Selective aryne formation via Grob fragmentation from the [2+2] cycloadducts of 3-triflyloxyarynes

Article abstract of DOI:10.1021/Jacs.6b12161

A chemoselective ring-opening protocol of the formal [2+2] cycloadducts of 3-triflyloxyarynes was developed to generate 2,3-aryne intermediate via Grob fragmentation. A variety of 1,3-di- and 1, 2, 3-trisubstituted arenes could be readily accessed through this [2+2] cycloaddition-2,3-aryne formation sequence. The regioselectivity in these transformations originates from the steric repulsion of the aliphatic chain.

Full text of DOI:10.1021/Jacs.6b12161

Subscriber access provided by Fudan University
Communication
Selective Aryne Formation via Grob Fragmentation
from the [2+2] Cycloadducts of 3-Triflyloxyarynes
Jiarong Shi, Hai Xu, Dachuan Qiu, Jia He, and Yang Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Dec 2016
Downloaded from http://pubs.acs.org on December 30, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Selective Aryne Formation via Grob Fragmentation from the
[2+2] Cycloadducts of 3-Triflyloxyarynes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jiarong Shi,† Hai Xu,† Dachuan Qiu, Jia He, Yang Li*
School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, P. R. China,
400030
Supporting Information Placeholder
ducts? Herein we would like to present our discovery on the conꢀ
venient regioselective multifunctionalization of 3ꢀ
triflyloxybenzyne (i), where its formal [2+2] cycloadducts with
ketene silyl acetals (KSAs) could be readily converted to 2,3ꢀ
aryne intermediates through Grob fragmentation.
ABSTRACT: A chemoselective ring opening protocol of the
formal [2+2] cycloadducts of 3ꢀtriflyloxyarynes was developed to
generate 2,3ꢀaryne intermediate via Grob fragmentation. A variety
of 1,3ꢀdiꢀ and 1,2,3ꢀtrisubstituted arenes could be readily accessed
through this [2+2] cycloadditionꢀ2,3ꢀaryne formation sequence.
The regioselectivity in these transformations originates from the
steric repulsion of the aliphatic chain.
It is worth mentioning that this protocol can readily reach pheꢀ
nylacetic acid framework that plays important pharmacological
roles in medicines, such as Fexofenadine and a variety of pain
relievers (Ibuprofen, Carprofen, Fenoprofen, and Bromofenec,
etc.) (Figure 1). Further elaboration of the aliphatic side chain
could afford benzoates or benzamides, such as the structure of
anticancer drug Niraparib.8
In the past a few decades, aryne chemistry earned fruitful
achievements in the areas of nucleophilic reactions, pericyclic
reactions, and transitionꢀmetalꢀcatalyzed reactions.1 Recent adꢀ
vances in this field were greatly boosted by mild generation conꢀ
ditions for these highly reactive intermediates, i.e. the methods
developed by Kobayashi1f,1g,2 and Hoye.3 Toward aromatic comꢀ
pounds with over two substituents, however, a simple aryne inꢀ
termediate cannot fulfill the task. Alternatively, building blocks
that can generate multiple triple bonds on a benzene ring, i.e.
benzdiyne4 and benztriyne5 equivalents, were investigated, which
could furnish a benzene analog with up to six substituents. In
view of the vast existence of natural products as well as drug molꢀ
ecules containing multifunctionalized arene structural motifs, the
convenient, practical, and/or transitionꢀmetalꢀfree production of
these aromatic frameworks remains one of the top goals to purꢀ
suit.
Scheme 1. Background and Our Design.
Figure 1. Selected Medicines.
In line with our interest in the efficient preparation of multisubꢀ
stituted arenes via aryne chemistry,6,9 we were curious that, after
3ꢀtriflyloxybenzyne (i) undergoes [2+2] cycloaddition to form a
fourꢀmembered ring, whether it is plausible to kick out the C3ꢀ
OTf group and generate a 2,3ꢀaryne intermediate. With this conꢀ
sideration in mind, we commenced our study by seeking possible
further conversion means from the [2+2] cycloadduct of 3ꢀ
triflyloxybenzyne (i). Upon ring opening, benzocyclobutenols or
benzocyclobutenones intend for either distal CꢀC bond cleavage
(Scheme 1b, path a) or proximal CꢀC bond cleavage (Scheme 1b,
path b). In general, thermolytic ring opening prefers path a via oꢀ
xylylene intermediates (Scheme 1c).10 Recently, Dong11 and othꢀ
ers12 developed transitionꢀmetal insertion approaches to these
strained rings, which enabled the selective CꢀC bond cleavage via
path b (Scheme 1d). As shown in Scheme 1e, we conceived that
both the excellent leaving ability and electron withdrawing charꢀ
acter of an OTf group might be able to alter the ringꢀopening
As a recently emerged aryne intermediate, 3ꢀtriflyloxybenzyne
(i) has been found versatile to prepare various multisubstituted
arenes through the iterative generation of two aryne intermediates,
namely 1,2ꢀ and 2,3ꢀarynes (Scheme 1a).6 Mechanistic perception
of this process, however, reveals that a nucleophile is necessary to
act as the “vanguard” to attack intermediate i in an SN2’ manner
in order to trigger the following steps. In sharp contrast, whenever
a pericyclic reaction takes place, both the 1ꢀ and 2ꢀpositions on i
are locked simultaneously, which would then prohibit the generaꢀ
tion of the 2,3ꢀaryne intermediate.7 Is it really obligatory that no
second aryne could be produced after i is “locked” by its cycloadꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
means towards path b and result in the generation of 2,3ꢀaryne
yields, respectively, both of which showed excellent selectivity.
1
2
3
4
5
6
7
8
species (also see Scheme 1b, X = OTf), the process of which is
also seen as a Grob fragmentation.13 Although Grob fragmentaꢀ
tion is wellꢀknown to form alkenes and alkynes with numerous
synthetic applications, this fragmentation approach has yet to be
utilized in aryne generation.14
[3+2] Cycloaddition with Nꢀtertꢀbutylꢀαꢀphenylnitrone and benzyl
azide afforded 9 and 10, respectively, in good to high regioselecꢀ
tivities. However, when 2ꢀmethyl furan was reacted with 1i, the
reaction gave products 11a and 11a’ in a ratio of 1.4:1. With an
effort to increase the steric repulsion by using 2ꢀtrimethylsilyl
furan as the substrate, the product ratio of 11b:11b’ only slightly
enhanced to 2.8:1. Moreover, the insertion reactions of the generꢀ
ated 2,3ꢀaryne with both σꢀbond and double bond were tested.
Single product 12a was obtained in 68% yields when pꢀtolyl cyꢀ
anamide18 was utilized. In the presence of ethyl bromoacetate,
aryne insertion into the S=O bond of pꢀtolyl methyl sulfoxide19
gave 13a as the product in high selectivity and good yield as well.
The structures of 10b and 12a were unambiguously determined by
their Xꢀray single crystal analysis, and the stereochemistry of the
other major products was determined by NOE study (Table 1).
Scheme 2. Study on Various Leaving Groups.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To test our hypothesis, we commenced our study by examining
a series of [2+2] cycloadducts 1 prepared from 3ꢀsubstituted benꢀ
zynes and KSAs, the regioselective construction of which have
been established by Suzuki and others5,7a,15 (Scheme 2, also see
Supporting Information for their preparation). Satisfyingly, when
1a with an OTf as the leaving group (LG) was tested, its Dielsꢀ
Alder reaction with furan afforded 2a in 78% yield. Interestingly,
1b with a 6ꢀBr group could also afford 2a in 66% yield. However,
both 1c and 1d with 6ꢀOTs and 6ꢀCl groups, respectively, either
gave trace amount of 2a or had no desired product at all. These
results indicate that the groups on the C6 position of 1 dramaticalꢀ
ly affect aryne generation efficiency. To the best of our
knowledge, this is the first example exhibiting the generation of
an aryne intermediate via Grob fragmentation from a benzocycloꢀ
butenol analog along with the concomitant disconnection of three
chemical bonds, namely OꢀSi, CꢀC, and CꢀO bonds. Because the
OTf group is superior over other LGs in this transformation,1f,1g in
addition with the convenient preparation of 1a, we decided to
carry on our study using OTf as the leaving group.
Scheme 3. Reactions of Morpholine with Aryne Precursors 1.
After establishing this ring opening, 2,3ꢀaryne formation protoꢀ
col, morpholine was chosen as the nucleophile to examine the
reactivity of this method (Scheme 3). A challenge was encounꢀ
tered on this stage: there would be lack of regioselective control
on intermediate iii (Scheme 1e) when 1a is employed. Indeed,
when 1a reacted with morpholine, a mixture of regioisomers 3a
and 3a’ were obtained in a ratio of ~1.7:1. Similar ratios were also
found with 1e and 1f, when a methoxy or a tertꢀbutoxy group is
present (Scheme 3). How to differentiate the two reaction sites on
intermediate iii, namely the metaꢀ and orthoꢀpositions, in order to
enhance the regioselectivity becomes an urgent demand for this
work. Gratifyingly, gradually increasing the steric congestion on
the C2ꢀposition (Scheme 3, 1g to 1j) could dramatically affect the
metaꢀtoꢀortho selectivity and eventually reach the sole products 3i
and 3j. Preliminary modeling study revealed that the excellent
selectivity originates from the prominent steric repulsion of the
bulky gemꢀdimethyl or gemꢀdimethoxy groups. Although EW
conductive effect has been extensively investigated in aryne
chemistry to regulate the regioselectivity,1c,16 there are only limꢀ
ited successes on steric repulsionꢀcontrolled aryne chemistry.17
Moreover, compounds 1 with additional substituents, such as Me
(1k and 1l), Br (1m), and Ph (1n) groups, on the benzene ring
were tested; all of them could afford the desired products in good
to high yields with excellent regioselectivity.
conditions: 1 (0.2 mmol), morpholine (0.4 mmol) and CsF (0.4
mmol) in MeCN (4 mL) at rt.
To elucidate the relationship between reaction type and product
structure, a close analysis of the examples in Table 1 disclosed
that our approach has a tendency to give excellent meta selectivity
whenever a nucleophile is employed or the first step of the reacꢀ
tion with the 2,3ꢀaryne is more or less nucleophilic. For example,
the formal [2+2] cycloaddition with arynes is known to be a firstꢀ
step nucleophilic process,5,15 which is also the same scenario with
both aryl cyanamide and sulfoxide. In contrast, in the pericyclic
transformations with furan derivatives, the ratios of products 11
are significantly diminished, indicating that the steric repulsion
does not dramatically affect the regioselectivity in concerted proꢀ
cesses. As for the [3+2] cycloadditions with phenylnitrone and
benzyl azide, the medium product ratios might be attributed to an
overall effect of the nucleophilic and the steric characters of these
substrates.
After identifying both gemꢀdimethyl and gemꢀdimethoxy
groups as the ideal regulation factors with morpholine, we proꢀ
ceeded to study their reactivity with various arynophiles. As
shown in Table 1, different nucleophiles, such as Nꢀmethylaniline,
imidazole, phenol, and thiophenol, could all afford the desired
products 4ꢀ7 in distinct metaꢀselection. Because arynes are supeꢀ
rior in making fused rings, we then tested different cycloaddition
reactions with 1i and 1j. The formal [2+2] cycloaddition of 1,1ꢀ
dimethoxyethene with 1i and 1j gave 8a and 8b in 73% and 54%
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
as a potent antitumor PARP inhibitor, especially in the treatment
Table 1. The reactions with Aryne Precursors 1i and 1j.
of ovarian cancer.8 As shown in Scheme 4c, [3+2] Cycloaddition
of 1j with 16 afforded 17 in 42% yield along with 50% of the
other isomer 17’. The following twoꢀstep oneꢀpot conversion of
17 to benzamide using the conditions developed in Scheme 4a
could afford racemic Niraparib in 65% overall yield. Although the
regioselectivity in the [3+2] cycloaddition step is not satisfactory,
the core of compound 17’ also shows PARP inhibition activity,
the framework of which cannot be readily synthesized via tradiꢀ
tional ways.21 All of these examples suggest that our protocol is
amenable and could be used in broad synthetic applications.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Synthetic Elaboration.
a.
O
O
O
N
N
N
O2, Cu2O
NH3-H2O, 120 o
C
TFA-H2O
60 oC, 87%
CO2H
80%
NH2
CO2Me
MeO OMe
O
14
O
3j
15
b.
PhO
i. PhOH, CsF
MeCN,
i. p-chloroaniline
H
N
CsF, MeCN, 71%
(single isomer)
(10:1 ratio)
Me
Me
OH
1h
Cl
ii. Pd(OAc)2
PivOH, 57%
iii. 10% NaOH
MeOH, 90%
ii. 10% NaOH
MeOH
(51% in two steps)
OH
O
O
Fenoprofen
Carprofen
OMe
c.
OMe
MeO
OTf
MeO
O-
OTBS
OMe
CsF
O
O
MeO
MeO
+
+
O
MeCN
92%
N
N+
OMe
N
N
ArBoc
N
ArBoc
Ar
OMe
1j
N
Boc
16
17
(1 : 1.2)
17'
i. TFA-H2O, 60 o
ii. Cu2O, O2,
C
Ar =
NH3-H2O, 120 o
(65% in two steps)
C
NH
These examples are the first to exhibit that 3ꢀtriflyloxybenzyne
H2N
O
(i) can be involved in unprecedented reaction sequences, namely
cycloadditionꢀnucleophilic and cycloadditionꢀcycloaddition reacꢀ
tions. Moreover, with the success of this strategy, we wonder if
we could track back this transformation to 3ꢀtriflyloxybenzyne (i)
stage. As an exhibition, gramꢀscale of 3ꢀtriflyloxybenzyne (i)
precursor was treated with KSA first and, upon reaction compleꢀ
tion, CsF and furan were then added. Finally, 2a was isolated in a
total 60% yield in this oneꢀpot process (eq 1).
N
N
Ar
Niraparib
In summary, toward arene multifunctionalization, we have deꢀ
veloped a unique protocol with 3ꢀtriflyloxyaryne intermediates, in
which a chemoselective ring opening method was exquisitely
designed from their [2+2] cycloadducts via Grob fragmentation in
order to allow the generation of the consequent 2,3ꢀaryne interꢀ
mediate. This strategy is general, highly efficient, and transitionꢀ
metalꢀfree, which could be utilized in various combinations of
arynophiles as well as in drug syntheses. The regioselectivity of
this protocol is influenced by steric repulsion and preferentially
favors nucleophilicꢀtype transformations. Our ongoing work inꢀ
cludes other synthetic applications of this protocol.
Study on the phenylacetic acid framework of the products disꢀ
closed that this protocol could not only provide convenient further
elaboration opportunities but also be used in practical synthesis of
valuable molecules. It was noticed that the successful utilization
of gemꢀdimethoxy analog 1j in this transformation is distinct,
because this side chain could be converted to various other funcꢀ
tional groups. As an exhibition, ketone acid 14 was readily obꢀ
tained in 87% yield from compound 3j in wet trifluoroacetic acid.
Further decarboxylative conversion of 14 produced benzamide 15
in 80% yield (Scheme 4a).20 Consequently, the aliphatic sideꢀ
chain from our ringꢀopening products could also be seen as an
equivalent of either benzoate or benzamide, which shed the light
on a broader spectrum of applications for this methodology.
ASSOCIATED CONTENT
Supporting Information. Experimental details for all chemical
reactions and measurements and Xꢀray single crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
y.li@cqu.edu.cn
Because phenylacetic acid is an important structural motif on
many drug molecules, we picked Fenoprofen and Carprofen as
our synthetic targets. As shown in Scheme 4b, Fenoprofen was
synthesized in two steps from 1h, and Carprofen was made in one
extra step, both of which gave high regioselectivity in the ringꢀ
opening step. In order to further exhibit the synthetic applicability
of our protocol, Niraparib was chosen, which is recently emerged
Author Contributions
†Shi, J. and Xu, H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(12) For selected examples, see: a) Ishida, N.; Sawano, S.; Masuda,
The authors gratefully acknowledge research support of this work
by NSFC (21372268), Fundamental Research Funds for the Cenꢀ
tral Universities (106112016CDJZR228806), and Graduate Scienꢀ
tific Research and Innovation Foundation of Chongqing (Grant
No. CYB16033).
Y.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17502ꢀ17504; b) Li,
Y.; Lin, Z. J. Org. Chem. 2013, 78, 11357ꢀ11365; c) Ding, L.; Ishida,
N.; Murakami, M.; Morokuma, K. J. Am. Chem. Soc. 2014, 136, 169ꢀ
178; d) Xia, Y.; Liu, Z.; Liu, Z.; Ge, R.; Ye, F.; Hossain, M.; Zhang,
Y.; Wang, J. J. Am. Chem. Soc. 2014, 136, 3013ꢀ3015; e) Yu, J.; Yan,
H.; Zhu, C. Angew. Chem., Int. Ed. 2016, 55, 1143ꢀ1146.
(13) For selected recent reviews, see: a) Prantz, K.; Mulzer, J.
Chem. Rev. 2010, 110, 3741ꢀ3766; b) Drahl, M. A.; Manpadi, M.;
Williams, L. J. Angew. Chem., Int. Ed. 2013, 52, 11222ꢀ11251.
(14) Similar ring opening manners were elaborated, however, no
aryne generation was detected under these conditions: a) Gokhale, A.;
Schiess, P. Helv. Chim. Acta 1998, 81, 251ꢀ267; b) Hosoya, T.;
Hamura, T.; Kuriyama, Y.; Miyamoto, M.; Matsumoto, T.; Suzuki, K.
Synlett 2000, 520ꢀ522.
1
2
3
4
5
6
7
8
REFERENCES
(1) For recent reviews, see: a) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502ꢀ528; b) Pellissier, H.;
Santelli, M. Tetrahedron 2003, 59, 701ꢀ730; c) Sanz, R. Org. Prep.
Proced. Int. 2008, 40, 215ꢀ291; d) Gampe, C. M.; Carreira, E. M.
Angew. Chem., Int. Ed. 2012, 51, 3766ꢀ3778; e) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550ꢀ3577; f) Bhunia, A.; Yetra,
S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140ꢀ3152; g)
Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org. Biomol.
Chem. 2013, 11, 191ꢀ218; h) Goetz, A. E.; Shah, T. K.; Garg, N. K.
Chem. Commun. 2015, 51, 34ꢀ45.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) a) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Suzuki, K.
Tetrahedron Lett. 1995, 36, 3377ꢀ3380; b) Stevens, R. V.; Bisacchi,
G. S. J. Org. Chem. 1982, 47, 2393ꢀ2396.
(2) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211ꢀ1214.
(16) For selected recent examples, see: a) Goetz, A. E.; Garg, N. K.
Nat. Chem. 2013, 5, 54ꢀ60; b) Medina, J. M.; Mackey, J. L.; Garg, N.
K.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 15798ꢀ15805.
(17) For selected recent examples, see: a) Akai, S.; Ikawa, T.;
Takayanagi, S.ꢀI.; Morikawa, Y.; Mohri, S.; Tsubakiyama, M.; Egi,
M.; Wada, Y.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 7673ꢀ7676;
b) Ikawa, T.; Takagi, A.; Kurita, Y.; Saito, K.; Azechi, K.; Egi, M.;
Kakiguchi, K.; Kita, Y.; Akai, S. Angew. Chem., Int. Ed. 2010, 49,
5563ꢀ5566; c) Bronner, S. M.; Mackey, J. L.; Houk, K. N.; Garg, N.
K. J. Am. Chem. Soc. 2012, 134, 13966ꢀ13969.
(18) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314ꢀ317.
(19) Liu, F.ꢀL.; Chen, J.ꢀR.; Zou, Y.ꢀQ.; Wei, Q.; Xiao, W.ꢀJ. Org.
Lett. 2014, 16, 3768ꢀ3771.
(20) Song, Q.; Feng, Q.; Yang, K. Org. Lett. 2014, 16, 624ꢀ627.
(21) Ingenito, R.; Jones, P.; Llauger Bufi, L.; Ontoria Ontoria, Jeꢀ
sus M.; Scarpelli, R. WO 2009112832A1, 2009.
(3) For examples, see: a) Hoye, T. R.; Baire, B.; Niu, D.;
Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208ꢀ212; b) Niu,
D.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature
2013, 501, 531ꢀ534; c) Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34ꢀ
40.
(4) For selected examples of benzdiyne equivalents, see: a) Hart,
H.; Lai, C.; Nwokogu, G.; Shamouilian, S.; Teuerstein, A.;
Zlotogorski, C. J. Am. Chem. Soc. 1980, 102, 6649ꢀ6651; b) Chen, C.ꢀ
L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128, 13696ꢀ
13697; c) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki, K.
Angew. Chem., Int. Ed. 2006, 45, 6842ꢀ6844; d) Schuler, B.; Colꢀ
lazos, S.; Gross, L.; Meyer, G.; Pérez, D.; Guitián, E.; Peña, D. Anꢀ
gew. Chem., Int. Ed. 2014, 53, 9004ꢀ9006; e) Ikawa, T.; Masuda, S.;
Takagi, A.; Akai, S. Chem. Sci. 2016, 7, 5206ꢀ5211; f) Du, C.ꢀJ. F.;
Hart, H.; Ng, K.ꢀK. D. J. Org. Chem. 1986, 51, 3162ꢀ3165.
(5) For selected examples of 1,3,5ꢀbenztriyne equivalents, see: a)
Hamura, T.; Ibusuki, Y.; Uekusa, H.; Matsumoto, T.; Suzuki, K. J.
Am. Chem. Soc. 2006, 128, 3534ꢀ3535; b) Hamura, T.; Ibusuki, Y.;
Uekusa, H.; Matsumoto, T.; Siegel, J. S.; Baldridge, K. K.; Suzuki, K.
J. Am. Chem. Soc. 2006, 128, 10032ꢀ10033; c) Shinozaki, S.;
Hamura, T.; Ibusuki, Y.; Fujii, K.; Uekusa, H.; Suzuki, K. Angew.
Chem., Int. Ed. 2010, 49, 3026ꢀ3029.
(6) a) Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am. Chem. Soc.
2015, 137, 5670ꢀ5673; b) Qiu, D.; He, J.; Yue, X.; Shi, J.; Li, Y. Org.
Lett. 2016, 18, 3130ꢀ3133; c) Li, L.; Qiu, D.; Shi, J.; Li, Y. Org. Lett.
2016, 18, 3726ꢀ3729.
(7) a) Yoshida, S.; Uchida, K.; Igawa, K.; Tomooka, K.; Hosoya,
T. Chem. Commun. 2014, 50, 15059ꢀ15062; b) Ikawa, T.; Kaneko, H.;
Masuda, S.; Ishitsubo, E.; Tokiwa, H.; Akai, S. Org. Biomol. Chem.
2015, 13, 520ꢀ526.
(8) a) Jones, P.; Altamura, S.; Boueres, J.; Ferrigno, F.; Fonsi, M.;
Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J. M.; Orsale,
M. V.; Palumbi, M. C.; Pesci, S.; Roscilli, G.; Scarpelli, R.; Schultzꢀ
Fademrecht, C.; Toniatti, C.; Rowley, M. J. Med. Chem. 2009, 52,
7170ꢀ7185; b) Jones, P.; Wilcoxen, K.; Rowley, M.; Toniatti, C. J.
Med. Chem. 2015, 58, 3302ꢀ3314.
(9) a) Qiu, D.; Shi, J.; Li, Y. Synlett 2015, 26, 2194ꢀ2198; b) Li,
Y.; Qiu, D.; Gu, R.; Wang, J.; Shi, J.; Li, Y. J. Am. Chem. Soc. 2016,
138, 10814ꢀ10817.
(10) For examples, see: a) Jefford, C. W.; Bernardinelli, G.; Wang,
Y.; Spellmeyer, D. C.; Buda, A.; Houk, K. N. J. Am. Chem. Soc.
1992, 114, 1157ꢀ1165; b) Iida, K.; Saito, M.; Yoshioka, M. J. Org.
Chem. 2000, 65, 4909ꢀ4912; c) Hamura, T.; Miyamoto, M.;
Matsumoto, T.; Suzuki, K. Org. Lett. 2002, 4, 229ꢀ232; d) Suzuki, T.;
Hamura, T.; Suzuki, K. Angew. Chem., Int. Ed. 2008, 47, 2248ꢀ2252.
(11) For examples, see: a) Xu, T.; Dong, G. Angew. Chem., Int. Ed.
2012, 51, 7567ꢀ7571; b) Xu, T.; Ko, H. M.; Savage, N. A.; Dong, G.
J. Am. Chem. Soc. 2012, 134, 20005ꢀ20008; c) Chen, P.ꢀH.; Xu, T.;
Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1674ꢀ1678; d) Deng, L.;
Xu, T.; Li, H.; Dong, G. J. Am. Chem. Soc. 2016, 138, 369ꢀ374.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
Insert Table of Contents artwork here
3
4
5
6
7
8
X
OTf
OTBS
Y
O
CsF
arynophiles
O
OR1
R2
OR1
-TBSF
-CsOTf
OR1
R2 R3
R3
R2 R3
Grob fragmentation
three-bond cleavage
convertable
side chain
9
diverse aryne chemistry
1,3-di- & 1,2,3-trisubstituted arenes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
steric repulsion-controlled regioselectivity
5
ACS Paragon Plus Environment