Site-selective cross-coupling of dichlorinated benzo-fused nitrogen-heterocycles with Grignard reagents

Article abstract of DOI:10.1248/cpb.58.1255

Site-selective cross-coupling of dihaloarenes constitutes a useful method for synthesis of multi-substituted arenes. In this paper, we report the site-selective cross-coupling of dichlorinated benzo-fused nitrogen-heterocycles having two chloro groups on the benzene ring. These dichlorinated heterocycles reacted with Grignard reagents in the presence of PdCl₂(PCy ₃)₂ at the positions ortho to the nitrogen-based substituents with high selectivities. A mechanism in which interaction between Lewis acidic Mg and Cl of the ortho position facilitates C-Cl bond cleavage is proposed.

Full text of DOI:10.1248/cpb.58.1255

September 2010
Note
Chem. Pharm. Bull. 58(9) 1255—1258 (2010)
1255
Site-Selective Cross-Coupling of Dichlorinated Benzo-Fused Nitrogen-
Heterocycles with Grignard Reagents
Hideyuki KONISHI, Tatsuya ITOH, and Kei MANABE*
School of Pharmaceutical Sciences, University of Shizuoka; 52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.
Received May 11, 2010; accepted June 8, 2010; published online June 10, 2010
Site-selective cross-coupling of dihaloarenes constitutes a useful method for synthesis of multi-substituted
arenes. In this paper, we report the site-selective cross-coupling of dichlorinated benzo-fused nitrogen-heterocy-
cles having two chloro groups on the benzene ring. These dichlorinated heterocycles reacted with Grignard
reagents in the presence of PdCl2(PCy3)2 at the positions ortho to the nitrogen-based substituents with high selec-
tivities. A mechanism in which interaction between Lewis acidic Mg and Cl of the ortho position facilitates C–Cl
bond cleavage is proposed.
Key words catalysis; cross-coupling; palladium; site-selective; Grignard reagent; heterocycle
Site-selective cross-coupling of dihaloarenes constitutes a restricted for the benzo-fused heterocycles, while that of the
useful method for synthesis of multi-substituted arenes.1—3) anilines is not. We were interested in effects of the restricted
For dihalobenzenes having two substituents of the same halo- conformation on site-selectivity. Herein we report the
gen atom, however, site-selective cross-coupling involving site-selective cross-coupling of dichlorinated benzo-fused
selective conversion of one of the halogen atoms to another nitrogen-heterocycles having two chloro groups on the
group still remains unestablished. Therefore, developing a benzene ring. The substrates reacted with Grignard reagents
new method of such cross-coupling is an important issue for in the presence of PdCl2(PCy3)2 at the positions ortho to
synthesis of multi-substituted benzenes.
the nitrogen-based substituents with high selectivities.
Recently, we developed a new site-selective cross-coupling
Substrates 1a—c, which were easily prepared according to
in which chloro groups at a position ortho to a directing literature procedures,12—15) were subjected to cross-coupling
group such as OH, NH2, CH2OH, NHAc, or NHBoc reacted with 4-methoxyphenylmagnesium bromide in the presence of
with Grignard reagents in the presence of a catalyst based on PdCl2(PCy3)2 at 50—70 °C. We were pleased to find that
Pd and PCy3 with high site-selectivities (Chart 1).4—6) This highly site-selective reactions occurred to give products 2a—
reaction system has several unique features: (1) although c (Table 1). Although the yields of 2a and 2b were modest
electron-donating groups typically retard the oxidative addi-
Table 1. Site-Selective Cross-Coupling of Dichlorinated Benzo-Fused
Nitrogen-Heterocycles
tion step in cross-coupling reactions, the presence of elec-
tron-donating groups such as OH and NH2 is essential in the
reactions for acceleration at the ortho-position; (2) substrates
with protic substituents react faster than those with a non-
protic substituent such as a methoxy group; (3) this type of
high ortho-selectivity was not observed in Suzuki–Miyaura
coupling with boronic acids.
To expand the utility of this catalytic system, we planned
to apply it to benzo-fused heterocycles such as indole, indo-
line, and tetrahydroquinoline, which are frameworks ubiqui-
tous in natural products and pharmaceuticals.7—11) There are
some examples of site-selective cross-coupling of dibromi-
nated or dichlorinated benzo-fused heterocycles.1,2) For sub-
strates having two halo groups on the benzene ring, however,
no examples of highly selective cross-coupling have been
reported. Therefore, development of site-selective cross-
coupling of these benzo-fused heterocycles should be val-
uable. In addition, these benzo-fused heterocycles have a
feature distinct from N-unsubstituted anilines that we pre-
viously used as substrates: rotation of the Cipso–N bonds is
Entry
1
Substrate 1
Temperature (°C) Yield (%) of 2
70
50
70
60
(2a)
2
3
41
(2b)
87
(2c)
Chart 1. Previous ortho-Selective Cross-Coupling
∗ To whom correspondence should be addressed. e-mail: manabe@u-shizuoka-ken.ac.jp
© 2010 Pharmaceutical Society of Japan

1256
Vol. 58, No. 9
(entries 1, 2), neither isomers 3 nor doubly cross-coupled 10, which cannot generate a Mg amide, was used as a sub-
products 4 were obtained in any cases. In all cases, the strate. As shown in Eq. 2, no cross-coupled products were
homo-coupling product of the Grignard reagent was ob- obtained (homo-coupling of the Grignard reagent was ob-
served as the major by-product.
served). This result suggests that the formation of the Mg
We next carried out reactions of 1c with various Grignard amides is the key for the acceleration at the ortho-positions
reagents. As shown in Table 2, the reactions proceeded to in the cross-coupling of these benzo-fused nitrogen-heterocy-
give the products with high site-selectivities. Not only aryl cles.
Grignard reagents but also heteroaryl and alkenyl Grignard
Although the origin of the site-selectivity remains unclear,
reagents worked well. In all cases, the para Cl group of 1c we assume that the mechanism shown in Fig. 1 operates to
did not react. When n-octylmagnesium bromide was used, facilitate C–Cl bond cleavage at the ortho-position. That is,
the desired cross-coupled product was obtained only in a interaction of the Lewis acidic Mg of the Mg amide with the
very small amount, and instead, a reduced compound in Cl atom activates the ortho-C–Cl bond to accelerate the ox-
which the ortho-chloro group was converted to hydrogen was idative addition step,16—18) which is the selectivity-determin-
obtained.
The preference of the reaction at the ortho-position was
ing step and presumably the rate-determining step.
To support this proposed mechanism, we conducted a pre-
also observed in a competitive reaction between two sub- liminary study using density functional theory (DFT) calcu-
strates. Thus, 7-chloroindole (6) preferentially reacted over lations (B3LYP/6-31G*) on Mg amides 11a—c derived from
5-chloroindole (7) as shown in Eq. 1.
1a—c (Fig. 2). One molecule of dimethyl ether, which is a
For substrates 1a—c, the proton on the nitrogen atom must simplified surrogate of THF, was included as a solvent coor-
be deprotonated with a Grignard reagent under the reaction dinated to Mg. In the structures of 11a—c, the ortho-C–Cl
conditions to generate the corresponding Mg amides. We as- bonds were found to be significantly longer than the para-
sume that formation of the Mg amides is important for accel- C–Cl bonds; the differences between the ortho- and para-
eration of the reactions at the position ortho to the Mg amido C–Cl bond lengths are 0.028 Å, 0.028 Å, and 0.038 Å for
groups. To support this assumption, N-methylated compound 11a—c, respectively. In the structures of the parent com-
pounds (1a—c), the differences between the ortho- and para-
C–Cl bond lengths are less than 0.008 Å. The elongation of
the ortho-C–Cl bonds of Mg amides 11a—c is likely to re-
sult from an interaction between Cl and the Lewis acidic Mg.
This interaction should activate the ortho-C–Cl bond for the
oxidative addition step.
Table 2. Site-Selective Cross-Coupling of 1c with Various Grignard
Reagents
Although rotation of the Cipso–N bond is restricted for the
benzo-fused heterocycles compared with anilines, high site-
selectivity was still observed as in the cases of the aniline
substrates. This suggests that the conformations shown in the
calculated structures are plausible as the transition states.
Entry
1
RMgBr
Product 5
Yield (%)
78
2
76
3
4
77
53
Fig. 1. Proposed Mechanism of Activation of ortho-C–Cl Bond

September 2010
1257
ceived. Compounds 1a,12,13) 1b,14) and 1c15) were prepared according to pre-
viously reported procedures.
N-Methyl-6,8-dichloro-1,2,3,4-tetrahydroquinoline (10) N-Methyl-
1,2,3,4-tetrahydroquinoline was obtained by methylation of 1,2,3,4-tetrahy-
droquinoline in the presence of formaldehyde and sodium cyanoborohydride
in 75% yield.24) To a solution of N-methyl-1,2,3,4-tetrahydroquinoline
(180 mg, 1.22 mmol) in CH2Cl2 (30 ml) was added N-chlorosuccinimide
(360 mg, 2.69 mmol) at 0 °C and the resulting mixture was stirred at 0 °C for
1 h then at 40 °C for 42 h. The reaction mixture was diluted with CH2Cl2,
successively washed with H2O and brine, and then dried over anhydrous
Na2SO4. After filtration, all volatiles were evaporated and the crude mixture
was purified by column chromatography (hexane : Et2Oϭ10 : 1) to give 10 as
1
a yellow oil (215 mg, 82%). H-NMR (CDCl3) d: 1.83—1.85 (2H, m), 2.77
(2H, t, Jϭ6.5 Hz), 2.87 (3H, s), 3.12—3.17 (2H, m), 6.95 (1H, s), 7.18 (1H,
d, Jϭ2.3 Hz). 13C-NMR (CDCl3) d: 16.9, 27.8, 42.7, 51.8, 122.1, 126.2,
127.8, 127.9, 132.2, 144.6. IR (ATR): 2938, 2862, 1686, 1466, 1449, 1416,
1161, 905, 808 cmϪ1. HR-MS (ESI): Calcd for C10H12Cl2N (MϩH)ϩ
216.0341, Found 216.0329.
Representative Experimental Procedure for Site-Selective Cross-
Coupling (Table 1, Entry 1) To a solution of 1a (81.0 mg, 0.500 mmol)
and PdCl2(PCy3)2 (4 mol%) in THF (0.25 M) was slowly added a 0.5 M solu-
tion of 4-methoxyphenylmagnesium bromide in THF (3.00 ml, 1.50 mmol,
3 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and
then at 70 °C for 18 h. The reaction was quenched by a saturated NH4Cl
aqueous solution. After AcOEt was added, the layers were separated, and
the aqueous layer was extracted with AcOEt. Combined organic phase was
washed with brine and dried over anhydrous Na2SO4. After filtration, all
volatiles were evaporated and the crude mixture was purified by pre-
parative TLC (hexane : AcOEtϭ5 : 1) to give 2a (78.0 mg, 0.303 mmol,
61%) as a white solid. Note: in case that a biphenyl-type by-product
which was obtained through homocoupling of the Grignard reagent was
contaminated after preparative TLC separation, yields of the products were
determined by 1H-NMR analysis, and analytically pure compounds were
obtained by further purification using preparative TLC. The structures of
regioisomers were determined through conversion of the products to the
corresponding dechlorinated compound (Pd/C, HCOONa) whose structures
could be determined by NMR.
5-Chloro-7-(4-methoxyphenyl)indole (2a) White solid. mp 142—
145 °C. 1H-NMR (CDCl3) d: 3.89 (3H, s), 6.54—6.55 (1H, m), 7.05 (2H, d,
Jϭ8.5 Hz), 7.15 (1H, d, Jϭ1.2 Hz), 7.23 (1H, t, Jϭ2.9 Hz), 7.53 (2H, d,
Jϭ8.5 Hz), 7.57 (1H, d, Jϭ1.2 Hz), 8.38 (1H, br). 13C-NMR (CDCl3) d:
55.4, 102.8, 114.7, 118.7, 121.7, 125.5, 125.8, 126.4, 129.1, 129.2, 130.3,
132.3, 159.4. IR (ATR): 3326, 1611, 1516, 1502, 1463, 1238, 1175,
722 cmϪ1. HR-MS (ESI, negative mode): Calcd for C15H11ClNO (MϪH)Ϫ
256.0535, Found 256.0502.
Fig. 2. Selected Bond Lengths in 11a—c and 1a—c Calculated Using a
DFT Method (B3LYP/6-31G*)
The results shown in this paper strongly support the mecha-
nism that the Mg–Cl interaction is the key for the accelera-
tion of the cross-coupling at the position ortho to the nitro-
gen-based substituents, while further studies including those
on transition states of the oxidative addition are necessary to
clarify the precise mechanism for the site-selectivity.19—24)
In summary, we found that nitrogen-heterocycles fused
with a dichlorobenzene ring underwent site-selective cross-
coupling with Grignard reagents in the presence of a Pd cata-
lyst. The reactions occurred at the position ortho to the nitro-
gen-based substituents with high selectivities. Experimental
and computational studies suggest that Mg–Cl interaction
plays an important role in the acceleration of the cross-cou-
pling at the ortho-position. This work should expand the util-
ity of site-selective cross-coupling and shed light on the
mechanism of the reaction.
5-Chloro-7-(4-methoxyphenyl)indoline (2b) The reaction was per-
formed with 1b (94.0 mg, 0.500 mmol) at 50 °C. Purification by preparative
TLC (hexane : AcOEtϭ1 : 1) afforded 2b (54.0 mg, 0.208 mmol, 41%) as a
yellow-white solid. mp 118—122 °C. 1H-NMR (CDCl3) d: 3.06 (2H, t,
Jϭ8.2 Hz), 3.53 (2H, t, Jϭ8.2 Hz), 3.84 (3H, s), 3.98 (1H, br), 6.96 (2H, d,
Jϭ8.5 Hz), 7.02—7.02 (2H, m), 7.44 (2H, d, Jϭ8.5 Hz). 13C-NMR (CDCl3)
d: 30.0, 47.6, 55.3, 114.2, 123.2, 123.4, 123.5, 126.6, 129.0, 130.7, 131.4,
147.7, 158.8. IR (ATR): 3377, 2924, 1609, 1510, 1460, 1236, 1173 cmϪ1
.
HR-MS (ESI): Calcd for C15H15ClNO (MϩH)ϩ 260.0837, Found 260.0804.
6-Chloro-8-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline (2c) The
reaction was performed with 1c (68.0 mg, 0.336 mmol). Purification by
preparative TLC (hexane : AcOEtϭ7 : 1) afforded 2c (80.0 mg, 0.293 mmol,
87%) as a yellow-white solid. mp 117—120 °C. 1H-NMR (CDCl3) d: 1.91—
1.93 (2H, m), 2.80 (2H, t, Jϭ6.2 Hz), 3.23 (2H, t, Jϭ6.2 Hz), 3.85 (3H, s),
4.02 (1H, br), 6.87 (1H, s), 6.91 (1H, d, Jϭ1.1 Hz), 6.97 (2H, d, Jϭ8.5 Hz),
7.31 (2H, d, Jϭ8.5 Hz). 13C-NMR (CDCl3) d: 21.6, 27.3, 41.8, 55.3, 114.3,
120.6, 122.7, 127.5, 127.7, 128.0, 130.3, 130.5, 140.5, 159.0. IR (ATR):
3401, 2835, 1609, 1513, 1493, 1238, 1177 cmϪ1. HR-MS (ESI): Calcd for
C16H16ClNO (M)ϩ 273.0915, Found 273.0909.
Experimental
General All reactions were performed in oven dried or flame dried
glassware under argon atmosphere. Reactions were monitored by TLC on
Merck silica gel 60 F254 plates visualized by UV lump at 254 nm. Column
chromatography was performed on MERCK Silica Gel 60 and preparative
TLC was performed on Merck silica gel 60 F254 0.5 mm plates. NMR spec-
tra were measured on a JEOL ECA-500 NMR spectrometer at 500 MHz for
1H spectra and 125 MHz for 13C spectra, and for 1H-NMR, tetramethylsilane
(TMS) (dϭ0) in CDCl3 served as an internal standard. For 13C-NMR,
CDCl3 (dϭ77.00) served as an internal standard. Infrared spectra were
measured on a SHIMADZU IR Prestige-21 spectrometer (ATR). High reso-
lution-mass spectra (HR-MS) were measured on a BRUKER DALTONICS
micrOTOF (electrospray ionization (ESI)). Melting point was measured
using a YAZAWA MICRO MELTING POINT BY-1.
6-Chloro-8-phenyl-1,2,3,4-tetrahydroquinoline (5a) The reaction was
performed with 1c (89.6 mg, 0.443 mmol) and a 1 M solution of phenylmag-
nesium bromide in THF (1.33 ml, 1.33 mmol). Purification by preparative
TLC (hexane : AcOEtϭ7 : 1) afforded 5a (86.3 mg, 0.344 mmol, 78%) as a
1
yellow-white solid. mp 101—104 °C. H-NMR (CDCl3) d: 1.90—1.95 (2H,
m), 2.80 (2H, t, Jϭ6.5 Hz), 3.23 (2H, t, Jϭ6.5 Hz), 4.03 (1H, br), 6.89 (1H,
d, Jϭ2.3 Hz), 6.93 (1H, d, Jϭ2.3 Hz), 7.33—7.45 (5H, m). 13C-NMR
(CDCl3) d: 21.6, 27.4, 41.8, 120.7, 122.8, 127.4, 127.4, 127.7, 128.2, 128.9,
129.2, 138.3, 140.3. IR (ATR): 3420, 2926, 1487, 1420, 1356, 1261,
1072 cmϪ1. HR-MS (ESI): Calcd for C15H14ClN (M)ϩ 243.0809, Found
Materials Tetrahydrofuran (THF) was distilled from Na/benzophenone
and used immediately. PdCl2(PCy3)2, all Grignard reagents, 7-chloroindole
(6) and 5-chloroindole (7) were purchased from Aldrich and used as re-

1258
Vol. 58, No. 9
243.0838.
References
6-Chloro-8-(3-methoxyphenyl)-1,2,3,4-tetrahydroquinoline (5b) The
1) Schröter S., Stock C., Bach T., Tetrahedron, 61, 2245—2267 (2005).
2) Fairlamb I. J. S., Chem. Soc. Rev., 36, 1036—1045 (2007).
3) Wang J.-R., Manabe K., Synthesis, 1405—1427 (2009).
4) Ishikawa S., Manabe K., Org. Lett., 9, 5593—5595 (2007).
5) Manabe K., Ishikawa S., Synthesis, 2645—2649 (2008).
6) Ishikawa S., Manabe K., Synthesis, 3180—3182 (2008).
7) Sundberg R. J., “Comprehensive Heterocyclic Chemistry II,” Vol. 2,
ed. by Katritzky A. R., Ress C. W., Scriven E. F. V., Bird C. W., Perga-
mon Press, Oxford, 1996, pp. 119—206.
reaction was performed with 1c (57.6 mg, 0.285 mmol) and a 1 M solution of
3-methoxyphenylmagnesium bromide in THF (0.855 ml, 0.855 mmol). Pu-
rification by preparative TLC (hexane : AcOEtϭ9 : 1, developed twice) af-
forded 5b (59.6 mg, 0.218 mmol, 76%) as a yellow-white solid. mp 88—
92 °C. 1H-NMR (CDCl3) d: 1.91—1.95 (2H, m), 2.80 (2H, t, Jϭ6.5 Hz),
3.24 (2H, t, Jϭ5.7 Hz), 3.84 (3H, s), 4.09 (1H, br), 6.88—6.93 (4H, m), 6.96
(1H, d, Jϭ7.9 Hz), 7.34 (1H, t, Jϭ7.9 Hz). 13C-NMR (CDCl3) d: 21.6, 27.4,
41.8, 55.3, 113.1, 114.6, 120.5, 121.4, 122.7, 127.3, 127.4, 128.2, 130.0,
139.7, 140.2, 160.0. IR (ATR): 3406, 2930, 1585, 1485, 1462, 1356, 1290,
1227, 1034, 864, 781, 702 cmϪ1. HR-MS (ESI): Calcd for C16H16ClNO
(M)ϩ 273.0915, Found 273.0913.
8) Gribble G. W., “Comprehensive Heterocyclic Chemistry II,” Vol. 2, ed.
by Katritzky A. R., Ress C. W., Scriven E. F. V., Bird C. W., Pergamon
Press, Oxford, 1996, pp. 207—258.
6-Chloro-8-(2-thienyl)-1,2,3,4-tetrahydroquinoline (5c) The reaction
was performed with 1c (59.0 mg, 0.292 mmol) and a 1 M solution of 2-
thienylmagnesium bromide in THF (0.876 mg, 0.876 mmol). Purification by
preparative TLC (hexane : AcOEtϭ5 : 1) afforded 5c (55.6 mg, 0.223 mmol,
9) Kawasaki T., Higuchi K., Nat. Prod. Rep., 22, 761—793 (2005).
10) Somei M., Yamada F., Nat. Prod. Rep., 22, 73—103 (2005).
11) Katritzky A. R., Rachwal S., Rachwal B., Tetrahedron, 52, 15031—
15070 (1996).
77%) as a yellow oil. 1H-NMR (CDCl3) d: 1.91—1.96 (2H, m), 2.79 (2H, t, 12) Bartoli G., Palmieri G., Tetrahedron Lett., 30, 2129—2132 (1989).
Jϭ6.2 Hz), 3.29 (2H, t, Jϭ6.2 Hz), 4.46 (1H, br), 6.93 (1H, d, Jϭ2.3 Hz),
7.04 (1H, d, Jϭ2.3 Hz), 7.10—7.11 (1H, m), 7.13—7.14 (1H, m), 7.35 (1H,
13) Teng X., Degterev A., Jagtap P., Xing X., Choi S., Denu R., Yuan J.,
Cuny G. D., Bioorg. Med. Chem. Lett., 15, 5039—5044 (2005).
dd, Jϭ5.1, 1.1 Hz). 13C-NMR (CDCl3) d: 21.4, 27.4, 41.8, 119.7, 120.4, 14) Nomura S., Yamamoto Y., WO 2006080577 (2006) [PCT Int. Appl.].
123.0, 125.6, 126.3, 127.5, 128.2, 128.8, 139.6, 141.0. IR (ATR): 3418, 15) Su D.-S., Anthony N. J., Lim J. J., Tinney E., Williams T. M., WO
2928, 2837, 1489, 1439, 1425, 1354, 1287, 1190, 851 cmϪ1. HR-MS (ESI):
Calcd for C13H12ClNS (M)ϩ 249.0373, Found 249.0381.
2007146230 A2 (2007) [PCT Int. Appl.].
16) Activation of C–X bonds by coordination to Mg has been reported.
See: Terao J., Ikumi A., Kuniyasu H., Kambe N., J. Am. Chem. Soc.,
125, 5646—5647 (2003).
6-Chloro-8-(2-methylprop-1-en-1-yl)-1,2,3,4-tetrahydroquinoline (5d)
The reaction was performed with 1c (55.0 mg, 0.272 mmol) and a 0.5 M solu-
tion of 2-methylpropen-1-ylmagnesium bromide in THF (1.63 ml, 17) Yoshikai N., Mashima H., Nakamura E., J. Am. Chem. Soc., 127,
0.816 mmol). Purification by preparative TLC (hexane : AcOEtϭ7 : 1) af-
17978—17979 (2005).
18) Saeki T., Takashima Y., Tamao K., Synlett, 1771—1774 (2005).
forded 5d (31.7 mg, 0.143 mmol, 53%) as a yellow oil. 1H-NMR (CDCl3) d:
1.72 (3H, d, Jϭ1.1 Hz), 1.90 (3H, d, Jϭ1.1 Hz), 1.91—1.94 (2H, m), 2.75 19) Fairlamb I. J. S., O’Brien C. T., Linb Z., Lam K. C., Org. Biomol.
(2H, t, Jϭ6.5 Hz), 3.32 (2H, t, Jϭ6.5 Hz), 3.83 (1H, br), 5.88 (1H, s), 6.78
(1H, d, Jϭ2.3 Hz), 6.82 (1H, d, Jϭ2.3 Hz). 13C-NMR (CDCl3) d: 19.4, 21.7,
26.0, 27.2, 41.9, 119.8, 120.1, 122.2, 124.4, 127.0, 127.1, 138.4, 140.8. IR
(ATR): 3426, 2928, 2853, 1489, 1447, 1352, 1292, 1179, 1070, 880,
Chem., 4, 1213—1216 (2006).
20) Handy S. T., Zhang Y., Chem. Commun., 299—301 (2006).
21) Legault C. Y., Garcia Y., Merlic C. A., Houk K. N., J. Am. Chem. Soc.,
129, 12664—12665 (2007).
866 cmϪ1. HR-MS (ESI): Calcd for C13H16ClN (M)ϩ 221.0966, Found 22) Garcia Y., Schoenebeck F., Legault C. Y., Merlic C. A., Houk K. N., J.
221.0975. Am. Chem. Soc., 131, 6632—6639 (2009).
Experimental Procedure for a Competitive Reaction of Compounds 6 23) Schaub T., Fischer P., Steffen A., Braun T., Radius U., Mix A., J. Am.
and 7 To a solution of 7-chloroindole (6) (71.0 mg, 0.468 mmol), 5-
chloroindole (7) (71.0 mg, 0.468 mmol) and PdCl2(PCy3)2 (17.3 mg,
0.0234 mmol, 5 mol%) in THF (0.125 M) was slowly added 4-
methoxyphenylmagnesium bromide (0.5 M in THF, 3.74 ml, 1.87 mmol, 4 eq)
at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and then at
70 °C for 18 h. The reaction was quenched with a saturated NH4Cl aqueous
solution. After AcOEt was added, the layers were separated, and the aqueous
layer was extracted with AcOEt. Combined organic phase was washed with
brine and dried over anhydrous Na2SO4. After filtration, all volatiles were
evaporated, and the crude mixture was analyzed by 1H-NMR spectra with
comparison to literature data25) to obtain yields of products 8 and 9.
Chem. Soc., 130, 9304—9317 (2008).
24) Shaffer C. L., Morton M. D., Hanzlik R. P., J. Am. Chem. Soc., 123,
8502—8508 (2001).
25) Prieto M., Zurita E., Rosa E., Munoz L., Williams L. P., Giralt E., J.
Org. Chem., 69, 6812—6820 (2004).
26) Kong J., White C. A., Krylov A. I., Sherrill C. D., Adamson R. D.,
Furlani T. R., Lee M. S., Lee A. M., Gwaltney S. R., Adams T. R.,
Ochsenfeld C., Gilbert A. T. B., Kedziora G. S., Rassolov V. A., Mau-
rice D. R., Nair N., Shao Y., Besley N. A., Maslen P. E., Dombroski J.
P., Daschel H., Zhang W., Korambath P. P., Baker J., Byrd E. F. C., Van
Voorhis T., Oumi M., Hirata S., Hsu C.-P., Ishikawa N., Florian J.,
Warshel A., Johnson B. G., Gill P. M. W., Head-Gordon M., Pople J.
A., J. Computational Chem., 21, 1532—1548 (2000).
Computational Analysis All the molecular calculations were per-
formed with Spartan ’04.26) Geometry optimizations in the gas phase were
carried out with the B3LYP/6-31G(d) DFT method.27,28)
27) Kohn W., Becke A. D., Parr R. G., J. Phys. Chem., 100, 12974—12980
(1996).
Acknowledgment We thank Takeda Science Foundation for financial 28) Becke A. D., J. Chem. Phys., 98, 5648—5652 (1993).
support.