N-alkenyl indoles as useful intermediates for alkaloid synthesis

Article abstract of DOI:10.1021/jo201955c

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K₃PO₄ as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C₂-position of the indole ring. An alternative strategy for selective functionalization at the C₂-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.

Full text of DOI:10.1021/jo201955c

Article
pubs.acs.org/joc
N-Alkenyl Indoles as Useful Intermediates for Alkaloid Synthesis
Hao Li, Nawong Boonnak, and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling
procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and
20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K3PO4 as the base. When treated with acid,
these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A
cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic
indole derivatives with a quaternary stereocenter attached to the C2-position of the indole ring. An alternative strategy for
selective functionalization at the C2-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical
cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca
alkaloids, including the tetrahydroisoquinocarbazole RS-2135.
INTRODUCTION
■
The vinca family of indole alkaloids occupies a central place in
natural product chemistry because of the wide range of complex
structural variation in its molecular framework.1,2 Members of
the vinca family exhibit strong vasodilation activity which brings
about an enhancement of the overall cerebral blood flow.3 The
development of synthetic methods for constructing this family
of alkaloids has attracted much attention for several decades
Figure 1. Skeleta of some vinca alkaloids.
due to the important pharmacological properties and diverse
structures of this class of natural products.4−11 Although several
the indole scaffold, we became interested in accessing indole
strategies for the synthesis of vinca alkaloids have been
reported,12 the search for more efficient and general methods
derivatives substituted at the N-position with various alkenyl
groups. Such derivatives, in addition to incorporating structural
elements that expand the potential for natural product
synthesis, also provide an opportunity for manipulating the
electronic characteristics of the indole ring itself. Surprisingly,
N-alkenyl indoles are not well represented in the chemical
literature,18 and their application as an enamine equivalent in
electrophilic reactions has not been investigated in any detail.
In this paper, we report a synthetically useful procedure that
allows generation of a variety of N-alkenyl indoles and a study
of their acid-promoted electrophilic addition reactions as well
as their radical cyclizations. Our intention was to carry out
some model studies with these systems which we hoped could
eventually be used in a total synthesis of the vinca alkaloid RS-
2135 (1).
which provide flexible entries to structural analogues of the
pentacyclic core still remains a challenging goal. In particular,
RS-2135 (1), a pentacyclic tetrahydroisoquinocarbazole ana-
logue of the vinca alkaloid eburnamonine (2), attracted our
attention due to its potent antiarrhythmic activity.13 We
envisaged that the tetracyclic core (i.e., 3) of RS-2135 could
be quickly assembled by cyclization of an appropriately
substituted N-alkenyl indole with a suitable tethered functional
group at the C2-position of the ring (vide infra) (Figure 1).
In recent years, the utilization of transition-metal-catalyzed
reactions for the synthesis of 2,3-disubstituted alkenyl indoles,
starting from o-alkynylanilines or derivatives thereof14 as well as
o-haloanilines,15 has been intensively studied. Another effective
strategy for the introduction of an alkenyl side chain into the
indole skeleton is the palladium-catalyzed oxidative reaction of
alkenes via C−H bond cleavage.16 The alkenylation generally
occurs at the electron-rich C3-position of the indole ring due to
the electrophilic nature of the reaction.17 In an effort to further
expand the diversity of substituents that can be positioned on
Received: September 26, 2011
Published: October 18, 2011
© 2011 American Chemical Society
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RESULTS AND DISCUSSION
Scheme 2
■
N-Alkenylation has previously been carried out employing a
variety of methods including mercuric acetate/sulfuric-acid-
catalyzed alkenylation of NH-heteroaromatics with vinyl
acetate,19a alkylation with dibromoethane followed by elimi-
nation,19b palladium(II)-catalyzed alkenylation of amides with
electron-deficient acrylates,19c palladium(0)-catalyzed alkenyla-
tion with alkenyl bromides19d and triflates,19e and cesium-
hydroxide-catalyzed addition of alcohols and amine derivatives
to alkynes and styrenes.19f The drawbacks of these methods are
the need to use elevated temperatures and a lack of generality
and/or substrate scope. We found that, by using a N-
alkenylation protocol originally developed by Lam and co-
workers18a and more recently employed by Xi,20a,b we were able
to prepare a series of N-alkenyl indoles in good yield.20c The
coupling procedure involved treating a NH-indole with various
alkenyl bromides using a combination of 10 mol % of copper(I)
iodide and 20 mol % of ethylenediamine as the catalyst in
dioxane at 110 °C in the presence of K3PO4 as the base
(Scheme 1). Thus, the parent N−H and 3-substituted N−H
Scheme 3
Scheme 1
In a subsequent study, we opted to examine the bromination
reactions of these N-alkenyl-substituted indoles as a potential
method for further elaboration of their scaffold. This
electrophilic reaction was initially explored by exposing N-
alkenyl indole 5 to bromine/Et3N at −78 °C, which resulted in
the formation of allyl bromide 16, but only in 13% yield.
However, when N-bromosuccinimide (NBS) was used as the
brominating reagent,22 the yield of 16 improved to 65%
(Scheme 4). In a related manner, N-indolyl bromide 17 was
indole system underwent ready coupling with 2-bromoprop-1-
ene as well as 2-bromobut-1-ene to give the corresponding N-
alkenyl-substituted indoles 4−8 in good to excellent yields.
This effective coupling reaction tolerates both electron-rich
(e.g., 6) and electron-deficient substituents (e.g., 5, 7, and 8).
Enamines are among the most widely used building blocks in
organic synthesis.21 A conventional enamine acts as a
nucleophile in a chemical transformation by enlisting its
nitrogen lone pair toward nucleophilic attack. We became
interested in examining the extent of interaction between the
indole nitrogen lone pair of electrons and the enamine double
bond present in systems such as 4−8. In particular, we
recognized that N-alkenyl-substituted indoles represent a
unique class of enamines that bear a multitude of nucleophilic
sites and which could lead to various products (i.e., 9−11)
when allowed to react with an electrophile (Scheme 2).
We first examined the behavior of N-alkenyl indole 5 toward
Brønsted or Lewis-acid-promoted electrophilic additions.
Exposure of 5 to 1.0 equiv of p-toluene sulfonic acid
monohydrate (p-TsOH·H2O) in CH2Cl2 at 25 °C for 1 h
afforded methyl 1H-indole-3-carboxylate (12) in 99% yield by a
standard hydrolysis reaction. However, when 5 was allowed to
react with a milder Lewis acid such as MgI2, the dimeric indole
13 was formed in 63% yield (Scheme 3). We assume that the
formation of 13 proceeds by protonation of the enamine π-
bond of 5 to give iminium ion 14. Further reaction of 14 with
another equivalent of N-alkenyl indole 5 leads to a second
iminium ion 15, which rapidly undergoes deprotonation to give
dimer 13.
Scheme 4
also prepared in 54% yield from indole 7. (E)-Methyl 1-(1-
bromobut-2-en-2-yl)-1H-indole-3-carboxylate (18) was also
obtained as the major product when N-alkenyl indole 8 was
subjected to the bromination conditions, and its E-sterochem-
istry was confirmed by NOE experiments.
Allylic halides are known to be active reaction partners with
cyclic enamines generally producing α-alkylated ketones in high
yield.21 With the N-indolyl allylic bromides 16 and 17 in hand,
alkylation of these substrates with cyclic enamines 19 and 20
was next investigated (Scheme 5). We found that these N-
indolyl allylic bromides reacted smoothly with enamines 19 and
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iodide.26 Previous work in this field suggests that cyclization
should occur regioselectively at the 2-position of the indole
ring.27 Indeed, the radical derived from xanthate 31 (AIBN, n-
Bu3SnH)28 undergoes a smooth 6-exo-trig-cyclization onto the
indole ring to give the 1H-cyclopenta[3,4]-pyrido[1,2-a]indole
derivative 34 in 67% yield. The same sequence was applied to
the xanthates 32 and 33, which afforded tetracyclic indole
derivatives 35 and 36 in comparable overall yield (Scheme 7).
Scheme 5
Scheme 7
20 to afford the α-allyl-substituted ketones 22−24 in good yield
after an aqueous workup. The simpler cyclopentanone 21 was
also prepared but by a two-step sequence starting from N-
alkenyl indole 4 because the corresponding allylic bromide
intermediate derived from indole 4 is not stable when exposed
to air.
The Grignard addition of MeMgCl to ketone 22 afforded the
expected tertiary alcohol 25 as a 3:1 mixture of diastereomers in
80% yield. However, all of our attempts to induce an acid-
catalyzed cyclization of 25 to 27 failed. Instead, the only
product that was obtained in 32% yield corresponded to
tetrahydrofuran 29 (Scheme 6). This compound is formed by
Scheme 6
Compound 35 represents the core structure of the vinca
alkaloid RS-2135.29 Formation of the cis-fused ring can be
attributed to the steric constraints imposed by the ring system
as well as stereoelectronic effects in the transition state for the
radical cyclization.30 Presumably, an important factor for the
efficiency of the radical cyclization is the presence of an
electron-withdrawing substituent on the 3-position of the
indole ring that stabilizes the radical intermediate, thereby
facilitating the overall reaction. When treated with TFA, indole
34 underwent smooth double bond isomerization to give 37 in
quantitative yield. The exocyclic double bond present in 34 can
also serve as a handle to access structurally diverse tetracyclic
indole derivatives due to its enamine characteristics. For
example, reaction of 34 with Eschenmoser’s salt afforded the
tetracyclic indole derivative 38 in 89% yield. Oxidative cleavage
of the exocyclic double bond of 34 using a protocol developed
by Rapoport31 led to lactam 39 (78%) (Scheme 8).31
To further expand the scope of the radical cyclization
reaction, we have also examined the NaBH3CN reduction of
tosylhydrazone 40 as an alternative method for assembling the
tetracyclic core of several indole alkaloid derivatives. Earlier
reports by Kim32 and Taber33 have shown that alkyl radicals
can be prepared efficiently from ketones by NaBH3CN
reduction of the derived tosylhydrazones. The alkyl radicals
generated in this manner underwent efficient cyclization to give
the thermodyamically less stable cis-1,2-dialkylcyclopentane
derivatives. With this in mind, we carried out the reaction of
hydrazone 40 with NaBH3CN. This resulted in the formation
of the same tetracyclic indole derivative 34 as was obtained
from the xanthate-induced cyclization but in somewhat lower
yield (i.e., 46%). The high degree of diastereoselectivity for the
an initial protonation of the enamine double bond to give
iminium ion 28, which is subsequently trapped by the
neighboring hydroxyl group. In contrast to this result, when
the related phenyl-substitued tertiary alcohol 26 was treated
with acid, the tetracyclic indole derivative 30 was the only
product isolated in 56% yield. The reactivity difference between
alcohols 25 and 26 can be attributed to the formation of a more
stable benzylic cationic intermediate from 26, which allows for
cylization onto the indole nucleus followed by proton loss and
double bond isomerization.23 This overall reaction constitutes a
rapid approach to a tetracyclic indole derivative with a
quaternary stereocenter attached to the C2-position of the
indole ring.
An alternative strategy for selective functionalization at the
C2-position of a N-alkenyl-substituted indole derivative is via a
radical cyclization.24 In a preliminary study, xanthates 31−33
were easily prepared in reasonable yield by an initial reduction
of ketones 22−24 with L-selectride25 followed by reaction of
the resulting secondary alcohols with NaH, CS2, and methyl
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Scheme 8
Scheme 9
7.6 Hz), 3.92 (s, 3H), 5.26 (s, 1H), 5.30 (s, 1H), 7.26−7.29 (m, 2H),
7.50−7.52 (m, 1H), 7.87 (s, 1H), and 8.18−8.20 (m, 1H).
formation of 34 may be explained by the assumption of a highly
ordered cyclic transition state during radical addition to the
aromatic system (Scheme 9).
Dimethyl 1,1′-(4-methylpent-1-ene-2,4-diyl)bis(1H-indole-3-
carboxylate) (13). To a 48 mL pressure tube charged with methyl
1H-indole-3-carboxylate (2.1 g, 12 mmol) were sequentially added
K3PO4 (4.24 g, 20 mmol), CuI (190 mg, 1 mmol), 10 mL of degassed
dioxane, and ethane-1,2-diamine (0.13 mL, 2 mmol). This was
followed by the addition of 0.9 mL (10 mmol) of 2-bromoprop-1-ene
in one portion. The pressure tube was sealed with a PTFE plug, and
the mixture was heated at 110 °C for 24 h. The mixture was cooled to
room temperature, and ethyl acetate (20 mL) was added followed by
filtration through a short plug of Celite. The organic phase was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel chromatography to furnish 1.83 g (85%) of
methyl 1-(prop-1-en-2-yl)-1H-indole-3-carboxylate (5) as a pale
In summary, we have investigated a mild cross-coupling
reaction to access several N-alkenyl-substituted indoles. When
treated with acid, these unique enamines produce a dimeric
product derived from a preferred protonation reaction at the
enamine π-bond. A cationic cyclization reaction was utilized to
construct tetracyclic indole derivatives with a quaternary
stereocenter attached to the C2-position of the indole ring.
This work also highlights the synthetic utility of the radical
cyclization of several N-alkenyl-substituted indoles and provides
an attractive route to the tetracyclic core of some vinca
alkaloids, including the tetrahydroisoquinocarbazole RS-2135.
Further studies concerning the total synthesis of various vinca
alkaloids using these versatile N-alkenyl indoles will be reported
in due course.
yellow oil: IR (thin film) 2945, 1704, 1654, and 1537 cm−1 1H
;
NMR (600 MHz, CDCl3) δ 2.28 (s, 3H), 3.92 (s, 3H), 5.23 (s, 1H),
5.26 (s, 1H), 7.27−7.29 (m, 2H), 7.57−7.59 (m, 1H), 7.90 (s, 1H),
and 8.19−8.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 51.2,
108.5, 109.3, 112.1, 121.9, 122.4, 123.4, 127.1, 132.7, 136.2, 140.2, and
165.5; HRMS calcd for [C13H13NO2 + H+] 216.1019, found 216.1018.
To a flame-dried glass microwave tube charged with the above N-
alkenyl indole 5 (43 mg, 0.2 mmol) in toluene (2 mL) was added MgI2
(1.0 equiv, 56 mg, 0.2 mmol) at room temperature under an argon
atmosphere. The microwave reaction vial was sealed with a septum cap
and was heated to 100 °C for 19 h under microwave irradiation. The
reaction mixture was cooled to room temperature and filtered through
a short plug of Celite. The filtrate was concentrated under reduced
pressure and was purified by silica gel column chromatography to give
27 mg (63%) of 13 as a colorless oil: IR (thin film) 2947, 1700, 1558,
and 1535 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.66 (s, 6H), 3.41 (s,
2H), 3.87 (s, 6H), 4.86 (s, 1H), 5.16 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H),
7.19 (d, J = 7.2 Hz, 1H), 7.21−7.24 (m, 2H), 7.26−7.29 (m, 1H), 7.48
(s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 8.03−8.05 (m, 1H),
and 8.10 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3,
44.6, 51.0, 51.2, 59.5, 106.3, 108.6, 111.4, 113.4, 114.8, 121.8, 121.9,
122.3, 122.5, 123.5, 126.8, 128.4, 132.2, 132.8, 135.3, 135.9, 139.6,
165.1, and 165.4; HRMS calcd for [C26H26N2O4 + Na+] 453.1784,
found 453.1781.
EXPERIMENTAL SECTION
■
3-Methyl-1-(prop-1-en-2-yl)-1H-indole (6). To a 48 mL
pressure tube charged with 3-methyl-1H-indole (1.57 g, 12 mmol)
were sequentially added K3PO4 (4.24 g, 20 mmol), CuI (190 mg, 1
mmol), 10 mL of degassed dioxane, and ethane-1,2-diamine (0.13 mL,
2 mmol). This was followed by the addition of 0.9 mL (10 mmol) of
2-bromoprop-1-ene in one portion. The pressure tube was sealed with
a PTFE plug, and the mixture was heated at 110 °C for 24 h. The
mixture was cooled to room temperature, and ethyl acetate (20 mL)
was added followed by filtration through a short plug of Celite. The
organic phase was concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography to furnish
1
1.47 g (86%) of the titled compound 6 as a pale yellow oil: H NMR
(300 MHz, CDCl3) δ 2.27 (s, 3H), 2.34 (s, 3H), 5.00 (s, 1H), 5.13 (s,
1H), 7.02 (s, 1H), 7.14 (t, 1H, J = 7.5 Hz), 7.21 (t, 1H, J = 7.2 Hz),
7.57 (d, 1H, J = 7.5 Hz), and 7.63 (d, 1H, J = 8.1 Hz).
Methyl 1-(but-1-en-2-yl)-1H-indole-3-carboxylate (8). To a
48 mL pressure tube charged with methyl 1H-indole-3-carboxylate
(2.10 g, 12 mmol) were sequentially added K3PO4 (4.24 g, 20 mmol),
CuI (190 mg, 1 mmol), 10 mL of degassed dioxane, and ethane-1,2-
diamine (0.13 mL, 2 mmol). This was followed by the addition of 1.02
mL (10 mmol) of 2-bromobut-1-ene in one portion. The pressure
tube was sealed with a PTFE plug, and the mixture was heated at 110
°C for 24 h. The mixture was cooled to room temperature, and ethyl
acetate (20 mL) was added followed by filtration through a short plug
of Celite. The organic phase was concentrated under reduced pressure,
and the resulting residue was purified by silica gel chromatography to
Methyl 1-(1-bromobut-2-en-2-yl)-1H-indole-3-carboxylate
(18). To a 10 mL round-bottom flask charged with alkenyl indole 8
(46 mg, 0.2 mmol) were sequentially added 2 mL of dry THF and
NBS (36 mg, 0.2 mmol). The reaction mixture was stirred at 25 °C for
120 h and was then quenched with 100 mL of a saturated aqueous
NaHCO3 solution. The mixture was extracted with ether, and the
combined organic phase was washed with brine, dried over anhydrous
MgSO4, filtered through a short plug of Celite, and concentrated
under reduced pressure. The resulting residue was purified by silica gel
chromatography to furnish 23 mg (38%) of the titled compound 18 as
1
1
furnish 2.06 g (90%) of the titled compound 8 as a colorless oil: H
a colorless oil: H NMR (400 MHz, CDCl3) δ 1.99 (d, 3H, J = 7.6
NMR (400 MHz, CDCl3) δ 1.07 (t, 3H, J = 7.6 Hz), 2.60 (q, 2H, J =
Hz), 3.92 (s, 3H), 4.33 (s, 2H), 6.01 (q, 1H, J = 7.2 Hz), 7.26−7.32
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(m, 3H), 7.89 (s, 1H), and 8.19−8.21 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 27.4, 51.3, 108.4, 110.8, 122.0, 122.5, 123.4, 126.6,
130.1, 134.0, 134.4, 137.0, and 165.5.
111.7, 121.9, 122.6, 123.6, 127.0, 132.8, 136.6, 142.5, 165.4 and 219.2;
HRMS calcd for C18H19NO3 297.1359, found 297.1358.
Methyl 1-(3-(2-oxocyclohexyl)prop-1-en-2-yl)-1H-indole-3-
carboxylate (23). To a 250 mL round-bottom flask charged with
methyl 1-(3-bromoprop-1-en-2-yl)-1H-indole-3-carboxylate (16) (1.0
g, 3.4 mmol) were sequentially added 34 mL of CH3CN and 1-
(cyclohex-1-en-1-yl)pyrrolidine (20) (1.1 mL, 6.8 mmol). After
stirring at 25 °C for 3 h, the reaction mixture was concentrated
under reduced pressure, and the resulting residue was purified by silica
gel chromatography to furnish 0.73 g (65%) of the titled compound
23 as a pale yellow solid: mp 60−62 °C; IR (thin film) 2943, 1706,
2-(2-(1H-Indol-1-yl)allyl)cyclopentanone (21). To a 48 mL
pressure tube charged with 1H-indole (1.40 g, 12 mmol) were
sequentially added K3PO4 (4.24 g, 20 mmol), CuI (190 mg, 1 mmol),
10 mL of degassed dioxane, and ethane-1,2-diamine (0.13 mL, 2
mmol). This was followed by the addition of 0.9 mL (10 mmol) of 2-
bromoprop-1-ene in one portion. The pressure tube was sealed with a
PTFE plug, and the reaction mixture was heated at reflux at 110 °C for
24 h. The mixture was cooled to room temperature, and ethyl acetate
(20 mL) was added followed by filtration through a short plug of
Celite. The organic phase was concentrated under reduced pressure,
and the resulting residue was purified by silica gel chromatography to
furnish 1.24 g (79%) of 1-(prop-1-en-2-yl)-1H-indole (4) as a pale
yellow oil which was used in the next step without any further
1
1651, and 1535 cm−1; H NMR (600 MHz, CDCl3) δ 1.30−1.37 (m,
1H), 1.45−1.52 (m, 1H), 1.56−1.64 (m, 1H), 1.78−1.81 (m, 1H),
2.00−2.04 (m, 1H), 2.10−2.21 (m, 3H), 2.35−2.41 (m, 2H), 3.29 (dd,
1H, J = 15.6 and 4.8 Hz), 3.92 (s, 3H), 5.31 (s, 1H), 5.32 (s, 1H),
7.27−7.30 (m, 2H), 7.51−7.53 (m, 1H), 7.85 (s, 1H), and 8.19−8.20
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 25.1, 27.9, 33.8, 35.4, 42.2,
47.6, 51.3, 108.7, 111.7, 111.9, 121.9, 122.5, 123.6, 127.0, 132.8, 136.6,
142.4, 165.5 and 211.4; HRMS calcd for C19H21NO3 311.1516, found
311.1516.
1
purification: H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 5.07 (s,
1H), 5.17 (s, 1H), 6.57 (d, 1H, J = 3.2 Hz), 7.12 (t, 1H, J = 7.6 Hz),
7.22 (t, 2H, J = 7.6 Hz), and 7.63 (d, 2H, J = 7.2 Hz).
To a 10 mL round-bottom flask charged with the above alkenyl
indole (32 mg, 0.2 mmol) were sequentially added 2 mL of dry THF
and NBS (36 mg, 0.2 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C for 2 h and was then quenched with 2 mL of a saturated
aqueous NaHCO3 solution. The mixture was extracted with ether, and
the combined organic phase was washed with brine, dried over
anhydrous MgSO4, filtered through a short plug of Celite, and
concentrated under reduced pressure. The resulting residue was taken
up in CH3CN (2 mL) in a 10 mL round-bottom flask and 1-
(cyclopent-1-en-1-yl)pyrrolidine (19) (58 μL, 0.4 mmol) was
subsequently added at 25 °C. After stirring for 2 h, the reaction
mixture was concentrated under reduced pressure, and the resulting
residue was purified by silica gel chromatography to furnish 10 mg
(20% over two steps) of the titled compound 21 as a colorless oil: 1H
NMR (600 MHz, CDCl3) δ 1.45−1.52 (m, 1H), 1.57−1.64 (m, 1H),
1.89−1.93 (m, 1H), 1.95−2.07 (m, 3H), 2.25 (dd, 1H, J = 19.2 and 7.8
Hz), 2.37 (dd, 1H, J = 15.6 and 10.2 Hz), 3.26 (dd, 1H, J = 15.6 and
3.0 Hz), 5.20 (s, 1H), 5.23 (s, 1H), 6.57 (d, 1H, J = 3.0 Hz), 7.13 (t,
1H, J = 7.8 Hz), 7.19 (d, 1H, J = 5.4 Hz), 7.22 (t, 1H, J = 7.8 Hz), 7.57
(d, 1H, J = 8.4 Hz), and 7.62 (d, 1H, J = 7.8 Hz); 13C NMR (150
MHz, CDCl3) δ 20.5, 29.5, 36.1, 37.9, 47.2, 103.4, 108.4, 111.4, 120.4,
121.2, 122.5, 126.4, 129.4, 136.0, 143.0, and 219.9.
Methyl 1-(3-(2-hydroxy-2-methylcyclopentyl)prop-1-en-2-
yl)-1H-indole-3-carboxylate (25). To a 10 mL round-bottom
flask charged with methyl 1-(3-(2-oxo-cyclopentyl)prop-1-en-2-yl)-
1H-indole-3-carboxylate (22) (89 mg, 0.3 mmol) were sequentially
added 3 mL of dry THF and MeMgCl (3.0 M in THF, 0.3 mL, 0.9
mmol) at −78 °C. The reaction mixture was slowly allowed to warm
to −35 °C, and after stirring at this temperature for 4 h, the mixture
was quenched by the addition of 4 mL of a saturated aqueous
NaHCO3 solution and then warmed to room temperature. The
mixture was extracted with ether, and the combined organic phase was
washed with water and brine, dried over anhydrous MgSO4, filtered
through a short plug of silica gel, and concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatog-
raphy to furnish 75 mg (80%) of the titled compound 25 as a colorless
oil as a 3:1 mixture of diastereomers: IR (thin film) 3461, 2955, 1702,
1
1652, and 1535 cm−1; H NMR (400 MHz, CDCl3) major isomer δ
1.22 (s, 3H), 1.35−1.50 (m, 3H), 1.53−1.73 (m, 4H), 2.51 (dd, 1H, J
= 14.8 and 10.4 Hz), 2.92 (dd, 1H, J = 14.8 and 3.6 Hz), 3.92 (s, 3H),
5.26 (s, 1H), 5.32 (s, 1H), 7.27−7.30 (m, 2H), 7.52−7.55 (m, 1H),
7.88 (s, 1H), and 8.18−8.20 (m, 1H); 13C NMR (100 MHz, CDCl3)
major isomer δ 20.8, 26.1, 29.9, 35.0, 41.8, 46.6, 51.3, 80.0, 108.5,
110.6, 111.9, 121.8, 122.4, 123.4, 126.9, 132.9, 136.6, 144.2, and 165.6;
HRMS calcd for C19H23NO3 313.1672, found 313.1670.
Methyl 1-(3-(2-oxocyclopentyl)prop-1-en-2-yl)-1H-indole-3-
carboxylate (22). To a 250 mL round-bottom flask charged with N-
alkenyl indole 5 (3.30 g, 15.4 mmol) were sequentially added 150 mL
of dry THF and NBS (2.73 g, 15.4 mmol). The reaction mixture was
stirred at 25 °C for 48 h and was then quenched with 100 mL of a
saturated aqueous NaHCO3 solution. The mixture was extracted with
ether, and the combined organic phase was washed with brine, dried
over anhydrous MgSO4, filtered through a short plug of Celite, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to furnish 2.93 g (65%) of
methyl 1-(3-bromoprop-1-en-2-yl)-1H-indole-3-carboxylate (16) as a
Methyl 1-(2,6a-dimethylhexahydro-2H-cyclopenta[b]furan-
2-yl)-1H-indole-3-carboxylate (29). To a 10 mL round-bottom
flask charged with alcohol 25 (31 mg, 0.1 mmol) were sequentially
added 2 mL of dry CH2Cl2 and BF3·OEt2 (25 μL, 0.2 mmol) at 25 °C.
After stirring for 10 min, the reaction mixture was quenched with 2 mL
of a saturated aqueous NaHCO3 solution. The reaction mixture was
then extracted with ether, and the combined organic phase was washed
with brine, dried over anhydrous MgSO4, filtered through a short plug
of silica gel, and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to furnish 10 mg
(32%) of a colorless oil which consisted of a 4:1 mixture of
diastereomers of the titled compound 29: IR (thin film) 2949, 1701,
1
white solid: mp 72−73 °C; H NMR (400 MHz, CDCl3) δ 3.92 (s,
3H), 4.34 (s, 2H), 5.50 (s, 1H), 5.71 (s, 1H), 7.29−7.33 (m, 2H),
7.43−7.45 (m, 1H), 7.93 (s, 1H), and 8.20−8.23 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 31.5, 51.4, 109.3, 111.2, 105.2, 122.0, 122.7,
123.8, 126.8, 133.0, 136.8, 140.6, and 165.3.
1
and 1531 cm−1; H NMR (400 MHz, CDCl3) major isomer δ 1.22−
1.27 (m, 1H), 1.35−1.42 (m, 2H), 1.49 (s, 3H), 1.53−1.61 (m, 1H),
1.68−1.76 (m, 4H), 1.96−2.04 (m, 1H), 2.46−2.52 (m, 1H), 2.69 (dd,
1H, J = 14.0 and 9.2 Hz), 2.77 (dd, 1H, J = 14.0 and 4.0 Hz), 3.91 (s,
3H), 7.22−7.25 (m, 2H), 7.63−7.66 (m, 1H), and 8.17−8.19 (m,
2H); 13C NMR (100 MHz, CDCl3) major isomer δ 24.8, 27.8, 30.3,
32.7, 40.5, 45.0, 49.2, 51.1, 96.2, 97.9, 106.4, 113.6, 121.8, 121.9, 122.4,
128.2, 132.0, 135.1, and 166.0; HRMS calcd for C19H23NO3: 313.1672,
found 313.1671.
To a 250 mL round-bottom flask charged with the above bromide
16 (1.18 g, 4.0 mmol) were sequentially added 40 mL of CH3CN and
1-(cyclopent-1-en-1-yl)pyrrolidine (19) (1.16 mL, 8.0 mmol). After
stirring at 25 °C for 4 h, the mixture was concentrated under reduced
pressure, and the resulting residue was purified by silica gel
chromatography to furnish 0.82 g (70%) of the titled compound 22
as a pale yellow solid: mp 64−66 °C; IR (thin film) 2949, 1735, 1702,
1
and 1535 cm−1; H NMR (400 MHz, CDCl3) δ 1.41−1.51 (m, 1H),
Methyl 1-(3-(2-hydroxy-2-phenylcyclopentyl)prop-1-en-2-
yl)-1H-indole-3-carboxylate (26). To a 10 mL round-bottom
flask charged with methyl 1-(3-(2-oxocyclopentyl)prop-1-en-2-yl)-
1H-indole-3-carboxylate (22) (89 mg, 0.3 mmol) were sequentially
added 3 mL of dry THF and PhMgCl (3.0 M in ether, 0.3 mL, 0.9
mmol) at −78 °C. The reaction was slowly warmed to −10 °C, and
1.58−1.66 (m, 1H), 1.89−2.10 (m, 4H), 2.27 (dd, 1H, J = 20.0 and 8.8
Hz), 2.41 (dd, 1H, J = 15.6 and 10.0 Hz), 3.24 (dd, 1H, J = 15.6 and
3.2 Hz), 3.92 (s, 3H), 5.31 (s, 1H), 5.35 (s, 1H), 7.27−7.31 (m, 2H),
7.52−7.55 (m, 1H), 7.88 (s, 1H), and 8.19−8.21 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.5, 29.5, 35.8, 37.7, 46.9, 51.3, 108.8, 111.6,
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after stirring at this temperature for 20 h, the mixture was quenched
with 4 mL of a saturated aqueous NaHCO3 solution and was then
allowed to warm to room temperature. The reaction mixture was
extracted with ether, and the combined organic phase was washed with
water and brine, dried over anhydrous MgSO4, filtered through a short
plug of silica gel, and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography to furnish
67 mg (60%) of the titled compound 26 as a colorless oil: IR (thin
123.5, 126.9, 132.7, 136.6, 142.9, 165.5 and 215.3; HRMS calcd for
C20H23NO3S2 389.1113, found 389.1112.
Methyl 1-(3-(2-(((methylthio)carbonothioyl)oxy)cyclohexyl)-
prop-1-en-2-yl)-1H-indole-3-carboxylate (32). To a 100 mL
round-bottom flask charged with methyl 1-(3-(2-oxocyclohexyl)-
prop-1-en-2-yl)-1H-indole-3-carboxylate (23) (0.42 g, 1.35 mmol)
were sequentially added 14 mL of dry THF and L-selectride (1.0 M in
THF, 2.70 mL, 2.70 mmol) at −78 °C. After stirring at −78 °C for 4 h,
the mixture was quenched by the addition of 14 mL of a saturated
aqueous NH4Cl solution and then warmed to room temperature. The
resulting mixture was extracted with ether, and the combined organic
phase was washed with water and brine, dried over anhydrous MgSO4,
filtered through a short plug of silica gel, and concentrated under
reduced pressure. The resulting residue was taken up in 14 mL of dry
THF at 0 °C, and a sample of imidazole (5 mg, 0.07 mmol) and NaH
(60% dispersion in mineral oil, 270 mg, 6.75 mmol) was sequentially
added. The mixture was then warmed to 25 °C and was stirred for 0.5
h. This was followed by the dropwise addition of CS2 (0.41 mL, 6.75
mmol), and the solution was kept at 25 °C for 1 h. To this mixture was
slowly added MeI (0.42 mL, 6.75 mmol). After stirring at 25 °C for 1
h, the solution was quenched with 14 mL of a saturated aqueous
NH4Cl solution and was then warmed to room temperature. The
mixture was extracted with ether, and the combined organic phase was
washed with water and brine, dried over anhydrous MgSO4, filtered
through a short plug of Celite, and concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatog-
raphy to furnish 0.24 g (45% over the two steps) of the titled xanthate
32 as a pale yellow oil: IR (thin film) 2925, 2854, 1709, 1537, and
1201 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.13−1.20 (m, 1H), 1.24−
1.30 (m, 1H), 1.35−1.58 (m, 5H), 1.69 (d, 1H, J = 13.8 Hz), 2.12 (dd,
1H, J = 13.8 and 2.4 Hz), 2.55−2.59 (m, 4H), 2.67 (dd, 1H, J = 14.4
and 6.6 Hz), 3.92 (s, 3H), 5.22 (s, 1H), 5.28 (s, 1H), 5.72 (s, 1H),
7.24−7.29 (m, 2H), 7.55−7.58 (m, 1H), 7.86 (s, 1H), and 8.17−8.20
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 18.9, 20.6, 24.8, 27.6, 28.9,
38.0, 38.3, 51.2, 81.2, 108.7, 111.8, 112.0, 121.7, 122.4, 123.5, 126.9,
132.4, 136.5, 141.5, 165.3 and 215.2; HRMS calcd for C21H25NO3S2
403.1270, found 403.1268.
1
film) 3480, 2949, 1686, 1652, and 1535 cm−1; H NMR (400 MHz,
CDCl3) δ 1.59−1.70 (m, 2H), 1.78−1.93 (m, 4H), 1.98−2.04 (m,
1H), 2.51 (dd, 1H, J = 14.8 and 10.4 Hz), 2.68 (dd, 1H, J = 15.2 and
3.2 Hz), 3.91 (s, 3H), 5.16 (s, 1H), 5.21 (s, 1H), 7.20 (t, 1H, J = 8.0
Hz), 7.24−7.30 (m, 6H), 7.36 (d, 1H, J = 8.0 Hz), 7.55 (s, 1H), and
8.18 (d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5, 29.4,
34.3, 43.7, 48.5, 51.2, 84.0, 108.3, 111.0, 111.9, 121.7, 122.4, 123.4,
125.0, 126.9, 128.5, 128.7, 133.0, 136.5, 143.8, 144.9, and 165.4;
HRMS calcd for C24H25NO3 375.1829, found 375.1826.
Methyl 5-methyl-11b-phenyl-2,3,3a,11b-tetrahydro-1H-
cyclopenta[3,4]pyrido-[1,2-a]indole-11-carboxylate (30). To a
10 mL round-bottom flask charged with alcohol 26 (38 mg, 0.1 mmol)
were sequentially added 2 mL of dry CH2Cl2 and BF3·OEt2 (25 μL,
0.2 mmol) at 25 °C. After stirring for 10 min, the reaction mixture was
quenched with 2 mL of saturated aqueous NaHCO3 solution. The
mixture was then extracted with ether, and the combined organic
phase was washed with brine, dried over anhydrous MgSO4, filtered
through a short plug of silica gel, and concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatog-
raphy to furnish 20 mg (56%) of the titled compound 30 as a colorless
1
oil: IR (thin film) 2947, 1708, 1528, and 1447 cm−1; H NMR (400
MHz, CDCl3) δ 1.41−1.51 (m, 1H), 1.76−1.90 (m, 2H), 1.97−2.04
(m, 1H), 2.51−2.65 (m, 5H), 3.03 (ddd, 1H, J = 13.6 Hz, 8.4 Hz, and
4.0 Hz), 3.56 (s, 3H), 5.25 (d, 1H, J = 5.2 Hz), 7.05−7.08 (m, 2H),
7.12−7.15 (m, 1H), 7.19−7.25 (m, 4H), 7.78−7.80 (m, 1H), and
8.12−8.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 24.7, 33.9,
42.1, 49.5, 50.9, 52.5, 106.4, 113.3, 113.8, 121.6, 122.0, 122.9, 125.8,
125.9, 128.1, 131.9, 134.2, 148.0, 150.5 and 165.3; HRMS calcd for
[C24H23NO2 + H+] 358.1801, found 358.1798.
O-2-(2-(3-Cyano-1H-indol-1-yl)allyl)cyclopentyl (S)-methyl
carbonodithioate (33). To a 48 mL pressure tube charged with
methyl 1H-indole-3-carbonitrile (1.70 g, 12 mmol) were sequentially
added K3PO4 (4.24 g, 20 mmol), CuI (190 mg, 1 mmol), 10 mL of
degassed dioxane, and ethane-1,2-diamine (0.13 mL, 2 mmol). This
was followed by the addition of 0.9 mL (10 mmol) of 2-bromoprop-1-
ene in one portion. The pressure tube was sealed with a PTFE plug,
and the mixture was heated at 110 °C for 24 h. The mixture was
cooled to room temperature, and ethyl acetate (20 mL) was added
followed by filtration through a short plug of Celite. The organic phase
was concentrated under reduced pressure, and the resulting residue
was purified by silica gel chromatography to furnish 1.78 g (98%) of 1-
(prop-1-en-2-yl)-1H-indole-3-carbonitrile (7) as an off white solid: mp
48−50 °C; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 5.29 (s, 1H),
5.30 (s, 1H), 7.31 (t, 1H, J = 7.2 Hz), 7.36 (t, 1H, J = 7.2 Hz), 7.60 (d,
1H, J = 8.0 Hz), 7.69 (s, 1H), and 7.77 (d, 1H, J = 8.4 Hz).
Methyl 1-(3-(2-(((methylthio)carbonothioyl)oxy)-
cyclopentyl)prop-1-en-2-yl)-1H-indole-3-carboxylate (31). To
a 250 mL round-bottom flask charged with methyl 1-(3-(2-oxocyclo-
pentyl)prop-1-en-2-yl)-1H-indole-3-carboxylate (22) (0.93 g, 3.13
mmol) were sequentially added 31 mL of dry THF and L-selectride
(1.0 M in THF, 6.26 mL, 6.26 mmol) at −78 °C. After stirring at −78
°C for 3 h, the mixture was quenched with 30 mL of a saturated
aqueous NH4Cl solution and warmed to room temperature. The
solution was extracted with ether, and the combined organic phase was
washed with water and brine, dried over anhydrous MgSO4, filtered
through a short plug of silica gel, and concentrated under reduced
pressure. The resulting residue was taken up in 30 mL of dry THF at 0
°C and imidazole (11 mg, 0.16 mmol) and NaH (60% dispersion in
mineral oil, 626 mg, 15.65 mmol) were sequentially added. The
mixture was warmed to 25 °C and stirred at this temperature for 0.5 h.
This was followed by the dropwise addition of CS2 (0.94 mL, 15.65
mmol), and the mixture was kept at 25 °C for 1 h. To this solution was
slowly added MeI (0.98 mL, 15.65 mmol), and after stirring for 1 h,
the mixture was quenched with 30 mL of a saturated aqueous NH4Cl
solution and was warmed to room temperature. The mixture was then
extracted with ether, and the combined organic phase was washed with
water and brine, dried over anhydrous MgSO4, filtered through a short
plug of Celite, and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to furnish 0.55 g
(45% over the two steps) of the titled xanthate 31 as a colorless oil: IR
To a 250 mL round-bottom flask charged with the above N-alkenyl
indole 7 (1.13 g, 6.21 mmol) were sequentially added 62 mL of dry
THF and NBS (1.32 g, 7.45 mmol). The reaction mixture was stirred
at 25 °C for 96 h and was then quenched with 100 mL of a saturated
aqueous NaHCO3 solution. The mixture was extracted with ether, and
the combined organic phase was washed with brine, dried over
anhydrous MgSO4, filtered through a short plug of Celite, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to furnish 0.87 g (54%) of 1-(3-
bromoprop-1-en-2-yl)-1H-indole-3-carbonitrile (17) as a white solid:
1
(thin film) 2948, 1704, 1651, 1536, and 1198 cm−1; H NMR (400
1
mp 85−86 °C; H NMR (400 MHz, CDCl3) δ 4.33 (s, 2H), 5.54 (s,
MHz, CDCl3) δ 1.50−1.61 (m, 2H), 1.73−1.82 (m, 2H), 1.85−1.92
(m, 3H), 2.57 (s, 3H), 2.71 (dd, 1H, J = 15.2 and 7.6 Hz), 2.87 (dd,
1H, J = 15.2 and 8.0 Hz), 3.93 (s, 3H), 5.26 (s, 1H), 5.30 (s, 1H),
5.77−5.79 (m, 1H), 7.26−7.31 (m, 2H), 7.51−7.55 (m, 1H), 7.86 (s,
1H), and 8.17−8.22 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 19.2,
22.2, 30.0, 32.3, 35.3, 42.4, 51.3, 87.4, 108.7, 111.3, 111.8, 121.8, 122.5,
1H), 5.79 (s, 1H), 7.32−7.40 (m, 2H), 7.47−7.49 (m, 1H), 7.76 (s,
1H), and 7.78−7.80 (m, 1H).
To a 100 mL round-bottom flask charged with the above bromide
17 (0.4 g, 1.53 mmol) were sequentially added 15 mL of CH3CN and
1-(cyclopent-1-en-1-yl)pyrrolidine (19) (0.46 mL, 3.06 mmol). After
stirring at 25 °C for 4 h, the reaction mixture was concentrated under
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reduced pressure and the resulting residue was purified by silica gel
chromatography to furnish 0.31 g (77%) of 1-(3-(2-oxocyclopentyl)-
prop-1-en-2-yl)-1H-indole-3-carbonitrile (24) as a pale yellow solid:
the titled compound 35 as a colorless oil: IR (thin film) 2921, 2850,
1
1697, 1647, and 1543 cm−1; H NMR (400 MHz, CDCl3) δ 1.41−
1.60 (m, 4H), 1.75−1.77 (m, 3H), 2.01−2.04 (m, 1H), 2.33−2.39 (m,
2H), 3.01 (t, 1H, J = 14.4 Hz), 3.87−3.93 (m, 4H), 4.89 (s, 1H), 5.35
(s, 1H), 7.20−7.27 (m, 2H), 7.79−7.82 (m, 1H), and 8.14−8.17 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 20.5, 26.3, 28.2, 30.7, 32.7, 32.8,
36.0, 51.1, 99.0, 103.6, 113.3, 121.8, 122.7, 128.4, 134.5, 142.0, 151.7
and 166.1; HRMS calcd for [C19H21NO2 + H+] 296.1645, found
296.1643.
1
mp 74−75 °C; H NMR (400 MHz, CDCl3) δ 1.44−1.52 (m, 1H),
1.64−1.71 (m, 1H), 1.92−2.22 (m, 4H), 2.29 (dd, 1H, J = 19.2 and 8.4
Hz), 2.43 (dd, 1H, J = 15.2 and 9.6 Hz), 3.19 (dd, 1H, J = 15.2 and 3.2
Hz), 5.34 (s, 1H), 5.40 (s, 1H), 7.32 (td, 1H, J = 8.0 and 1.2 Hz), 7.36
(td, 1H, J = 7.2 and 1.2 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.68 (s, 1H),
and 7.77 (d, 1H, J = 7.2 Hz).
To a 50 mL round-bottom flask charged with the above compound
24 (216 mg, 0.82 mmol) were sequentially added 8 mL of dry THF
and L-selectride (1.0 M in THF, 1.64 mL, 1.64 mmol) at −78 °C. After
stirring at −78 °C for 3 h, the reaction mixture was quenched with 8
mL of a saturated aqueous NH4Cl solution and was then warmed to
room temperature. The mixture was then extracted with ether, and the
combined organic phase was washed with water and brine, dried over
anhydrous MgSO4, filtered through a short plug of silica gel, and
concentrated under reduced pressure. The resulting residue was taken
up in 8 mL of dry THF at 0 °C and imidazole (3 mg, 0.04 mmol) and
NaH (60% dispersion in mineral oil, 164 mg, 4.10 mmol) were
sequentially added. The solution was warmed to 25 °C and was stirred
at this temperature for 0.5 h. This was followed by the dropwise
addition of CS2 (0.25 mL, 4.10 mmol), and the solution was kept at 25
°C for 1 h. To this mixture was slowly added MeI (0.26 mL, 4.10
mmol). After stirring for 1 h, the mixture was quenched with 8 mL of a
saturated aqueous NH4Cl solution and was warmed to room
temperature. The solution was then extracted with ether, and the
combined organic phase was washed with water and brine, dried over
anhydrous MgSO4, filtered through a short plug of Celite, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromato-graphy to furnish 132 mg (45% over the
two steps) of the titled xanthate 33 as a white solid: mp 92−93 °C; IR
5-Methylene-2,3,3a,4,5,11b-hexahydro-1H-cyclopenta[3,4]-
pyrido[1,2-a]indole-11-carbonitrile (36). To a 100 mL round-
bottom flask connected to a condenser charged with xanthate 33 (53
mg, 0.15 mmol) was added 15 mL of dry benzene. A solution of AIBN
(12 mg, 0.075 mmol) and n-Bu3SnH (0.20 mL, 0.75 mmol) in 15 mL
of dry benzene was added via syringe pump over a period of 4 h at 80
°C. The reaction mixture was heated at reflux for 17 h under argon,
cooled to room temperature, and stirred for another 2 h. The mixture
was then concentrated under reduced pressure, and the resulting
residue was purified by silica gel chromatography to furnish 29 mg
(77%) of the titled compound 36 as a colorless oil: IR (thin film)
1
2958, 2212, 1658, and 1545 cm−1; H NMR (400 MHz, CDCl3) δ
1.50−1.58 (m, 1H), 1.65−1.81 (m, 3H), 1.99−2.07 (m, 1H), 2.38 (dd,
1H, J = 13.2 and 8.0 Hz), 2.50−2.57 (m, 2H), 2.62−2.69 (m, 1H),
3.64 (q, 1H, J = 8.4 Hz), 5.06 (d, 1H, J = 0.8 Hz), 5.37 (s, 1H), 7.27−
7.31 (m, 2H), 7.67−7.69 (m, 1H), and 7.73−7.76 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 25.3, 31.7, 34.1, 36.6, 36.8, 37.6, 101.9, 112.7,
116.3, 119.3, 122.9, 123.7, 128.7, 133.6, 139.7, and 150.8; HRMS calcd
for [C17H16N2 + H+] 249.1386, found 249.1384.
Methyl 5-methyl-2,3,3a,11b-tetrahydro-1H-cyclopenta[3,4]-
pyrido[1,2-a]indole-11-carboxylate (37). To a 5 mL round-
bottom flask charged with tetracyclic indole derivative 34 (14 mg,
0.05 mmol) were sequentially added 2 mL of CDCl3 and
trifluoroacetic acid (2 μL, 0.025 mmol) at 25 °C. After stirring for
10 min, the mixture was quenched by the addition of 2 mL of a
saturated aqueous NaHCO3 solution. The mixture was then extracted
with ether, and the combined organic phase was washed with brine,
dried over anhydrous MgSO4, and filtered through a short plug of
silica gel to furnish 14 mg (99%) of the titled compound 37 as a
colorless oil: IR (thin film) 2917, 1698, and 1558 cm−1; 1H NMR (600
MHz, CDCl3) δ 1.54−1.64 (m, 1H), 1.70−1.77 (m, 2H), 1.79−1.84
(m, 1H), 2.00−2.05 (m, 1H), 2.22−2.25 (m, 1H), 2.54 (s, 3H), 2.92
(bs, 1H), 3.93 (s, 3H), 4.08 (q, 1H, J = 9.0 Hz), 4.85 (s, 1H), 7.17 (t,
1H, J = 7.2 Hz), 7.21 (t, 1H, J = 7.2 Hz), 7.72 (d, 1H, J = 8.4 Hz), and
8.16 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 21.9, 23.7,
31.4, 33.8, 35.8, 37.2, 51.0, 104.3, 113.0, 115.9, 121.7, 121.9, 122.7,
127.6, 132.1, 134.9, 148.6, and 166.2; HRMS calcd for [C18H19NO2 +
H+] 282.1488, found 282.1487.
1
(thin film) 2945, 2223, 1657, and 1221 cm−1; H NMR (600 MHz,
CDCl3) δ1.54−1.59 (m, 2H), 1.75−1.81 (m, 2H), 1.85−1.92 (m, 3H),
2.57 (s, 3H), 2.70 (dd, 1H, J = 15.0 and 7.2 Hz), 2.85 (dd, 1H, J = 15.0
and 7.8 Hz), 5.28 (s, 1H), 5.35 (s, 1H), 5.75 (td, 1H, J = 5.4 and 2.4
Hz), 7.30 (t, 1H, J = 7.2 Hz), 7.34 (td, 1H, J = 7.8 and 1.2 Hz), 7.55
(d, 1H, J = 8.4 Hz), 7.66 (s, 1H), and 7.75 (d, 1H, J = 7.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 19.2, 22.1, 30.0, 32.3, 35.2, 42.4, 87.0,
87.7, 112.0, 112.2, 115.5, 120.0, 122.7, 124.6, 127.9, 133.3, 135.3, 142.5
and 215.2; HRMS calcd for C19H20N2OS2 356.1011, found 356.1010.
Methyl 5-methylene-2,3,3a,4,5,11b-hexahydro-1H-
cyclopenta[3,4]pyrido[1,2-a]indole-11-carboxylate (34). To a
50 mL round-bottom flask connected to a condenser charged with
xanthate 31 (39 mg, 0.1 mmol) was added 10 mL of dry benzene. A
solution of AIBN (8 mg, 0.05 mmol) and n-Bu3SnH (0.13 mL, 0.5
mmol) in 10 mL of dry benzene was added via syringe pump over a 4
h period at 80 °C. The reaction mixture was heated at reflux for 17 h
under argon, cooled to room temperature, and stirred for another 2 h.
The mixture was then concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography to furnish
19 mg (67%) of the titled compound 34 as a colorless oil: IR (thin
film) 2949, 1699, 1653, and 1540 cm−1; 1H NMR (600 MHz, CDCl3)
δ 1.42−1.49 (m, 1H), 1.57−1.69 (m, 2H), 1.71−1.79 (m, 1H), 1.96−
2.02 (m, 1H), 2.39−2.46 (m, 2H), 2.52−2.64 (m, 2H), 3.93 (s, 3H),
4.07 (q, 1H, J = 9.0 Hz), 5.03 (s, 1H), 5.34 (s, 1H), 7.22−7.26 (m,
2H), 7.72−7.74 (m, 1H), and 8.15−8.16 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 24.8, 32.4, 34.2, 36.5, 36.7, 38.1, 50.9, 101.8, 112.1,
121.7, 122.6, 122.7, 128.1, 130.9, 131.1, 134.3, 140.3, and 166.1;
HRMS calcd for [C18H19NO2 + H+] 282.1488, found 282.1485.
Methyl 6-methylene-1,2,3,4,4a,5,6,12b-octahydroindolo-
[2,1-a]isoquinoline-12-carboxylate (35). To a 250 mL round-
bottom flask connected to a condenser charged with xanthate 32 (190
mg, 0.47 mmol) was added 47 mL of dry benzene. A solution of AIBN
(39 mg, 0.24 mmol) and n-Bu3SnH (0.62 mL, 2.35 mmol) in 47 mL of
dry benzene was added via syringe pump over a period of 4 h at 80 °C.
The reaction mixture was heated at reflux for 17 h under argon, cooled
to room temperature, and stirred for another 2 h. The mixture was
then concentrated under reduced pressure, and the resulting residue
was purified by silica gel chromatography to furnish 98 mg (71%) of
Methyl 5-(2-(dimethylamino)ethyl)-2,3,3a,11b-tetrahydro-
1H-cyclopenta[3,4]-pyrido[1,2-a]indole-11-carboxylate (38).
To a 5 mL round-bottom flask charged with tetracyclic indole
derivative 34 (14 mg, 0.05 mmol) were sequentially added 2 mL of
CH2Cl2 and Eschenmoser’s salt (11 mg, 0.055 mmol) at 25 °C. After
stirring for 48 h, the mixture was quenched with 2 mL of a saturated
aqueous NaHCO3 solution. The reaction mixture was extracted with
CH2Cl2, and the combined organic phase was washed with brine, dried
over anhydrous MgSO4, filtered through a short plug of Celite, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to furnish 15 mg (89%) of the
titled compound 38 as a colorless oil: IR (thin film) 2947, 2869, 1698,
1
1558, and 1391 cm−1; H NMR (400 MHz, CDCl3) δ 1.60−1.84 (m,
4H), 1.98−2.08 (m, 1H), 2.17−2.23 (m, 1H), 2.28 (s, 6H), 2.44−2.57
(m, 2H), 2.85−2.91 (m, 2H), 3.16−3.24 (m, 1H), 3.94 (s, 3H), 4.08
(q, 1H, J = 9.2 Hz), 4.95 (s, 1H), 7.20−7.23 (m, 2H), 7.65−7.68 (m,
1H), and 8.15−8.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.8,
30.9, 32.6, 33.6, 36.0, 37.2, 45.6, 51.1, 58.2, 104.5, 112.7, 117.1, 121.7,
122.0, 123.1, 127.6, 134.4, 148.8, and 166.1; HRMS calcd for
[C21H26N2O2 + H+] 339.2067, found 339.2065.
Methyl 5-oxo-2,3,3a,4,5,11b-hexahydro-1H-cyclopenta[3,4]-
pyrido[1,2-a]indole-11-carboxylate (39). To a 50 mL round-
bottom flask charged with tetracyclic indole derivative 34 (14 mg, 0.05
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The Journal of Organic Chemistry
Article
mmol) were sequentially added 4 mL of THF, NaIO4 aqueous
solution (0.067 M, 2.2 mL, 0.15 mmol), and OsO4 (6 mg, 0.023
mmol) at 25 °C. After stirring for 24 h, the reaction mixture was
quenched with 4 mL of a saturated aqueous NaHCO3 solution. The
mixture was then extracted with benzene, and the combined organic
phase was washed with a saturated aqueous NaHCO3 solution and
brine, dried over anhydrous MgSO4, filtered through a short plug of
Celite, and concentrated under reduced pressure. The resulting residue
was purified by silica gel chromatography to furnish 11 mg (78%) of
the titled compound 39 as a colorless oil: IR (thin film) 2950, 2873,
1704, and 1568 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.57−1.76 (m,
2H), 1.88 −2.03 (m, 3H), 2.51−2.59 (m, 1H), 2.65 (dd, 1H, J = 16.8
and 12.4 Hz), 2.73 (dd, 1H, J = 16.8 and 5.6 Hz), 2.77−2.83 (m, 1H),
3.96 (s, 3H), 3.99−4.03 (m, 1H), 7.33−7.35 (m, 2H), 8.06−8.09 (m,
1H), and 8.47−8.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.6,
29.8, 31.3, 36.3, 37.7, 38.1, 51.5, 109.2, 116.4, 121.4, 125.0, 125.2,
127.6, 134.6, 149.3, 165.4, and 169.7; HRMS calcd for [C17H17NO3 +
H+] 284.1281, found 284.1280.
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yl)-1H-indole-3-carboxylate (40). To a 15 mL pressure tube
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data of various key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chemap@emory.edu.
ACKNOWLEDGMENTS
■
Financial support provided by the National Science Foundation
(CHE-1057350) is greatly appreciated. N.B. thanks the
Development and Promotion of Science and Technology
Talent Project (DPST) for financial support. Dr. Wenyong
Chen is acknowledged for helpful discussions.
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