Ortho lithiation of N-pivaloylfluoroanilines as a useful tool for either selective methylation or benzoxazole synthesis

Article abstract of DOI:10.1021/op0498969

Lithiation of N-pivaloyl-3,4-difluoroaniline (1a) with a slight excess of 2 mole equiv of n-butyllithium followed by methylation was studied. The reaction was found to be useful for either the selective methylation of 3,4-difluoroaniline or the synthesis of benzoxazole derivatives, depending on the reaction temperature. In the reaction of N-pivaloyl-3-chloro-4-fluoroaniline (1b) and N-pivaloyl-3-fluoroaniline (1c), the reaction proceeded rather sluggishly but benzoxazole formation predominated.

Full text of DOI:10.1021/op0498969

Organic Process Research & Development 2004, 8, 958−961
Ortho Lithiation of N-Pivaloylfluoroanilines as a Useful Tool for Either Selective
Methylation or Benzoxazole Synthesis
Yasuo Yoshida,* Yusuke Hamada, Kazuto Umezu, and Fumiya Tabuchi
Research and DeVelopment Department, Ihara Chemical Industry Co., Ltd.,
Fujikawa-cho, Ihara-gun, Shizuoka 421-3306, Japan
Abstract:
Results and Discussion
Lithiation of N-pivaloyl-3,4-difluoroaniline (1a) with a slight
excess of 2 mole equiv of n-butyllithium followed by methylation
was studied. The reaction was found to be useful for either the
selective methylation of 3,4-difluoroaniline or the synthesis of
benzoxazole derivatives, depending on the reaction temperature.
In the reaction of N-pivaloyl-3-chloro-4-fluoroaniline (1b) and
N-pivaloyl-3-fluoroaniline (1c), the reaction proceeded rather
sluggishly but benzoxazole formation predominated.
While ortho lithiation of N-protected anilines has been
studied widely, reactions of N-pivaloyl-3-halogeno (such as
3-chloro or 3-fluoro) anilines were known to form benzox-
azole derivatives as the main products via benzyne interme-
diates formed by the elimination of the halide ion.6-9 For
example, lithiation of N-pivaloyl-3,5-dichloroaniline by sec-
butyllithium at -95 °C followed by reaction with CO2 and
acidification gave a mixture of 75% of 5-chloro-2-tert-butyl-
7-benzoxazolecarboxylic acid and 25% of N-pivaloyl-4,6-di-
chloroanthranilic acid. The reaction employing tert-butyl-
lithium instead of sec-butyllithium gave 56% of the benzo-
xazolecarboxylic acid and 42% the anthranilic acid. On the
other hand, lithiation of N-(tert-butoxycarbonyl)-3,5-dichloro-
aniline with tert-butyllithium at the same temperature gave
an improved result with formation of the anthranilic acid
(65% yield).6 In these reactions, dehalogenation of the inter-
mediate carbanion and annulation to benzoxazoles mainly took
place even at a very low temperature (-95 °C). Other exam-
ples also showed benzoxazole formation as the main reaction
in similar systems.7-9 On the basis of these results, selective
ortho lithiation and alkylation of N-pivaloyl-3-halogenoani-
lines seemed to be overly difficult in contrast to the reaction
employing N-tert-butoxycarbonyl derivatives.10 However, we
conducted a feasibility study. At first N-pivaloyl-3,4-difluoro-
aniline (1a) was subjected to lithiation with 2.3 equiv of n-
butyllithium at -50 to -60 °C in THF and subsequent meth-
ylation with 1.1 mol equiv of methyl iodide at -40 to -55
°C. Then the mixture was warmed and stirred at room tem-
perature for 2 h and finally worked up. To our pleasant sur-
prise, recrystallization of the crude product gave 77% of pure
N-pivaloyl-2-methyl-3,4-difluoroaniline (3a). None of its re-
gioisomer or N-methylation product was observed, but 14.4%
of 2-tert-butyl-6-fluoro-7-methylbenzoxazole (8a) was formed
as the main byproduct (Scheme 1). We further studied the
effects of reaction temperature and differing halogen substit-
uents at the 3- and 4-position. These results are summarized
in Table 1.
Introduction
During the course of our study on the synthesis of recently
developed fluoroquinoline antimicrobial agents, 2-methyl-3,4-
difluoroaniline was found to be an important starting mater-
ial.1-3,5 But preparation of this compound was difficult
because of the unavailability of the aromatic raw material
having a methyl group at the desired position, and methodol-
ogy for the selective introduction of the methyl group is lim-
ited. If there was a suitable method for the selective intro-
duction of the methyl group at the ortho position of 3,4-di-
fluoroaniline, the desired compound could be obtained via
fewer reaction steps at a lower cost. In the literature, lithiation
is reported to be a useful tool for the regioselective intro-
duction of alkyl groups or other electrophiles onto aromatic
rings.4 Thus, 2-methyl-3,4-difluoroaniline recently was re-
ported to be obtained via lithiation and methylation of 3,4-
difluoroaniline protected by the tert-butoxycarbonyl group.5
However, di-tert-butyldicarbonate as the N-protecting agent
and tert-butyllithium as the lithiation agent were necessary,
but both of them were not suitable for industrial synthesis
because of their cost, availability, and difficulty in handling.
Thus we studied an alternative method for protecting 3,4-
difluoroaniline followed by ortho lithiation and alkylation.
One of the choices considered was to utilize pivaloyl chloride
as the protecting agent and n-butyllithium as the base instead
of di-tert-butyldicarbonate and tert-butyllithium.
* To whom correspondence should be addressed. Telephone: +81(545)81
3377. Fax: +81(545)81 3680. E-mail: yasuo.yoshida@iharachem.co.jp.
(1) A novel synthesis of the intermediate which can be useful for antimicro-
bacterial agent such as HSR-903 is described; see: Hamada, Y.; Umezu,
K. Patent Application No. JP11-035531.
(2) Hamada, Y.; Umezu, K. Patent Application No. JP11-158150.
(3) The conventional method for obtaining the desired fluoroquinoline was
reported as a multistep synthesis; see: (a) Ito, Y.; Kato, H.; Yasui, S.;
Kado, N.; Yoshida, T. Patent Application No. JP 07-309864. (b) Masuzawa,
K.; Suzue, S.; Hirai, K.; Ishizaki, T. Patent Application No. JP62-215572.
(4) Snieckus, V. Chem. ReV. 1990, 90, 879-933.
(6) Ekhato, I. V.; Huang, C. C. J. Labelled Compd. Radiopharm. 1993, 34(6),
505-512.
(7) Reavill, D. R.; Richardson, S. K. Synth. Commun. 1990, 20(10), 1423-1436.
(8) Clark, R. D.; Caroon, J. M. J. Org. Chem. 1982, 47, 2804-2806.
(9) Fisher, L. E.; Caroon, J. M. Synth. Commun. 1989, 19, 233-237.
(10) The ortho lithiation of N-pivaloylfluoroanilines followed by reaction with
ethyl trifluoroacetate was also reported but performed in relatively low
yield, probably caused by side reactions of the resulting carbonyl compounds
under the basic condition; see: Patel, M.; Ko, S. S.; McHugh, R. J., Jr.;
Marwalder, J. A.; Srivastava, A. S.; Cordova, B. C.; Klabe, R. M.; Erickson-
Vitanen, S.; Trainor, G. L.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1999, 9,
2805-2810.
(5) Carretero, J. C.; Ruano, J.-L. G.; Vicioso, M. Tetrahedron 1992, 48(35),
7373-7382.
958
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Vol. 8, No. 6, 2004 / Organic Process Research & Development
10.1021/op0498969 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/29/2004

Table 1.
1
productsb (%)
n-BuLi
(equiv)
CH3I
(equiv)
entry
R1
R2
temp /timea
1
3
7
8
others
1
2
F
F
F
F
2.3
2.2
1.1
1.1
(1) -50 to -60 °C/1 h
(2)-40 to-55 °C/1 h, rt/2 h
(1) -65 to -70 °C/1 h
(2) rt/1 h
-65 to -70 °C/5.5 h
(1) -15 to -20 °C/2 h
(2) 0 to 5 °C/2 h
2.3
6.4
80.2 (77)c
90.8
14.4
0.4
3.1
1.2
1.2
0.1
3
4
F
F
F
F
2.2
2.1
2.3d
1.1
12.3
5.3
84.2
1.4
2.0
13.7
81.0 (67)c
5
Cl
F
2.2
1.1
(1) -65 to -70 °C/1 h
25.1
1.0
3.0
64.9
6.0
(2) rt/1 h
6e
7
Cl
Cl
F
F
2.2
2.2
-15 to -20 °C/1 h
(1) -15 to -20 °C/1 h
(2) rt/1 h
(1) -65 to -70 °C/1 h
(2) rt/1 h
98.4 (89)c
0.8
1.6
3.3
1.3d
1.1
95.9 (94)c
7.3
8
F
H
2.2
85.1
5.1
0.5
4.2
a (1) After lithiation under the described conditions, methyl iodide was added at the same temp. (2) After methylation, the reaction mixture was warmed and stirred
under the described conditions. b The value shows area ratio determined by gas chromatography. c The parentheses show isolated yields.d Methyl bromide was used
instead of methyl iodide.e The reaction was quenched with water after lithiation under the described condition.
Scheme 1
Scheme 2
Lithiation and methylation of 1a took place in a similar
manner at -65 to -70 °C, but formation of 8a was
suppressed to give a higher yield of 3a (the crude compound
contained 90.8% of 3a). The crude 3a was then hydrolyzed
to give 3,4-difluoro-2-methylaniline (4) in 87% yield (two
steps). However, at -15 to -20 °C, 2-tert-butyl-6-fluoro-
7-methylbenzoxazole (8a) was formed as the main product
in 81.0% (67% isolated) yield (entry 4) with no 3a. Then
N-pivaloyl-3-chloro-4-fluoroaniline (1b) and N-pivaloyl-3-
fluoroaniline (1c) were subjected to this reaction. Lithiation
and methylation of 1b at -65 to -70 °C gave 2-tert-butyl-
6-fluoro-7-methylbenzoxazole 8b ()8a) as the main product
and only a trace of N-pivaloyl-3-chloro-4-fluoro-2-methy-
laniline (3b). No 3b but 98.4% (determined by GC) of 2-tert-
butyl-6-fluorobenzoxazole (7b) was formed when the reac-
tion was performed at -15 to -20 °C and quenched with
water (entry 6). In the case of N-pivaloyl-3-fluoroaniline (1c),
the reaction was considerably slower at -65 to -70 °C, and
the formation of 3c and 8c was 5.1% and 7.3%, respectively
(entry 8).11 Other components in this reaction mixture were
85.1% of 1c and 0.5% of 2-tert-butylbenzoxazole (7c). From
these results this reaction is considered to be highly affected
by the reaction temperature and the electronic effect of
substituents at the 3- and 4-position. In the case of N-piv-
aloyl-3-chloro-4-fluoroaniline (1b), the 2-position proton is
less acidic than that of 1a, so deprotonation by n-butyllithium
is rather slow at the same temperature (-65 to -70 °C).
Thus the conversion of entry 5 is ∼74.9% in contrast to that
of entry 2 (93.6%). In addition, the intermediate carbanion
resulting from 1b presumably is less stable than 1a, causing
rapid elimination of the chloride ion. In the case of
N-pivaloyl-3-fluoroaniline (1c), the 2-position proton is less
acidic than those of 1a and 1b, retarding the reaction
Vol. 8, No. 6, 2004 / Organic Process Research & Development
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959

at low temperature, but defluorination tends to occur to pro-
duce 7c and 8c.11 On the contrary, ortho lithiation and meth-
ylation of N-pivaloyl-3,4-difluoroaniline (1a) occurred se-
lectively in high yield, due to sufficient acidity and carbanion
stabilization effected by both 3- and 4-fluorine substituents.
The assumed reaction path is shown in Scheme 2.
proton), 7.31 (ddd, 1H, J ) 8.7 Hz, 3.9 Hz, 2.7 Hz, an
aromatic proton), 7.50 (bs, 1H, NH), 7.71 (dd, 1H, J ) 6.6
Hz, 2.7 Hz, an aromatic proton); 13C NMR (δ, CDCl3) 27.69
(s), 39.80 (s), 116.60 (d, JFC ) 21.8 Hz), 120.23 (d, JFC
)
6.8 Hz), 121.12 (d, JFC ) 14.5 Hz), 122.84 (s), 134.88 (s),
154.90 (JFC ) 244.3 Hz), 177.16 (s).
N-Pivaloyl-3-fluoroaniline (1c): mp ) 115-116 °C; IR
(KBr, cm-1) 3320, 2850-3000, 1650, 1610, 1540, 1190;
Conclusion
1
Mass (m/z) 195 (M+), 111 (M+ - C4H8 - CO); H NMR
In conclusion, selective ortho lithiation and methylation
of N-pivaloyl-3,4-difluoroaniline (1a) at -50 to -70 °C were
performed. The product was readily hydrolyzed to 3,4-
difluoro-2-methylaniline, an important starting material for
a fluoroquinoline antimicrobial agent, in high yield. But at
elevated temperature annulation to 2-tert-butyl-6-fluoro-7-
methylbebzoxazole took place via defluorination. In the case
of N-pivaloyl-3-chloro-4-fluoroaniline (1b) and N-pivaloyl-
3-fluoroaniline (1c), the reaction proceeded rather sluggishly,
and mainly benzoxazoles were obtained. The reaction gave
a useful tool for either selective methylation of a fluoroaniline
or benzoxazole derivatives depending on the reaction condi-
tions and substituents.
(δ, CDCl3) 1.29 (s, 9H, -C(CH3)3), 6.7-7.6 (m, 5H,
aromatic protons and NH); 13C NMR (δ, CDCl3) 27.71 (s),
39.88 (s), 107.84 (d, JFC ) 25.8 Hz), 111.01 (JFC ) 21.8
Hz), 113.55 (JFC ) 2.9 Hz), 130.09 (JFC ) 9.2 Hz), 139.87
(JFC ) 10.9 Hz), 163.16 (JFC ) 242.6 Hz), 177.11 (s).
Entry 1. To a 100-mL four-necked reaction flask
equipped with a reflux condenser, thermometer, and magnetic
stirrer were added 2.13 g (10.0 mmol) of 1a and 30 mL of
anhydrous tetrahydrofuran (THF). The mixture was cooled
with dry ice/acetone to -60 °C. After 7.2 g (22.5 mmol) of
n-butyllithium (20 wt % solution in cyclohexane) were added
at -60 to -50 °C, the solution was stirred at -55 °C for 1
h. Then 1.56 g (11.0 mmol) of methyl iodide in 3 mL of
THF were added at -40 to -55 °C. The reaction mixture
was then stirred at the same temperature for 1 h and then
warmed to room temperature and stirred for 2 h. Then the
reaction mixture was quenched with 100 mL of water and
extracted with 100 mL of ether. The ether extract was washed
with 100 mL of water and dried over anhydrous sodium
sulfate. After removal of ether, 2.46 g of crude product,
which contains 88.2% (determined by GC) of N-pivaloyl-
2-methyl-3,4-difluoroaniline (3a), were obtained. Recrystal-
lization of the crude product from n-hexane gave 1.76 g (Y
) 77%, P ) 99.2% by GC) of pure 3a as white crystals.
Mp 112-114 °C; IR (KBr, cm-1) 3310, 2860-3000, 1650,
Experimental Section
General. All reagents and solvents were obtained from
commercial suppliers and used without purification. THF was
dried over molecular sieves 4Å 1/16 before use. All reactions
were carried out under nitrogen atmosphere. 1H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded on a Varian
Mercury VX-300 spectrometer in deuteriochloroform as the
solvent. Infrared spectra were recorded on a JASCO FT/IR-
420 spectrometer. GC-MS (EI) spectra were obtained using
a Hewlett-Packard HP6890/MSD spectrometer using a DB-
5MS column (J&W Scientific), 25 m × 0.2 mm i.d., film
thickness 0.33 µm. GC analysis was performed by Shimadzu
GC-9A apparatus using a G-100 column (Chemical Evalu-
ation and Research Institute, Japan), 20 m × 1.2 mm i.d.,
film thickness 1 µm. The GC analysis data is reported in
area %, not adjusted to weight %.
1
1500; Mass (m/z) 227 (M+), 143 (M+ - CO - C4H8); H
NMR (δ, CDCl3) 1.33 (s, 9H, -C(CH3)3), 2.19 (d, 3H, J )
2 Hz, CH3), 6.8-7.8 (m, 3H, aromatic protons and NH);
13C NMR (δ, CDCl3) 9.78 (s), 27.59 (d, JFC ) 4.6 Hz),
121.14 (dd, JFC ) 6.5 Hz, 3.8 Hz), 132.55 (s), 148.58 (dd,
JFC ) 243.8 Hz, 13.1 Hz), 148.87 (dd, JFC ) 242.6 Hz, 12.6
Hz), 177.76 (s).
Starting Materials. N-Pivaloylfluoroanilines (1a-1c)
were prepared by the reaction of corresponding fluoroanilines
and pivaloyl chloride in the presence of triethylamine (molar
ratio ) 1:1:1) in toluene at ambient temperature.
Entry 2 (and Hydrolysis of Crude 3a). The reaction was
repeated at -65 to -70 °C using 7.0 g (21.9 mmol) of n-but-
yllithium and 1.50 g (10.6 mmol) of methyl iodide in a man-
ner similar to that for entry 1 to obtain 2.41 g of crude 3a.
Analytical results by GC are shown in Table 1. The product
was then refluxed in a mixture of 30 mL of ethanol and 30
mL of 35% hydrochloric acid for 24 h. Then the resulting
mixture was added to 100 mL of 10% NaOH solution and
extracted with 100 mL of ether. The ether extract was washed
twice with 100 mL of water and dried over anhydrous sodium
sulfate. After removal of the ether, 1.69 g of crude product
was obtained, which was distilled under reduced pressure
to give 1.25 g (Y ) 87%, P ) 94.2% by GC) of 3,4-difluoro-
2-methylaniline (4) with spectral data identical with those
of the sample obtained according to the literature.5 Bp 40-
N-Pivaloyl-3,4-difluoroaniline (1a): mp ) 123-124 °C;
IR (KBr, cm-1) 3300, 2850-3000, 1660, 1550, 1520, 1430,
1210, 1190; Mass (m/z) 213 (M+), 129 (M+ - C4H8 - CO);
1H NMR (δ, CDCl3) 1.32 (s, 9H, -C(CH3)3), 6.9-7.8 (m,
4H, aromatic protons and NH); 13C NMR (δ, CDCl3) 27.59
(s), 39.76 (s), 110.48 (d, JFC ) 21.8 MHz), 116.35 (dd, JFC
) 5.7 Hz, 3.4 Hz), 117.07 (d, JFC ) 16.6 Hz), 134.88 (dd,
JFC ) 5.2 Hz, 3.4 Hz), 146.94 (dd, JFC ) 228.0 Hz, 12.7
Hz), 150.19 (dd, JFC ) 231.8 Hz, 15.5 Hz), 177.36 (s).
N-Pivaloyl-3-chloro-4-fluoroaniline (1b): mp ) 136-
137 °C; IR (KBr, cm-1) 3290, 2850-3000, 1650, 1520,
1500, 1390, 1210, 1170; Mass (m/z) 231, 229 (M+) 147, 145
(M+ - C4H8 - CO); H NMR (δ, CDCl3) 1.30 (s, 9H,
-C(CH3)3), 7.04 (dd, 1H, J ) 8.7 Hz, 8.7 Hz, an aromatic
1
1
45 °C/0.133 kPa; Mass (m/z) 143 (M+), 124 (M+ - F); H
(11) In the similar reaction condition, the formation of 2-tert-butyl-7-ethylben-
zoxazole was reported in ref 8.
NMR (δ, CDCl3) 2.08 (d, 3H, JHF ) 2.0 Hz, -CH3), 3.1-
960
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Vol. 8, No. 6, 2004 / Organic Process Research & Development

4.2 (bs, 2H, -NH2), 6.34 (ddd, 1H, J ) 8.7 Hz, 4.2 Hz, 1.7
Hz, aromatic CFdCHdCH), 6.81 (ddd, 1H, J ) 8.7 Hz,
8.7 Hz, 8.7 Hz, CFdCHdCH).
n-butyllithium and 1.50 g (10.6 mmol) of methyl iodide in
a manner similar to that for entry 1 to obtain 2.60 g of crude
3a. The analytical result by GC and GC-MS is shown in
Table 1. The main components were 25.1% of 1b and 64.9%
of 8b (identical with the product of entry 4).
Entry 3. The lithiation was performed at -65 to -70 °C
for 1 h using 2.13 g (10.0mol) of 1a and 13.8 mL (21.9
mmol) of n-butyllithium (1.59 mol/L solution in n-hexane)
in 30 mL of anhydrous tetrahydrofuran (THF). Then 1.25 g
(13.2 mmol) of methyl bromide in 2 mL of THF was added.
After the mixture stirred for 3.5 h at the same temperature,
0.90 g (9.5 mmol) of methyl bromide in 2 mL of THF was
added, and stirring was continued for 2 h at the same
temperature. The reaction was then quenched with 40 mL
of water and worked up as usual to obtain 2.20 g of crude
material. Analytical results by GC are shown in Table 1.
The crude product was recrystallized twice with n-hexane
to give 1.30 g (Y ) 57%, P ) 97.6% GC) of 3a.
Entry 6. The reaction was repeated at -15 to -20 °C
using 2.30 g (10.0mol) of 1b and 14.4 mL (22.5 mmol) of
n-butyllithium (1.56mol/L solution in n-hexane) in a manner
similar to that of entry 4. Then the reaction was quenched
with 30 mL of water and extracted with 50 mL of toluene.
The aqueous layer was further extracted with 30 mL of
toluene. The combined toluene layer was washed with 80
mL of water and dried over anhydrous sodium sulfate. Work-
up and removal of the solvent gave 1.87 g of crude product.
Distillation by Kugelrohr gave 1.71 g of 2-tert-butyl-6-fluoro-
benzoxazole (7b) as a colorless oil (Y ) 89%, P ) 97.5%
by GC). Bp (Kugelrohr temp) ) 100-105 °C/0.133 kPa;
mp ) 40-41 °C, IR (KBr, cm-1) 2850-3000, 1620, 1570,
1480, 1120, 1100; Mass (m/z) 193 (M+), 178 (M+ - CH3),
137 (M+ - C4H8); 1H NMR (δ, CDCl3) 1.49 (s, 9H,
-C(CH3)3), 7.0-7.7 (m, 3H, aromatic protons); 13C NMR (δ,
CDCl3) 28.76 (s), 34.58 (s), 98.77 (d, JFC ) 28.1 Hz), 112.15
(d, JFC ) 24.1 Hz), 120.22 (d, JFC ) 10.4 Hz), 136.87 (JFC
) 1.1 Hz), 151.21 (s), 160.63 (JFC ) 241.4 Hz), 174.50 (s).
Entry 7. The reaction was repeated at -15 to -20 °C
using 2.30 g (10.0mol) of 1b and 14.4 mL (22.5 mmol) of
n-butyllithium (1.56 mol/L solution in n-hexane) in a manner
similar to that of entry 6. Methylation was performed by
adding 1.25 g (13.2 mmol) of methyl bromide in 5 mL of
THF. Workup and purification as in the case of entry 6 gave
1.94 g (Y ) 94%, P ) 98.2%) of 8b whose spectra were
identical with those of 8a of entry 4.
Entry 4. To a 100-mL four-necked reaction flask equip-
ped with a reflux condenser, thermometer, and magnetic
stirrer were added 2.13 g (10.0 mmol) of 1a and 30 mL of
anhydrous THF; the mixture was cooled to -20 °C with
dry ice/acetone. After 7.0 g (21.9 mmol) of n-butyllithium
(20 wt % solution in cyclohexane) was added at -10 to -15
°C, the solution was stirred at -15 to -20 °C for 1 h. Then
1.50 g (10.6 mmol) of methyl iodide in 3 mL of THF was
added at -15 to -5 °C. The reaction mixture was stirred at
-15 to -20 °C for 1 h and then warmed to 0 to 5 °C and
stirred for 2 h. The reaction mixture was quenched with 100
mL of water and extracted with 100 mL of ether. The ether
extract was washed with 100 mL of water and dried over
anhydrous sodium sulfate. After removal of the ether, 2.27
g of crude product was obtained. Vacuum distillation of the
crude oil gave 1.38 g of 2-tert-butyl-6-fluoro-7-methylben-
zoxazole (8a) (Y ) 67%, P ) 97% by GC). Bp (Kugelrohr
temp) ) 130-135 °C/0.133 kPa; IR (film, cm-1) 2850-
3000, 1610, 1570, 1490; Mass (m/z) 207 (M+), 192 (M+ -
Entry 8. The reaction was repeated at -65 to -70 °C
using 1.95 g (10.0 mmol) of 1c and 7.2 g (22.5 mmol) of
n-butyllithium and 1.50 g (10.6 mmol) of methyl iodide in
a manner similar to that of entry 1. The structure of the small
amount of products (3c, 7c, 8c) was estimated on the basis
of GC-MS analysis of the crude reaction mixture. 3c: m/z
) 209 (M+), 125 (M+ - COC4H9). 7c: m/z ) 175 (M+),
160 (M+ - CH3), 133 (M+ - CH3 - HCN). 8c: m/z ) 189
(M+), 174 (M+ - CH3), 147 (M+ - CH3 - HCN).
1
CH3), 150 (M+ - C4H9); H NMR (δ, CDCl3) 1.47 (s, 9H,
-C(CH3)3), 2.42 (dd, 3H, J ) 1.6 Hz, 0.4 Hz, CH3), 6.98
(dd, 1H, J ) 8.8 Hz,10.1 Hz, aromatic CHdCHsCFd), 7.44
(ddd,1H,J)8.8Hz,4.8Hz,0.4Hz,aromaticCHdCHsCNd);
13C NMR (δ, CDCl3) 8.52 (JFC ) 3.5 Hz), 28.64 (s), 34.45
(s), 108.80 (JFC ) 24.1 Hz), 111.63 (JFC ) 25.8 Hz), 116.75
(JFC ) 9.8 Hz), 136.90 (s), 150.37 (s), 158.75 (JFC ) 239.8
Hz), 173.96 (JFC ) 3.5 Hz).
Received for review May 23, 2004.
OP0498969
Entry 5. The reaction was repeated at -65 to -70 °C
using 2.30 g (10.0 mol) of 1b and 7.1 g (22.2 mmol) of
Vol. 8, No. 6, 2004 / Organic Process Research & Development
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