5% indicate the conversion observed by HPLC analysis
after the time shown. The yields of entries 1, 2, 7, and 8 are isolated
yields.
5
phase transfer catalysis, that the anion of phenylacetonitrile reacts
6
with 2-fluorocyanobenzene, and that the enolate of ethyl cyano-
7,8
acetate adds to either 4-fluoronitrobenzene or hexafluoroben-
aldehydes,21,22 carboxylic acids,23 and esters.24,25 In general, this
9
zene. However, the addition of a nitrile anion to a fluoroarene
class of compounds has been prepared by displacement of an
activated benzylic alcohol or halide with cyanide, followed by
two successive alkylations. While studying the synthesis of a drug
candidate, which featured a tertiary benzylic nitrile, we discovered
that the addition of a secondary nitrile anion onto a fluroarene
could be achieved under mild conditions.
To study the scope and limitation of this reaction, 2-fluoro-
anisole (1a) and isobutyronitrile (2a) were chosen as a model
system. It was determined that the optimal stoichiometry required
4 equiv of nitrile (2) and 1.5 equiv of the base. While the reaction
was very slow and would not reach completion at room temper-
ature, it proceeded at an acceptable rate when heated above 60
°C in THF. As shown in Table 1, potassium was the best
counterion when a hexamethyldisilazane (HMDS) base was used
not containing another electron withdrawing group has been
achieved only when it was first activated as a tricarbonylchromium
complex.10
Tertiary benzylic nitriles have proven to be not only biologically
active compounds, e.g., verapamil and related compounds as slow
calcium channel antagonists,1
1-15
but also very important synthetic
intermediates. For example, they have been used as precursors
to bicyclic amidines,16 lactones, primary amines,
17
18,19
pyridines,
20
(
1) Zoltewicz, J. A. Top. Curr. Chem. 1975, 59, 33-64.
2) March, J. In AdVanced Organic Chemistry, 3rd ed.; John Wiley and
(
Sons: New York, 1985; pp 576-607.
(
3) Broxton, T. J.; Muir, D. M.; Parker, A. J. J. Org. Chem. 1975, 40,
3
230-3233.
(
(
4) Vaslow, V. M. J. Fluorine Chem. 1993, 61, 193-216.
5) Loupy, A.; Philippon, N.; Pigeon, P.; Sansoulet, J.; Galons, H. Synth.
3
for the reaction (entries 4-6). The use of CsCO , LDA, or t-BuOK
Commun. 1990, 20, 2855-2864.
(
6) Sommer, M. B.; Begtrup, M.; Bogeso, K. P. J. Org. Chem. 1990, 55,
817-4821.
7) Zhang, X.-M.; Yang, D.-L.; Liu, Y.-C. J. Org. Chem. 1993, 58, 224-
did not provide the desired adduct (entries 1-3), and the addition
of 1.5 equiv of 18-crown-6 to KHMDS proved to slow the
reaction which never went to completion and provided a lower
yield (from 95 to 82%) (entry 7). Toluene proved to be similar
4
2
6
2
(
27.
(
8) Makosza, M.; Podraza, R.; Kwast, A. J. Org. Chem. 1994, 59, 6796-
799.
2
to THF (entry 8), while DMSO, i-Pr O, or NMP turned out to be
(
9) Plevey, R. G.; Sampson, P. J. Chem. Soc., Perkin Trans. 1 1987, 2129-
ineffective for this transformation (entries 9-11).
136.
(
10) Rose-Munch, F.; Aniss, K.; Rose, E. J. Organomet. Chem. 1990, 385,
To establish the scope of the reaction, the nucleophilic aromatic
substitution of several fluoroarenes (1) with a few secondary
nitriles (2) was carried out. As indicated in Table 2, the reaction
proceeds on electron-rich substrates containing ethers (entries
-5). Chemoselectivity was achieved as a fluoride reacts
preferentially over a chloride, and no product resulting from the
C1-C3.
(
11) Mannhold, R. In Recent AdVances in Receptor Chemistry; Melchiorre,
C., Giannella, M., Eds.; Elsevier Science Publishers: Amsterdam, 1988; p
1
47.
(
12) Dei, S.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Chiarini, A.;
Gualtieri, F. J. Med. Chem. 1991, 34, 2219-2225.
13) Mitani, K.; Sakurai, S.; Suzuki, T.; Morikawa, E.; Kato, H.; Ito, Y.;
Fujita, T. Chem. Pharm. Bull. 1988, 36, 4121-4135.
14) Christensen, S. B.; Guider, A.; Forster, C. J.; Gleason, J. G.; Bender,
1
(
(
(19) Okatani, T.; Koyama, J.; Tagahara, K. Heterocycles 1989, 29, 1809-
1814.
P. E.; Karpinski, J. M.; DeWolf, W. E., Jr.; Barnette, M. S.; Underwood, D.
C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.; Bochnowicz, S.; Osborn,
R. R.; Manning, C. D.; Grous, M.; Hillegas, L. M.; O’Leary Bartus, J.; Ryan,
M. D.; Eggleston, D. S.; Haltiwanger, R. C.; Torphy, T. J. J. Med. Chem.
(20) Chelucci, G.; Giocomeli, G.; Scano, G. Gazz. Chim. Ital. 1991, 121,
107-108.
(21) Pascal, C.; Dubois, J.; Gu e´ nard, D.; Tchertanov, L.; Thoret, S.; Gu e´ ritte,
F. Tetrahedron 1998, 54, 14737-14756.
1
998, 41, 821-835.
(
(
15) Theodore, L. J.; Nelson, W. L. J. Org. Chem. 1987, 52, 1309-1315.
(22) Chavan, S. P.; Ravindranathan, T.; Patil, S. S.; Dhondge, V. D.;
Dantale, S. W. Tetrahedron Lett. 1996, 37, 2629-2630.
(23) Leader, H.; Smejkal, R. M.; Payne, C. S.; Padilla, F. N.; Doctor, B.
P.; Gordon, R. K.; Chiang, P. K. J. Med. Chem. 1989, 32, 1522-1528.
(24) Bush, E. J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1997, 3531-
3536.
16) Convery, M. A.; Davis, A. P.; Dunne, C. J.; MacKinnon, J. W.
Tetrahedron Lett. 1995, 36, 4279-4282.
(
17) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D. Tetrahedron 1990,
4
6, 7139-7150.
(
18) Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankey, C. J.; Roark, W.
H.; Picard, J. A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.; Krause, B.
(25) Breukelman, S. P.; Meakins, G. D.; Roe, A. M. J. Chem. Soc., Perkin
Trans. 1 1985, 1627-1635.
R. J. Med. Chem. 1993, 36, 3300-3307.
1
0.1021/ja9933846 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/12/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 713
Table 2.
N
S Ar of Aryl Fluorides with Secondary Nitriles and
KHMDS
Figure 1. Chem3D representation of 3n and 3o obtained from X-ray
nitrile
T
yield
(%)
crystal structure.
entry
1
fluoride
(equiv) solvent (°C)
time
3 h
1a, 2-OMe
1b, 3-OMe
1c, 4-OMe
2a (4.0) toluene
2a (4.1) toluene 100
2a (4.0) THF
60 18 h
3a, 95
3b, 69
3c, 66
3d, 85
3e, 28
3f, 77
3g, 72
3h, 69
3i, 71
3j, 83
2
3
4
5
6
7
8
9
0
1
2
3
4
5
60 50 h
70 48 h
80 4 h
60 45 min
75 2 h
75 14 h
75 14 h
60 40 min
1d, 3,5-OMe 2a (4.0) toluene
1e, 3,4-OMe 2a (4.0) THF
Figure 2. Proposed mechanism for the addition of secondary nitriles to
fluoroarenes.
1f, 2-Cl
1g, 4-Cl
1h, H
1i, 3-Me
1j, 4-CN
2a (4.0) toluene
2a (4.0) THF
2a (4.0) THF
2a (4.0) THF
2a (4.0) toluene
2a (3.3) toluene
2a (3.9) toluene
2b (4.0) toluene
2c (4.0) THF
2d (4.0) THF
isovaleronitrile with 2-fluoroanisole all led to decomposition.
Furthermore, it appears as though the starting material must be a
nitrile since the addition of either N,N-2-trimethylpropionamide,
methyl isobutyrate, or 2,4-dimethyl-3-pentanone did not proceed.
The chemistry described is operationally straightforward. To
a solution of the aryl fluoride 1 in THF or toluene (0.3-0.8 M
final concentration) were added nitrile 2 (3.3-4.1 equiv) and
KHMDS (1.5 equiv). For the reactions in THF solid KHMDS
was used, while a 0.5 M toluene solution of base was employed
for the reactions in toluene. The reaction mixture was stirred under
the conditions indicated in Table 2, after which it was cooled to
room temperature, poured into 1 N HClaq, and extracted with tert-
butyl methyl ether or toluene. The organic extracts were washed
1
1
1
1
1
1
1k, 4-CF
1l
3
60 40 min 3k, 94
70 10 min
75 48 h
75 24 h
75 15 h
3l, 72
1a, 2-OMe
1a, 2-OMe
1a, 2-OMe
3m, 47a
3n, 67
3o, 70a
a
Provided exclusively the 2S isomer (exo aryl).
2 4
with H O, dried over MgSO , filtered, and concentrated. The crude
product was purified either by chromatography on silica gel or
by recrystallization to afford the desired product 3. In the case of
displacement of the chloride was observed (entries 6 and 7). The
reaction can also be carried on fluorobenzene (entry 8) or
3
-fluorotoluene (entry 9). In the case of 4-fluorobenzonitrile,
3e (entry 5), preparative HPLC was necessary in order to obtain
displacement of the fluoride was observed exclusively, and
addition to the benzonitrile did not occur (entry 10). In the
presence of an arene containing an electron-withdrawing group
material of analytically pure quality, which is partially reflected
in the low yield reported (28%).
(
entries 10 and 11) or a 2-fluoropyridine (entry 12), the reaction
A potential mechanism for the reaction is presented in Figure
2. It is possible that as the addition to the arene proceeds,
coordination of the potassium with the developing negative charge
occurs. Electron-rich arenes could also facilitate the coordination
of the metal prior to addition of the anion. As the product nitrile
is generated, cleavage of the nitrogen-potassium bond allows
for the generation of a potassium-arene complex, which subse-
quently eliminates to provide the desired product.
In summary, an efficient method for the addition of secondary
nitriles to fluoroarenes has been demonstrated. The reaction is
specific to KHMDS but proceeds on a variety of substrates,
allowing for a quick entry to a useful class of compounds.
was very rapid, as one would normally expect. Furthermore, the
anions of cyclopropyl cyanide (2b) (entry 13), 5-norbornene-2-
carbonitrile (2c) (entry 14), and 2-norbornanecarbonitrile (2d)
(
2
of interest since the product (3m) belongs to a class of nitrile
which has been used in the generation of imines for cyclopropyl
imine rearrangements.26 Interestingly, the addition of nitriles 2c
and 2d resulted in the exo adduct exclusively. The structures
and stereochemistry of products 3n and 3o were secured by single-
crystal X-ray crystallography.28 (Figure 1) However, there were
limitations on the structures of the nitriles which would undergo
addition. The anion must be sufficiently nucleophilic for the
aromatic substitution to proceed, since the anion of ethyl cyano-
acetate did not undergo reaction. Primary nitriles did not undergo
substitution, and reactions using either phenyl acetonitrile or
entry 15) all proceeded efficiently in the transformation with
-fluoroanisole (1a). The addition of cyclopropylcyanide (2b) is
27
Acknowledgment. We thank Dr. Jon Bordner and Ivan Samardjiev
of Pfizer Central Research for the determination of the single-crystal X-ray
structure of compounds 3n and 3o, Dr. Linda Lohr and Andrew Jensen
for the determination of the stereochemistry of the alkylation product of
2c with benzyl bromide, and Dr. Joel M. Hawkins for several helpful
(
26) Stevens, R. V. Acc. Chem. Res. 1977, 10, 193-198.
discussions.
(
27) We also demonstrated that the alkylation of nitrile 2c with benzyl
bromide using KHMDS in toluene also proceeds from the exo face, and the
Supporting Information Available: Experimental procedures and
spectral data for all compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
stereochemistry of the product was confirmed using several NMR experiments.
(28) The author has deposited atomic coordinates for structures 3n and 3o
with the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
JA9933846