Copper-Catalyzed Annulation of Indolyl α-Diazocarbonyl Compounds Leads to Structurally Rearranged Carbazoles

Article abstract of DOI:10.1021/acs.orglett.1c01965

Indolyl α-diazocarbonyl compounds have proven to be effective starting materials for the construction of various 2,3-ring fused indole frameworks. Activation of the diazo functional group under metal catalysis generates a spiro-cyclic indolenine-type intermediate which rearranges to provide two distinct carbazoles upon oxidation. The current study investigates the effects of the catalyst as well as the substituents on the migratory group involved in controlling the selectivity of the rearrangement.

Full text of DOI:10.1021/acs.orglett.1c01965

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Letter
Copper-Catalyzed Annulation of Indolyl α‑Diazocarbonyl
Compounds Leads to Structurally Rearranged Carbazoles
Sima Alavi, Jian-Bin Lin, and Huck K. Grover*
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ABSTRACT: Indolyl α-diazocarbonyl compounds have proven to
be effective starting materials for the construction of various 2,3-
ring fused indole frameworks. Activation of the diazo functional
group under metal catalysis generates a spiro-cyclic indolenine-type
intermediate which rearranges to provide two distinct carbazoles
upon oxidation. The current study investigates the effects of the
catalyst as well as the substituents on the migratory group involved
in controlling the selectivity of the rearrangement.
rearrangement from their corresponding starting materials (1
→ 4). Such transformations are synthetically useful in
accessing indole architecture that would be challenging to
synthesize by alternative strategies.3
he construction of 2,3-ring fused indoles via the
Tintramolecular C2−H functionalization has become a
well-established approach in the synthesis of complex indole-
containing molecules.1 Of considerable interest are such
annulation reactions which occur via a Wagner−Meerwein-
like 1,2-shift from a spiro-cyclic 3,3-disubstituted indolenine
intermediate (Scheme 1A).2 When selectivity over the
migratory group is controlled during the 1,2-shift, the power
of this transformation is revealed by providing access to 2,3-
ring fused indole variants which have undergone a structural
The utilization of indolyl α-diazocarbonyl compounds as
precursors to annulated indole products has previously been
established in the literature.4 In 2013 and 2018, the groups of
Doyle4d and Balamurugan4g independently showed the
annulation of indole 5 could be achieved in high yields
under Rh(II) catalysis (Scheme 1B). The dihydrocarbazole
products (6/7) obtained from these reactions are a result of a
net carbon−carbon bond formation between the indole C2
position and the diazo carbon. Conceivably, this new bond
could form via (i) a direct C2−H functionalization of the
indole and the metal carbenoid,5 (ii) the formation of a spiro-
cyclic indolenine intermediate followed by a selective 1,2-shift,
or (iii) through the formation of a cyclopropane-type
intermediate6 which, upon ring opening, would deliver the
2,3-fused indole product. While several reports have indicated
support for the formation of an indolenine intermediate in this
type of transformation,4a,b,e the skeletal rearranged 2,3-ring
fused isomers have not been isolated.
Scheme 1. Annulation Reactions of Indolyl α-Diazocarbonyl
Compounds
In 2017, Taylor and Unsworth disclosed that by varying the
catalyst/reaction conditions, six unique products could
selectively be prepared from the annulation of related indole
starting material 8, including carbazole 10 which was formed
under copper catalysis in the presence of an oxygen
atmosphere (Scheme 1C).4e Inspired by these previous studies
Received: June 13, 2021
Published: July 1, 2021
https://doi.org/10.1021/acs.orglett.1c01965
© 2021 American Chemical Society
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Table 1. Reaction Optimization
a
entry
catalysts
additive
solvent
temp (time)
13a:14a (yield)
b
c
1
2
3
4
5
6
7
8
Sc(OTf)3
In(OTf)3
air
air
air
N2
O2
O2
air
air
toluene
toluene
toluene
toluene
toluene
CHCl3
reflux (12 h)
80 °C (12 h)
reflux (12 h)
80 °C (4 h)
80 °C (1.25 h)
50 °C (30 h)
80 °C (1 h)
80 °C (3 h)
80 °C (6 h)
80 °C (3 h)
80 °C (1.5 h)
2.0:1.0
1.0:1.0
b
c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(ClO4)2 (hexahydrate)
Cu(ClO4)2 (hexahydrate)
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
1.0:1.2 (91%)
d
d
d
e
trace
1.1:1.0 (66%)
1.1:1.0 (47%)
3.0:1.0 (74%)
1.7:1.0 (56%)
toluene/EtOAc
EtOAc
toluene
toluene
toluene
d
c
9
10
11
NaClO4/N2
Bu4N(ClO4)/N2
Bu4N(ClO4)/air
1.0:1.0
2.5:1.0 (90%)
2.6:1.0 (78%)
a
b
c
d
e
1
Combined yield of 13a/14a. 15 mol % catalyst. Ratio determined by H NMR. 1 atm. Trace amounts of 13a/14a were present among an
intractable mixture of nonoxidized annulation products.
and motivated to develop and control rearrangement reactions
for indole derivatives, we began investigations into the
reactivity of indolyl α-diazocarbonyl compounds 11, with the
aim of accessing structurally rearranged annulation isomers
(13) that have not been identified in the previous reports4d
(Scheme 1D vs 1B).
(NMR analysis); however, several limiting factors impeded its
wider adoption in this project. Due to solubility problems of
this particular catalyst, the reaction required a mixture of
toluene and a polar solvent (ethyl acetate was the most
efficient) to proceed. Unfortunately, product isomer 13a
appears to be unstable under these conditions, a fact that is
indicated by entry 8, where we hypothesize that the decreased
yield and selectivity observed in this reaction are attributed to
facile decomposition of 13a. To overcome these limitations, we
proposed generating the copper(II) perchlorate in situ from
the anhydrous copper(II) triflate with a perchlorate salt
additive.10 The use of sodium perchlorate as an additive had
little influence on the selectivity of the reaction, leading to an
equal mixture of 13a and 14a (entry 9). The lack of selectivity
in this reaction is possibly due to the low solubility of this salt
in toluene, and thus, switching to the more soluble
tetrabutylammonium perchlorate salt re-established the high
90% yield and selectivity, forming 13a as the major product
(entry 10). Importantly, it appears that the perchlorate additive
not only influences the selectivity of the annulation reaction
but also acts as an efficient oxidant, providing the carbazole
products in 3 h while under an inert atmosphere. Further
attempts to optimize the reaction using increased perchlorate
loadings or reactions open to air resulted in slightly lower
yields (entry 11).
Satisfied with the copper(II) triflate/tetrabutylammonium
perchlorate reaction conditions, we sought to evaluate the
influence of substitution on both the migratory group and the
indole (Scheme 2). A series of experiments were first
performed in which starting materials containing varying
electronic substituents installed on the para-position of the aryl
migratory group were subjected to the annulation conditions
(Scheme 2A).
Analyzing these results showed a clear correlation between
the electronic property of the substituent and the selectivity of
the annulation, with the migratory aptitude increasing for
electron-donating groups (EDGs). In fact, the (p-OMe)-
phenyl-indole analog 11b undergoes annulation with complete
selectivity, exclusively providing carbazole isomer 13b in 75%
yield. In contrast, when a strong electron-withdrawing group
The study commenced by treating indole 11a4d with a series
of Lewis acid catalysts (Table 1). The use of scandium(III)
triflate as a catalyst7 proved effective in activating the starting
material and provided a 2:1 mixture of carbazole isomers
(13a:14a, entry 1). Although only small quantities of these
compounds were isolated, the formation of rearranged
carbazole 13a as the major isomer directly contrasts the
results obtained in the previous studies using rhodium as a
catalyst (Scheme 1B),4d and potentially indicated that the
selectivity of this annulation may be controlled by varying the
catalyst system. While many other metal catalysts evaluated
gave only low yields (<5%) of the desired carbazoles with little
to no selectivity (e.g., entry 2),8 the first substantial result was
observed when copper9 was employed as the catalyst (entries
3−11).
Treatment of 11a with copper(II) triflate in toluene at reflux
provided a 91% combined yield of carbazoles 13a and 14a in a
1.0:1.2 ratio, respectively (entry 3). Presumably, the copper
catalyst serves a dual purpose in the transformation first by
activating the diazocarbonyl moiety and then by aiding the
oxidation of the incipient dihydrocarbazole intermediate when
in the presence of advantageous oxygen from the atmosphere.
The utilization of air as an oxidant source in these initial
experiments was shown to be essential in order to obtain high
yields of the carbazoles. Reactions performed under inert
atmospheres (entry 4) furnished primarily nonoxidized
products, whereas reactions under oxygen (entry 5/6) suffered
from significantly decreased yields, presumably due to
oxidative decomposition of the products 13a/14a.
Through a screen of various copper reagents, copper(II)
perchlorate was identified as a promising catalyst, providing a
3:1 mixture of 13a:14a in a 74% yield (entry 7). This catalyst
system worked effectively with 11a such that when increased
copper loadings were used, selectivity up to 10:1 was observed
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a
N−H carbazole 14m. Divergent from the N-alkylated indoles,
when the indole nitrogen is substituted with a strong EWG
(11n)12 or a weak inductively withdrawing aryl group (11l), a
complete reversal of annulation selectivity is observed.
However, the most exaggerated effect on selectivity was
observed when the nitrogen is not substituted (11m),
providing carbazoles 13m and 14m in a 1.0:2.8 ratio. This
outcome may be due to the slight differences in nucleophilicity
between the indoles or the stability of the 3,3-disubstituted
indolenine intermediates (12, R = H vs Me) formed on the
path to each product (see Scheme 1D).
Scheme 2. Effect of Substitution on the Annulation
Although 14m is isolated as the major carbazole isomer from
the reaction of 11m, some valuable insights can be made about
the catalyst system. For instance, the formation of 13m as a
competing isomer in this experiment lends to the importance
of the new catalyst/reaction conditions in promoting the
rearrangement, a fact that is amplified when 11m is subjected
to the same reaction conditions without the perchlorate
additive, providing increased amounts of 14m (13m:14m,
1.0:4.5). Additionally, as shown previously by Doyle (Scheme
1B),4d when 11m is subjected to rhodium conditions,
compound 6 (enroute to 14m) is isolated with complete
selectivity, results that again highlight the role of the new
catalyst system in the rearrangement.
Having achieved complete control over the selectivity of the
annulation when the migratory group contained a methoxy
substituent, decreased selectivity when the benzenoid ring of
indole was substituted, and opposite selectivity when the
indole nitrogen is not substituted (N-H), we decided to
explore crossover type experiments to determine which
substitution location had the greatest effect on the selectivity
of the annulation (Scheme 3A). When the aryl migratory
group is substituted with an electron-donating group, the
selectivity of the annulation is highly biased to the rearranged
product, regardless of the benzenoid ring substitution, as
indicated by the isolation of 13o, 13p, and 13s as the sole or
major isomer of the annulation. In parallel crossover type
experiments, when the aryl migratory group is substituted with
a weak electron-withdrawing bromo-substituent (13q:14q and
13r:14r), a similar decrease in selectivity was observed to that
of the reaction of indole 11d, containing the same para-bromo-
substitutent on the aryl migratory group. Overall, the results
from these experiments indicated that the migratory group has
a larger effect on selectivity than the bezenoid substitution,
when the indole nitrogen is methyl substituted. A final
crossover type experiment was completed using indole 11t,
containing both indole N-H substitution and a (p-OMe)phenyl
migratory group. Interestingly, although rearranged isomer 13t
was still isolated as the major compound, this experiment
displayed a significant decrease in selectivity (1.6:1.0), once
again indicating the importance of N-substitution in the
selectivity of the annulation.
a
Yields represent the combined isolated yield of the two separable
b
c
isomers. Reaction without Bu4N(ClO4) = 1.0:4.5 (13m:14m). std =
standard reaction conditions.
(EWG), such as NO2 (11e), is installed on the starting
material, the annulation affords 14e in a slight excess along
with 13e in a 1.6:1.0 ratio respectively. These trends showcase
the importance of the migratory group on the selectivity of the
annulation.
Next, we examined the effect of substitution on the
benzenoid ring of the indole (Scheme 2B). While it appears
that substitution at this position of the starting material has
little effect on the yield of the annulation (75−87%), the
selectivity does decrease significantly in comparison to the
model substrate (11a), with the largest effects being observed
for C6-substituted indole substrates. This trend is most
noticeable by comparing the reaction of 11a, which provides
a 2.5:1.0 mixture of 13a:14a, and the reaction of 11i, which
provides a nearly equal mixture of 13i:14i (1.1:1.0). The one
outlier of this trend is the C6-NO2 substituted starting material
11j which, under the annulation conditions, furnishes 13j:14j
in a 2.3:1.0 ratio, nearly the same selectivity as 11a. Although it
is known in the literature that benzenoid substitution on indole
can display some influence in diazo-insertion reactions,11 the
reason for this decrease in selectivity is currently unclear, and
thus, these results certainly warrant further investigation.
One of the most profound influences over the annulation
selectivity observed in our study was due to the substitution on
the indole nitrogen (Scheme 2C). N-Alkylated indoles
underwent annulations with high selectivity favoring 13, with
N-benzyl substitution giving the highest selectivity (4.4:1.0,
13k:14m). Interestingly, the minor isomer isolated from this
reaction has undergone a benzyl group deprotection leading to
Intrigued by the high selectivity obtained with 11b, we next
evaluated the tolerance of other electron-rich ring systems to
our annulation conditions (Scheme 3B). (o-Me)Phenyl-indole
11u provided similar outcomes to the para-analog, delivering
13u as the major isomer with 3.1:1.0 selectivity. When the aryl
group is adorned with both methoxy and bromine substituents,
there is a noticeable decrease in selectivity; however, 13v is still
formed as the major isomer (4.2:1) in a moderate overall yield
of 73%. Two different dimethoxyphenyl-indoles (11w and
11x) underwent the annulation with variable success. We
believe the lower yields and decreased selectivity in these
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a
successfully underwent cyclization to afford 13y as the only
isomer in 31% yield, with the low yield attributed to the
relatively poor stability of the product and not necessarily
byproduct formation.
Scheme 3. Reaction Substrate Scope
Throughout this study, many notable byproducts were
identified and control experiments were performed to shed
light on the yields and importance of the catalyst (Scheme 4).
During several experiments, when the aryl migratory group was
substituted with an EDG, a complex mixture of unknown
compounds was isolated in addition to the desired carbazoles.
Attempts to separate and analyze these mixtures were met with
extreme difficulty, except in one case: the reaction of 11c
(Scheme 4A). In addition to carbazoles 13c and 14c, two
naphthalene products 15a and 15b were also isolated from this
reaction. It appears that the aryl ring interacts with the diazo
carbon instead of the indole, providing proposed spirocyclic
intermediate A.13 A similar result was noted by Doyle and co-
workers which furnished an indole-substituted dihydronap-
thalene.4d However, in contrast to Doyle’s work with rhodium,
under these copper-catalyzed conditions, elimination of indole
(recovered from the reaction) occurs to provide a mixture of
15a and 15b.14
In addition to the formation of naphthalene products, a third
carbazole isomer (e.g., 16) was also identified in the complex
byproduct mixtures of several annulation reactions. Analytically
pure 16 was isolated upon prolonged heating of 11a with
scandium(III) triflate open to air (Scheme 4B) and represents
a carbazole that likely arises via a Wolff type rearrangement15
similar to that reported by Taylor and Unsworth.4e While this
isomer is only formed in small quantities (if at all) under the
copper-catalyzed annulations conditions, its presence as a
major carbazole isomer under scandium catalysis is interesting
as there may be the potential to design reaction conditions that
are selective for the formation of this isomer.
Finally, to probe the importance of the catalyst on the
selectivity of the annulation reaction, a control experiment with
11b was performed using the annulation conditions developed
by Doyle (Scheme 4C).4d Treatment of 11b with rhodium
followed by oxidation delivered 13b and 14b as a 5:1 mixture,
which represents a significant decrease in selectivity when
compared to the copper catalyzed conditions. Although this
reaction sequence cannot be directly compared to copper
conditions (different solvents and temperatures), this result
indicates that while the nature of the migratory group is very
important, the catalyst also plays an impactful role in
controlling selectivity.
a
Yields represent the combined isolated yield of the two separable
b
isomers. Minor isomer was observed in trace quantities by crude
reaction H NMR; however, it could not be isolated.
1
examples are a result of competitive reaction pathways
involving the aryl ring, leading to undesired products (see
Scheme 4A). Finally, a furan-substituted indole (11y)
Scheme 4. Notable Byproducts and Control Experiments
In summary, a general copper-catalyzed ring-forming skeletal
rearrangement of indolyl α-diazocarbonyl compounds has been
developed. The current method provides access to a myriad of
highly decorated carbazoles, in good to excellent yields, with
serviceable to exceptional annulation selectivity. A variety of
important factors have been observed that contribute to the
selectivity of the reaction, including catalyst, migratory group
substitution, and indole nitrogen substitution. Future inves-
tigations into the role of the counteranion and solvent, along
with computational analysis of the annulation, are ongoing to
help fully characterize the selectivity of the transformation.
ASSOCIATED CONTENT
■
sı
* Supporting Information
a
b
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01965.
std = standard reaction conditions. Isolated with 13a (19%) and
14a (11%).
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Accession Codes
CCDC 2081553−2081554 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Huck K. Grover − Department of Chemistry, Memorial
University of Newfoundland, St. John’s, Newfoundland A1B
3X7, Canada; orcid.org/0000-0003-3471-678X;
Email: hgrover@mun.ca
Authors
Sima Alavi − Department of Chemistry, Memorial University
of Newfoundland, St. John’s, Newfoundland A1B 3X7,
Canada
Jian-Bin Lin − -CART, CREAIT Network, Memorial
University of Newfoundland, St. John’s, Newfoundland A1B
3X7, Canada
(5) The mechanism was not explored in these papers and may
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(8) For full optimization results, see the Supporting Information.
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(10) Please note that while we did not encounter any problems with
the reactions, several copper perchlorate reagents are known to be
explosive and care should be taken when running these reactions. All
reactions were quenched with water upon completion.
(11) For select diazocarbonyl reactions with indole, see:
(a) Tsyshchuk, I. E.; Vorobyeva, D. V.; Peregudov, A. S.; Osipov,
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(12) Note that under the current reaction conditions, the Boc group
is cleaved to provide N−H substituted carbazole products.
(13) Clarke, A. K.; Unsworth, W. P.; Taylor, R. J. K. Tetrahedron
2018, 74, 5374−5382.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01965
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) and Memorial University for
funding (H.K.G.). We are also grateful to Dr. C. Schneider
(MUN) and Dr. S. Egli (MUN) for the assistance with NMR
and mass spectrometry.
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