Aerobic palladium(II)-catalyzed dehydrogenation of cyclohexene-1-carbonyl indole amides: An indole-directed aromatization

Article abstract of DOI:10.1021/jo301088f

A palladium(II)-catalyzed oxidative dehydrogenation of cyclohexene-1- carbonyl indole amides yielding the corresponding benzoylindoles is reported. The new aromatization is also applied to functionalized indoles such as tryptamine and tryptophan. The tethered indole is likely acting as a directing group for allylic C-H bond activation, and there is evidence for a mechanism proceeding through 1,3-diene formation followed by aromatization.

Full text of DOI:10.1021/jo301088f

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Note
Aerobic Palladium(II)-Catalyzed Dehydrogenation of Cyclohexene-1-
carbonyl Indole Amides: An Indole-Directed Aromatization
Sandeep R. Kandukuri, and Martin Oestreich
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Sep 2012
Downloaded from http://pubs.acs.org on September 10, 2012
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Aerobic Palladium(II)-Catalyzed Dehydrogenation of Cyclohexene-1-carbonyl
Indole Amides: An Indole-Directed Aromatization
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Sandeep R. Kandukuri†,‡ and Martin Oestreich*,†
†Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 115, 10623
Berlin, Germany
‡NRW Graduate School of Chemistry, Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
martin.oestreich@tu-berlin.de
ABSTRACT: A palladium(II)-catalyzed oxidative dehydrogenation of cyclohexene-1-
carbonyl indole amides yielding the corresponding benzoyl indoles is reported. The new
aromatization is also applied to functionalized indoles such as tryptamine and
tryptophan. The tethered indole is likely acting as a directing group for allylic C–H bond
activation, and there is evidence for a mechanism proceeding through 1,3-diene
formation followed by aromatization.
Molecular oxygen and likewise hydrogen are clearly attractive oxidizing and reducing
agents, respectively. There are numerous reports on the selective hydrogenation of
alkenes1 but examples of aerobic oxidation of alkanes to alkenes are scarce.2 Aerobic
oxidation of alcohols is well-investigated3 whereas selective aerobic dehydrogenation of
alkanes remains elusive. A palladium(II)-catalyzed oxidative aromatization of cyclic
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alkenes, i.e., cyclohexenes, was reported by Trost and Metzner for the first time.4 The
dehydrogenation of substituted six-membered ring alkenes is a useful transformation as
it provides access to arenes with challenging substitution patterns.5 In this Article, we
report the serendipitous finding of a remarkable indole-directed aerobic oxidative
dehydrogenation of cyclohexene-1-carbonyl indole amides.
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We recently disclosed a diastereoselective C-2 alkenylation of indoles with tri- and
tetrasubstituted double bonds6 by using a typical Pd(OAc)2–pyridine ligand system for
aerobic palladium(II) catalysis.7 The important step in our two-step strategy is an endo
cyclization of alkenes onto indoles temporarily tethered to the indole nitrogen atom by an
amide linkage (I→II, Scheme 1).
SCHEME 1. Aerobic Palladium(II)-Catalyzed Intramolecular endo Cyclization of
Indoles
R1
R1
Pd(OAc)2 (2.5–10 mol %)
L1 or L2 (10–40 mol %)
O
2 (ballon)
R3
N
N
mesitylene
tBuCO2H
110 °C or 150 °C
O
R3
O
R2
R2
I
R1, R2, and R3
II
= alkyl and/or aryl
CO2Me
CN
N
N
L1
L2
We successfully applied this endo cyclization protocol to various di- and trisubstituted
acyclic alkenes.6 However, when precursor 1a containing a cyclohexenyl group was
subjected to the above reaction conditions, the expected ring closure to afford the 3H-
pyrrolo[1,2-a]indole-3-one 4a did not occur at all. Instead, benzoyl indole 2a derived
from aromatization of the appended cyclohexenyl group was formed in 60% yield along
with a trace amount of isoindolo[2,1-a]indole 3a (1a→2a along with 3a, Scheme 2). We
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suspect that the formation of 3a resulted from the known double C–H bond activation of
the intermediate benzoyl indole (1a→2a→3a but not 1a→4a→3a, Scheme 2).8
SCHEME 2. Aerobic Palladium(II)-Catalyzed Dehydrogenation of a Cyclohexene-1-
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carbonyl Indole Amide
Me
N
O
1a
Pd(OAc)2 (10 mol %) mesitylene
L2 (40 mol %)
2 (ballon)
tBuCO2H
110 °C, 13 h
O
Me
Me
Me
N
N
N
O
O
O
2a: 60%
3a: traces
4a: expected
but not observed
This unexpected result prompted us to further investigate the scope of this
dehydrogenation reaction (Table 1). Additional indole-tethered cyclohexenes 1b–1g
were prepared by amide coupling of an indole and cyclohexene-1-carboxyl chloride.
Optimizing experiments showed that all components of the Pd(OAc)2–pyridine ligand–
acid system as well as dioxygen as terminal oxidant are necessary; L1 emerged from a
screening of different pyridine ligands (as in ref. 6) as optimum. Full conversion9 was
found for all substrates but either substituents on the cyclohexene ring10 (Table 1,
entries 2–4 versus entry 1) or phenyl substitution at the indole C-3 position (Table 1,
entry 5 versus entry 1) were detrimental to the reaction rate. The former is assumed to
be due to hampered -hydride elimination with ring substitution. Functionalized indoles
such as tryptamine and tryptophan also reacted in reasonable yields9 (Table 1, entries 6
and 7).
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TABLE 1. Aerobic Palladium(II)-Catalyzed Aromatization of Indole-Tethered
Cyclohexene-1-carbonylsa
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entry cyclohexene conv [%]b t [h] arene
yield [%]c,d
71e
Me
N
1
2
3
4f
100
96
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67
49
39
O
2a
40 (10)
36 (22)
41e
97
98
5
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98
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55e
45e
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100
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aAll reactions were conducted by using a Pd(OAc)2:L1 1:4 ratio under O2 atmosphere (balloon) with a
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b
substrate concentration of 0.125 M in mesitylene with added tBuCO2H (30 equiv). Conversion was
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d
monitored by GLC analysis. Isolated yields. Yield in the parenthesis refers to the oxidative coupling
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e
f
product 3. Traces of oxidative coupling product 3 were observed. Ratio of alkene regioisomers 1d and
1d’ used (5-Me:3-Me = 69:31).
Moreover, benzoyl indoles (2a–2g) were all prone to subsequent double C–H bond
activation, affording isoindolo[2,1-a]indoles 3a–3g in various quantities;8 3b and 3c
derived from C-4-substituted cyclohexenes were even formed in substantial amounts
(Table 1, entries 2 and 3). To verify the formation of 3 from 2, parent benzoyl indole 2h
was subjected to our standard dehydrogenation conditions, and 3h formed in
reasonable yield (Scheme 3, upper). The observation of a double C–H coupling in these
systems is consistent with the previously reported examples.8 Another interesting
observation is that cyclohexene tethered to the unsubstituted indole 1h yielded both 3h
and 4h which was formed from the endo ring closure (Scheme 3, lower). We also
observed the formation of expected 2h by GLC analysis in these catalyses and were
able to monitor its conversion into 3h. We were also able to prove that 4h is not
converted into 3h in an independent experiment. The rate of the oxidative C–C coupling
with double C–H bond activation is faster for the parent indole than for 3-substituted
indoles.
SCHEME 3. Experiment Results for the Double C–H Coupling of Unsubstituted
Indoles
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Pd(OAc)2 (10 mol %)
L1 (40 mol %)
O2 (balloon)
N
N
tBuCO2H
mesitylene
130 °C, 17 h
O
O
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2h
3h: 57%
Pd(OAc)2
(10 mol %)
L1
(40 mol %)
O2 (ballon)
N
+
N
N
mesitylene
tBuCO2H
O
O
O
1h
3h
35
53
:
:
:
4h
65, 70%
47, 65%
110 °C, 23 h
150 °C, 17 h
At present, we do not know the reasons for the difference in reactivity exerted by
substitution at the indole C-3 carbon atom. Double C–H bond activation is fast and endo
cyclization is preferred over oxidative dehydrogenation in the absence of a substituent in
that position.
To probe the role of the indole core, or more precisely, the C–H bond at the C-2
position in the dehydrogenation, we subjected C-2-substituted indole 1i (Figure 1, left) to
the standard protocol. No dehydrogenation but slow decomposition (30% after 16 h) was
observed. Likewise, anilide 5 (middle) and enamide 6 (right) were also reluctant to
undergo aromatization. While 5 was stable, 6 had decomposed to certain extent (40%
after 24 h). This set of test substrates corroborates the involvement of the indole C–H
bond in the oxidation of cyclohexene and supports the directing group ability of indole.
Also, the amide carbonyl group is equally crucial for aromatization as deoxygenated 1a,
that is an indole tethered to a 1-cyclohexene-1-ylmethyl group, slowly decomposed
(47% after 15 h).
Me
H
Me
N
N
N
O
O
O
1i
5
6
FIGURE 1. Groups Not Facilitating Oxidative Dehydrogenation
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Further insight was gained from an experiment with d4-acetic acid instead of pivalic acid
(Scheme 4). After 2 h reaction time, the deuteration grade was high for both aromatized
d1-2a and unreacted d1-1a. While the result is not totally conclusive evidence for an
indole-directed allylic C–H bond activation in the cyclohexene, it clearly demonstrates
that palladium(II)-catalyzed C–H bond activation occurs reversibly at the indole C-2
position. Pd(OAc)2 is necessary for deuterium incorporation. As to a tentative
mechanism,11 we believe that an indole-directed allylic C–H bond activation produces a
π allyl palladium(II) complex that is followed by the formation of a 1,3-diene.4 The latter
is detected by GLC-MS analysis.12 The 1,3-diene then transforms into the fully
aromatized product. A mechanism for the oxidative coupling, via the double C–H bond
activation, was previously discussed.8b
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SCHEME 4. Control Experiment with d4-Acetic Acid
In summary, we discovered a new palladium(II)-catalyzed aerobic dehydrogenation of
cyclohexenes connected to the nitrogen atom of indoles having a C–H bond at the C-2
position. Allylic C–H bond activation in the cyclohexene is assumed to occur
intramolecularly subsequent to palladium(II)-mediated C–H bond activation of the indole,
thereby directing the palladium(II) atom into the proximity of an allylic C–H bond. Yields
are not outstanding but reasonable for such a transformation.
EXPERIMENTAL SECTION
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General experimental details were reported before.6 Literature-known compounds N-
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benzoylindole
(2h),8c
N-methyl-N-phenylcyclohex-1-enecarboxamide
(5),13
N-
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methylcyclolohex-1-enecarboxamide (6),14 4-tert-butylcyclohex-1-enecarboxylic acid
(7),15 5-methylcyclohex-1-enecarboxylic acid/3-methylcyclohex-1-enecarboxylic acid
(9a/9a’),15 and 3-phenylindole (10)16 were prepared according to reported procedures.
General Procedure for the Indole-Directed Oxidative Dehydrogenation. A flame-
dried Schlenk tube is charged with Pd(OAc)2 (10 mol %), tetracosane (40 mol %,
internal standard), pivalic acid (30 equiv), L1 (40 mol %), and the compound 1 (1.0
equiv). The tube is then evacuated and backfilled with O2 (three cycles) and mesitylene
(0.125 M for 1) is added. If compound 1 is a liquid, it is dissolved in mesitylene and the
resulting solution is added. The reaction mixture is then heated to the indicated
temperature and monitored by GLC analysis. The reaction mixture is cooled to room
temperature, diluted with tert-butyl methyl ether, and washed with H2O (1 ) and
saturated aqueous NaHCO3 (1 ). The aqueous layers are extracted with tert-butyl
methyl ether (3 ), and the combined organic phases are dried over Na2SO4. After
evaporation of the solvents under reduced pressure, purification of the residue by flash
column chromatography on silica gel (cyclohexane/tert-butyl methyl ether solvent
mixtures as eluent) affords the title compound 2.
N-Benzoyl-3-methylindole (2a, Table 1, entry 1): Prepared from 1a (29.9 mg, 0.125
mmol, 1.00 equiv) according to the general procedure. Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1) afforded
analytically pure 2a (20.8 mg, 71%) as a light yellow oil. GLC (HP-5MS): tR = 22.3 min.
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Rf = 0.5 (cyclohexane:tert-butyl methyl ether = 5.5:1). IR and NMR spectra were in
agreement with reported data.17 HRMS (ESI) exact mass for [M+Na]+ (C16H13NONa):
calcd m/z 258.0889, found 258.0892.
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N-(4-tert-Butylbenzoyl)-3-methylindole and 9-tert-Butyl-11-methyl-6H-isoindolo[2,1-
a]indol-6-one (2b and 3b, Table 1, entry 2): Prepared from 1b (36.9 mg, 0.125 mmol,
1.00 equiv) according to the general procedure. Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1) afforded
analytically pure 2b (14.4 mg, 40%) as a light yellow solid (m.p. = 62–64 °C) along with
3b (3.8 mg, 10%) as a yellow solid (m.p. = 173–175 °C). 2b: GLC (HP-5MS): tR = 25.9
min. Rf = 0.6 (cyclohexane:tert-butyl methyl ether = 9:1). IR (ATR):  = 1676 (s, C=O)
cm–1. 1H NMR (400 MHz, CDCl3):  = 1.38 (s, 9H), 2.26 (d, J = 1.3 Hz, 3H), 7.12 (q, J =
1.3 Hz, 1H), 7.33 (ddd, J = 8.8 Hz, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.39 (ddd, J = 8.4 Hz, J =
7.3 Hz, J = 1.3 Hz, 1H), 7.52-7.55 (m, 3H), 7.66-7.69 (m, 2H), 8.41 (ddd, J = 8.2 Hz, J =
13
1.8 Hz, J = 0.7 Hz, 1H) ppm. C NMR (100 MHz, CDCl3):  = 9.8, 31.3, 35.2, 116.6,
117.6, 118.9, 123.7, 124.7, 125.0, 125.6, 129.2, 131.9, 132.1, 136.4, 155.4, 168.6 ppm.
HRMS (ESI) exact mass for [M+H]+ (C20H22NO): calcd m/z 292.1696, found 292.1690.
3b: GLC (HP-5MS): tR = 28.3 min. Rf = 0.6 (cyclohexane:tert-butyl methyl ether = 9:1).
IR (ATR):  = 1719 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):  = 1.39 (s, 9H), 2.46 (s,
3H), 7.16 (ddd, J = 8.6 Hz, J = 7.6 Hz, J = 1.1 Hz, 1H), 7.27-7.29 (m, 1H), 7.35 (dd, J =
8.1 Hz, J = 1.7 Hz, 1H), 7.39 (ddd, J = 7.8 Hz, J = 1.9 Hz, J = 0.9 Hz, 1H), 7.57 (dd, J =
1.7 Hz, J = 0.6 Hz, 1H), 7.68 (dd, J = 8.1 Hz, J = 0.7 Hz, 1H), 7.86 (ddd, J = 8.0 Hz, J =
13
1.7 Hz, J = 0.8 Hz, 1H) ppm. C NMR (100 MHz, CDCl3):  = 9.8, 31.3, 35.6, 113.4,
114.9, 118.3, 120.2, 123.5, 125.2, 125.6, 126.5, 131.6, 133.7, 135.1, 135.5, 136.0,
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157.8, 162.8 ppm. HRMS (ESI) exact mass for [M+H]+ (C20H20NO): calcd m/z 290.1539,
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found 290.1531.
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N-(4-Methylbenzoyl)-3-methylindole and 9,11-Dimethyl-6H-isoindolo[2,1-a]indol-6-
one (2c and 3c, Table 1, entry 3): Prepared from 1c (31.6 mg, 0.125 mmol, 1.00 equiv)
according to the general procedure. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether = 19:1) afforded analytically pure 2c (11.2
mg, 36%) as a light yellow solid (m.p. = 107–109 °C) along with 3c (6.8 mg, 22%) as a
yellow solid (m.p. = 135–137 °C). 2c: GLC (HP-5MS): tR = 23.6 min. Rf = 0.6
1
(cyclohexane:tert-butyl methyl ether = 9:1). IR (ATR):  = 1664 (s, C=O) cm–1. H NMR
(400 MHz, CDCl3):  = 2.25 (d, J = 1.3 Hz, 3H), 2.46 (s, 3H), 7.09 (q, J = 1.3 Hz, 1H),
7.31-7.34 (m, 3H), 7.38 (ddd, J = 8.4 Hz, J = 7.2 Hz, J = 1.3 Hz, 1H), 7.52-7.55 (m, 1H),
7.60-7.65 (m, 2H), 8.37 (ddd, J = 8.2 Hz, J = 1.8 Hz, J = 0.7 Hz, 1H) ppm. 13C NMR (100
MHz, CDCl3):  = 9.8, 21.7, 116.6, 117.7, 118.9, 123.7, 124.6, 125.0, 129.3, 129.4,
131.9, 132.2, 136.5, 142.4, 168.6 ppm. HRMS (ESI) exact mass for [M+Na]+
(C17H15NONa): calcd m/z 272.1046, found 272.1045. 3c: GLC (HP-5MS): tR = 25.8 min.
Rf = 0.6 (cyclohexane:tert-butyl methyl ether = 9:1). IR (ATR):  = 1704 (s, C=O) cm–1.
1H NMR (400 MHz, CDCl3):  = 2.43 (s, 3H), 2.44 (s, 3H), 7.10 (d, J = 7.8 Hz, 1H), 7.15
(t, J = 7.5 Hz, 1H), 7.27-7.29 (m, 1H), 7.36-7.38 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.85
(d, J = 8.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):  = 9.6, 22.2, 113.3, 115.1, 120.2,
122.0, 123.5, 125.3, 126.5, 129.0, 131.6, 133.7, 134.8, 135.5, 135.9, 144.5, 162.6 ppm.
HRMS (ESI) exact mass for [M+H]+ (C17H14NO): calcd m/z 248.1070, found 248.1070.
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N-(3-Methylbenzoyl)-3-methylindole (2d, Table 1, entry 4): Prepared from 1d/1d’ (31.6
mg, 0.125 mmol, 1.00 equiv) according to the general procedure. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1)
afforded analytically pure 2d (12.7 mg, 41%) as a light yellow oil. GLC (HP-5MS): tR =
23.3 min. Rf = 0.6 (cyclohexane:tert-butyl methyl ether = 9:1). IR (ATR):  = 1672 (s,
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C=O) cm–1. H NMR (400 MHz, CDCl3):  = 2.25 (d, J = 1.3 Hz, 3H), 2.45 (s, 3H), 7.06
(q, J = 1.3 Hz, 1H), 7.33 (ddd, J = 8.7 Hz, J = 7.6 Hz, J = 1.3 Hz, 1H), 7.36-7.40 (m, 3H),
7.48-7.50 (m, 1H), 7.52-7.54 (m, 2H), 8.37 (ddd, J = 8.2 Hz, J = 1.8 Hz, J = 0.7 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3):  = 9.8, 21.5, 116.6, 117.8, 118.9, 123.7, 124.6,
125.0, 126.2, 128.4, 129.6, 131.9, 132.4, 135.1, 136.4, 138.6, 168.7 ppm. HRMS (ESI)
exact mass for [M+H]+ (C17H16NO): calcd m/z 250.1226, found 250.1224.
N-Benzoyl-3-phenylindole (2e, Table 1, entry 5): Prepared from 1e (37.6 mg, 0.125
mmol, 1.00 equiv) according to the general procedure. Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1) afforded
analytically pure 2e (20.4 mg, 55%) as a light yellow solid [m.p. = 143–145 °C (lit.18 151–
153 °C)]. GLC (HP-5MS): tR = 29.5 min. Rf = 0.57 (cyclohexane:tert-butyl methyl ether =
5.5:1). IR (ATR):  = 1677 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):  = 7.36-7.47 (m,
6H), 7.53-7.57 (m, 2H), 7.60-7.62 (m, 3H), 7.78-7.80 (m, 2H), 7.86 (ddd, J = 7.8 Hz, J =
1.2 Hz, J = 0.7 Hz, 1H), 8.48 (ddd, J = 8.2 Hz, J = 1.4 Hz, J = 0.7 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3):  = 116.8, 120.0, 123.6, 124.4, 124.5, 125.5, 127.6, 128.1, 128.8,
129.0, 129.3, 129.5, 132.1, 133.5, 134.7, 136.9, 168.8 ppm. HRMS (ESI) exact mass for
[M+H]+ (C21H16NO): calcd m/z 298.1226, found 298.1219.
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Benzyl [2-(1-benzoyl-1H-indol-3-yl)ethyl]carbamate (2f, Table 1, entry 6): Prepared
from 1f (50.3 mg, 0.125 mmol, 1.00 equiv) according to the general procedure.
Purification by flash column chromatography on silica gel (cyclohexane:tert-butyl methyl
ether = 2:1) afforded analytically pure 2f (22.4 mg, 45%) as a colourless oil. GLC (HP-
5MS): tR = 26.5 min. Rf = 0.52 (cyclohexane:tert-butyl methyl ether = 1:2). IR (ATR):  =
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3334 (s, NH), 1677 (s, C=O) cm–1. H NMR (400 MHz, CDCl3):  = 2.90 (t, J = 6.7 Hz,
2H), 3.50 (td, J = 6.7 Hz, J = 5.7 Hz, 2H), 4.99 (t, J = 5.7 Hz, 1H), 5.09 (s, 2H), 7.13 (s,
1H), 7.30-7.36 (m, 6H), 7.39 (ddd, J = 8.3 Hz, J = 7.3 Hz, J = 1.1 Hz, 1H), 7.50 (t, J = 7.6
Hz, 2H), 7.60 (m, 2H), 7.70 (m, 2H), 8.40 (ddd, J = 8.2 Hz, J = 1.7 Hz, J = 0.7 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3):  = 25.7, 40.6, 66.7, 116.7, 118.9, 119.0, 123.9,
124.9, 125.3, 128.1, 128.2, 128.6, 128.7, 129.1, 130.7, 131.9, 134.7, 136.5, 136.6,
156.4, 168.5 ppm. HRMS (ESI) exact mass for [M+Na]+ (C25H22N2O3Na): calcd m/z
421.1523, found 421.1512.
(S)-Methyl-2-{[(benzyloxy)carbonyl]amino}-3-(1-benzoyl-1H-indol-3-yl)propanoate
(2g, Table 1, entry 7): Prepared from 1g (57.6 mg, 0.125 mmol, 1.00 equiv) according to
the general procedure. Purification by flash column chromatography on silica gel
(cyclohexane:tert-butyl methyl ether = 2:1) afforded analytically pure 2g (29.1 mg, 51%)
as a white solid (m.p. = 128–130 °C). GLC (HP-5MS): tR = 29.4 min. Rf = 0.33
(cyclohexane:tert-butyl methyl ether = 2:1). IR (ATR):  = 3320 (s, NH), 1734 (m, C=O),
1
1679 (s, C=O) cm–1. H NMR (400 MHz, CDCl3):  = 3.18 (dd, J = 14.7 Hz, J = 5.4 Hz,
1H), 3.27 (dd, J = 14.7 Hz, J = 5.5 Hz, 1H), 3.60 (s, 3H), 4.72 (ddd, J = 7.8 Hz, J = 5.5
Hz, J = 5.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 5.09 (d, J = 12.4 Hz, 1H), 5.38 (d, J = 7.8
Hz, 1H), 7.09 (s, 1H), 7.27-7.35 (m, 6H), 7.39 (ddd, J = 8.3 Hz, J = 7.2 Hz, J = 0.9 Hz,
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1H), 7.49 (m, 3H), 7.59 (tt, J = 7.3 Hz, J = 1.3 Hz, 1H), 7.69 (m, 2H), 8.37 (ddd, J = 8.3
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Hz, J = 1.7 Hz, J = 0.7 Hz, 1H) ppm. C NMR (100 MHz, CDCl3):  = 27.9, 52.5, 54.1,
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67.1, 116.3, 116.6, 118.8, 124.0, 125.4, 125.8, 128.1, 128.3, 128.6, 128.7, 129.2, 130.8,
132.0, 134.6, 136.2, 136.3, 155.7, 168.4, 172.0 ppm. HRMS (ESI) exact mass for
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[M+Na]+ (C27H24N2O5Na): calcd m/z 479.1577, found 479.1574. []D +47.8 (c 1.0,
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CHCl3).
6H-Isoindolo[2,1-a]indol-6-one (3h, Scheme 3): Prepared from 2h (44.2 mg, 0.200
mmol, 1.00 equiv) according to the general procedure. Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 32:1) afforded
analytically pure 3h (25.0 mg, 57%) as a yellow solid [m.p. = 157–159 °C (lit.8a 154–155
°C)]. GLC (HP-5MS): tR = 22.9 min. Rf = 0.47 (cyclohexane:tert-butyl methyl ether =
5.5:1). IR and NMR spectra were in agreement with reported data.8b HRMS (ESI) exact
mass for [M+H]+ (C15H10NO): calcd m/z 220.0757, found 220.0755.
7,8,9,10-Tetrahydro-6H-isoindolo[2,1-a]indol-6-one (4h, Scheme 3): Prepared from
1h (28.2 mg, 0.125 mmol, 1.00 equiv) according to the general procedure. Purification
by flash column chromatography on silica gel (cyclohexane:tert-butyl methyl ether =
19:1) afforded a mixture of 3h and 4h (19.2 mg, 70%). GLC (HP-5MS): tR = 23.2 min. Rf
= 0.47 (cyclohexane:tert-butyl methyl ether = 5.5:1). IR (ATR):  = 1697 (s, C=O) cm–1.
1H NMR (400 MHz, CDCl3):  = 1.73-1.79 (m, 4H), 2.28-3.32 (m, 2H), 2.40-2.44 (m, 2H),
6.24 (d, J = 0.5 Hz, 1H), 7.03 (ddd, J = 8.6 Hz, J = 7.6 Hz, J = 1.0 Hz, 1H), 7.21 (ddd, J
= 8.6 Hz, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.26-7.29 (m, 1H), 7.64 (ddd, J = 7.9 Hz, J = 1.1
Hz, J = 0.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):  = 20.6, 21.7, 21.8, 22.4, 104.1,
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112.1, 122.5, 122.7, 126.7, 134.0, 134.6, 134.7, 142.2, 144.2, 165.6 ppm. HRMS (ESI)
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exact mass for [M+H]+ (C15H14NO): calcd m/z 224.1070, found 224.1066.
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N-Cyclohexene-1-carbonyl-3-methylindole (1a, Table 1, entry 1): Prepared from 3-
methylindole (0.520 g, 3.96 mmol, 1.00 equiv) and cyclohex-1-enecarboxylic acid (1.0 g,
7.9 mmol, 2.0 equiv) according to the reported procedure.6 Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 49:1) afforded
analytically pure 1a (0.84 g, 88%) as a light yellow solid (m.p. = 113–115 °C). GLC (HP-
5MS): tR = 22.6 min. Rf = 0.5 (cyclohexane:tert-butyl methyl ether = 5.5:1). IR (ATR):  =
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1664 (s, C=O) cm–1. H NMR (400 MHz, CDCl3):  = 1.70-1.83 (m, 4H), 2.25-2.31 (m,
2H), 2.28 (d, J = 1.1 Hz, 3H), 2.43-2.47 (m, 2H), 6.25-6.26 (m, 1H), 7.23 (q, J = 1.1 Hz,
1H), 7.29 (ddd, J = 8.7 Hz, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.35 (ddd, J = 8.3 Hz, J = 7.3 Hz,
J = 1.3 Hz, 1H), 7.51 (ddd, J = 7.6 Hz, J = 1.5 Hz, J = 0.7 Hz, 1H), 8.36 (ddd, J = 8.2 Hz,
J = 1.3 Hz, J = 0.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):  = 9.8, 21.6, 22.1, 25.3,
25.6, 116.5, 117.0, 118.8, 123.4, 124.3, 124.8, 132.0, 134.4, 135.9, 136.0, 169.9 ppm.
HRMS (ESI) exact mass for [M+Na]+ (C16H17NONa): calcd m/z 262.1202, found
262.1210.
N-(4-tert-Butylcyclohexene-1-carbonyl)-3-methylindole (1b, Table 1, entry 2):
Prepared from 3-methylindole (0.240 g, 1.83 mmol, 1.00 equiv) and 4-tert-butylcyclohex-
1-enecarboxylic acid15 (7, 0.500 g, 2.74 mmol, 1.50 equiv) according to the reported
procedure.6 Purification by flash column chromatography on silica gel (cyclohexane:tert-
butyl methyl ether = 19:1) afforded analytically pure 1b (0.324 g, 60%) as a white solid
(m.p. = 103–105 °C). GLC (HP-5MS): tR = 26.2 min. Rf = 0.6 (cyclohexane:tert-butyl
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methyl ether = 5:1). IR (ATR):  = 1667 (s, C=O) cm–1. H NMR (400 MHz, CDCl3):  =
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0.94 (s, 9H), 1.26-1.44 (m, 1H), 1.98-2.08 (m, 2H), 2.28 (d, J = 1.3 Hz, 3H), 2.31-2.46
(m, 2H), 2.59-2.65 (m, 1H), 6.29-6.32 (m, 1H), 7.23 (q, J = 1.3 Hz, 1H), 7.30 (ddd, J =
8.7 Hz, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.35 (ddd, J = 8.3 Hz, J = 7.3 Hz, J = 1.3 Hz, 1H),
7.50-7.57 (m, 1H), 8.36 (ddd, J = 8.2 Hz, J = 1.3 Hz, J = 0.7 Hz, 1H) ppm. 13C NMR (100
MHz, CDCl3):  = 9.8, 23.7, 27.0, 27.2, 27.3, 32.4, 43.5, 116.5, 117.0, 118.8, 123.4,
124.3, 124.8, 132.0, 134.2, 136.1, 136.5, 169.8 ppm. HRMS (ESI) exact mass for
[M+H]+ (C20H26NO): calcd m/z 296.2009, found 296.2015.
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N-(4-Methylcyclohexene-1-carbonyl)-3-methylindole (1c, Table 1, entry 3): Prepared
from 3-methylindole (0.280 g, 2.13 mmol, 1.00 equiv) and 4-methylcyclohex-1-
enecarboxylic acid15 (8, 0.600 g, 4.28 mmol, 2.00 equiv) according to the reported
procedure.6 Purification by flash column chromatography on silica gel (cyclohexane:tert-
butyl methyl ether = 19:1) afforded analytically pure 1c (0.404 g, 75%) as a white solid
(m.p. = 58–60 °C). GLC (HP-5MS): tR = 23.2 min. Rf = 0.6 (cyclohexane:tert-butyl methyl
ether = 9:1). IR (ATR):  = 1665 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):  = 1.05 (d,
J = 6.3 Hz, 3H), 1.37-1.42 (m, 1H), 1.75-1.92 (m, 3H), 2.27 (d, J = 1.2 Hz, 3H), 2.34-2.52
(m, 3H), 6.25-6.26 (m, 1H), 7.21 (d, J = 1.2 Hz, 1H), 7.29 (ddd, J = 8.7 Hz, J = 7.6 Hz, J
= 1.3 Hz, 1H), 7.35 (ddd, J = 8.6 Hz, J = 7.4 Hz, J = 1.4 Hz, 1H), 7.50 (ddd, J = 7.6 Hz, J
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= 1.4 Hz, J = 0.6 Hz, 1H), 8.35 (ddd, J = 8.3 Hz, J = 1.8 Hz, J = 0.7 Hz, 1H) ppm. C
NMR (100 MHz, CDCl3):  = 9.8, 21.7, 25.7, 27.8, 30.4, 33.8, 116.5, 117.1, 118.8, 123.4,
124.2, 124.8, 132.0, 134.1, 135.5, 136.1, 169.9 ppm. HRMS (ESI) exact mass for
[M+H]+ (C17H20NO): calcd m/z 254.1539, found 254.1538.
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N-(5-Methylcyclohexene-1-carbonyl)-3-methylindole and N-(3-methylcyclohexene-
1-carbonyl)-3-methylindole (1d and 1d’, Table 1, entry 4): Prepared from 3-
methylindole (0.280 g, 2.13 mmol, 1.00 equiv) and 69:31 mixture of 5-methylcyclohex-1-
enecarboxylic acid and 3-methylcyclohex-1-enecarboxylic acid15 (9a and 9a’, 0.600 g,
4.28 mmol, 2.00 equiv) according to the reported procedure.6 Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1)
afforded analytically pure 1d and 1d’ as a 69:31 regioisomeric mixture (0.377 g, 70%) as
a colourless oil. GLC (HP-5MS): tR = 22.9 min., 23.1 min. Rf = 0.6 (cyclohexane:tert-
butyl methyl ether = 9:1). IR (ATR):  = 1674 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):
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 = 1.06 (d, J = 6.5 Hz, 3H), 1.10 (d, J = 7.0 Hz, 1.4H), 1.30-1.35 (m, 2H), 1.78-1.83 (m,
4H), 1.98-2.01 (m, 1.5H), 2.21-2.34 (m, 8H), 2.39-2.42 (m, 2H), 2.53-2.58 (m, 1H), 6.11-
6.12 (m, 0.4H), 6.25-6.28 (m, 1H), 7.21-7-29 (m, 1.5H), 7.29 (ddd, J = 8.5 Hz, J = 7.6
Hz, J = 1.2 Hz, 1.8H), 7.35 (ddd, J = 8.5 Hz, J = 7.4 Hz, J = 1.4 Hz, 1.8H), 7.49-7.51 (m,
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1.6H), 8.35 (m, 1.4H) ppm. C NMR (100 MHz, CDCl3):  = 9.8, 9.9, 21.0, 21.1, 21.7,
25.6, 25.7, 28.3, 29.9, 30.4, 30.6, 33.8, 116.5, 117.1, 117.2, 118.8, 123.4, 124.2, 124.8,
132.0, 133.6, 134.0, 135.6, 136.1, 141.4, 169.9, 170.0 ppm. HRMS (ESI) exact mass for
[M+H]+ (C17H20NO): calcd m/z 254.1539, found 254.1532.
N-Cyclohexene-1-carbonyl-3-phenylindole (1e, Table 1, entry 5): Prepared from 3-
phenylindole16 (10, 0.400 g, 2.07 mmol, 1.00 equiv) and cyclohex-1-enecarboxylic acid
(3.31 g, 2.48 mmol, 1.20 equiv) according to the reported procedure.6 Purification by
flash column chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 19:1)
afforded analytically pure 1e (0.31 g, 50%) as a light yellow oil. GLC (HP-5MS): tR = 29.9
min. Rf = 0.57 (cyclohexane:tert-butyl methyl ether = 5.5:1). IR (ATR):  = 1680 (s, C=O)
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cm–1. H NMR (400 MHz, CDCl3):  = 1.70-1.76 (m, 2H), 1.78-1.83 (m, 2H), 2.25-2.30
(m, 2H), 2.47-2.51 (m, 2H), 6.38-6.41 (m, 1H), 7.31-7.42 (m, 3H), 7.45-7.49 (m, 2H),
7.57 (s, 1H), 7.62-7.65 (m, 2H), 7.82 (ddd, J = 7.8 Hz, J = 0.8 Hz, J = 0.6 Hz, 1H), 7.83
(m, 1H) ppm. 13C NMR (100 MHz, CDCl3):  = 21.6, 22.0, 25.5, 25.6, 116.6, 119.8,
122.7, 123.9, 124.2, 125.1, 127.4, 128.0, 128.9, 129.5, 133.7, 134.3, 136.5, 137.2,
170.0 ppm. HRMS (ESI) exact mass for [M+H]+ (C21H20NO): calcd m/z 302.1539, found
302.1535.
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Benzyl-[2-(cyclohexene-1-carbonyl-1H-indol-3-yl)ethyl]carbamate (1f, Table 1, entry
6): Prepared from indol-3-ylethylcarbamic acid benzylester (0.778 g, 2.64 mmol, 1.00
equiv) and cyclohex-1-enecarboxylic acid (0.500 g, 3.96 mmol, 1.50 equiv) according to
the reported procedure.6 Purification by flash column chromatography on silica gel
(cyclohexane:tert-butyl methyl ether = 2:1) afforded analytically pure 1f (0.504 g, 50%)
as a colourless oil. GLC (HP-5MS): tR = 26.8 min. Rf = 0.52 (cyclohexane:tert-butyl
methyl ether = 1:2). IR (ATR):  = 3347 (s, NH), 1672 (s, C=O) cm–1. 1H NMR (400 MHz,
CDCl3):  = 1.70-1.80 (m, 4H), 2.25-2.28 (m, 2H), 2.42-2.46 (m, 2H), 2.93 (t, J = 6.9 Hz,
2H), 3.54 (m, 2H), 4.85 (br s, 1H), 5.11 (s, 2H), 6.27-6.30 (m, 1H), 7.27-7.37 (m, 8H),
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7.54 (d, J = 7.7 Hz, 1H), 8.34 (ddd, J = 8.2 Hz, J = 1.2 Hz, J = 0.7 Hz, 1H) ppm. C
NMR (100 MHz, CDCl3):  = 21.5, 22.0, 25.4, 25.5, 25.7, 40.7, 66.7, 116.6, 118.0, 118.7,
123.5, 124.7, 124.9, 128.1, 128.2, 128.6, 130.8, 134.2, 136.2, 136.6, 136.7, 156.5,
169.8 ppm. HRMS (ESI) exact mass for [M+Na]+ (C25H26N2O3Na): calcd m/z 425.1836,
found 425.1832.
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(S)-Methyl-2-{[(benzyloxy)carbonyl]amino}-3-(cyclohexene-1-carbonyl-1H-indol-3-
yl)propanoate (1g, Table 1, entry 7): Prepared from N-Carbobenzyloxy-L-tryptophan
methyl ester (0.838 g, 2.38 mmol, 1.00 equiv) and cyclohex-1-enecarboxylic acid (0.600
g, 4.76 mmol, 2.00 equiv) according to the reported procedure.6 Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 2:1) afforded
analytically pure 1g (0.75 g, 68%) as a white solid (m.p. = 126–128 °C). GLC (HP-5MS):
tR = 29.7 min. Rf = 0.33 (cyclohexane:tert-butyl methyl ether = 2:1). IR (ATR):  = 3340
(s, NH), 1735 (s, C=O), 1692 (s, C=O), 1668 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):
 = 1.67-1.80 (m, 4H), 2.20-2.26 (m, 2H), 2.41-2.4 (m, 2H), 3.18 (dd, J = 14.8 Hz, J = 5.6
Hz, 1H), 3.26 (dd, J = 14.8 Hz, J = 5.5 Hz, 1H), 3.68 (s, 3H), 4.75 (ddd, J = 8.1 Hz, J =
5.6 Hz, J = 5.5 Hz, 1H), 5.08 (d, J = 12.5 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 5.34 (d, J =
8.1 Hz, 1H), 6.25-6.26 (m, 1H), 7.24-7.26 (m, 2H), 7.31-7.36 (m, 6H), 7.47 (d, J = 7.7
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Hz, 1H), 8.32 (ddd, J = 8.2 Hz, J = 1.2 Hz, J = 0.7 Hz, 1H) ppm. C NMR (100 MHz,
CDCl3):  = 21.5, 22.0, 25.4, 25.5, 28.0, 52.6, 54.0, 67.1, 115.3, 116.5, 118.7, 123.6,
125.1, 125.6, 128.1, 128.3, 128.6, 130.9, 134.1, 135.9, 136.2, 137.1, 155.7, 169.8,
172.1 ppm. HRMS (ESI) exact mass for [M+Na]+ (C27H28N2O5Na): calcd m/z 483.1890,
found 483.1886. []D20 +40.4 (c 1.0, CHCl3).
N-Cyclohexene-1-carbonylindole (1h, Scheme 3): Prepared from indole (0.300 g, 2.55
mmol, 1.00 equiv) and cyclohex-1-enecarboxylic acid (0.386 g, 3.06 mmol, 1.20 equiv)
according to the reported procedure.6 Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether = 19:1) afforded analytically pure 1h
(0.286 g, 50%) as a colourless liquid. GLC (HP-5MS): tR = 21.6 min. Rf = 0.48
(cyclohexane:tert-butyl methyl ether = 5.5:1). IR (ATR):  = 1676 (s, C=O) cm–1. 1H NMR
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(400 MHz, CDCl3):  = 1.72-1.81 (m, 4H), 2.26-2.29 (m, 2H), 2.45-2.49 (m, 2H), 6.31-
6.34 (m, 1H), 6.58 (dd, J = 7.7 Hz, 0.7 Hz, 1H), 7.27 (ddd, J = 8.4 Hz, J = 7.6 Hz, J = 1.1
Hz, 1H), 7.35 (ddd, J = 8.3 Hz, J = 7.3 Hz, J = 1.3 Hz, 1H), 7.46 (d, J = 3.7 Hz, 1H), 7.58
(ddd, J = 7.7 Hz, J = 1.3 Hz, J = 0.8 Hz, 1H), 8.37 (ddd, J = 8.2 Hz, J = 1.7 Hz, J = 0.8
Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):  = 21.6, 22.1, 25.4, 25.6, 107.8, 116.4,
120.8, 123.6, 124.7, 127.4, 130.9, 134.2, 135.8, 136.9, 170.2 ppm. HRMS (ESI) exact
mass for [M+H]+ (C15H16NO): calcd m/z 226.1226, found 226.1225.
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N-Cyclohexene-1-carbonyl-2,3-dimethylindole (1i, Figure 1): Prepared from 2,3-
dimethylindole (0.296 g, 2.04 mmol, 1.00 equiv) and cyclohex-1-enecarboxylic acid
(0.515 g, 4.08 mmol, 2.00 equiv) according to the reported procedure.6 Purification by
flash column chromatography on silica gel (cyclohexane:tert-butyl methyl ether = 49:1)
afforded analytically pure 1i (0.31 g, 60%) as a light yellow solid (m.p. = 49–51 °C). GLC
(HP-5MS): tR = 23.0 min. Rf = 0.5 (cyclohexane:tert-butyl methyl ether = 5.5:1). IR
(ATR):  = 1662 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3):  = 1.69-1.76 (m, 2H), 1.77-
1.83 (m, 2H), 2.20 (d, J = 0.7 Hz, 3H), 2.20-2.25 (m, 2H), 2.40 (d, J = 0.7 Hz, 3H), 2.45-
2.50 (m, 2H), 6.38-6.41 (m, 1H), 7.16 (ddd, J = 9.3 Hz, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.17
(ddd, J = 9.1 Hz, J = 7.2 Hz, J = 1.9 Hz, 1H), 7.40-7.44 (m, 1H), 7.56-7.61 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3):  = 8.7, 13.1, 21.6, 22.2, 24.8, 25.9, 113.7, 114.1, 118.1,
121.9, 122.8, 130.7, 132.8, 135.8, 136.5, 140.3, 171.2 ppm. HRMS (ESI) exact mass for
[M+H]+ (C17H20NO): calcd m/z 254.1539, found 254.1533.
4-Methylcyclohex-1-enecarboxylic acid (8): Prepared from 4-methylcyclohexanone
(5.0 g, 44 mmol, 1.0 equiv) and bromoform (44.4 g, 176 mmol, 4.00 equiv) according to
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the reported procedure,15 affording analytically pure 8 (4.93 g, 80%) as a white solid
(m.p. = 115–117 °C). GLC (HP-5MS): tR = 10.9 min. IR (ATR):  = 1670 (s, C=O) cm–1.
1H NMR (400 MHz, CDCl3):  = 0.98 (d, J = 6.5 Hz, 3H), 1.20-1.25 (m, 1H), 1.75-1.85
(m, 3H), 2.14-2.24 (m, 1H), 2.27-2.42 (m, 2H), 7.08-7.11 (m, 1H), 11.8 (br s, 1H) ppm.
13C NMR (100 MHz, CDCl3):  = 21.5, 24.5, 27.6, 30.4, 33.9, 132.0, 135.0, 170.8 ppm.
HRMS (ESI) exact mass for [M+H]+ (C8H13O2): calcd m/z 141.0910, found 141.0907.
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Acknowledgments. S.R.K. thanks the NRW Graduate School of Chemistry for a
predoctoral fellowship (2009–2012). M.O. is indebted to the Einstein Foundation (Berlin)
for an endowed professorship.
Supporting Information. GLC-MS traces on 1,3-diene formation as well as copies of 1H
and 13C NMR spectra of all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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(1)
(2)
(a) Nishimura, S. In Handbook of Heterogeneous Catalytic Hydrogenation for
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Yields are generally moderate due to decomposition through aerobic oxidation of
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(10) We also tested a ring size other than six to see whether partial dehydrogenation
would be possible. The indole amide with a cyclopentene instead of a
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