Addition of Indolyl and Pyrrolyl Grignard Reagents to 1-Acylpyridinium Salts

Article abstract of DOI:10.1021/jo049943v

Certain indolyl and pyrrolyl Grignard reagents add to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine to give the corresponding 1-acyl-2-heteroaryl-2,3-dihydro-4-pyridones in good to high yield. When the 1-acyl group contained a chiral auxiliary, (±)-trans-2-(α -cumyl)cyclohexyloxy, addition of the indolyl Grignards resulted in a separable mixture of diastereomeric 2,3-dihydro-4-pyridones.

Full text of DOI:10.1021/jo049943v

SCHEME 1
Ad d ition of In d olyl a n d P yr r olyl Gr ign a r d
Rea gen ts to 1-Acylp yr id in iu m Sa lts
J effrey T. Kuethe and Daniel L. Comins*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
dan_comins@ncsu.edu
Received J anuary 8, 2004
Abstr a ct: Certain indolyl and pyrrolyl Grignard reagents
add to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine
to give the corresponding 1-acyl-2-heteroaryl-2,3-dihydro-
4-pyridones in good to high yield. When the 1-acyl group
contained a chiral auxiliary, (()-trans-2-(R-cumyl)cyclohexyl-
oxy, addition of the indolyl Grignards resulted in a separable
mixture of diastereomeric 2,3-dihydro-4-pyridones.
pyrrole derivatives, to serve as intermediates for alkaloid
synthesis prompted us to investigate the addition of
Grignard reagents derived from substituted indoles and
pyrrole to 1-acylpyridinium salt 1.
The indole nucleus in an important feature in a wide
variety of structurally diverse and biologically active
natural products.1 Indoles bearing a highly functionalized
piperidine ring in either the 2- or 3-position encompass
several structural classes of natural products including
Aspidosperma, Strychnos, Eburnan, Corynanthean, and
Rauwolfia families of alkaloids.2 In addition, pyrrolidinyl
alkaloids such as the biogenetically intriguing smipine
also possess a substituted piperidine ring in the 2-posi-
tion.3 Methods for the construction of the polycyclic
framework found in many of these alkaloids rely on the
preparation of synthetic intermediates in enantiomeri-
cally pure form.
Grignard reagents obtained from commercial or readily
available alkyl and aryl halides add to 1 in high yield
and high diastereoselectivity.4-6 While oxidative addition
of metallic magnesium to alkyl or aryl halides has been
widely employed for the preparation of Grignard re-
agents, the reaction of metallic magnesium with halo-
indoles and pyrroles fails to bring about Grignard forma-
tion.7 The metalation of N-substituted indoles and pyr-
roles most often involves direct lithiation or lithium-
halogen exchange reactions which are typically conducted
at low temperature (-78 °C).8 Few reports on the
preparation of Grignard reagents derived from N-sub-
stituted indoles and pyrroles have appeared in the
literature.7,9
To verify whether indolyl and pyrrolyl Grignard re-
agents would add to 1, we examined the addition of the
simple Grignard reagents 610 and 9 (Scheme 2).11 For
example, slow addition of 6 to pyridinium salt 5 at -40
°C, prepared from 4-methoxy-3-(triisopropylsilyl)pyridine
and benzyl chloroformate, followed by acid hydrolysis
(2) For leading references, see: (a) Kalaus, I. G.; Greiner; Sza´ntay,
C. In Studies in Natural Products Chemistry. Structure and Chemistry
(part E); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19,
pp 89-116. (b) Cordell, G. A. In The Alkaloids, Manske, R. H. F.,
Rodrigo, R. G. A., Eds.; Academic Press: New York, 1979; Vol. 17, pp
199-384. (c) Saxton, J . E. Nat. Prod. Rep. 1993, 10, 349. (d) Kisakurek,
M. V.; Leeuwenberg, A. J . M.; Hesse, M. In Alkaloids: Chemical and
Biological Perspectives; Peletier, S. W., Ed.; J ohn Wiley and Sons: New
York, 1983; Vol. 1, Chapter 5. (e) Atta-ur-Rahman; Basha, A. In
Biosynthesis of Indole Alkaloids; Clarendon Press: Oxford, 1983. (f)
Woodson, R. R.; Youngken, H. W.; Schlittler, E.; Schneider, J . A. In
Rauwolfia: Botany, Pharmacognosy, Chemistry, and Pharmacology;
Little Brown and Co: Boston, 1957.
The addition of Grignard reagents4 or certain other
organometallics5 to chiral 1-acylpyridinium salts 1 is a
useful synthetic method for the synthesis of 2-substituted
1-acyl-2,3-dihydro-4-pyridones of type 2 (Scheme 1).
These compounds have proven to be valuable building
blocks for alkaloid synthesis because of their ease of
preparation in either enantiomerically pure form, as well
as the facility with which ring substituents can be
introduced in a regio- and stereocontrolled manner.6 The
potential of heterocycles 3 and 4, and the corresponding
(3) Fitch, W. L.; Dolinger, P. M.; Djerassi, C. J . Org. Chem. 1974,
39, 2974.
(4) (a) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem.
Soc. 1994, 116, 4719. (b) Comins, D. L.; Gurra-Weltzien, L. Tetrahedron
Lett. 1996, 37, 3807 and references cited therein.
(5) Comins, D. L.; Kuethe, J . T.; Hong, H.; Lakner, F. J . J . Am.
Chem. Soc. 1999, 121, 2651 and references therein.
(6) Comins, D. L.; J oseph, S. P. In Advances in Nitrogen Heterocycles;
Moody, C. J ., Ed.; J AI Press: Greenwich, Vol. 2, p 251 and references
therein.
(7) Kondo, Y.; Yoshida, A.; Sato, S.; Sakamoto, T. Heterocycles 1996,
42, 105.
(8) (a) Rewcastle, G. W.; Katritzky, A. R. Adv. Heterocycl. Chem.
1993, 56, 155 and references cited therein. (b) Wakefield, B. J . The
Chemistry of Organolithium Compounds; Pergamon Press: Oxford,
1974. (c) Wakefield, B. J . Organolithium Method; Academic Press:
London, 1988.
(1) (a) Sundberg, R. J . The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Sundberg, R. J . Pyrroles and Their Benzoderiva-
tives: Synthesis and Applications. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 4, pp 313-376. (c) Sundberg, R. J . In Best Synthetic Methods,
Indoles; Academic Press: New York, 1996; pp 7-11. (d) J oule, J . A.
Indole and its Derivatives. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Thomas, E. J ., Ed.; George
Thieme Verlag: Stuttgart, 2000; Category 2, Vol. 10, Chapter 10.13.
(e) Brown, R. K. In Indoles; Houlihan, W. J ., Ed.; Wiley-Interscience:
New York, 1972.
10.1021/jo049943v CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
J . Org. Chem. 2004, 69, 2863-2866
2863

SCHEME 2
SCHEME 3
provided dihydropyridone 7 in 74% isolated yield. The
use of the preformed Grignard reagent was crucial for
the success of the reaction. When indole was added
directly to pyridinium salt 5, no reaction occurred. The
indole nitrogen of dihydropyridone 7 was easily protected
by reaction with (Boc)2O and catalytic DMAP to afford 8
in 94% yield. Reaction of 5 with Grignard reagent 9 also
proceeded smoothly; however, a mixture of dihydropyri-
dones 10 and 11 was obtained in 72% and 8% yield,
respectively. These isomers were easily separated by
chromatography on silica gel.
Our attention next turned to the preparation and
addition of N-substituted indolyl Grignard reagents to 5
(Scheme 3). Reaction of 5 with Grignard reagent 12,
prepared from 1-tert-butoxycarbonyl-2-iodoindole12 by
treatment with EtMgBr at rt in THF, gave dihydropy-
ridone 13 in 78% yield after acid hydrolysis. The protect-
ing group could easily be removed by reaction with TFA
at rt to afford indole 14 in 94% yield. When pyridinium
salt 5 was allowed to react with Grignard reagent 15,7
dihydropyridone 16 was obtained in 94% yield. There was
no apparent isomerization of the Grignard reagent to the
2-position prior to reaction with 5.7,13 Interestingly, the
corresponding isomeric Grignard reagents 17 and 18
failed to add to pyridinium salt 5. The only observed
products were the dehalogenated indoles 19 and 20,
respectively, and other unidentified decomposition prod-
ucts.
afforded dihydropyridones 22a and 22b in 82% combined
yield. Analysis of the crude reaction mixture revealed
that the diastereomeric excess (de) was 35%. The indi-
vidual diastereomers were easily separated by chroma-
tography. Reaction of 21 with Grignard 15 provided a
separable mixture of 23a and 23b in 62% combined yield
(de ) 48% by HPLC). The reaction of 21 with 12
furnished 24 in 70% overall yield (de ) 50% by HPLC).
The diastereomeric mixture 24 proved difficult to sepa-
rate by chromatography. Treatment of the mixture with
TFA in refluxing chloroform removed both the Boc
protecting group and the triisopropylsilyl group and gave
25a and 25b as a separable mixture of diastereomers in
81% yield. The relative stereochemistry of dihydropyri-
dones 22-25 was determined by H1 NMR.4a
In conclusion, we have demonstrated that certain
indolyl and pyrrolyl Grignard reagents add to 1-acylpy-
ridinium salts in good to excellent yield. While this work
used racemic staring materials, the diastereoselectivity
of the reaction lends itself to the preparation of enan-
tiopure intermediates using (+)- or (-)-TCC chlorofor-
mate.14 This approach should be amenable to the syn-
thesis of more complex indole alkaloids possessing a
piperidine moiety in either the 2- or 3-position of the
indole ring.
Having established that certain indolyl Grignard re-
agents readily add to 1-acylpyridinium salt 5, the addi-
tion of these reagents to pyridinium salt 21 (R* ) (()-
trans-2-(R-cumyl)cyclohexyl, (()-TCC)14 was examined in
order to gauge the diastereoselectivity of the process
(Scheme 4). Slow addition of 6 to pyridinium salt 21
Exp er im en ta l Section
(9) (a) Faul, M. M.; Winneroski, L. L. Tetrahedron Lett. 1997, 38,
4749. (b) Kondo, Y.; Toshida, A.; Sakamoto, T. J . Chem. Soc., Perkin
Trans 1 1996, 2331 and references therein. (c) Minato, A.; Suzuki, K.;
Tamao, K.; Kumada, M. J . Chem. Soc., Chem Commun. 1984, 511. (d)
Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada, M. Tetra-
hedron Lett. 1981, 22, 5319.
(10) Brown, J . B.; Henbest, H. B.; J ones, E. R. J . Chem. Soc. 1952,
3172.
(11) Robles, E. S. J .; Ellis, A. M.; Miller, T. A. J . Phys. Chem. 1992,
96, 8791 and references therein.
(12) Kline, T. J . Heterocycl. Chem. 1985, 22, 505.
(13) For the isomerization of 3-lithiated indoles see: Saulnier, M.
G.; Gribble, G. W. J . Org. Chem. 1982, 47, 757.
(14) (a) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656.
(b) (+)- and (-)-TCC alcohols are available from Aldrich Chemical Co.
1-[(Ben zyloxy)ca r bon yl]-2-(3-in d olyl)-5-(tr iisop r op ylsi-
lyl)-2,3-d ih yd r o-4-p yr id on e (7). To a solution of 86 mg (0.734
mmol) of indole in 10 mL of THF was added dropwise 0.25 mL
of a 3 M solution of MeMgBr. The resulting mixture was heated
to reflux for 1 h and cooled to rt. The mixture was cannulated
into a solution (-40 °C) of pyridinium salt 5 which was formed
from 150 mg (0.565 mmol) of 4-methoxy-3-(triisopropylsilyl)-
pyridine and 96.4 mg (0.565 mmol) of benzyl chloroformate in
toluene at -23 °C for 40 min. After 2 h, 15 mL of aqueous 10%
HCl was added, and the mixture was allowed to warm to rt.
The mixture was extracted with ethyl acetate. The organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by radial PLC (silica gel,
2864 J . Org. Chem., Vol. 69, No. 8, 2004

SCHEME 4
EtOAc/hexanes) to give 216 mg (74%) of 7 as a white foam: IR
and then cooled to rt. The resulting solution was cannulated into
a solution (-40 °C) of pyridinium salt 5 which was formed from
123 mg (0.462 mmol) of 4-methoxy-3-(triisopropylsilyl)pyridine
and 79.0 mg (0.462 mmol) of benzyl chloroformate in toluene at
-23 °C for 40 min. After 2 h, 15 mL of aqueous 10% HCl was
added, and the mixture was allowed to warm to rt. The mixture
was extracted with ethyl acetate. The organic extracts were dried
over MgSO4 and concentrated under reduced pressure, and the
residue was purified by radial PLC (silica gel, EtOAc/hexanes).
The first product to elute (151 mg, 72%) was identified as 10:
white solid; mp 132-133 °C; IR (thin film) 3437, 2943, 1713,
1655, 1566, 1326, 1255 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.98
(d, 9H, J ) 7.4 Hz), 1.04 (d, 9H, J ) 7.4 Hz), 1.27 (m, 3H), 2.86
(d, 1H, J ) 15.9 Hz), 3.02 (dd, 1H, J ) 15.9, 7.2 Hz), 5.27 (d,
1H, J ) 12.1 Hz), 5.40 (d, 1H, J ) 12.1 Hz), 5.70 (d, 1H, J ) 6.9
Hz), 6.07 (m, 2H), 6.67 (m, 1H), 7.41 (m, 5H), 7.66 (s, 1H), 8.76
(br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 11.3, 18.9, 40.2, 50.1,
69.4, 108.2, 111.6, 118.4, 128.3, 128.5, 128.6, 128.7, 129.0, 135.0,
145.4, 156.9, 196.2. Anal. Calcd for C26H36N2O3Si: C, 68.99; H,
8.02; N, 6.19. Found: C, 68.81; H, 8.13; N, 6.10.
(thin film) 3368, 2939, 2851, 1727, 1650, 1567, 1457, 1391, 1287,
1
1246, 1116 cm-1
;
H NMR (CDCl3, 300 MHz) δ 1.01 (m, 18H),
1.31 (m, 3H), 2.81 (d, 1H, J ) 15.7 Hz), 3.14 (dd, 1H, J ) 15.7,
7.0 Hz), 5.24 (s, 2H), 6.09 (d, 1H, J ) 6.4 Hz), 6.99 (s, 1H), 7.07
(t, 1H, J ) 7.4 Hz), 7.18 (t, 1H, J ) 7.7 Hz), 7.29 (m, 6H), 7.65
(d, 1H, J ) 6.1 Hz), 7.94 (s, 1H), 8.21 (br s, 1H); 13C NMR (CDCl3,
75 MHz) δ 11.4, 19.0, 42.7, 49.8, 69.1, 111.4, 111.6, 114.3, 119.4,
120.1, 122.2, 122.7, 125.8, 128.3, 128.7, 128.8, 135.3, 136.3, 147.6,
153.0, 197.0. Anal. Calcd for C30H38N2O3Si: C, 71.67; H, 7.62;
N, 5.57. Found: C, 71.71; H, 7.69; N, 5.50.
1-[(Ben zyloxy)ca r bon yl]-2-[(1-ter t-bu toxyca r bon yl)-3-in -
d olyl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (8). To
a stirred solution of 65 mg (0.129 mmol) of 7 in 4 mL of CH2Cl2
at rt was added 34 mg (0.156 mmol) of di-tert-butyl dicarbonate,
29 mg (0.29 mmol) of triethylamine, and 2 mg of DMAP. After
being stirred for 1 h, the reaction mixture was diluted with water
and extracted with CH2Cl2, and the organic extracts were dried
over MgSO4. The solvent was removed under reduced pressure
and the residue purified by radial PLC (silica gel, EtOAc/
hexanes) to give 73 mg (94%) of 8 as a white foam: IR (thin
film) 2942, 2867, 1734, 1664, 1588, 1453, 1371, 1251, 1154, 1081
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.04 (m, 18H), 1.32 (m, 3H),
1.60 (s, 9H), 2.79 (d, 1H, J ) 15.6 Hz), 3.13 (dd, 1H, J ) 15.6,
7.1 Hz), 5.24 (s, 2H), 6.01 (d, 1H, J ) 6.3 Hz), 7.29 (m, 8H), 7.54
(m, 1H), 8.02 (s, 1H), 8.17 (d, 1H, J ) 8.2 Hz); 13C NMR (CDCl3,
75 MHz) δ 11.4, 19.1, 28.3, 41.9, 49.7, 69.2, 84.1, 112.0, 115.7,
118.2, 119.0, 122.9, 123.0, 125.1, 128.2, 128.7, 128.8, 135.2, 136.0,
142.3, 147.4, 149.4, 152.8, 195.7; HRMS calcd for C35H46N2O5Si
603.3254 [M + H]+, found 603.3277 [M + H]+.
The second product to elute (17 mg, 8%) was identified as 11:
clear oil; IR (neat) 3307, 2942, 1707, 1660, 1522, 1302 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 0.96 (d, 9H, J ) 7.2 Hz), 1.01 (d, 9H,
J ) 7.2 Hz), 1.26 (m, 3H), 2.82 (d, 1H, J ) 16.0 Hz), 3.04 (dd,
1H, J ) 16.0, 7.3 Hz), 5.28 (m, 3H), 5.68 (d, 1H, J ) 6.4 Hz),
6.09 (s, 1H), 6.79 (s, 1H), 7.37 (m, 5H), 7.67 (s, 1H), 9.40 (br s,
1H); 13C NMR (CDCl3, 75 MHz) δ 11.3, 18.9, 39.9, 49.9, 69.8,
109.9, 115.5, 123.2, 128.4, 128.5, 128.7, 129.0, 134.2, 134.8, 136.3,
160.8, 195.6. HRMS calcd for C26H36N2O3Si 453.2573 [M + H]+,
found 453.2568 [M + H]+.
1-[(Ben zyloxy)ca r bon yl]-2-(2-p yr r olyl)-5-(tr iisop r op ylsi-
lyl)-2,3-d ih yd r o-4-p yr id on e (10) a n d 1-[(Ben zyloxy)ca r bo-
n yl]-2-(3-p yr r olyl)-5-(t r iisop r op ylsilyl)-2,3-d ih yd r o-4-p y-
r id on e (11). To a solution of 63.1 mg (0.94 mmol) of pyrrole in
10 mL of THF was added dropwise 0.28 mL of a 3 M solution of
MeMgBr. The resulting mixture was heated to reflux for 1 h
1-[(Ben zyloxy)ca r bon yl]-2-[(1-ter t-bu toxyca r bon yl)-2-in -
d olyl]-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (13). To
a solution of 250 mg (0.729 mmol) of 1-tert-butoxycarbonyl-2-
iodoindole12 in 15 mL of THF was added dropwise 0.25 mL of a
3 M solution of MeMgBr. The resulting mixture was stirred for
1 h at rt. The mixture was cannulated into a solution (-40 °C)
J . Org. Chem, Vol. 69, No. 8, 2004 2865

of pyridinium salt 5 which was formed from 150 mg (0.565 mmol)
of 4-methoxy-3-(triisopropylsilyl)pyridine and 96.4 mg (0.565
mmol) of benzyl chloroformate in toluene at -23 °C for 40 min.
After 2 h, 15 mL of aqueous 10% HCl was added, and the
mixture was allowed to warm to rt. The mixture was extracted
with ethyl acetate. The organic extracts were dried over MgSO4
and concentrated under reduced pressure. The residue was
purified by radial PLC (silica gel, EtOAc/hexanes) to give 266
mg (78%) of 13 as a colorless solid: mp 116-117 °C; IR (thin
135.0, 135.2, 138.3, 147.5, 152.6, 195.3. Anal. Calcd for
36H42N2O5SSi: C, 67.26; H, 6.59; N, 4.36. Found: C, 67.37; H,
6.68; N, 4.33.
C
(2S*- a n d 2R*)-2-(3-In d olyl)-1-[((1R*,2S*)-2-(1-m eth yl-1-
p h en yleth yl)cycloh exyloxy)ca r bon yl]-5-(tr iisop r op ylsilyl)-
2,3-d ih yd r o-4-p yr id on es (22). To a solution of 200 mg (1.71
mmol) of indole in 25 mL of THF was added dropwise 0.57 mL
of a 3 M solution of MeMgBr. The resulting mixture was heated
to reflux for 1 h and cooled to rt. The resulting mixture was
cannulated into a solution (-78 °C) of pyridinium salt 21 which
was formed from 150 mg (0.565 mmol) of 4-methoxy-3-(triiso-
propylsilyl)pyridine and 0.57 mL of a 1 M solution of (1R*,2S*)-
2-(R-cumyl)cyclohexyl chloroformate in toluene at -23 °C for 40
min. After 2 h, 35 mL of aqueous 10% HCl was added, and the
mixture was allowed to warm to rt. The mixture was extracted
with ethyl acetate. The organic extracts were dried over MgSO4,
concentrated under reduced pressure, and the residue was
purified by radial PLC (silica gel, EtOAc/hexanes). The first
product to elute (173 mg, 50%) was identified as the major
diastereomer 22a : white solid; mp 162-163 °C; IR (thin film)
1
film) 2936, 1728, 1661, 1578, 1453, 1327, 1298, 1240 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.05 (m, 18H), 1.31 (m, 3H), 1.64 (s,
9H), 2.87 (d, 1H, J ) 16.0 Hz), 3.13 (dd, 1H, J ) 16.0, 7.7 Hz),
5.21 (m, 2H), 6.36 (s, 1H), 6.54 (d, 1H, J ) 7.2 Hz), 7.25 (m,
8H), 8.04 (d, 1H, J ) 8.2 Hz), 8.17 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 11.4, 18.9, 19.1, 28.3, 41.8, 52.0, 69.2, 85.0, 107.7, 112.2,
116.1, 120.6, 123.3, 124.5, 127.9, 128.7, 128.8, 135.2, 137.1, 138.0,
148.1, 150.3, 195.7. Anal. Calcd for C35H46N2O5Si: C, 69.73; H,
7.69; N, 4.65. Found: C, 69.85; H, 7.75; N, 4.56.
1-[(Ben zyloxy)ca r bon yl]-2-(3-in d olyl)-5-(tr iisop r op ylsi-
lyl)-2,3-d ih yd r o-4-p yr id on e (14). To a stirred solution of 40
mg (0.066 mmol) of 13 in 15 mL of CH2Cl2 was added 61 mg
(0.531 mmol) of TFA. The resulting mixture was stirred for 3 h
at rt, quenched with saturated NaHCO3, and extracted with CH2-
Cl2. The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by radial PLC (silica gel, EtOAc/hexanes) to afford 31 mg (94%)
of 14 as a white foam: IR (neat) 3392, 2940, 2868, 1720, 1664,
1571, 1453, 1387, 1335, 1305, 1253 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.97 (d, 9H, J ) 7.5 Hz), 1.03 (d, 9H, J ) 7.5 Hz), 1.27
(m, 3H), 2.90 (d, 1H, J ) 16.1 Hz), 3.11 (dd, 1H, J ) 16.1, 7.2
Hz), 5.29 (d, 1H, J ) 11.7 Hz), 5.46 (d, 1H, J ) 11.7 Hz), 6.39 (s,
2H), 7.07 (t, 1H, J ) 7.7 Hz), 7.17 (t, 1H, J ) 7.5 Hz), 7.42 (m,
6H), 7.52 (d, 1H, J ) 7.7 Hz), 7.70 (s, 1H), 8.67 (br s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 11.3, 18.9, 40.1, 50.4, 69.7, 102.7, 111.0,
112.1, 120.2, 121.1, 122.9, 127.6, 128.4, 128.8, 129.1, 135.0, 135.3,
136.1, 145.6, 154.0, 196.0; HRMS calcd for C30H38N2O3Si 503.2730
[M + H]+, found 503.2730 [M + H]+.
1
3359, 2931, 1712, 1648, 1568, 1322, 1290, 1242 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.80-1.61 (m, 34H), 1.97 (m, 2H), 2.42 (m,
1H), 2.72 (m, 1H), 4.19 (m, 1H), 4.78 (m, 1H), 6.71 (s, 1H), 7.18
(m, 4H), 7.39 (m, 5H), 7.96 (s, 1H), 8.06 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 11.4, 19.1, 21.5, 24.7, 25.9, 26.9, 31.1, 32.7,
39.7, 42.7, 48.9, 51.1, 78.3, 110.4, 111.4, 114.7, 119.2, 119.7,
120.8, 122.4, 125.3, 125.5, 128.4, 136.3, 148.3, 153.0, 153.1, 196.8.
Anal. Calcd for C38H52N2O3Si: C, 74.47; H, 8.55; N, 4.57.
Found: C, 74.41; H, 8.60; N, 4.62.
The second product to elute (112 mg, 32%) was identified as
the minor diastereomer 22b: white solid; mp 173-174 °C; IR
(thin film) 3359, 2942, 1717, 1653, 1568, 1322, 1285, 1253 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.46 (m, 37H), 2.78 (d, 1H, J )
15.6 Hz), 3.07 (dd, 1H, J ) 15.6, 6.7 Hz), 4.94 (m, 1H), 5.96 (d,
1H, J ) 6.4 Hz), 6.91 (s, 1H), 7.20 (m, 7H), 7.60 (m, 1H), 7.74
(d, 1H, J ) 7.5 Hz), 8.07 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
11.5, 19.2, 24.7, 25.7, 26.9, 27.3, 34.1, 40.3, 42.7, 49.7, 51.6, 78.3,
110.6, 111.4, 114.4, 119.5, 120.1, 122.1, 122.6, 125.5, 125.7, 125.9,
128.2, 136.4, 147.6, 150.7, 151.9, 197.0. Anal. Calcd for
1-[(Ben zyloxy)car bon yl]-2-[1-(ph en ylsu lfon yl)-3-in dolyl]-
5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p yr id on e (16). To a solu-
tion of 390 mg (0.734 mmol) of 3-iodo-1-phenylsulfonylindole7
in 20 mL of THF was added dropwise 1.00 mL of a 1 M solution
of EtMgBr. The resulting mixture was stirred for 1 h at rt. The
mixture was cannulated into a solution (-40 °C) of pyridinium
salt 5, which was formed from 135 mg (0.509 mmol) of 4-meth-
oxy-3-(triisopropylsilyl)pyridine and 87.0 mg (0.509 mmol) of
benzyl chloroformate in toluene at -23 °C for 40 min. After 2 h,
20 mL of aqueous 10% HCl was added, and the mixture was
allowed to warm to rt. The mixture was extracted with ethyl
acetate. The organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by radial PLC (silica gel, EtOAc/hexanes) to give 309 mg (94%)
of 16 as a white solid: mp 136-137 °C; IR (thin film) 2944, 2860,
C
38H52N2O3Si: C, 74.47; H, 8.55; N, 4.57. Found: C, 74.30; H,
8.59; N, 4.48.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for
financial support of this research. NMR and mass
spectra were obtained at NCSU instrumentation labo-
ratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (Grants CHE-9509532 and CHE-
0078253).
1725, 1664, 1572, 1447, 1378, 1280, 1241, 1175, 1119, 1019 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.06 (m, 18H), 1.32 (m, 3H), 2.72
(d, 1H, J ) 15.4 Hz), 3.14 (dd, 1H, J ) 15.4, 7.2 Hz), 5.22 (s,
2H), 5.96 (d, 1H, J ) 5.9 Hz), 7.19-7.51 (m, 12H), 7.79 (d, 2H,
J ) 7.7 Hz), 7.92 (d, 1H, J ) 8.2 Hz), 8.04 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 11.3, 19.0, 41.7, 49.5, 69.3, 111.9, 113.9, 119.7,
120.5, 123.1, 123.6, 125.4, 126.9, 128.2, 128.6, 128.8, 129.5, 134.1,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedure for compounds 23-25 and copies of H and 13C NMR
spectra for 8, 11, 14, and 23b. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O049943V
2866 J . Org. Chem., Vol. 69, No. 8, 2004