Dearomatizing Spiroannulation Reagents: Direct Access to Spirocycles from Indoles and Dihalides

Article abstract of DOI:10.1021/acs.orglett.8b01248

Unfunctionalized indoles can be directly converted into 3,3′-spirocyclic indolenines and indolines upon reaction with electrophilic dihalides in the presence of t-BuOK/BEt₃. This double C-C bond forming reaction, which simultaneously generates a quaternary spirocyclic center, typically proceeds in high yield and has good functional group tolerance. In contrast to existing dearomatizing spirocyclization approaches, there is no need to prepare a prefunctionalized aromatic precursor, enabling faster access to valuable spirocyclic products from simple, commercially available aromatics in one step.

Full text of DOI:10.1021/acs.orglett.8b01248

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Dearomatizing Spiroannulation Reagents: Direct Access to
Spirocycles from Indoles and Dihalides
John T. R. Liddon, James A. Rossi-Ashton, Richard J. K. Taylor,* and William P. Unsworth*
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
*
S Supporting Information
ABSTRACT: Unfunctionalized indoles can be directly
converted into 3,3′-spirocyclic indolenines and indolines
upon reaction with electrophilic dihalides in the presence of
t-BuOK/BEt . This double C−C bond forming reaction,
3
which simultaneously generates a quaternary spirocyclic
center, typically proceeds in high yield and has good functional
group tolerance. In contrast to existing dearomatizing
spirocyclization approaches, there is no need to prepare a prefunctionalized aromatic precursor, enabling faster access to
valuable spirocyclic products from simple, commercially available aromatics in one step.
pirocycles have been the focus of much research in recent
preparation of the requisite starting materials (1b) is often not
trivial, which can serve as a barrier to the uptake of the method.
In this work, we describe a strategy by which this barrier can be
removed, through the development of a series of simple, easily
prepared bifunctional dearomatizing spiroannulation (DSA)
reagents capable of undergoing two bond-forming reactions
directly onto commercially available aromatics (Figure 1b).
To the best of our knowledge, there is remarkably little
precedent for such an approach, even when all aromatic
frameworks are considered. Taking indoles as an example, the
S
years, in large part due to their utility in medicinal
1
chemistry. Spirocycles are typically rigid molecules with
relatively predictable shapes, and often have a high “3D
character”, meaning that they can be used to probe regions of
pharmaceutical space that historically have been underex-
2
plored. In view of this, significant effort has gone into the
development of effective ways to prepare diversely function-
alized spirocycles, with dearomatization approaches among the
3
most popular. Existing dearomatizing spirocyclization methods
6
only reported reactions that adhere to our design criteria are
almost always involve the preparation of a monosubstituted
cyclization precursor, which then undergoes spriocyclization
upon activation with a suitable reagent or catalyst (1a → 1b →
7
,8
summarized in Scheme 1. Thus, Banerji et al. reported a
double conjugate addition of indole 2a with Michael acceptor 3
1
c, Figure 1a).
Scheme 1. Literature DSA-Type Approaches
Several efficient methods of this type have been reported,
4
5
both by ourselves and others, but a drawback is that the
Received: April 19, 2018
Figure 1. Spiroannulation strategies.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
a
to form indolenine 4 (Scheme 1a), while Enders et al. isolated
indolenine 6 from C2-substituted indole 2b and bis-electrophile
5
BF , failed to provide the desired spirocycle (entries iii−iv).
3
Pleasingly, switching to a t-BuOK/BEt3 reaction system,
7
b
14
(Scheme 1b). Both products were isolated in <10% yield,
adapted from conditions published by Yang and co-workers
although it is important to stress that spirocycle synthesis was
not the main objective in either of these studies. Arguably the
best precedent is found in a 2015 report by Sun, Xu, and co-
workers, who showed that spirocycles 8 could be prepared in
good yields via a double C−C bond forming process using
(entries v−ix), enabled spirocycle 11a to be formed in
quantitative yield following a reductive quench. Using these
optimized conditions (2.2 equiv t-BuOK, 2.0 equiv BEt , 1.1
3
equiv 9a, THF, reflux, then NaBH reduction) spirocyclic
4
indoline 11a was also prepared in 99% yield on gram scale
(entry x). Finally, while a reductive quenching step was
generally used, it is not essential; by omitting the reductive
quench, indolenine 10a was isolated in quantitative yield after
filtration, concentration and column chromatography (entry
xi). Mechanistically, the reaction likely proceeds through
sequential inter- and intramolecular C-3 indole alkylation
reactions, via the mechanism proposed by Yang and co-workers
7c
benzaldehyde derivatives 7 (Scheme 1c). Rare DSA-type
9
reactions have also been reported for phenol derivatives, but
we were unable to find a precedent for similar approaches being
adopted on any other class of aromatic system. Hence, this
appears to be an underexplored area that could significantly
expedite the synthesis of valuable spirocycles. The proof-of-
concept results reported herein illustrate the potential value of
this strategy through the development of a one-pot procedure
for the direct spiroannulation of unfunctionalized indoles and
azaindoles using simple dihalide reagents.
14
in their related study, with the borane reagent helping to
minimize competing N-1 and C-2 alkylation side reactions.
Pleasingly, no C2 annulated products were detected in any of
the unpurified reaction mixtures, which is notable, given the
proclivity of 3,3-disubstituted indolenines to undergo 1,2-
We decided to focus this proof-of-concept study on the use
of simple, commercially available indole starting materials, in
part due to our recent experience in the development of indole
12,15
migration.
10
dearomatization methods. Simplicity in the DSA reagents was
a priority, which influenced our decision to use simple dihalide
bis-electrophiles, all of which were either commercially available
or easily prepared by short literature sequences (see Supporting
Information (SI)). Our aim was to develop a dearomatizing
spirocyclization procedure based on a one-pot, double
alkylation process, starting with the reaction of commercially
available 1,2-bis(bromomethyl)benzene 9a and indole 2a
With the optimized conditions in hand, we next examined
the reaction of dibromide 9a with other commercially available
indole derivatives (Scheme 2). Thus, using the standard
Scheme 2. Spiroannulation with Dibromide 9a
(Table 1). Note that because spiroindolenine product 10a
Table 1. Reaction of indole 2a with DSA reagent 9a
entry
conditions for step i
yield/%
a
i
n-BuLi, ZnCl , rt, 18 h
0
2
a
ii
MeMgCl, rt, 18 h
<63
0
a
iii
iv
v
t-BuOK (2.0 equiv), rt, 18 h
t-BuOK (2.2 equiv), BF ·Et O (2.0 equiv), rt, 18 h
a
0
3
2
a
a
a
a
c
t-BuOK (1.1 equiv), BEt (1.0 equiv), rt, 18 h
70
3
c
vi
vii
t-BuOK (2.2 equiv), BEt (1.0 equiv), rt, 18 h
33
3
c
t-BuOK (1.1 equiv), BEt (2.0 equiv), rt, 18 h
76
3
viii t-BuOK (2.2 equiv), BEt (2.0 equiv), rt, 18 h
98
3
a
ix
x
t-BuOK (2.2 equiv), BEt (2.0 equiv), reflux, 1 h
quant
3
b
Conditions ix on gram scale
99
xi
to isolate 10a, conditions ix, then filtration (without
reduction step (ii).
quant (10a)
a
b
c
LiAlH reduction. NaBH reduction. In these cases, the quoted
4
4
1
yield was based on the ratio of 2a:11a in the H NMR spectra of the
unpurified reaction mixture.
a
b
Step ii using LiAlH . Step ii using NaBH .
4 4
exists as an equilibrating mixture of monomer and trimeric
compounds in solution, a reductive quench was typically used
conditions (Table 1, conditions ix), both 2-methyl and 2-
phenyl indole reacted to give the expected 2-alkyl indolines 11b
and 11c, respectively, demonstrating that the C2 position can
be unsubstituted or derivatized in our procedure (in contrast to
Scheme 1c, in which all published examples have C-2 alkyl
substituents). Likewise, both electron-rich (11d) and
electron-poor (11e−g) functionalities were tolerated at the
indole 5-position. Finally, electron-deficient aza-indole hetero-
11
(
10a → 11a; LiAlH or NaBH ) to simplify product isolation
4
4
and characterization, as is commonly done in related
1
2
processes.
7
c
Organometallic-based conditions for indole C3 alkylation
(
entries i−ii) either failed completely or provided a low yield of
1
3
impure product. Likewise, the use of t-BuOK, with or without
B
DOI: 10.1021/acs.orglett.8b01248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Spiroannulation of Indoles 2a and 2d
a
b
c
Formed in ∼1:1 dr; Step ii using LiAlH . Step ii using NaBH .
4
4
1
6
cycles were found to give usable quantities of spiro-annulated
product (11h,i), albeit in lower yields. As before, a reductive
quench was preferred for ease of handling, but was not a
requirement, as exemplified by the high yielding isolation of
indolenines 10a and 10b when omitting the reduction step.
Next, we turned our attention to examining the scope with
respect to the dihalide DSA reagent. Thus, a range of simple
dihalides 9b−m were tested, on both indole 2a and 2-
methylindole 2d, to establish whether indoles with and without
C2 substitution are compatible with each dihalide reagent
X-ray crystallographic data. While (Z)-1,4-dibromobut-2-ene
9e reacted with 2-methylindole to provide cyclopentene 11q in
reasonable yield, the analogous reaction with indole 2a was
complicated by competing intermolecular S 2′ reactions, which
N
led to product 11p being obtained in a much lower yield of
25% (see SI for further details). Other benzannulated DSA
reagents are well tolerated, and examples include substrates
substituted with functional groups amenable to further
derivatization, including protected benzylic alcohols, aryl
bromides, anisoles, and aryl esters (11r−z, Scheme 3B). In
addition, benzyl alcohol 11t could be formed in a protecting
group-free reaction from reagent 9g directly. 1,8-Bis-
(bromomethyl)naphthalene 9k reacted with both indole and
2-methylindole to form 6-carbon spirocycles 11za and 11zb in
near quantitative yield (Scheme 3C). Spiroannulation was also
possible with 1,2-bis(bromomethyl)naphthalene 9l, although in
a lower yield (50−53%), possibly due to the formation of
orthoquinone dimethide decomposition products. Nitrogen
(Scheme 3). First, simple alkyl halides 9b and 9c reacted with
indole and 2-methylindole to provide cyclopentyl and cyclo-
hexyl spirocycles 11j−m in high yields (Scheme 3A).
Remarkably, no competing elimination reactions or other side
reactions were observed during the reactions of these
unactivated bis-electrophiles. In addition, the use of 2-
bromoethyl ether 9d afforded tetrahydropyran derivatives
11n,o in moderate yields, with both structures supported by
C
DOI: 10.1021/acs.orglett.8b01248
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Letter
heterocycle quinoxaline 9m also reacted productively with both
indole and 2-methylindole, despite incomplete starting indole
consumption. While indoline 11ze was formed in good yield,
the 2-methyl analogue was best isolated as indolenine 10g
without reduction. Three bis-functionalized products were also
prepared by combining orthogonally functionalized indoles and
DSA reagents (Scheme 3D); 5-bromo-2g, 5-methoxy-2f and 5-
carbomethoxy-indoles-2i, were combined with DSA reagents
ACKNOWLEDGMENTS
■
The authors thank the EPSRC (EP/M018601/01, J.T.R.L.),
the University of York (J.A.R.-A.), and the Leverhulme Trust
for an Early Career Fellowship, ECF-2015-13, W.P.U.) for
(
financial support.
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ASSOCIATED CONTENT
■
*
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Supporting Information
The Supporting Information is available free of charge on the
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Experimental procedures, spectroscopic data and NMR
spectra (PDF)
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Accession Codes
CCDC 1555786−1555787 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
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Cambridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
■
(c) Wang, P.-F.; Chen, C.; Chen, H.; Han, L.-S.; Liu, L.; Sun, H.;
Corresponding Authors
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*
E-mail: richard.taylor@york.ac.uk.
*E-mail: william.unsworth@york.ac.uk.
ORCID
William P. Unsworth: 0000-0002-9169-5156
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b01248
Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.8b01248
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