Indolidenes and Indolidenium Intermediates in the Synthesis of Cyclopent[b]indoles: Mechanistic Studies on Intramolecular Cyclizations

Article abstract of DOI:10.1021/acs.joc.5b01777

Tetracyclic products featuring predominantly a trans-hexahydroindane unit annelated onto the C(2)/C(3) positions of indole can be accessed by intramolecular cyclocondensation of tethered alkenyl sulfides with either indolidene or indolidenium cation intermediates. Studies with geometrically pure E- and Z-alkenyl sulfide isomers reveal a likely dichotomy of reaction paths that provide mixtures of both regioisomers and stereoisomers of the hexahydroindane adducts.

Full text of DOI:10.1021/acs.joc.5b01777

Article
pubs.acs.org/joc
Indolidenes and Indolidenium Intermediates in the Synthesis of
Cyclopent[b]indoles: Mechanistic Studies on Intramolecular
Cyclizations
Ken S. Feldman,* Inanllely Y. Gonzalez, and Christopher M. Glinkerman
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
*
S Supporting Information
ABSTRACT: Tetracyclic products featuring predominantly a trans-
hexahydroindane unit annelated onto the C(2)/C(3) positions of indole
can be accessed by intramolecular cyclocondensation of tethered alkenyl
sulfides with either indolidene or indolidenium cation intermediates.
Studies with geometrically pure E- and Z-alkenyl sulfide isomers reveal a
likely dichotomy of reaction paths that provide mixtures of both regioisomers and stereoisomers of the hexahydroindane adducts.
INTRODUCTION
The Woodward−Hoffmann rules, as systemized in The
Conservation of Orbital Symmetry, have provided reliable
guidance for the broad field of pericyclic reactions for over
0 years. Prompted by the rather brief but timelessly
Indolidene and indolidenium cation intermediates have
played pivotal roles in the construction of complex natural
■
3
,5
1
products.
indolidenes and indolidenium cations was first noted by
Buchi in the acid-catalyzed condensation of voacangine with
vobasinol for the synthesis of the alkaloids voacamine and
For example, the proposed intermediacy of
̈
5
provocative Chapter 12 (“Violations. There are none!”), we
sought to explore the possibility that a recently discovered
formal [10π + 2π] photochemical cycloaddition might, in
actuality, be a concerted process under the Woodward−
Hoffmann umbrella. Legitimate concerted photochemical
processes are rare, and pericyclic transformations involving
2π electrons rarer still. Nevertheless, we probed this issue by
asking the simplest and most fundamental question with our
2π electron system: Is alkene geometry preserved upon bond
formation? This necessary but insufficient condition is a first
step in probing concertedness; the experimental evidence is
encouraging. The context of this inquiry is a recently reported
photoinitiated cascade reaction sequence starting with allenyl
azide substrates and passing through a putative indolidene
intermediate en route to the [10π + 2π] cycloaddition product.
Indolidenes and the related indolidenium cations are highly
reactive intermediates that are susceptible to nucleophilic
addition at the C(3) and C(8) positions (Figure 1). These
3a
voacorine. These highly electrophilic intermediates were
reported to be unstable and not isolable. Further efforts
through the years have been centered on the synthesis o4f
vinblastine, an alkaloid currently used as a anticancer drug,
through the direct coupling of the naturally occurring3
catharanthine and vindoline via these reactive species.
However, it was not until 2009 that Boger et al. reported the
1
1
use an FeCl
3
-mediated single-step biomimetic coupling of
catharanthine and vindoline via an indolidenium intermediate
3k
to generate vinblastine in moderate yield. Other natural
products and their structural analogues also have been accessed
through indolidene/indolidenium cation intermediates: actino-
2
m,n
5a
5b
3a,5c
phyllic acid,
aspeverin, gilbertine, ibogaine,
mersi-
2
l
3a
2p,5d
3a,5e
carpine, normacusine, tronoharine,
yuehchukene,
biomimetic syntheses of borreverine
voacamine,
2
e,5f,g
5h
and yuremamine. In addition, the
5
i,k
5i
and isoborreverine,
were achieved through
5i−k
as well as flinderoles B and C,
dimerization via the intermediacy of these highly reactive
species.
Our group has been interested in the preparation and C−C
bond-forming processes of these indolidene and indolidenium
intermediates. We initially identified novel conditions for the
synthesis of indolidene intermediates via the thermolysis or
Figure 1. Indolidene and indolidenium electrophiles.
6
photolysis of allenyl azide substrates (3) (Scheme 1). This
transformation is presumed to pass through the formation of
triazoline intermediate 4, which extrudes nitrogen to generate
electrophilic species occasionally have been utilized for the
formation of C−C bonded products at these positions; they
typically have been formed as transient intermediates by
removal of a leaving group at the C(8) position of an indole
precursor through acid catalysis, rearrangements, and elimi-
Special Issue: 50 Years and Counting: The Woodward-Hoffmann
Rules in the 21st Century
Received: July 31, 2015
2
,3,5
nation reactions.
©
XXXX American Chemical Society
A
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Scheme 1. Generation of Indolidene and Indolidenium
Cation Reactive Intermediates
Figure 2. Representative terpene−indole alkaloids.
RESULTS
■
Substrate Syntheses. The alkenyl sulfide substrate 15a
required for the allenyl azide cyclization was synthesized from
known aldehyde 11 via a three-step procedure (Scheme 3). A
7
Wittig reaction on 11 afforded the methyl vinyl sulfide adduct
indolidene intermediate 1. This reactive electrophile sub-
sequently can be intercepted by nucleophiles at either the C(3)
or C(8) positions. In addition, we have identified mild
experimental conditions for the formation of the putative
indolidenium intermediate 2 via the Lewis acid mediated
12a as a mixture of geometrical isomers in good yield. 2-
Azidobenzaldehyde (13) was coupled with the anion derived
from 12a, and the resulting alkoxide was trapped with acetic
anhydride to afford 14a in very good yield. The alkenyl sulfide
substrate 15a was obtained by methylating alkyne 14a using
7
solvolysis of 2-(methyl alcohol) derivatives 5 (Scheme 1). A
excess Me CuBr complex. Importantly, further reaction of the
limitation of allenyl azide substrates 3 is that R ≠ H or the
2
resulting allenyl azide with the organocuprate reagent was not
observed. Two allenyl azide substrates with alternate pendant
alkenes, the methyl vinyl ether analogue 15b and a simple
alkene 19, also were accessed using the same approach as that
employed for the alkenyl sulfide substrate 15a (Scheme 3). The
N-H-containing Lewis acid mediated cyclization precursors 16a
and 16b were synthesized via either irradiation or thermolysis
of their respective allenyl azide substrates 15a and 15b in
methanol. In addition, the N-Bn substrate was prepared
successfully by two distinct approaches; either via addition of
intermediate triazoline readily isomerizes to a triazole
6
c
product.
Recently, we reported an intramolecular [3 + 2] cyclo-
condensation reaction that features the addition of nucleophilic
alkenes to these electrophilic intermediates to form cyclopent-
7
[
b]indoles 7 (Scheme 2). Fundamental regiochemical and
Scheme 2. Scope of the Work: Regiochemistry and
Stereochemistry of Cyclization as a Function of (a) Alkene
Geometry, (b) Nature of X, and (c) Electrophilicity of the
Activated Indole (Indolidene vs Indolidenium)
10
lithiated indole 22 to the ketone of 21 or by the direct
benzylation of the N-H species 16b.
Cyclization Studies. Irradiation of alkenyl sulfide 15a
(
1.25:1 E/Z mixture) at 350 nm in CH CN afforded a mixture
3
of products 25−27 (Scheme 4 and Table 1, entry 1). The
major tricyclized product 25a featured a C−C bond to C(3)
with the trans hexahydroindane substructure favored over the
cis ring juncture alternative (25a + 25b:25c) by about 5:1. As a
foundational experiment, this result demonstrated the feasibility
of the [3 + 2] indolidene-based cyclocondensation sequence for
the formation of cyclopent[b]indole products. The structural
assignment for compounds 25a−c was secured from a
combination of NMR studies including HMBC, HMQC, and
DEPT (Scheme 5). The relative stereochemistry of adducts
2
5a−c was assigned on the basis of the comparison of the
observed coupling constant values between H −H (Scheme 5)
a
b
with the calculated values for this coupling derived from
energy-minimized structures (see the Supporting Information
for calculational details). In addition, the alkenyl sulfide moiety
was removed from pure 25a using Superhydride, and the
spectral data for the reduced product 28a were compared to the
data reported for authentic 28a and 28c, which were prepared
stereochemical questions, such as competition between C−C
bond formation (to give 7) and C−N bond formation (to give
8), and the stereochemical preference at C(12) and C(13),
were brought out in this preliminary investigation.
2h
by different methods. A mixture of the trans- and cis-ring-
Herein, we examine the scope of the [3 + 2] cyclo-
condensation reaction, including the regiochemical and stereo-
chemical outcome as a function of (1) alkene geometry, (2)
nature of the nucleophilic alkene, and (3) the electrophilicity of
the activated indole derivative. The cyclopent[b]indole product
maps precisely onto the skeleton of the indolosesquiterpene
family of natural products, as illustrated in the representative
fused diastereomers (25a/25c = 3.7:1) also was submitted to
the reduction conditions, and the same ratio of cis-to-trans ring
fused products was obtained for the desulfurized products 28a
and 28c (Scheme 5). The preference for the trans stereo-
chemistry at the ring junction addresses the challenges of
synthesizing indole-fused trans hexahydroindanes, which are
less thermodynamically stable than the cis isomers.
This photochemical tricyclization reaction displayed a strong
solvent effect. Irradiation in the less polar solvents toluene and
11
8
9
members lecanindole B (9) and penitrem D (10), Figure 2.
B
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Scheme 3. Substrate Syntheses
Scheme 4. Photochemical [3 + 2] Cyclocondensation of Alkenyl Sulfide Substrate 15a
Table 1. Product Yields as a Function of Solvent for the
Photochemical [3 + 2] Cyclocondensation of 15a
°C as in entry 1) or lower concentration (3 mM vs 10 mM in
entry 1) resulted in a mixture of products similar to those
a
a
a
b
b
observed in entry 1. Inclusion of catalytic amounts of In(OTf)
3
entry
solvent
25a
25b
25c
26
27
6b
or CuI, under entry 1 conditions, led to decomposition of the
starting material, and no characterizable products were
identified. Furthermore, the results obtained under thermal
conditions did not resemble the results under photochemical
1
2
3
4
CH CN
44
trace
trace
trace
2
9
9
3
3
toluene
20
CH Cl2
22
2
DMF
73
a
conditions; upon reflux in CH CN, substrate 15a was
3
Isolated yield of pure 25a/25b/25c combined; ratio determined by
integration of characteristic signals in the H NMR spectrum. Percent
yield of isolated, pure products.
1
b
converted largely to the alkene product 27 (40% yield).
The sulfide unit of the nucleophilic alkene was a key
component in the success of this [3 + 2] cyclocondensation
reaction. In our initial studies, the methyl vinyl ether analogue
CH Cl only led to trace amounts of the cyclopent[b]indole
products (Table 1, entries 2 and 3). In addition, in the more
polar solvent DMF, the tricyclized product was not isolated
Table 1, entry 4). Photochemical reaction in the preferred
solvent CH CN at either lower temperature (0 °C instead of 28
2
2
1
5b was screened under photochemical conditions in CH CN,
3
but no characterizable material was isolated. Moreover, when
the simple alkene analogue 19 was employed, only a mixture of
alkene products 29 was formed via a formal ene-type reaction
(
3
C
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Scheme 5. Structural and Stereochemical Assignments for
reaction of the original E/Z mixture of substrates (Scheme 6
and Table 2, entry 1). Switching to lower UV wavelengths (300
and 254 nm) also resulted in the formation of the C−C bonded
product 25a as the major product but with decreased yields
2
5a−c
(
Table 2, entries 2 and 3, respectively). On the other hand,
irradiation of the Z isomer 15a-Z at all three wavelengths
afforded the C−C-bonded products as a 1:1 mixture of trans
(
25a) and cis (25c) isomers in very low yields with a plethora
of decomposition products (Table 2, entries 4−6). Thus, the
encouraging results obtained upon irradiation of the original
E:Z mixture of alkenyl sulfides was largely due to the favorable
reactivity of the E-alkenyl isomer! The less clean results
obtained for the E-alkenyl sulfide isomer under the 300 and 254
nm irradiations could be rationalized by examining the UV/vis
absorption spectra for the indole-containing product 25a (see
the Supporting Information). The electronic spectrum of the
C−C-bonded product 25a exhibits significant UV absorption at
both 254 and 300 nm but very little at 350 nm; thus, product
destruction at the lower wavelengths is a real possibility. In fact,
control experiments indicated that irradiation of pure 25a at
either 254 nm or at 300 nm led to complete compound
destruction within 1 h, whereas only some decomposition of
2
5a attended a similar experiment at 350 nm (vide infra).
The cyclization reactions for the E- and Z-alkenyl sulfide
substrates 15a-E and 15a-Z, respectively, also were monitored
over time, and the results are depicted in Tables 3 and 4. After
(
eq 1). Apparently, there is a mismatch in reactivity between
these alkene nucleophiles and the indolidene intermediate,
which is overcome by switching to the sulfur analogue.
3
0 min, there was 59% conversion of 15a-E to the major C−C
bonded product 25a and only 18% of unreacted 15a-E
remained (Table 3, entry 1). At no point was any alkene
isomer 15a-Z detected. After 1 h, there was full consumption of
the starting material and no formal “ene”-type product 27-E
was observed (Table 3, entry 4). When the reaction time was
prolonged for an additional 1 h, significant decomposition
products resulted. A control experiment showed that irradiation
of a mixture of product diastereomers at the MeS-bearing
carbon (25a:25b, 13:1) for 1 h led to a decreased ratio of the
It is worth noting that the cyclization precursor 15a was used
as a mixture of E and Z isomers (1.25:1 E:Z). Thus, it was not
possible to assess the role that alkene geometry might play in
the reaction course. In order to probe this point, the mixture of
E- and Z-alkenyl sulfide allenyl azide isomers 15a was separated
via column chromatography using silver nitrate impregnated
silica gel following by a separate chromatography on regular
silica gel to remove trace Ag contaminants. Each purified
isomer then was subjected to the cyclization conditions
1
isomers (eq 2). Using triphenylmethane as an internal H
1
2
(
Schemes 6 and 7) at the original 350 nm wavelength, and
also, in separate runs, at 300 and 254 nm as well. To our
surprise, irradiation of the strictly E isomer 15a-E at 350 nm in
CH CN provided the C−C bonded species 25a as the
NMR standard revealed that both isomers 25a/25b slowly
decomposed under these conditions, but the major isomer 25a
appeared to decompose faster.
3
predominant product in very good yield with enhanced control
of stereochemistry and regiochemistry compared to the
Scheme 6. Photochemical [3 + 2] Cyclocondensation of Pure E-Alkenyl Sulfide Substrate 15a-E
D
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Scheme 7. Photochemical [3 + 2] Cyclocondensation of Pure Z-Alkenyl Sulfide Substrate 15a-Z
Table 2. Products Yields as a Function of Wavelength for the
Photochemical [3 + 2] Cyclocondensation of Pure E-Alkenyl
Sulfide 15a-E
The photochemical reaction of 15a-E also was monitored by
taking the UV/vis absorption spectrum of the reaction mixture
every minute. Unfortunately, there was no intermediate
detected (see the Supporting Information). Thus, the putative
indolidene species must be trapped rapidly and never builds up
to any detectable concentrations. Attempts to trap this putative
indolidene intermediate by spiking the reaction at an
intermediate time point with MeOH, which has been shown
to outcompete the alkenyl sulfide nucleophile (Scheme 3, 15a
wavelength
(nm)
27-E or
a
a
a
a
a
entry substrate
25a
25b
25c
26a
27-Z
1
2
3
4
5
6
15a-E
15a-E
15a-E
15a-Z
15a-Z
15a-Z
350
300
254
350
300
254
70
50
42
13
13
18
3
3
3
9
13
3
2
trace
9
5
2
2
1
14
19
16
trace
trace
trace
3
2
4
→
16a), also proved unsuccessful.
The cyclization reaction with the pure Z-alkenyl sulfide
a
1
compound 15a-Z also was monitored over time (Scheme 7).
After 30 min, only 21% of the C−C bonded products were
present along with 8% of unreacted starting material in addition
to decomposition products (Table 4, entry 1). Furthermore,
there was absolutely no isomerization of the Z-isomer 15a-Z
into the E-isomer 15a-E. The ratio of diastereomeric cyclized
products did not change significantly over time and prolonging
the reaction resulted in further decomposition. Moreover, there
was practically no C−N-bonded products present throughout
the reaction process with the Z-alkenyl sulfide substrate 15a-Z
Percent yields determined by integration of the H NMR spectra of
the crude reaction mixtures relative to the internal standard 1,4-
dimethoxybenzene.
Table 3. Products Yields as a Function of Reaction Time for
the Photochemical [3 + 2] Cyclocondensation of Pure E-
Alkenyl Sulfide Substrate 15a-E
a
a
a
a
a
a
a
entry time (min) 15a-E 15a-Z
25a
25b 25c
26
27-E
1
2
3
4
30
45
50
60
18
4
59
66
1
3
5
3
1
3
4
3
10
6
5
3
4
(
Table 4, entries 1−3) compared to a small but detectable
b
b
b
5
65
3
amount in the E-isomer experiments (Table 3, entries 1−4). In
both cases, C−C bond formation is strongly favored over C−N
bond formation.
70
9
aPercent yields determined through integration of the 1H NMR
spectra of the crude reaction mixtures relative to the internal standard
b
The indolidenium cation chemistry was explored via the
Lewis acid-mediated cyclization of 16a with catalytic amounts
of indium triflate in a variety of solvents (Scheme 8). The
methanol adduct 16a was first exposed to indium triflate in
toluene, and a mixture of C−C and C−N bonded products was
obtained (Table 5, entry 1). Optimization studies revealed that
more polar solvents, such as CH Cl and CH CN, resulted in
1
,4-dimethoxybenzene. Isolated yield of pure 25a/25b/25c com-
1
bined; ratio by integration of characteristic signals in the H NMR
spectrum.
Table 4. Product Yields as a Function of Reaction Time for
the Photochemical [3 + 2] Cyclocondensation of Pure Z-
Alkenyl Sulfide Substrate 15a-Z
2
2
3
the formation of the desired C−C bonded products 25a/25b
time
(min)
a
a
a
a
a
a
(
Table 5, entries 2 and 3). Replacing In(OTf) with Sc(OTf)
entry
15a-E 15a-Z 25a
25b
25c
26
27-Z
3
3
led to essentially the same results (Table 5, entry 4 vs entry 3).
A control experiment was designed to probe the possibility that
isomer 26 was converted into isomer 25 under the reaction
conditions in entries 2−4. Resubmitting pure N-cyclized
product 26 to the same reaction conditions resulted in
decomposition, demonstrating that not only did compound
1
2
3
30
60
8
10
16
13
11
20
6
12
3
trace
trace
2
120
14
1
trace
a
Percent yields determined by integration of the H NMR spectra of
the crude reaction mixtures relative to the internal standard 1,4-
dimethoxybenzene.
26 fail to isomerize to the C-cyclized product 25, but also that
in these solvents, any C−N bonded product formed was
Intriguingly, the formal ene-type product 27-E was observed
at early time points while monitoring the time-course of the
reaction (Table 3, entries 1−3), but after full consumption of
the starting material, it was not detected (Table 3, entry 4). A
control experiment indicated that decomposition was the issue,
as submitting pure 27-E to the reaction conditions resulted in
significant destruction with no characterizable material isolated.
immediately destroyed.
The stereochemistry at the ring junction of the C−C bonded
products 25 was exclusively trans in toluene solvent. However,
there appears to be some erosion of this selectivity in more
polar solvents, although still favoring the trans stereochemistry
at the ring junction (Table 5, entry 1 vs entries 2−4). Thus, the
E
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Scheme 8. Lewis Acid Mediated [3 + 2] Cyclocondensation of Alkenyl Sulfide Indole Substrate 16a
Table 5. Product Yields as a Function of Lewis Acid and
Solvent for the [3 + 2] Cyclocondensation of Alkenyl Sulfide
Indole Substrate 16a
Scheme 10. Indium Triflate Mediated [3 + 2]
Cyclocondensation of N-Benzylindole Alkenyl Sulfide
Substrate 23
a
a
a
b
entry
acid (0.2 equiv)
solvent
25a
25b
25c
26
38
1
2
3
4
In(OTf)3
In(OTf)3
In(OTf)3
Sc(OTf)3
toluene
CH Cl
46
18
34
37
6
2
4
5
trace
13
2
2
CH CN
3
CH CN
13
3
a
Isolated percent yield of pure 25a/25b/25c combined; ratio
Table 6. Product Yields as a Function of Solvent for the
1
determined by integration of characteristic signals in the H NMR
spectrum Percent yield of isolated, pure product.
In(OTf) -Mediated [3 + 2] Cyclocondensation of N-
b
3
Benzylindole Alkenyl Sulfide Substrate 23
a
a
results of this Lewis acid mediated cyclization seem to be
strongly dependent on the choice of solvent.
entry
solvent
31a
31b
1
2
3
CH CN
61
30
25
24
12
19
3
Interestingly, when methyl vinyl ether nucleophile substrate
6b was employed, the desired C−C-bonded product was not
toluene
1
CH Cl2
2
observed, even in trace amounts (Scheme 9). Instead, the C−
N-bonded product 30 was obtained exclusively as a mixture of
diastereomers. The stereochemistry of 30a−d was assigned on
the basis of the comparison of the observed coupling constant
values between H −H (Scheme 9) to the calculated values for
a
Isolated percent yields of pure 31a/31b combined; ratio determined
by integration of characteristic signals in the H NMR spectrum.
1
dimerization, the concentrations of the reactants were
drastically reduced (80 to 4 mM), and although no
dimerization was observed, the desired cyclization product
could not be detected.
a
b
this coupling derived from energy-minimized structures.
One obvious way to suppress the formation of the N-cyclized
products in this indolidenium chemistry is to block the indole
nitrogen (Scheme 10). Thus, this Lewis acid-mediated
cyclization was performed with the N-benzylated substrate
DISCUSSION
■
2
3. The alkenyl sulfide cyclization precursor 23 was exposed to
The interaction of a putative indolidene or indolidenium cation
intermediate with the pendant alkenyl sulfide nominally
produces a new C−C bond to C(8) and a new C−C (or C−
N) bond to C(3) (or N). The overriding issue of concerted
(but not synchronous) bond formation vs stepwise bond
formation lies at the heart of any mechanistic description of the
overall process. The strongest evidence that speaks to this issue
derives from the observed stereochemical outcome of the
reactions of the pure E- and Z-alkenyl sulfide isomers. At one
extreme, both E- and Z-alkenyl sulfide isomers 15a could be
operating via a completely stepwise mechanism perhaps
promoted by a photoinitiated single-electron transfer (SET)
indium triflate in CH CN, which resulted in a mixture of
3
epimers 31a and 31b in excellent yield (Table 6, entry 1). In an
attempt to improve the stereochemical outcome of the
cyclization, the less polar solvents toluene and CH Cl were
2
2
screened as well, but they led to a decrease in both overall yield
and stereoselectivity (Table 6, entries 2 and 3).
When the methyl vinyl ether equivalent of the N-benzylated
substrate 24 was exposed to indium triflate, not even trace
amounts of the C−C bonded products were observed. Instead,
acetal 32 and an unknown dimer (MS and NMR identification)
were the sole products isolated (eq 3). In order to suppress
(
Scheme 11). In this scenario, irradiation of 15a would
generate the indolidene intermediate 33 as a mixture of
geometrical isomers, which might easily interconvert under
irradiation; the calculated barrier to alkene isomerization in a
6c
similar model system is about 33 kcal/mol. In any event,
either or both isomers 33-E and 33-Z could undergo
Scheme 9. Lewis Acid Mediated [3 + 2] Cyclocondensation of Enol Ether Indole Substrate 16b
F
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Scheme 11. Stepwise Single Electron Transfer Mediated
Mechanistic Proposal for Indolidene Cyclization of 15a To
Give Tetracyclic Products
photochemical cycloaddition. The basis for this claim lies with
the observation that the major cyclized products (25a and 26a)
derived from 15a-E retained the geometrical information on
the starting alkene (Scheme 12). The LUMO of an indolidene,
Scheme 12. Alternative Mechanistic Proposal for the
Indolidene-to-Tetracycle Transformation with the E-Alkenyl
Substrate 15a-E; Possible Intervention of a Concerted
Photochemical [10π + 2π] Cycloaddition
as modeled by the simple species 37 (DFT calculation at the
B3LYP/6-31G** level with Jaguar V7.8, see the Supporting
Information) displays an evident suprafacial symmetry
mismatch with the alkenyl sulfide HOMO. However, computa-
tional studies by Dreyer and Klessinger on the photochemistry
14
of fulvene suggest a workaround to this problem. They
propose that upon excitation fulvene undergoes an approx-
imately 90° rotation about the exocyclic alkene to afford a
singlet twisted “alkene”. Extrapolating from this model to the
related indolidene suggests that a twisted intermediate like 37a
may be accessible. This intermediate, by virtue of its geometry,
then might allow sufficient orbital overlap with the alkene
HOMO’s lobes to achieve concerted but not necessarily
synchronous bond formation at C(8) and C(3) (or at N), as
illustrated in 38a. Just the reverse of this cycloaddition process,
the concerted (but asynchronous) discharge of N2 from
triazoline 4, emerged as a viable pathway through computa-
tional analysis. Note that a pseudoaxial placement of the
thioalkenyl moiety (e.g., 38b) would not have the proper
juxtaposition for the cycloaddition to occur with equal facility.
This concerted pathway might be disfavored for the Z-alkene
isomer 15a-Z due to untoward steric interactions that could
arise between the now pseudoequatorial methylthio appendage
and the twisted indolidene moiety in the transition state
(modeled as 39). Thus, it is possible that the Z isomer 15a-Z,
which loses alkene geometrical information upon cyclopentane
formation, proceeds through a nonconcerted photoinitiated
photoinitiated single-electron transfer to arrive at the same
singlet diradical indole-based zwitterionic species 34. Continu-
ing with this line of reasoning, this intermediate (34) can
undergo diradical closure through either of two chairlike
transition states extending from 34a and 34b to generate the
dipolar intermediates 35a and 35b, respectively, featuring either
a pseudoequatorial thionium cation appendage (e.g., 35a) or a
pseudoaxial thionium cation alternative (e.g., 35b). The
intervention of dipolar intermediates 35a and 35b in this
SET-based mechanistic proposal is reminiscent of the proposed
intermediates operating in the stepwise reaction of alkenes with
fulvenes in a formal [6 + 2] manner. Nucleophilic addition of
either the indole C(3) carbon or the nitrogen to the sulfur-
stabilized carbocation in 35 can result in the formation of
cyclized products 25/26, each as a mixture of stereoisomers
derived from the newly formed C(12) and C(13) stereogenic
positions.
6d
13
An alternative and highly speculative concerted mechanistic
pathway for the E-alkenyl sulfide isomer 15a-E merits
discussion as well; a formal (and unprecedented) [10π + 2π]
G
DOI: 10.1021/acs.joc.5b01777
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The Journal of Organic Chemistry
Article
SET process, whereas the E-isomer might utilize an
unprecedented concerted cycloaddition. In addition, since
trace amounts of 25b and 25c, which do not retain the
stereochemical information on the parent E-alkene, were also
observed for the E isomer, it also could be possible that both
the concerted and SET pathways are operating during the
course of the 15a-E reaction.
Scheme 13. Proposal for the Formation of the Minor Formal
“Ene” Products 27 and 29
Many cycloadditions with total π electron counts greater
13,15
than six have been reported;
both thermal and photo-
chemical conditions have been described, and the evidence in
each case for the claim of “cycloaddition” extends no further
than noting that the alkene geometrical information on the
starting materials is preserved in the products. The subset of
higher π electron count 4n cycloaddition claims is much
smaller, extending to a [14π + 2π] thermal reaction of
heptafulvene and tetracyanoethylene with the 14π component
1
5a
reacting in an antarafacial manner,
promoted [6π + 2π] addition of singlet oxygen to an
15c
the photochemically
1
5b
azepine, alkene/benzene [6π + 2π] photocycloadditions,
and a [14π + 2π] thermal cycloaddition of dimethyl acetylene
15d
dicarboxylate with an annulene.
Interestingly, [10π + 2π]
cycloadditions, promoted by either light or heat, have not yet
been described.
Scheme 14. Mechanistic Proposal for the In(OTf) -Mediated
Bicyclization of Substrates 16a and 23
1
6
3
One interesting observation that emerges from the present
work is that the product ratios upon reaction of the E-alkene
isomer 15a-E and the Z-alkene isomer 15a-Z are very different.
This divergence of results suggests that either (a) these starting
materials do not converge in their mechanism to a common
intermediate like 34 in the SET proposal or (b) they do
converge, but C−C single-bond rotation in this putative
common intermediate is slower than closure of the new C−C
bond to C(3) (or C−N bond to nitrogen). These possibilities
cannot be distinguished at present. If, in fact, C−C bond
rotation is faster than ring closure, then (i) the E-alkene and the
Z-alkene isomers must operate through a different mechanism,
and (ii) the Z-isomer must operate through a stepwise process
to account for the loss of alkene geometrical information. This
circumstance builds supports the case that a concerted
cycloaddition with the E-alkene isomer 15a-E occurs upon
irradiation.
The formation of the “ene” type product 27 is presumed to
occur via a formal [1,7]-hydride shift of H (or H to form 29)
a
b
in the indolidene intermediate 33 to either the C(3) carbon or
the nitrogen to afford a mixture of geometrical isomers (27/29)
(Scheme 13). The rate of this formal “ene” type reaction seems
to be slow compared to the addition of the alkene under
photochemical conditions. If the alkene is not nucleophilic
enough, however, the formation of the “ene” type product 27 is
favored, as evidenced with the cyclization of the simple alkene
nucleophile 19 (eq 1). With this substrate, the alkene isomer
29a was formed as well.
The results for the Lewis acid mediated cyclization can be
accommodated by the formation of a putative indolidenium
cation intermediate 41, which then can be captured by either
the pseudoequatorially or pseudoaxially aligned alkene
nucleophile to afford the sulfur-stabilized cationic intermediate
42 (Scheme 14). This sulfur-stabilized carbocation 42 can be
intercepted by either the C(3) carbon (for the R = H and R =
Bn systems) or the nitrogen (for the R = H substrate) to
generate cyclized products 25/26/31, each as a mixture of
stereoisomers.
The observed stereoselectivity for the trans isomer also can
be attributed to the preference for the alkenyl sulfide moiety to
reside in a pseudoequatorial position (e. g., 42a) as opposed to
the energetically disfavored pseudoaxial position (e. g., 42b).
Moreover, the exclusive formation of N-cyclized products with
H
DOI: 10.1021/acs.joc.5b01777
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The Journal of Organic Chemistry
Article
the oxygen-bearing substrate 16b can be rationalized by noting
that in the proposed intermediates 42a and 42b the “soft”
sulfur-stabilized carbocation might be a better reactivity match
for the softer C(3) carbon nucleophile compared to the “hard”
oxocarbenium ion, which might prefer the “harder” N
nucleophile.
pyridine complex (28.4 g, 178 mmol). The reaction solution was
stirred at room temperature for 1 h, at which time the reaction mixture
was washed with satd CuSO (aq) (2 × 200 mL), distilled water (2 ×
4
2
00 mL), and satd NaCl (aq) (2 × 200 mL), dried over Na SO , and
2 4
concentrated in vacuo. The crude product was purified via SiO flash
2
column chromatography, using 10% ethyl acetate in hexanes as eluent,
1
to afford 4.27 g (87%) of alkynal 11 as a pale yellow oil: H NMR
In summary, we have demonstrated the utility of indolidene/
indolidenium chemistry in [3 + 2] cyclocondensation reactions.
We have identified the conditions necessary to perform
successful bicyclizations and tricyclizations that likely proceed
via indolidenium cation and indolidene intermediates,
respectively. The results obtained for the geometrically pure
E- and Z-alkenyl sulfide isomers speak to a possible dichotomy
of mechanisms. The E-alkenyl sulfide allenyl azide cyclization
proved to be a powerful transformation since it not only creates
two C−C bonds, one C−N bond, and three fused rings, but it
does so with control of both stereochemistry and regiochem-
istry, and in very good yield. Thus, this chemistry might prove
useful for synthesis efforts directed toward the indolosesqui-
terpenes. Moreover, the remarkable stereoselectivity observed
with the E-alkenyl sulfide isomer suggests the possibility that a
new reaction, a [10π + 2π] photochemical concerted
cycloaddition, might be involved.
(
300 MHz, CDCl ) δ 9.72 (s, 1H), 2.42 (td, J = 7.2, 1.2 Hz, 2H), 2.16
3
(
td, J = 7.0, 2.6 Hz, 2H), 1.92 (t, J = 2.6 Hz, 1H), 1.81−1.71 (m, 2H),
1.60−1.52 (m, 2H). Spectral data are in agreement with the values
published.
1
7
Methyl(oct-1-en-7-yn-1-yl)sulfane (12a). To a 0 °C suspension of
(methylthio)methyl)triphenylphosphonium chloride (9.94 g, 27.7
(
mmol) in 100 mL of THF was added 1.8 M PhLi in dibutyl ether
(
14.7 mL, 26.5 mmol). The reaction mixture was allowed to stir for 30
min and then a solution of alkynal 11 (2.77 g, 25.2 mmol) in 100 mL
of THF was added dropwise. The resulting suspension was allowed to
stir for 3 h at 0 °C, at which time a satd solution of NH Cl (aq) (100
mL) was added. The aqueous layer was extracted with Et O (3 × 50
mL), and the combined organic layers were washed with satd NaCl
(aq) (100 mL), dried over Na SO , and concentrated in vacuo. The
crude product was purified via SiO
4
2
2
4
flash column chromatography,
2
using hexanes as eluent, to afford 2.49 g (69%) of thio enol ether 12a
−1 1
(
(
1.25:1 E:Z) as a pale yellow oil: IR (neat) 3297, 2360 cm ; H NMR
300 MHz, CDCl ) δ 5.98 (d, J = 15.0 Hz, 1H, E isomer), 5.89 (d, J =
3
9
7
.4 Hz, 1H, Z isomer), 5.47 (m, 1H, E and Z isomers), 2.30−2.09 (m,
13
H), 1.95−1.93 (m, 1H), 1.69−1.39 (m, 4H); C NMR (75 MHz,
) δ 128.7, 127.2, 126.9, 124.0, 84.4, 68.2, 32.5, 28.5, 28.2, 27.8,
18.2, 17.0, 15.0; LRMS (ESI-TOF) m/z (relative intensity) 154.1 (9%,
EXPERIMENTAL SECTION
■
CDCl
3
General Methods. All reactions were performed using Schlenk
glassware unless otherwise indicated. Solvents were purified by passage
through activated alumina columns. All reagents were used as supplied
without further purification unless otherwise noted. Chromatography
specifying “deactivation by triethylamine” indicates that triethylamine
was added to the eluent during column packing, after which the
column was used with untreated eluent.
+
M); HRMS (ESI-TOF) m/z [M] calcd for C
154.0820.
H14S 154.0816, found
9
1-Methoxyoct-1-en-7-yne (12b). To a 0 °C solution of potassium
tert-butoxide (6.53 g, 58.2 mmol) in 100 mL of THF was added
(methoxymethyl)triphenylphosphonium chloride (22.7 g, 66.0 mmol).
The mixture was allowed to stir for 15 min, and then a solution of
alkynal 11 (4.27 g, 38.8 mmol) in 100 mL of THF was added
dropwise. The resulting suspension was allowed to stir for 30 min at 0
°C, at which time the reaction mixture was washed with satd NH
(aq) (2 × 100 mL), distilled water (2 × 100 mL), and satd NaCl (aq)
(2 × 100 mL), dried over Na SO , and concentrated in vacuo. The
crude product was purified via SiO flash column chromatography,
General Procedure 1: Irradiation of the Allenyl Azide. The
allenyl azide substrate in the indicated solvent (10 mM) under a
nitrogen atmosphere was irradiated in a Rayonet photoreactor at 350
nm for the indicated time, with TLC monitoring. When TLC indicated
consumption of the starting material, the reaction mixture was
concentrated in vacuo and purified by flash column chromatography
with the indicated support/eluent.
General Procedure 2. Thermolysis of the Allenyl Azide. The
allenyl azide in the indicated solvent (10 mM) was heated to reflux and
held there, with TLC monitoring. When TLC indicated consumption
of the starting material, the solution was concentrated in vacuo, and
the product was purified via flash column chromatography with the
indicated support/eluent to afford the indicated product.
Cl
4
2
4
2
after deactivation with 2% triethylamine, using 5% ethyl acetate in
hexanes as eluent, to afford 2.7 g (50%) of enol ether 12b (1.7:1 E:Z)
as a pale yellow oil: IR (neat) 3298, 2163 cm ; H NMR (300 MHz,
CDCl ) δ 6.26 (d, J = 12.6 Hz, 1H, E isomer), 5.85 (dt, J = 6.2, 1.3 Hz,
−1 1
3
1H, Z isomer), 4.73 (dt, J = 14.6, 7.3 Hz, 1H, E isomer), 4.29 (q, J =
7.2 Hz, 1H, Z isomer), 3.55 (s, 3H, Z isomer), 3.48 (s, 3H, E isomer),
2.21−2.13 (m, 2H), 2.10−2.00 (m, 1H), 1.96−1.88 (m, 2H), 1.55−
1.43 (m, 4H); 13C NMR (75 MHz, CDCl ) δ 147.2, 146.2, 106.3,
General Procedure 3. Lewis Acid Mediated Cyclization. A
solution of the substrate in the indicated solvent (40−50 mM) was
added to a heterogeneous solution of 0.2 equiv of indium triflate in
solvent at 0 °C under a N2 atmosphere (final concentration of
substrate: 30−40 mM). The resulting solution was allowed to stir for 1
h under N , and then a satd NaHCO (aq) solution was added. The
3
102.4, 84.5, 68.1, 59.4, 55.7, 29.7, 28.7, 27.9, 27.7, 27.1, 23.1, 18.2;
LRMS (ESI-TOF) m/z (relative intensity) 139.1 (44%, M + H );
HRMS (ESI-TOF) m/z [M + H] calcd for C H O 139.1123, found
139.1117.
+
+
9
15
2-Azidobenzaldehyde (13). A solution of 2-nitrobenzaldehyde (7.0
g, 46 mmol) and sodium azide (9.0 g, 140 mmol) in 60 mL of DMF
was heated to 60 °C and held at that temperature for 96 h. The
2
3
aqueous layer was extracted with Et O (3×), and the combined
2
organic layers were washed with satd NaCl (aq), dried over Na SO ,
2
4
and concentrated in vacuo. The product was purified via flash column
reaction mixture was diluted with Et O, and the aqueous layer was
2
chromatography with the indicated support/eluent.
washed with dichloromethane (5 × 30 mL). The combined organic
layers were washed with satd NaCl (aq) (2 × 30 mL), dried over
Na SO , and concentrated in vacuo. The crude product was purified
General Procedure 4. Removal of Thiomethyl Ether Unit. A 1
M Superhydride solution in THF (5 equiv) was added to a solution of
the thiomethyl ether substrate in THF (37 mM) under a N2
atmosphere. The resulting mixture was stirred for the indicated time,
2
4
via SiO flash chromatography, using 0−20% ethyl acetate in hexanes
2
as eluent, to afford 5.60 g (83%) of azidoaldehyde 13 as a pale yellow
1
and then a satd NH Cl (aq) solution was added. The aqueous layer
crystalline solid: mp 32−33 °C; H NMR (300 MHz, CDCl ) δ 10.23
4
3
was extracted with Et O (3×), and the combined organic layers were
(s, 1H), 7.79 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 (m, 1H), 7.17 (m, 2H).
Spectral data are in agreement with the values published.
2
18
washed with satd NaCl (aq), dried over Na SO , and concentrated in
2
4
vacuo. The crude product was purified via flash column chromatog-
raphy with the indicated support/eluent.
Hept-6-ynal (11). To a room-temperature solution of hept-6-yn-1-
1-(2-Azidophenyl)-9-(methylthio)non-8-en-2-yn-1-yl Acetate
(14a). To a solution of thio enol ether 12a (1.25:1 E/Z, 2.60 g,
17.1 mmol) in 250 mL of THF at −78 °C was added 2.5 M n-BuLi in
hexanes (7.5 mL, 19 mmol). The reaction mixture was allowed to stir
for 1 h at −78 °C, at which time a solution of azidoaldehyde 13 (2.51
ol (5.0 g, 45 mmol) in 600 mL of a 2:1 mixture of CH Cl /DMSO was
2
2
added triethylamine (31.0 mL, 220 mmol) followed by sulfur trioxide
I
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The Journal of Organic Chemistry
Article
+
g, 17.1 mmol) in 75 mL of THF was added dropwise. The resulting
solution was allowed to stir for 2.5 h at 0 °C, at which time acetic
anhydride (2.0 mL, 19 mmol) was added. The reaction mixture was
allowed to stir and warm to room temperature overnight. A saturated
(relative intensity) 272.1 (42%, M − N + H ); HRMS (ESI-TOF) m/
2
+
z [M − N + H] calcd for C H NS 272.1473, found 272.1476.
Separation of E- and Z-Alkenyl Sulfide Isomers 15a. The E- and
Z-alkenyl sulfide allenyl azide isomers were separated via column
chromatography using silver nitrate impregnated silica gel and 0−5%
Et O in hexanes as the eluent. A second column chromatography was
2
17 22
12
solution of NH Cl (aq) (100 mL) was added to the reaction mixture,
4
the aqueous layer was extracted with Et O (3 × 50 mL), and the
2
2
combined organic layers were washed with satd NaCl (aq) (100 mL),
dried over Na SO , and concentrated in vacuo. The crude product was
performed for each stereoisomer, using 100% hexanes as the eluent, to
remove any trace amount of silver.
2
4
purified via SiO2 flash chromatography using 5% ethyl acetate in
hexanes as eluent to afford 5.20 g (89%) of thio alkynyl azide 14a
(E)-(9-(2-Azidophenyl)-7-methylnona-1,7,8-trien-1-yl)(methyl)-
−1
1
sulfane (15a-E): IR (neat) 2360, 2338, 2023 cm ; H NMR (300
−
1
MHz, CDCl ) δ 7.36 (d, J = 7.7 Hz, 1H), 7.23−7.18 (m, 1H), 7.13−
(
1.25:1 E:Z) as a viscous light orange oil: IR (neat) 2123, 1740 cm ;
3
1
7.03 (m, 2H), 6.31 (s, 1H), 5.95 (d, J = 14.9 Hz, 1H), 5.44−5.35 (m,
H NMR (300 MHz, CDCl ) δ 7.68 (d, J = 7.5 Hz, 1H), 7.38 (t, J =
3
1
4
1
H), 2.20 (s, 3H), 2.14−2.02 (m, 4H), 1.79 (s, 3H), 1.56−1.42 (m,
7
.7 Hz, 1H), 7.18 (m, 2H), 6.61 (s, 1H), 5.95 (d, J = 15.0 Hz, 1H, E
isomer), 5.87 (d, J = 9.4 Hz, 1H, Z isomer), 5.52−5.35 (m, 1H, E and
Z isomers), 2.27−2.21 (m, 5H), 2.14−2.08 (m, 5H), 1.55−1.46 (m,
H); 13C NMR (75 MHz, CDCl ) δ 203.4, 136.1, 128.0, 127.6, 127.5,
3
27.4, 124.8, 123.8, 118.5, 103.6, 88.4, 33.8, 33.0, 29.2, 26.9, 18.8, 15.1;
H); 13C NMR (75 MHz, CDCl ) δ 169.4, 137.7, 130.0, 129.2, 128.5,
LRMS (ESI-TOF) m/z (relative intensity) 272.1 (27%, M − N +
2
4
1
2
3
3
+
+
H ); HRMS (ESI-TOF) m/z [M − N + H] calcd for C H NS
2
17 22
28.2, 127.0, 123.9, 118.1, 88.0, 61.1, 32.4, 28.5, 28.4, 28.0, 27.8, 27.6,
0.9, 18. 6, 16.9, 14.9; LRMS (ESI-TOF) m/z (relative intensity)
44.1 (30%, M + H ); HRMS (ESI-TOF) m/z [M + H] calcd for
2
72.1473, found 272.1476.
+
+
(Z)-(9-(2-Azidophenyl)-7-methylnona-1,7,8-trien-1-yl)(methyl)-
−
1 1
sulfane (15a-Z): IR (neat) 2116, 1950 cm ; H NMR (300 MHz,
C H N O S 344.1433, found 344.1430.
18
22
3
2
CDCl ) δ 7.36 (d, J = 7.7 Hz, 1H), 7.23−7.18 (m, 1H), 7.13−7.04 (m,
3
1
-(2-Azidophenyl)-9-methoxynon-8-en-2-yn-1-yl Acetate (14b).
2
1
1
1
2
H), 6.31 (q, J = 2.6 Hz, 1H), 5.86 (d, J = 9.4 Hz, 1H), 5.53−5.45 (m,
To a solution of enol ether 12b (1.7:1 E:Z, 2.70 g, 19.5 mmol) in 75
mL of THF at −78 °C was added 2.5 M n-BuLi in hexanes (8.3 mL, 21
mmol). The reaction mixture was allowed to stir for 45 min, at which
time a solution of azidoaldehyde 13 (2.87 g, 19.5 mmol) in 75 mL of
THF was cannulated into the reaction mixture. The resulting solution
was allowed to stir for 2.5 h at −78 °C, at which time acetic anhydride
H), 2.25 (s, 3H), 2.14−2.02 (m, 4H), 1.80 (d, J = 2.7 Hz, 3H), 1.56−
.41 (m, 4H); 13C NMR (75 MHz, CDCl ) δ 203.4, 136.1, 128.8,
3
28.0, 127.6, 127.5, 126.9, 124.8, 118.5, 103.7, 88.3, 33.9, 29.0, 28.7,
7.2, 18.8, 17.2; LRMS (ESI-TOF) m/z (relative intensity) 272.1
+
+
(72%, M − N + H ); HRMS (ESI-TOF) m/z [M − N + H] calcd
2
2
for C H NS 272.1473, found 272.1461.
17
22
(
2.0 mL, 22 mmol) was added. The reaction mixture was allowed to
Irradiation of E-Alkenyl Sulfide Isomer (15a-E). Following general
procedure 1, a solution of E-alkenyl sulfide 15a-E (100 mg, 0.33
mmol) in 36 mL of acetonitrile was irradiated through Pyrex at 350
nm for 50 min and then concentrated in vacuo. The crude product was
stir and warm to room temperature overnight. The reaction solution
was washed with satd NH Cl (aq) (2 × 50 mL), distilled water (2 ×
4
5
0 mL), and satd NaCl (aq) (2 × 50 mL), dried over Na SO , and
2 4
concentrated in vacuo. The crude product was purified via SiO flash
2
purified via basic Al O3 flash chromatography using 0−8% ethyl
2
chromatography, after deactivation with 2% triethylamine, using 0−5%
ethyl acetate in hexanes as eluent, to afford 4.27 g (67%) of alkynyl
azide 14b (1.7:1 E/Z) as a viscous light orange oil: IR (neat) 2128,
acetate in hexanes as eluent to afford 0.067 g (74%) of 25 as a mixture
of stereoisomers (25a/25b/25c, 16:1.3:1). In addition, 3% of the C−
N-bonded product 26a, 4% of the formal “ene”-type product 27, and
−
1 1
1
1
2
745 cm ; H NMR (300 MHz, CDCl ) δ 7.68 (dd, J = 7.6, 1.6 Hz,
3
5
% of starting material 15a-E also were isolated.
H), 7.39 (td, J = 7.9, 1.4 Hz, 1H), 7.18 (t, J = 7.8 Hz, 2H), 6.16 (t, J =
.0 Hz, 1H), 6.27 (d, J = 12.6 Hz, 1H, E isomer), 5.87 (dt, J = 6.2, 1.5
−1 1
2
5a: IR (neat) 3396 cm ; H NMR (300 MHz, CDCl ) δ 7.96 (s,
3
1
3
H), 7.82−7.79 (m, 1H), 7.34−7.31 (m, 1H), 7.17−7.15 (m, 2H),
Hz, 1H, Z isomer), 4.68 (dt, J = 14.6, 7.3 Hz, 1H, E isomer), 4.29 (q, J
7.3 Hz, 1H, Z isomer), 3.56 (s, 3H, Z isomer), 3.49 (s, 3H, E
isomer), 2.25 (dt, J = 7.1, 1.9 Hz, 2H), 2.09 (s, 3H), 1.93 (q, J = 7.2
.83 (d, J = 10.0 Hz, 1H), 2.30−2.15 (m, 1H), 2.03 (s, 3H), 2.02−1.92
=
13
(m, 2H), 1.82−1.30 (m, 6H), 1.06 (s, 3H); C NMR (75 MHz,
CDCl ) δ 152.8, 139.3, 124.6, 120.9, 120.1, 118.6, 116.4, 111.8, 60.5,
1
3
3
Hz, 1H), 1.54−1.17 (m, 5H); C NMR (75 MHz, CDCl ) δ 169.5,
3
4
6.7, 42.4, 34.9, 26.8, 21.9, 21.2, 18.5, 11.5; LRMS (ESI-TOF) m/z
1
8
47.2, 146.3, 137.8, 130.1, 129.3, 128.6, 124.9, 118.2, 106.3, 102.5,
8.2, 61.2, 59.4, 55.8, 29.8, 28.8, 27.8, 27.6, 26.9, 23.1, 21.0, 18.6;
LRMS (ESI-TOF) m/z (relative intensity) 328.1 (12%, M + H );
HRMS (ESI-TOF) m/z [M + H] calcd for C H N O 328.1661,
+
(relative intensity) 272.1 (12%, M + H ); HRMS (ESI-TOF) m/z [M
+
+
H] calcd for C H NS 272.1473, found 272.1468.
17 22
+
1
2
6a: H NMR (300 MHz, CDCl ) δ 7.95 (d, J = 7.0 Hz, 1H), 7.55
3
+
18
22
3
3
(d, J = 7.0 Hz, 1H), 7.15−7.04 (m, 2H), 6.13 (s, 1H), 4,95 (d, J = 10.3
Hz, 1H), 2.31−2.19 (m, 1H), 2.19−2.05 (m, 1H), 2.02−1.87 (m, 2H),
found 328.1666.
9-(2-Azidophenyl)-7-methylnona-1,7,8-trien-1-yl)(methyl)-
(
1
1
1
2
.85 (s, 3H), 1.80−1.62 (m, 3H), 1.61−1.49 (m, 1H), 1.46−1.31 (m,
sulfane (15a). To a solution of copper(I) iodide (28.7 g, 151 mmol)
and lithium bromide (13.1, 151 mmol) in 2.0 L of THF at 0 °C was
13
H), 1.10 (s, 3H); C NMR (75 MHz, CDCl ) δ 153.0, 133.0, 132.4,
3
20.9, 120.8, 119.5, 110.6, 90.9, 63.9, 56.8, 40.2, 34.7, 26.2, 21.2,
added 3 M methylmagnesium bromide in Et O (50.0 mL, 151 mmol).
2
0.9.1, 19.3, 9.9; LRMS (ESI-TOF) m/z (relative intensity) 272.1
The reaction mixture was allowed to stir and warm to room
temperature over 1 h, at which time thio alkynyl azide 14a (1.25:1 E/
Z, 5.17 g, 15.1 mmol) in 100 mL of THF was cannulated into the
reaction mixture. The resulting solution was allowed to stir for 30 min.
+
+
(43%, M + H ); HRMS (ESI-TOF) m/z [M + H] calcd for
C H NS 272.1473, found 272.1452.
17
22
Irradiation of the E-Alkenyl Sulfide Isomer 15a-E Monitored by
UV/vis Absorption. A diluted solution of the E isomer 15-E in
acetonitrile (estimate concentration: < 100 μM) was irradiated at 350
nm in a quartz cuvette and monitored every minute with a UV−vis
absorption spectrophotometer (see the Supporting Information for the
resulting graph of the absorption spectra over time). The cyclization
reaction with the Z alkene was also monitored with the UV−vis
absorption spectrophotometer, and the spectrum looked almost
identical to the spectrum obtained for the E isomer.
The reaction mixture was washed with satd NH Cl (aq) (2 × 200
4
mL), distilled water (3 × 200 mL), and satd NaCl (aq) (3 × 200 mL),
dried over Na SO , and concentrated in vacuo. The crude product was
2
4
purified via SiO flash chromatography, after deactivation with 2%
2
triethylamine, using 0−4% ethyl acetate in hexanes as eluent to afford
3
.72 g (82%) of allenyl azide 15a (1.25:1 E/Z) as a viscous yellow oil:
−1 1
IR (neat) 2116, 1950 cm ; H NMR (300 MHz, CDCl ) δ 7.36 (d, J
3
=
7.7 Hz, 1H), 7.23−7.18 (m, 1H), 7.13−7.04 (m, 2H), 6.31 (q, J =
1-Azido-2-(9-methoxy-3-methylnona-1,2,8-trien-1-yl)benzene
(15b). To a solution of copper(I) iodide (24.8 g, 130 mmol) and
lithium bromide (11.3 g, 130 mmol) in 1.5 L of THF at 0 °C was
2
1
.6 Hz, 1H), 5.93 (d, J = 14.9 Hz, 1H, E isomer), 5.86 (d, J = 9.4 Hz,
H, Z isomer), 5.53−5.36 (m, 1H, E and Z isomers), 2.25 (s, 3H, Z
isomer), 2.20 (s, 3H, E isomer), 2.14−2.02 (m, 4H), 1.80 (d, J = 2.7
added 3 M methylmagnesium bromide in Et O (43.4 mL, 130 mmol).
2
13
Hz, 3H), 1.56−1.42 (m, 4H); C NMR (75 MHz, CDCl ) δ 203.3,
The reaction mixture was allowed to stir and warm to room
temperature over 30 min, at which time alkynyl azide 14b (1.7:1 E:Z,
4.27 g, 13.0 mmol) in 125 mL of THF was cannulated into the
3
1
2
35.9, 128.7, 127.5, 126.7, 124.7, 123.6, 118.4, 103.5, 88.2, 33.8, 32.9,
9.1, 28.9, 28.6, 27.0, 26.8, 18.7, 17.0, 15.0; LRMS (ESI-TOF) m/z
J
DOI: 10.1021/acs.joc.5b01777
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
reaction mixture. The resulting solution was allowed to stir for 45 min.
to stir for 1.5 h at 0 °C, at which time acetic anhydride (0.16 mL, 1.7
The reaction mixture was washed with satd NH Cl (aq) (2 × 500
mmol) was added. The reaction mixture was allowed to stir and warm
4
mL), distilled water (10 × 500 mL), and satd NaCl (aq) (2 × 500
to room temperature overnight. A saturated solution of NH Cl (aq)
4
mL), dried over Na SO , and concentrated in vacuo. The crude
(10 mL) was added to the reaction mixture, and the aqueous layer was
2
4
product was purified via SiO flash chromatography, after deactivation
extracted with Et O (3 × 10 mL). The combined organic layers were
2
2
with 2% triethylamine, using 0−4% ethyl acetate in hexanes as eluent,
washed with satd NaCl (aq) (10 mL), dried over Na SO , and
2
4
to afford 2.88 g (78%) of allenyl azide 15b (1.7:1 E:Z) as a viscous
concentrated in vacuo. The crude product was purified via SiO flash
2
−1 1
yellow/orange oil: IR (neat) 2117, 1951 cm ; H NMR (300 MHz,
chromatography using 0−5% ethyl acetate in hexanes as eluent to
afford 0.12 g (28%) of 18 as a light yellow oil.
CDCl ) δ 7.36 (dd, J = 7.7, 1.4 Hz, 1H), 7.21−7.07 (m, 3H), 6.31 (p, J
3
=
3.1 Hz, 1H), 6.24 (d, J = 12.6 Hz, 1H, E isomer), 5.85 (dt, J = 6.2,
To a solution of copper(I) iodide (1.04 g, 3.36 mmol) and lithium
bromide (0.474 g, 5.45 mmol) in 70.0 mL of THF at 0 °C was added
1
.4 Hz, 1H, Z isomer), 4.69 (dt, J = 14.6, 7.3 Hz, 1H, E isomer), 4.31
(
q, J = 7.3 Hz, 1H, Z isomer), 3.55 (s, 3H, Z isomer), 3.47 (s, 3H, E
3.0 M methylmagnesium bromide in Et O (1.80 mL, 5.45 mmol). The
2
13
isomer), 2.10−2.05 (m, 3H), 1.80 (s, 3H), 1.52−1.28 (m, 5H);
NMR (75 MHz, CDCl ) δ 203.3, 147.0, 146.1, 135.9, 127.9, 127.4,
C
reaction mixture was allowed to stir and warm to room temperature
over 1 h, at which time substrate 18 (0.162 g, 0.545 mmol) in 7 mL of
THF was added to the reaction mixture. The resulting solution was
3
124.7, 118.3, 106.7, 103.7, 103.6, 102.9, 88.1, 59.4, 55.8, 33.8, 30.4,
2
9.4, 27.4, 27.1, 26.8, 23.6, 18.7; LRMS (ESI-TOF) m/z (relative
allowed to stir for 30 min and diluted with 50 mL of Et O. The
2
+
intensity) 256.2 (63%, M − N + H ); HRMS (ESI-TOF) m/z [M −
N + H] calcd for C H NO 256.1701, found 256.1688.
reaction mixture was washed with satd NH Cl (aq) (2 × 200 mL),
2
4
+
distilled water (3 × 200 mL), and satd NaCl (aq) (3 × 200 mL), dried
2
17 22
2
-(2-Methoxy-8-(methylthio)oct-7-en-2-yl)-1H-indole (16a).
over Na SO , and concentrated in vacuo. The crude product was
2
4
Method A: Following general procedure 2, a solution of allenyl
azide 15a (1.25:1 E:Z, 0.51 g, 1.7 mmol) in 175 mL of methanol was
brought to reflux and held there for 84 h. At that time, concentration
of the reaction mixture led to a crude product that was purified via
purified via SiO flash chromatography using 100% hexanes as eluent
2
to afford 0.082 g (60%) of allenyl azide 19 as a viscous yellow oil: IR
−1 1
(neat) 2120 cm ; H NMR (300 MHz, CDCl ) δ 7.36 (d, J = 7.7 Hz,
3
1H), 7.23−7.18 (m, 1H), 7.13−7.04 (m, 2H), 6.31−6.22 (m, 1H),
SiO flash chromatography using 5% ethyl acetate in hexanes as eluent
5.88−5.67 (m, 1H), 5.05−4.85 (m, 2H), 2.13−1.90 (m, 4H), 1.80 (d, J
2
13
to afford 0.46 g (88%) of methanol adduct 16a (1.25:1 E/Z) as a
viscous yellow oil. Method B: Following general procedure 1, a
solution of thio allenyl azide 15a (1.25:1 E/Z, 50.0 mg, 0.17 mmol) in
= 2.7 Hz, 3H), 1.56−1.40 (m, 4H); C NMR (75 MHz, CDCl ) δ
3
203.5, 139.0, 136.1, 128.1, 127.6 (2), 124.9, 118.5, 114.5, 103.7, 88.4,
34.0, 33.7, 28.7, 27.1, 18.8; LRMS (ESI-TOF) m/z (relative intensity)
+
+ H]+
17 mL of methanol was irradiated through Pyrex at 350 nm for 1.8 h.
226.1 (43%, M − N
2
+ H ); HRMS (ESI-TOF) m/z [M − N
2
The reaction mixture was concentrated in vacuo and purified as in
calcd for C16
H
20N 226.1596, found 226.1604.
−1 1
method A: yield 23 mg (45%, 1.25:1 E/Z); IR (neat) 3307 cm ; H
8-(Methylthio)oct-7-en-2-one (21). A solution of [(methylthio)-
methyl]triphenylphosphonium chloride (0.97 g, 2.7 mmol) and 1.8 M
PhLi in dibutyl ether (1.5 mL, 2.7 mmol) in 5 mL of THF was stirred
at −78 °C for 45 min. This solution was added dropwise to a solution
NMR (300 MHz, CDCl ) δ 8.38 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H),
3
7
1
.36 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.2 Hz,
H), 6.35 (s, 1H), 5.92 (d, J = 15.0 Hz, 1H, E isomer), 5.83 (d, J = 9.4
2
0
Hz, 1H, Z isomer), 5.51−5.30 (m, 1H, E and Z isomers), 3.11 (s, 3H),
of alkynal 20 (0.315 g, 2.46 mmol) in 10 mL of THF. The resulting
2
2
.25 (s, 3H, E isomer), 2.19 (s, 3H, Z isomer), 2.07 (p, J = 6.9 Hz,
suspension was allowed to stir for 2 h at room temperature, at which
13
H), 1.89 (q, J = 6.6 Hz, 2H), 1.59 (s, 3H), 1.37−1.10 (m, 4H);
C
time a satd solution of NH
layer was extracted with Et
layers were washed with satd NaCl (aq) (10 mL), dried over Na
4
Cl (aq) (15 mL) was added. The aqueous
NMR (75 MHz, CDCl ) δ 142.2, 135.8, 128.6, 128.1, 127.3, 126.7,
2
O (3 × 5 mL), and the combined organic
3
1
2
23.7, 121.7, 120.3, 119.5, 110.8, 100.7, 50.6, 40.7, 40.6, 32.9, 29.8,
2
SO
4
,
9.1, 28.9, 23.5, 23.4, 22.1, 17.0, 15.0; LRMS (ESI-TOF) m/z (relative
and concentrated in vacuo. The crude product was purified via SiO
2
+
+
intensity) 304.2 (40%, M + H ); HRMS (ESI-TOF) m/z [M + H]
flash chromatography using 5% ethyl acetate in hexanes as eluent to
afford 0.22 g (52%) of ketone 21 as a viscous light yellow oil (mixture
calcd for C H NOS 304.1735, found 304.1723.
18
26
−1 1
2
-(2,8-Dimethoxyoct-7-en-2-yl)-1H-indole (16b). Method A:
Following general procedure 2, allenyl azide 15b (1.7:1 E/Z, 0.77 g,
.7 mmol) in 50 mL of methanol was brought to reflux and held there
of 2 isomers, E:Z 1.8:1): IR (neat) 1710 cm ; H NMR (300 MHz,
CDCl ) δ 5.98 (d, J = 15.0 Hz, 1H, E isomer), 5.88 (d, J = 9.4 Hz, 1H,
3
2
Z isomer), 5.53−5.38 (m, 1H, E and Z isomers), 2.43−2.41 (m, 2H),
2.25 (s, 3H, Z isomer), 2.21 (s, 3H, E isomer), 2.12−2.08 (m, 5H),
for 120 h. At that time, concentration of the reaction mixture led to a
13
crude product that was purified via SiO flash chromatography, after
1.61−1.57 (m, 2H), 1.38−1.36 (m, 2H); C NMR (75 MHz, CDCl )
3
2
deactivation with 2% triethylamine, using 10% ethyl acetate in hexanes
as eluent, to afford 0.75 g (96%) of methanol adduct 16b (1.7:1 E/Z)
as a viscous yellow oil. Method B: Following general procedure 1, a
solution of thio allenyl azide 15b (1.7:1 E/Z, 50.0 mg, 0.18 mmol) in
δ 209.3, 209.2, 128.4, 127.2, 127.0, 124.2, 43.6, 43.6, 33.0, 30.0, 29.1,
28.8, 28.5, 23.5, 23.4, 23.3, 17.2, 15.2; LRMS (EI-TOF) m/z (relative
+
intensity) 172.1 (22%, M); HRMS (EI-TOF) m/z [M] calcd for
C
H
16OS 172.0922, found 172.0927.
9
17 mL of methanol was irradiated through Pyrex at 350 nm for 20
2-(1-Benzyl-1H-indol-2-yl)-8-(methylthio)oct-7-en-2-ol (23). To a
2
1
min. The reaction mixture was concentrated in vacuo and purified as in
solution of 1-benzyl-2-bromo-1H-indole (0.52 g, 1.8 mmol) in 75
mL of THF at −78 °C was added 2.5 M n-BuLi in hexanes (0.72 mL,
1.8 mmol) dropwise, and the mixture was warmed to 0 °C and stirred
for 20 min. The reaction mixture was then cooled to −78 °C, and a
solution of ketone 21 (0.26 g, 1.5 mmol, E/Z 1.8:1) in 5 mL of THF
was cannulated into the reaction mixture. The resulting solution was
−1 1
method A: yield 33 mg (63%, 1.7:1 E:Z); IR (neat) 3308 cm ; H
NMR (300 MHz, CDCl ) δ 8.32 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H),
3
7.35 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.1 Hz, 1H), 7.09 (t, J = 7.5 Hz,
1H), 6.35 (d, J = 1.9 Hz, 1H), 6.23 (d, J = 12.6 Hz, 1H, E isomer),
5.83 (d, J = 6.2 Hz, 1H, Z isomer), 4.66 (dt, J = 12.6, 7.3 Hz, 1H, E
isomer), 4.28 (q, J = 7.3 Hz, 1H, Z isomer), 3.55 (s, 3H, Z isomer),
warmed to room temperature and stirred for 3 h. A satd NH
solution (20 mL) was added at that time, and the aqueous layer was
extracted with Et O (3 × 20 mL). The combined organic layers were
washed with satd NaCl (aq) (20 mL), dried over Na SO , and
concentrated in vacuo. The crude product was purified via SiO flash
4
Cl (aq)
3
1
1
5
.45 (s, 3H, E isomer), 3.10 (s, 3H), 1.91−1.83 (m, 3H), 1.58 (s, 3H),
13
.43−1.03 (m, 5H); C NMR (75 MHz, CDCl ) δ 147.0, 146.1,
2
3
42.3, 135.9, 128.1, 121.7, 120.3, 119.5, 110.8, 106.7, 102.8, 100.7,
2
4
9.4, 55.8, 50.5, 40.5, 31.0, 30.0, 27.5, 23.3, 22.1; LRMS (ESI-TOF)
2
+
m/z (relative intensity) 288.2 (58%, M + H ); HRMS (ESI-TOF) m/z
chromatography using 5% ethyl acetate in hexanes as eluent to afford
0.42 g (74%) of alcohol 23 as a viscous yellow oil (mixture of 2
+
[
M + H] calcd for C H NO 288.1964, found 288.1982.
18 26 2
−
1
1
(
9-(2-Azidophenyl)-7-methylnona-1,7,8-trien-1-yl)(methyl)-
isomers, E/Z 1.8:1): IR (neat) 3402 cm ; H NMR (300 MHz,
19
sulfane (19). To a solution of alkene 17 (0.21 g, 1.4 mmol) in 22
mL of THF at −78 °C was added 2.5 M n-BuLi in hexanes (0.56 mL,
CDCl ) δ 7.61−7.59 (m, 1H), 7.24−7.18 (m, 3H), 7.14−7.05 (m,
3
3H), 6.93 (d, J = 7.0 Hz, 2H), 6.46 (s, 1H), 5.93−5.81 (m, 2H), 5.71
(d, J = 17.4 Hz, 1H), 5.44−5.29 (m, 1H, E and Z isomers), 2.23 (s,
3H, Z isomer), 2.18 (s, 3H, E isomer), 1.99−1.81 (m, 4H), 1.73−1.68
1
°
5
.4 mmol). The reaction mixture was allowed to stir for 30 min at −78
C, at which time a solution of azidoaldehyde 13 (0.15 g, 1.4 mmol) in
13
mL of THF was added dropwise. The resulting solution was allowed
(m, 4H), 1.43−0.96 (m, 4H); C NMR (75 MHz, CDCl ) δ 144.1,
3
K
DOI: 10.1021/acs.joc.5b01777
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(
7
44.0, 138.9 (2), 138.6, 138.5, 128.7, 128.6, 127.5, 127.1 (2), 126.8
2), 125.6, 123.7, 122.0, 121.9, 120.5, 119.8 (2), 110.2, 100.7, 100.6,
2.8, 48.3, 41.9 (2), 32.9, 29.5, 28.9 (3), 24.2 (2), 17.1, 15.1; LRMS
J = 7.1 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 6.57 (m, 1H), 6.02 (d, J =
15.0 Hz, 1H, E isomer), 5.91 (d, J = 9.4 Hz, 1H, Z isomer), 5.58−5.40
(m, 1H, E and Z isomers), 5.33 (s, 1H), 5.09 (s, 1H), 2.56−2.49 (m,
2H), 2.28 (s, 3H, E isomer), 2.23 (s, 3H, Z isomer), 2.22−2.13 (m,
+
(
AP-TOF) m/z (relative intensity) 362.2 (59%, M − OH + H );
+
13
HRMS (ESI-TOF) m/z [M − OH + H] calcd for C H NS
3
2H), 1.70−1.60 (m, 2H), 1.56−1.45 (m, 2H); C NMR (75 MHz,
24
28
62.1942, found 362.1939.
CDCl ) δ 140.1, 138.2, 136.5, 128.8, 127.0, 122.7, 120.8, 120.0, 110.7,
3
(
S)-1-Benzyl-2-(2,8-dimethoxyoct-7-en-2-yl)-1H-indole (24). A
109.3, 101.0, 34.2, 29.0, 28.8, 28.6, 17.2; LRMS (ESI-TOF) m/z
+
solution of substrate 16b (0.132 g, 0.459 mmol) and KOH (0.077
g, 1.4 mmol) in 6.6 mL of DMF was stirred at 0 °C for 1 h. Benzyl
bromide (82 μL, 0.69 mmol) was added, and the reaction mixture was
allowed to stir at room temperature for 1 h. Water (5 mL) and diethyl
ether (5 mL) were added, and the aqueous layer was extracted with
(relative intensity) 272.1 (36%, M + H ); HRMS (ESI-TOF) m/z [M
+
+ H] calcd for C H NS 272.1473, found 272.1461.
17
22
Irradiation of the C−C-Bonded Product 25. A solution of the C-
cyclized product 25a/25b (0.021 g, 0.078 mmol) in 9.4 mL of
acetonitrile was irradiated through Pyrex at 350 nm for 1 h and
concentrated. Triphenylmethane (0.019 g, 0.078 mmol) was added as
an internal standard and the 1H NMR of the mixture showed
significant decomposition. The major isomer 25a appeared to
decompose faster than the minor isomer 25b, therefore changing
Et O (3 × 5 mL). The combined organic layers were washed with satd
2
NaCl (aq) (10 mL), dried over Na SO , and concentrated in vacuo.
The crude product was purified via SiO flash chromatography using
00% benzene as eluent to afford 0.145 g (84%) of the benzylated
product 24 as a viscous light yellow oil: H NMR (360 MHz, CDCl )
2
4
2
1
1
1
3
the isomers ratio (13:1 → 6.7:1). H NMR yield of 25a/25b: 34%.
δ 7.63−7.59 (m, 1H), 7.27−7.18 (m, 3H), 7.13−7.07 (m, 3H), 6.97
4a-Methyl-10-(methylthio)-1,2,3,4,4a,5,10,10a-octahydroindeno-
[1,2-b]indole (25a/25b/25c) and 10a-Methyl-6-(methylthio)-
6a,7,8,9,10,10a-hexahydro-6H-isoindolo[2,1-a]indole (26). In aceto-
nitrile: Following general procedure 3, indole 16a (77 mg, 0.25 mmol,
1.25:1 E/Z) in 6.5 mL of acetonitrile was cannulated into a suspension
of indium triflate (0.029 g, 0.051 mmol) in 0.5 mL of acetonitrile at 0
°C. The resulting solution was allowed to stir for 1 h, and then a satd
(
d, J = 7.0 Hz, 2H), 6.50 (s, 1H), 6.18 (d, J = 12.6 Hz, 1H, E isomer),
5
5
7
3
.94, (dd, J = 17.4, 3.3 Hz, 1H), 5.81 (d, J = 6.2 Hz, 1H, Z isomer),
.64, (d, J = 17.4 Hz, 1H), 4.63−4.54 (m, 1H, E isomer), 4.23 (q, J =
.2 Hz, 1H), 3.53 (s, 3H, Z isomer), 3.45 (s, 3H, E isomer), 3.02 (s,
13
H), 1.95−1.65 (m, 4H), 1.59 (s, 3H), 1.15−0.80 (m, 4H); C NMR
(
90 MHz, CDCl ) δ 147.1, 146.1, 141.5, 141.4, 138.8, 138.6, 128.6,
3
1
1
2
27.2 (2), 126.9, 126.8, 125.9, 122.1, 122.0, 120.5, 119.8 (2), 110.4,
06.8, 103.8, 103.7, 103.0, 77.9, 59.5, 56.0, 50.7, 47.7, 40.3, 40.2, 30.9,
9.9, 27.6, 24.1, 23.9, 23.8, 23.1; LRMS (ESI-TOF) m/z (relative
NaHCO
extracted with Et
washed with satd NaCl (aq) (10 mL), dried over Na
concentrated in vacuo. The crude product was purified via SiO
3
(aq) solution (5 mL) was added. The aqueous layer was
O (3 × 5 mL), and the combined organic layers were
SO , and
flash
2
2
4
+
+
intensity) 378.2 (100%, M + H ); HRMS (EIS-TOF) m/z [M + H]
2
calcd for C H NO 378.2433, found 378.2438.
chromatography using 5% ethyl acetate in hexanes as eluent to afford
35 mg (51%) of the C-cyclized product as a mixture of 3 isomers
(25a/25b/25c, 8:1:3) as a viscous yellow oil. In dichloromethane:
yield 20% of the C-cyclized product as a mixture of two isomers (25a/
25
32
2
4
a-Methyl-10-(methylthio)-1,2,3,4,4a,5,10,10a-octahydroindeno-
1,2-b]indole (25a/25b/25c), 10a-Methyl-6-(methylthio)-
a,7,8,9,10,10a-hexahydro-6H-isoindolo[2,1-a]indole (26), and 2-
8-(Methylthio)octa-1,7-dien-2-yl)-1H-indole (27). In acetonitrile:
Following general procedure 1, a solution of thio allenyl azide 15a
1.25:1 E/Z, 50 mg, 0.17 mmol) in 17 mL of acetonitrile was
irradiated through Pyrex at 350 nm for 2.5 h. The reaction mixture was
concentrated in vacuo. The crude product was purified via basic Al O
[
6
(
2
5b, 8:1). In toluene: yield 52% of the C-cyclized product as a mixture
of two isomers (25a/25b, 8:1) and 38% of the N-cyclized product 26
as a mixture of three isomers.
(
2
-(8-(Methylthio)octa-1,7-dien-2-yl)-1H-indole (27). Following
2
3
general procedure 2, allenyl azide 15a (1.25:1, E/Z, 50.0 mg, 0.17
mmol) in 50 mL of acetonitrile was brought to reflux and held there
for 20 h. At that time, concentration of the reaction mixture led to a
crude product that was purified via basic Al O flash chromatography
flash chromatography using 0−4% ethyl acetate in hexanes as eluent to
afford 26 mg (55%) of the C-cyclized products 25 as a viscous yellow
oil (mixture of three isomers, 18:1:4, 25a/25b/25c) as well as 1 mg
2
3
(
3%) of the alkene 27 and 4 mg (9%) of the N-cyclized products 26 as
using 2% ethyl acetate in hexanes as eluent to afford 0.018 g (40%,
a mixture of three isomers. The major isomer 25a was isolated via
preparatory HPLC and fully characterized (vide infra). The isomers’
relative stereochemistries were determined by the comparison of H
1
.25:1 E/Z) of the alkene 27 as a viscous yellow oil (only trace
1
amounts of the cyclized product 25a were observed by H NMR).
4aR,10aS)-4a-Methyl-1,2,3,4,4a,5,10,10a-octahydroindeno[1,2-
1
(
NMR coupling constants for H to predicted values. The predicted
b]indole (28a). Following general procedure 4, a 1 M Superhydride
solution in THF (0.60 mL, 0.55 mmol) was added to a solution of the
cyclized adduct 25a (30 mg, 0.11 mmol) in THF (3 mL) under a N2
atmosphere. The resulting mixture was stirred for 12 h at room
a
values were generated from structures optimized via molecular
mechanics calculations. It is not possible to distinguish between the
structures 25b and 25c by this method; however, a mixture of the
three isomers were subjected to desulfurization conditions (vide infra)
temperature, and then a satd NH Cl (aq) solution (5 mL) was added.
4
1
and the H NMR spectral data of the reduction (desulfurization)
The aqueous layer was extracted with Et O (3 × 10 mL), and the
2
2
h
product from 25c was found to match those of the cis-fused isomer.
In dichloromethane: yield 20% of the alkene product 27 (only trace
amounts of the desired C-cyclized product were seen by H NMR). In
toluene: yield 22% of the N-cyclized product 26 as a mixture of 3
combined organic layers were washed with satd NaCl (aq) (10 mL),
dried over Na SO , and concentrated in vacuo. The crude product was
2
4
1
purified via basic Al O flash chromatography using 5% ethyl acetate in
2 3
hexanes as eluent to afford 23 mg (92%) of the desulfurized product
−1 1
isomers (only trace amounts of the C-cyclized product were seen by
28a as a viscous light yellow oil: IR (neat) 3402 cm ; H NMR (300
1
H NMR). Another stereoisomer of the N-cyclized product (labeled as
MHz, CDCl ) δ 7.86 (s, 1H), 7.49−7.44 (m, 1H), 7.35−7.30 (m, 1H),
3
2
6b) was isolated and fully characterized, but the ring juncture
7.12−7.07 (m, 2H), 2.73−2.66 (m, 1H), 2.47−2.31 (m, 2H), 2.04−
1.98 (m, 1H), 1.88−1.82 (m, 1H), 1.74−1.65 (m, 4H), 1.50−1.30 (m,
stereochemistry could not be assigned. In DMF: yield 73% of the
2H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl ) δ 153.1, 139.3, 125.2,
formal “ene” product 27 (only trace amounts of the C-cyclized
3
1
product were seen by H NMR).
120.3, 119.6, 118.6, 116.8, 111.6, 55.7, 42.2, 34.9, 28.0, 26.8, 24.7, 21.3,
1
2
6b: H NMR (300 MHz, CDCl ) δ 7.57 (t, J = 7.0 Hz, 2H), 7.15−
17.1; LRMS (ESI-TOF) m/z (relative intensity) 226.2 (96%, M +
3
+
+
7
.04 (m, 2H), 6.10 (s, 1H), 5.50 (d, J = 6.0 Hz, 1H), 2.70 (q, J = 6.3
Hz, 1H), 2.46 (s, 3H), 2.10−1.75 (m, 4H), 1.65−1.35 (m, 4H), 1.32
s, 3H); 13C NMR (75 MHz, CDCl ) δ 152.4, 133.5, 133.0, 121.0,
H ); HRMS (ESI-TOF) m/z [M + H] calcd for C H N 226.1613,
16 20
found 226.1596.
(
4a-Methyl-1,2,3,4,4a,5,10,10a-octahydroindeno[1,2-b]indole
(28a/28c). Following general procedure 4, a 1 M Superhydride
solution in THF (0.61 mL, 0.55 mmol) was added to a solution of the
cyclized adduct 25 (33 mg, 0.12 mmol, 3.7:1 25a/25c) in THF (4
3
120.9, 120.0, 119.9, 91.7, 70.1, 53.4, 40.3, 35.5, 27.0, 24.4, 24.1, 22.3,
1
8.0; LRMS (ESI-TOF) m/z (relative intensity) 272.1 (12%, M +
+
+
H ); HRMS (ESI-TOF) m/z [M + H] calcd for C H NS 272.1473,
17
22
found 272.1468.
7: IR (neat) 3395, 1640 cm ; H NMR (300 MHz, CDCl ) δ
mL) under a N atmosphere. The resulting mixture was stirred for 12
2
−1 1
2
h at room temperature, and then a satd NH Cl (aq) solution (5 mL)
3
4
8.17 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.21 (t,
was added. The aqueous layer was extracted with Et O (3 × 10 mL),
2
L
DOI: 10.1021/acs.joc.5b01777
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
and the combined organic layers were washed with satd NaCl (aq) (10
mL), dried over Na SO , and concentrated in vacuo. The crude
31a: H NMR (300 MHz, CDCl ) δ 7.75−7.90 (m, 1H), 7.30−7.25
3
(m, 3H), 7.17−7.08 (m, 3H), 7.05−6.98 (m, 2H), 5.34 (s, 2H), 3.88
(d, J = 10.0 Hz, 1H), 2.27−2.19 (m, 1H), 2.05 (s, 3H), 2.02−1.96 (m,
1H), 1.43−1.83 (m, 1H), 1.78−1.50 (m, 4H), 1.37−1.30 (m, 2H),
2
4
product was purified via basic Al O flash chromatography using 5%
2
3
ethyl acetate in hexanes as eluent to afford 23 mg (85%) of the
desulfurized product 28 as a mixture of two isomers (28a/28c, 3.6:1).
1.00 (s, 3H); 13C NMR (75 MHz, CDCl
) δ 153.9, 140.2, 138.0,
3
1
The structural assignment of 28c is based upon comparison of its H
128.7, 127.4, 126.0, 124.6, 120.8, 119.8, 118.7, 115.8, 110.1, 60.7, 48.0,
46.5, 43.1, 35.4, 26.6, 21.9, 21.2, 18.1, 11.5; LRMS (ESI-TOF) m/z
(relative intensity) 362.2 (59%, M + H ); HRMS (ESI-TOF) m/z [M
H] calcd for C H NS 362.1942, found 362.1948. A pure sample
1
NMR values to the H NMR values of the authentic cis-fused isomer
2h
+
2
8c published by Harrison and co-workers.
E)-2-(Octa-2,7-dien-2-yl)-1H-indole (29a/29b). Following general
+
+
(
24 28
of 31b could not be isolated; hence, its structural assignment is based
upon analogy to the results of the nonbenzylated series. The tentative
stereochemical assignment is based upon analysis at the MeS-CH
coupling constant.
procedure 1, a solution of alkene 19 (10 mg, 0.039 mmol) in 4.0 mL of
acetonitrile was irradiated through Pyrex at 350 nm for 1.5 h and then
the solution was concentrated in vacuo. The crude product was
purified via basic Al O3 flash chromatography using 0−5% ethyl
2
1
-Benzyl-2-(2,8,8-trimethoxyoctan-2-yl)-1H-indole (32). Follow-
acetate in hexanes as eluent to afford 6.0 mg (68%) of the elimination
product as a mixture of two inseparable regioisomers (29a/29b,
ing general procedure 3, a solution of methanol adduct 24 (0.027 mg,
0.074 mmol) in 1 mL of toluene was added to a suspension of
−1
1
1
.4:1): IR (neat) 2162 cm ; H NMR (400 MHz, CDCl ) δ 8.13 (s,
3
In(OTf) (78 mg, 0.14 mmol) in 0.2 mL of toluene at −10 °C. The
1H), 7.61 (q, J = 8.1 Hz, 1H), 7.34 (q, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6
3
resulting solution was allowed to stir for 2 h at that temperature. A
Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.56 (s, 1H 29a), 6.48 (s, 1H, 29b),
saturated solution of NaHCO (aq) (5 mL) was added, the aqueous
3
5
5
5
7
.90−5.77 (m, 1H), 5.53−5.59 (m, 1H, 29b E or Z isomer), 5.45−
.35 (m, 1H, 29b E or Z isomer), 5.32 (s, 1H, 29a), 5.08 (s, 1H, 29a),
.05−4.92 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H, 29a), 2.45−2.35 (q, J =
.5 Hz, 2H, 29b Z or E isomer), 2.33−2.23 (q, J = 7.4 Hz, 2H, Z or E
layer was extracted with ethyl acetate (3 × 5 mL), and the combined
organic layers were washed with satd NaCl (aq) (10 mL), dried over
Na SO , and concentrated in vacuo. The crude product was purified
2
4
via spherical SiO flash chromatography using 0−5% ethyl acetate in
2
isomer), 2.20−2.04 (m, 2H for 29a, and 5H for 29b), 1.70−1.33 (m,
H for 29a, and 2H for 29b); 1 C NMR (75 MHz, CDCl ) δ 29a:
3
hexanes as eluent to afford 7 mg (23%) of 32 as a clear oil. There were
4
1
1
3
1
no trace amounts of the desired C−C bonded product: H NMR (300
40.1, 139.0, 138.2, 136.5, 128.9, 122.7, 120.8, 120.1, 114.6, 110.7,
09.2, 101.0, 34.3, 33.74, 28.8, 28.6; LRMS (ESI-TOF) m/z (relative
MHz, CDCl ) δ 7.65−7.57 (m, 1H), 7.30−7.18 (m, 3H), 7.15−7.05
3
(
m, 3H), 6.98 (d, J = 7.4 Hz, 2H), 6.49 (s, 1H), 5.94 (d, J = 17.5 Hz,
H), 5.63 (d, J = 17.5 Hz, 1H), 4.27 (t, J = 5.7 Hz, 1H), 3.27 (s, 6H),
+
+
intensity) 226.2 (38%, M + H ); HRMS (ESI-TOF) m/z [M + H]
1
3
2
1
1
2
calcd for C H N 226.1596, found 226.1606.
16
20
.02 (s, 3H), 1.79 (t, J = 7.8 Hz, 2H), 1.59 (s, 3H), 1.48 (q, J = 7.2 Hz,
6
-Methoxy-10a-methyl-6a,7,8,9,10,10a-hexahydro-6H-isoindolo-
13
H), 1.20−0.80 (m, 6H); C NMR (75 MHz, CDCl ) δ 141.3, 138.8,
3
[
2,1-a]indole (30a−d). Following general procedure 3, a solution of
38.6, 128.6, 127.2, 126.8, 125.9, 122.1, 120.5, 119.8, 110.4, 104.5,
03.8, 77.9, 76.8, 52.7, 52.6, 50.6, 47.7, 40.4, 32.5, 29.5, 24.6, 24.5,
3.1; LRMS (ESI-TOF) m/z (relative intensity) 410.2 (87%, M +
methanol adduct 16b (200 mg, 0.70 mmol) in 8 mL of toluene was
added to a suspension of In(OTf) (78 mg, 0.14 mmol) in 1 mL of
3
toluene at 0 °C. The resulting solution was allowed to stir for 8 h. The
+
+
H ); HRMS (ESI-TOF) m/z [M + H] calcd for C H NO
2
6
36
3
reaction mixture was washed with satd NaHCO (aq) (2 × 10 mL),
3
4
10.2695, found 410.2711.
distilled water (2 × 10 mL), and satd NaCl (aq) (2 × 10 mL), dried
over Na SO , and concentrated in vacuo. The crude product was
2
4
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01777.
■
purified via spherical SiO flash chromatography, after deactivation
2
S
with 2% triethylamine, using 0−5% ethyl acetate in hexanes as eluent
to afford 91 mg (51%) of 30 as a pale yellow oil (mixture of four
diastereomers in a ratio of 10:9:7:1, 30a/30b/30c/30d). Compound
3
0b was isolated and characterized (vide infra). The remaining
Detailed calculation procedures, including prediction of
coupling constants and determination of the molecular
orbital for the LUMO of the indolidene; UV/vis
absorption spectra for compounds 15a-E, 15a-Z, 25a,
and the E isomer 15a-E irradiation over time; H and C
NMR spectra for 12a,b, 14a, 14b, 15a, 15a-E, 15a-Z,
isomers’ identities were provisionally determined by the comparison of
1
H NMR coupling constants for H to predicted values. These values
a
were generated from structures optimized via molecular mechanics
calculations. LC−LRMS and LC−HRMS were employed to ensure
that all isomers did indeed have the appropriate mass.
1
13
−1 1
3
0b: IR (neat) 2359 cm ; H NMR (400 MHz, CDCl ) δ 7.55 (d,
3
15b, 16a,b, 19, 21, 23, 24, 25a (plus HMBC, HMQC,
J = 7.6 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.0 Hz, 1H), 7.08
t, J = 7.0 Hz, 1H), 6.14 (s, 1H), 5.47 (d, J = 5.6 Hz, 1H), 3.63 (s,
(
DEPT), 26a,b, 27, 28a, 29a/b, 30b, 31a/b, and 32 (plus
3
3
1
H), 2.42 (m, 1H), 1.94−1.71 (m, 5H), 1.61−1.44 (m, 3H), 1.41 (s,
DEPT) (PDF)
H); 13C NMR (75 MHz, CDCl ) δ 155.1, 133.2, 132.7, 120.7, 120.5,
3
19.6, 110.2, 91.5, 90.8, 58.3, 52.0, 38.3, 36.5, 23.5, 22.9, 22.4, 21.6;
AUTHOR INFORMATION
Corresponding Author
E-mail: ksf@chem.psu.edu.
+
■
LRMS (ESI-TOF) m/z (relative intensity) 256.1 (100%, M + H , all
isomers); HRMS (ESI-TOF) m/z [M + H] calcd for C H NO
+
17
22
*
2
56.1701, found 256.1692.
4aR,10S,10aR)-5-Benzyl-4a-methyl-10-(methylthio)-
,2,3,4,4a,5,10,10a-octahydroindeno[1,2-b]indole (31a/31b). In
(
Notes
1
The authors declare no competing financial interest.
acetonitrile: Following general procedure 3, a solution of alcohol 23
(
52 mg, 0.14 mmol, E/Z 1.6:1) in acetonitrile (3 mL) was added to a
ACKNOWLEDGMENTS
We thank the Chemical Synthesis Division of the National
Science Foundation for funding (CHE1361260).
■
suspension of indium triflate (15 mg, 0.027 mmol) in 0.5 mL of
acetonitrile at 0 °C. The resulting solution was allowed to stir for 15
min, and then Et O (5 mL) and a satd NaHCO (aq) solution (5 mL)
2
3
were added. The aqueous layer was extracted with Et O (3 × 5 mL)
2
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■
2
4
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DOI: 10.1021/acs.joc.5b01777
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DOI: 10.1021/acs.joc.5b01777
J. Org. Chem. XXXX, XXX, XXX−XXX