Coupling cyclizations with fragmentations for the preparation of heteroaromatics: Quinolines from o-alkenyl arylisocyanides and boronic acids

Article abstract of DOI:10.1039/c5cc04391c

Stereoelectronic restrictions on homoallylic ring expansion in alkyne cascades can be overcome by using alkenes as synthetic equivalents of alkynes in reaction cascades that are terminated by C-C bond fragmentation. Implementation of this approach using Mn(iii)-mediated reaction of o-alkenyl isocyanides and boronic acids leads to efficient synthesis of substituted quinolines.

Full text of DOI:10.1039/c5cc04391c

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DOI: 10.1039/C5CC04391C
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Coupling cyclizations with fragmentations for the preparation of
heteroaromatics: quinolines from o-alkenyl arylisocyanides and
boronic acids
Received 00th January 20xx,
Accepted 00th January 20xx
Christopher J. Evoniuk, Michelle Ly and Igor V. Alabugin*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Stereoelectronic restrictions on homoallylic ring expansion in endo-trig cyclization of o-alkenyl arylisonitriles. We will show
alkyne cascades can be overcome by using alkenes as synthetic that it overcomes limitations faced by the analogous radical
equivalents of alkynes in reaction cascades that are terminated by alkyne cyclizations5 where mostly the 5-exo-dig closure was
C-C bond fragmentation. Implementation of this approach using observed (with a single exception6).
Mn(III)-mediated reaction of o-alkenyl isocyanides and boronic
acids lead to efficient synthesis of substituted quinolines.
Undeterred by the earlier literature reports of 5-exo
preference in radical cyclizations of o-alkenyl arylisocyanides,7
we took advantage of our recent finding that 5-exo/6-endo-
trig completion in similar all-carbon systems can be controlled
by alkene substitution (Scheme 1) and, for R=alkyl, the formal
6-endo products are formed efficiently and can aromatize to
Due to the ubiquity of alkenes and alkynes, control of their
cyclization reactions has fundamental importance for organic
chemistry. In particular, alkynes serve as a high energy,
carbon-rich starting point for the atom-economical access to
conjugated molecules and materials.1 In this context, the 6-
endo-dig cyclization of alkynes provides an attractive direct
route to aromatics (Fig. 1). Unfortunately, the effective
implementation of the radical version of this process still poses
an unresolved challenge due to the competition with the
stereoelectronically favorable 5-exo-dig ring closures.2 The
selectivity problem is exacerbated for alkynes where the
products of exo-cyclizations cannot be “recycled” in the 6-
endo-products via homoallylic ring expansion, a process which
is well-documented in alkene chemistry (Fig. 1, right).3 Such
expansion is impossible in alkyne chemistry because the vinyl
radicals produced in exo-dig cyclizations are constrained to

-Sn naphthalenes via C-C bond scission in situ.4,3
The results below indicate that conjugating substituents at
the alkene terminus should be avoided and that presence of
an appropriate fragmenting group is needed for aromatization
into the quinoline product.
orthogonality relative to the target 
-system (Fig. 1, left).4
An innovative solution to the design of formal endo-dig
radical cyclizations of alkynes involves combination of endo-
trig cyclizations of alkenes with fragmentations. Alkenes
undergo homoallylic expansion readily and, even though the
products of alkene cyclizations are not fully conjugated, a C-Z
bond scission in the initial product can lead to aromatization
(Fig. 1, top) that provides the formal 6-endo-dig product.3 This
cascade illustrates how alkenes can be used as
stereoelectronically flexible synthetic analogues of alkynes.
In this work, we describe the first application of such
concept to the synthesis of heterocycles based on radical 6-
Fig.
1 Left: Stereoelectronic restriction on the 5-exo-dig  6-endo-dig
homoallylic ring expansion. Right: “Recycling” of 5-exo-trig products into 6-endo-
trig products via homoallylic ring expansion.
Department of Chemistry and Biochemistry,
Florida State University, Tallahassee, Florida
32306-4390. E-mail: alabugin@chem.fsu.edu
† Electronic supplementary information (ESI)
available: Experimental procedures and
characterization data for new compounds. For
ESI see DOI: 10.1039/x0xx00000x
Scheme 1. Alkene substitution controls regioselectivity in enyne cyclizations5,7
and enables endo-trig/fragmentation cascades
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When choosing the suitable leaving group, we took Table 1. Optimization of reaction conditions
advantage of our earlier findings that both alkoxy and phenyl
groups can provide adequate stabilization to the fragmenting
radical in the carbon systems in Scheme 1.3,5
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DOI: 10.1039/C5CC04391C
The isocyanide substrates with a pendant alkene can be
Entry
Oxidant
Equiv
Solvent
Temp
◦C
90
90
90
Reflux
rt
50
Yield
%
prepared via several synthetic pathways (Scheme 2). We have
demonstrated that the routes based on Suzuki, Heck and
Wittig couplings provide the target isocyanides in good yields.
For the Suzuki/Heck routes to the corresponding isocyanide,
the overall scheme consists of three steps – a) formylation of
the starting aniline, b) Pd catalyzed coupling with an alkene,
b
1
2
3
5
6
7
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(OAc)3
∙2H2O
1
2
3
3
3
3
3
C7H8
C7H8
C7H8
C7H8
C7H8
C7H8
17
64
86
82
0
and c) amide
 isocyanide conversion. The Wittig route
59
consisted of four steps that included the installation of
pendant alkene via the Wittig reaction followed by functional
group manipulations that transform the nitro group into
isocyanide (Scheme 2, see SI section for full experimental
details). The largest difference between the Suzuki/Heck and
the Wittig routes is that the latter provides the target alkenes
as a mixture of Z and E isomers whereas only the E isomer is
formed with the Suzuki/Heck routes. In our case, no significant
difference in yield was observed when an E/Z mixture was
used instead of the pure E-isomer.
With substrates in hand, and the knowledge that -CH2Ph, -
CH2OMe groups can facilitate the desired radical
fragmentation pathway, we focused our efforts on expanding
the utility of these substrates. In the initial attempts, the
PhCH2-substituted alkene did not form the target quinolines in
the presence of radical species. Interestingly, use of
Bu3SnH/AIBN conditions leads to a mixture with predominately
5-exo product formation. This suggests that the steric bulk of
SnBu3 and/or fast H-abstraction can terminate the cascade
prematurely. In search of an alternative, we turned to
organoboron reagents that provide an increasingly popular
choice as radical precursors.8 The synthetic value of this
approach is amplified by the large number of commercially
available boronic acids. An additional advantage of such
compounds (e.g., RB(OH)2) is that the oxidative approach to
their activation via the assistance of mild oxidants such as
Mn(III) allows potential fine-tuning of the oxidation state of
the cyclizing species.
8
C7H8
90
67
9
10
Mn(OAc)2
Cu(OAc)2
AgNO3/
3
3
C7H8
C7H8
DCM/
H2O
MeCN
C6H6
DMF
90
90
0
0
0.2/3
11
90
0
Na2S2O8
12
13
14
Mn(acac)3
Mn(acac)3
Mn(acac)3
3
3
3
Reflux
Reflux
90
79
84
trace
Reaction conditions: Isocyanide (0.1 mmol), boronic acid (1.5 equiv),
specified amount of oxidant in 3 mL of solvent. Reactions were allowed to
stir for 4 hours, with exception of r.t. reaction that was allowed to react for
24 hours. aNMR yield based on 1a
.
The Bn substituted alkene 1a provided higher conversions than
its -CH2OMe analogue 1b (Table 2) and was chosen for the
further optimization.
The screening process is depicted in Table 1. The use of 1.5
boronic acid equivalents with 3 equivalents of Mn(III) in
toluene at 90oC provided the best results, in agreement with
the literature data on the cyclizations of biphenyl
isocyanides.15 Slight excess of organoboron species was used
to compensate for partial radical dimerization. Moderately
elevated temperatures were required to reach the full
conversion (entries 3, 6, 7). Along with Mn(III), several other
oxidants were screened. With the optimized conditions, we set
forth to better understand the scope and limitation of the new
reaction.
Substrate scope was further evaluated by incorporating a
variety of different pendant groups at the alkene moiety (Table
2). It was observed that only the -CH2OMe, and -CH2Ph groups
selectively afforded the 6-endo/fragmentation product
(mechanism shown in Scheme 3).
To our delight, both the -CH2Ph, and -CH2OMe substrates
selectively
underwent
the
desired
6-endo
cyclization/fragmentation sequence.9
The slightly higher yields observed for the -CH2Ph group are
consistent with the stabilities of the fragmenting radicals
(Bn>CH2OR>alkyl).3,9 On the other hand,
a structurally
constrained substrate (1c in Table 2) yielded only the 6-endo
product without fragmentation (mechanism shown in Scheme
4). A switch in regioselectivity was observed for a phenyl
substituted alkene where exclusive formation of a 5-exo
product was observed. Presumably, when the radical formed
upon 5-exo cyclization is stabilized by benzylic resonance, this
stabilization deactivates this species towards the further
rearrangement.3,10
An interesting result was obtained for an alkyl substituent
(propyl), which should not prevent the ring expansion of the
Scheme 2. Synthesis of o-alkenyl isocyanide substrates
2 | Chem. Commun., 2015, 00, 1-3
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Table 2. Optimization of pendant alkene moiety
Table 3. Scope of boronic acids
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DOI: 10.1039/C5CC04391C
[a] Yield of isolated product from starting materials. [b] 3 equivalents of boronic
acid was used.
Reaction conditions: Isocyanide (0.1mmol), boronic acid (1.5 equiv),
Mn(acac)3 (3 equiv), and toluene (3 mL) were heated at 90◦C for 4 hours.
Complete conversion was observed in all cases. aIsolated yield. bNMR yield
based on starting material. cProduct yield of isolated major product with
trace components identified as mixture of product Q1 and other six
member cycles.
5-exo-radical but cannot provide stabilization to the
fragmentation step.The major observed product was the 5-exo
indole product Q4, along with 8% of the desired quinoline Q1
(Table 2).
The scope of reaction is quite broad, and a variety of
functional groups was tolerated (Table 3). High yields were
observed for both donor and acceptors. The importance of >2-
fold excess of the oxidant for achieving the full conversion
suggests the possibility of further one-electron oxidation of the
intermediate radical(s). A similar possibility was suggested for
the Mn(III)/RB(OH)2-mediated cyclization of biphenyl
isocyanides where one-electron oxidation by the second
equivalent of Mn(III) generates a cationic intermediate that
undergoes a proton loss to rearomatize in the products.11 We
Scheme 3 Proposed radical pathway for 6-endo/5-exo product formation.
place without deleterious effects in the presence of added
nucleophiles. In fact, when the 4:1 CH3CN/H2O solvent mixture
was used to trap the cationic species, the yield was slightly
improved over the reaction in dry CH3CN (79% vs. 84%).
The combination of available experimental data suggests
the following mechanistic picture (Scheme 3). The reaction is
initiated by an aryl radical formed in the reaction of Mn(III) and
the boronic acid. The regioselective intermolecular addition
generates iminoyl radical A1 capable of following the reaction
routes outlined in Scheme 3. The formal 6-endo-product Q1
may be produced via homoallylic ring expansion of the initially
have considered
a similar cationic mechanism in our
system.12,13 However, additional experimental studies did not
support the cationic pathway. For example, the introduction of
nucleophilic species into the reaction mixture did not trap any
of the putative intermediate cations or the fragmented benzyl
cation. In particular, we did not detect formation of the
respective ethers in the presence of alcohols (MeOH, BnOH)
and diisopropyl benzyl amine in the presence of i-Pr2NH.
Similarly, no N-benzylacetamide was formed in the presence of
CH3CN/H2O, where nucleophilic trapping of the cation could be
provided by acetonitrile. Instead, the full reaction cascade took
formed 5-exo-trig radical A2 3
. Such expansion would be
impossible for alkynyl systems but becomes possible when
alkenes are used as synthetic equivalents of alkynes in radical
transformations. The 6-endo product formation via the
pathway outlined in Scheme 3 was observed exclusively when
suitable fragmenting groups were used (e.g. CH2OMe, and
CH2Ph). To further evaluate the stereoelectronic effect on the
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(a) Mondal, S.; Gold, B.; Mohamed, R. K.; Alabugin, I. V.
View Article Online
Chem. Eur. J. 2014, 20, 8664. (b) Mondal, S.; Mohamed, R. K.;
DOI: 10.1039/C5CC04391C
Manoharan, M.; Phan, H., Alabugin, I. V. Org. Lett., 2013, 15,
5650. (c) Mondal, S.; Gold, B.; Mohamed, R.; Phan, H.;
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Scheme 4 Radical pathway for C-H bond cleavage in a stereoelectronically
restricted cycle
C-C bond scission step, we have prepared 3-(2-
isocyanophenyl)-1H-indene 1c, as shown in Scheme 4. Example
1c was observed to yield solely the 6-endo product Q2, but
without the C-C fragmentation. This is due to the fused 5-
member system “locking” the cycles into a planar structure.
This constraint places the intermediate radical C4
perpendicular to the C-C bond that would usually fragment,
which aligns it with a C-H bond. The stereoelectronic
alignment leads to this C-H bond scission and prevents the C-C
fragmentation.
In conclusion, we have developed a synthetic equivalent of
6-endo-dig cyclization for the synthesis of quinolines from
isonitriles using a combination of an endo-trig cyclization and
fragmentation. A variety of functional groups is tolerated. This
reaction utilizes inexpensive Mn(III) salts and readily available
5
6
Review on radical chemistry of isocyanides: Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. Rev. 1996, 96, 177.
Photochemical cyclizations in the presence of heteroatomic
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7
boronic acids. Successful utilization of cyclization
/
8
9
Mn-Mediated reactions of boronic acids: (a) Yan, G.; Yang,
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S.; Reis, Ö.; Emrullahoglu, M. J. Org. Chem. 2002, 68, 578.
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fragmentation sequences expands the use of alkenes as alkyne
equivalency towards heterocycle synthesis.
ACKNOWLEDGMENT
10 (a) Alabugin, I. V.; Gilmore, K. Chem. Commun., 2013, 49,
11246. (b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011. 111,
6513. (c) Alabugin, I. Gilmore, K.; Manoharan, M. J. Am.
Chem. Soc. 2011, 133, 12608. (d) Peterson, P. W.; Mohamed,
R. K.; Alabugin, I. V. Eur. J. Org. Chem., 2013, 2013, 2505.
11 Selected examples of biphenyl isocyanide cyclizations:
Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem.
Int. Ed. 2012, 51, 11363. Wang, H.; Yu, Y.; Hong, X.; Xu, B.
Chem. Commun. 2014, 50, 13485. Leifert, D.; Daniliuc, C. G.;
Studer, A. Org. Lett. 2013, 15, 6286. Pan, C.; Zhange, H.;
Han, J.; Cheng, Y.; Zhu, C. Chem. Commun., 2015, 51, 3786.
Xia, Z.; Huang, J.; He, Y.; Zhao, J.; Lei, J.; Zhu, Q. Org. Lett.
2014, 16, 2546.
We thank Dr. Brian Gold, Dr. Sayantan Mondal and Rana
Mohamed for helpful discussions. I. A. is grateful to the
National Science Foundation (CHE-1465142) for support of this
research.
Notes and references
1
(a) Acetylene Chemistry: Chemistry, Biology and Material
Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.;
Wiley-VCH: Weinheim, Germany, 2005.(b) E.T. Chernick, R. R.
Tykwinski, J. Phys. Org. Chem. 2013, 26, 742. (c) Alabugin, I.
V.; Gold, B. J. Org. Chem., 2013, 78, 7777. (d) Wille, U. Chem.
Rev. 2013, 113, 813.
12 Zhuo, L.-G.; Zhang, J.-J.; Yu, Z.-X. J. Org. Chem. 2012, 77,
8527.
13 For review on isocyanide insertion chemistry: (a) Qiu, G.;
Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257. (b)
Nenajdenko, V.G. Isocyanide Chemistry: Applications in
2
Alabugin I.V.; Manoharan, M. J. Am. Chem. Soc. 2005, 127,
12583.
Synthesis and Material Science. Wiley Press. (2012)
.
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