Study of the addition of Grignard reagents to 2-aryl-3H-indol-3-ones

Article abstract of DOI:10.1021/jo020715f

Grignard reagents are added to the carbonyl group of 2-aryl-3H-indol-3-ones to generate 3-alkyl-(or phenyl)-2-aryl-3H-indol-3-ols, which are in turn rearranged to yield 2-alkyl(or phenyl)-2-aryl-1,2-dihydro-3H-indol-3-ones.

Full text of DOI:10.1021/jo020715f

Stu d y of th e Ad d ition of Gr ign a r d Rea gen ts to
2-Ar yl-3H-in d ol-3-on es1
Yahua Liu and William W. McWhorter, J r.*
Medicinal Chemistry Research, Pharmacia Corporation, Kalamazoo, Michigan 49001
william.w.mcwhorter@pharmacia.com
Received November 26, 2002
Grignard reagents are added to the carbonyl group of 2-aryl-3H-indol-3-ones to generate 3-alkyl-
(or phenyl)-2-aryl-3H-indol-3-ols, which are in turn rearranged to yield 2-alkyl(or phenyl)-2-aryl-
1,2-dihydro-3H-indol-3-ones.
SCHEME 1
Indol-3-ones having a quaternary center at the 2
position are potentially useful intermediates in the
synthesis of alkaloids and pharmaceutical agents. 2,2-
Diaryl-1,2-dihydro-3H-indol-3-ones were originally pre-
pared by Lednicer and Emmert using the base-induced
rearrangement of 2,3-diaryl-3H-indol-3-ols, which were
obtained from 4H-3,1-benzoxazines.2 The thermally in-
duced rearrangement of a 2-aryl-3-methyl-3H-indol-3-ol
to 2-aryl-2-methyl-1,2-dihydro-3H-indol-3-one has also
been observed.3 This type of rearrangement is well-known
when the migrating group is tethered to the indoline
nucleus, and it can be induced thermally, under acidic
conditions, or under basic conditions.4 It has been el-
egantly employed as a key step in the synthesis of natural
products such as austamide, brevianamide, and aristo-
telone.5 The driving force for this type of rearrangement
is the gain in the resonance stabilization of the vinylogous
amide present in the rearrangement product relative to
the lack of such stabilization in the tertiary alcohol and
imine present in the starting material.
TABLE 1. Yield sa of 2 a n d 3 fr om Rea ction in Sch em e 1
RMgX
yielda (%)
entry
R
X
2
3
a
b
c
d
e
f
Me
Et
i-Pr
t-Bu
Br
Br
Cl
Cl
Br
Br
Br
Cl
87 (59)
81 (51)
73 (25)
67 (14)
92
1.1 (6)
2 (8)
8.7 (12)
15 (55)
0
Indol-3-ones having a quaternary center at the 2
position have also been prepared by the addition of
dialkyl malonate anion to 2-phenyl-3H-indol-3-one.6 Mar-
chetti and co-workers have studied the addition of
Grignard reagents to 2-phenyl-3H-indol-3-one (1).7 They
vinyl
allyl
Ph
78
5.8
g
h
91 (92)
73 (0)
0 (0)
22 (93)
Bn
a
Results of Marchetti et al.7 are in the parentheses.
(1) Presented in preliminary form: Liu, Y.; McWhorter, W. W., J r.
Abstracts of Papers, 224th National Meeting of the American Chemical
Society, Boston, MA, Aug 17-22, 2002; American Chemical Society:
Washington, DC, 2002; ORGN 698.
(2) Lednicer, D.; Emmert, D. E. J . Heterocycl. Chem. 1970, 575-
581.
observed that simple alkyl Grignard reagents appeared
to add primarily to the carbonyl group to yield tertiary
alcohols (2) often accompanied by a small amount of
2-alkyl-2-phenyl-1,2-dihydro-3H-indol-3-ones (3), while
addition of benzyl and tert-butyl Grignard reagents to the
same compound appeared to yield directly the 2-benzyl-
(or tert-butyl)-2-phenyl-1,2-dihydro-3H-indol-3-ones (3d
or 3h ) as the exclusive or preponderant product (Scheme
1 and the data in the parentheses of Table 1). To account
for this divergence in products formed, Marchetti and co-
workers proposed a single electron-transfer mechanism
(Scheme 2) to account for what they believed to be the
direct formation of 2-alkyl-2-phenyl-1,2-dihydro-3H-indol-
3-ones (3). When benzyl and tert-butyl Grignard reagents
were added to 1, they proposed that the single electron-
transfer mechanism was the predominant pathway.7
(3) Robinson, B.; Uppal Zubair, M. Pak. J . Sci. Ind. Res. 1976, 19,
214-214.
(4) (a) Witkop, B J . Am. Chem. Soc. 1950, 72, 614-620. (b) Patrick,
J . B.; Witkop, B. J . Am. Chem. Soc. 1950, 72, 633-634. (c) Witkop, B.;
Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 1558-1564. (d) Witkop, B.;
Patrick, J . B. J . Am. Chem. Soc. 1951, 73, 2188-2195.
(5) For examples, see: (a) Hutchison, A. J .; Kishi, Y. Tetrahedron
Lett. 1978, 539-542. (b) Hutchison, A. J .; Kishi, Y. J . Am. Chem. Soc.
1979, 101, 6786-6788. (c) Williams, R. M.; Glinka, T.; Kwast, E.;
Coffman, H.; Stille, J . K. J . Am. Chem. Soc. 1990, 112, 808-821. (d)
Stoermer, D.; Heathcock, C. H. J . Org. Chem. 1993, 58, 564-568.
(6) (a) Adam, J .-M.; Winkler, T. Helv. Chim. Acta 1984, 67, 2186-
2191. (b) Ling, K.-Q. Chin. J . Chem. 1996, 14, 265-270. (c) Tommasi,
G.; Bruni, P.; Greci, L.; Sgarabotto, P.; Right, L. J . Chem. Soc., Perkin
Trans. 1 1999, 681-686
(7) Berti, C.; Greci, L.; Marchetti, L. J . Chem. Soc., Perkin Trans. 2
1979, 233-236.
10.1021/jo020715f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/04/2003
2618
J . Org. Chem. 2003, 68, 2618-2622

Grignard Additions to 2-Aryl-3H-indol-3-ones
SCHEME 2
SCHEME 3
TABLE 2. Yield s of 8 a n d 9 fr om Rea ction in Sch em e 3
RMgX
yield (%)
entry
R
X
8
9
a
b
c
d
e
f
Me
Et
Br
Br
Cl
Cl
Br
Br
Br
Cl
92
90
83
59
93
89
96
90
0
1
5
6.2
0
2.9
0
5.2
i-Pr
t-Bu
vinyl
allyl
Ph
g
h
Bn
When planning to carry out a total synthesis of
hinckdentine A (6), we initially sought to apply the
observations of Marchetti and co-workers to the direct
construction of the quaternary center of the hinckdentine
A structure.8 We felt that if Marchetti and co-workers7
tulated radical anion intermediate could favor addition
of the Grignard reagent to the carbonyl group as we
observed. Therefore, we decided to examine the addition
of allylmagnesium bromide to 2-phenyl-3H-indol-3-one
(1) (Scheme 1, R ) allyl). In this case, we again observed
the addition of allylmagnesium bromide to the carbonyl
group to yield 3-allyl-2-phenyl-3H-indol-3-ol (2f), which
could be rearranged under acidic conditions (HCO2H/
toluene) to 2-allyl-2-phenyl-1,2-dihydro-3H-indol-3-one
(3f).
As a result, we began a systematic reexamination of
the results reported by Marchetti and co-workers.7 In
each case, we observed the formation of 3-alkyl(or phen-
yl)-2-phenyl-3H-indol-3-ols (2) as the major or exclusive
product when a Grignard reagent was added to 2-phenyl-
3H-indol-3-one (1) (Scheme 1 and Table 1). Further, we
found that each of these compounds could be rearranged
to the corresponding 2-alkyl(or phenyl)-2-phenyl-1,2-
dihydro-3H-indol-3-ones (3) (the minor products of the
first reaction, except in the cases of the vinyl and phenyl
Grignard reagents) under acidic conditions. We also
found that the acid-induced rearrangements were par-
ticularly fast in the case of the tert-butyl (2d ) and benzyl
(2h ) derivatives. In fact, in these cases, significant (15-
22%) rearrangement apparently took place during the
Grignard addition reactions or during the workup of
these reactions. We believe that addition of the Grignard
reagent always takes place at the carbonyl group and
that in some cases the minor products, 2-alkyl-2-phenyl-
1,2-dihydro-3H-indol-3-ones (3), arise by rearrangement
of the resulting tertiary alcohol (2) during the course of
the reaction or the workup of the reaction (Scheme 4).
Thus, it is possible that acidic or basic2 conditions
arising either during the reactions or during the workup
caused Marchetti and co-workers7 to miss the formation
of 3-benzyl-2-phenyl-3H-indol-3-ol (2h ) and to greatly
underestimate the extent to which 3-tert-butyl-2-phenyl-
3H-indol-3-ol (2d ) is formed. We have worked up the
were correct, an allyl Grignard reagent would behave
similarly to benzyl and tert-butyl Grignard reagents and
add to the imine rather than the carbonyl group of the
indol-3-one. The major product obtained from the addi-
tion of allylmagnesium bromide to 2-(2-bromophenyl)-3H-
indol-3-one (7) was somewhat unstable and was found
to rearrange with time to a ketone, the minor product of
the initial reaction (Scheme 3 and Table 2, R ) allyl).
We found that this rearrangement could be induced to
occur very cleanly by treating the initial adduct under
acidic condition (HCOOH/toluene). We identified the
rearrangement product as 2-allyl-2-(2-bromophenyl)-1,2-
dihydro-3H-indol-3-one (9f) and found the initial adduct
to be 3-allyl-2-(2-bromophenyl)-3H-indol-3-ol (8f). This
result appeared to be inconsistent with the reaction
mechanism proposed by Marchetti and co-workers.7
It could be argued that the presence of the bromine
atom might cause the 2-aryl substituent to rotate too far
out of the plane of the 3H-indol-3-one ring, thus making
the radical anion intermediate 4 proposed by Marchetti
and co-workers7 less stable. Lower stability of the pos-
(8) Liu, Y.; McWhorter, W. W. Synthesis of 8-Desbromohinckdentine
A. J . Am. Chem. Soc. 2003, 125, in press.
J . Org. Chem, Vol. 68, No. 7, 2003 2619

Liu and McWhorter
SCHEME 4
SCHEME 6
TABLE 4. Yield of Rea r r a n gem en t of 8 in to 9
entry
R
yield (%) of 9
aa
b
Me
Et
51
88
65
76
90
96
96
96
c
i-Pr
t-Bu
vinyl
allyl
Ph
db
e
SCHEME 5
f
g
h
Bn
a
b
At reflux for 2 h. In chloroform and at room temperature for
17 h.
In conclusion, we have studied the addition of Grignard
TABLE 3. Yield of Rea r r a n gem en t of 2 in to 3
reagents to 2-phenyl-3H-indol-3-one and 2-(2-bromophen-
yl)-3H-indol-3-one. The additions of the Grignard re-
agents take place at the carbonyl group, and the resulting
tertiary alcohols are rearranged to the 2-alkyl(or phenyl)-
2-aryl-1,2-dihydro-3H-indol-3-ones under acidic condi-
tions. Our results and literature reports show that the
rearrangement of 2 to 3 often takes place with great
facility under acidic or basic conditions or that it may be
thermally induced. It may be that the apparent addition
of malonate anion to the imine of indol-3-ones6 is in fact
an addition to the carbonyl group followed by a base-
mediated rearrangement to the observed products. Thus,
we believe that nucleophiles add to the carbonyl group
of indol-3-ones and that the resulting adducts rearrange
or can easily be caused to rearrange to 2,2-disubstituted-
1,2-dihydro-3H-indol-3-ones.
entry
R
yield (%) of 3
aa
b
Me
Et
30
84
89
65
88
89
88
88
c
i-Pr
t-Bu
vinyl
allyl
Ph
db
e
f
g
h
Bn
a
b
At reflux for 2 h. In chloroform and at room temperature for
17 h.
formation of 2d and 2h according to the published
experimental procedures of Marchetti and co-workers.7
In so doing, we obtained a higher percentage of rear-
rangement products 3d and 3h , but we did not observe
exclusive formation of 3h or as high a percentage of 3d
as previously reported.7 Since Marchetti and co-workers7
published only a general experimental procedure, it is
likely that an unpublished detail of their experimental
procedure accounts for this difference. Apparently, they
did not realize that 2 can be rearranged to 3 and
consequently proposed the mechanism shown in Scheme
2, which we believe is superseded by the data presented
herein.
After investigating a variety of conditions, we found
that the rearrangement of 2 into 3 occurred most ef-
ficiently upon refluxing a solution of 2 in toluene in the
presence of formic acid for 30 min (Scheme 5), except in
the case of 2d to 3d (R ) t-Bu) where the rearrangement
was best carried out with formic acid in chloroform at
room temperature for 17 h. The results of the rearrange-
ment reaction are presented in Table 3.
We have also explored the addition of Grignard re-
agents to 2-(2-bromophenyl)-3H-indol-3-one (7). The reac-
tions were also carried out in THF at room temperature
(Scheme 3) and results similar to those shown in Table
1 were observed (Table 2). The rearrangement reactions
of 8 were also explored (Scheme 6), and the results are
presented in Table 4. Like the rearrangement of 2d to
3d , the rearrangement of 8d to 9d was carried out in a
solution of formic acid in chloroform at room temperature.
Exp er im en ta l Section
Gen er a l. Proton magnetic resonance spectra were recorded
on a 400 MHz spectrometer and are reported in ppm on the δ
scale (J values are given in Hz). Infrared spectra (IR) and high-
resolution mass spectra (HRMS) were determined by the
Analytical Chemistry Department of Pharmacia. Anhydrous
THF was distilled prior to use from sodium metal/benzophe-
none. Brine refers to a saturated aqueous sodium chloride
solution. Solvent removal was accomplished by a rotary
evaporator operating at house vacuum (40-50 Torr). Column
chromatography was performed with silica gel 60 (230-400
mesh ASTM).
2-P h en yl-3-vin yl-3H-in d ol-3-ol (2e). Indolone 1 (207.2
mg, 1 mmol) was dissolved in dry THF (80 mL). Under
protection of nitrogen and at room temperature, a solution of
vinylmagnesium bromide in THF (1.0 M, 1.1 mL, 1.1 mmol)
was added dropwise and slowly. After stirring for 2 h, the
reaction mixture was concentrated under reduced pressure at
25-28 °C to a small volume, diluted with EtOAc (100 mL),
and washed with 10% NH4Cl solution (30 mL). The aqueous
wash was extracted with EtOAc (3 × 10 mL). The combined
EtOAc extracts were washed with brine (20 mL) and dried over
Na2SO4 for 50 min. Evaporation of solvent and then chroma-
tography with a mixture of hexane and EtOAc afforded 2e (217
mg, 92%): 1H NMR (CDCl3) 2.55 (br s, 1H, OH), 5.35 (dd, J )
10.6 and 1.0, 1H, dCH2), 5.73 (dd, J ) 17.1 and 1.0, 1H, d
CH2), 5.90 (dd, J ) 17.1 and 10.6, 1H, dCH), 7.26 (ddd, J )
7.4, 7.3 and 1.0, 1H, ArH), 7.38-7.51 (5H, ArH), 7.61 (d, J )
2620 J . Org. Chem., Vol. 68, No. 7, 2003

Grignard Additions to 2-Aryl-3H-indol-3-ones
7.6, 1H, ArH), 8.31 (dd, J ) 8.3 and 1.5, 2H, ArH); HRMS calcd
for C16H14NO (MH+) 236.1075, found 236.1069.
1H, ArH), 8.11 (dd, J ) 7.8 and 1.3, 1H, ArH); HRMS C18H19-
BrNO (MH+) calcd 344.0650, found 344.0651.
3-Meth yl-2-ph en yl-3H-in dol-3-ol (2a): yield 87%; 1H NMR
(CDCl3) 1.73 (s, 3H, CH3), 2.40 (br s, 1H, OH), 7.26 (ddd, J )
7.4, 7.1 and 1.0, 1H, ArH), 7.40 (ddd, J ) 7.6, 7.5 and 1.2, 1H,
ArH), 7.48-7.54 (4H, ArH), 7.59 (d, J ) 7.7, 1H, ArH), 8.37
(dd, J ) 8.3 and 1.8, 2H, ArH); HRMS C15H14NO (MH+) calcd
224.1075, found 224.1070.
2-(2-Br om op h en yl)-3-vin yl-3H-in d ol-3-ol (8e): yield 93%;
1H NMR (CDCl3) 2.53 (s, 1H, OH), 5.34 (dd, J ) 10.6 and 1.0,
1H, dCH2), 5.54 (dd, J ) 17.1 and 1.0, 1H, dCH2), 5.82 (dd, J
) 17.1 and 10.6, 1H, dCH), 7.30-7.41 (4H, ArH), 7.46 (ddd,
J ) 7.7, 7.5 and 1.5, 1H, ArH), 7.64 (dd, J ) 7.7 and 1.7, 1H,
ArH), 7.67 (d, J ) 7.7, 1H, ArH), 7.72 (dd, J ) 8.0 and 1.1,
1H, ArH); HRMS C16H13BrNO (MH+) calcd 314.0181, found
314.0184.
3-Allyl-2-(2-br om op h en yl)-3H-in d ol-3-ol (8f): yield 89%;
1H NMR (CDCl3) 2.53 (s, 1H, OH), 2.53 (dd, J ) 14.0 and 7.9,
1H, CH2), 2.75 (dd, J ) 14.0 and 6.8, 1H, CH2), 5.09 (dd, J )
17.0 and 1.5, 1H, dCH2), 5.14 (dd, J ) 10.2 and 1.5, 1H, d
CH2), 5.67 (dddd, J ) 17.0, 10.2, 7.9 and 6.8, 1H, dCH), 7.30-
7.36 (2H, ArH), 7.41-7.47 (3H, ArH), 7.66 (d, J ) 7.7, 1H,
ArH), 7.74 (dd, J ) 8.0 and 1.1, 1H, ArH), 7.78 (dd, J ) 7.7
and 1.7, 1H, ArH); HRMS C17H15BrNO (MH+) calcd 328.0337,
found 328.0329.
3-Eth yl-2-p h en yl-3H-in d ol-3-ol (2b): yield 81%; 1H NMR
(CDCl3) 0.51 (t, J ) 7.5, 3H, CH2CH3), 1.83 (s, 1H, OH), 2.16
(dq, J ) 13.3 and 7.5, 1H, CH2Me), 2.30 (dq, J ) 13.3 and 7.5,
1H, CH2Me), 7.27-7.56 (6H, ArH), 7.61 (d, J ) 7.5, 1H, ArH),
8.38 (dd, J ) 8.1 and 1.7, 2H, ArH); HRMS C16H16NO (MH+)
calcd 238.1232, found 238.1237.
1
2-P h en yl-3-iso-p r op yl-3H-in d ol-3-ol (2c): yield 73%; H
NMR (CDCl3) 0.37 (d, J ) 6.8, 3H, CHCH3), 1.33 (d, J ) 6.8,
3H, CHCH3), 1.55 (br s, 1H, OH), 2.51 (septet, J ) 6.8, 1H,
CHMe2), 7.26 (ddd, J ) 7.9, 7.5 and 0.8, 1H, ArH), 7.41 (dd, J
) 7.5 and 7.4, 1H, ArH), 7.47-7.54 (4H, ArH), 7.59 (d, J )
7.7, 1H, ArH), 8.39 (dd, J ) 6.8 and 1.2, 2H, ArH); HRMS
2-(2-Br om op h en yl)-3-p h en yl-3H-in d ol-3-ol (8g): yield
1
17H18NO (MH+) calcd 252.1388, found 252.1397.
3-ter t-Bu tyl-2-p h en yl-3H-in d ol-3-ol (2d ): yield 67%; H
96%; H NMR (CDCl3) 2.78 (br s, 1H, OH), 6.99 (dd, J ) 7.6
C
1
and 1.4, 1H, ArH), 7.17 (ddd, J ) 7.6, 7.5 and 1.2, 1H, ArH),
7.20-7.35 (9H, ArH), 7.49 (m, 1H, ArH), 7.64 (dd, J ) 8.0 and
1.0, 1H, ArH), 7.74 (d, J ) 7.7, 1H, ArH); HRMS C20H15BrNO
(MH+) calcd 364.0337, found 364.0333.
NMR (CDCl3) 0.93 (s, 9H, C(CH3)3), 2.43 (br s, 1H, OH), 7.22
(ddd, J ) 7.6, 7.5 and 1.0, 1H, ArH), 7.38 (dd, J ) 7.5 and 7.3,
1H, ArH), 7.41-7.48 (4H, ArH), 7.55 (d, J ) 7.5, 1H, ArH),
8.16 (dd, J ) 6.8 and 1.2, 2H, ArH); HRMS C18H20NO (MH+)
calcd 266.1545, found 266.1545.
3-Ben zyl-2-(2-br om op h en yl)-3H-in d ol-3-ol (8h ): yield
1
90%; H NMR (CDCl3) 2.47 (br s, 1H, OH), 2.81 (d, J ) 13.7,
1H, PhCH2), 3.28 (d, J ) 13.7, 1H, PhCH2), 6.65 (d, J ) 6.9,
1H, ArH), 7.07-7.09 (2H, ArH), 7.15 (ddd, J ) 7.6, 7.5 and
0.9, 1H, ArH), 7.26-7.47 (7H, ArH), 7.65 (d, J ) 7.7, 1H, ArH),
7.77 (dd, J ) 8.1 and 1.0, 1H, ArH), 7.91 (dd, J ) 7.7 and 1.7,
1H, ArH); HRMS C21H17BrNO (MH+) calcd 378.0494, found
378.0483.
1
3-Allyl-2-p h en yl-3H-in d ol-3-ol (2f): yield 78%; H NMR
(CDCl3) 2.50 (br s, 1H, OH), 2.73 (dd, J ) 13.7 and 7.7, 1H,
CH2), 3.03 (dd, J ) 13.7 and 6.8, 1H, CH2), 4.83 (dd, J ) 17.0
and 1.4, 1H, dCH2), 4.92 (dd, J ) 10.2 and 1.4, 1H, dCH2),
5.37 (dddd, J ) 17.0, 10.2, 7.7 and 6.8, 1H, dCH), 7.27 (ddd,
J ) 7.6, 7.5 and 1.0, 1H, ArH), 7.41 (dd, J ) 7.7 and 7.4, 1H,
ArH), 7.46 (d, J ) 7.5, 1H, ArH), 7.48-7.54 (3H, ArH), 7.58
(d, J ) 7.7, 1H, ArH), 8.37 (dd, J ) 8.3 and 1.8 Hz, 2H, ArH);
HRMS C17H16NO (MH+) calcd 250.1232, found 250.1223.
2,3-Dip h en yl-3H-in d ol-3-ol (2g): yield 91%; 1H NMR
(CDCl3) 2.72 (s, 1H, OH), 7.17-7.44 (11H, ArH), 7.67 (d, J )
7.7, 1H, ArH), 8.09 (dd, J ) 8.3 and 1.4, 2H, ArH); HRMS
2-P h en yl-2-vin yl-1,2-d ih yd r o-3H-in d ol-3-on e (3e). In-
dolol 2e (141.1 mg, 0.6 mmol) was dissolved in toluene (20 mL),
and 88% aqueous formic acid (5 mL) was added. After stirring
and refluxing for 30 min, the reaction mixture was cooled to
room temperature and carefully poured into saturated Na2-
CO3 solution (100 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic layers were washed with brine (10 mL) and
dried over Na2SO4. Evaporation of solvent and chromatography
with a mixture of hexane and EtOAc afforded 3e (124.2 mg,
88%). IR 3348 (N-H), 3088, 3057, 3030, 1726, 1690, 1676,
1620, 1586, 1494, 1410, 1003, 980, 928, 894, 751, 730, 700
cm-1; 1H NMR (CDCl3) 5.00 (br s, 1H, NH), 5.33 (dd, J ) 10.4
and 0.8, 1H, dCH2), 5.50 (dd, J ) 17.1 and 0.8, 1H, dCH2),
6.33 (dd, J ) 17.1 and 10.4, 1H, dCH), 6.89 (ddd, J ) 7.8, 7.1
and 0.7, 1H, ArH), 6.98 (d, J ) 8.1, 1H, ArH), 7.29-7.39 (3H,
ArH), 7.49-7.54 (3H, ArH), 7.64 (d, J ) 7.9, 1.3 and 0.8, 1H,
ArH); HRMS calcd for C16H14NO (MH+) 236.1075, found
236.1069.
C
20H16NO (MH+) calcd 286.1232, found 286.1241.
3-Ben zyl-2-ph en yl-3H-in dol-3-ol (2h ): yield 73%; 1H NMR
(CDCl3) 2.52 (s, 1H, OH), 3.11 (d, J ) 13.3, 1H, PhCH2), 3.60
(d, J ) 13.3, 1H, PhCH2), 6.77 (d, J ) 7.1, 2H, ArH), 7.04-
7.20 (5H, ArH), 7.35 (ddd, J ) 7.7, 7.5 and 1.3, 1H, ArH), 7.46
(d, J ) 7.5, 1H, ArH), 7.52-7.57 (3H, ArH), 8.09 (dd, J ) 8.3
and 1.9, 2H, ArH); HRMS C21H18NO (MH+) calcd 300.1388,
found 300.1395.
2-(2-Br om op h en yl)-3-m eth yl-3H-in d ol-3-ol (8a ): yield
1
92%; H NMR (CDCl3) 1.59 (s, 3H, CH3), 2.32 (br s, 1H, OH),
7.32-7.37 (2H, ArH), 7.42-7.47 (2H, ArH), 7.50 (ddd, J ) 7.3,
1.5 and 0.6, 1H, ArH), 7.63-7.66 (2H, ArH), 7.74 (dd, J ) 8.0
and 1.2, 1H, ArH); HRMS C15H13BrNO (MH+) calcd 302.0181,
found 302.0177.
2-Meth yl-2-ph en yl-1,2-dih ydr o-3H-in dol-3-on e (3a): yield
30% (at reflux for 2 h); IR (selected) 3370 (N-H), 1660 (CdO)
cm-1; 1H NMR (CDCl3) 1.60 (s, 3H, CH3), 5.97 (br s, 1H, NH),
6.87 (ddd, J ) 7.8, 7.2 and 0.6, 1H, ArH), 6.97 (d, J ) 8.3, 1H,
ArH), 7.27-7.38 (3H, ArH), 7.50-7.54 (3H, ArH), 7.63 (ddd,
J ) 7.9, 1.3 and 0.8, 1H, ArH); HRMS C15H14NO (MH+) calcd
224.1075, found 224.1081.
2-(2-Br om oph en yl)-3-eth yl-3H-in dol-3-ol (8b): yield 90%;
1H NMR (CDCl3) 0.79 (t, J ) 7.5, 3H, CH2CH3), 1.88 (dq, J )
13.7 and 7.5, 1H, CH2Me), 2.07 (dq, J ) 13.7 and 7.5, 1H, CH2-
Me), 2.40 (br s, 1H, OH), 7.32-7.36 (2H, ArH), 7.41-7.48 (3H,
ArH), 7.66 (d, J ) 7.7, 1H, ArH), 7.75 (dd, J ) 8.1 and 1.0,
1H, ArH), 7.82 (dd, J ) 7.7 and 1.7, 1H, ArH); HRMS C16H15
-
2-Eth yl-2-p h en yl-1,2-d ih yd r o-3H-in d ol-3-on e (3b): yield
BrNO (MH+) calcd 316.0337, found 316.0339.
84%; IR (selected) 3369 (N-H), 1666 (CdO) cm-1 1H NMR
;
2-(2-Br om op h en yl)-3-iso-p r op yl-3H-in d ol-3-ol (8c): yield
(CDCl3) 0.89 (t, J ) 7.5, 3H, CH2CH3), 2.19 (q, J ) 7.5, 2H,
CH2CH3), 5.03 (br s, 1H, NH), 6.84 (ddd, J ) 7.9, 7.0 and 0.8,
1H, ArH), 6.99 (d, J ) 8.3, 1H, ArH), 7.26-7.38 (3H, ArH),
7.50 (ddd, J ) 8.2, 7.2 and 1.3, 1H, ArH), 7.56-7.60 (3H, ArH);
HRMS C16H16NO (MH+) calcd 238.1232, found 238.1234.
2-P h en yl-2-iso-p r op yl-1,2-d ih yd r o-3H-in d ol-3-on e (3c):
1
83%; H NMR (CDCl3) 0.62 (d, J ) 6.8, 3H, CHCH3), 1.22 (d,
J ) 6.8, 3H, CHCH3), 2.25 (septet, J ) 6.8, 1H, CHMe2), 2.48
(br s, 1H, OH), 7.28-7.35 (2H, ArH), 7.40-7.50 (3H, ArH),
7.67 (d, J ) 7.5, 1H, ArH), 7.76 (dd, J ) 8.1 and 0.8, 1H, ArH),
8.00 (dd, J ) 7.8 and 1.6, 1H, ArH); HRMS C17H17BrNO (MH+)
calcd 330.0494, found 330.0498.
yield 89%; IR (selected) 3338 (N-H), 1678 (CdO) cm-1 1H
;
2-(2-Br om op h en yl)-3-ter t-bu tyl-3H-in d ol-3-ol (8d ): yield
59%; 1H NMR (CDCl3) 0.98 (s, 9H, C(CH3)3), 2.42 (s, 1H, OH),
7.25-7.30 (2H, ArH), 7.37 (ddd, J ) 7.7, 7.5 and 1.2, 1H, ArH),
7.42 (ddd, J ) 7.7, 7.5 and 1.2, 1H, ArH), 7.49 (d, J ) 7.3, 1H,
ArH), 7.64 (d, J ) 7.7, 1H, ArH), 7.74 (dd, J ) 8.1 and 1.3,
NMR (CDCl3) 0.84 (d, J ) 6.6, 3H, CH3), 0.87 (d, J ) 6.6, 3H,
CH3), 2.85 (septet, J ) 6.6, 1H, CHMe2), 5.10 (br, 1H, NH),
6.80 (ddd, J ) 7.8, 7.1 and 0.7, 1H, ArH), 7.01 (d, J ) 8.3, 1H,
ArH), 7.25-7.37 (3H, ArH), 7.48 (ddd, J ) 8.3, 7.1 and 1.2,
1H, ArH), 7.55 (ddd, J ) 7.9, 1.2 and 0.8, 1H, ArH), 7.62 (dd,
J . Org. Chem, Vol. 68, No. 7, 2003 2621

Liu and McWhorter
J ) 7.9 and 1.3, 2H, ArH); HRMS C17H18NO (MH+) calcd
252.1388, found 252.1380.
2-Allyl-2-(2-b r om op h e n yl)-1,2-d ih yd r o-3H -in d ol-3-
on e (9f): yield 96%; IR (selected) 3345 (N-H), 1680 (CdO)
cm-1; H NMR (CDCl3) 2.90 (dd, J ) 14.0 and 7.1, 1H, CH2),
1
2-Allyl-2-p h en yl-1,2-d ih yd r o-3H-in d ol-3-on e (3f): yield
89%; IR (selected) 3339 (N-H), 1677 (CdO) cm-1
;
1H NMR
3.30 (dd, J ) 14.0 and 7.3, 1H, CH2), 5.03 (d, J ) 10.0, 1H,
dCH2), 5.18 (dd, J ) 17.0 and 1.3 , 1H, dCH2), 5.37 (dddd, J
) 17.0, 10.0, 7.3 and 7.1, 1H, dCH), 5.95 (br s, 1H, NH), 6.84
(dd, J ) 7.7 and 7.3, 1H, ArH), 6.88 (d, J ) 8.3, 1H, ArH),
7.17 (ddd, J ) 7.8, 7.5 and 1.5, 1H, ArH), 7.31 (ddd, J ) 7.9,
7.3 and 1.2, 1H, ArH), 7.47 (ddd, J ) 8.3, 7.0 and 1.3, 1H,
ArH), 7.64-7.69 (3H, ArH); HRMS C17H15BrNO (MH+) calcd
328.0337, found 328.0340.
2-(2-Br om op h en yl)-2-p h en yl-1,2-d ih yd r o-3H -in d ol-3-
on e (9g): yield 96%; IR (selected) 3336 (N-H), 1689 (CdO)
cm-1; 1H NMR (CDCl3) 6.33 (s, 1H, NH), 6.87 (dd, J ) 7.7 and
7.3, 1H, ArH), 6.99 (d, J ) 8.3, 1H, ArH), 7.21-7.38 (7H, ArH),
7.53 (ddd, J ) 8.3, 7.1 and 1.2, 1H, ArH), 7.63-7.68 (3H, ArH);
HRMS C20H15BrNO (MH+) calcd 364.0337, found 364.0327.
2-Be n yl-2-(2-b r om op h e n yl)-1,2-d ih yd r o-3H -in d ol-3-
on e (9h ): yield 96%; IR (selected) 3346 (N-H), 1690 (CdO)
cm-1; 1H NMR (CDCl3) 3.46 (d, J ) 13.5, 1H, PhCH2), 3.84 (d,
J ) 13.5, 1H, PhCH2), 6.21 (br s, 1H, NH), 6.65-6.68 (2H,
ArH), 7.07-7.36 (8H, ArH), 7.53 (dd, J ) 8.4 and 1.0, 1H, ArH),
7.70 (dd, J ) 8.0 and 1.4, 1H, ArH), 7.77 (dd, J ) 7.9 and 1.7,
1H, ArH); HRMS C21H17BrNO (MH+) calcd 378.0494, found
378.0483.
(CDCl3) 2.66 (dd, J ) 13.9 and 8.5, 1H, CH2), 3.08 (dd, J )
13.9 and 5.8, 1H, CH2), 5.05 (br s, 1H, NH), 5.10 (dd, J ) 10.2
and 2.4, 1H, dCH2), 5.19 (dd, J ) 17.1 and 2.4, 1H, dCH2),
5.37 (dddd, J ) 17.1, 10.2, 8.5 and 5.8, 1H, dCH), 6.86 (ddd,
J ) 7.9, 7.1 and 0.8, 1H, ArH), 6.99 (d, J ) 8.1, 1H, ArH),
7.28-7.39 (3H, ArH), 7.51 (ddd, J ) 8.3, 7.1 and 1.2, 1H, ArH),
7.59 (ddd, J ) 7.9, 1.2 and 0.6, 1H, ArH), 7.64 (dd, J ) 8.3
and 1.4, 2H, ArH); HRMS C17H16NO (MH+) calcd 250.1232,
found 250.1228.
2,2-Diph en yl-1,2-dih ydr o-3H-in dol-3-on e (3g): yield 88%;
IR (selected) 3351 (N-H), 1676 (CdO) cm-1; 1H NMR (CDCl3)
5.20 (s, 1H, NH), 6.90 (ddd, J ) 7.9, 7.1 and 0.8, 1H, ArH),
6.96 (d, J ) 8.1, 1H, ArH), 7.31-7.37 (6H, ArH), 7.41-7.44
(4H, ArH), 7.52 (ddd, J ) 8.3, 7.1 and 1.2, 1H, ArH), 7.68 (d,
J ) 7.5, 1H, ArH); HRMS C20H16NO (MH+) calcd 286.1232,
found 286.1231.
2-Ben zyl-2-ph en yl-1,2-dih ydr o-3H-in dol-3-on e (3h ): yield
88%; IR (selected) 3327 (N-H), 1675 (CdO) cm-1 1H NMR
;
(CDCl3) 3.25 (d, J ) 13.7, 1H, PhCH2), 3.54 (d, J ) 13.7, 1H,
PhCH2), 4.97 (br s, 1H, NH), 6.79 (ddd, J ) 7.8, 7.1 and 0.7,
1H, ArH), 6.87 (d, J ) 8.3, 1H, ArH), 6.95-6.98 (2H, ArH),
7.15-7.18 (3H, ArH), 7.30-7.39 (3H, ArH), 7.43 (ddd, J ) 8.3,
7.0 and 1.2, 1H, ArH), 7.56 (ddd, J ) 7.9, 1.2 and 0.6, 1H,
ArH), 7.66 (dd, J ) 8.9 and 1.4, 2H, ArH); HRMS C21H18NO
(MH+) calcd 300.1388, found 300.1396.
2-ter t-Bu tyl-2-p h en yl-1,2-d ih yd r o-3H-in d ol-3-on e (3d ).
Indolol 2d (106.1 mg, 0.4 mmol) was dissolved in chloroform
(32 mL), and 88% aqueous formic acid (100 µL) was added.
After stirring for 17 h at room temperature, the reaction
mixture was concentrated under reduced pressure to a small
volume, diluted with EtOAc (40 mL), and washed with 2 M
Na2CO3 solution (20 mL). The aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic solution was
washed with brine (10 mL) and dried over Na2SO4. Evapora-
tion of solvent and chromatography with 16:1 hexane/EtOAc
afforded 3d (69 mg, 65%): IR 3329 (N-H), 3056, 2976, 1658,
2-(2-Br om op h en yl)-2-m et h yl-1,2-d ih yd r o-3H -in d ol-3-
on e (9a ): yield 51% (at reflux for 2 h); IR (selected) 3306 (N-
H), 1688 (CdO) cm-1; 1H NMR (CDCl3) 1.82 (s, 3H, CH3), 5.42
(br s, 1H, NH), 6.87-6.91 (2H, ArH), 7.19 (ddd, J ) 7.7, 7.5
and 1.7, 1H, ArH), 7.34 (ddd, J ) 7.9, 7.5 and 1.2, 1H, ArH),
7.51 (ddd, J ) 8.1, 7.3 and 1.5, 1H, ArH), 7.62 (dd, J ) 7.9
and 1.5, 1H, ArH), 7.63 (dd, J ) 7.9 and 1.7, 1H, ArH), 7.73
(ddd, J ) 7.9, 1.5 and 0.6, 1H, ArH); HRMS C15H13BrNO
(MH+) calcd 302.0181, found 302.0186.
2-(2-Br om op h e n yl)-2-e t h yl-1,2-d ih yd r o-3H -in d ol-3-
on e (9b): yield 88%; IR (selected) 3303 (N-H), 1685 (CdO)
cm-1; 1H NMR (CDCl3) 0.84 (t, J ) 7.5, 3H, CH2CH3), 2.22 (dq,
J ) 13.9 and 7.5, 1H, CH2Me), 2.52 (dq, J ) 13.9 and 7.5, 1H,
CH2Me), 6.01 (br s, 1H, NH), 6.82 (ddd, J ) 7.8, 7.1 and 0.7,
1H, ArH), 6.89 (d, J ) 8.3, 1H, ArH), 7.15 (ddd, J ) 7.9, 7.3
and 1.7, 1H, ArH), 7.29 (ddd, J ) 7.5, 7.3 and 1.3, 1H, ArH),
7.47 (ddd, J ) 8.3, 7.1 and 1.2, 1H, ArH), 7.62-7.66 (2H, ArH),
7.68 (ddd, J ) 7.9, 1.3 and 0.8, 1H, ArH); HRMS C16H15BrNO
(MH+) calcd 316.0337, found 316.0333.
1619, 1496, 1467, 1447, 1330, 1300, 1097, 893, 746, 716 cm-1
;
1H NMR (CDCl3) 1.03 (s, 9H, C(CH3)3), 5.40 (br s, 1H, NH),
6.77 (ddd, J ) 7.7, 7.0 and 0.6, 1H, ArH), 6.91 (d, J ) 8.3, 1H,
ArH), 7.26-7.36 (3H, ArH), 7.43 (ddd, J ) 8.2, 7.1 and 1.3,
1H, ArH), 7.58 (ddd, J ) 7.7, 1.2 and 0.8, 1H, ArH), 7.76 (dd,
J ) 7.5 and 1.5, 2H, ArH); HRMS C18H20NO (MH+) calcd
266.1545, found 266.1547.
2-(2-Br om op h en yl)-2-ter t-bu tyl-1,2-d ih yd r o-3H-in d ol-
3-on e (9d ): yield 76%; IR (selected) 3434 (N-H), 1684 (CdO)
1
cm-1; H NMR (CDCl3) 1.08 (s, 9H, C(CH3)3), 6.73 (ddd, J )
7.8, 7.1 and 0.7, 1H, ArH), 6.92 (d, J ) 8.3, 1H, ArH), 7.07 (s,
1H, NH), 7.11 (ddd, J ) 8.0, 7.2 and 1.7, 1H, ArH), 7.30 (ddd,
J ) 8.1, 7.3 and 1.7, 1H, ArH), 7.43 (ddd, J ) 8.3, 7.1 and 1.2,
1H, ArH), 7.55-7.60 (2H, ArH), 8.42 (dd, J ) 8.3 and 1.7, 1H,
ArH); HRMS calcd for C18H19BrNO (MH+) 344.0650, found
344.0672.
2-(2-Br om op h en yl)-2-iso-p r op yl-1,2-d ih yd r o-3H-in d ol-
3-on e (9c): yield 65%; IR (selected) 3395 (N-H), 1680 (CdO)
cm-1; 1H NMR (CDCl3) 0.92 (d, J ) 6.8, 6H, CH3), 2.85 (septet,
J ) 6.8, 1H, CHMe2), 6.29 (br s, 1H, NH), 6.78 (ddd, J ) 7.8,
7.1 and 0.7, 1H, ArH), 6.87 (d, J ) 8.3, 1H, ArH), 7.13 (ddd, J
) 7.9, 7.3 and 1.7, 1H, ArH), 7.30 (ddd, J ) 8.7, 7.3 and 1.5,
1H, ArH), 7.45 (ddd, J ) 8.3, 6.9 and 1.3, 1H, ArH), 7.62-
7.64 (2H, ArH), 7.83 (dd, J ) 8.0 and 1.8, 1H, ArH); HRMS
Ack n ow led gm en t. We are grateful to Pharmacia
Corporation for supporting a postdoctoral fellowship for
Y.L. We thank the Analytical Chemistry Department
of Pharmacia for acquiring the infrared spectra and the
high-resolution mass spectra. We are grateful to Prof.
Edwin Vedejs for reading our manuscript and suggest-
ing improvements to the text.
C
17H17BrNO (MH+) calcd 330.0494, found 330.0497.
2-(2-Br om op h e n yl)-2-vin yl-1,2-d ih yd r o-3H -in d ol-3-
on e (9e): yield 90%; IR (selected) 3284 (N-H), 1672 (CdO)
cm-1; H NMR (CDCl3) 5.35 (d, J ) 10.2, 1H, dCH2), 5.49 (d,
1
J ) 17.2, 1H, dCH2), 5.52 (br s, 1H, NH), 6.33 (dd, J ) 17.1
and 10.4, 1H, dCH), 6.89 (dd, J ) 7.7 and 7.3, 1H, ArH), 6.93
(d, J ) 8.3, 1H, ArH), 7.21 (ddd, J ) 7.8, 7.6 and 1.6, 1H, ArH),
7.34 (ddd, J ) 7.7, 7.5 and 1.2, 1H, ArH), 7.50 (ddd, J ) 8.3,
7.2 and 1.1, 1H, ArH), 7.59 (dd, J ) 8.0 and 1.6, 1H, ArH),
7.63 (dd, J ) 7.9 and 1.0, 1H, ArH), 7.70 (d, J ) 7.7, 1H, ArH);
HRMS C16H13BrNO (MH+) calcd 314.0181, found 314.0170.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
2a -h , 3a -h , 8a -h , 9a -h . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O020715F
2622 J . Org. Chem., Vol. 68, No. 7, 2003