Direct and selective arylation of tertiary silanes with rhodium catalyst

Article abstract of DOI:10.1021/jo8008148

(Chemical Equation Presented) We have developed a convenient and efficient approach to the arylation of tertiary silanes under mild conditions. A variety of arylsilanes were synthesized in a one-step process with good to excellent yields in the presence of a rhodium catalyst with a base. The reaction was highly solvent dependent, and amides were the most effective of the various solvents used. This common catalyst system is highly tolerant of the various sensitive functional groups on the substrates, which might be difficult to extract by other methods. The rhodium-promoted silylation of aryl halides with electron-donating groups occurred more efficiently than the silylation of aryl halides substituted with electron-withdrawing groups. Heteroaromatic halides were also found to be readily silylated with tertiary silanes. The successful application of this reaction to the synthesis of a TAC-101 analogue, which is a trialkylsilyl-containing synthetic retinoid benzoic acid derivative with selective binding affinity for retinoic acid receptor-α, is also described.

Full text of DOI:10.1021/jo8008148

Direct and Selective Arylation of Tertiary Silanes with Rhodium
Catalyst
Yoshinori Yamanoi* and Hiroshi Nishihara*
Department of Chemistry, School of Science, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
yamanoi@chem.s.u-tokyo.ac.jp; nisihara@chem.s.u-tokyo.ac.jp
ReceiVed April 16, 2008
We have developed a convenient and efficient approach to the arylation of tertiary silanes under mild
conditions. A variety of arylsilanes were synthesized in a one-step process with good to excellent yields
in the presence of a rhodium catalyst with a base. The reaction was highly solvent dependent, and amides
were the most effective of the various solvents used. This common catalyst system is highly tolerant of
the various sensitive functional groups on the substrates, which might be difficult to extract by other
methods. The rhodium-promoted silylation of aryl halides with electron-donating groups occurred more
efficiently than the silylation of aryl halides substituted with electron-withdrawing groups. Heteroaromatic
halides were also found to be readily silylated with tertiary silanes. The successful application of this
reaction to the synthesis of a TAC-101 analogue, which is a trialkylsilyl-containing synthetic retinoid
benzoic acid derivative with selective binding affinity for retinoic acid receptor-R, is also described.
Introduction
attracted the interest of many synthetic chemists. Although
arylsilanes have been classically prepared by the reaction of
Grignard or with organolithium reagents with silicon electro-
philes,4 these protocols lack wide applicability; however, an
efficient synthesis of functionally substituted arylsilanes has been
elusive.
Transition metal-catalyzed C-C coupling reactions have been
recognized as powerful tools in multiple organic transforma-
tions.5 Transition metal-catalyzed C-Si bond-forming reactions
are also potent methods for the preparation of arylsilanes, and
Arylsilanes and their derivatives have been widely studied
in material science for their unique properties. Recently, these
compounds have been discussed as potential candidates as
intermediates for Hiyama coupling,1 organic phosphorescent
materials,2 and medicinal products.3 For this reason, the efficient
synthesis and functionalization of arylsilane derivatives have
* To whom correspondence should be addressed. Phone: +81-3-5841-4346.
Fax: +81-3-5841-8063.
(1) For reviews of Hiyama coupling, see: (a) Hiyama, T. In Metal-Catalyzed
Cross Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, Germany, 1998; p 421. (b) Hiyama, T.; Shirakawa, E. In Topics in
Current Chemistry; Miyaura, N., Ed.; Springer-Verlag: Heidelberg, Germany,
2002; Vol. 219, p 61. (c) Horn, K. A. Chem. ReV. 1995, 95, 1317. (d) Hatanaka,
Y.; Hiyama, T. Synlett 1991, 845. (e) Denmark, S. E.; Baird, J. D. Chem. Eur.
J. 2006, 12, 4954. (f) Nakao, Y.; Sahoo, A. K.; Imanaka, H.; Yada, A.; Hiyama,
T. Pure Appl. Chem. 2006, 78, 435. (g) Handy, C. J.; Manoso, A. S.; McElroy,
W. T.; Seganish, M.; DeShong, P. Tetrahedron 2005, 61, 12201.
(2) For example, see: (a) You, Y.; An, C.-G.; Kim, J.-J.; Park, S. Y. J. Org.
Chem. 2007, 72, 6241. (b) Liu, X.-M.; He, C.; Haung, J.; Xu, J. Chem. Mater.
2005, 17, 434.
(3) For example, see: (a) Bains, W.; Tacke, R. Curr. Opin. Drug DiscoVery
DeV. 2003, 6, 526. (b) Showwell, G. A.; Mills, J. S. Drug DiscoVery Today
2003, 8, 551. (c) Daiss, J. O.; Burschka, C.; Mills, J. S.; Montana, J. G.; Showell,
G. A.; Fleming, I.; Gaudon, C.; Ivanova, D.; Gronemeyer, H.; Tacke, R.
Organometallics 2005, 24, 3192.
(4) (a) The Chemistry of Organic Silicon Compounds; Patai, S., Rappoport,
Z., Eds.; Wiley & Sons: New York, 2000. (b) Colvin, E. W. Silicon Reagents in
Organic Synthesis; Academic Press: London, UK, 1988.
(5) For reviews, see the following: (a) Whitcombe, N. J.; Hii, K. K.; Gibson,
S. E. Tetrahedron 2001, 57, 7449. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009. (c) Corbert, J.-P.; Mignani, G. Chem. ReV. 2006, 106,
2651. (d) Hassan, J.; Svignon, M.; Gozzi, C.; Schulz, E.; Lamaire, M. Chem.
ReV. 2002, 102, 1359. (e) Tsuji, J. Transition Metal Reagents and Catalysts:
InnoVations in Organic Synthesis; John Wiley & Sons: Chichester, UK, 2000.
(f) Hartwig, J. F. Synlett 2006, 1283. (g) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131. (h) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: New York, 2002.
(i) Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Vol. 1. (j) Cross-Coupling Reactions.
A Practical Guide; Miyaura, N., Ed.; Springer: Berlin, Germany, 2002.
10.1021/jo8008148 CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6671–6678 6671

Yamanoi and Nishihara
SCHEME 1. Direct Arylation of Tertiary Silanes
several examples of synthesis with transition metal catalysts have
been reported. The silylation of aromatic C-H bonds is the
most straightforward and atom-economical route to arylsilane
derivatives.6 However, only limited protocols have been reported
in the literature. The reaction usually requires a long reaction
time and high temperatures (often above 150 °C), has a low
yield, and is limited by the small range of potential starting
materials.
Generally, hydrosilanes have been widely used as mild
reducing reagents for fine organic syntheses.7 Since the pioneer-
ing work of Murata et al., Manoso and DeShong, Denmark and
Kallemyn, Komuro et al., and Ito, transition metal-catalyzed
cross-coupling reactions of aryl halides with trialkoxysilane have
emerged as an alternative and promising method for Si-C bond
formation.8 This method has received much attention because
it can produce important synthetic building blocks that are
difficult to prepare with other technologies. However, in most
cases trialkylsilanes were not suitable silylating reagents because
of their strong reducing power toward aryl halides in the
presence of catalyst.9 For example, Chatgilialoglu et al. reported
that the addition of a catalytic amount of palladium dichloride
to a mixture of 4-iodoanisole and triethylsilane in ether at room
temperature exclusively produced the corresponding reduction
product, anisole (Scheme 1, route A).10 In the course of our
study of the synthetic use of trialkylsilanes, we recently reported
the palladium- and rhodium-catalyzed cross coupling of tri-
alkylsilanes with aryl iodides under mild conditions with good
to high yields.11,12 In the present work, the scope and limitations
of this silylation are evaluated by testing a wide variety of aryl
halides and tertiary silanes reacted with a rhodium catalyst
(Scheme 1, route B). The application of silylation to the total
synthesis of a TAC-101 analogue,13 a synthetic retinobenzoic
acid with selective binding affinity for retinoic acid receptor
(RAR)-R,14 is also demonstrated.
Results and Discussion
Rhodium-Catalyzed Arylation of Tertiary Silane. To
demonstrate the feasibility of rhodium-catalyzed arylation of a
tertiary silane, we examined the triethylsilylation of 2-iodoani-
sole (1a) using a series of catalysts, bases, and solvents, as
summarized in Table 1. As we reported previously, the
palladium-catalyzed reaction of a sterically hindered ortho-
substituted aryl iodide gave a trace amount of silylated product
2 and a much larger quantity of 3. In short, [Rh(cod)2]BF4 and
RhCl(CO)(PPh3)2 appear to be the best catalysts for producing
the silylated product 2, with almost complete conversion at room
temperature in amide solvent (entries 7 and 8).15 The yield of
silylated product 2 was slightly reduced at 50 °C, although the
reaction time became shorter with lower catalyst loading (entries
9 and 10). In addition to K3PO4,16 several other bases (K2CO3,
KOAc, and Et3N) were tested in the protocol, but none of these
yielded better results than K3PO4 (entries 12-14).
Next, we focused our attention on a range of possible leaving
groups on the aromatic ring. As outlined in Table 2, iodide,
bromide, chloride, and triflate17 were tested as leaving groups.
The iodide substrates exhibited much higher reactivity than their
bromide, triflate, or chloride analogues. When we examined the
reaction of 2-bromoanisole with triethylsilane in the presence
of an additional equal amount of tetraethylammonium iodide,
the yield of silylated product was slightly increased. These
results clearly indicate that the iodide anion plays a key role in
suppressing the undesired reduction reaction. For further
comparison, we note that our attempt to use hexamethyldisilane
(Me3SiSiMe3) or iodotrimethylsilane (I-SiMe3) instead of hy-
(6) For representative reports, see: (a) Ezbiansky, K.; Djurovich, P. I.;
LaForest, M.; Sinning, D. J.; Zayes, R.; Berry, D. Organometallics 1998, 17,
1455. (b) Sakakura, T.; Tokunaga, Y.; Sodeyama, T.; Tanaka, M. Chem. Lett.
1987, 2375. (c) Murata, M.; Fukuyama, N.; Wada, J.-I.; Watanabe, S.; Masuda,
Y. Chem. Lett. 2007, 910. (d) Tsukada, N.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 5022. (e) Kakiuchi, F.; Matsumoto, M.; Tsuchiya, K.; Igi, K.;
Hayamizu, T.; Chatani, N.; Murai, S. J. Organomet. Chem. 2003, 686, 134. (f)
Kakiuchi, F.; Tsuchiya, K.; Matsumoto, M.; Mizushima, E.; Chatani, N. J. Am.
Chem. Soc. 2004, 126, 12792. (g) Uchimaru, Y.; El Sayed, A. M. M.; Tanaka,
M. Organometallics 1993, 12, 2065. (h) Gustavson, W. A.; Epstein, P. S.; Curtis,
M. D. Organometallics 1982, 1, 884. (i) Kakiuchi, F.; Igi, K.; Matsumoto, M.;
Chatani, N.; Murai, S. Chem. Lett. 2001, 422. (j) Kakiuchi, F.; Igi, K.; Matsumoto,
M.; Hayamizu, T.; Chatani, N.; Murai, S. Chem. Lett. 2002, 396. (k) Ishikawa,
M.; Okazaki, S.; Naka, A.; Sakamoto, H. Organometallics 1992, 11, 4135.
(7) (a) Pietruszka, J. In Science of Synthesis; Bellus, D., Ley, S. V., Noyori,
R., Regitz, M., Reider, P. J., Schaumann, E., Shinkai, I., Thomas, E. J., Trost,
B. M., Eds.; Thieme: Stuttgart, Germany, 2002; Vol. 4, p 159. (b) Brook, M. A.
Silicon in Organic, Organometallic Polymer Chemistry; Wiley: New York, 2000;
p 171.
(8) (a) Murata, M.; Yamasaki, H.; Ueta, T.; Nagata, M.; Ishikura, M.;
Watanabe, S.; Masuda, Y. Tetrahedron 2007, 63, 4087. (b) Murata, M.; Ishikura,
M.; Nagata, M.; Watanabe, S.; Masuda, Y. Org. Lett. 2002, 4, 1843. (c) Murata,
M.; Ota, K.; Yamasaki, H.; Watanabe, S.; Masuda, Y. Synlett 2007, 1387. (d)
Murata, M.; Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
8569. (e) Murata, M.; Ohara, H.; Oiwa, R.; Watanabe, S.; Masuda, Y. Synthesis
2006, 1771. (f) Murata, M.; Yamasaki, H.; Uogishi, K.; Watanabe, S.; Masuda,
Y. Synthesis 2007, 2944. (g) Manoso, A. S.; DeShong, P. J. Org. Chem. 2001,
66, 7449. (h) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137. (i)
Denmark, S. E.; Kallemeyn, J. M. Org. Lett. 2003, 5, 3483. (j) Komuro, K.;
Ishizaki, K.; Suzuki, H. Touagousei-kenkyu-nenpo 2003, 6, 24. (k) Ishizaki, K.;
Komuro, K.; Suzuki, H. Jpn. Kokai Tokkyo Koho JP2004097975, 2004. (l) Ito,
M. Jpn. Kokai Tokkyo Koho JP2004284963, 2004.
(9) For representative reducing systems based on the combination of silanes/
transition metal complexes, see: (a) Villemin, D.; Nechab, B. J. Chem. Res. (S)
2000, 432. (b) Barr, K. J.; Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1994, 59,
4323. (c) Breeden, S. W.; Lawrence, N. J. Synlett 1994, 833. (d) Keinan, E.
Pure Appl. Chem. 1989, 61, 1737, and references cited therein.
(10) Boukherroub, R.; Chatgilialoglu, C.; Manuel, G. Organometallics 1996,
15, 1508.
(11) (a) Yamanoi, Y. J. Org. Chem. 2005, 70, 9607. (b) Yamanoi, Y.;
Nishihara, H. Tetrahedron Lett. 2006, 47, 7157. (c) Yamanoi, Y.; Taira, T.;
Sato, J.-I.; Nakamula, I.; Nishihara, H. Org. Lett. 2007, 9, 4543.
(12) For the reports of other groups, see: (a) Hamze, A.; Provot, O.; Alami,
M.; Brion, J.-D. Org. Lett. 2006, 8, 931. (b) Gu, W.; Liu, S.; Silverman, R. B.
Org. Lett. 2002, 4, 4171. (c) Liu, S.; Gu, W.; Lo, D.; Ding, X.; Ujiki, M.; Adrian,
T. E.; Soff, G. A.; Silverman, R. B. J. Med. Chem. 2005, 48, 3630. (d) Iizuka,
M.; Kondo, Y. Eur. J. Org. Chem. 2008, 1161. (e) Karshtedt, D.; Bell, A. T.;
Tilley, T. D. Organometallics 2006, 25, 4471.
(13) (a) Yamakawa, T.; Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Shudo,
K. J. Med. Chem. 1990, 33, 1430. (b) Rizvi, N. A.; Marshall, J. L.; Ness, E.;
Hawkins, M. J.; Kessler, C.; Jacobs, H.; Brenckman, W. D., Jr.; Lee, J. S.; Petros,
W.; Hong, W. K.; Kurie, J. M. J. Clin. Oncol. 2002, 20, 3522.
(14) Kagechika, H.; Shudo, K. J. Med. Chem. 2005, 48, 5875.
(15) RhCl(CO)(PPh3)2 and [Rh(cod)2]BF4 are commercially available from
Strem Chemicals.
(16) K3PO4 was dried at 100 °C for 2 h under vacuum before use.
(17) 2-Methoxyphenyl trifluoromethanesulfonate was prepared by Ritter’s
method. See: Ritter, K. Synthesis 1993, 735.
6672 J. Org. Chem. Vol. 73, No. 17, 2008

Arylation of Tertiary Silanes with Rhodium Catalyst
TABLE 1. Reaction of 2-Iodoanisole with Triethylsilane under Various Conditionsa
ratiob
entry
1c
2
3
4
5
6
7
8
catalyst
base
solvent
temp
rt
rt
rt
rt
rt
rt
rt
rt
50 °C
50 °C
rt
rt
rt
rt
rt
rt
rt
time/h
1a
2
3
yield of 2 (%)
Pd(P(t-Bu)3)2
PdCl2(dppf)
Pd(PCy3)
IrCl(CO)(PPh3)2
RhCl(PPh3)3
[RhCl(nbd)]2
RhCl(CO)(PPh3)2
[Rh(cod)2]BF4
RhCl(CO)(PPh3)2
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
RhCl(CO)(PPh3)2
[Rh(cod)2]BF4
[Rh(cod)2]BF4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
none
K2CO3
Et3N
KOAc
K3PO4
K3PO4
K3PO4
NMPd
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
THF
5
96
96
96
96
96
96
96
10
10
96
96
96
96
96
96
96
e
<1
2
<1
e
99
46
43
25
97
59
4
f
f
f
f
52
57
75
1
e
e
e
<1
e
28
36
25
2
e
3
2
f
41
96
96
89
84
e
59
60
94
53
60
4
32
88
91
83
81
f
40
49
82
50
54
f
4
9c
10c
11
12
13
14
15
16
17
11
16
72
5
15
4
47
37
35
toluene
61
a Reaction conditions: 2-iodoanisole (0.5 mmol), triethylsilane (1.0 mmol), catalyst (0.025 mmol), base (1.5 mmol), and solvent (1.0 mL). b The ratio
was determined by GC analysis of the crude reaction mixture. c The reaction was carried out in the presence of 1 mol % of catalyst. d NMP:
N-methylpyrrolidinone. e No detection. f The silylated product could not be isolated by column chromatography.
TABLE 2. Electrophile Compatibilitya
In the reactions of aryl iodides containing electron-donating
groups on the aromatic ring, the desired silanes were success-
fully obtained with good to high yields (entries 1-26).19,20
Conversely, the presence of an electron-withdrawing group
bound to an arene ring slightly reduced the yield of the silylated
ratiob
product (entries 32, 33, 35, 36, 38, 39, 41, and 42). The presence
of amino (-NH2), hydroxy (-OH), ester (-CO2Et),21,22 cyano
(-CN),22 or acetyl (-COCH3)22 functionalities on the aromatic
ring was tolerated in this reaction (entries 18-23, 32, 33, 35,
36, 41, and 42). In the traditional methods of Grignard or with
organolithium reagents, the protection of these functional groups
is frequently required. Thus, our protocol is particularly useful
for the preparation of functionalized arylsilanes. Furthermore,
sterically hindered ortho-substituted aryl iodides were also
effectively coupled with hydrosilanes without difficulty, in sharp
contrast to palladium-catalyzed silylation (entries 1-3, 9, 12,
14, 17, 18, 21, 24-26, and 29), although the larger alkyl group
resulted in a reduced yield of the silylated product (t-Bu,23 0%
> i-Pr, 68% > Et, 79% > Me, 99%). Unfortunately, attempts
at the silylation of ortho-substituted electron-deficient aryl
iodides were unsuccessful (entries 28, 31, 34, 37, and 40).24
We also examined the effects of other hydrosilanes under similar
entry
X
additive time/d 1a-d
2
3
yield of 2 (%)
c
d
1
2
3
4
5
I (1a)
4
20
20
20
20
96
4
91
48
c
Br (1b)
Br (1b)
Cl (1c)
OTf (1d)
<1
51 49
60 40
d
Et4NI
60
c
d
e
88
54
12
46
c
d
e
a Reaction conditions: aryl (pseudo)halide (0.5 mmol), triethylsilane
(1.0 mmol), [Rh(cod)2]BF4 (0.025 mmol), K3PO4 (1.5 mmol), and NMP
(1.0 mL) at rt. b The ratio was determined by GC analysis. c No
additive. d No detection. e The silylated product could not be isolated.
drosilane in the coupling reaction under similar conditions
resulted in failure, giving complete recovery of aryl iodide,
demonstrated by GC-MS measurements.18
As summarized in Table 3, various aryl halides substituted
with electron-donating or electron-withdrawing groups were
converted to the corresponding arylsilanes with good to high
yields when the reactions were performed under optimized
conditions. In all cases, the reduction of the Ar-I bonds
occurred as a side reaction to produce volatile aromatic
compounds, as revealed by GC-MS analysis.
(19) 3-Iodo-N,N-dimethylaniline and 4-iodo-N,N-dimethylaniline were pre-
pared from 3-iodoaniline and 4-iodoaniline, respectively, by reductive methylation
with formaldehyde and NaBH3CN in the presence of acetic acid. (a) Borch,
R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673. (b) Jian, H.; Tour, J. M. J.
Org. Chem. 2003, 68, 5091. (c) Giumanini, A. G.; Chiavari, G.; Musiani, M. M.;
Rossi, P. Synthesis 1980, 9, 743. (d) Raeppel, S.; Toussaint, D.; Suffert, J. Synlett
1998, 537.
(18) Transition metal-catalyzed silylations of aryl halides with disilanes in
the presence of fluoride anion as activator or at high temperature have been
reported. For example, see: (a) McNeill, E.; Barder, T. E.; Buchwald, S. L. Org.
Lett. 2007, 9, 3785. (b) Goossen, L. J.; Ferwanah, A.-R. S. Synlett 2000, 1801.
(c) Shirakawa, E.; Kurahashi, T.; Yoshida, H.; Hiyama, T. Chem. Commun. 2000,
1895. (d) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1987, 28, 4715. (e) Eaborn,
C.; Griffiths, R. W.; Pidcock, A. J. Organomet. Chem. 1982, 225, 331. (f) Babin,
P.; Bennetau, B.; Theurig, M.; Dunogues, J. J. Organomet. Chem. 1993, 446,
135. (g) Matsumoto, H.; Nagashima, S.; Yoshihiro, K.; Nagai, Y. J. Organomet.
Chem. 1975, 85, C1. (h) Azarian, D.; Dua, S. S.; Eaborn, C.; Walton, D. R. M.
J. Organomet. Chem. 1976, 117, C55.
(20) 2-Iodo-N,N-dimethylaniline was prepared from 2-iodoaniline by me-
thylation with iodomethane in the presence of K2CO3. Bunnett, J. F.; Mitchel,
E.; Galli, C. Tetrahedron 1985, 41, 4119.
(21) Murata et al. reported the reaction of ethyl 4-iodobenzoate with
triethylsilane in DMF at 80 °C in the presence of [Rh(cod)(MeCN)2]BF4 to
produce the corresponding silylated product with a 53% GLC yield. See ref
8a.
(22) Quite recently, Iizuka and Kondo reported the triethylsilylation of
4-iodobenzonitrile, 4-iodoacetophenone, and methyl 4-iodobenzoate using tri-
ethylsilane in the presence of Pd(OAc)2 as catalyst. The yields of the
triethylsilylated products were 46%, 38%, and 35%, respectively. See 12d.
J. Org. Chem. Vol. 73, No. 17, 2008 6673

Yamanoi and Nishihara
TABLE 3. Scope of Rhodium-Catalyzed Silylation with Aryl Iodides with Hydrosilanesa
entry
R
R3′
Et3
Ph3
PhMe2
Et3
catalystb
solventc
time/d
product
yield (%)
1
2
3
4
5
6
7
8
2-MeO
2-MeO
2-MeO
3-MeO
4-MeO
4-MeO
4-MeO
4-MeO
2-Me2N
3-Me2N
4-Me2N
2-MeS
4-MeS
2-Me
A
A
A
A
A
A
A
A
B
B
A
A
B
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
B
A
A
A
B
A
A
A
A
B
B
A
A
B
A
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMI
4
4
7
4
4
4
4
4
30
4
4
7
4
4
4
4
4
4
4
4
4
4
4
7
7
7
10
10
7
10
10
4
4
10
4
4
10
4
4
10
4
2-MeOC6H4SiEt3 (2)
2-MeOC6H4SiPh3 (4)
91
99
2-MeOC6H4SiMe2Ph (5)
3-MeOC6H4SiEt3 (6)
4-MeOC6H4SiEt3 (7)
4-MeOC6H4Sii-Pr3 (8)
4-MeOC6H4Sit-BuMe2 (9)
4-MeOC6H4SiPh2Me (10)
2-Me2NC6H4SiEt3 (11)
3-Me2NC6H4SiEt3 (12)
4-Me2NC6H4SiEt3 (13)
2-MeSC6H4SiEt3 (14)
4-MeSC6H4SiEt3 (15)
2-MeC6H4SiEt3 (16)
3-MeC6H4SiEt3 (17)
4-MeC6H4SiEt3 (18)
4-MeC6H4SiEt3 (19)
2-HOC6H4SiEt3 (20)
3-HOC6H4SiEt3 (21)
4-HOC6H4SiEt3 (22)
2-H2NC6H4SiEt3 (23)
3-H2NC6H4SiEt3 (24)
4-H2NC6H4SiEt3 (25)
2-EtC6H4SiEt3 (26)
2-EtC6H4SiPh3 (27)
2-i-PrC6H4SiEt3 (28)
-
69
78
99
83
99
98
37
81
69
99
75
99
74
91
76
99
99
80
99
98
99
79
93
68
d
Et3
i-Pr3
t-BuMe2
Ph2Me
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Ph3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
Et3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
NMP
NMP
NMP
TMU
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMA
NMP
NMP
DMA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
3-Me
4-Me
2,4-Me2
2-HO
3-HO
4-HO
2-H2N
3-H2N
4-H2N
2-Et
2-Et
2-i-Pr
2-t-Bu
2-Ph
-
d
89
d
1-C10H7
2,4,6-Me3
2-EtO2C
3-EtO2C
4-EtO2C
2-MeCO
3-MeCO
4-MeCO
2-CF3
3-CF3
4-CF3
2-NC
3-NC
1-C10H7SiEt3 (29)
-
-
d
3-EtO2CC6H4SiEt3 (30)
4-EtO2CC6H4SiEt3 (31)
-
3-MeCOC6H4SiEt3 (32)
4-MeCOC6H4SiEt3 (33)
-
3-CF3C6H4SiEt3 (34)
4-CF3C6H4SiEt3 (35)
-
3-NCC6H4SiEt3 (36)
4-NCC6H4SiEt3 (37)
C6H5Sin-Pr3 (38)
77e
68e
d
83e
57e
d
72e
51e
d
Et3
Et3
n-Pr3
72e
53e
89
4-NC
4
4
H
a Reaction was performed with aryl iodide (0.5 mmol), hydrosilane (1.0 mmol), K3PO4 (1.5 mmol), and rhodium catalyst (5 mol %) in solvent (1.0
mL) at rt. b A: [Rh(cod)2]BF4, B: RhCl(CO)(PPh3)2. c NMP: N-methylpyrolidinone; DMI: N,N-dimethylimidazolidinone; TMU: N,N,N′,N′-tetramethy-
lurea; DMA: N,N-dimethylacetamide. d No detection. e Aryl iodide (0.5 mmol), hydrosilane (0.6 mmol), K3PO4 (1.5 mmol), and rhodium catalyst (5 mol
%) in solvent (1.0 mL).
reaction conditions (entries 2, 3, 6-8, 25, and 43). This
rhodium-catalyzed silylation was also practical at a 20 mmol
scale, without deleterious effects.25
We continued our investigation by exploring the reaction of
tertiary silanes with heteroaryl iodides. The scope of the
silylation was explored by using heteroaryl iodides, as outlined
in Table 4. Different heteroaryl iodides, such as thiophene and
pyridine derivatives, were successfully coupled to triethylsilane
under the same reaction conditions to produce the desired
compounds with good yields (entries 1 and 2). It should also
be noted that coupling diiodo- and triiodobenzene to triphenyl-
silane produced the oligoarylsilanes with good yields in this
catalytic system (entries 4-6). Thus, the present reactions offer
a convenient method for directly synthesizing oligoarylsilanes,
which have wide applications in material science, from di- and
triiodoaromatics. As another application of this work, we found
that it is possible to efficiently couple vinyl and alkynyl iodide
to hydrosilane under conditions similar to those used for the
corresponding aryl compounds (entries 7 and 8).26 This type of
compound has been the focus of considerable interest, notably
(23) 2-Iodo-tert-butylbenzene was prepared according with a modified method
based on the literature. (a) Fey, N.; Howell, J. A. S.; Lovatt, J. D.; Yates, P. C.;
Cunningham, D.; McArdle, P.; Gottlieb, H. E.; Coles, S. J. Dalton Trans. 2006,
5464. (b) Åkermark, B.; Ljungqvist, A. J. Organomet. Chem. 1978, 149, 97.
(24) The silylation reactions with aryl iodides containing a formyl group
gave unsatisfactory results because complex mixtures were obtained, resulting
from the high reactivity of the aldehyde moiety. Although the silylated products
could not be isolated in a pure form, the yields were estimated to be less than
10% based on GC-MS analysis of the reaction mixture.
(25) In a 20 mmol scale experiment under the reaction conditions described,
the silylation shown in Table 1 entry 1 proceeded to an 85% yield.
(26) For earlier work on the palladium-catalyzed coupling of alkenyl iodides
with tertiary silanes, see: Murata, M.; Watanabe, S.; Masuda, Y. Tetrahedron
Lett. 1999, 40, 9255.
6674 J. Org. Chem. Vol. 73, No. 17, 2008

Arylation of Tertiary Silanes with Rhodium Catalyst
TABLE 4. Rhodium-Catalyzed Silylation of Heteroaryl Iodides, Di- or Triiodo Aromatic Compounds, and Alkynyl-, Alkenyl-, Allyl-, and
Alkyl Iodides
a Conditions: (A) R-I (0.5 mmol), HSiR3 (2.0 equiv), K3PO4 (3.0 equiv), RhCl(CO)(PPh3)2 (5 mol %), NMP (1.0 mL), rt, 4 d. (B) R-I (0.5 mmol),
HSiR3 (2.0 equiv), [Rh(cod)2]BF4 (5 mol %), NMP (1.0 mL), rt, 6 d. (C) Ph3SiH (1.0 mmol), R-I (3.0 equiv), K3PO4 (3.0 equiv), rt, 4 d. (D) Ph3SiH
(1.0 mmol), R-I (3.0 equiv), K3PO4 (3.0 equiv), 0 °C, 6 d. b The yield was based on the amount of triphenylsilane. No silylated product was obtained.
as a precursor to polyarylsilanes.27 Disappointingly, allyl and
alkyl iodides did not produce even trace amounts of the
corresponding organosilane compounds (entries 9 and 10).
Reaction Mechanism. Rh complexes exhibit Si-H bond
activation chemistry because these metals can support mono-
nuclear silyl complexes in a variety of oxidation states.28
Although several mechanisms may be considered for the
silylation reaction, we have formulated a possible mechanism
for the Rh-catalyzed arylation of hydrosilane, as described in
Scheme 2, based on 1H and 29Si NMR analyses during the course
of the stoichiometric reaction (Rh catalyst, RhCl(CO)(PPh3)2);
aryl halide, 4-iodoanisole; hydrosilane, H-SiEt3 [ratio 1:1:1] in
(28) For representative reports on the organosilane complexes of rhodium(V),
see: (a) Fernandez, M.-J.; Maitlis, P. M. J. Chem. Soc., Chem. Commun. 1982,
310. (b) Cook, K. S.; Incarvito, C. D.; Webster, C. E.; Fan, Y.; Hall, M. B.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 5474. (c) Fernandez, M.-J.;
Bailey, P. M.; Bentz, P. O.; Ricci, J. C.; Koetzle, T. F.; Maitilis, P. M. J. Am.
Chem. Soc. 1984, 106, 5458. (d) Nagashima, H.; Tatebe, K.; Ishibashi, T.;
Nakaoka, A.; Sakakibara, J.; Itoh, K. Organometallics 1995, 14, 2868.
(27) For reviews, see: (a) Langkopf, E.; Schinzer, D. Chem. ReV. 1995, 95,
1375. (b) Fleming, I.; Dunogues, J.; Smithers, R. H. Org. React. 1989, 37, 57.
(c) Colvin, E. W. Silicon Reagents in Organic Synthesis; Academic Press:
London, UK, 1988.
J. Org. Chem. Vol. 73, No. 17, 2008 6675

Yamanoi and Nishihara
SCHEME 2. Plausible Mechanism for Rhodium-Catalyzed Silylation
DMF-d7, at room temperature).29The catalytic cycle of the
reaction is initiated by the reaction of the rhodium catalyst
A with hydrosilane to produce a silyl metal hydride complex
B. Although a hydrosilane as well as an aryl halide can be
added oxidatively to Rh(I) complexes, the NMR studies
indicated that the oxidative addition of hydrosilane occurred
predominantly under the conditions used. Consequently, a
mechanism involving the initial oxidative addition of an aryl
halide can effectively be ruled out in the present reaction.
The elimination of HX with the aid of a base, followed by
the further oxidative addition of H-SiR3, would produce the
intermediate formulated as Rh(H)(SiR3)2 C,30 which is the
key intermediate in this transformation and has peaks at 1.00
(t) and 0.73 ppm (q) in the triethyl moiety, and -9.69 (br s)
and -10.64 ppm (br s) in the hydride region. The integral
ratio of the triethylsilyl moiety to the hydride region supports
the structure of the intermediate.31,32 Only one peak at 22.0
ppm was observed by the measurement of 29Si NMR,33 which
supports the existence of a stable intermediate during the
catalysis. K3PO4 is essential for the formation of inter-
mediate C. As the reaction progresses, the coordination or
oxidative addition of aryl halide to intermediate C takes place
to produce the Rh(III) intermediate D or the Rh(V) intermediate
D′. In the presence of base, the rapid base-promoted reductive
elimination of HX, the subsequent reductive elimination of Ar-
SiR3, and the oxidative addition of H-SiR3 dominates, to
generate intermediate C. In this case, another cycle that produces
the reduced product is competitive with this route, producing
catalyst C through intermediate E, and steric and electronic
factors have a significant effect on this step.34–36 The signals
of 9.1 and 13.4 ppm in the 29Si NMR spectra, corresponding to
the Et3SiOSiEt3 and Et3SiOH, appeared as the reaction pro-
ceeded, and we believe that Et3SiOSiEt3 and Et3SiOH are the
compounds most likely to have been formed via the hydrolysis
(29) For 1H and 29Si NMR spectra, see the Supporting Information.
(30) (a) Sun et al. reported the intermediate “(Ph3P)2Rh(H)(SiEt3)2” in the
hydrosilylation of cyclopropyl ketones, see: Sun, C.; Tu, A.; Slough, G. A. J.
Organomet. Chem. 1999, 582, 235. (b) Osakada et al. reported “cyclic
fac-[Rh(SiMe2CH2CH2SiMe2)H(PMe3)3]” prepared in situ from RhCl(PMe3)n and
NaSPh with Me2HSiCH2CH2SiHMe2, see: Osakada, K.; Hataya, K.; Nakamura,
Y.; Tanaka, M.; Yamamoto, T. J. Chem. Soc. Chem. Commun. 1993, 576.
(31) The integral ratio of δ 1.00 (-CH3)/hydride region (Rh-H) was 18/1.
Because of the overlapping peaks, the integration of the methylene group could
not be determined.
(32) 4-Iodoanisole was not completely reacted under the stoichiometric
conditions. To complete the reaction, more than 2 equiv of triethylsilane for
rhodium catalyst was necessary from the NMR studies. This result also provides
some support for the existence of Rh(H)(SiEt3)2 as a key intermediate.
(33) For representative 29Si NMR data of rhodium(III) silyl complexes, see:
(a) CpRh(C2H4)(SiEt3)(H) 41.6 ppm: Duckett, S. B.; Haddleton, D. M.; Jackson,
S. A.; Perutz, R. N.; Paliakoff, M.; Upmacis, R. K. Organometallics 1988, 7,
1526. (b) CpRh(Si(i-Pr)3)(C2H4)(H) 49.3 ppm: Duckett, S. B.; Perutz, R. N.
Organometallics 1992, 11, 90. (c) mer-RhCl(H)(SiHPh2)(PMe3)3 14.9 ppm:
Osakada, K.; Sarai, S.; Koizumi, T.; Yamamoto, T. Organometallics 1997, 16,
3973. (d) RhCl(H)(Si(OEt)2Me)(PPh3)3 15.4 ppm: Nishihara, Y.; Takemura, M.;
Osakada, K. Organometallics 2002, 21, 825. (e) fac-Tris[(8-quinolyl)dimethyl-
silyl]rhodium(III) 23.6 ppm: Djurovich, P. I.; Safir, A. L.; Keder, N. L.; Watts,
R. J. Inorg. Chem. 1992, 31, 3195.
(34) Recently, Tilley and co-workers studied the reaction of chlorobenzene
with triethylsilane in the presence of a rhodium complex bearing chelating
nitrogen-based ligands. They pointed out the Rh(V) intermediates in the catalytic
process. See ref 12e.
(35) Okazaki et al. reported that the reaction of the (2-phosphinoethyl)silyl
rhodium(I) complex with excess PhMe2SiH proceeded spontaneously at rt to
give the dihydrido rhodium(III) complex and (PhMe2Si)2 through a rhodium(V)
intermediate. See: Okazaki, M.; Ohshitani, S.; Tobita, H.; Ogino, H. Chem. Lett.
2001, 952.
FIGURE 1. Structure of TAC-101.
6676 J. Org. Chem. Vol. 73, No. 17, 2008

Arylation of Tertiary Silanes with Rhodium Catalyst
SCHEME 3. Application of the Rh-Catalyzed Si-C Bond Formation to the Synthesis of TAC-101 Analoguea
a Reagents and conditions: (i) 4-H2NC6H4CO2Me, EDC-HCl, Et3N, HOBt, DMF, 50 °C, 2 d, 81%; (ii) [Rh(cod)2]BF4 (5 mol%), Et3SiH, DMPU, rt, 4 d,
68%; (iii) aqueous NaOH/EtOH, rt, 1 d, 99%.
of Et3SiX.37–39 Although there was a possibility of the generation
of hexaethyldisilane as a side product, the peak derived from
disilane compound (-20 ppm) was not observed by 29Si NMR
during the catalysis.
silylation, which we reported previously. The reactivity order
of aryl halides was Ar-I > Ar-Br > Ar-Cl, Ar-OTf, and
the effects of the substituent groups on the aromatic rings of
the aryl halides were electron-donating > electron-withdrawing.
In the case of aryl bromide, the yield of silylated product was
slightly increased by treatment with an additional equal amount
of tetraethylammonium iodide. By using this reaction as the
key step, a concise synthesis of a pharmaceutical was achieved.
The importance of Rh(H)(SiR3)2 as the key catalytic species
and the reaction mechanism were discussed based on the results
Application. To demonstrate the utility of these reactions,
we undertook the short-step synthesis of a TAC-101 (4-[[[3,5-
bis(trimethylsilyl)phenyl]carbonyl]amino]benzoic acid) ana-
logue, which is a synthetic retinobenzoic acid with selective
binding affinity for RAR-R (Figure 1).13 Kagechika and Shudo
et al. have reported a synthetic process for the preparation of
TAC-101 in five steps using 1,3,5-tribromobenzene as the staring
material (total 3.4% yield). We have now developed a new
synthetic route for the TAC-101 derivative in three steps, using
the present Rh-catalyzed arylation of hydrosilane as a key step,
starting from 3,5-diiodobenzoic acid. The synthesis is outlined
in Scheme 3. Thus, 3,5-diiodobenzoic acid and methyl 4-ami-
nobenzoate were treated with 1-ethyl-3-(3-dimethylaminoproyl)-
carbodiimide hydrochloride (EDC-HCl) at 50 °C to produce the
corresponding amide product 47 with an 81% yield. The
introduction of trialkylsilyl groups with triethylsilane to the
aromatic ring using the rhodium catalyst proceeded smoothly
in DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)
at room temperature to produce the corresponding bistriethyl-
silylated product 48 with a 68% yield.40 The hydrolysis of the
ester group was performed with NaOH to produce the TAC-
101 derivative 49 with an almost quantitative yield. This new
arylation reaction is a straightforward method for the preparation
of an RAR-R-selective agonist for use in the treatment of liver
cancer.
1
of H and 29Si NMR measurements during the catalysis. It is
anticipated that these new reactions will begin to replace the
use of aryl organometallics in the synthesis of tetraorganosilanes
and that this new reactivity will facilitate the design of other
catalytic Si-H bond functionalities. Further applications of this
method to the preparation of other useful organosilane products
are currently under investigation.
Experimental Section
All the experiments were carried out under an argon atmosphere
in oven-dried glassware. Unless otherwise noted, the tertiary silanes
and aryl halides were purchased from commercial sources and used
without purification.
Typical Procedure for the Rhodium-Catalyzed Silylations
of Aryl (Pseudo)halides with Trialkylsilane. An oven-dried
Schlenk flask with a magnetic stirring bar was charged with
RhCl(CO)(PPh3)2 or [Rh(cod)2]BF4 (0.025 mmol) and K3PO4 (1.5
mmol) in air. Aryl (pseudo)halides (0.5 mmol) and tertiary silanes
(1.0 mmol) were also added at this time if the solid form of these
reagents was used. The flask was capped with a rubber septum,
evacuated, and then flushed with argon. Solvent (1 mL), aryl
(pseudo)halides (if a liquid, 0.5 mmol), and tertiary silanes (if a
liquid, 1.0 mmol) were then added successively with a syringe,
and the reaction mixture was stirred at room temperature for several
days. The reaction was quenched with water when the starting
material was not detected on thin-layer chromatography (TLC). The
aqueous layer was extracted three times with CH2Cl2 and dried
over Na2SO4. The solvent was evaporated under reduced pressure,
and column chromatography on silica gel produced the pure
silylated product.
Conclusion
In summary, we have developed a general method for the
silylation of aryl halides using tertiary silanes as the silylating
reagent. A variety of substrates with different functional groups
(electron-withdrawing and electron-donating groups) in para,
meta, and ortho positions were successfully coupled in the
presence of K3PO4 and a rhodium catalyst. The scope of the
potential substrates is broader than those of palladium-catalyzed
(2-Methoxyphenyl)triethylsilane (2).11b Colorless oil; 1H NMR
(500 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 6.94 (t, 2H, J ) 7.2
Hz), 6.82 (d, 1H, J ) 8.1 Hz), 3.77 (s, 3H), 0.93 (t, 9H, J ) 7.8
Hz), 0.78 (q, 6H, J ) 8.1 Hz); 13C NMR (125 MHz, CDCl3) δ
164.5 (Cq), 136.0 (CH), 130.5 (CH), 125.1 (Cq), 120.3 (CH), 109.3
(CH), 54.8 (CH3), 7.6 (CH3), 3.5 (CH2); EI-MS m/z 222 (M+).
(36) For reviews of Rh(V) complexes as reaction intermediates, see: (a)
Marciniec, B. Appl. Organomet. Chem. 2000, 14, 527. (b) Corey, J. Y.; Braddock-
Wilking, J. Chem. ReV. 1999, 99, 175.
(37) The formation of Et3SiOSiEt3 and Et3SiOH was also identified by GC-
MS analysis of the reaction mixture and by comparing the data with those of
authentic samples.
(38) Kunai et al. reported that the reaction of trialkylsilane and alkyl or aryl
iodide in the presence of palladium dichloride gave corresponding iodosilane
with a good to high yield, see: Kunai, A.; Sakurai, T.; Toyoda, E.; Ishikawa,
M.; Yamamoto, Y. Organometallics 1994, 13, 3233.
(39) As one of the referees pointed out, when we reacted Ph3SiH in K3PO4
with RhCl(CO)(PPh3)2 in NMP (in the absence of Ar-I), Ph3Si-O-SiPh3 was
obtained with ca. 50% conversion because of the reduction of amide to amine.
The presence of N-methylpyrrolidine has been confirmed by GC-MS. Igarashi
and Fuchikami have reported the transition-metal-complex-catalyzed reduction
of amides with hydrosilanes, see: Igarashi, M.; Fuchikami, T. Tetrahedron Lett.
2001, 42, 1945.
1
(3-Methoxyphenyl)triethylsilane (4). Colorless oil; H NMR
(500 MHz, CDCl3) δ 7.29 (t, 1H, J ) 7.7 Hz), 7.07 (d, 1H, J )
7.1 Hz), 7.03 (d, 1H, J ) 2.7 Hz), 6.89 (ddd, 1H, J ) 8.3, 2.8, 0.9
Hz), 3.82 (s, 3H), 0.96 (t, 9H, J ) 7.8 Hz), 0.81-0.76 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 158.8 (Cq), 139.2 (Cq), 128.8 (CH),
126.5 (CH), 119.9 (CH), 113.6 (CH), 55.0 (CH3), 7.4 (CH3), 3.3
(CH2); EI-MS m/z 222 (M+). Anal. Calcd for C13H22OSi: C, 70.21;
H, 9.97. Found: C, 70.11; H, 10.01.
J. Org. Chem. Vol. 73, No. 17, 2008 6677

Yamanoi and Nishihara
Synthetic Procedure for TAC-101 Derivative 49. (i) To a
solution of 3,5-diiodobenzoic acid41 (0.32 g, 0.86 mmol), methyl
4-aminobenzoate (0.19 g, 1.26 mmol), EDC-HCl (0.33 g, 1.72
mmol), and HOBt (0.21 g, 0.91 mmol) in DMF (4 mL) was added
Et3N (0.3 mL, 2.15 mmol) at rt under an argon atmosphere, and
the mixture was stirred at 50 °C for 2 d. The reaction was quenched
with sat. NaHCO3 aqueous solution and the organic layer was
separated. The aqueous layer was extracted five times with CH2Cl2.
The combined extracts were washed with 1 M HCl and dried over
Na2SO4, then the solvent was evaporated under reduced pressure.
The residue was purified by chromatography on silica gel (eluent:
hexane/EtOAc ) 8/1) to produce 47 as a colorless solid (0.35 g,
81%). (ii) To a mixture of 47 (109 mg, 0.21 mmol), K3PO4 (365
mg, 1.72 mmol), and [Rh(cod)2]BF4 (11 mg, 0.025 mmol) in DMPU
(1.0 mL) was added Et3SiH (0.12 mL, 0.75 mmol) at rt under Ar.
After being stirred for 4 d, the reaction was quenched with H2O
and the products were extracted five times with CH2Cl2. The solvent
was removed under reduced pressure. Purification was by column
chromatography on silica gel (eluent: hexane/EtOAc ) 5/1) to give
48 (71 mg, 68%). (iii) To a solution of 48 (281 mg, 0.58 mmol) in
EtOH (10 mL) was added 1 M NaOH solution (1.2 mL) and the
reaction was monitored by TLC. The reaction was quenched with
1 M HCl to pH 3, as indicated by pH paper. The quenched reaction
was extracted with CH2Cl2 five times and the combined extracts
were dried over Na2SO4. The solvent was removed under reduced
pressure to produce the TAC-101 analogue 49 (267 mg, 99%).
4-[[[3,5-Bis(triethylsilyl)phenyl]carbonyl]amino]benzoic acid
(49). Colorless cubes (recrystallized from hexane-CH2Cl2); Mp
222.5-225.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.26 (d, 2H, J )
8.8 Hz), 7.91 (br s, 1H), 7.81 (d, 2H, J ) 1.0 Hz), 7.81-7.78 (m,
3H), 0.99 (t, 18H, J ) 7.8 Hz), 0.87-0.82 (m, 12H); 13C NMR
(125 MHz, CDCl3) δ 171.5 (CdO), 167.1 (CdO), 144.0 (Cq), 143.0
(Cq), 137.5 (CH), 133.1 (Cq), 132.9 (CH), 131.6 (CH), 124.9 (Cq),
119.3 (CH), 7.4 (CH3), 3.3 (CH2); EI-MS m/z 469 (M+). Anal.
Calcd for C26H39NO3Si2: C, 66.48; H, 8.37; N, 2.98. Found: C,
66.30; H, 8.33; N, 2.98.
Acknowledgment. We thank Ms. Kimiyo Saeki of the
Elemental Analysis Center of the University of Tokyo for the
elemental analyses. This work was financially supported by
CREST from JST, by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and by the Global COE Program for
Chemistry Innovation, Japan.
Supporting Information Available: Compound character-
ization data, copies of the 1H and 13C NMR spectra, and the 1H
and 29Si NMR spectra used to monitor the reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(40) Because trimethylsilane is a volatile compound (bp 6.7 °C), triethylsi-
lylated retinoid benzoic acid 49 was prepared instead of TAC-101.
(41) 3,5-Diiodobenzoic acid is commercially available from Tyger Scientific
Inc. (Princeton, NJ, USA).
JO8008148
6678 J. Org. Chem. Vol. 73, No. 17, 2008