Study on the NBS-induced rearrangement of 2-tert-prenyltryptamines

Article abstract of DOI:10.1055/s-0029-1218811

Treatment of 2-tert-prenyltryptamines with N-bromosuccinimide gives clean access to the marine natural product flustramine C and analogues with the tert-prenyl group shifted to the 3a-position of the resulting pyrrolo[2,3-b]indole (70-80%). Dihydroflustramine C was obtained by DIBAL-H reduction of flustramine C. Bromination or N-methylation of the indole moiety does not influence the course of the rearrangement. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218811

PAPER
2161
Study on the NBS-Induced Rearrangement of 2-tert-Prenyltryptamines
N
S
BS-Induce
d
a
Rearrange
m
n
ent of 2-tert-Prenyl
o
tryptamine
s
sh Kumar Adla, Gregor Golz, Peter G. Jones, Thomas Lindel*
Technische Universität Braunschweig, Institutes of Organic, Inorganic and Analytical Chemistry, Hagenring 30, 38106 Braunschweig,
Germany
Fax +49(531)3917744; E-mail: th.lindel@tu-bs.de
Received 20 April 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90 birthday
th
7
many tryptophan-derived natural products, we investi-
Abstract: Treatment of 2-tert-prenyltryptamines with N-bromo-
gated the scope of the facile NBS-induced oxidative cy-
succinimide gives clean access to the marine natural product flus-
clization/rearrangement.
tramine C and analogues with the tert-prenyl group shifted to the
3
a-position of the resulting pyrrolo[2,3-b]indole (70–80%). Dihy-
Debromoflustrabromine (3, Scheme 2) was chosen as
droflustramine C was obtained by DIBAL-H reduction of flustra-
mine C. Bromination or N-methylation of the indole moiety does
not influence the course of the rearrangement.
starting material, which was obtained in four steps from
8
tryptamine by applying Danishefsky’s tert-prenylation to
3
N -formyl-N -methyltryptamine. After treatment with
b
b
Key words: alkaloids, flustramines, indole, marine natural prod-
ucts, prenyl migration
9
NBS in AcOH–HCO H (3:1), the 6-brominated product
2
5
(53%) predominated over 4-bromoindole 4 (20%). In
1
the H NMR spectrum of 5 (CDCl ), a doublet with a large
3
coupling constant (J = 8.4 Hz) was observed for each of
the rotamers (d = 7.29, 7.49, respectively), which coupled
with C-3 (d = 107.1, 108.0, respectively) in the HMBC ex-
periment. The doublets with the small coupling constant
Indole alkaloids functionalized with 1,1-dimethylallyl
(
tert-prenyl) moieties constitute an important group of
natural products. In particular, the indole 3-position may
be tert-prenylated. Examples from the marine environ-
ment include flustramine C (1) from the bryozoan Flustra
(
J = 1.6 Hz, 7-H) did not couple with C-3.
1
foliacea (Scheme 1).
Me
Me
O
N
NH
Me
NH
H
a
9
7%
N
H
N
H
Br
Br
2
N
NBS, THF
N
3
6
N
H
Me
b
c
71%
rac-flustramine C (rac-1)
deformylflustrabromine (2)
Me
Scheme 1 Title reaction
O
Br
4
N
H
In 2007, we reported that the 2-tert-prenylated natural
product deformylflustrabromine (2) can be converted to
flustramine C (1) in one oxidative step employing tert-
N
2
N
H
N
Me
4
(20%)
7
BuOCl/Et N via N-chlorination of the side chain, fol-
3
3
lowed by cyclization and tert-prenyl shift. Treatment of
+
Me
2
1
2
with N-bromosuccinimide (NBS) in THF afforded rac-
in even higher yield. A related rearrangement affording
-oxoindoles with a free 3-tert-prenyl group has been re-
O
H
N
a
4
deformylflustrabromine (2)
H
98%
Br
6
ported by Williams and co-workers, who used oxaziri-
dines for oxidation and achieved the total synthesis of
c
71%
N
H
4
5
notoamide C and versicolamide B. Williams also
showed that the biosynthesis of 3-tert-prenylated tryp-
tophan derivatives can proceed via 2-tert-prenylated pre-
5
(53%)
rac-flustramine C (rac-1)
Scheme 2 Two examples of sequential cyclization and 2,3-tert-
prenyl transfer affording pyrrolo[2,3-b]indoles. Reagents and condi-
tions: (a) aq 32% NaOH–EtOH (1:15), r.t., 48 h; (b) NBS (1 equiv),
6
cursors, as in the case of the paraherquamides.
Since regioselective introduction of tert-prenyl moieties AcOH–HCO H (3:1), r.t., 30 min; (c) NBS (1 equiv), THF, 0 °C, 1 h.
2
at the indole nucleus is important for the synthesis of
Probably, the indole 3-position is protonated in AcOH–
HCO H (3:1) affording the indoleninium ion. S Ar reac-
tion will then be favored at the indole 4- and 6-positions,
2
E
SYNTHESIS 2010, No. 13, pp 2161–2170
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Advanced online publication: 02.06.2010
DOI: 10.1055/s-0029-1218811; Art ID: C02610SS
Georg Thieme Verlag Stuttgart · New York
which are located at the meta-positions with respect to the
©

2
162
S. K. Adla et al.
PAPER
protonated iminium nitrogen and in the ortho- and para- analysis clarified that bromide was the counterion. In the
positions of the indole 3-position.
case of N ,N -dimethyl-2-tert-prenyltryptamine 10, oxi-
b b
dation with NBS was carried out in acetone for solubility
reasons. After aqueous NaOH workup and chromatogra-
phy on silica gel, we isolated 3-bromoindole 11 (21%,
Scheme 3) and hydrobromide 12 (58%) as major prod-
ucts.
Alkaline hydrolysis of 5 and 3 afforded the 6-brominated
deformylflustrabromine (2) and the nonbrominated sec-
ondary amine 6, respectively (Scheme 2). On treatment of
2
and 6 with NBS (1 equiv) in THF at 0 °C, cyclization
and tert-prenyl 2,3-migration took place affording pyrro-
lo[2,3-b]indoles 1 and 7 in yields of 71%. No side prod- It was unclear whether the cyclization/rearrangement se-
ucts were isolated. Since bromination of the benzene quence would also occur in the absence of side-chain
section of the indole did not influence the reaction, further methylation (Scheme 4). For the synthesis of the free
reactions addressed nonbrominated substrates.
amine, we had to start from phthalimide protected
tryptamine 14, which underwent tert-prenylation at the in-
dole 2-position affording 15, and was subsequently hy-
drazinolyzed to 16. NBS-induced cyclization/2-tert-
prenyl shift again occurred, albeit in a somewhat lower
yield (17, 55%). The monoformyl compound 18, howev-
er, did not yield any isolable cyclization product; only
starting material (73% after column chromatography) was
recovered.
We wondered whether indole and side chain nitrogens
could be methylated while still allowing cyclization and
tert-prenyl migration. Indole-N -methylated compound 8
a
was obtained in two steps from 3. N ,N -Dimethyl-2-tert-
b
b
prenyltryptamine 10 was obtained by DIBAL-H reduction
of 3 (Scheme 3). We were pleased to observe that our
NBS-induced cyclization-shift sequence also worked with
N -methylindole 8 affording N,N¢-dimethylamidinium
a
salt 9, which precipitated from EtOAc (63% yield). X-ray
i. Et3N, t-BuOCl
–78 °C; prenyl-9-BBN
THF, –78 °C to r.t.
O
O
N
N
O
ii. 3 M NaOH
H2O2, 0 °C, 1 h
O
5
1%
N
H
N
H
1
4
15
NH2NH2⋅H2O (2.8 equiv)
CH2Cl2–MeOH (1:1)
r.t., 48 h
58%
NH2
NBS (1.1 equiv)
THF, 0 °C, 35 min
N
N
55%
N
H
H
1
7
16
i. Ac2O–HCO2H (2.5 equiv, 1:1)
0 °C, 1 h
ii. CH2Cl2, r.t., 2 h
6
97%
O
H
NBS (1.0 equiv)
THF, 0 °C, 90 min
HN
N
N
starting material
recovered (73%)
N
H
O
1
9
18
Scheme 4 Synthesis of 2-tert-prenyltryptamine (16) and its formy-
lated analogue 18, and their behavior on treatment with NBS in THF
Scheme 5 outlines our current interpretation of the results.
We expect that the reaction sequence follows the order
bromination, cyclization, tert-prenyl migration with com-
peting pathways depending on side chain substitution. In
Scheme 3 Behavior of 2-tert-prenylated N -methyltryptamine 8 and the first step, the 3-bromoindolenine 22 is formed. In an
a
of 2-tert-prenylated N ,N -dimethyltryptamine 10. Reagents and con- NMR experiment in acetone-d at room temperature
b
b
6
ditions: (a) i. NaH, DMF, 0 °C, 20 min, ii. MeI, r.t., 45 min; (b) aq
2% NaOH–EtOH (1:8), r.t., 48 h; (c) NBS (1 equiv), THF, 0 °C, 20
min; (d) DIBAL-H (1.9 equiv), THF, r.t., 24 h; (e) i. NBS (1 equiv),
acetone, 0 °C, 50 min, ii. Et O, aq 2 M NaOH, iii. chromatography;
(
Scheme 3), we observed that N ,N -dimethyl-2-tert-pre-
b
b
3
nyltryptamine 10 was quantitatively converted to bro-
moindolenine 13 on addition of NBS (1 equiv).
Succinimide accounted for the only other major signals.
2
(
f) NBS (1 equiv), acetone-d , r.t., 45 min.
6
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

PAPER
NBS-Induced Rearrangement of 2-tert-Prenyltryptamines
2163
Characteristically, the olefinic proton of the tert-prenyl can be explained by nucleophilic attack of hydroxide. We
1
group was shifted in the H NMR spectrum from 6.19 to did not observe intramolecular formation of a dimethyl-
1
3
6
.55 ppm. In the C NMR spectrum, a downfield-shifted aziridinium ion in acetone-d . Concomitant formation of
6
+
signal at d = 186.6 (indole C-2) indicated the presence of hydrobromide 12 (Scheme 3) requires reduction of Br to
an imine carbon.
bromide, probably by disproportionation of hypobromite
in aqueous sodium hydroxide during workup.
R1
R1
It has been shown that 3-bromoindoleninium ions such as
N
R2
Br
N
R2
12
2
2 can brominate other indoles. This reaction may be the
NBS
1
2
fastest pathway if R = Me and R = CHO in THF
Scheme 5, path a), as in compound 3.
(
N
R3
N
R3
In summary, our experiments indicate that the NBS-
induced oxidative cyclization and rearrangement of 2-
tert-prenyltryptamines with primary or secondary amine
side chains is a robust reaction. 6-Bromination of the in-
dole does not influence the outcome of the reaction, nor is
the presence of the indole NH proton required.
2
0
21
NBS
R1
indole
a
N
R2
Br
N
path a
core
bromination
b
R1 = CHO
Finally, rac-flustramine C (rac-1) was reduced diastereo-
selectively to rac-dihydroflustramine C (rac-25) with
DIBAL-H in 93% yield (Scheme 6). Dihydroflustramine
2
R
= Me
R3
2
2
path b
13
OH
has been reported as a marine natural product. Similarly,
1
2
R ,R
not CHO
R1 = R2 = Me
R1 = R2 = Me
R3 = H
rac-debromodihydroflustramine C (26) was obtained
from compound 7 (73%).
workup
Br
11
R1
N
R2
N
DIBAL-H (1.8 equiv)
THF, r.t., 24 h
R3
X
X
N
N
2
3
N
N
Me
H
Me
H
R2 = H
– H
rac-1: X = Br
25: X = Br
tert.-
prenyl
shift
rac-flustramine C
rac-dihydroflustramine C
N
Br
7: X = H
26: X = H
1, 7, 9, 17
N
R1
R3
Scheme 6 DIBAL-H reduction to rac-dihydroflustramine C (25,
3%) and its debromo analogue 26 (73%).
9
2
4
Scheme 5 Formation and reactions of a common 3-bromoindolen-
ine intermediate 22
NMR spectra were taken with a Bruker DRX-400 (400.1 MHz for
1
1
13
H, 100.6 MHz for C) and a Bruker AV III-400 (400.1 MHz for
13
H, 100.6 MHz for C) referenced to solvent signal or TMS. All
Regarding the formation of the 3-bromoindolenines them-
selves, side chain N-bromination is likely to be the first
step of the sequence for all starting materials with non-
measurements were carried out at 300 K. Mass spectra were ob-
tained with a ThermoFinnigan MAT95XL, a ThermoFisher Scien-
tific LTQ Orbitrap Velos, and a JMS-T100GC spectrometer
formylated side chains (2, 6, and 8). N-Halogenation of coupled with an Agilent 6890 gas chromatograph. IR spectra were
1
0
amines with NBS and NCS is possible, and it has been recorded with a Bruker Tensor 27 spectrometer. UV/Vis spectra
were measured with a Varian Cary 100 Bio UV/Vis-spectrometer.
reported that secondary amines catalyze bromination of
aromatic compounds with NBS via N-bromoamines.11
Chemicals were purchased from commercial suppliers and used
without further purification. Petroleum ether (PE) refers to the frac-
Side chain halogenation has also been observed when us-
tion boiling in the range 50–60 °C. Silica gel 60 (40–63 mm, Merck)
3
ing tert-BuOCl.
and silica gel 200 (63–200 mm, Merck) were used for column chro-
matography.
The 3-bromoindolenines are only converted into pyrro-
lo[2,3-b]indoles if the side chain is neither formylated nor
dimethylated. In that case, tricyclic intermediate 23 is
deprotonated and loses bromide affording an azaxylylene-
N-{2-[6-Bromo-2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl]ethyl}-
N-methylformamide (5) and N-{2-[4-Bromo-2-(2-methylbut-3-
en-2-yl)-1H-indol-3-yl]ethyl}-N-methylformamide (4)
type intermediate 24. Prenyl shift then leads to indole-N- To a stirred solution of debromoflustrabromine (3; 3, 0.8 g, 2.98
protonated or -alkylated flustramine C-type products 1, 7, mmol, 1.0 equiv) in AcOH–HCO H (24.1 mL, 3:1) was added a so-
2
lution of NBS (0.6 g, 3.1 mmol, 1.0 equiv) in AcOH–HCO H (15
mL, 3:1). The solution was stirred at r.t. for 30 min, before it was
9
, and 17.
2
1
2
In the case of N ,N -dimethylation (R = R = Me), depro-
tonation of 23 is not possible and loss of bromide would
b
b
added to a mixture of Et O (50 mL) and ice (50 g) and was diluted
2
with Et O (100 mL). The combined organic layers were washed
2
generate an unlikely dication. On workup with sodium hy- with H O (3 × 50 mL) and aq 1 M NaOH (50 mL), washed again
2
droxide, loss of the side chain of the 3-bromoindolenine with H
O (2 × 50 mL), dried (MgSO ), filtered, and concentrated in
4
2
vacuo. The crude solid was washed with MeOH (3 × 4 mL). Re-
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

2
164
S. K. Adla et al.
PAPER
CH =CH(CH ) C-H ], 5.13 [dd, J = 5.5 Hz, J = 0.8 Hz, 1 H,
3
2
maining solvent was removed under reduced pressure, followed by
column chromatography (silica gel, PE–EtOAc, 1:1) affording flus-
trabromine 5 (0.55 g, 1.57 mmol, 53%) as a colorless solid;
Rf = 0.43 (PE–EtOAc, 1:1); mp 218–220 °C.
2
3 2
E
CH =CH(CH ) C-H ], 3.48–3.43 [m, 2 H, CCH CH N(CH )CHO],
2
3 2
Z
2
2
3
3.23–3.19 (m, 2 H, CCH CH N(CH )CHO], 2.93 [s, 3 H,
2
2
3
CCH CH N(CH )CHO], 1.48 [s, 6 H, CH =CH(CH ) C].
2
2
3
2
3 2
IR (ATR): 3435 (m, br), 3087 (w), 3054 (w), 2972 (w), 2929 (w),
13C NMR (100 MHz, CDCl ): d (major) = 162.8 (CHO), 145.4
3
2
1
7
872 (w), 1653 (s, br), 1463 (m, br), 1392 (m), 1334 (w), 1222 (m),
164 (m), 1067 (w), 1043 (w), 995 (w), 909 (m), 863 (m), 804 (m),
84 (m), 728 (m), 695 (m), 661 (m), 633 (w), 620 (w), 590 (m), 539
[CH =CH(CH ) C], 141.6 (indole C-2), 135.5 (indole C-7a), 126.6
2
3 2
(indole C-3a), 124.6 (indole C-5), 122.4 (indole C-6), 113.0 (indole
C-4), 112.4 [CH =CH(CH ) C], 110.2 (indole C-7), 107.9 (indole
2
3 2
–
1
cm (w).
C-3), 51.7 (CCH CH N(CH )CHO], 38.8 [CNHCC(CH ) CH],
2 2 3 3 2
2
9.8 [CCH CH N(CH )CHO], 27.6 [2 C, CH =CH(CH ) C], 24.6
2 2 3 2 3 2
NMR: Ratio of rotamers in CDCl = 1:0.8.
3
[
CCH CH N(CH )CHO].
2 2 3
1
H NMR (400 MHz, CDCl ): d (major) = 8.21 (br s, 1 H, indole
3
1H NMR (400 MHz, CDCl
NH), 8.00 (s, 1 H, CHO), 7.21–7.17 (m, 2 H, indole 5-H, indole 7-
H), 6.87 (dd, J = 7.8 Hz, 1 H, indole 6-H), 6.07 [dd, J = 17.4, 10.5
Hz, 1 H, CH
CH =CH(CH
CH =CH(CH ) C-H ], 3.58–3.54 [m, 2 H, CCH CH N(CH )CHO],
3
): d (minor) = 8.03 (br s, 1 H, indole
3
NH), 7.99 (s, 1 H, CHO), 7.49 (d, J = 8.4 Hz, 1 H, indole 4-H), 7.46
(
1
CH =CH(CH ) C], 5.21–5.15 [dd, J = 17.5 Hz, J = 1.2 Hz, 1 H,
CH =CH(CH ) C-H )], 5.21–5.15 [dd, J = 10.4 Hz, J = 1.2 Hz, 1
4
4
3
d, J = 1.7 Hz, 1 H, indole 7-H), 7.20 (dd, J = 1.7 Hz, J = 8.4 Hz,
3
3
3
H, indole 5-H), 6.10 [dd, J = 17.5, 10.4 Hz,
1
H,
3
2
3
2
2
=CH(CH
3 2
) C], 5.15 [dd, J = 8.4 Hz, J = 0.9 Hz, 1 H,
2
3 2
3
2
3
2
2
3
)
2
C-H ], 5.11 [dd, J = 2.2 Hz, J = 0.9 Hz, 1 H,
E
2
3 2
E
2
3 2
Z
2
2
3
H,
CH =CH(CH ) C-H ],
3.53–3.38
3.06–2.99
[m,
[m,
2
H,
H,
2
3 2
Z
3
.23–3.19 [m, 2 H, CCH CH N(CH )CHO], 3.02 [s, 3 H,
2 2 3
CCH CH N(CH )CHO],
2
2
2
3
CCH CH N(CH )CHO], 1.55 [s, 6 H, CH =CH(CH ) C].
2
2
3
2
3 2
CCH CH N(CH )CHO], 2.96 [s, 3 H, CCH CH N(CH )CHO],
2
2
3
2
2
3
1
3
1
.52 [s, 6 H, CH =CH(CH ) C].
C NMR (100 MHz, CDCl ): d (minor) = 162.2 (CHO), 145.3
3
2
3 2
1
3
[CH
indole C-3a), 124.4 (indole C-5), 122.0 (indole C-6), 112.7 (indole
C-4), 112.4 [CH =CH(CH ) C], 110.0 (indole C-7), 108.4 (indole
2 3 2
=CH(CH ) C], 142.2 (indole C-2), 135.5 (indole C-7a), 126.6
C NMR (100 MHz, CDCl ): d (major) = 162.5 (CHO), 145.5
3
(
[
CH =CH(CH ) C], 140.9 (indole C-2), 135.0 (indole C-7a), 128.1
2
3 2
2
3 2
(indole C-3a), 122.9 (indole C-5), 119.9 (indole C-4), 115.0 (indole
C-3), 46.9 [CCH CH N(CH )CHO], 39.1 [CNHCC(CH ) CH],
3
2
2
3
3 2
C-6), 113.7 (indole C-7), 112.4 [CH =CH(CH ) C], 107.1 (indole
2
3 2
5.1 [CCH CH N(CH )CHO], 27.6 [2 C, CH =CH(CH ) C], 22.6
2 2 3 2 3 2
C-3), 50.2 [CCH CH N(CH )CHO], 38.9 [NHCC(CH ) CH=CH ],
2
2
3
3 2
2
[
CCH CH N(CH )CHO].
2 2 3
3
0.1 [CCH CH N(CH )CHO], 27.6 [2 C, CH =CH(CH ) C], 24.9
2 2 3 2 3 2
+
+
[
CCH CH N(CH )CHO].
MS (EI, 70 eV): m/z (%) = 348 ([M] , 18), 289 ([M – C H ] , 9),
5 9
276 ([M – C
2
2
3
+
1
3 6
H NO] , 100).
H NMR (400 MHz, CDCl ): d (minor) = 8.07 (br s, 1 H, indole
3
4
79
21
81
+
NH), 8.00 (s, 1 H, CHO), 7.43 (d, J = 1.3 Hz, 1 H, indole 7-H), 7.29
(
1
CH =CH(CH ) C], 5.21–5.15 [dd, J = 17.6 Hz, J = 1.2 Hz, 1 H,
CH =CH(CH ) C-H ], 5.21–5.15 [dd, J = 10.4 Hz, J = 1.2 Hz, 1
GC-HRMS (EI): m/z calcd for C H BrN O [M] : 348.0832;
found: 348.0826; m/z calcd for C H BrN O [M] : 350.0811;
17 21 2
found: 350.0809.
1
7
2
3
4
3
+
d, J = 8.4 Hz, 1 H, indole 4-H), 7.19 (dd, J = 1.7 Hz, J = 8.4 Hz,
3
H, indole 5-H), 6.13–6.08 [dd, J = 17.6, 10.4 Hz, 1 H,
3
2
2
3 2
UV (MeCN): lmax (lg e) = 289 (3.86), 232 (4.56), 200 nm (4.41).
3
2
2
3 2
E
H,
CH =CH(CH ) C-H ],
3.53–3.38
3.06–2.99
[m,
[m,
2
H,
H,
2
3 2
Z
N-Methyl-2-[2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl]ethan-
amine (6)
To a solution of debromoflustrabromine (3; 1 g, 3.70 mmol, 1.0
equiv) in EtOH (150 mL) was added aq 32% NaOH (11 mL). The
CCH CH N(CH )CHO],
CCH CH N(CH )CHO], 2.95 [s, 3 H, CCH CH N(CH )CHO],
2
2
2
3
2
2
3
2
2
3
1
.55 [s, 6 H, CH =CH(CH ) C].
2 3 2
1
3
C NMR (100 MHz, CDCl ): d (minor) = 162.5 (CHO), 145.5
reaction mixture was refluxed for 48 h and cooled to r.t. H O (100
3
2
[
CH =CH(CH ) C], 140.5 (indole C-2), 134.9 (indole C-7a), 128.5
mL) was added and the mixture was extracted with EtOAc (3 × 100
2
3 2
(indole C-3a), 122.7 (indole C-5), 119.5 (indole C-4), 114.9 (indole
mL). The combined organic phases were washed with H O (4 × 100
2
C-6), 113.4 (indole C-7), 112.3 [CH =CH(CH ) C], 108.0 (indole
mL) and dried (Na SO ). The solvent was removed under reduced
2
3
2
2
4
C-3), 45.5 [CCH CH N(CH )CHO], 39.0 [NHCC(CH ) CH=CH ],
pressure affording 6 (870 mg, 3.59 mmol, 97%) as an orange oil.
2
2
3
3 2
2
3
5.1 [CCH CH N(CH )CHO], 27.6 [2 C, CH =CH(CH ) C], 22.6
2
2
3
2
3 2
IR (ATR): 3434 (w), 3298 (w, br), 3185 (w, br), 3080 (w), 3056 (w),
[
CCH CH N(CH )CHO].
2 2 3
2
967 (m), 2932 (w), 2870 (w), 2798 (w), 1632 (w), 1460 (m), 1360
+
+
MS (ESI): m/z (%) = 348 ([M] , 25), 289 ([M – C H ] , 33), 276
(w), 1339 (w), 1303 (w), 1232 (w), 1129 (w), 1103 (w), 1008 (m),
5
9
+
–1
(
[M – C H NO] , 100).
914 (m), 738 (s), 597 cm (w).
3
6
7
9
+
1
HRMS (ESI): m/z calcd for C H BrN O [M] : 348.0837; found:
H NMR (400 MHz, CDCl ): d = 7.89 (br s, 1 H, indole NH), 7.56
1
7
21
2
3
4
3
4
3
48.0838.
(dd, J = 2.0 Hz, J = 6.4 Hz, 1 H, indole 4-H), 7.30 (dd, J = 2.2 Hz,
3
J = 6.6 Hz, 1 H, indole 7-H), 7.16–7.02 (m, 2 H, indole 5-H, 6-H),
UV (MeCN): lmax (lg e) = 288 (3.85), 232 (4.58), 200 nm (4.41).
3
6
2
2
.13 [dd, J = 17.4, 10.5 Hz, 1 H, CH =CH(CH ) C], 5.20–5.11 [m,
2
3 2
H, CH =CH(CH ) C], 3.09–2.98 [m, 2 H, CH NHCH CH C],
2
3 2
3
2
2
4
-Bromoindole 4
.89–2.81 (m,
2
H, CH NHCH CH C), 2.48 (s,
3 H,
3
2
2
Compound 4 was isolated by column chromatography (silica gel,
eluent: PE–EtOAc, 1:1) from the above product mixture; yield:
0%; R = 0.58 (PE–EtOAc, 1:1); mp 155 °C (dec.).
CH CH NHCH ), 1.54 [s, 6 H, CH =CH(CH ) C], 1.50 (br s, 1 H,
CCH CH NHCH ).
2
2
3
2
3 2
2
2
3
2
f
1
3
C NMR (100 MHz, CDCl ): d = 146.0 [CH =CH(CH ) C], 139.5
3
2
3 2
IR (ATR): 3295 (m, br), 3081 (w), 3055 (w), 2970 (w), 2930 (w),
872 (w), 1655 (s, br), 1463 (m, br), 1390 (m), 1333 (w), 1246 (w),
223 (w), 1160 (m), 1067 (w), 1044 (w), 997 (w), 909 (m), 862 (w),
(
indole C-2), 134.1 (indole C-7a), 129.8 (indole C-3a), 121.3 (in-
2
1
8
dole C-6), 119.1 (indole C-5), 118.3 (indole C-4), 111.9
[CH
(
(CH CH NHCH ), 27.7 [2 C, CH =CH(CH ) C], 25.6
(CCH CH NHCH ).
2 2 3
–
1
2
=CH(CH
3
)
2
C], 110.3 (indole C-7), 109.0 (indole C-3), 53.1
39.0 [NHCC(CH ) CH], 36.5
03 (m), 728 (m), 694 (m), 659 (w), 590 cm (w).
CH CH NHCH ),
2
2
3
3 2
NMR: Ratio of rotamers in CDCl : 1:0.8.
3
2 2 3 2 3 2
1
H NMR (400 MHz, CDCl ): d (major) = 8.13 (s, 1 H, CHO), 8.08
br s, 1 H, indole NH), 7.21–7.17 (m, 2 H, indole 5-H, indole 7-H),
3
(
6
1
+
MS (EI, 70 eV): m/z (%) = 242 ([M] , 5), 199 (100), 184 ([M –
C H N] , 83), 172 ([M – C H ] , 7), 168 (44).
3
3
.90 (dd, J = 7.8 Hz, 1 H, indole 6-H), 6.06 [dd, J = 17.4, 10.5 Hz,
+
+
3
8
5
9
3
2
H, CH =CH(CH ) C], 5.17 [dd, J = 12.3 Hz, J = 0.8 Hz, 1 H,
2
3 2
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

PAPER
NBS-Induced Rearrangement of 2-tert-Prenyltryptamines
2165
+
GC-HRMS (EI): m/z calcd for C H N [M] : 242.1778; found:
CH =CH(CH ) C-H ], 3.72 [s, 3 H, CN(CH )C], 3.45–3.41 [m, 2 H,
1
6
22
2
2
3 2
E
3
2
42.1758.
CCH CH N(CH )CHO],
3.24–3.19
[m,
2
H,
2
2
3
CCH CH N(CH )CHO], 2.98 [s, 3 H, CCH CH N(CH )CHO],
2
2
3
2
2
3
UV (CHCl ): l (lg e) = 283 (3.86), 239 (3.98), 233 nm (3.79).
3
max
1
.62 [s, 6 H, CH =CH(CH ) C].
2 3 2
1
3
rac-Debromoflustramine C (7)
C NMR (100 MHz, CDCl ): d (major) = 162.5 (CHO), 147.4
2 3 2
3
To a solution of debromodeformylflustrabromine (6; 200 mg, 0.83
mmol, 1.0 equiv) in THF (20 mL) was added NBS (147 mg, 0.83
mmol, 1.0 equiv). The reaction mixture was stirred at 0 °C for 1 h
[CH =CH(CH ) C], 140.7 (indole C-2), 137.7 (indole C-7a), 128.1
(indole C-3a), 121.8 (indole C-6), 119.3 (indole C-5), 117.4 (indole
C-4), 112.1 [CH =CH(CH ) C], 108.9 (indole C-7), 107.6 (indole
2
3 2
and diluted with Et O (50 mL). The organic layer was washed with
C-3), 51.3 [CCH CH N(CH )CHO], 40.7 [CN(CH )CC(CH ) CH],
2
2 2 3 3 3 2
aq 2 N NaOH (3 × 50 mL) and H O (3 × 50 mL), dried (Na SO ),
33.2 [CHCN(CH )C], 30.1 [CCH CH N(CH )CHO], 29.4 [2 C,
3 2 2 3
2
2
4
filtered, and concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, EtOAc) affording rac-debromof-
lustramine C (7; 156 mg, 0.61 mmol, 71%) as a colorless oil;
Rf = 0.2 (EtOAc).
CH =CH(CH ) C], 25.5 [CCH CH N(CH )CHO].
2 3 2 2 2 3
1
H NMR (400 MHz, CDCl ): d (minor) = 8.06 (s, 1 H, CHO), 7.64
3
3
(
d, J = 7.0 Hz, 1 H, indole 4-H), 7.26–7.18 (m, 2 H, indole 6-H, in-
3
dole 7-H), 7.14–7.01 (m, 1 H, indole 5-H), 6.18 [dd, J = 17.5, 10.6
Hz, 1 H, CH =CH(CH ) C], 5.09 [dd, J = 10.6 Hz, J = 1.0 Hz, 1
H, CH =CH(CH ) C-H ], 4.94 [t, J = 1.0 Hz,
3
2
IR (ATR): 3059 (w), 2969 (w), 2930 (w), 2877 (w), 2796 (w), 1633
2 3 2
3
(
1
s), 1576 (s), 1446 (m), 1412 (m), 1380 (w), 1364 (w), 1307 (w),
278 (m), 1216 (m), 1181 (m), 1154 (w), 1103 (w), 1007 (w), 987
w), 915 (m), 848 (w), 818 (w), 765 (s), 747 (s), 685 (w), 656 cm
w).
1
H,
2
3
2
Z
CH =CH(CH ) C-H ], 3.71 [s, 3 H, CN(CH )C], 3.52–3.48 [m, 2 H,
2
3 2
E
3
–
1
(
(
1
CCH CH N(CH )CHO],
3.24–3.19
[m,
2
H,
2
2
3
CCH CH N(CH )CHO], 2.96 [s, 3 H, CCH CH N(CH )CHO],
2
2
3
2
2
3
4
3
1.66 [s, 6 H, CH =CH(CH ) C].
2 3 2
H NMR (400 MHz, CDCl ): d = 7.17 (dt, J = 1.3 Hz, J = 7.6 Hz,
3
4
3
13
1
H, 6-H), 7.11 (dd, J = 0.8 Hz, J = 7.8 Hz, 1 H, 5-H), 7.09–7.07
m, 1 H, 4-H), 6.80 (dt, J = 1.2 Hz, J = 7.4 Hz, 1 H, 7-H), 6.08–
.01 [m, 1 H, CH =CH(CH ) C], 5.07 [s, 1 H, CH =CH(CH ) C-
C NMR (100 MHz, CDCl ): d (minor) = 162.4 (CHO), 147.7
3
4
3
(
6
[CH =CH(CH ) C], 140.6 (indole C-2), 137.6 (indole C-7a), 128.5
2
3 2
(indole C-3a), 121.6 (indole C-6), 119.1 (indole C-5), 118.0 (indole
2
3 2
2
3 2
3
2
H ], 5.04 [dd, J = 7.0 Hz, J = 1.2 Hz, 1 H, CH =CH(CH ) C-H ],
3
3
C-4), 111.9 [CH =CH(CH ) C], 108.6 (indole C-7), 108.4 (indole
Z
2
3 2
E
2
3 2
3
2
.95 [ddd, J = 6.3, 3.9 Hz, J = 12.7 Hz, 1 H, (CH )NCH CH C],
.40 [dt, J = 10.1, 1.0 Hz, 1 H, (CH )NCH CH C], 3.05 (s, 3 H,
C-3), 46.6 [CCH CH N(CH )CHO], 40.8 [CN(CH )CC(CH ) CH],
3
2
2
2 2 3 3 3 2
3
35.1 [CCH CH N(CH )CHO], 33.2 [CHCN(CH )C], 29.5 [2 C,
2 2 3 3
3
2
2
2
3
NCH ), 2.39 [ddd, J = 6.1, 0.7 Hz, J = 13.1 Hz, 1 H,
CH =CH(CH ) C], 23.1 [CCH CH N(CH )CHO].
3
2 3 2 2 2 3
3
2
(
(
CH )NCH CH C], 2.11 [ddd, J = 7.7, 5.8 Hz, J = 16.0 Hz, 1 H,
CH )NCH CH C], 1.01 [s, 3 H, CH =CH(CH ) C], 0.87 [s, 3 H,
+
+
3
2
2
MS (EI, 70 eV): m/z (%) = 284([M] , 20), 212 ([M – C H NO] ,
3
6
3
2
2
2
3 2
+
1
00), 198 ([M – C H NO] , 10), 182 (55).
4 8
CH =CH(CH ) C].
2
3 2
+
GC-HRMS (EI): m/z calcd for C H N O [M] : 284.1883; found:
1
3
18 24
2
C NMR (100 MHz, CDCl ): d = 187.0 (C-8a), 160.8 (C-7a), 143.7
2 3 2
3
2
84.1859.
[
CH =CH(CH ) C], 138.2 (C-3b), 128.5 (C-6), 123.5 (C-4), 119.6
UV (CHCl ): l (lg e) = 290 (3.84), 240 nm (4.09).
(
C-7), 115.7 (C-5), 113.3 [CH =CH(CH ) C], 66.1 (C-3a), 59.9 (C-
3
max
2
3 2
2
), 43.1 [N=CCC(CH ) CH=CH ], 33.4 (NCH ), 27.9 (C-3), 22.8
3 2 2 3
N-Methyl-2-[1-methyl-2-(2-methylbut-3-en-2-yl)-1H-indol-3-
yl]ethanamine (8)
To a solution of N-methyl-N-{2-[1-methyl-2-(2-methylbut-3-en-2-
yl)-1H-indol-3-yl]ethyl}formamide (600 mg, 2.11 mmol, 1.0
equiv) in EtOH (80 mL) was added aq 32% NaOH (8 mL). The re-
[
CH =CH(CH ) C], 21.6 [CH =CH(CH ) C].
2 3 2 2 3 2
+
+
MS (EI, 70 eV): m/z (%) = 240 ([M] , 15), 172 ([M – C H + H] ),
5
9
+
(
30), 171 ([M – C H ] , 100), 130 (30).
5 9
+
GC-HRMS (EI): m/z calcd for C H N [M] : 240.1621; found:
1
6
20
2
2
40.1638.
action mixture was refluxed for 48 h and cooled to r.t. H O (50 mL)
2
was added and the mixture was extracted with EtOAc (3 × 100 mL),
UV (CHCl ): l (lg e) = 283 (3.83), 239 (3.62), 231 nm (3.55).
3
max
washed with H O (4 × 100 mL), dried (Na SO ), and filtered. The
2
2
4
solvent was removed under reduced pressure affording the pure title
compound 8 (436 mg, 1.702 mmol, 81%) as a yellow oil.
N-Methyl-N-{2-[1-methyl-2-(2-methylbut-3-en-2-yl)-1H-indol-
-yl]ethyl}formamide
3
NaH (60% suspension in mineral oil, 222 mg, 5.552 mmol, 1.5
equiv) was washed with pentane (5 mL) and dried under high vac-
uum. At 0 °C under Ar, a solution of debromoflustrabromine (3; 1.0
g, 3.701 mmol, 1.0 equiv) in DMF (30 mL) was added. After 30 min
at 0 °C, a solution of MeI (580 mg, 4.072 mmol, 1.1 equiv) in DMF
IR (ATR): 3314 (w, br), 3050 (w), 2968 (w), 2933 (w), 2880 (w),
2791 (w), 1472 (s), 1355 (m), 1319 (m), 1233 (m), 1131 (w), 1109
(w), 1085 (w), 1015 (w), 995 (w), 912 (m), 739 (s), 707 (m), 686
–
1
(w), 562 cm (w).
1
4
3
H NMR (400 MHz, CDCl ): d = 7.60 (dt, J = 0.8 Hz, J = 7.8 Hz,
3
(10 mL) was added dropwise, and the reaction mixture was stirred
1
(
1
H, indole 4-H), 7.23–7.17 (m, 2 H, indole 6-H, indole 7-H), 7.09
dd, J = 1.6 Hz, J = 6.4 Hz, 1 H, indole 5-H), 6.17 [dd, J = 17.5,
0.6 Hz, 1 H, CH =CH(CH ) C], 5.07 [dd, J = 10.6 Hz, J = 1.0
at r.t. for 45 min. H O (40 mL) was added cautiously and the mix-
4
3
3
2
ture was extracted with EtOAc (3 × 100 mL). The combined organ-
3
2
2 3 2
ic layers were washed with H O (3 × 100 mL) and brine (100 mL),
3
2
2
Hz, 1 H, CH =CH(CH ) C-H ], 4.95 [dd, J = 17.5 Hz, J = 1.0 Hz,
2
3 2
Z
dried (Na SO ), filtered, and concentrated in vacuo to afford the
2
4
1
H, CH =CH(CH ) C-H ], 3.70 [s, 3 H, CN(CH )C], 3.19 (t,
2 3 2 E 3
pure title compound (1.04 g, 3.66 mmol, 99%) as a yellow oil.
3
3
J = 7.7 Hz, 2 H, CH NHCH CH C], 2.83 (t, J = 7.7 Hz, 2 H,
3
2
2
IR (ATR): 3050 (w), 2970 (w), 2930 (w), 2873 (w), 1669 (s), 1474
CH NHCH CH C), 2.47 (s, 3 H, CH CH NHCH ), 1.70 (br s, 1 H,
3
2
2
2
2
3
(
1
m), 1383 (m), 1355 (m), 1320 (w), 1232 (w), 1177 (w), 1148 (w),
081 (m), 1015 (w), 995 (w), 913 (m), 741 (s), 562 cm (w).
CH CH NHCH ), 1.63 [s, 6 H, CH =CH(CH ) C].
2 2 3 2 3 2
–
1
13
C NMR (100 MHz, CDCl ): d = 147.9 [CH =CH(CH ) C], 140.2
3
2
3 2
NMR: Ratio of rotamers in CDCl = 1.7:1.
(indole C-2), 137.6 (indole C-7a), 128.8 (indole C-3a), 121.5 (in-
dole C-6), 118.9 (indole C-5), 118.2 (indole C-4), 111.8
3
1
H NMR (400 MHz, CDCl ): d (major) = 8.02 (s, 1 H, CHO), 7.47
3
3
[CH
(CH
(CH
2
2
2
=CH(CH ) C], 109.8 (indole C-3), 108.5 (indole C-7), 54.3
3 2
(
d, J = 7.0 Hz, 1 H, indole 4-H), 7.26–7.18 (m, 2 H, indole 6-H, in-
3
CH
2
NHCH
3
),
), 33.2 [CHCN(CH
CH NHCH
3
40.8
[N(CH
3
)CC(CH
)CC], 29.6 [2 C,
).
3
)
2
CH],
36.5
dole 7-H), 7.14–7.01 (m, 1 H, indole 5-H), 6.17 [dd, J = 17.5, 10.5
Hz, 1 H, CH =CH(CH ) C], 5.10 [dd, J = 10.6 Hz, J = 0.9 Hz, 1
H, CH =CH(CH ) C-H ], 4.99 [t, J = 1.0 Hz,
3
2
CH
2
NHCH
3
3
2
3 2
3
CH
2
=CH(CH
3
)
2
C], 25.9 (CCH
2
2
1
H,
2
3
2
Z
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

2
166
S. K. Adla et al.
PAPER
1 H, indole 7-H), 7.12 (dt, J = 1.4 Hz, J = 7.5 Hz, 1 H, indole 6-
+
+
4
3
MS (EI, 70 eV): m/z (%) = 256 ([M] , 6), 213 ([M – C H N + H] ,
2
5
+
+
4
3
1
1
00), 212 ([M – C H N] , 64), 199 (10), 198 ([M – C H N] , 70),
82 (35).
H), 7.07 (dt, J = 1.2 Hz, J = 7.4 Hz, 1 H, indole 5-H), 6.13 [dd,
2
5
3
8
3
2
2
3
J = 17.4, 10.6 Hz, 1 H, CH =CH(CH ) C], 5.17 [dd, J = 17.4 Hz,
2
3
2
3
+
J = 1.0 Hz, 1 H, CH
2
=CH(CH
3
)
2
C-H
E
], 5.15 [dd, J = 10.5 Hz,
GC-HRMS (EI): m/z calcd for C H N [M] : 256.1934; found:
1
7
24
2
J = 1.1 Hz, 1 H, CH =CH(CH ) C-H ], 3.04–3.00 [m, 2 H,
2
3 2
Z
2
56.1961.
CCH CH N(CH ) ], 2.56–2.47 [m, 2 H, CCH CH N(CH ) ], 2.35
2
2
3 2
2
2
3 2
UV (CHCl ): l (lg e) = 290 (3.84), 240 (4.10), 232 nm (3.75).
3
max
[s, 6 H, CCH CH N(CH ) ], 1.54 [s, 6 H, CH =CH(CH ) C].
2 2 3 2 2 3 2
1
3
C NMR (100 MHz, CDCl ): d = 145.9 [CH =CH(CH ) C], 139.3
3
2
3 2
1
,8-Dimethyl-3a-(2-methylbut-3-en-2-yl)-1,2,3,3a-tetrahydro-
(
indole C-2), 134.2 (indole C-7a), 129.7 (indole C-3a), 121.3 (in-
pyrrolo[2,3-b]indolium Bromide (9)
dole C-6), 119.2 (indole C-5), 118.1 (indole C-4), 112.0
To a solution of 8 (233 mg, 0.91 mmol, 1.0 equiv) in THF (16 mL)
at 0 °C was added NBS (165 mg, 0.91 mmol, 1.0 equiv). After 20
min, the precipitate that had formed was washed with EtOAc (20
mL) and dried in vacuo to afford compound 9 (192 mg, 0.57 mmol,
[
[
CH =CH(CH ) C], 110.4 (indole C-7), 108.9 (indole C-3), 60.4
2 3 2
CCH CH N(CH ) ], 45.5 [2 C, CCH CH N(CH ) ], 38.9 [NH-
2
2
3 2
2
2
3 2
CC(CH ) CH],
27.7
[2
C,
CH =CH(CH ) C],
23.4
3
2
2
3 2
[
CCH CH N(CH ) ].
2
2
3 2
6
3%) as a colorless amorphous solid; mp 166 °C.
IR (ATR): 3403 (w, br), 3328 (w), 3157 (w), 3080 (w), 3030 (w),
006 (w), 2960 (w), 2895 (w), 2797 (w), 1772 (w), 1691 (s), 1608
m), 1456 (m), 1433 (m), 1402 (m), 1373 (m), 1348 (w), 1329 (m),
294 (m), 1178 (m), 1151 (m), 1105 (m), 1005 (w), 933 (m), 811
+
+
MS (EI, 70 eV): m/z (%) = 256 ([M] , 7), 198 ([M – C H N] , 10),
3
8
+
1
83 ([M – C H N + H] , 10), 58 (100).
4 10
3
(
1
+
GC-HRMS (EI): m/z calcd for C H N [M] : 256.1934; found:
17 24 2
256.1944.
–
1
(
m), 775 (s), 709 (w), 639 cm (m).
UV (CHCl ): l (lg e) = 284 (3.87), 240 nm (3.99).
3
max
1
4
3
H NMR (400 MHz, D O): d = 7.58 (dt, J = 1.3 Hz, J = 7.9 Hz, 1
2
4
3
H, 6-H), 7.42 (dd, J = 1.2 Hz, J = 7.6 Hz, 1 H, 4-H), 7.32–7.27 (m,
2
CH =CH(CH ) C], 5.26 [dd, J = 10.8 Hz, J = 0.8 Hz, 1 H,
CH =CH(CH ) C-H ], 5.21 [dd, J = 17.4 Hz, J = 0.8 Hz, 1 H,
CH =CH(CH ) C-H ], 4.56 [ddd, J = 6.3, 9.5 Hz, J = 11.7 Hz, 1
H, =CN(CH )CH CH C], 4.16 [ddd, J = 11.5, 10.1 Hz,
H, =CN(CH )CH CH C], 3.83 [s, 3 H, CN (CH )=CN(CH )], 3.72
[
3-Bromo-2-(2-methylbut-3-en-2-yl)-1H-indole (11)
3
H, 5-H, 7-H), 6.03 [dd, J = 17.4, 10.8 Hz,
1
H,
To a solution of N ,N -dimethyl-2-tert-prenyltryptamine 10 (400
b
b
3
2
mg, 1.56 mmol, 1.0 equiv) in acetone (20 mL) was added NBS (308
mg, 1.72 mmol, 1.1 equiv) at 0 °C. The reaction mixture was stirred
at 0 °C for 50 min and diluted with Et O (100 mL). The Et O layer
2
3 2
3
2
2
3 2
Z
3
2
2
3 2
E
2
2
3
1
was separated, washed with aq 2 M NaOH (2 × 50 mL), followed
3
2
2
+
by H O (3 × 50 mL), dried (Na SO ), and concentrated in vacuo.
3
2
2
3
3
2
2
4
+
3
2
s, 3 H, CN (CH )=CN(CH )], 2.79 [dd, J = 6.0 Hz, J = 13.4, 1 H,
The residue was purified by column chromatography (silica gel,
3
3
3
2
N(CH )CH CH C], 2.49 [dt, J = 9.7, 3.6 Hz, J = 13.3 Hz, 1 H,
CHCl –MeOH, 9:1) to afford compound 11 (88 mg, 0.33 mmol,
3
2
2
3
N(CH )CH CH C], 1.14 [s, 3 H, CH =CH(CH ) C), 0.96 [s, 3 H,
21%) as a dark green oil and compound 12 (305 mg, 0.91 mmol,
3
2
2
2
3 2
CH CH(CH ) C].
58%) as a yellow oil.
2
3 2
1
3
C NMR (100 MHz, D O): d = 180.9 (C-8a), 152.0 (C-7a), 144.6
2 3 2
2
3
-Bromoindole 11
[
CH =CH(CH ) C], 134.4 (C-3b), 132.5 (C-6), 127.9 (C-4), 126.8
Rf = 0.73 (acetone–PE, 1:2).
(
2
C-7), 118.7 [CH =CH(CH ) C], 113.3 (C-5), 71.8 (C-3a), 68.0 (C-
2 3 2
+
),
48.8
[N (CH )=CCC(CH ) CH=CH ],
38.0
IR (ATR): 3151 (w, br), 3059 (w, br), 2964 (m), 2925 (m), 1704
(w), 1641 (w), 1617 (m), 1455 (m), 1385 (w), 1363 (w), 1259 (w),
3
3 2
2
+
+
[
[
[
N (CH )=CN(CH )CH ], 34.0 [N (CH )=CN(CH )CH ], 30.0
3 3 2 3 3 2
–
1
CCH CH N(CH )C],
25.8
[CH =CH(CH ) C],
24.7
1211 (w), 1101 (m), 1011 (m), 913 (w), 802 (m), 746 cm (s).
2
2
3
2
3 2
CH =CH(CH ) C].
1
2
3 2
H NMR (400 MHz, CDCl ): d = 8.07 (br s, 1 H, indole NH), 7.55–
3
+
+
MS (ESI): m/z (%) = 255 ([M] , 100), 186 ([M – C H ] , 16), 185
7.50 (m, 1 H, indole 4-H), 7.30–7.26 (m, 1 H, indole 7-H), 7.20–
7.13 (m, 2 H, indole 5-H, indole 6-H), 6.17 [dd, J = 17.4, 10.6 Hz,
1 H, CH
5
9
3
(
5).
3
2
+
+
2 3 2
=CH(CH ) C], 5.24 [dd, J = 7.0 Hz, J = 1.0 Hz, 1 H,
HRMS (ESI): m/z calcd for C H N [M] : 255.1856; found:
1
7
23
2
3
2
CH =CH(CH ) C-H ], 5.21 [dd, J = 13.4 Hz, J = 1.0 Hz, 1 H,
2
3 2
Z
2
55.1855.
CH =CH(CH ) C-H ], 1.63 [s, 6 H, CH =CH(CH ) C].
2
3 2
E
2
3 2
UV (DMSO): lmax (lg e) = 296 (3.39), 275 (3.55), 253 nm (3.51).
13
C NMR (100 MHz, CDCl ): d = 144.3 [CH =CH(CH ) C], 139.5
3
2
3 2
(indole C-2), 133.3 (indole C-7a), 129.0 (indole C-3a), 122.5 (in-
N,N-Dimethyl-2-[2-(2-methylbut-3-en-2-yl)-1H-indol-3-
yl]ethanamine (10)
At r.t., DIBAL-H (17% in toluene, 6.22 mL, 6.218 mmol, 4.2 equiv)
was added dropwise to a solution of debromoflustrabromine (3; 400
mg, 1.48 mmol, 1.0 equiv) in THF (10 mL) under argon. After 24 h,
the reaction mixture was added in portions to ice water (150 mL).
Aq 12 M HCl (10 mL) was added at 0 °C (pH 2) and the organic lay-
dole C-6), 120.4 (indole C-5), 118.6 (indole C-4), 113.5
[
[
CH =CH(CH ) C], 110.7 (indole C-7), 87.9 (indole C-3), 39.0
2 3 2
NHCC(CH ) CH], 26.4 [2 C, CH =CH(CH ) C].
3
2
2
3 2
+
MS (EI, 70 eV): m/z (%) = 263 ([M] , 24), 169 (100), 167 (18), 127
(31).
79
+
GC-HRMS (EI): m/z calcd for C H BrN [M] : 263.0304; found:
1
3
14
2
er was extracted with Et O (3 × 30 mL). The aqueous layer was
brought to pH 11 by addition of aq 12 M NaOH (12 M, 20 mL) and
2
2
63.0295.
UV (CHCl ): l (lg e) = 279 (3.86), 272 (3.87), 240 nm (4.00).
was extracted with Et O (3 × 50 mL). The combined organic layers
3
max
2
were washed with H O (3 × 100 mL), dried (Na SO ) and concen-
2
2
4
Hydrobromide 12
Rf = 0.49 (acetone–PE, 1:2).
trated in vacuo to afford compound 10 (325 mg, 1.27 mmol, 86%)
as a colorless oil.
IR (ATR): 3270 (w, br), 2966 (w, br), 2666 (w, br), 2462 (w), 1469
IR (ATR): 3434 (w), 3255 (w, br), 3055 (w), 2968 (m), 2936 (m),
(
(
1
s), 1342 (w), 1307 (w), 1236 (w), 1008 (m), 956 (m), 918 (m), 744
s), 716 cm (m).
2
867 (w), 2828 (w), 2789 (w), 1638 (w), 1459 (s), 1360 (w), 1341
–
1
(
1
w), 1302 (w), 1247 (w), 1229 (w), 1137 (w), 1098 (w), 1029 (m),
008 (m), 736 (s), 597 cm (m).
–
1
H NMR (400 MHz, CDCl ): d = 8.15 (br s, 1 H, indole NH), 7.57
3
3
4
3
1
(d, J = 7.6 Hz, 1 H, indole 4-H), 7.35 (dd, J = 1.3 Hz, J = 7.5 Hz,
1 H, indole 7-H), 7.14 (dt, J = 1.4 Hz, J = 7.5 Hz, 1 H, indole 6-
H NMR (400 MHz, CDCl ): d = 7.83 (br s, 1 H, indole NH), 7.53
3
4
3
3
4
3
(
d, J = 7.5 Hz, 1 H, indole 4-H), 7.27 (dd, J = 1.2 Hz, J = 7.6 Hz,
4
3
H), 7.09 (dt, J = 1.2 Hz, J = 7.4 Hz, 1 H, indole 5-H), 6.10 [dd,
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

PAPER
NBS-Induced Rearrangement of 2-tert-Prenyltryptamines
2167
3
3
13
J = 17.5, 10.5 Hz, 1 H, CH =CH(CH ) C], 5.17 [dd, J = 14.4 Hz,
C NMR (100 MHz, CDCl ): d = 168.4 [2 C, N(C(=O)CCHCH) ],
2
3
2
3
2
2
2
3
J = 0.9 Hz, 1 H, CH =CH(CH ) C-H ], 5.15 [dd, J = 7.4 Hz,
136.2 (indole C-7a), 133.8 [2 C, N(C(=O)CCHCH) ], 132.2 [2 C,
N(C(=O)CCHCH)2], 127.4 (indole C-3a), 123.2 [2 C,
2
3 2
E
2
J = 0.9 Hz, 1 H, CH =CH(CH ) C-H ], 3.32–3.28 [m, 2 H,
2
3 2
Z
CCH CH N(CH ) ], 3.00–2.96 [m, 2 H, CCH CH N(CH ) ], 2.72
N(C(=O)CCHCH) ], 122.1 (indole C-6), 122.0 (indole C-2), 119.5
2
2
3 2
2
2
3
2
2
[
s, 6 H, CCH CH N(CH ) ], 1.54 [s, 6 H, CH =CH(CH ) C].
(indole C-5), 118.9 (indole C-4), 112.5 (indole C-3), 111.1 (indole
2
2
3 2
2
3 2
1
3
C-7), 38.5 (CNHCHCCH
2
CH
2
N), 24.5 (CNHCHCCH CH N).
2 2
C NMR (100 MHz, CDCl ): d = 145.6 [CH =CH(CH ) C], 140.3
3
2
3 2
+
(
indole C-2), 134.2 (indole C-7a), 128.8 (indole C-3a), 121.7 (in-
MS (EI, 70 eV): m/z (%) = 290 ([M] , 29), 143 (36), 130 ([M –
+
dole C-6), 119.7 (indole C-5), 117.7 (indole C-4), 112.2
C H NO ] , 100), 77 (11).
9
6
2
[
[
CH =CH(CH ) C], 110.8 (indole C-7), 105.2 (indole C-3), 58.2
+
2
3 2
GC-HRMS (EI): m/z calcd for C H N O [M] : 290.1050; found:
1
8
14
2
2
CCH CH N(CH ) ], 43.3 [2 C, CCH CH N(CH ) ], 38.8 [NH-
2
2
3 2
2
2
3 2
2
90.1071.
CC(CH ) CH],
[
27.7
[2
C,
CH =CH(CH ) C],
20.9
3
2
2
3 2
UV (MeCN): l (lg e) = 354 (2.28), 289 (3.80), 281 (3.84), 240
CCH CH N(CH ) ].
max
2
2
3 2
(
4.10), 220 (4.84), 194 nm (4.49).
+
+
MS (ESI): m/z (%) = 257 ([M] , 67), 212 ([M – C H N] , 100).
2
7
+
HRMS (ESI): m/z calcd for C H N [M] : 257.2012; found:
2-{2-[2-(2-Methylbut-3-en-2-yl)-1H-indol-3-yl]ethyl}isoindo-
1
7
25
2
2
57.2011.
line-1,3-dione (15)
To a solution of 14 (2.2 g, 7.58 mmol, 1.0 equiv) in THF (45 mL)
UV (CH Cl ): l (lg e) = 282 (3.86), 239 (3.91), 233 nm (3.68).
2
2
max
14
and Et N (1.4 mL, 10.34 mmol, 1.2 equiv) was added t-BuOCl
3
(
1.17 mL, 10.34 mmol, 1.2 equiv) at –78 °C. The reaction mixture
2
-[3-Bromo-2-(2-methylbut-3-en-2-yl)-3H-indol-3-yl]-N,N-
was stirred for 30 min at –78 °C, before a freshly prepared solution
dimethylethanamine (13, NMR Experiment)
To a solution of 10 (60 mg, 0.23 mmol, 1.0 equiv) in acetone-d (0.6
mL) in an NMR tube was added NBS (42 mg, 0.23 mmol, 1.0 equiv)
at r.t. The NMR tube was shaken for 5 min and after 25 min, the
NMR spectra were recorded.
1
5
of prenyl-9-BBN (0.5 M, 34.5 mL, 17.24 mmol, 2.0 equiv) in THF
was added dropwise. After 30 min, the mixture was allowed to
warm to r.t. and was stirred for 1 h. Aq 3 M NaOH (18 mL) and
H O (30%, 18 mL) were added dropwise. The reaction mixture was
stirred at r.t. for 1 h and diluted with Et O (200 mL). The organic
layer was washed with brine–H O (1:1, 3 × 50 mL), dried (MgSO ),
filtered, and concentrated in vacuo. The residual yellow oil was re-
crystallized from CHCl –hexane (1:5, 30 mL) to afford compound
1
146 °C.
6
2
2
2
1
3
H NMR (400 MHz, acetone-d ): d = 7.53 (d, J = 7.4 Hz, 1 H, in-
6
2
4
3
4
dole 4-H), 7.47 (d, J = 6.7 Hz, 1 H, indole 7-H), 7.38 (dt, J = 1.2
3
4
3
Hz, J = 7.6 Hz, 1 H, indole 6-H), 7.30 (dt, J = 1.1 Hz, J = 7.4 Hz,
1
CH =CH(CH ) C], 5.30 [d, J = 17.5 Hz, 1 H, CH =CH(CH ) C-
H ], 5.19 [d, J = 10.6 Hz, 1 H, CH =CH(CH ) C-H ], 2.88–2.75
3
3
H, indole 5-H), 6.55 [dd, J = 17.5, 10.7 Hz, 1 H,
5 (1.37 g, 3.83 mmol, 50%) as a yellow amorphous solid; mp 143–
3
2
3 2
3
2
3
2
E
2
3 2
Z
IR (ATR): 3355 (m), 3084 (w), 3031 (w), 2970 (w), 2936 (w), 2867
(
1
[
m, 2 H, CCH CH N(CH ) ], 2.68 [s, 4 H, (CH CO) NH], 2.01 [s,
2 2 3 2 2 2
w), 1766 (w), 1696 (s), 1463 (m), 1430 (w), 1394 (s), 1354 (m),
336 (m), 1245 (w), 1170 (w), 1103 (m), 1017 (m), 920 (m), 898
6
1
H, CCH CH N(CH ) ], 1.97–1.88 [m, 1 H, CCH CH N(CH ) ],
2 2 3 2 2 2 3 2
.71–1.65 [m,
1
H, CCH CH N(CH ) ], 1.67 [s,
3
H,
2
2
3 2
–1
(
w), 871 (m), 747 (s), 714 (s, br), 608 (m), 566 cm (w).
1H NMR (400 MHz, CDCl
): d = 7.91 (br s, 1 H, indole NH), 7.88–
.83 [m, 2 H, N(C(=O)CCHCH) ], 7.79–7.77 (m, 1 H, indole 4-H),
CH =CH(CH ) C], 1.62 [s, 3 H, CH =CH(CH ) C].
2
3 2
2
3 2
1
3
3
C NMR (100 MHz, acetone-d ): d = 186.6 (indole C-2), 179.0 [2
6
7
7
2
C, (CH CO) NH], 151.9 (indole C-7a), 145.0 (CH =CH(CH ) C),
1
2
2
2
3 2
.73–7.68 [m, 2 H, N(C(=O)CCHCH) ], 7.32–7.27 (m, 1 H, indole
2
41.2 (indole C-3a), 130.5 (indole C-6), 127.6 (indole C-5), 123.3
7
-H), 7.16–7.10 (m, 2 H, indole 5-H, indole 6-H), 6.17 [dd,
(
(
indole C-4), 121.3 (indole C-7), 113.5 [CH =CH(CH ) C], 63.9
indole C-3), 54.9 [CCH CH N(CH ) ], 45.1 [2 C,
2
3 2
3
3
J = 17.4, 10.6 Hz, 1 H, CH =CH(CH ) C], 5.22 [dd, J = 10.4 Hz,
J = 1.0 Hz, 1 H, CH =CH(CH ) C-H ], 5.19 [dd, J = 3.5 Hz,
J = 1.0 Hz, 1 H, CH =CH(CH ) C-H ], 3.93–3.89 (m, 2 H,
2
3 2
2
2
3
2
2
2
3
2
3
2
Z
CCH CH N(CH ) ],
44.3
[N=CC(CH ) CH=CH ],
37.8
2
2
3 2
3 2
2
2
3 2
E
[
[
CCH CH N(CH ) ], 30.2 [2 C, (CH CO) NH], 29.6
CH =CH(CH ) C], 27.7 [CH =CH(CH ) C].
2
2
3 2
2
2
CCH CH N), 3.20–3.15 (m, 2 H, CCH CH N), 1.62 [s, 6 H,
CH =CH(CH ) C].
2
2
2
2
2
3 2
2
3 2
2
3 2
1
3
2
-[2-(1H-indol-3-yl)ethyl]isoindoline-1,3-dione (14)
C NMR (100 MHz, CDCl ): d = 168.3 [2 C, N(C(=O)CCHCH) ],
3 2
Phthalic anhydride (4.03 g, 27.0 mmol, 1.1 equiv) was added to a
145.6 [CH =CH(CH ) C], 140.1 (indole C-2), 134.1 (indole C-7a),
2 3 2
solution of tryptamine (3.9 g, 24.33 mmol, 1.0 equiv) in toluene (50
133.8 [2 C, N(C(=O)CCHCH) ], 132.3 [2 C, N(C(=O)CCHCH) ],
2
2
mL), followed by addition of Et N (3.75 mL, 27.0 mmol, 1.1 equiv).
129.6 (indole C-3a), 123.1 [2 C, N(C(=O)CCHCH) ], 121.5 (indole
3
2
The reaction mixture was refluxed at 125 °C for 8 h, cooled to r.t.
and added to ice water (100 mL). The yellow precipitate was recrys-
tallized from MeOH (5 mL of MeOH/g) to obtain compound 14
C-6), 119.6 (indole C-5), 118.3 (indole C-4), 112.3
[CH =CH(CH ) C], 110.4 (indole C-7), 107.1 (indole C-3), 38.9
2
3 2
[CNHCC(CH ) CH], 38.4 (CNHCCCH CH N), 27.7 [2 C,
3
2
2
2
(
5.52 g, 19.01 mmol, 77%) as a brown solid; mp 164–166 °C.
CH =CH(CH ) C], 24.6 (CNHCCCH CH N).
2 3 2 2 2
+
+
IR (ATR): 3379 (m), 3352 (br, m), 3043 (w), 2979 (w), 2861 (w),
MS (EI, 70 eV): m/z (%) = 358 ([M] , 100), 290 ([M – C H + H] ,
5
9
+
1
1
767 (m), 1696 (s, br), 1617 (m), 1460 (m), 1430 (m), 1395 (s),
355 (m), 1327 (m), 1230 (m), 1186 (w), 1169 (w), 1097 (m), 1058
12), 289 ([M – C H ] , 25), 210 (32).
5 9
+
HRMS (EI): m/z calcd for C H N O [M] : 358.1676; found:
2
3
22
2
2
(
6
m), 1011 (w), 985 (m), 867 (m), 821 (w), 741 (s), 707 (s), 654 (m),
32 (m), 586 (m), 529 cm (s).
3
58.1676.
–
1
UV (CHCl ): l (lg e) = 283 (3.97), 242 nm (4.21).
1
3
max
H NMR (400 MHz, CDCl ): d = 8.01 (br s, 1 H, indole NH), 7.82
3
3
3
[
dd, J = 5.8, 3.2 Hz, 2 H, N(C(=O)CCHCH) ], 7.73 (d, J = 8.32
2
2
-[2-(2-Methylbut-3-en-2-yl)-1H-indol-3-yl]ethanamine (16)
To a solution of N -phthalic-2-tert-prenyltryptamine 15 (1.0 g, 2.79
mmol, 1.0 equiv) in CH Cl –MeOH (1:1, 30 mL) was added
NH NH ·H O (0.38 mL, 7.82 mmol, 2.8 equiv) at r.t. The reaction
mixture was stirred for 48 h and poured into H O (60 mL). After ex-
traction with Et O (4 × 100 mL), the combined organic extracts
were washed with aq 1 M HCl (50 mL) and brine (50 mL), dried
3
Hz, 1 H, indole 4-H), 7.69 [dd, J = 5.8, 3.1 Hz, 2 H,
N(C(=O)CCHCH) ], 7.34 (d, J = 7.8 Hz, 1 H, indole 7-H), 7.17
3
b
2
3
2
2
2
(
ddd, J = 13.7, 6.1 Hz, J = 1.3 Hz, 1 H, indole 6-H), 7.10 (dd,
J = 7.0 Hz, J = 1.2 Hz, 1 H, indole 5-H), 7.08 (s, 1 H, indole 2-H),
.00 (t, J = 7.8 Hz, 2 H, CCH CH N), 3.15 (t, J = 7.8 Hz, 2 H,
3
4
2
2
2
3
3
2
4
2 2
2
CCH CH N).
2
2
(
MgSO ), filtered, and concentrated in vacuo. Chromatography of
4
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

2
168
S. K. Adla et al.
PAPER
the residual oil (silica gel, CHCl –MeOH, 6:1) afforded compound
UV (CHCl ): l (lg e) = 258 nm (3.73).
3
3
max
1
6 (0.43 g, 1.61 mmol, 58%) as a colorless oil; R = 0.23 (CHCl –
f 3
MeOH, 6:1).
N-{2-[2-(2-Methylbut-3-en-2-yl)-1H-indol-3-yl]ethyl}form-
amide (18)
IR (ATR): 3432 (w), 3140 (w), 3057 (w), 2965 (m), 2928 (m), 2871
A mixture of Ac O (0.23 mL, 2.42 mmol, 2.5 equiv) and HCO H
2
2
(
m), 1585 (m), 1460 (m), 1360 (w), 1340 (w), 1306 (m), 1228 (w),
–
1
(0.1 mL, 2.42 mmol, 2.5 equiv) was stirred at 60 °C for 1 h. After
cooling to r.t., a solution of 2-tert-prenyltryptamine 16 (221 mg,
0.97 mmol, 1.0 equiv) in CH Cl (10 mL) was added dropwise. The
1
031 (w), 1009 (m), 905 (s, br), 734 cm (s, br).
1
H NMR (400 MHz, CDCl ): d = 7.90 (br s, 1 H, indole NH), 7.55
3
2
2
3
4
3
(
d, J = 7.8 Hz, 1 H, indole 4-H), 7.28 (dt, J = 0.9 Hz, J = 7.8 Hz,
reaction mixture was stirred at r.t. for 2 h. Upon completion, the
mixture was added to aq 12 M NaOH (14 mL) and ice (15 g). The
alkaline mixture was diluted with CH Cl (50 mL) and the aqueous
4
3
1
H, indole 7-H), 7.12 (dt, J = 1.3 Hz, J = 7.5 Hz, 1 H, indole 6-
4
3
H), 7.07 (dt, J = 1.2 Hz, J = 7.4 Hz, 1 H, indole 5-H), 6.13 [dd,
2
2
3
2
2
3
J = 17.4, 10.6 Hz, 1 H, CH =CH(CH ) C], 5.17 [dd, J = 9.4 Hz,
J = 1.0 Hz, 1 H, CH =CH(CH ) C-H ], 5.14 [dd, J = 2.5 Hz,
J = 1.0 Hz, 1 H, CH =CH(CH ) C-H ], 3.02 (br s, 4 H,
2
3 2
layer was extracted with CH Cl (3 × 30 mL). The combined organ-
2
2
3
2
3
2
Z
ic layers were washed with aq 2 M HCl (2 × 30 mL), H O (3 × 50
2
2
3 2
E
mL), dried (Na SO ), filtered, and concentrated in vacuo to afford
2
4
+
+
CCH CH NH Cl), 2.34 (br s, 3 H, CCH CH NH Cl), 1.54 [s, 6 H,
2
2
3
2
2
3
compound 18 (240 mg, 0.94 mmol, 97%) as an oil.
CH =CH(CH ) C].
2
3 2
IR (ATR): 3299 (w, br), 3056 (w), 2968 (w), 2868 (w), 1660 (s, br),
1
3
C NMR (100 MHz, CDCl ): d = 146.0 [CH =CH(CH ) C], 139.7
3
2
3 2
1517 (w), 1460 (m), 1435 (m), 1383 (m), 1338 (w), 1304 (w), 1238
(
indole C-2), 134.1 (indole C-7a), 129.8 (indole C-3a), 121.4 (in-
–1
(
m, br), 1173 (w), 1006 (w), 915 (m), 741 cm (s, br).
dole C-6), 119.2 (indole C-5), 118.3 (indole C-4), 112.0
CH =CH(CH ) C], 110.4 (indole C-7), 108.4 (indole C-3), 43.0 (2
NMR: Ratio of rotamers in CDCl = 1:0.2.
3
[
2
3 2
1
C, CNHCCCH CH N), 39.0 [CNHCC(CH ) CH], 27.8 [2 C,
H NMR (400 MHz, CDCl ): d (major) = 8.12 (s, 1 H, CHO), 8.02
2
2
3
2
3
4
3
CH =CH(CH ) C].
(br s, 1 H, indole NH), 7.55 (dt, J = 0.5 Hz, J = 7.7 Hz, 1 H, indole
2
3 2
4
3
+
+
4-H), 7.30 (dt, J = 0.9 Hz J = 8.0 Hz, 1 H, indole 7-H), 7.14 (td,
MS (EI, 70 eV): m/z (%) = 229 ([M + H] , 4), 228 ([M] , 23), 198
100), 183 (56), 168 (41).
4
3
3
4
J = 1.3 Hz J = 7.4 Hz, 1 H, indole 6-H), 7.09 (td, J = 1.2 Hz
(
3
J = 7.4 Hz, 1 H, indole 5-H), 6.12 [dd, J = 17.7, 10.3 Hz, 1 H,
+
GC-HRMS (EI): m/z calcd for C H N [M] : 228.1621; found:
3
1
5
20
2
CH =CH(CH ) C], 5.67 (br s, 1 H, CH NHCHO), 5.17 [dd, J = 6.2
Hz, J = 0.9 Hz, 1 H, CH =CH(CH ) C-H ], 5.14 [d, J = 1.2 Hz, 1
H, CH =CH(CH ) C-H ], 3.58 (q, J = 13.8, 6.9 Hz, 2 H,
CCH CH NHCHO), 3.08 (t, J = 7.3 Hz, 2 H, CCH CH NHCHO),
2
2
3 2
2
2
28.1630.
2
2
3 2
Z
3
UV (CHCl ): l (lg e) = 283 (3.83), 240 nm (3.92).
2
3
2
E
3
max
3
2
2
2
2
1
13
.54 [s, 6 H, CH =CH(CH ) C].
3
a-(2-Methylbut-3-en-2-yl)-2,3,3a,8-tetrahydropyrrolo[2,3-
2 3 2
b]indole (17)
C NMR (100 MHz, CDCl ): d (major) = 161.2 (CHO), 145.8
3
To a solution of 2-tert-prenyltryptamine 16 (100 mg, 0.38 mmol,
[
CH =CH(CH ) C], 140.2 (indole C-2), 134.2 (indole C-7a), 129.6
2 3 2
1
.0 equiv) in THF (15 mL) was added NBS (79 mg, 0.44 mmol, 1.16
equiv) at r.t. The reaction mixture was stirred at 0 °C for 35 min, be-
fore CHCl (50 mL) was added. The organic layer was washed with
(indole C-3a), 121.5 (indole C-6), 119.6 (indole C-5), 118.1 (indole
C-4), 112.1 [CH =CH(CH ) C], 110.5 (indole C-7), 107.4 (indole
C-3), 39.0 [NHCC(CH ) CH], 38.8 (CCH CH NHCHO), 27.8 [2 C,
CH =CH(CH ) C], 24.9 (CCH CH NHCHO).
2 3 2 2 2
2
3 2
3
3 2 2 2
aq 2 M NaOH (3 × 40 mL) and H O (3 × 40 mL), dried (Na SO ),
filtered, and concentrated in vacuo. The residual green solid was pu-
rified by column chromatography over silica gel (CHCl –MeOH,
2
2
4
1
H NMR (400 MHz, CDCl ): d (minor) = 7.97 (s, 1 H, CHO), 7.94
br s, 1 H, indole NH), 7.45 (dt, J = 0.6 Hz, J = 7.8 Hz, 1 H, indole
3
3
4
3
(
7
:1 to 5:1) to afford compound 17 (47 mg, 0.21 mmol, 55%) as a
4
3
4
-H), 7.31 (dt, J = 0.9 Hz J = 7.9 Hz, 1 H, indole 7-H), 7.15 (td,
green amorphous solid; R = 0.45 (CHCl –MeOH; 5:1); mp 160 °C.
f
3
4
3
J = 1.4 Hz J = 6.7 Hz, 1 H, indole 6-H), 7.15–7.06 (m, 1 H, indole
IR (ATR): 3053 (w), 2968 (m), 2929 (m), 2874 (m), 2819 (m), 2738
w), 1672 (s), 1638 (w), 1608 (m), 1455 (s), 1419 (m), 1380 (w),
331 (m), 1233 (m), 1196 (m), 1153 (m), 1106 (m), 999 (m), 921
3
5
-H), 6.12 [dd, J = 17.7, 10.3 Hz, 1 H, CH =CH(CH ) C], 5.67 (br
2 3 2
(
1
3
2
s, 1 H, CH NHCHO), 5.18 [dd, J = 6.7 Hz, J = 1.2 Hz, 1 H,
CH =CH(CH ) C-H ], 5.14 [s, 1 H, CH =CH(CH ) C-H ], 3.54–
3
CCH CH NHCHO), 1.53 [s, 6 H, CH =CH(CH ) C].
13
2
2
3
2
Z
2
3
2
E
–
1
(
(
1
s), 816 (m), 798 (w), 741 (s), 708 (s), 654 (m), 610 (m), 539 cm
m).
.46 (m, 2 H, CCH CH NHCHO), 3.13–3.04 (m, 2 H,
2 2
2
2
2
3 2
4
H NMR (400 MHz, CDCl ): d = 7.28 (br s, 8-H), 7.17 (dt, J = 1.3
3
C NMR (100 MHz, CDCl ): d (minor) = 164.3 (CHO), 145.9
3
2 3 2
3
4
3
Hz, J = 7.7 Hz, 1 H, 6-H), 7.11 (dd, J = 0.8 Hz, J = 7.4 Hz, 1 H,
[
(
CH =CH(CH ) C], 140.2 (indole C-2), 134.2 (indole C-7a), 129.6
indole C-3a), 121.7 (indole C-6), 119.4 (indole C-5), 117.8 (indole
4
3
4
4
-H), 6.89 (dd, J = 1.1 Hz, J = 8.3 Hz, 1 H, 5-H), 6.86 (dd, J = 1.0
3
3
Hz, J = 7.5 Hz, 1 H, 7-H), 6.03 [dd, J = 17.1, 11.0 Hz, 1 H,
C-4), 112.0 [CH =CH(CH ) C], 110.7 (indole C-7), 106.6 (indole
C-3), 42.1 (CCH CH NHCHO), 39.0 [NHCC(CH ) CH], 28.1 [2 C,
CH =CH(CH ) C], 25.3 (CCH CH NHCHO).
2 3 2 2 2
2
3 2
CH =CH(CH ) C], 5.05 [s, 1 H, CH =CH(CH ) C-H ], 5.01 [dd,
2
3 2
2
2
3 2
Z
2
2
3
2
3
3
3
3
3
J = 8.0 Hz, J = 1.2 Hz, 1 H, CH =CH(CH ) C-H ], 3.93 (ddd,
J = 9.3, 5.8 Hz, J = 12.4 Hz, 1 H, CNHC=NCH CH C), 3.82 (dd,
J = 9.0 Hz, J = 12.4 Hz, 1 H, CNHC=NCH CH C), 2.43 (dd,
J = 5.2 Hz, J = 13.0 Hz, 1 H, CNHC=NCH CH C), 2.13 (dt,
2
3 2
E
2
2
2
+
NO]+,
2
MS (EI, 70 eV): m/z (%) = 256 ([M] , 27), 198 ([M – C H
100), 184 ([M – C
2 4
2
2
+
2
H NO] , 9), 168 (48).
3 6
2
2
2
+
J = 6.4 Hz, J = 16.7 Hz, 1 H, CNHC=NCH CH C), 1.03 [s, 3 H,
GC-HRMS (EI): m/z calcd for C H N [M] : 256.1576; found:
2
2
15 20
2
CH =CH(CH ) C], 0.95 [s, 3 H, CH =CH(CH ) C].
256.1572.
UV (CHCl ): l (lg e) = 283 (3.79), 240 (3.88), 232 nm (3.69).
2
3 2
2
3 2
1
3
C NMR (100 MHz, CDCl ): d = 183.1 (C-8a), 152.5 (C-7a), 143.6
3
3
max
[
CH =CH(CH ) C], 134.4 (C-3b), 128.3 (C-6), 124.7 (C-4), 120.4
2 3 2
(
C-7), 113.2 [CH =CH(CH ) C], 112.0 (C-5), 65.5 (C-3a), 57.5 (C-
rac-Dihydroflustramine C (25)
2
3 2
2
), 43.4 [CNHC(=N)CC(CH ) CH], 32.1 (C-3), 22.9
At r.t., DIBAL-H (20% in toluene, 0.48 mL, 0.57 mmol, 1.8 equiv)
was added dropwise to a solution of rac-flustramine C (1; 100 mg,
0.31 mmol, 1.0 equiv) in THF (10 mL) under Ar. The reaction mix-
ture was stirred at r.t. for 26 h and then added dropwise to ice water
3
2
[
CH =CH(CH ) C], 21.9 [CH =CH(CH ) C].
2 3 2 2 3 2
+
+
MS (EI, 70 eV): m/z (%) = 226 ([M] , 20), 157 ([M – C H ] , 100),
1
5
9
56 (30), 130 (32).
(
250 mL). The mixture was diluted with Et O (75 mL) and made
2
+
HRMS (EI): m/z calcd for C H N [M] 226.1465; found:
2
1
5
18
2
strongly alkaline with aq 12 M NaOH (35 mL). The aqueous layer
26.1464.
was extracted with Et O (3 × 50 mL), washed with H O (3 × 50
2
2
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

PAPER
NBS-Induced Rearrangement of 2-tert-Prenyltryptamines
2169
+
+
mL), dried (Na SO ), filtered, and concentrated in vacuo to afford
rac-dihydroflustramine C (25; 94 mg, 0.293 mmol, 93%) as a yel-
MS (EI, 70 eV): m/z (%) = 242 ([M] , 22), 174 ([M – C H + H] ,
2
4
5
9
+
24), 173 ([M – C H ] , 100), 130 (42).
5 9
low oil; R = 0.2 (hexanes–EtOAc, 1:1).
+
f
GC-HRMS (EI): m/z calcd for C H N [M] : 242.1778; found:
1
6
22
2
IR (ATR): 3413 (w, br), 3260 (w, br), 3081 (w), 3033 (w), 2965 (m),
242.1762.
2
935 (m), 2870 (w), 2843 (w), 2790 (w), 1595 (s), 1481 (s), 1446
UV (CHCl ): l (lg e) = 294 (3.37), 243 nm (3.75).
3
max
(
s), 1414 (m), 1380 (w), 1365 (m), 1349 (m), 1310 (m), 1249 (m,
br), 1155 (m), 1120 (m), 1097 (w), 1072 (m), 1048 (m), 1004 (s),
9
X-ray Structure Determination
42 (w), 910 (s), 886 (m), 834 (m), 789 (s), 687 (m), 605 cm–1 (m).
Intensity data were recorded on an Oxford Diffraction Xcalibur E
diffractometer at –173 °C using monochromated Mo-Ka radiation
(l = 0.71073 Å) (Table 1). Absorption corrections were performed
on the basis of multiscans. Structures were refined anisotropically
1
3
H NMR (300 MHz, CDCl ): d = 6.95 (d, J = 7.0 Hz, 1 H, 4-H),
3
4
3
4
6
.77 (dd, J = 1.7 Hz, J = 8.0 Hz, 1 H, 5-H), 6.67 (d, J = 1.7 Hz, 1
3
H, 7-H), 5.96 [dd, J = 17.4 Hz, 10.8 Hz, 1 H, CH =CH(CH ) C],
5
[
2
3 2
3
2
2
16
.07 [dd, J = 10.8 Hz, J = 1.2 Hz, 1 H, CH =CH(CH ) C-H ], 5.01
on F using SHELXL-97. Hydrogens of NH groups were refined
freely, other H using a riding model or rigid methyl groups. Solvent
molecules were well-ordered.
2
3
2
Z
3
2
dd, J = 17.4 Hz, J = 1.2 Hz, 1 H, CH =CH(CH ) C-H ], 4.39 (s,
2 3 2 E
3
1
H, 8a-H), 4.26 (br s, 1 H, 8-H), 2.59 (ddd, J = 6.9, 4.2, 2.1 Hz,
J = 11.7 Hz, 1 H, CH CH NCH ), 2.52 (ddd, J = 6.1, 4.9, 3.7 Hz,
J = 1.2 Hz, 1 H, CH CH NCH ), 2.37 (s, 3 H, NCH ), 2.27 (ddd,
2
3
2
2
3
2
3
3
2
2
2
3
3
J = 9.7, 7.1, 2.0 Hz, J = 12.2 Hz, 1 H, CH CH NCH ), 1.79 (ddd,
2
2
3
Table 1 Details of X-ray Structure Analyses of Compounds 9 and
2
J = 5.5, 5.0 Hz, J = 12.0 Hz, 1 H, CH CH NCH ), 1.03 [s, 3 H,
17
2
2
3
1
2
CH =CH(CH ) C], 0.99 [s, 3 H, CH =CH(CH ) C].
2
3 2
2
3 2
13C
NMR (75.5 MHz, CDCl ): d = 152.0 (C-7a), 144.6
2 3 2
Parameters
Formula
Mr
9·CH
Cl
12·CDCl
3
3
2
2
(
CH =CH(CH ) C), 132.6 (C-3b), 126.2 (C-4), 121.2 (C-6), 120.6
C H BrCl N
C H DBrCl N
18 25 3 2
(
C-5), 113.1 [CH =CH(CH ) C], 111.5 (C-7), 84.4 (C-8a), 63.9 (C-
18 25
2
2
2
3 2
3
2
a), 53.0 (C-2), 41.2 [HNCHCC(CH ) ], 36.8 (NCH ), 34.7 (C-3),
3.1 [CH =CH(CH ) C], 22.3 [CH =CH(CH ) C].
3 2 3
420.21
457.68
2
3
2
2
3 2
+
+
Space group
a (Å)
P(-1)
P2 /n
MS (EI, 70 eV): m/z (%) = 320 ([M] , 22), 249 ([M – C H ] , 100),
1
5
9
2
07 (32), 172 (43).
7.7569(3)
10.4033(4)
12.9292(6)
73.847(4)
78.274(4)
72.065(4)
945.43
2
9.2879(3)
22.6454(6)
10.3652(3)
90
7
9
+
GC-HRMS (EI): m/z calcd for C H BrN [M] : 320.0883; found:
1
6
21
2
8
1
+
3
3
20.0883; m/z calcd for C H BrN2 [M] : 322.0862; found:
b (Å)
1
6
21
22.0864.
c (Å)
UV (MeOH): lmax (lg e) = 308 (3.58), 251 (3.75), 228 nm (3.91).
a (°)
rac-Debromodihydroflustramine C (26)
At r.t., DIBAL-H (1.0 M in toluene, 0.6 mL, 0.61 mmol, 1.85 equiv)
was added dropwise to a solution of rac-debromoflustramine C (7;
0 mg, 0.33 mmol, 1.0 equiv) in THF (5 mL) under argon. The re-
action mixture was stirred at r.t. for 24 h and then added dropwise
b (°)
105.571(4)
90
g (°)
8
V (Å3)
2100.1
4
to ice water (60 mL). Et O (30 mL) was added, followed by aq 12
2
M NaOH (20 mL). After extraction with Et O (3 × 20 mL), the
Z
2
combined ethereal layers were washed with H O (3 × 30 mL) and
2
D
(g/cm3)
1.476
1.444
brine (20 mL), and dried (Na SO ). Concentration in vacuo and col-
x
2
4
umn chromatography (silica gel, CHCl –MeOH, 5:1) afforded rac-
3
m (/mm)
2.5
2.3
debromodihydroflustramine C (26; 58 mg, 0.24 mmol, 73%) as a
yellow oil; R = 0.2 (CHCl –MeOH, 5:1).
f
3
F(000)
432
936
IR (ATR): 3259 (w, br), 3082 (w), 2964 (m), 2932 (m), 2872 (w),
790 (w), 2659 (w), 2469 (w), 1669 (w), 1604 (m), 1483 (m), 1467
s), 1414 (w), 1381 (w), 1365 (w), 1350 (w), 1316 (w), 1257 (w),
Habit
colorless prism
0.3 × 0.2 × 0.15
60
colorless lath
2
(
–
1
Size
0.4 × 0.2 × 0.1
56.6
1
153 (m), 1077 (w), 1004 (m), 913 (m), 740 (s), 689 cm (w).
1
H NMR (400 MHz, CDCl ): d = 7.13 (ddd, 4J = 0.4, 1.2 Hz,
2q (max) (°)
No. of refl.
Unique refl.
R(int)
3
3
4
3
J = 7.5 Hz, 1 H, 4-H), 7.08 (dt, J = 1.2 Hz, J = 7.6 Hz, 1 H, 6-H),
4
3
3
58212
5457
68893
5197
6
.74 (dt, J = 1.0 Hz, J = 7.5 Hz, 1 H, 5-H), 6.65 (d, J = 7.8 Hz, 1
3
H, 7-H), 5.99 [dd, J = 17.4, 10.8 Hz, 1 H, CH =CH(CH ) C], 5.10
2
3 2
3
2
[
dd, J = 1.3 Hz, J = 10.8 Hz, 1 H, CH =CH(CH ) C-H ], 5.03 [dd,
2 3 2 Z
3
2
J = 1.3 Hz, J = 17.3 Hz, 1 H, CH =CH(CH ) C-H ], 4.82 (br s, 1
2
3 2
E
0.030
0.057
229
H, 8a-H), 2.993–2.92 [m, 1 H, (CH )NCH CH C], 2.59–2.51 [m, 1
3
2
2
3
H, (CH )NCH CH C], 2.54 (s, 3 H, NCH ), 2.45 [ddd, J = 9.5, 6.5
No. of parameters
wR2 (all data)
R1 [I > 4s(I)]
S
212
3
2
2
3
2
3
Hz, J = 12.2, 1 H, (CH )NCH CH C], 1.98 (ddd, J = 5.7, 3.2 Hz,
3
2
2
2
0.052
0.063
0.028
0.94
J = 12.4 Hz,
1
H, CH NCH CH C), 1.08 [s,
3
H,
3
2
2
CH =CH(CH ) C], 1.03 [s, 3 H, CH =CH(CH ) C].
2
3 2
2
3 2
0.021
13C
NMR (100 MHz, CDCl ): d = 150.0 (C-7a), 144.3
3
[
CH =CH(CH ) C], 132.2 (C-3b), 128.3 (C-6), 125.0 (C-4), 118.9
0.99
2
3 2
(
3
3
C-5), 113.7 [CH =CH(CH ) C], 109.4 (C-7), 88.4 (C-8a), 64.5 (C-
a), 53.2 (C-2), 41.3 [NHCHCC(CH ) CH=CH ], 36.3 (NCH ),
3 2 2 3
2 3 2
3
Max. Dr (e/Å )
0.68
0.74
3.9 (C-3), 23.2 [CH =CH(CH ) C], 22.5 [CH =CH(CH ) C].
2
3 2
2
3 2
Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York

2
170
S. K. Adla et al.
PAPER
(7) Transition metal-catalyzed 3-tert-prenylation of indole:
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am.
Chem. Soc. 2005, 127, 4592. (b) Usui, I.; Schmidt, S.;
Keller, M.; Breit, B. Org. Lett. 2008, 10, 1207. (c) Gruber,
S.; Zaitsev, A. B.; Wörle, M.; Pregosin, P. S.
Acknowledgment
Organometallics 2008, 27, 3796..
This work was supported by generous donation of solvents (BASF
AG, Honeywell) and chromatography materials (Merck KGaA).
(
8) (a) Schkeryantz, J. M.; Woo, J. C. G.; Danishefsky, S. J.
J. Am. Chem. Soc. 1995, 117, 7025. (b) Schkeryantz, J. M.;
Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 1999, 121, 11964.
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Synthesis 2010, No. 13, 2161–2170 © Thieme Stuttgart · New York