Solvent-Controlled Bifurcated Cascade Process for the Selective Preparation of Dihydrocarbazoles or Dihydropyridoindoles

Article abstract of DOI:10.1002/chem.201403268

A solvent-controlled cascade process has been identified for the dual purpose of the preparation of either dihydrocarbazoles or dihydropyridoindoles from identical N-aryl-α,β-unsaturated nitrones and electron-deficient allene starting materials. These reactions proceed smoothly under mild metal-free conditions affording a range of two types of skeletally distinct indole-based heterocycles in high yield and diastereoselectivity. These transformations demonstrate the use of a bifurcated cascade process that hinges on the ring-opening event of a benzazepine intermediate for the synthesis of skeletally diverse heterocyclic products and rapid access to biologically-significant, indole-based structures.

Full text of DOI:10.1002/chem.201403268

DOI: 10.1002/chem.201403268
Full Paper
&
Organic Methods
Solvent-Controlled Bifurcated Cascade Process for the Selective
Preparation of Dihydrocarbazoles or Dihydropyridoindoles
Dong-Liang Mo, Donald J. Wink, and Laura L. Anderson*[a]
Abstract: A solvent-controlled cascade process has been
identified for the dual purpose of the preparation of either
dihydrocarbazoles or dihydropyridoindoles from identical N-
aryl-a,b-unsaturated nitrones and electron-deficient allene
starting materials. These reactions proceed smoothly under
mild metal-free conditions affording a range of two types of
skeletally distinct indole-based heterocycles in high yield
and diastereoselectivity. These transformations demonstrate
the use of a bifurcated cascade process that hinges on the
ring-opening event of a benzazepine intermediate for the
synthesis of skeletally diverse heterocyclic products and
rapid access to biologically-significant, indole-based
structures.
Introduction
The development of new synthetic methods that efficiently
access distinct molecular scaffolds from simple reagents is cru-
cial to the generation of spatially diverse chemical libraries for
biological screening.[1] Cascade reactions are important and
proficient transformations that rapidly build molecular com-
plexity and have been employed for the synthesis of complex
molecules in both target- and diversity-oriented syntheses.[2–4]
While pursuing our interest in the reactivity of a,b-unsaturated
N-aryl nitrones as precursors to highly functionalized mole-
cules, we decided to test their reactivity toward electron-defi-
cient allenes (Scheme 1).[5] To our delight, we discovered that
either dihydrocarbazoles 1 or dihydropyridoindoles 2 can be
formed as the sole products of the reaction of N-aryl-a,b-unsa-
turated nitrones 3 with electron-deficient allenes 4 depending
on the choice of solvent (Scheme 1).[6] These new transforma-
tions rapidly build structural complexity from simple starting
materials through a diastereoselective addition and rearrange-
ment process that can bifurcate at the ring-opening event of
a benzazepine intermediate by simply changing the reaction
medium.[7] Herein, we describe the optimization and scope of
both processes. Preliminary mechanistic evidence for the bifur-
cated reaction pathway will also be presented to highlight key
aspects of these transformations that efficiently and selectively
access two structurally distinct indole-based heterocycles in
a single step from simple, non-heterocyclic starting materials.[8]
Scheme 1. Synthetic applications of N-aryl-a,b,-unsaturated nitrones.
Results and Discussion
Single-Step Preparation of Dihydrocarbazoles from a,b-Un-
saturated N-Aryl Nitrones and Allenes
Dihydrocarbazole 1a was initially observed when a mixture of
nitrone 3a and allenoate 4a were heated to 808C in toluene
(Table 1, entry 1). The structure of 1a was unambiguously de-
termined by X-ray diffraction. Optimization of this transforma-
tion revealed that toluene was the most effective reaction
medium (Table 1, entries 1–6). Although iPrOH was equally effi-
cient to toluene, samples of 1a prepared in iPrOH contained
an undesired byproduct.[9] To improve the yield, a variety of
Lewis and Brønsted acids were screened and silica gel was
identified as the most effective additive to enable the forma-
tion of dihydrocarbazole 1a in 82% yield (entries 7–10). Al-
though the reaction could be run at lower temperatures with
longer reaction times (entries 11–12), the conversion was sig-
nificantly diminished. Consequently, the optimal conditions
[a] Dr. D.-L. Mo, Dr. D. J. Wink, Dr. L. L. Anderson
Department of Chemistry
University of Illinois at Chicago
845 W. Taylor St., Chicago, IL 60607 (USA)
E-mail: lauralin@uic.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403268.
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Table 1. Optimization of the dihydrocarbazole synthesis.
Table 2. Scope of nitrone reagent for the synthesis of dihydrocarbazoles.
R1 (3)
R2 (3)
1 (Yield, [%])[a]
Entry
Solvent
Additive
T [8C]
Yield [%][a]
Entry
1
2
3
4
5
6
7
8
PhMe
DCE
THF
none
none
none
none
none
none
4 ꢁ MS[b]
BF3·Et2O[c]
HOAc[d]
80
80
80
80
80
80
80
80
80
80
60
25
52
42
8
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a (82)[b]
1b (71)
1c (85)
1d (75)
1e (62)
1 f (60)
1g (74)
1h (81)
1i (79)
1j (68)
1k (90)
1l (89)
1m (67)
1n (65)[c]
4-OMe(C6H4)
4-NO2(C6H4)
4-Br(C6H4)
3,5-Me2(C6H4)
2-OMe(C6H4)
Ph
DMF
10
50
52
10
trace
20
82
68
25
MeCN
iPrOH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
4-OMe(C6H4)
4-CF3(C6H4)
4-Br(C6H4)
Ph
Ph
9
9
4-Cl(C6H4)
2-furanyl
CH2=CH2Ph
Ph
Ph
Ph
[e]
10
11
12
SiO2
10
11
12
13
14
[e]
SiO2
Ph
[e]
SiO2
CH2=CH2Ph
Me
H
[a] % Yield determined by 1H NMR spectroscopy using CH2Br2 as a refer-
ence: 3a (1 equiv), 4a (3 equiv), 0.1m, 18 h, sealed reaction vessel.
[b] MS=molecular
[e] 200 wt%.
sieves
(100 wt%).
[c] 1 equiv
[d] 20 mol%.
[a] % Isolated yield. Conditions: 3a–3n (1 equiv), 4a (3 equiv), SiO2, 0.1m
in PhMe, 808C, 18 h. [b] 1 mmol scale reaction gave a 65% yield. [c] No
SiO2.
shown in Table 1, entry 10 were selected to explore the scope
of the transformation for the efficient preparation of dihydro-
carbazoles from non-indole precursors.[10]
ents showed similar electronic trends, and sterically hindered
meta-substituents were shown to be able to control the regio-
selectivity of CÀC bond formation to produce the N-heterocy-
cle as a single regioisomer (entries 8–10). ortho-Substituents
were not tested due to the fact that methods to access these
substrates are currently unavailable. The tolerance of the reac-
tion for a variety of N-aryl substituents illustrates the generality
of this method for the preparation of a range dihydrocarba-
zoles.
Once optimal conditions were determined for the prepara-
tion of dihydrocarbazole 1a, several a,b-unsaturated N-tolyl ni-
trones were examined to determine the scope of the nitrone
component of the reaction. As shown in Table 2, efficient con-
version of chalcone-derived nitrones 3b–3i to dihydrocarba-
zoles 1b–1i revealed that a variety of both electron-poor and
electron-rich aryl groups are tolerated. These include both
nitro- and bromo-substituted arenes that can be used for fur-
ther functionalization of the products (Table 2, entries 1–9).
Furanyl-substituted dihydrocarbazole 1j was similarly prepared
from furanyl-substituted nitrone 3j and dienyl- and dibenzyli-
dene acetone-derived nitrones 3k and 3l provided the corre-
sponding styrenyl-substituted dihydrocarbazoles 1k and 1l in
excellent yield (entries 10–12). Alkyl-substituted a,b-unsaturat-
ed nitrone 3m was also cleanly converted to dihydrocarbazole
1m and even aldehyde-derived nitrone 3n could be trans-
formed to 1n if SiO2 was excluded (entries 13–14).[11] The ma-
jority of the nitrones used to synthesize the dihydrocarbazoles
described in Table 2 can be easily prepared by a copper-medi-
ated CÀN bond coupling of oximes and arylboronic acids.[12]
The versatility of the addition and rearrangement process for
a variety of different R1- and R2 functional groups demon-
strates the efficacy of this method for the preparation of a di-
verse range of dihydrocarbazoles.
Table 3. Scope of N-aryl nitrone substituent for the synthesis of dihydro-
carbazoles.
Entry
X, 3
1 (Yield, [%])[a]
1
2
3
4
5
4-OMe, 3o
4-OBn, 3p
4-SMe, 3q
4-NMe2, 3r
H, 3s
1o (86)
1p (89)
1q (91)
1r (90)
1s (74)
6
7
4-CF3, 3t
4-Br, 3u
1t (46)
1u (59)
8
9
10
3,5-Me2, 3v
3-OMe, 3w
3-tBu, 3x
1v (60)
The N-aryl functionality on the nitrone-component of the re-
action mixture was also screened to ascertain its effect on the
preparation of dihydrocarbazoles 1. As shown in Table 3, elec-
tron-donating groups facilitated the transformation (entries 1–
4) and electron-withdrawing groups provided the correspond-
ing products in attenuated yields (entries 6–7). meta-Substitu-
1w (85, 3:1)[b]
1x (75, >20:1)[c]
[a] % Isolated yield. Conditions: 3o–3x (1 equiv), 4a (3 equiv), SiO2, 0.1m
in PhMe, 808C, 18 h. [b] regioselectivity=3:1; 5-OMe:6-OMe. [c] regiose-
lectivity = >20:1; 5-(tBu): 6-(tBu).
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Next, the identity of the electron-withdrawing group on the
allene was examined using nitrone 3a. To our delight, we
found that the dihydrocarbazole synthesis tolerates a broad
range of electron-deficient allenes (Table 4). In addition to a di-
verse array of allenoates, allenes with sulfonyl-, cyano-, and
thioester substituents were efficiently converted to dihydrocar-
bazoles 6-11 (entries 1–6). Phosphoryl groups, however, afford-
ed dihydrocarbazole 12 with an attenuated yield (entry 7). If
the reaction was performed at 258C, even allenone 4i could
be converted to ketone-substituted dihydrocarbazole 13
(entry 8). The breadth of functional group tolerance for the
allene component of the dihydrocarbazole synthesis is particu-
larly appealing due to the potential for further elaboration of
the resulting dihydrocarbazole scaffolds.
exposure to Boc-deprotection conditions, we observed sponta-
neous cyclization to afford dihydrocarbazole 18 (Scheme 2b).
We recognized that if our process was proceeding through
this proposed mechanism, diastereoselective dihydrocarbazole
formation might be possible using a-substituted nitrones if
the cyclization and proton transfer sequence was rendered
stereoselective.[16]
Table 4. Scope of allene reagent for the synthesis of dihydrocarbazoles.
Entry
1
EWG
# (Yield, [%])[a]
6 (65)
-CO2(tBu), 4b
2
7 (81)
Scheme 2. Proposed mechanism for dihydrocarbazole formation.
4c
3
8 (76)
Diastereoselective Synthesis of Dihydrocarbazoles
4d
-SO2Ph, 4e
-CN, 4 f
-C(O)SPh, 4g
-P(O)(OEt)2, 4h
-C(O)Ph, 4i
To investigate the relative stereoselectivity of the preparation
of dihydrocarbazoles from N-aryl-a,b-unsaturated nitrones and
allenes, a,b-disubstituted nitrones such as 3y–3aa were exam-
ined. As shown in Scheme 3, we were delighted to discover
that when nitrone 3y was treated with allene 4a, dihydrocar-
bazole 1y was formed with >20:1 diastereoselectivity favoring
the trans-isomer.[17] Further screening demonstrated that high
diastereoselectivity can be obtained for both linear- and cyclic
disubstituted a,b-unsaturated nitrones. Compounds 3z and
3aa were similarly converted to dihydrocarbazoles 1z and 1aa
in ꢀ10:1 d.r., albeit in moderate yield.[18] These data suggest
that the relative stereochemistry of the dihydrocarbazole prod-
ucts can be controlled for a,b-disubstituted nitrones and un-
derscore the synthetic utility of this new process.
4
5
6
7
8
9 (80)
10 (74)
11 (70)
12 (35)
13 (69)[b]
[a] % Isolated yield. Conditions: 3a (1 equiv), 4b–4i (3 equiv), SiO2, 0.1m
in PhMe, 808C, 18 h. [b] 258C.
Proposed Mechanism for Dihydrocarbazole Synthesis
The formation of dihydrocarbazoles is proposed to occur from
the addition and rearrangement of N-aryl nitrones and elec-
tron-deficient allenes as shown in Scheme 2a.[13] An initial
[3+2]-cycloaddition of nitrone 3a and allene 4a regioselective-
ly provides exomethylene isoxazolidine 14a, which then un-
dergoes a [3,3]-rearrangement to give benzazepine 5a.[14]
A
retro-aza-Michael addition followed by intramolecular conden-
sation of the resulting aniline 15a then affords dienyl indole
16a. This dienyl indole then undergoes a subsequent 6p-elec-
trocyclization or conjugate addition to ultimately provide dihy-
drocarbazole 1a after proton transfer.[15] We were able to vali-
date several of these proposed reactive intermediates by ex-
periment. First, during our optimization, a side product match-
ing the spectral features of benzazepine 5a was observed in
the absence of silica gel, and could be converted to 1a by sub-
sequent treatment with SiO2. Second, to support the interme-
diacy of dienyl indole 16a in the cascade sequence, we inde-
pendently synthesized N-Boc-protected dienyl indole 17. Upon
Scheme 3. Diastereoselective synthesis of dihydrocarbazoles.
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With a variety of new dihydrocarbazoles in hand, we decid-
ed to test their reactivity under simple reduction and oxidation
conditions. As shown in Scheme 4a, hydrogenation of dihydro-
carbazole 1a gave tetrahydrocarbazole 19 in good yield and
high diastereoselectivity. Oxidation of 1a was shown to be de-
pendent on reaction conditions (Scheme 4b). Treatment of 1a
with m-chloroperoxybenzoic acid (m-CPBA) resulted in cleav-
age of the electron-rich indole to form 20. In contrast, oxida-
tion with OsO4 and N-methylmorpholine-N-oxide (NMO) lead
to spirocyclic indolinone 21.[19] These transformations indicate
that not only can the a,b-unsaturated N-aryl nitrone addition
and rearrangement cascade provide rapid access to dihydro-
carbazoles from simple starting materials but that these prod-
ucts can be used as versatile synthetic intermediates.
Scheme 5. Potential bifurcated pathway for cascade reaction.
Table 5. Effect of solvent on the reaction of nitrone 3a with allenoate
4a.
Entry
Solvent
Yield [%][a]
1a:2a[b]
2a (trans/cis)[b]
1
2
3
4
5
6
7
8
9
PhMe
DCE
THF
MeCN
DMF
DMSO
iPrOH
EtOAc
iPrOAc
52
42
8
55
12
20
65
33
36
>20:1
>20:1
>20:1
15:1
7:1
3:1
–
–
–
3:1
2:1
2.2:1
2.5:1
1:1.6
1:1.2
Scheme 4. Functionalization of dihydrocarbazoles.
4:1
1:10[c]
1:10[c]
Single-Step Preparation of Pyrido[1,2-a]indoles from a,b-Un-
saturated N-Aryl Nitrones and Allenes
[a] % Isolated yield. Conditions: 3a (1 equiv), 4a (3 equiv), 0.1m, 808C,
18 h, sealed reaction vessel. [b] Determined by 1H NMR spectroscopy.
[c] Determined by isolation.
Upon further examination of the mechanism for dihydrocarba-
zole formation illustrated in Scheme 2, we became curious to
determine if the fragmentation of benzazepine 5 could be con-
trolled by changing the reaction conditions to favor an alterna-
tive pathway. In particular, we wanted to target a retro-Man-
nich reaction to produce imine 22, which could rearrange to
form different N-heterocyclic scaffolds (Scheme 5).[20,21] This
conjecture was explored by screening different solvents to
examine the impact on the outcome of the reaction between
nitrone 3a and allene 4a at 808C (Table 5). We observed that
in polar protic and polar aprotic reaction media the formation
of dihydropyrido[1,2-a]indole 2a competed with the synthesis
of dihydrocarbazole 1a (entries 4–7). The use of EtOAc and
iPrOAc strongly favored the formation of 2a, albeit with atte-
nuated yield and modest diastereoselectivity (entries 8–9).
These initial results showed that the cascade process could be di-
verted away from the generation of dihydrocarbazole and
toward the formation of dihydropyridoindole by simply changing
solvent selection.
tries 1–3). The combined effect of these two reagents was ad-
ditive (entry 4). Replacement of silica gel with substoichiomet-
ric additions of either p-toluenesulfonic acid or benzoic acid
proved detrimental to both the efficiency and the selectivity of
the process (entries 5–6). In contrast, the addition of 10 mol%
of thiourea 23 significantly increased the diastereoselectivity of
trans-2a formation (entry 7), and the addition of molecular
sieves with 23 further improved the yield of the reaction
(entry 8). Both the efficiency and selectivity of the process
were sensitive to the substituents of the thiourea catalyst: the
yield and the diastereoselectivity decreased when the more
electron-rich thiourea 24 was used (entry 9).[22] The trans/cis
ratio of 2a also does not change during the course of the reac-
tion under the reaction conditions described in entries 7 and 8.
Having identified optimal conditions for the preparation of di-
hydropyridoindole 2a, the scope of the reaction was next in-
vestigated to determine the generality of the process for the
efficient preparation of these important heterocycles.[23]
Once the outcome of the cascade process had been divert-
ed by changing the nature of the solvent, several additives
were screened to optimize both the yield and diastereoselec-
tivity of the synthesis of dihydropyridoindole 2a (Table 6). Mo-
lecular sieves were shown to increase the chemoselectivity of
the transformation, and silica gel was observed to increase the
yield as well as the trans/cis ratio of the desired product (en-
The scope of the nitrone component of the cascade process
for the preparation of dihydropyridoindoles 2 was similar to
the tolerance of the complimentary synthesis of dihydrocarba-
zoles 1.[24] As shown in Table 7, chalcone-derived nitrones with
a variety of electron-rich and electron-poor arene substituents,
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Table 6. Effect of additives on the synthesis of dihydropyridoindoles.
Table 7. Scope of nitrone reagent for dihydropyridoindole synthesis.
R1 (3)
R2 (3)
2 (Yield [%][a], d.r.[b]
)
Entry Additive
Yield [%][a] 1a/2a[b] 2a (trans/cis)[c]
Entry
1
2
3
4
5
6
none
MS
SiO2 (100 wt%)
SiO2 (100 wt%), MS
TsOH (20 mol%)
BzOH (20 mol%)
36
20
67
71
45
25
1:10
1:20
1:5
1:6
2:1
1:1.2
1.5:1
3:1
3.5:1
2.5:1
2.1:1
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a (77, >20:1)
2b (83, >20:1)
2c (68, 19:1)
2d (73, >20:1)
2e (80, 13:1)
2 f (82, >20:1)
2g (85, >20:1)
2h (72, 12:1)
2i (75, 15:1)
2j (78, >20:1)
2k (70, 12:1)
2l (71, 11:1)
2m (<10, n.d.)
hydrolysis
4-OMe(C6H4)
4-NO2(C6H4)
4-Br(C6H4)
3,5-Me2(C6H4)
2-OMe(C6H4)
Ph
1.5:1
4-OMe(C6H4)
4-CF3(C6H4)
4-Br(C6H4)
Ph
Ph
7[d]
69
1:13
15:1
9
4-Cl(C6H4)
2-furanyl
CH2=CH2Ph
Ph
Ph
Ph
10
11
12
13
14
Ph
(10 mol%)
CH2=CH2Ph
Me
H
8
9
77
48
1:10
1:13
16:1
5:1
[a] % Isolated yield. Conditions: 3a–3n (1 equiv), 4a (3 equiv), 23
(10 mol%), 4 ꢁ MS, 0.1m in iPrOAc, 808C, 18 h. [b] d.r.=trans/cis.
(10 mol%), MS
(10 mol%), MS
as in the corresponding dihydrocarbazole synthesis: nitrones
bearing ethereal-, thioethereal-, amino-, halo-, and alkyl groups
were smoothly converted to dihydropyridoindoles 2o–2v in
good yields (entries 1–7). The diastereoselectivity of the pro-
cess, however, varied with functional group and while the
trans/cis ratio for most of the dihydropyridoindole products
were >10:1, slight attenuation of diastereoselectivity was ob-
served with 4- thiomethyl- or 4-bromo-substituted nitrones
(entries 3 and 6). Arenes with electron-donating groups gave
consistently higher yields than those with electron-withdraw-
ing groups. Sterically-demanding meta-substituents had
a strong preference for a single regioisomer of the dihydropyri-
doindole, while electron-donating meta-substituents gave re-
gioisomeric mixtures (entries 8–9). The tolerance of the trans-
formation for halide and vinyl functional groups provides the
opportunity for further functionalization of products 2u and
2bb (entries 6 and 10). The reactivity trends observed for dihy-
dropyridoindole formation with various N-aryl nitrones are
analogous to those observed for the complimentary dihydro-
carbazole synthesis and suggest that this fragment of the ni-
trone plays a similar role in the formation of both 1 and 2.
The identity of the electron-withdrawing substituent on the
allene-component was next evaluated to further explore the
scope and limitations of dihydropyridoindole formation
(Table 9).[26] In comparison to the dihydrocarbazole synthesis,
we found that a similar range of allenoates could be exposed
to our optimal conditions to access dihydropyridoindoles
25–28 in good yield (entries 1–4). Even amide-substituted al-
lenes 4k and 4l smoothly afforded dihydropyridoindoles 29
and 30 (entries 5 and 6).[27] In contrast, dihydropyridoindoles
could not be formed from cyano-, thioester-, phosphoryl-, sul-
fonyl- or ketone-substituted allenes 4e–4i. The greater sensi-
tivity of dihydropyridoindole formation toward the allene com-
[a] % Isolated yield. Conditions: 3a (1 equiv), 4a (3 equiv), 0.1m in
iPrOAc, 808C, 18 h. [b] Determined by isolation. [c] Determined by
1H NMR spectroscopy. MS=4 ꢁ molecular sieves. [d] When run in PhMe:
51%, 1a/2a=1:10, trans/cis 15:1.
as well as heterocycles such as the furanyl-group in 3j,
smoothly underwent the desired transformation. Dihydropyri-
doindoles 2a–2j were isolated in good yields with high diaste-
reoselectivity—with most formed in excess of >20:1 (en-
tries 1–10). Dienyl nitrone 3k and dibenzylideneacetone-de-
rived nitrone 3l were also well-tolerated by the redirected cas-
cade reaction as illustrated by the efficient preparation of 2k
and 2l, respectively (entries 11–12). The dihydropyridoindole
substitution patterns provided by many of these reagents
allow for further functionalization of the products in analogy
to the dihydrocarbazole synthesis described in Table 2. Differ-
ences between the two solvent-controlled, divergent pathways
emerged when nitrones 3m and 3n were subjected to the
iPrOAc-mediated reaction conditions: 3m was converted to
the corresponding dihydrocarbazole 1m in low yield, while
submission of nitrone 3n to the reaction conditions led to the
isolation of hydrolysis products (entries 13–14). The data in
Table 7 clearly show the remarkable generality of the two di-
vergent cascade pathways to provide efficient and selective
access to a variety of dihydropyridoindoles 2 or dihydrocarba-
zoles 1 from identical nitrone and allenoate reagents.
The scope of dihydropyridoindole formation was next inves-
tigated by exposing a series of differentially substituted N-aryl
nitrones to the optimal reaction conditions (Table 8).[25] We
found that a similar range of N-aryl substituents were tolerated
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diastereoselective. As shown in Scheme 6, (À)-menthol alle-
noate 4m and (À)-oxazolidinone-substituted allene 4n were
tested to explore this possibility. Both reagents smoothly un-
derwent the addition and rearrangement cascade to provide
the corresponding dihydropyridoindoles trans-31 and trans-
32.[26] While reasonable stereoselectivity was observed using
the chiral, non-racemic menthol ester, oxazolidinone-substitut-
ed allene 4n afforded trans-32 with excellent diastereoselectiv-
ity. These transformations indicate that both the relative- and
absolute stereochemistry of dihydropyridoindole formation can
be controlled through the cascade process using oxazolidinone
chiral auxiliaries.
Table 8. Scope of N-aryl nitrone substituent for dihydropyridoindole syn-
thesis.
Entry
X, 3
2 (Yield [%][a], d.r.[b]
)
1
2
3
4
5
6
7
8
9
4-OMe, 3o
4-OBn, 3p
4-SMe, 3q
4-NMe2, 3r
H, 3s
2o (80, 10:1)
2p (83, 20:1)
2q (80, 8:1)
2r (77, 15:1)
2s (74, 13:1)
2u (61, 10:1)
2v (63, 13:1)
2w (79, 10:1)[c]
2x (65, 20:1)[d]
2bb (70, 14:1)
4-Br, 3u
3,5-Me2, 3v
3-OMe, 3w
3-tBu, 3x
4-vinyl, 3bb
10
[a] % Isolated yield. Conditions: 3o–3x, 3bb (1 equiv), 4a (3 equiv), 23
(10 mol%), 4 ꢁ MS, 0.1m in iPrOAc, 808C, 18 h. [b] d.r.=trans/cis. [c] re-
gioselectivity=3:1; 5-OMe:6-OMe. [d] regioselectivity= >20:1; 5-(tBu): 6-
(tBu).
ponent of the reaction mixture suggests that these electron-
withdrawing functionalities play a critical role in stabilizing or
destabilizing reactive intermediates in this cascade process.
While the tolerance of the allene component varies between
the optimal conditions for the preparation of 1 and 2, these
differences have provided some insight into the mechanistic
factors that control these transformations and provide a variety
of structurally distinct functionalized heterocycles that are
amenable to further synthetic elaboration.
Scheme 6. Synthesis of dihydropyridoindoles using allenes with chiral func-
tional groups.
Proposed Mechanism for Dihydropyridoindole Synthesis
Table 9. Scope of allene reagent for dihydropyridoindole synthesis.
A proposed mechanism for the preparation of dihydropyridoin-
dole 2a is shown in Scheme 7. Following a [3+2]-cycloaddition
of 3a and 4a and subsequent [3,3]-rearrangement of 14a to
give benzazepine 5a, a retro-Mannich reaction forms imine
22a.[20.21] This compound could then undergo a [4+2] cycload-
dition or a stepwise 1,4-addition of the b-ketoester enolate to
the a,b-unsaturated imine to give dihydropyridoindole 2a
after a subsequent elimination.[28] While electrocyclization or
conjugate addition of dienyl indole 16a at the N-position of
the indole could potentially afford 2a, this mechanism appears
unlikely because of the arrangement of the substituents in
products such as 2j–2l prepared from nitrones with distinct
functionalities at the R1 and R2 positions. If electrocyclization or
conjugate addition at the N-position of 16j–16l was occurring,
the connectivity of R1 and R2 would be reversed in these prod-
ucts. In an effort to observe some of the proposed intermedi-
ates along the reaction pathway, a solution of nitrone 3a was
treated with allenoate 4a at 258C. Analysis of this reaction
mixture by NMR spectroscopy after 2 h revealed a 3:1 mixture
of imine 22a and benzazepine 5a (Scheme 7b). Addition of
10 mol% thiourea 23 to this mixture produced a>10:1 mix-
ture of dihydropyridoindole 2a and dihydrocarbazole 1a—the
exact same ratio observed upon direct treatment of nitrone 3a
and allenoate 4a with thiourea 23 in iPrOAc.[29,30] This experi-
Entry
1
EWG
# (Yield [%][a], d.r.[b]
)
-CO2(tBu), 4b
25 (58, 10:1)
2
26 (79, >20:1)
27 (82, 13:1)
4c
3
4d
4
5
6
-CO2Ph, 4j
-C(O)NPh2, 4k
-C(O)N(allyl)Ph, 4l
28 (65, 11:1)
29 (64, 20:1)
30 (62, 20:1)
[a] % Isolated yield. Conditions: 3a (1 equiv), 4b–4d, 4j–4l (3 equiv), 23
(10 mol%), 4 ꢁ MS, 0.1m in iPrOAc, 808C, 18 h. [b] d.r. = trans/cis.
Asymmetric Synthesis of Dihydropyridoindoles
The sensitivity of dihydropyridoindole formation to the identity
of the electron-withdrawing group on the allene prompted us
to investigate chiral auxiliaries to render our cascade reaction
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ment suggested: (1) that both benzazepine 5a and imine 22a
are intermediates along the reaction pathway to 2a; and (2)
that thiourea catalyst 23 is required for the conversion of the
imine-intermediate to the product but not required for the
preparation of imine 22a.
Scheme 8. Solvent-controlled, bifurcated cascade process for the synthesis
of dihydrocarbazoles and dihydropyridoindoles.
residue was purified by medium pressure chromatography (1:20 to
1:5 ethyl acetate/hexanes) to give 1 as a yellow oil or solid.
General procedure for the synthesis of dihydropyridoindoles 2:
A
Teflon-sealed reaction flask was charged with nitrone 3
(1.0 equiv), thiourea 23 (10 mol%), and 4 ꢁ molecular sieves
(0.200 g). The flask was then flushed onto a Schlenk line, and
placed under N2 with a needle and a septum. A scintillation vial
was charged with allene 4 (3.0 equiv) and placed under N2 with
a needle and a septum. The allene was then diluted with iPrOAc to
form a 0.1m solution which was transferred to the reaction flask
containing the nitrone via syringe. The reaction flask was then
sealed with a Teflon cap and stirred at 258C for 1 min. The reaction
mixture was then heated to 808C for 18–24 h. At this time, the sol-
vent was removed from the reaction mixture under vacuum and
the residue was purified by medium pressure chromatography
(1:50 to 1:10 ethyl acetate/hexanes) to give 2 as a yellow oil or
solid.
Scheme 7. Proposed mechanism for dihydropyridoindole synthesis.
Conclusion
We have identified a new cascade process for the addition and
rearrangement of N-aryl-a,b,-unsaturated nitrones and allenes
that can be bifurcated by a simple change in solvent to access
either dihydrocarbazoles 1 or dihydropyridoindoles 2 in high
yield and with high diastereoselectivity (Scheme 8). This mild
and metal-free, transformation provides rapid access to two
indole-based heterocycles from identical starting materials.[31]
This reaction also represents a new approach to the develop-
ment of divergent processes by targeting the bifurcation of
a cascade pathway that hinges on a key benzazepine fragmen-
tation event. Ongoing work in our laboratory is aimed at de-
veloping a better understanding of this transformation and ac-
cessing other alternative cascade pathways through solvent,
additive, and catalyst effects.
Acknowledgements
We gratefully acknowledge generous funding from ACS-PRF
(DNI 50491), NSF (NSF-CHE 1212895), and UIC. We would like
to thank Professor T. G. Driver (UIC) for insightful discussions
and chemicals and Mr. Furong Sun (UIUC) for mass spectrome-
try data.
Keywords: Cascade
dihydropyridoindole · nitrone · solvent effect
reaction
·
dihydrocarbazole
·
Experimental Section
General procedure for the synthesis of dihydrocarbazoles 1: A
Teflon-sealed reaction flask was charged with SiO2 (0.200 g), flush-
ed onto a Schlenk line, and placed under N2 with a needle and
a septum. A scintillation vial was charged with nitrone 3 (1.0 equiv)
and allene 4 (3.0 equiv) and placed under N2 with a needle and
a septum. The nitrone and allene mixture was then diluted with
toluene to form a 0.1m solution. This solution was transferred to
the reaction flask via syringe. The reaction flask was then sealed
with a Teflon cap and stirred at 258C for 5 min. The reaction mix-
ture was then heated to 808C for 18–24 h. At this time, the solvent
was removed from the reaction mixture under vacuum and the
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cating that the 2:1 ratios for all of these reactions were greater than or
equal to 10:1.
[25] Less than 5% 1o–1x, 1bb were separated during purification of 2o–
2x, 2bb indicating that the 2:1 ratios for all of these reactions were
greater than or equal to 10:1.
[26] Less than 5% 6–8 were separated during purification of 25–27 and less
than 5% of the corresponding dihydrocarbazoles were separated from
28–32 indicating that the 2:1 ratios for all of these reactions were
greater than or equal to 10:1.
[27] Irrespective of the reaction media, amide substitution on the allene
strongly favors the formation of dihydropyridoindoles, and mixtures of
1 and 2 were even observed when these reagents were subjected to
toluene-mediated reaction conditions previously optimized for dihydro-
carbazole synthesis.
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[29] Allene 4a (2 equiv) was also added to the mixture of 22a and 5a that
was heated to give 2a and 1a to remain consistent with the optimized
reaction conditions which use an excess of allene 4a.
[30] When the mixture of 22a and 5a were heated in the absence of 23,
analogous results to those described in Table 5, entry 9 were observed.
[31] Dihydrocarbazoles 1 and dihydropyridoindoles 2 have been stored for
more than 6 months at À408C with no change in the 1H NMR spec-
trum. Dihydrocarbazoles 1 that have been prepared from ketone-de-
rived nitrones are stable in air at 258C and only begin to oxidize slowly
to the corresponding carbazoles at higher temperatures (5–10% after
18 h at 808C). Dihydrocarbazoles 1 that have been prepared from alde-
hyde-derived nitrones are stable at À408C but slowly oxidize at 258C
in air and more quickly at higher temperatures (~50% after 18 h at
808C). Dihydropyridoindoles 2 show no sign of oxidation when heated
in air for 18 h at 808C.
Received: April 26, 2014
Published online on August 28, 2014
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim