Intramolecular Benzyne–Phenolate [4+2] Cycloadditions

Article abstract of DOI:10.1002/anie.202003131

An intramolecular benzyne–phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen-sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph₃MgLi or nBuLi for halogen–metal exchange to form various benzobarrelenes.

Full text of DOI:10.1002/anie.202003131

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Accepted Article
Title: Intramolecular Benzyne–Phenolate [4+2] Cycloadditions
Authors: Hiroshi Takikawa, Arata Nishii, Hiromu Takiguchi, Hirotoshi
Yagishita, Masato Tanaka, Keiichi Hirano, Masanobu
Uchiyama, Ken Ohmori, and Keisuke Suzuki
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003131
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10.1002/anie.202003131
Angewandte Chemie International Edition
COMMUNICATION
Intramolecular Benzyne–Phenolate [4+2] Cycloadditions
Hiroshi Takikawa,[a] Arata Nishii,[a] Hiromu Takiguchi,[a] Hirotoshi Yagishita,[a] Masato Tanaka,[a] Keiichi
Hirano,[b] Masanobu Uchiyama,[b,c] Ken Ohmori,*[a] and Keisuke Suzuki*[a]
In memory of the late Professor Rolf Huisgen
Abstract: Intramolecular benzyne–phenolate [4+2] cycloaddition is
Surprisingly, a model reaction using iodoaryl triflate 1a16,17 did
not give the expected product 3, but instead cycloadduct 2a in
excellent yield.
reported, opening an effective route to various benzobarrelenes.
Benzyne, a versatile reactive species in organic chemistry,1,2
was historically postulated about 70 years ago for explaining
unusual observations in nucleophilic aromatic substitutions. The
pioneering works of Wittig (1942)3 and Huisgen (1954)4 were
for rationalizing the reaction of phenyllithium and fluorobenzene,
generating biphenyllithium, while Roberts’ 14C-tracer experiment
(1953)5 addressed the rearrangements on the amination of aryl
halides by metal amides. Another important reactivity of
benzyne was discovered by Wittig (1955), 6 i.e., the [4+2]
cycloaddition that has been extensively exploited in organic
synthesis, including the reactions with arenes as arynophiles.7,8
Some of the foregoing reactions of aromatic compounds must
have unconsciously exploited benzyne species, as exemplified
by the historical Dow phenol process (Scheme 1a), 9 in which
the product distribution, phenol and side products I–III, is
consistent with the intermediacy of a benzyne. Theoretical
calculation supported three side reaction pathways, 10 but
interestingly, suggested that the [4+2] cycloaddition may also
be a competing pathway, albeit not reported (Scheme 1b). To
our knowledge, there has been essentially no literature
precedence on the [4+2] cycloadditions of benzyne to phenols
or phenolates,11 except for a single example described in
Hoye’s recent report: Upon thermal generation of a benzyne via
cycloisomerization, 12 the reaction with one special phenol
presents the single example where the [4+2] cycloadduct was
formed as a minor byproduct, while the predominant path was
the ortho-C-addition.13
(a)
NaOH
HO–
Cl
OH
phenol
O–
OH
+
+
O
OH
I
II
O–
III
O–
(b)
–
O
O–
para-C-addition
[4+2]
O-addition
ortho-C-addition
ΔG‡
+8.4
+15.9
+16.7
+13.3
Scheme 1. (a) Dow phenol process, (b) theoretical comparison of competing
pathways (kcal/mol, B3LYP/6-31+G*, counter cation: Li+·2THF, gas phase).
This discovery clearly showed that, if the mutual spatial
relationship was suitably set by tethering, a benzyne and a
phenolate could indeed undergo selective [4+2] cycloadditions.
Leaving the original aim aside, we further explored this finding.
In this communication, we now pleasingly report the broad
scope of the intramolecular benzyne–phenolate [4+2]
cycloadditions,
allowing
facile
access
to
various
In our recent synthetic study on cavicularin, a natural product
with an unusual polycyclophane structure, we incidentally
benzobarrelene scaffolds often embedded in bioactive
compounds18 and useful materials.19
discovered the benzyne–phenolate [4+2] cycloaddition
14
(Scheme 2).
Our original aim was to construct
(a)
dihydrophenanthrene VI via the para-C-addition of an internal
phenolate to benzyne IV11f followed by dienone–phenol shift.15
O
OH
V
VI
[a] Dr. H. Takikawa, Dr. A. Nishii, Dr. H. Takiguchi, H. Yagishita, M. Tanaka,
Prof. Dr. K. Ohmori, Prof. Dr. K. Suzuki
O–
OH
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
E-mail: kohmori@chem.titech.ac.jp
IV
O–
[4+2]
E-mail: ksuzuki@chem.titech.ac.jp
VII
Dr. H. Takikawa
(b)
Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
[b] Dr. K. Hirano, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
[c] Prof. Dr. M. Uchiyama
MeO
MeO
MeO
OH
OTf
I
nBuLi
(4.0 equiv)
O
THF, –78 °C
10 min
OH
91%
Cluster of Pioneering Research (CPR), Advanced Elements Chemistry
Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
1a
2a
3
Scheme 2. (a) Reactions of benzyne with an internal phenolate, (b)
Incidental discovery. THF = tetrahydrofuran, Tf = trifluoromethanesulfonyl.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under: https ://doi.org/.
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10.1002/anie.202003131
Angewandte Chemie International Edition
COMMUNICATION
Scheme
3
shows the generality of the process by the
scission of 7a by n-butyl anion as in A.
successful reactions of iodoaryl triflates 1b–d, which were
prepared from known compounds in 4–5 steps.20 By treatment
with nBuLi (THF, –78 °C, 10 min), substrates with C–O and C–
S tether, 1b and 1c, underwent smooth cycloadditions, giving
the corresponding cycloadducts 2b21 and 2c in high yields. By
contrast, the reaction of 1d having a C–N tether gave 2d in low
yield, which could be attributed to the competing attack of the
nitrogen to benzyne.
An optimization study (Table 1) revealed a suitable set of
conditions for smooth conversion to diol 8a. The reaction of 6a
with nBuLi (2.2 equiv) at 0 °C did not give silyl ether 7a, but diol
8a in 55% yield (entry 2). However, the reaction was not
complete (18% recovery of 6a), suggesting the need of further
loading of nBuLi. Indeed, when 3.5 equiv of nBuLi were used,
the starting material 6a was fully consumed to give 8a in 90%
yield (entry 3). When Ph3MgLi was employed instead,8,23 the
yield was further improved even with less amount of reagent
(2.2 equiv), giving diol 9a (n.b., R = Ph) in 95% yield (entry 4).
We reasoned that Ph2Mg, generated in situ, is nucleophilic
enough for cleaving the distorted Si–O bond in 7a.
MeO
MeO
OH
OTf
I
nBuLi
(4.0 equiv)
THF, –78 °C
10 min
X
OH
X = O (1b), S (1c), NMe (1d)
MeO
X
Table 1. Optimization.[a]
X = O (2b), S (2c), NMe (2d)
OH
OH
Br
nBuLi
or
Ph3MgLi
MeO
OH
OH
MeO
OH
OTs
+
THF
T, 10 min
iPr2Si
O
OH
iPr2Si
O
iPr2SiR OH
NMe
S
O
6a
7a
8a (R = nBu)
9a (R = Ph)
2b (73%)
2c (73%)
2d (33%)
Scheme 3. Reactions with substrates having C–O, C–S, and C–N tethers.
Yield of
8s or 9a
[%][c]
Reagent
(equiv)
T
[°C]
Yield of
Recovery
of 6a [%]
Entry
7a [%][c]
Scheme 4 shows that silylaryl triflate 4 was also a viable
precursor for this benzyne reaction.22 Upon treatment of 4 with
KF and 18-crown-6, the [4+2] cycloaddition proceeded slowly,
but steadily to give cycloadduct 2a in 89% yield.
1[b]
2
nBuLi (2.2)
nBuLi (2.2)
nBuLi (3.5)
–78
0
23
–
26 (8a)
55 (8a)
90 (8a)
95 (9a)
3
18
–
3
0
–
4
Ph3MgLi (2.2)
0
–
–
MeO
MeO
OH
OTf
[a] 0.05 M. [b] See Scheme 5. [c] Isolated yield.
KF
18-crown-6
SiMe3
THF, RT
5 h
To gain mechanistic insights, we performed density functional
theory (DFT) calculations using an aryne intermediate (IM),
bearing a phenolate moiety, generated from bromoaryl tosylate
6a (Scheme 6). The cycloaddition was computed to be a
concerted process, albeit highly asynchronous in terms of the
two C–C bond formations, giving the cycloadduct (PD). This is
consistent with the fact that none of the corresponding para-C-
adduct was observed, corresponding to an “interrupted” product
during the cycloaddition. It turned out that the activation barrier
(IM→TS) is remarkably low (+0.3 kcal/mol), probably due to the
entropic benefit from the intramolecularity.
OH
89%
4
2a
Scheme 4. Reactions with silylaryl triflate 4.
To further explore the scope, we tested a cleavable tether that
we recently developed, i.e., silyl chloride 5a, which were
prepared from 2,6-dibromophenol in four steps,20 as a platform
to link the benzyne precursor with various arynophiles (Scheme
5).8 Bromoaryl tosylate 6a was prepared in 75% yield by the
reaction of 5a and hydroquinone (imidazole, DMF, 0 °C→RT).
Upon treatment of bromoaryl tosylate 6a with nBuLi (THF, –
78 °C), two products were isolated and identified as silyl ether
7a (23% yield) and diol 8a (26% yield), arising from Si–O bond
‡
OLi
3.48
+0.3
–36.5
Br
iPr2Si
Br
2.27
O
OLi
imidazole
iPr2Si
O
OTs
+
HO
OH
DMF
0 °C→RT
OTs
iPr2Si
IM (0.0)
(from 6a)
PD (–36.2)
iPr2SiCl
O
OH
5a
benzyne platform
75%
6a
TS (0.3)
OH
OH
OH
O–
Scheme 6. DFT calculation results for the intramolecular benzyne–phenolate
[4+2] cycloaddition using PCM(THF)/M06-2X/6-311++G**. Energy changes
and bond lengths are shown in kcal·mol–1 and Å, respectively. Two THF
coordinated to the Li cation and hydrogens are omitted for clarity.
nBuLi
(2.2 equiv)
+
THF, –78 °C
10 min
iPr2Si
O
iPr2Si
nBu
8a (26%)
iPr2Si
nBu–
O
Table 2 shows the scope of the silicon-tether protocol. Entries
1–3 show variation in the aryl moiety. Upon treatment with
Ph3MgLi (2.2 equiv), substrates 6b and 6c, having a methoxy
or a fluoro group located meta to the silyl groups, smoothly
7a (23%)
A
Scheme 5. Preparation and reaction of bromoaryl tosylate 6a. Ts = p-
toluenesulfonyl, DMF = N,N-dimethylformamide.
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10.1002/anie.202003131
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gave the cycloadducts 9b and 9c in high yields, respectively
(entries 1 and 2). A dimethoxy-substituted precursor 6d also
underwent smooth cycloaddition (entry 3). However, the
product was silyl ether 7b, retaining the Si–O bond, which could
be rationalized by the steric effect of the methoxy group ortho to
the silyl group, retarding the nucleophilic attack of a phenyl
anion.
75% yield, along with silyl ether 7c in 13% yield (entry 6). The
benzyne–naphtholate cycloaddition was also possible: the
reaction of naphthol 6h under the standard conditions gave
dibenzobarrelene 9h in 92% yield (entry 7).
Furthermore, we examined the length of the tether by the
reactions of bromoaryl tosylates 6i and 6j, whose tethers are
longer by one carbon or two carbons, respectively. While 6i
underwent a cycloaddition to give alcohol 10 in 57% yield (entry
8), the reaction of 6j did not give cycloadduct 11 (entry 9).
Entries 4–9 show variation of the phenol moiety. A methyl
substituent on the phenol at the o- or m-position of the hydroxy
group does not interfere, and cycloadducts 9e and 9f were
obtained in high yields (entries 4 and 5). In the case of phenol
6g having a bicyclic phenol, cycloadduct 9g was obtained in
Table 2. Substrate scope.[a]
OH
Br
R1
Ph3MgLi
R1
iPr2SiPh OH
cycloadduct
R2
OTs
THF, 0 °C
10 min
iPr2Si
O
OH
R2
substrate
Entry
substrate
cycloadduct
Yield [%][b]
Entry
substrate
cycloadduct
Yield [%][b]
Br
MeO
Br
OH
OH
MeO
OTs
O
OTs
iPr2Si
1
93
86
99
6
75
iPr2Si
OH
O
OH
iPr2SiPh OH
iPr2SiPh OH
9b
9g
6b
6g
F
Br
OH
OH
F
OTs
2
13
iPr2Si
O
OH
iPr2SiPh OH
iPr2Si
O
9c
7c
6c
Br
MeO
MeO
OH
OH
Br
OTs
O
iPr2Si
MeO
OTs
7
92
3
OH
MeO
iPr2Si
iPr2Si
O
O
OH
iPr2SiPh OH
9h
7b
6d
6h
Br
Br
OH
OH
OTs
OTs
O
8
57
iPr2Si
4
94
iPr2Si
O
OH
iPr2SiPh OH
iPr2Si
O
OH
9e
10
6e
6i
Br
OH
OH
Br
OTs
OH
9
n.d.
iPr2Si
5
87
OTs
O
OH
iPr2Si
iPr2Si
iPr2SiPh OH
O
O
6j
9f
11
6f
[a] Reactions were performed with phenol 6 (1.0 equiv) and Ph3MgLi (2.2 equiv) in THF (0.05 M) at 0 °C for 10 min and quenched by sat. NH4Cl. [b] Isolated yield.
Next, we examined the reactions of phenols 6k and 6l with a
methoxy substituent on the phenol moiety, where interesting
results were obtained (Scheme 6). Upon treatment of 6k and 6l
with Ph3MgLi, the cycloaddition proceeded to give the
corresponding vinyl ethers VIII and VIII’, which turned out to be
fairly unstable. Thus, we chose quenching with sat. NH4Cl,
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10.1002/anie.202003131
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where ketones 12a and 12b were obtained in modest yields,
respectively. Upon further experimentation, we found that nBuLi
was more effective for these instances: Upon the reaction of 6k
and 6l with nBuLi (3.2 equiv, THF, 0 °C, 10 min) and quenching
with 1 M HCl, ketones 13a and 13b were obtained in 84% and
91% yield, respectively.
for the Promotion of Science (JSPS) (Grant Nos. JP16H06351
and JP18K06548). RIKEN HOKUSAI-GreatWave and
HOKUSAI-BigWaterfall provided the computer resources for the
DFT calculations.
Keywords: benzyne · phenol · intramolecular reaction · [4+2]
cycloaddition · silicon tether
OH
OH
[1]
[2]
R. W. Hoffmann, Dehydrobenzene and Cycloalkynes, Academic Press,
New York, 1967.
Br
Ph3MgLi
or
nBuLi
O
OMe
For selected recent reviews on benzyne, see: a) H. H. Wenk, M.
Winkler, W. Sander, Angew. Chem. Int. Ed. 2003, 42, 502–528; Angew.
Chem. 2003, 115, 518–546; b) R. Sanz, Org. Prep. Proced. Int. 2008,
40, 215–291; c) T. Kitamura, Aust. J. Chem. 2010, 63, 987–1001; d) C.
Wentrup, Aust. J. Chem. 2010, 63, 979–986; e) S. Yoshida, T. Hosoya,
Chem. Lett. 2015, 44, 1450–1460; f) J. Shi, Y. Li, Y. Li, Chem. Soc.
Rev. 2017, 46, 1707–1719; g) H. Pellissier, M. Santelli, Tetrahedron
2003, 59, 701–730; h) P. M. Tadross, B. M. Stoltz, Chem. Rev. 2012,
112, 3550–3577; i) C. M. Gampe, E. M. Carreira, Angew. Chem. Int.
Ed. 2012, 51, 3766–3778; Angew. Chem. 2012, 124, 3829–3842; j) A.
V. Dubrovskiy, N. A. Markina, R. C. Larock, Org. Biomol. Chem. 2013,
11, 191–218; k) A. E. Goetz, T. K. Shah, N. K. Garg, Chem. Commun.
2015, 51, 34–45; l) J.-A. García-López, M. F. Greaney, Chem. Soc.
Rev. 2016, 45, 6766–6798; m) T. Roy, A. T. Biju, Chem. Commun.
2018, 54, 2580–2594; n) H. Takikawa, A. Nishii, T. Sakai, K. Suzuki,
Chem. Soc. Rev. 2018, 47, 8030–8056; o) Y. Nakamura, S. Yoshida, T.
Hosoya, Heterocycles 2019, 98, 1623–1677.
OTs
THF, 10 min;
1 M HCl
iPr2Si
iPr2SiR OH
OH
O
OH
OMe
VIII
Ph3MgLi: 35% (12a, R = Ph)
nBuLi: 84% (13a, R = nBu)
6k
OH
OH
Br
as above
OTs
O
OMe
iPr2Si
iPr2SiR OH
OH
O
OH
VIII’
Ph3MgLi: 51% (12b, R = Ph)
nBuLi: 91% (13b, R = nBu)
6l
MeO
Scheme 6. Reactions of phenols 6k and 6l
Scheme
7
demonstrates further elaborations of the
cycloadducts, using 9 as a model substrate. Protodesilylation of
9a by treatment with tetrabutylammonium fluoride in the
presence of MS4A gave diol 14 in quantitative yield. The silyl
group served also as an equivalent to a hydroxy group: upon
treatment of 8b with tBuOOH (DMF, 50 °C), Tamao–Fleming
oxidation proceeded to give phenol 15 in 85% yield. 24 In
addition, bromination of the bridged alkene in 14 triggered a
skeletal rearrangement 25 via an aryl shift from bromonium
intermediate IX, giving benzobicyclo[3.2.1]octadienone 1626 in
91% yield.27
[3]
[4]
[5]
G. Wittig, Naturwissenschaften 1942, 30, 696–703.
R. Huisgen, H. Rist, Naturwissenschaften 1954, 41, 358–359.
J. D. Roberts, H. E. Simmons, Jr., L. A. Carlsmith, C. W. Vaughan, J.
Am. Chem. Soc. 1953, 75, 3290–3291.
[6]
[7]
G. Wittig, L. Pohmer, Angew. Chem. 1955, 67, 348.
For selected examples of the [4+2] cycloaddition of benzyne with
arenes, see: a) R. G. Miller, M. Stiles, J. Am. Chem. Soc. 1963, 85,
1798–1800; b) J. P. N. Brewer, H. Heaney, Tetrahedron Lett. 1965, 6,
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290; h) W. J. Houlihan, Y. Uike, V. A. Parrino, J. Org. Chem., 1981, 46,
4515–4517; i) P. W. Rabideau, Org. Prep. Proced. Int., 1986, 18, 113–
116; j) N. J. Hales, H. Heaney, J. H. Hollinshead, M. F. L. Steven, P.
Singh, Tetrahedron 1995, 51, 7777–7790; k) M. E. Şengül, D. D.
Gültekin, S. Eşsiz, E. Şahin, A. Daştan, Tetrahedron 2009, 65, 4859–
4865; l) T. R. Hoye, B. Baire, D. Niu, P. H. Willoughby, B. P. Woods,
Nature 2012, 490, 208–211; m) M. Schlesinger, M. Hofmann, T. Rüffer,
D. Schaarschmidt, H. Lang, S. Theilacker, M. Schürmann, K.
Jurkschat, M. Mehring, Eur. J. Inorg. Chem. 2013, 2930–2939; n) V. D.
Pogula, T. Wang, T. R. Hoye, Org. Lett. 2015, 17, 856–859.
tBuOOH
nBu4N+F–
NaH, MS4A
OH
OH
OH
nBu4N+F–
MS4A
DMF, 50 °C
THF, RT
H
OH
iPr2SiPh OH
OH OH
15 (85%)
14 (quant.)
9a
Br+
HO
Br
HO
HO
NBS
CH2Cl2
0 °C
OH
OH
O
16 (91%)
IX
[8]
[9]
A. Nishii, H. Takikawa, K. Suzuki, Chem. Sci. 2019, 10, 3840–3845.
W. J. Hale, E. C. Britton, Ind. Eng. Chem. 1928, 20, 114–124.
Scheme 7. Synthetic transformations. MS = molecular sieves, NBS = N-
bromosuccinimide
[10] For details of the DFT calculation, see the supporting information.
[11] For selected reports on the intermolecular O- and C-additions of
phenol(ate) to benzyne, see: a) G. W. Dalman, F. W. Neumann, J. Am.
Chem. Soc. 1968, 90, 1601–1605; b) B. Bates, K. D. Janda, J. Org.
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3209; e) T. Truong, O. Daugulis, Chem. Sci. 2013, 4, 531–535; For the
intramolecular variants, see: f) D. H. Hey, J. A. Leonard, C. W. Rees, J.
Chem. Soc. 1963, 5266–5270; g) S. V. Kessars, S. Batra, S. S.
Gandhi, Indian J. Chem. 1970, 8, 468–469; h) T. Kametani, S. Shibuya,
K. Kigasawa, M. Hiragi, O. Kusama, J. Chem. Soc. C 1971, 2712–
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Suau, M. C. Vidal, Tetrahedron Lett. 1983, 24, 2295–2298; j) D. W.
Knight, P. B. Little, J. Chem. Soc., Perkin Trans. 1 2001, 1771–1777;
k) G. B. Bajracharya, O. Daugulis, Org. Lett. 2008, 10, 4625–4628.
In summary, we have demonstrated the unprecedented
intramolecular benzyne cycloaddition with phenolates. A variety
of tethers proved applicable, among which the cleavable Si–O
tether demonstrated a broad substrate scope, enabling access
to various benzobarrelene derivatives. The synthetic utility of
this methodology was further confirmed by transformations of
the cycloadducts. Further investigation is in progress.
Acknowledgments
We are grateful to Central Glass Co., Ltd. for the gift of triflic
anhydride. We thank Prof. Dr. Jun Takaya for X-ray analysis.
This work was supported by Grant-in-Aid from Japan Society
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For details, see the supporting information.
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[20] See the supporting information.
[21] Cycloadduct 2b contained a small amount of n-butylated product (5%
by NMR), which was chromatographically inseparable. The yield of 2b
was calibrated by 1H NMR analysis. For details, see the supporting
information.
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for this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.au.uk/data_request/cif.
[27] A minor amount (6%) of the isomeric product via the vinyl shift was
obtained. For details, see the supporting information.
This article is protected by copyright. All rights reserved.

10.1002/anie.202003131
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hiroshi Takikawa, Arata Nishii, Hiromu
Takiguchi, Hirotoshi Yagishita, Masato
Tanaka, Keiichi Hirano, Masanobu
Uchiyama, Ken Ohmori,* and Keisuke
Suzuki*
benzyne
OH
Ph3MgLi
or
nBuLi
X
O–
OSO2R
[4+2]
phenolate
OH
Page No. – Page No.
The Intramolecular benzyne–phenolate [4+2] cycloaddition has been developed.
Benzyne precursors, having vicinal halogen–sulfonate functionalities, linked with a
phenol(ate) by various tether groups undergo efficient intramolecular [4+2]
cycloaddition by treatment of Ph3MgLi or nBuLi for halogen–metal exchange to form
various benzobarrelenes. The method is characterized by wide availability of
reaction precursors and high yield for the products.
Intramolecular Benzyne–Phenolate
[4+2] Cycloadditions
This article is protected by copyright. All rights reserved.