Practical method for synthesis of 2,3-disubstituted indole derivatives promoted by β-(benzotriazol-1-yl)allylic O-stannyl ketyl radicals

Article abstract of DOI:10.1016/j.tetlet.2009.12.030

Treatment of β-aryl-β-(benzotriazol-1-yl)-α-primary alkyl (or aryl)-α,β-unsaturated ketones 1 with n-Bu₃SnH (4 equiv) in a catalytic amount of AIBN in PhH at reflux afforded 3-alkyl (or aryl)-2-arylindoles 8 in good yields. However, when tert-butyl group is bonded at α-position, 3-acyl (or aroyl)-2-arylindoles 9 were obtained as major products along with phenanthridines 5 as minor products.

Full text of DOI:10.1016/j.tetlet.2009.12.030

Tetrahedron Letters 51 (2010) 868–871
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Tetrahedron Letters
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Practical method for synthesis of 2,3-disubstituted indole derivatives
promoted by b-(benzotriazol-1-yl)allylic O-stannyl ketyl radicals
b
Taehoon Kim a, , Kyongtae Kim
*
a Kolon Life Science, Inc. 207-2, Mabuk-dong, Giheung-gu, Yongin-si, Gyeonggi-do 446-797, Republic of Korea
b Department of Chemistry, Seoul National University, Seoul 151-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of b-aryl-b-(benzotriazol-1-yl)-a-primary alkyl (or aryl)-a,b-unsaturated ketones 1 with
n-Bu3SnH (4 equiv) in a catalytic amount of AIBN in PhH at reflux afforded 3-alkyl (or aryl)-2-ary-
Received 17 October 2009
Revised 4 December 2009
Accepted 8 December 2009
Available online 11 December 2009
lindoles in good yields. However, when tert-butyl group is bonded at -position, 3-acyl (or
8
a
aroyl)-2-arylindoles 9 were obtained as major products along with phenanthridines 5 as minor
products.
Ó 2009 Elsevier Ltd. All rights reserved.
Radical cyclizations by n-Bu3SnH have attracted considerable
interest. The reactions of halides, alkenes, alkynes, sulfides, and
selenides that contain a suitably situated radical acceptor with
n-Bu3SnH can be utilized to produce cyclization products.1 In par-
ticular Enholm and Kinter2 have shown, among others that the
5- or 6-exo radical cyclization yielding cyclic alcohol via O-stannyl
ketyl radical.3
In continuation of our study on exploring the utility of benzotri-
azole as an synthetic auxiliary,4 we became interested in the gener-
ation of b-(benzotriazol-1-yl)allylic O-stannyl ketyl radical 2,
because its canonical form 3, aryl(benzotriazol-1-yl)[b-(O-stan-
nyl)vinyl]methyl radical, is structurally analogous to diaryl-
(benzotriazol-1-yl)methyl radical reported.5 And the radical 2 could
be readily generated in one step by treatment of 1 with tributyltin
reaction of tributyltin radical with
a,b-unsaturated carbonyl
undergoes free radical cyclizations to give substituted cyclopen-
tane rings and bicyclo[3,3,0]ring systems. Similarly, the reaction
of aldehyde with tributyltin radical was reported to undergo
N
N
N
N
N
N
N
N
N
R1
R1
n
-Bu3Sn.
R1
R2
SnBu3
Ar
R2
SnBu3
Ar
Ar
R2
O
O
O
2
1
3
O
R1
-N2
H2O
O
R2
Ar
+
N
R2
N
R1
4
5
Scheme 1.
* Corresponding author. Tel.: +82 31 280 8723; fax: +82 31 280 8760.
E-mail address: kth419@unitel.co.kr (T. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.030

T. Kim, K. Kim / Tetrahedron Letters 51 (2010) 868–871
869
N
N
N
N
N
K2Cr2O7,
H2SO4
N
N
N
R2MgX
R1
R1
R1
N
THF
THF
Ar
R2
Ar
R2
Ar
H
25oC, 1h
25oC, 1h
HO
O
O
6
7
1
Scheme 2.
Table 1
Yields of products 1 and 7, and the ratio of the stereoisomers
We report now a novel method for the title compounds using
benzotriazole as a synthetic auxiliary in this Letter. Compound 1
(Scheme 2) was prepared by Grignard reaction followed by oxida-
tion reaction of 2,3-disubstituted-3-(benzotriazol-1-yl)propanal 6
whose synthesis was previously described.4a Yields of 1 and 7
along with the (E)/(Z) ratios are summarized in Table 1.
Ar
R1
R2
Yielda (%)
7 (E:Z)b
1 (E:Z)b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
2-Furyl
Ph
2-Naphthyl
2-Thienyl
4-MeC6H4
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Ph
1-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
1-Naphthyl
2-Thienyl
Ph
Ph
Me
90 (1.21:1)
90 (2.97:1)
77 (1.45:1)
73 (3.12:1)
80 (2.22:1)
87 (3.29:1)
85 (3.16:1)
80 (6.17:1)
84 (2.68:1)
89 (1.97:1)
86 (6.01:1)
92c
87 (1.28:1)
88 (2.86:1)
82 (1.56:1)
79 (2.91:1)
81 (2.44:1)
85 (3.08:1)
89 (2.94:1)
82 (4.83:1)
89 (2.84:1)
81 (1.89:1)
78 (5.31:1)
82c
Treatment of 1f (Ar = 3-MeC6H4, R1 = R2 = Ph) with n-Bu3SnH
(1.0 equiv) in the presence of azobisisobutyronitrile (AIBN)
(0.5 equiv) in PhH for 2 h at reflux gave 2-(3-methylphenyl)-3-
phenylindole 8f (Ar = 3-MeC6H4, R1 = Ph) and 2-(3-methylphenyl)-3-
benzoyl-3-phenyl-3H-indole 4f (Ar = 3-MeC6H4, R1 = R2 = Ph) in 38%
and 44% yields, respectively6 (Scheme 3). Upon increasing the con-
centration of n-Bu3SnH (2.5 equiv) under the same conditions, the
yield of 8f increased to 79% at the expense of that of 4f (10%). A
further increase of n-Bu3SnH (4.0 equiv) resulted in a yield of 8f
to 86% and no 4f was detected. In addition, compound 4f was con-
verted to compound 8f in 92% yield using n-Bu3SnH under the
same foregoing conditions.
Ph
3-MeC6H4
3-MeC6H4
3-MeC6H4
2,3-Me2C6H3
4-FC6H4
Ph
Ph
Ph
Ph
2-MeC6H4
2,5-Me2C6H3
4-MeOC6H4
4-MeOC6H4
71c
84c
85c
83c
83 (7.07:1)
80 (5.93:1)
89 (2.77:1)
71c
84d
82e
To find the locus of the R2CO moiety detached in the course of
the conversion from 4 to 8, the selected compound 1c (Ar = R1 = Ph,
R2 = 1-naphthyl) was subjected to the same conditions as de-
scribed in expectation of a solid by-product (Scheme 4). From the
reaction using n-Bu3SnH were isolated 8c, 4c, and 1-naphthalde-
hyde 10a (X = H) in 76%, 11%, and 52% yields, respectively, along
with a small amount of n-hexabutylditin, whose structure was
confirmed on the basis of the 1H NMR spectroscopy. When n-
84 (2.78:1)
4-MeOC6H4
78c
a
Isolated yields.
The ratios of stereoisomers were determined based on the 1H NMR (300 MHz,
b
CDCl3) spectroscopic data.
c
(E)-isomer only.
Yield of (E)-1o from pure (E)-7o.
Yield of (E)-1p from pure (E)-7p.
d
e
radical whereas the reported radical was generated by lithiation of
diaryl(benzotriazol-1-yl)methanes followed by addition of iodine
in two steps. Furthermore, the applicability of the radical generated
according to the literature method, organic synthesis does not ap-
pear to be promising despite the existence of the mechanistic signif-
icance. The radical 3 could be expected to induce the ring opening by
loss of nitrogen, and the subsequent by cyclization to give indole
derivatives 4 as well as phenanthridine derivatives 5, if any, as in a
fashion to diaryl(benzotriazol-1-yl)methyl radical (Scheme 1).
Bu3SnD was used, we obtained the same products, and a-deute-
rio-naphthalene-1-carbaldehyde (10b) instead of 10a.
In the meantime, R1 = t-Bu, 3-acyl (or aroyl)-2-arylindoles 9 to-
gether with a significant amount of phenanthridines 5 were iso-
lated. Yields of compounds 5, 8, and 9 are summarized in Table 2.
The formation of the products 4, 5, 8, and 9 may be initiated by
the generation of b-(benzotriazol-1-yl)allylic O-stannyl ketyl radi-
cal 2 whose canonical form 3 undergoes the ring opening by loss of
nitrogen to give N-a,b-unsaturated alkylidenaminophenyl radical
i
R1
O
R1
R1 : pri-alkyl, aryl
R2
Ar
N
Ar
+
N
H
8
4
i
1
O
R2
Ar
R1 = tert-Bu
O
+
N
R2
N
H
t
-Bu
9
5
Scheme 3. Reagents and conditions: (i) n-Bu3SnH (2.5 equiv), AIBN (0.5 equiv), PhH, 80 °C, 2 h.

870
T. Kim, K. Kim / Tetrahedron Letters 51 (2010) 868–871
N
N
O
X
N
n-Bu3SnX(2.5 equiv.)
AIBN (0.5equiv)
8c
4c
+
+
PhH, 80oC, 2h
O
10a. X = H
10b. X = D
1c
Scheme 4.
comprising a mixture of conformational isomers 11a and 11b be-
cause of the occurrence of a rapid inversion of the imino nitrogen
(Scheme 5). The intramolecular cyclization of the conformer 11a
would afford an O-stannyl ketyl radical 12, which is reverted to
compound 4 by loss of n-Bu3SnÁ. Alternatively the ketyl radical 12
abstracts a hydrogen atom followed by hydrolysis to give an inter-
mediate alcohol 13, which rapidly undergoes an oxidative C–C
bond cleavage to give compound 8 and aldehyde (R2CHO). An at-
tempt was made to prepare 13 (Ar = R1 = Ph, R2 = 1-naphthyl) by
treating compound 4c with NaBH4 (2 equiv) in EtOH for 15 min
at room temperature. However, only compound 8c was isolated
in 91% yield. None of the desired alcohol was detected. The result
suggests that compound having the structure analogous to the
intermediate 13 is very unstable. No literature precedents have
been found. Consequently the reactions give compound 8 as major
products in the presence of excess amount of n-Bu3SnH. On the
other hand, when R1 = t-Bu, the O-stannyl ketyl radical 12 is envis-
aged to readily extrude tert-butyl radical to produce 3-alkyliden-
3H-indolin 14, which undergoes hydrolysis, compounds 5 may be
formed by an intramolecular aromatic radical substitution reaction
of the conformer 11b followed by hydrolysis.
Consequently, the reactions give compounds 8 as major prod-
ucts in the presence of excess amount of n-Bu3SnH. On the other
hand, when R1 = t-Bu, the O-stannyl ketyl radical 12 is envisaged
to readily extrude tert-butyl radical to produce 3-alkyliden-3H-
indolin 14, which undergoes hydrolysis, compounds 5 may be
formed by an intramolecular aromatic radical substitution reaction
of the conformer 11b followed by hydrolysis. It is interesting to
note that compounds 5 were isolated only in the cases where
R1 = t-Bu. Moreover, with Ar bearing one ortho substituent, yields
of 5o (20%) and 5p (trace) were comparable to that of 5l (27%)
bearing no ortho substituent. The result may be ascribed to the ste-
ric bulkiness of the tert-butyl group which causes the equilibrium
concentration of 11b to be significant to avoid the steric repulsion
arising from the bulky tert-butyl group and the phenyl radical.
In summary, b-(benzotriazol-1-yl)allylic O-stannyl ketyl radical
produced from b-aryl-b-(benzotriazol-1-yl)-a-primary alkyl (or
aryl)- ,b-unsaturated ketones can be utilized as precursors for
a
N
N
R2
Ar
Ar R2
R1
n
-Bu3Sn
- N2
N
R1
2
3
OSnBu3
N
OSnBu3
Ar
R2
R1
N
O
1
11b
11a
- H
R2
R1:
p
aryl
-alkyl,
R2
n
-Bu3Sn
R1
-(Bu3Sn)2
R1
O
R2
OSnBu3
Ar
Ar
n
-Bu3Sn
N
N
OSnBu3
N
4
R1:
p
aryl
-alkyl,
t
-Bu
12
n
-Bu3SnH
H2O
R2
R2
OH
H
OSnBu3
R1
R1
R1:
-Bu
t
-Bu
H2O
H
-
t
O
Ar
Ar
R2
N
N
N
Bu
t
-
13
5
R2
O
R1
OSnBu3
Ar
R2
Ar
H2O
R2CHO
Ar
+
N
N
N
H
8
H
14
9
Scheme 5.

T. Kim, K. Kim / Tetrahedron Letters 51 (2010) 868–871
871
Table 2
1986; (b) Motherwell, W. B.; Crich, D. Free Radicals Chain Reactions in
Organic Synthesis; Academic Press: New York, 1992; (c) Giese, B.; Kopping,
B.; Göbel, T.; Dickhaut, J.; Thoma, G.; Kuicke, K. J.; Trach, F. Org. React.
1996, 48, 301; (d) Curran, D. P. Synthesis 1988, 489–513; (e) Flisin´ ska, J.;
Les´niaka, S.; Nazarskib, R. B. Tetrahedron 2004, 60, 8181–8188; (f) Benati,
L.; Bencivenni, G.; Leardini, R.; Minozzi, M.; Nanni, D.; Scialpi, R.;
Spagnolo, P.; Zanardi, G. J. Org. Chem. 2005, 70, 3046–3053; (g) Kim, I.
S.; Dong, G. R.; Jung, Y. H. J. Org. Chem. 2007, 72, 5424–5426; (h)
Edetanlen-Elliot, O.; Fitzmaurice, R. J.; Wilden, J. D.; Caddick, S. Tetrahedron
Lett. 2007, 48, 8926–8929; (i) Hirasawa, S.; Tajima, Y.; Kameda, Y.;
Nagano, H. Tetrahedron 2007, 63, 10930–10938.
Yields of compounds 5, 8, and 9
Ar
R1
R2
Yielda (%)
8
9
5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
2-Furyl
Ph
2-Naphthyl
2-Thienyl
4-MeC6H4
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Ph
1-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
1-Naphthyl
2-Thienyl
Ph
Ph
Me
857
757,b
767,b
718,b
84
86
87
90
Ph
2. (a) Enholm, E. J.; Kimter, K. S. J. Am. Chem. Soc. 1991, 113, 7784–7785; (b)
Enholm, E. J.; Kinter, K. S. J. Org. Chem. 1995, 60, 4850–4855.
3. (a) Parsons, A. F.; Pettifer, R. M. Tetrahedron Lett. 1997, 38, 5907–5910; (b)
Bebbington, D.; Bentley, Jon.; Nilsson, P. A.; Parsons, A. F. Tetrahedron Lett. 2000,
41, 8941–8945.
4. (a) Kim, T.; Kim, K.; Park, Y. J. Eur. J. Org. Chem. 2002, 493–502; (b) Kim, T.; Kim,
K. Tetrahedron Lett. 2002, 43, 3021–3024; (c) Choi, Y.-A.; Kim, K.; Park, Y. J.
Tetrahedron Lett. 2003, 44, 7507–7511; (d) Kim, T.; Kim, K. J. Heterocycl. Chem.,
accepted for publication.
3-MeC6H4
3-MeC6H4
3-MeC6H4
2,3-Me2C6H3
4-FC6H4
Ph
Ph
Ph
Ph
2-MeC6H4
2,5-Me2C6H3
4-MeOC6H4
4-MeOC6H4
81
899
7310
6711
61
64
69
16
27
30
28
20
—
13
25
5. Katritzky, A. R.; Yang, B. J. Org. Chem. 1998, 63, 1467–1472.
6. Typical procedure: To a solution of 1f (130 mg, 0.31 mmol) in benzene (20 mL)
were added n-Bu3SnH (91 mg, 0.31 mmol) and AIBN (25 mg, 0.16 mmol) at
room temperature. The mixture was heated for 2 h at reflux followed by
addition of water (30 mL) and was extracted with CH2Cl2 (20 mL Â 3). The
combined organic extracts were dried over MgSO4. After removal of the
solvent in vacuo, the residue was chromatographed on a silica gel column
c
74
7512
66
4-MeOC6H4
a
Isolated yields when n-Bu3SnH (4.0 equiv) was used.
When n-Bu3SnH (2.5 equiv) was used, not only compound 8b–d but also
b
(70–230 mesh, 3 Â 10 cm, EtOAc/n-hexane
(33 mg, 38%): mp 109–111 °C (n-hexane); IR (KBr) 3378, 3046, 3023, 2911,
1602, 1500, 1454, 1332, 1243, 1012, 769, 701 cmÀ1 1H NMR (CDCl3) d 2.40 (s,
= 1:7) to give compound 8f
compounds 4b (Ar = R1 = R2 = Ph, 13%) and 4c (Ar = R1 = Ph, R2 = 1-naphthyl, 11%)
were isolated. However, no 4d (Ar = R2 = Ph, R1 = Me) was formed.
;
3H, CH3), 7.15–7.26 (m, 4H, ArH), 7.31–7.42 (m, 3H, ArH), 7.45–7.57 (m, 5H,
ArH), 7.80 (d, J = 7.8 Hz, 1H, ArH), 8.27 (s, 1H, NH); 13C NMR (CDCl3) d 22.0,
111.4, 115.4, 120.1, 120.9, 123.1, 126.0, 126.7, 128.9, 129.0, 129.1, 129.2,
130.7, 133.1, 134.8, 135.7, 136.3, 138.8. Anal. Calcd for C21H17N: C, 89.01; H,
6.05; N, 4.94. Found: C, 88.95; H, 6.11; N, 5.08 and 4f (52 mg, 44%): mp 152–
154 °C (EtOAc/n-hexane); IR (KBr) 3058, 2921, 2854, 1673, 1596, 1525, 1446,
c
Trace (it was not isolated.)
the synthesis of 3-alkyl (and aryl)-2-arylindoles and 3-acyl (and ar-
oyl)-2-arylindoles.
1268, 1203, 1147, 848, 696 cmÀ1 1H NMR (CDCl3) d 2.34 (s, 3H, CH3), 7.13 (t,
;
J = 8.3 Hz, 2H, ArH), 7.18–7.30 (m, 7H, ArH), 7.31–7.37 (m, 4H, ArH), 7.41 (d,
J = 7.5 Hz, 1H, ArH), 7.45 (t, J = 7.5 Hz, 1H, ArH), 7.60–7.65 (m, 1H, ArH), 7.84
(d, J = 7.7 Hz, 1H, ArH), 7.96 (s, 1H, ArH); 13C NMR (CDCl3) d 21.8, 78.6, 122.3,
124.1, 127.3, 127.5, 128.0, 128.4, 128.7, 128.8, 129.0, 129.7, 129.8, 132.6,
133.0, 133.1, 137.7, 138.4, 138.8, 142.9, 155.8, 178.7, 197.0 (signal of one
aromatic C atom not visible). Anal. Calcd for C28H21NO: C, 86.79; H, 5.46; N,
3.61; O, 4.13. Found: C, 86.92; H, 5.52; N, 3.52.
Acknowledgments
This work was supported by the S.N.U. foundation of Overhead
Research Fund and Kolon Life Science Inc. Spectroscopic data were
obtained from the Korea Basic Science Institute, Seoul branch.
7. (a) Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli, F.; Parisi, L. M. Synthesis 2003,
728–734; (b) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.;
Spagnolo, P.; Strazzari, S.; Zanardi, G. J. Org. Chem. 2003, 68, 3454–3464; (c)
Nakamura, Y.; Ukita, T. Org. Lett. 2002, 4, 2317–2320.
Supplementary data
8. Furstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468–4475.
9. (a) Buu-Hoi, N. P.; Hoan, N.; Jacquignon, P. Recl. Trav. Chim. Pays-Bas 1949, 68,
781–785; (b) Zhang, H.-C.; Ye, H.; White, K. B.; Maryanoff, B. E. Tetrahedron Lett.
2001, 42, 4751–4754.
10. Kaneko, C.; Fujii, H.; Kawai, S.; Hashiba, K.; Karasawa, Y.; Wakai, M.; Hayashi,
R.; Somei, M. Chem. Phrm. Bull. 1982, 30, 74–86.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.030.
References and notes
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Synthesis: Formation of Carbon–Carbon Bonds; Pergamon Press: New York,