Regioselective synthesis of 3-alkylindoles mediated by zinc triflate

Article abstract of DOI:10.1021/jo010996b

Zinc triflate was found to be an effective reagent for the C3-alkylation of indoles by alkyl halides in the presence of Huenig's base and tetrabutylammonium iodide. This new method for indole alkylation proceeds by a SN1-like pathway, and is general for allylic, benzylic, and tertiary halides.

Full text of DOI:10.1021/jo010996b

J . Org. Chem. 2002, 67, 2705-2708
2705
Regioselective Syn th esis of 3-Alk ylin d oles
Med ia ted by Zin c Tr ifla te
Xiuwen Zhu and A. Ganesan*
Department of Chemistry, University of Southampton,
Southampton SO17 1BJ , United Kingdom
ganesan@soton.ac.uk
Received October 12, 2001
Abstr a ct: Zinc triflate was found to be an effective reagent
for the C3-alkylation of indoles by alkyl halides in the
presence of H u¨ nig’s base and tetrabutylammonium iodide.
This new method for indole alkylation proceeds by a SN1-
like pathway, and is general for allylic, benzylic, and tertiary
halides.
The alkylation of indole by a prenyl electrophile (eq 1)
1
has been reported on a number of occasions. However,
it suffers from several fundamental problems. First, there
is the question of regioselectivity with respect to the
indole: alkylation at C-3 versus C-2 and N-1 to give 1-3
respectively. Second, there is a regiochemical issue with
the alkylating agent, as varying amounts of the ‘reverse-
under several Pd(0)-catalyzed conditions was unsuccess-
ful, and we are unaware of any precedents for similar
reactions.
Studies of N- versus C-protonation and alkylation with
5
prenyl’ isomer 4 arising from S
N
2′ attack are also
ambident metal indolyl salts indicate that reaction at
produced. Finally, the desired product 1 remains reactive
C-3 is favored by more covalently coordinated metals, soft
leaving groups, and nonpolar solvents. With this as our
starting point, we screened a set of 10 metal triflates
(excluding alkali or alkaline earth metals) for their ability
to effect the prenylation of indole. Metal triflates were
chosen because of numerous examples of their ability to
promote C-C bond-forming reactions under mild condi-
tions, as well as their commercial availability at relatively
to further alkylation, resulting in diprenylated com-
2
pounds such as 5. In their seminal studies, Wenkert et
al. investigated several approaches for a high yielding
synthesis of 1. Treatment of indole with a Grignard
reagent to form the indolylmagnesium salt, a common
3
method of activating indole prior to alkylation, afforded
only 34% of 1 and 4 in a 17:1 ratio, together with small
quantities of 3 and 5. The preferred route involved
protecting the nitrogen of 3-bromoindole as a sulfonamide
followed by low-temperature generation of the 3-lithio
species with tert-butyllithium, transmetalation to the
cuprate, reaction with prenyl bromide, and sulfonamide
deprotection. The ratio of 1:4 was undisclosed, but was
6
low cost. Furthermore, the elegant work by Carreira has
shown that metal acetylides are generated by reaction
of an acetylene with a metal triflate and a tertiary amine.
Since indole is significantly more acidic (pK
a
∼ 16) than
acetylenes, it was anticipated that the indolylmetal salt
would be generated in situ, thus avoiding the need for
strong bases such as a Grignard reagent.
4
reported to be 4:1 in the related alkylation of a N-silyl-
protected 3-cuproindole.
The results (Table 1) indicate that all the triflates
studied are capable of effecting prenylation, although the
yield and regioselectivity is highly dependent on the
nature of the metal. Zinc triflate gave by far the highest
yield, and it was selected for further optimization of
reaction conditions. Switching the solvent from toluene
In the course of synthetic studies directed toward
alkaloid natural products, we needed access to indoles
containing an isoprenoid unit at C-3. As the multistep
sequence via metalation appeared impractical for scale-
up, we reinvestigated the direct alkylation of indole with
prenyl bromide. An early attempt involved transition
metal catalyzed cross-coupling reactions. However, the
coupling of indoles with either prenyl bromide or acetate
2 2
to THF, CH Cl , or DMF was less satisfactory by HPLC
analysis of the reaction mixture. This result is consistent
with a lower degree of dissociation of the nitrogen-metal
bond in a nonpolar medium, promoting C-alkylation.
Several tertiary amine bases were examined, and N,N-
diisopropylethylamine found to give the best result (yields
and ratio of 1:4 given in parentheses): N,N-diisopropyl-
ethylamine (59%, 20:1), pempidine (36%, 23:1), pyridine
(1) For early examples, see: (a) Casnati, G.; Francioni, M.; Guare-
schi, A.; Pochini, A. Tetrahedron Lett. 1969, 2485-2487. (b) Somei,
M.; Natsume, M. Tetrahedron Lett. 1973, 27, 2451-2454. (c) Bocchi,
V.; Casnati, G.; Marchelli, R. Tetrahedron 1978, 34, 929-932. (d) Araki,
S.; Manabe, S.; Butsugan, Y. Bull. Chem. Soc. J pn. 1984, 57, 1433-
1
434. (e) De Renzi, A.; Lombardi, A.; Panunzi, A.; Saporito, A. Gazz.
Chim. Ital. 1988, 118, 657-660.
2) Wenkert, E.; Angell, C.; Ferreira, V. F.; Michelotti, E. L.; Piettre,
S. R.; Sheu, J .-H.; Swindell, C. S. J . Org. Chem. 1986, 51, 2343-2351.
3) For a review, see: Sundberg, R. J . Indoles; Academic Press:
London, 1996; pp 105-118.
4) (a) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J . J . Org.
(35%, 12:1), DBU (45%, 18:1). Compared to zinc triflate,
(
(5) (a) Powers, J . C.; Meyer, W. P.; Parsons, T. G. J . Am. Chem.
(
Soc. 1967, 89, 5812-5820. (b) Nunomoto, S.; Kawakami, Y.; Ya-
mashita, Y.; Takeuchi, H.; Eguchi, S. J . Chem. Soc., Perkin Trans. 1
1990, 111-114.
(6) Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J . Am. Chem. Soc.
1999, 121, 11245-11246.
(
Chem. 1994, 59, 10-11. (b) Amat, M.; Sathyanarayana, S.; Hadida,
S.; Bosch, J . Heterocycles 1996, 43, 1713-1718.
1
0.1021/jo010996b CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/21/2002

2
706 J . Org. Chem., Vol. 67, No. 8, 2002
Notes
Ta ble 1. Scr een in g of Meta l Tr ifla tes for th e P r om otion
of In d ole P r en yla tion
triflates than zinc were poorer reagents (Table 1). It is
possible that zinc represents the optimal balance in its
ability to both activate the halide and coordinate to the
indole nitrogen.
Zinc triflate has previously been employed in the ring
opening of N-acylaziridines by indole, although the reac-
metal triflate
yield of 1 + 4 (%)a
ratio of 1:4b
Cu(I)
Cu(II)
Ag(I)
Zn(II)
Hg(II)
In(III)
Sn(II)
Sc(III)
La(III)
Yb(III)
18
5
29
55
36
30
2
2
4
13
2:1
1:1
7
32:1
10:1
>80:1
13:1
N
tion is likely to be S 2 in character, and yields were
8
higher with scandium triflate, unlike our alkylation. The
9
c
c
closest precedent to our reaction is a Russian report of
nd
nd
nd
c
c
Friedel-Crafts indole alkylation with benzylic and ter-
tiary halides using zinc chloride-pyridine in nitromethane
as solvent. However, an attempt to follow their procedure
for prenylation gave only a 28% yield of 1:4 in a 4.5:1
ratio.
c
c
37:1
a
Reaction conditions: 0.43 mmol of prenyl bromide, 2 equiv of
indole, 1.2 equiv of metal triflate, and 2.2 equiv of Et3N in 2.5 mL
anhydrous toluene, stirred overnight at room temperature. The
yield refers to isolated pure material after preparative TLC and
The synthesis of 13 and 14 highlights the application
of our methodology in the conjugation of indoles to the
natural products (-)-carveol and cholest-4-en-3-ol. Com-
pared to the results with prenyl bromide, with the more
complex geranyl and farnesyl-derived isoprenoid halides,
we did not observe any ‘reverse-prenyl’ isomers ac-
companying 16-21. The synthesis of 3-geranylindole 18
exemplifies the effectiveness of our methodology: previ-
ously, this compound was prepared10 in only 35% yield
using 8 equiv of the indolylmagnesium salt. The mildness
of the reaction conditions can also be discerned by the
tolerance of epoxides during the synthesis of 19-21.
In summary, we have developed a simple one-pot pro-
cedure for the direct formation of 3-alkylindoles in good
yield from indole and alkyl halides that can react by a
b
is based on prenyl bromide. The ratio was determined by NMR
c
peak integration. Yields estimated by HPLC, ratio of 1:4 not
determined.
both zinc bromide (44%, 37:1) and zinc acetate (33%,
4
5:1) gave enhanced regioselectivity disfavoring the
formation of reverse-prenyl isomer 4, but at the expense
of poorer yields.
By HPLC analysis, the zinc triflate mediated preny-
lation was complete within 1.5 h at room temperature,
or 4 h at 0 °C. The reaction was also carried out with
substoichiometric (0.25, 0.5) molar equivalents of zinc
triflate. However, as yields were decreased and longer
reaction times were required, we prefer to use a full
equivalent of zinc triflate. Changing the electrophile from
prenyl bromide to the iodide (either preformed from the
bromide by Finkelstein exchange or more simply by in
situ generation with tetrabutylammonium iodide) dra-
matically improved the regioselectivity, the ratio of 1:4
now being >70:1. The major isolable byproduct (∼10%)
is the isomeric 2-prenylindole 2, with traces of 3 and 5
also observed.
N
S 1 pathway. The indole nitrogen does not require prior
protection and the avoidance of strong bases for depro-
tonation permits compatibility with a wide range of func-
tional groups. Our method nicely complements the clas-
sical alkylation of indolylmagnesium salts, which pro-
N
ceeds by a S 2-like pathway. Further applications of this
alkylation protocol to alkaloid total synthesis and bio-
mimetic polyene cyclizations will be reported in due
course.
The optimized reaction conditions were then tested
with substituted indoles as well as other alkyl halides
(
Chart 1). Two molar equivalents of indole were employed
Exp er im en ta l Section
throughout to minimize the formation of dialkylation
products, and yields were calculated based on the limiting
Gen er a l. All chemicals obtained commercially were used
without further purification. TLC was carried out with precoated
silica plates: analytical (60 F-254) and preparative-scale (1 mm
thick). Column chromatography was performed on silica (70-
(and usually significantly more expensive) alkyl bromide.
Since 58% of the total indole used was recovered during
the formation of 4, this does not limit the method with
more valuable indole substrates. All the successful alky-
lations occurred with tertiary, allylic, or benzylic halides,
1
13
230 mesh). H and C NMR spectra were recorded at 300 and
75 MHz, respectively. Low resolution mass spectra were obtained
by electron impact (EI) or electrospray (ESI) ionization, with
relative abundances of ions indicated in parentheses.
N
which can presumably react by a S 1-like pathway.
Gen er a l P r oced u r e for In d ole Alk yla tion . To a mixture
of the indole (2 equiv), zinc triflate (1.2 equiv), and tetrabuty-
lammonium iodide (1 equiv) in anhydrous toluene (ca. 3 mL per
mmol indole) was added N,N-diisopropylethylamine (2.2 equiv)
at room temperature under argon. The reaction mixture was
stirred for 15 min at room temperature, followed by addition of
the alkyl bromide (1 equiv). Upon completion as judged by TLC,
Meanwhile, no product was observed in the reaction with
isoamyl bromide, a saturated primary alkyl halide.
Mechanistically, this suggests that the zinc species is
mainly serving as a Lewis acid in activating the halide,
1
and this is supported by H NMR experiments. Upon
addition of zinc triflate (1 equiv), the proton spectrum of
prenyl bromide immediately shows additional sets of
signals. In the case of the less acidic zinc acetate, such
changes only began to appear after 2 h. On the other
hand, no changes in NMR spectrum were observed with
zinc triflate and an unactivated halide such as isoamyl
bromide. These facts are counter to our initial premise
that the primary role of the metal triflate would be the
formation of an indolylmetal species. Nevertheless, this
hypothesis does not appear to be completely unfounded,
as evidenced by the poorer yield of 12 with N-methylin-
dole, which cannot form an indolylmetal salt. Further-
more, several metals that form stronger Lewis acidic
the reaction mixture was quenched with saturated aq NH
diluted with water, and extracted with ether. The combined
4
Cl,
organics were washed with water, dried over Na
trated, and purified by column chromatography.
2 4
SO , concen-
3-(3-Meth ylbu t-2-en yl)in dole (1), 3-ben zyl-1H-in dole (10),
a n d 3-ter t-Bu tylin d ole (11). The spectroscopic properties of
(
7) Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073-
076.
8) Bennani, Y. L.; Zhu, G.-D.; Freeman, J . C. Synlett 1998, 754-
756.
4
(
(9) Budylin, V. A.; Ermolenko, M. S.; Kost, A. N. Khim. Geterotsikl.
Soedin. 1978, 921-924.
(10) Mirand, C.; de Maindreville, M. D.; L e´ vy, J . Tetrahedron Lett.
1985, 26, 3985-3988.

Notes
J . Org. Chem., Vol. 67, No. 8, 2002 2707
Ch a r t 1. In d oles P r ep a r ed by th e Zin c Tr ifla te Alk yla tion Meth od , w ith % Yield s
these known compounds were identical to that reported in the
literature.
7-Ch lor o-3-(3-m eth yl-bu t-2-en yl)-1H-in d ole (9). From the
alkylation of 7-chloroindole with prenyl bromide. Chromatog-
raphy eluent 20% ether in petroleum ether. Pale yellow oil; IR
4
-Nitr o-3-(3-m eth yl-bu t-2-en yl)-1H-in d ole (6). From the
alkylation of 4-nitroindole with prenyl bromide, which was
carried out in 1:3 CH Cl :toluene due to the poor solubility of
-
1 1
ν 3421, 1620 cm ; H NMR δ 1.76 (s, 6H), 3.43 (d, J ) 6.6 Hz,
2
2
2H), 5.40 (br t, J ) 6.6 Hz, 1H), 7.03 (m, 2H), 7.18 (d, J ) 7.4
1
3
the indole in toluene alone. Chromatography eluent 50% ether
Hz, 1H), 7.48 (d, J ) 7.4 Hz, 1H), 8.09 (br s, 1H); C NMR δ
in hexanes. Orange-red solid, mp 107-108 °C; IR ν 3369, 1536
17.8, 24.2, 25.7, 116.5, 117.3, 117.7, 119.9, 121.3, 121.8, 122.6,
-
1
1
+
cm ; H NMR δ 1.69 (s, 3H), 1.73 (s, 3H), 3.52 (d, J ) 7.0 Hz,
128.9, 132.3, 133.7; ESI MS m/z 218 (M - 1, 12), 143 (24).
2
8
H), 5.30 (br t, J ) 7.0 Hz, 1H), 7.17-7.22 (m, 2H), 7.59 (d, J )
1-Meth yl-3-(3-m eth yl-bu t-2-en yl)-1H-in d ole (12). From
the alkylation of N-methylindole with prenyl bromide. Chroma-
tography eluent 15% ethyl acetate in hexanes. Colorless oil; IR
.0 Hz, 1H), 7.77 (d, J ) 8.0 Hz, 1H), 8.43 (br s, 1H); 13C NMR
δ 17.8, 25.7, 26.1, 116.0, 116.8, 117.2, 119.2, 120.6, 122.8, 126.3,
1
+
-1 1
32.9, 139.2, 143.5; ESI MS m/z 229 (M -1, 5), 146 (100).
-Ben zyloxy-3-(3-m eth yl-bu t-2-en yl)-1H-in d ole (7). From
ν 1613 cm ; H NMR δ 1.75 (s, 3H), 1.76 (s, 3H), 3.43 (d, J )
6.6 Hz, 2H), 3.70 (s, 3H), 5.42 (m, 1H), 6.78 (s, 1H), 7.05-7.28
(m, 3H), 7.58 (d, J ) 8.1 Hz, 1H); 13C NMR δ 17.8, 24.0, 25.7,
32.5, 109.1, 114.5, 118.5, 119.1, 121.4, 123.3, 126.0, 127.7, 131.7,
5
the alkylation of 5-benzyloxyindole with prenyl bromide. Chro-
matography eluent 20% ether in hexanes. Pale yellow solid, mp
6
(
(
2
(
1
1
0-62 °C; IR ν 3400, 1619 cm-1; H NMR δ 1.74 (s, 6H), 3.38
1
137.1; EI MS m/z 199 (M , 100), 184 (98), 168 (77), 144 (86).
+
d, J ) 6.6 Hz, 2H), 5.10 (s, 2H), 5.40 (br t, J ) 6.6 Hz, 1H), 6.85
d, J ) 2.2 Hz, 1H), 6.91 (dd, J ) 2.2, 8.8 Hz, 1H), 7.10 (d, J )
3-(5-Isopr open yl-2-m eth ylcycloh ex-2-en yl)-1H-in dole (13).
From the alkylation of indole with (-)-carveyl bromide (prepared
from (-)-carveol by MsCl, Et N; LiBr). Chromatography eluent
3
.2 Hz, 1H), 7.16 (d, J ) 8.8 Hz, 1H), 7.25-7.50 (m, 5H), 7.72
1
3
br s, 1H); C NMR δ 17.8, 24.1, 25.7, 71.0, 102.6, 111.7, 112.7,
15% ethyl acetate in hexanes. Obtained as a 3.2:1 mixture of
the equatorial (colorless oil) and axial (colorless plates upon
recrystallization) diastereomers. The identity of the axial isomer
was established by X-ray crystallography.
15.7, 122.1, 123.0, 127.6, 127.7, 128.5, 131.78, 131.87, 137.7,
+
52.9; ESI MS m/z 290 (M -1, 100), 143 (92).
6
-Ch lor o-3-(3-m eth yl-bu t-2-en yl)-1H-in d ole (8). From the
Equatorial cis-isomer: IR ν 3412, 1738, 1642 cm 1; 1H NMR
δ 1.48 (s, 3H), 1.74 (s, 3H), 1.82-2.45 (m, 5H), 3.63 (m, 1H),
4.70 (m, 2H), 5.65 (m, 1H), 7.00 (d, J ) 2.2 Hz, 1H), 7.05-7.22
(m, 2H), 7.34 (d, J ) 8.1 Hz, 1H), 7.63 (d, J ) 8.1 Hz, 1H), 7.87
(br s, 1H); 13C NMR δ 20.8, 21.8, 31.4, 37.6, 39.4, 42.1, 108.5,
111.1, 119.1, 119.56, 119.64, 121.74, 121.80, 122.5, 126.6, 136.2,
-
alkylation of 6-chloroindole with prenyl bromide. Chromatog-
raphy eluent 20% ether in petroleum ether. Pale yellow solid,
-
1
1
mp 84-85 °C; IR ν 3400, 1610 cm ; H NMR δ 1.75 (s, 6H),
.41 (d, J ) 7.3 Hz, 2H), 5.40 (br t, J ) 7.3 Hz, 1H), 6.90 (d, J
1.5 Hz, 1H), 7.06 (dd, J ) 1.5, 8.1 Hz, 1H), 7.28 (d, J ) 2.2
3
)
1
3
Hz, 1H), 7.46 (d, J ) 8.1 Hz, 1H), 7.82 (br s, 1H); C NMR δ
+
1
1
7.8, 23.9, 25.7, 110.9, 116.3, 119.84, 119.88, 121.8, 122.6, 126.1,
27.8, 132.3, 136.7; ESI MS m/z 218 (M -1, 22), 143 (100).
136.5, 150.0; ESI MS m/z 251 (M , 100), 236 (45), 182 (91), 167
+
(89).

2
708 J . Org. Chem., Vol. 67, No. 8, 2002
Notes
Axial trans-isomer: mp 67-69 °C; IR ν 3400, 1738, 1643 cm-1
;
Hz, 1H), 7.52 (d, J ) 7.4 Hz, 1H), 7.86 (br s, 1H); 13C NMR δ
16.1, 17.8, 25.8, 26.5, 27.0, 39.6, 99.5, 110.3, 119.6, 119.8, 120.1,
120.9, 124.1, 129.0, 131.8, 135.9, 138.2, 138.6; EI MS m/z 253
1
H NMR δ 1.61 (s, 3H), 1.70 (s, 3H), 1.70-2.00 (m, 3H), 2.15-
2
.30 (m, 2H), 3.68 (m, 1H), 4.61 (m, 2H), 5.65 (m, 1H), 6.85 (d,
+
J ) 2.2 Hz, 1H), 7.10-7.25 (m, 2H), 7.34 (d, J ) 7.4 Hz, 1H),
(M , 85), 185 (100), 168 (68).
7
3
1
9
.66 (d, J ) 8.1 Hz, 1H), 7.89 (br s, 1H); 13C NMR δ 21.0, 22.6,
3
-(3,7,11-Tr im eth yld od eca -2,6,10-tr ien yl)-1H-in d ole (3-
1.1, 34.2, 35.8, 36.7, 108.4, 111.1, 118.8, 119.1, 119.3, 121.8,
F a r n esylin d ole) (18). From the alkylation of indole with
+
22.5, 122.8, 127.2, 134.8, 136.5, 150.0; ESI MS m/z 251 (M ,
farnesyl bromide. Chromatography eluent 15% ether in hexanes.
5), 236 (37), 182 (95), 167 (86).
-1 1
Pale yellow oil; IR ν 3412 cm ; H NMR δ 1.60 (s, 6H), 1.67 (s,
3
-(4-Ch olesten yl)-1H-in d ole (14). From the alkylation of
indole with cholest-4-en-3-yl bromide (prepared from cholest-4-
en-3-ol by MsCl, Et N; LiBr). Chromatography eluent 15% ethyl
3
5
1
7
2
1
H), 1.76 (s, 3H), 1.90-2.20 (m, 8H), 3.46 (d, J ) 6.7 Hz, 2H),
.10 (m, 2H), 5.45 (br t, J ) 7.3 Hz, 1H), 6.90 (d, J ) 1.5 Hz,
H), 7.00-7.25 (m, 2H), 7.31 (d, J ) 7.4 Hz, 1H), 7.58 (d, J )
3
acetate in hexanes. Obtained as a white foam, 1:1 mixture of
diastereomers.
13
.4 Hz, 1H), 7.83 (br s, 1H); C NMR δ 16.0, 16.1, 17.7, 24.0,
5.7, 26.6, 26.7, 39.70, 39.74, 111.0, 116.1, 119.03, 119.09, 121.2,
21.9, 122.9, 124.2, 124.4, 127.4, 131.3, 135.0, 135.6, 136.4; EI
Diastereomer 1: IR ν 3400, 1738, 1643 cm-1; 1H NMR δ 0.69
(
(
(
s, 3H), 0.85 (d, J ) 1.5 Hz, 3H), 0.87 (d, J ) 1.5 Hz, 3H), 0.90
d, J ) 6.6 Hz, 3H), 1.07 (s, 3H), 0.70-2.15 (m, 27H), 2.22-2.38
m, 1H), 3.69 (m, 1H), 5.49 (d, J ) 5.2 Hz, 1H), 6.85 (d, J ) 2.2
+
MS m/z 321 (M , 10), 184 (84), 168 (41).
3
-[5-(3,3-Dim et h yloxir a n yl)-3-m et h ylp en t -2E-en yl]-1H-
in d ole (19). From the alkylation of indole with ω-epoxygeranyl
Hz, 1H), 7.08-7.34 (m, 2H), 7.32 (d, J ) 8.1 Hz, 1H), 7.64 (d, J
bromide. Chromatography eluent 15% ethyl acetate in petroleum
1
3
)
7.2 Hz, 1H), 7.85 (br s, 1H); C NMR δ 12.0, 18.7, 19.3, 21.6,
-1 1
ether. Pale yellow oil; IR ν 3410, 3333 cm ; H NMR δ 1.25 (s,
2
3
1
2.6, 22.8, 23.8, 24.3, 25.3, 28.0, 28.3, 31.8, 32.7, 33.2, 33.9, 35.8,
6.1, 36.2, 37.3, 39.5, 40.0, 42.6, 54.9, 56.28, 56.33, 111.2, 118.98,
19.08, 120.5, 120.9, 121.8, 122.7, 126.7, 136.7, 146.1.
3
2
H), 1.26 (s, 3H), 1.63-1.72 (m, 2H), 1.78 (s, 3H), 2.09-2.27 (m,
H), 2.73 (t, J ) 6.3 Hz, 1H), 3.46 (d, J ) 7.3 Hz, 2H), 5.49 (dt,
J ) 1.5, 7.1 Hz, 1H), 6.90 (d, J ) 2.2 Hz, 1H), 7.06-7.22 (m,
2
s, 1H); C NMR δ 16.1, 18.7, 24.0, 24.8, 27.4, 36.3, 58.4, 64.2,
1
-
1 1
Diastereomer 2: IR ν 3413 cm ; H NMR δ 0.72 (s, 3H), 0.86
H), 7.31 (d, J ) 8.1 Hz, 1H), 7.57 (d, J ) 8.1 Hz, 1H), 7.96 (br
(
3
3
(
(
2
3
1
d, J ) 1.5 Hz, 3H), 0.88 (d, J ) 1.5 Hz, 3H), 0.91 (d, J ) 6.6 Hz,
13
H), 1.12 (s, 3H), 0.85-2.10 (m, 27H), 2.20-2.35 (m, 1H), 3.56-
.60 (m, 1H), 5.47 (s, 1H), 6.95 (d, J ) 2.2 Hz, 1H), 7.06-7.20
11.0, 115.7, 118.9, 119.0, 121.2, 121.8, 123.6, 127.3, 134.5, 136.4;
+
EI MS m/z 269 (M , 19), 170 (67), 130 (100).
m, 2H), 7.33 (d, J ) 7.4 Hz, 1H), 7.65 (d, J ) 7.4 Hz, 1H), 7.86
13
3-[9-(3,3-Dim eth yloxir a n yl)-3,7-d im eth yln on a -2E,6E-d i-
en yl]-1H-in d ole (20). From the alkylation of indole with
ω-epoxyfarnesyl bromide. Chromatography eluent 20% ether in
br s, 1H); C NMR δ 12.0, 18.7, 19.5, 21.4, 22.6, 22.9, 23.9,
4.3, 27.6, 28.0, 28.3, 32.6, 33.4, 34.4, 35.8, 36.1, 36.2, 37.2, 37.9,
9.5, 40.0, 42.5, 54.6, 56.2, 56.3, 111.1, 119.0, 119.5, 120.3, 121.7,
-1 1
+
hexanes. Pale yellow oil; IR ν 3413 cm ; H NMR δ 1.24 (s, 3H),
21.8, 123.2, 126.7, 136.6, 145.0; ESI MS m/z 485 (M , 14), 468
1
2
.30 (s, 3H), 1.61 (s, 3H), 1.55-1.65 (m, 2H), 1.75 (s, 3H), 1.90-
.20 (m, 6H), 2.71 (t, J ) 5.8 Hz, 1H), 3.45 (d, J ) 6.6 Hz, 2H),
(
100), 438 (57).
1
-(4-Ch olesten yl)-1H-in d ole (15). Byproduct (22%) in the
-
1
1
5.18 (t, J ) 6.6 Hz, 1H), 5.45 (br t, J ) 7.1 Hz, 1H), 6.90 (d, J )
preparation of 14. IR ν 1737 cm ; H NMR δ 0. 70 (s, 3H), 0.86
1
(
2
.5 Hz, 1H), 7.00-7.20 (m, 2H), 7.32 (d, J ) 8.1 Hz, 1H), 7.58
d, J ) 7.4 Hz, 1H), 8.09 (br s, 1H); 13C NMR δ 15.9, 16.0, 18.7,
3.9, 24.9, 26.4, 27.4, 36.3, 39.5, 58.5, 64.3, 111.0, 115.9, 118.9,
(
3
4
d, J ) 1.5 Hz, 3H), 0.88 (d, J ) 1.5 Hz, 3H), 0.91 (d, J ) 6.6 Hz,
H), 1.08 (s, 3H), 0.70-2.40 (m, 28H), 4.92 (m, 1H), 5.48 (d, J )
.4 Hz, 1H), 6.44 (d, J ) 2.9 Hz, 1H), 7.00-7.30 (m, 3H), 7.39
1
3
119.0, 121.3, 121.8, 123.2, 124.8, 127.4, 134.0, 135.3, 136.5; ESI
(
d, J ) 8.1 Hz, 1H), 7.63 (d, J ) 7.4 Hz, 1H); C NMR δ 12.0,
+
MS m/z 337 (M , 7), 249 (96), 192 (100), 130 (75).
1
3
5
1
8.63, 18.66, 21.5, 22.6, 22.8, 23.8, 24.3, 25.7, 28.0, 28.2, 32.61,
2.69, 33.3, 35.8, 35.9, 36.1, 37.5, 39.5, 39.8, 42.5, 50.0, 54.4,
6.05, 56.18, 99.6, 109.5, 116.5, 119.3, 120.9, 121.0, 127.0, 129.2,
3
-[5-(3,3-Dim et h yloxir a n yl)-3-m et h ylp en t -2E-en yl]-2-
m eth yl-1H-in d ole (21). From the alkylation of 2-methylindole
with ω-epoxygeranyl bromide. Chromatography eluent 15% ethyl
+
35.3, 152.2; EI MS m/z 368 (M -117, 29), 147 (64), 105 (70).
-(3,7-Dim eth ylocta -2,6-d ien yl)-1H-in d ole (3-Ger a n ylin -
-
1 1
acetate in hexanes. Yellow oil; IR ν 3321, 1694, 1582 cm ; H
NMR δ 1.22 (s, 6H), 1.55-1.70 (m, 2H), 1.83 (s, 3H), 2.03-2.18
3
d ole) (16). From the alkylation of indole with geranyl bromide.
(
m, 2H), 2.34 (s, 3H), 2.68 (t, J ) 6.3 Hz, 1H), 3.39 (d, J ) 6.6
Chromatography eluent 15% ether in petroleum ether. Pale
-
1
1
Hz, 2H), 5.33 (dt, J ) 1.5, 6.6 Hz, 1H), 7.00-7.15 (m, 2H), 7.17
yellow oil; IR ν 3410 cm ; H NMR δ 1.60 (s, 3H), 1.68 (s, 3H),
13
(
d, J ) 6.6 Hz, 1H), 7.44 (d, J ) 8.1 Hz, 1H), 7.76 (br s, 1H);
NMR δ 11.7, 16.2, 18.7, 23.1, 24.8, 27.3, 36.2, 58.4, 64.2, 110.1,
11.0, 118.2, 119.0, 120.8, 124.5, 128.6, 130.5, 133.3, 135.2; EI
C
1
(
7
1
1
1
.75 (s, 3H), 2.05-2.15 (m, 4H), 3.45 (d, J ) 6.7 Hz, 2H), 5.15
m, 1H), 5.45 (dt, J ) 1.5, 6.6 Hz, 1H), 6.87 (d, J ) 1.5 Hz, 1H),
1
.05-7.18 (m, 2H), 7.28 (d, J ) 8.0 Hz, 1H), 7.59 (d, J ) 7.4 Hz,
+
H), 7.73 (br s, 1H); 13C NMR δ 16.0, 17.7, 24.0, 25.7, 26.6, 39.7,
MS m/z 283 (M , 19), 144 (100).
11.0, 116.0, 119.0, 119.1, 121.2, 121.9, 122.9, 124.4, 127.4, 131.4,
+
35.6, 136.4; EI MS m/z 253 (M , 74), 184(100), 168 (65).
Su p p or tin g In for m a tion Ava ila ble: Spectral character-
2
-(3,7-Dim eth ylocta -2,6-d ien yl)-1H-in d ole (2-Ger a n ylin -
1
ization data ( H NMR) for all new compounds and crystallo-
1
d ole) (17). Byproduct (9%) in the preparation of 16. H NMR δ
.63 (s, 3H), 1.71 (s, 3H), 1.72 (s, 3H), 2.05-2.16 (m, 4H), 3.50
d, J ) 7.3 Hz, 2H), 5.12 (br t, J ) 6.6 Hz, 1H), 5.40 (dt, J ) 1.5,
.3 Hz, 1H), 6.23 (s, 1H), 7.00-7.15 (m, 2H), 7.28 (d, J ) 8.1
graphic information files for trans-13. This material is avail-
able free of charge via the Internet at http://www.pubs.acs.org.
1
(
7
J O010996B