1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles

Article abstract of DOI:10.1039/c6sc00798h

We have devised a novel 1,3-benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two triple bonds in a single benzene ring under fluoride-mediated mild conditions, and the regiocontrol of each benzyne reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is given in the convergent synthesis of the antipsychotic drug risperidone. A similar strategy has also been applied to a 1,4-benzdiyne equivalent to construct linearly benzo-fused heteroaromatics.

Full text of DOI:10.1039/c6sc00798h

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1
,3- and 1,4-Benzdiyne Equivalents for Regioselective Synthesis of
Polycyclic Heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Takashi Ikawa,* Shigeaki Masuda, Akira Takagi, and Shuji Akai*
DOI: 10.1039/x0xx00000x
We have devised a novel 1,3-benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne
generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two
triple bonds in a single benzene ring under fluoride-ion-mediated mild conditions, and the regiocontrol of each benzyne
reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic
compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is
given in the convergent synthesis of the antipsychotic drug risperidone. A similar strategy has also been applied to a 1,4-
benzdiyne equivalent to construct linearly benzo-fused heteroaromatics.
www.rsc.org/
Crucial factors in the design of these benzdiyne equivalents
include suitable functional groups which enable the generation
of the second benzyne without further transformations, and a
way to control the regiochemistry of each benzyne reaction.
The work of Suzuki et al. involving their original 1,4ꢀbenzdiyne
Introduction
The reactions of benzynes with arynophiles are widely utilized
for introducing substituents to adjacent carbons of benzene
1
rings. The direct installation of fused rings onto benzenes is an
equivalent meets these requirements, which uses nꢀbutyllithum
advantage specific to the benzyne reaction and is not possible
through other methods. Furthermore,
6b
to generate the benzynes. Very recently, Peña et al. have
demonstrated that triple bonds were sequentially generated
twice under fluorideꢀmediated mild conditions from 1,4ꢀ
benzdiyne equivalents and reacted with two different
a variety of new
arynophiles have been recently reported, enriching the diversity
2
of the method.
The reactions of benzdiynes, possessing two triple bonds in
a single benzene ring, and two arynophiles, would provide a
fewꢀstep synthesis for the convergent preparation of multiꢀ
fused benzenes. However, benzdiynes are observed only under
7
arynophiles in both stepwise and oneꢀpot manners. In contrast,
there have been no reports of a suitable 1,3ꢀbenzdiyne
5,8,9
equivalent.
We have attempted sequential benzyne reactions starting
3
gasꢀphase conditions due to their extreme instability, and it
from 1,3ꢀbenzdiyne equivalents
Scheme 1). This method was designed to afford
unsymmetrically substituted polycyclic aromatic compounds
possessing consecutive fusedꢀrings, as are often seen in
1, with various arynophiles
would be impossible to react one with two different arynophiles
for the synthesis of unsymmetrically fused benzene rings.
An alternative approach is to use benzdiyne equivalents,
where two benzynes are generated sequentially in one pot to
provide substituted acenes and polycyclic aromatic compounds.
If we could control the regiochemistry of consecutive benzyne
reactions, starting from benzdiyne equivalents, each with
different arynophiles, we could produce a wide range of multiꢀ
ring fused unsymmetrical aromatic compounds. However, only
a limited number of such reactions have been reported, and
most of them require several steps for functional group
transformations to generate the second benzyne. Therefore,
the development of more sophisticated benzdiyne equivalents is
needed to facilitate twoꢀstep sequential benzyne reactions.
(
3
,
10
material and pharmaceutical science. While compounds like
3
4
R
R
'
R
1
SiMe
3
arynophile
(I and II)
R1
R2
R2
TfO
OTf
R4
II
R4
F–
2
I
SiR
3
R3
R3
5
,6
1
3
R1
R2
R1
R3
R4
I
II
1
3
F–
TfO
F
–
R
2
SiR
3
5
4
controlling
controlling
Scheme 1 Design of benzdiyne precursor 1 that can sequentially generate
two triple bonds in a single benzene ring and control the regiochemistry of
two benzyne reactions by the substituents next to each triple bond.
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SiMe
3
SiMe3
Me
Me
O
(
for 1a)
TfO
Me
TfO
Me
O
7
O
TfO
Me
(1)
O
Me
3
Si
Me
Me
Me
SiMe
3
6a
8, 41%
9
, 0%
6
a (3.0 equiv)
TfO
OTf
Me
Me
Me
O
Me
O
CsF (3.0 equiv)
MeCN, rt
SiR
= SiMe
b: SiR3 = Si(t-Bu)Me2
3
1
1
a: SiR
3
3
6a (3.0 equiv)
O
O
Me
TfO
Me (t-Bu)Si
TfO
Me (t-Bu)Si
Me
(2)
(for 1b)
CsF (3.0 equiv)
MeCN, rt, 19 h
O
O
Me
Me
Me
Me
2
2
Me
6
a
Me
4a
1
0a, 78%
6a
5a
3a, 90%
syn/anti mixture)
(
Scheme 2 Sequential benzyne generation from benzdiyne equivalents 1a and 1b followed by Diels-Alder reaction with furan 6a.
have been mainly synthesized via linear, multiꢀstep routes, our that the double cycloaddition product 3a was not detected by
approach is convergent and rapid, proceeding by the GC analysis of the crude reaction mixture after 30 min (see
combination of
1 and two different arynophiles (I and II), and ESI†). This may be due to the lower reactivity of the Me2(t-
allows a rational design for the production of a library of Bu)Si group, even in the presence of excess CsF and 6a. The
compounds. We were particularly interested in its application to generation of the second benzyne 5a was achieved after long
the synthesis of benzoꢀfused heterocycles for medicinal reaction time (19 h) under the same reaction conditions using
chemistry. Therefore, we planned reactions using heteroatomic CsF to give 3a in 90% isolated yield.
1
,3ꢀdipoles, such as azides, nitrones, diazo compounds, and
nitrile oxides, as the arynophiles.
We aimed to develop a synthetic methodology in which (1) All reactions of 3ꢀsilylbenzyne 4a with arynophiles 6b
two benzynes ( and ) are chemoselectively generated in a provided cycloaddition products 10 with good regioselectivities
stepwise manner without any additional functionalization steps, due to synergetic effect of the neighboring Me (t-Bu)Si and
We attempted to synthesize compounds 3b
stepwise benzyne cycloaddition reactions from 1b (Table 1).
–3f through
–
e
4
5
1
1f
2
1
3
(
2) each benzyne is generated under mild conditions using a the distant triflyloxy (TfO) groups. Among them, unexpected
fluoride, and (3) the two cycloaddition reactions of and with proximal regioselectivity (proximal
10d distal 10d = 78 : 22)
and II proceed in a highly regioselective manner (Scheme 1). was observed in the reaction between 3ꢀsilylbenzyne 4a and
In this article, we report the preparation of a new 1,3ꢀbenzdiyne nitrone 6d (entry 4ꢀ1), which was opposite to the previously
equivalent 1b [SiR = Si(t-Bu)Me ], and a method for the reported reactions of 3ꢀsilylbenzynes with nitrones (For
preparation of unsymmetrical, angular, and multiꢀring fused structural determinations, see ESI†).11f–h This result is probably
heterocyclic compounds , which satisfies the above criteria. due to the inductively electronꢀwithdrawing effect of the TfO
One significant advantage of this method is the high group at C4. The reaction of 4a with sydnone 6e to give
regioselectivity of both benzyne reactions, in which the first distalꢀ2
ꢀindazole 10e selectively (entry 5ꢀ1) is particularly
4
5
ꢀ
:
ꢀ
I
3
2
3
1
3a
H
1
1
step is controlled by the traceless directing group, R
and the second step by the cyclic systems of 5.
3
Si of
4,
noteworthy, as the reactions of unsymmetrical benzynes such as
3ꢀmethoxybenzyne with sydnones have been reported to afford
mixtures of regioisomers in 1:1 ratio. The reaction of
benzynes with arynophiles 6b and 6f 6g provided polycyclic
compounds 3b 3f. This is the first report of the generation and
1
2
2
f
5
–
Results and discussion
–
reaction of 4,5ꢀbenzotriazolyne 5b (entry 2ꢀ2), 6,7ꢀ
benzisoxazolyne 5c (entry 3ꢀ2), 4,5ꢀbenzisoxazolinyne 5d
We synthesized two 1,3ꢀbenzdiyne equivalents, 1a and 1b
which were treated with CsF in the presence of 2,4ꢀ
dimethylfuran 6a. The reaction of 1a with 6a produced the
,
(
entry 4ꢀ2), and 6,7ꢀ2Hꢀindazolyne 5e (entry 5ꢀ2). The
regioselectivity of these reactions is higher than that of
sterically similar 4,5ꢀindolyne (see preliminary theoretical
undesired cycloaddition product
8 via benzyne 7 (Scheme 2).
However, the reaction of 1b afforded the desired cycloaddition
product 10a (78% yield) through the Diels–Alder reaction of
the expected benzyne 4a with 6a. An important observation is
1
2a,b
discussion of these regioselectivities in ESI†).
of 5c with 6b and 5e with 6g provided distal
exclusively (entries 3ꢀ2 and 5ꢀ2).
The reactions
3d and proximal
ꢀ
ꢀ
3
f
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a
Table 1 Reactions of 1b with two different arynophiles 6 for the synthesis of angular polycycles 3
Next, oneꢀpot sequential benzyne cycloadditions from 1b
We applied these findings to the convergent synthesis of the
were demonstrated for the synthesis of angular tricyclic antipsychotic drug risperidone 14 (Scheme 4). The silylbenzyne
2
e
heterocycles
of 1b (1.0 equiv), benzylazide 6b (1.1 equiv) and CsF (4.0 mixture of 1b and a chloroꢀoxime 11 and then reacted in situ to
equiv) in MeCN was stirred at room temperature for 30 min, 2ꢀ form distal 10f as a single regioisomer. The next reaction of
methylfuran 6h (3.0 equiv) and 18ꢀcrownꢀ6 (4.0 equiv) were 6,7ꢀbenzisoxazolyne 5f, generated by BnMe
added and then the reaction mixture was stirred for 16 h at 0 °C fluoride 6j, provided 3h with excellent regioselectivity. Finally,
Scheme 3ꢀ1). Gratifyingly, proximal 3g was obtained as a the synthesis was completed by the ꢀdeprotection of 3h to
main product (proximal 3g distal 3g = 63 : 37, total 56%). give 12 and the alkylation with 13 This result suggests that
The tricyclic compound, distal 3e was also synthesized as the 1b should be useful tool for the expeditious divergent synthesis
predominant product (distal 3e proximal 3e = 93 : 7, total of a wide variety of biologically active compounds and their
8%) by a similar oneꢀpot combination of arynophiles, nitrone derivatives by choosing different arynophiles once 1b become
and 6b (Scheme 3ꢀ2). The yield and regioselectivity of these easily available (For the first synthesis of 1b, see ESI†).
3 without isolating 10 (Scheme 3). After a mixture 4a and a nitrile oxide 6i were simultaneously generated from a
ꢀ
1
4,15
3
NF
and a
(
ꢀ
N
1
6
ꢀ
:
ꢀ
.
ꢀ
ꢀ
:
ꢀ
3
6
6d
products were comparable to those obtained by the stepwise
method (Table 1, entries 4ꢀ1 and 4ꢀ2).
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time, under which conditions, generation of the second benzyne
does not occur (see ESI†). The monoꢀcycloaddition products
1
7
, obtained as a mixture of two regioisomers, were subjected
to the second reaction with arynophiles II, without separation
2
0
of the regioisomers, to afford the multicyclic compounds 19
.
1
3a
11e
Due to the dual effect of TfO group and Me
3
Si group of
1
6
, the all first benzyne reactions proceeded in a regioselective
manner beyond expectation (Table 2, entries 1ꢀ1, 2ꢀ1 and 3ꢀ1),
although these selectivities were only a little lower than those
of the 1,3ꢀbenzdiyne equivalent 1b (see, Table 1). Interestingly,
the second benzyne reactions also regioselectively provided
cycloaddition products 19 probably because of the inductive
effect of heteroatoms such as nitrogen and oxygen constructing
heterocycles (entries 2ꢀ2 and 3ꢀ2). These results provide useful
information for regioselectivity control of benzyne
cycloadditions from distant positions. Importantly, the oneꢀpot
Scheme 3 One-pot synthesis of unsymmetrical angular heterocycles 3.
We also report the synthesis of linearly fused, synthesis of a linear tricyclic compound 19a from 15
, 6b and 6l
1
7–19
unsymmetrical polycyclic aromatics 19 using 15
as a 1,4ꢀ was also successfully achieved (see entry 1ꢀ2).
benzdiyne equivalent (Table 2). The first benzyne generation
proceeds using CsF at room temperature in MeCN for a short
Scheme 4 Application of 1,3-benzdiyne precursor 1b to the synthesis of risperidone 14.
a
Table 2 Reactions of a 1,4-benzdiyne equivalent 15 with two different arynophiles 6 for the synthesis of linear polycycles 19
4
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4
5
For a review on the synthesis of acenes using aromatic ynes
including benzdiynes, see: (a) J. Li and Q. Zhang, Synlett
013, 24, 686. (b) D. Pérez, D. Peña and E. Guitián, Eur. J.
Org. Chem., 2013, 5981
For papers on the 1,3ꢀbenzdiyne equivalents that generate two
triple bonds by a stepꢀbyꢀstep manner, see: (a) T. Hamura, Y.
Ibusuki, K. Sato, T. Matsumoto, Y. Osamura and K. Suzuki,
,
Conclusions
2
In conclusion, we have developed a novel synthetic route to
multiꢀring fused heterocycles by the combination of benzdiyne
equivalents and arynophiles. In this study, the newly generated
azoleꢀfused benzynes were found to exhibit higher
regioselectivities than those of sterically similar 4,5ꢀ
Org. Lett., 2003,
5, 3551; (b) Y.ꢀL. Chen, J.ꢀQ. Sun, X. Wei,
1
2b
indolyne.
This method has facilitated the convergent
W.ꢀY. Wong and A. W. M. Lee, J. Org. Chem., 2004, 69,
synthesis of the antipsychotic risperidone. Therefore, we
believe that this synthetic methodology will be invaluable to
drug discovery. Work is ongoing into easier, scalable synthetic
methods for these benzdiyne equivalents, analysis of the
origin of the regioselectivity (see ESI†), and applications to
medicinal chemistry.
7190; For papers on the 1,3,5ꢀbenztriyne equivalents, see: (c)
T. Hamura, Y. Ibusuki, H. Uekusa, T. Matsumoto and K.
Suzuki, J. Am. Chem. Soc., 2006, 128, 3534; (d) T. Hamura,
Y. Ibusuki, H. Uekusa, T. Matsumoto, J. S. Siegel, K. K.
1
9
Baldridge and K. Suzuki, J. Am. Chem. Soc., 2006, 128
,
10032.
6
For selected papers on 1,4ꢀbenzdiyne equivalents that
generate two triple bonds by a stepꢀbyꢀstep manner, see: (a)
Acknowledgements
S.ꢀH. Chan, C.ꢀY. Yick and H. N. C. Wong, Tetrahedron
,
2
002, 58, 9413; (b) T. Hamura, T. Arisawa, T. Matsumoto
We thank Dr. N. Kotoku of Osaka University for analyzing
NMR data. This work was financially supported by the JSPS
KAKENHI (grant numbers 23790017 and 25460018), the
Platform for Drug Discovery, Informatics, and Structural Life
Science from the MEXT and the Hoansha foundation.
and K. Suzuki, Angew. Chem. Int. Ed., 2006, 45, 6842; (c) D.
Chun, Y. Cheng and F. Wudl, Angew. Chem. Int. Ed., 2008,
4
7
, 8380; (d) K. Gondo and T. Kitamura, Adv. Synth. Catal.
,
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014, 356, 2107; (e) K. Gondo, J. Oyamada and T. Kitamura,
Heterocycles, 2015, 90, 681. See also ref. 5b.
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(a) B. Schuler, S. Collazos, L. Gross, G. Meyer, D. Pérez, E.
Guitián and D. Peña, Angew. Chem. Int. Ed., 2014, 53, 9004;
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8a
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7
c
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,
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,
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1
2 For selected fused fiveꢀmembered ring directed benzyne
reactions, see: (a) A. N. Garr, D. Luo, N. Brown, C. J.
Cramer, K. R. Buszek and D. VanderVelde, Org. Lett., 2010,
12, 96; (b) GꢀY. J. Im, S. M. Bronner, A. E. Goetz, R. S.
Paton, P. H.ꢀY. Cheong, K. N. Houk and N. K. Garg, J. Am.
Chem. Soc., 2010, 132, 17933; For various fused ring directed
benzyne reactions, see: (c) A. E. Goetz, S. M. Bronner, J. D.
Cisneros, J. M. Melamed, R. S. Paton, K. N. Houk and N. K.
Garg, Angew. Chem. Int. Ed., 2012, 51, 2758.
1
3 For unique 3ꢀ or 4ꢀTfO groupꢀdirected benzyne reactions,
see: (a) T. Ikawa, H. Kaneko, S. Masuda, E. Ishitsubo, H.
Tokiwa and S. Akai, Org. Biomol. Chem., 2015, 13, 520; (b)
S. Yoshida, K. Uchida, K. Igawa, K. Tomooka and T.
Hosoya, Chem. Commun., 2014, 50, 15059. See also ref 9c.
3
14 The use of BnMe NF as an anhydrous fluoride ion source was
necessary both for the benzyne generation and for the
nucleophilic addition of the fluoride ion because a significant
amount of the phenol derivative was formed when Bu
BuOH) was used. The latter results are probably owing to
the nucleophilic addition of contaminated water to generated
4
NFꢁ(t-
4
1
5
benzyne 5f.
1
1
1
5 For fluorination reactions of benzynes with fluoride anions,
see; T. Ikawa, S. Masuda, T. Nishiyama, A. Takagi and S.
Akai, Aust. J. Chem., 2014, 67, 475.
6 A. V. Dubrovskiy, P. Jain, F. Shi, G. H. Lushington, C.
Santini, P. Porubsky and R. C. Larock, ACS Comb. Sci.
013, 15, 193.
7 2,4ꢀBis(trimethylsilyl)ꢀ1,3ꢀ
bis(trifluoromethanesulfonyloxy)benzene 15 has been
recognized as oneꢀstep 1,4ꢀbenzdiyne precursor that
,
2
a
consecutively generates two triple bonds at the C1 and C4
positions of a single benzene to react with two equivalents of
4
,18
a single arynophile.
Peña et al. have recently used 15 as a
quasiꢀstepꢀbyꢀstep benzdiyne precursor for the synthesis of
polyaromatic hydrocarbon (PAH), in which the second
6
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