Synthesis of 2-Benzylphenyl Ketones by Aryne Insertion into Unactivated C-C Bonds

Article abstract of DOI:10.1021/acs.orglett.6b00578

A transition-metal-free procedure to access to functionalized 2-benzylphenyl ketones is described by direct insertion of arynes into benzylic C-C bonds. This reaction was promoted by cesium fluoride at room temperature, allowing the products to form in high selectivity and achieve good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.6b00578

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Benzylphenyl Ketones by Aryne Insertion into
Unactivated C−C Bonds
Bin Rao, Jinghua Tang, and Xiaoming Zeng*
Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi 710054, P. R.
China
S
* Supporting Information
ABSTRACT: A transition-metal-free procedure to access to
functionalized 2-benzylphenyl ketones is described by direct
insertion of arynes into benzylic C−C bonds. This reaction was
promoted by cesium fluoride at room temperature, allowing the
products to form in high selectivity and achieve good functional
group tolerance.
different from the oxidative addition-involving conversions, the
he development of efficient strategies to cleave C−C σ-
Tbonds followed by addition across unsaturated C−C direct insertion of arynes into C−C bonds provides an
bonds has recently attracted broad interests.1 Such a “cut and
sew” method provides a powerful and useful tool for the rapid
buildup of complex molecules in high atom economy, but the
cleavage of unactivated C−C bonds has long been a formidable
alternative strategy via the formation of a four-membered ring
intermediate,5,6 which was disclosed by Stoltz and Yoshida
using β-dicarbonyl precursors.7 In spite of the considerable
progress, strongly electron-withdrawing groups such as cyano,
ester, sulfonyl and phosphonate locating at the α position of
ketones are often indispensable for the cleavage of C−C bonds
(Scheme 1, eq 2).8 Note that Yoshida demonstrated that
trifluoromethyl or 9-fluorenyl-containing ketone undergo the
aryne insertion effectively, but suffer from a limited substrate
scope.9 In view of its efficiency in the rapid construction of
synthetically appealing structural motifs, further exploration of
new procedure with alternative substrates would be particularly
attractive.
challenge. Recent developments in the field mainly focused on
transition metal-catalyzed reactions, such as the expansion of
strained rings,2 chelation-assisted transformations,3 and addi-
tion to C−CN bonds4 (Scheme 1, eq 1). Mechanistically
Scheme 1. Straightforward Functionalization of Unactivated
C−C Bonds
2-Benzylphenyl ketones are fundamental building blocks
found in various drug molecules and complex natural
products.10 They have often been employed as crucial
precursors in preparing blue-emitting molecules,11 and hetero-
cycles such as isobenzofuran, isobenzothiophene, isoindazole,
phthalazine.12 We assumed that the direct insertion of arynes
into benzylic ketones allows these frameworks to form by the
cleavage of unactivated C−C bonds. That said, it may suffer
from a selectivity issue because of the competitive α-arylation of
ketone (Scheme 1, eq 3).13 Herein, we report a straightforward,
selective aryne insertion into benzylic C−C bonds enabled by
cesium fluoride, providing access to 2-benzylphenyl ketones at
room temperature in a simple operation (Scheme 1, eq 4).
Initially, 2-phenylacetophenone 2a was treated with 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate 1a for opti-
mizing reaction conditions. In the presence of cesium fluoride,
we were pleased to find that the resulting benzyne was allowed
to direct insert into benzylic C−C bonds in a solution of DME,
leading to (2-benzylphenyl) (phenyl)methanone (3a) in 67%
Received: February 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield (Table 1, entry 1). Note that the replacement of DME by
THF, toluene, DCE, DCM or ethyl ether completely inhibited
a,b
Table 1. Optimizing Reaction Conditions
c
entry
deviation from the standard conditions
none
3a (%)
3a/3a′
d
1
2
72 (67)
nd
20:1
toluene, DCE, CH2Cl2, THF, or ethyl ether
instead of DME
3
CH3CN or dioxane instead of DME
70 °C in CH3CN instead of rt in DME
70 °C in THF instead of rt in DME
105 °C in THF instead of rt in DME
0.1 M instead of 0.2 M
<10
4
45
4:1
24:1
23:1
23:1
12:1
10:1
<12:1
20:1
5
41
d
6
61 (56)
39
7
8
0.3 M instead of 0.2 M
69
9
KF and 18-C-6 instead of CsF
TBAT or TBAF instead of CsF
1a (1.5 equiv) instead of 1a (2 equiv)
38
10
11
<20
63
a
Standard conditions: 1a (0.2 mmol), 2a (0.1 mmol), CsF (0.4
b
mmol), DME (0.5 mL, 0.2 M), rt, 14 h. 1H NMR yield was
determined using dibromomethane as internal standard. The ratio
was determined by H NMR analysis of the crude product. Isolated
yield in parentheses. DCE = 1,2-dichloroethane, nd = not detected,
DME = 1,2-dimethoxylethane, 18-C-6 = 18-crown-6 ether, TBAF =
tetrabutylammonium fluoride, TBAT = tetrabutylammonium triphe-
nyldifluorosilicate.
c
d
1
the conversion, and 2a was recovered in these cases (Table 1,
entry 2). While the use of acetonitrile and dioxane led to a low
conversion (Table 1, entry 3). Inferior performance was
observed when heating the reaction mixture (Table 1, entries
4−6). Other fluoride salts including KF, TBAT and TBAF
cannot improve the transformation (Table 1, entries 9 and 10).
Having the optimal conditions, the substrate scope was next
investigated (Figure 1). The insertion of benzyne into
substituted 2-phenylacetophenone carried out effectively at
room temperature. A wide range of functional groups such as
alkoxy, cyano, fluoride, chloride, bromide, iodide, and
trifluoromethyl were tolerated by the protocol, forming diverse
substituted 2-benzylbenzophenones 3c−i in good to excellent
yields (68−96%). Meanwhile, installation of OBoc, OTs, OTf,
or amino carbonate onto the scaffold of aromatics has no
influence on the benzyne insertion (3j−m). The reaction with
1-(1-naphthyl)-2-phenylethanone proceeded smoothly, form-
ing the product 3r in 75% yield. Introducing a bromo
substituent into the ortho position of the benzyl scaffold did
not hamper the transformation (3u and 3v). 2-Thienylmethyl-
substituted benzophenone was formed in 80% yield (3y).
Furthermore, the extension of this protocol to the preparation
of ferrocenyl- and methyl-substituted ketone derivatives 3z−ab
was successful. Interestingly, the use of 1,3-diphenylacetone
gave an unexpected product 3ac by a double aryne insertion
into two benzylic C−C bonds. In addition, two-substituted
benzynes also underwent the reaction effectively under
standard conditions (3ae and 3af).14 It was noteworthy that
a single product of 3ag was formed with high regioselectivity
from an unsymmetric 3,5-dimethoxy-substituted benzyne for
the inductive effect of methoxyl groups.15
Figure 1. Aryne insertion into C−C bonds for the synthesis of 2-
benzylphenyl ketones. (a) Conditions: aryne precursor (0.4 mmol),
ketone (0.2 mmol), CsF (0.8 mmol), DME (1 mL), rt, 6−16 h.
Isolated yield was given. (b) 1a (0.8 mmol), 24 h.
Aiming to gain insight into the electronic effect on the
transformation, methoxy- or trifluoromethyl-substituted 1-(4-
methoxyphenyl)-2-phenylethanone (4a or 4b) was treated with
benzyne precursor (Scheme 2). A low conversion was obtained
Scheme 2. Investigation of the Electronic Influence of
Benzylic Ketones on the Conversion
a
The reaction was performed at 90 °C for 14 h.
B
DOI: 10.1021/acs.orglett.6b00578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
by use of 4-methoxy-containing ketone 4a (<10%). Conversely,
the reaction with 4b provided the corresponding product 5b in
81% yield. These results suggest that the electronic properties
on the benzyl scaffold affect the transformation, and support an
electron-deficient benzyl-favorable transformation because of its
facile formation of a carbanion in the transformation.
To explore a plausible mechanism for the aryne insertion, the
experiment by reacting alkyl phenyl ketones 6a−e with benzyne
was next carried out (Scheme 3). It was found that the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work by XJTU from a start-up fund and the
National Natural Science Foundation of China [Nos. 21202128
(X.Z.), 21572175] is gratefully acknowledged. We thank Prof.
Yan-Zhen Zheng (XJTU) and Mr. Guojun Zhou (XJTU) for X-
ray crystallographic analysis.
Scheme 3. Mechanistic Insights
REFERENCES
■
(1) (a) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410−9464.
(b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613−8661.
(c) Dermenci, A.; Coe, J. W.; Dong, G. Org. Chem. Front. 2014, 1,
567−581. (d) Dong, G. Synlett 2012, 24, 1−5. (e) Jun, C.-H. Chem.
Soc. Rev. 2004, 33, 610−618. (f) Perthuisot, C.; Edelbach, B. L.;
Zubris, D. L.; Simhai, N.; Iverson, C. N.; Muller, C.; Satoh, T.; Jones,
W. D. J. Mol. Catal. A: Chem. 2002, 189, 157−168. (g) Dong, G.;
Cramer, N. C−C Bond Activation; Springer, 2014; Vol. 346.
̈
(2) For selected examples, see: (a) Souillart, L.; Parker, E.; Cramer,
N. Angew. Chem., Int. Ed. 2014, 53, 3001−3005. (b) Chen, P.-h.; Xu,
T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1674−1678. (c) Xu, T.;
Ko, H. M.; Savage, N. A.; Dong, G. J. Am. Chem. Soc. 2012, 134,
̌ ̌ ́ ́
20005−20008. (d) Korotvicka, A.; Císarova, I.; Roithova, J.; Kotora,
M. Chem. - Eur. J. 2012, 18, 4200−4207. (e) Ishida, N.; Sawano, S.;
Masuda, Y.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17502−17504.
(f) Tamaki, T.; Ohashi, M.; Ogoshi, S. Angew. Chem., Int. Ed. 2011, 50,
12067−12070. (g) Kondo, T.; Taguchi, Y.; Kaneko, Y.; Niimi, M.;
Mitsudo, T.-a. Angew. Chem., Int. Ed. 2004, 43, 5369−5372.
(h) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976−13977.
(3) (a) Ko, H. M.; Dong, G. Nat. Chem. 2014, 6, 739−744. (b) Lutz,
J. P.; Rathbun, C. M.; Stevenson, S. M.; Powell, B. M.; Boman, T. S.;
Baxter, C. E.; Zona, J. M.; Johnson, J. B. J. Am. Chem. Soc. 2012, 134,
715−722. (c) Wentzel, M. T.; Reddy, V. J.; Hyster, T. K.; Douglas, C.
J. Angew. Chem., Int. Ed. 2009, 48, 6121−6123. (d) Dreis, A. M.;
Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412−413.
(4) (a) Nakao, Y. Bull. Chem. Soc. Jpn. 2012, 85, 731−745.
(b) Nakao, Y.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2010, 132,
10024−10026. (c) Hirata, Y.; Yukawa, T.; Kashihara, N.; Nakao, Y.;
Hiyama, T. J. Am. Chem. Soc. 2009, 131, 10964−10973. (d) Watson,
M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 12594−12595.
(e) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J.
Am. Chem. Soc. 2008, 130, 12874−12875. (f) Nakao, Y.; Hirata, Y.;
Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7420−7421. (g) Nakao, Y.;
Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 13904−13905.
(h) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303−
3306.
conversion did not proceed, even heating the mixture at 90 °C.
Comparing with this, the use of alkyl benzyl ketones (6f−h)
allows giving the desired products by the cleavage of benzylic
C−C bonds combining with some byproducts. These results
indicate that forming a carbanion A is indispensible for ensuring
the reaction to proceed, which can be produced by a
deprotonation of methenyl with fluoride salt. Subsequently, a
nucleophilic attack on benzyne followed by a process of
cyclization/ring-opening may lead to the product.
In summary, we have developed a transition metal-free,
operationally simple procedure that allows efficient buildup of
2-benzylphenyl ketones at room temperature. This reaction was
enabled by a simple salt of cesium fluoride via the direct
insertion of arynes into benzylic C−C bonds. A diverse range of
functionalities including fluoride, bromide, iodide, cyano, nitro,
ester, amide, epoxide, ferrocenyl, and thienyl groups are well
tolerated. Further studies on the application in the preparation
of complex molecules are ongoing in our laboratory.
(5) For selected reviews on aryne chemistry, see: (a) Yoshida, H.;
Takaki, K. Synlett 2012, 23, 1725−1732. (b) Tadross, P. M.; Stoltz, B.
́ ́
M. Chem. Rev. 2012, 112, 3550−3577. (c) Pena, D.; Perez, D.; Guitian,
̃
E. Angew. Chem., Int. Ed. 2006, 45, 3579−3581. (d) Bhunia, A.; Yetra,
S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140−3152. (e) Yoshida, S.;
Hosoya, T. Chem. Lett. 2015, 44, 1450−1460. (f) Wu, C.; Shi, F. Asian
J. Org. Chem. 2013, 2, 116−125. (g) Gampe, C. M.; Carreira, E. M.
Angew. Chem., Int. Ed. 2012, 51, 3766−3778. (h) Wenk, H. H.;
Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502−528.
(6) (a) Yoshida, S.; Yano, T.; Misawa, Y.; Sugimura, Y.; Igawa, K.;
Shimizu, S.; Tomooka, K.; Hosoya, T. J. Am. Chem. Soc. 2015, 137,
14071−14074. (b) Pawliczek, M.; Garve, L. K. B.; Werz, D. B. Org.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00578.
Detailed optimization data; experimental procedures;
Lett. 2015, 17, 1716−1719. (c) Li, Y.; Chakrabarty, S.; Muck-
̈
characterization data of all new compounds (PDF)
X-ray crstallographic data for 3af (CIF)
Lichtenfeld, C.; Studer, A. Angew. Chem., Int. Ed. 2016, 55, 802−806.
(d) Yoshida, H.; Yoshida, R.; Takaki, K. Angew. Chem., Int. Ed. 2013,
C
DOI: 10.1021/acs.orglett.6b00578
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
52, 8629−8632. (e) Shen, C.; Yang, G.; Zhang, W. Org. Lett. 2013, 15,
5722−5725. (f) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12,
168−171. (g) Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem.
Commun. 2007, 2405−2407. (h) Liu, Z.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112−13113. (i) Yoshida, H.; Terayama, T.; Ohshita,
J.; Kunai, A. Chem. Commun. 2004, 1980−1981. (j) Yoshida, H.;
Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43,
5052−5055. (k) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T.
Angew. Chem., Int. Ed. 2002, 41, 3247−3249. (l) Rao, B.; Zeng, X. Org.
Lett. 2014, 16, 314−317. (m) Yang, G.; Shen, C.; Quan, M.; Zhang,
W. Tetrahedron 2016, 72, 333−337. (n) Tadross, P. M.; Virgil, S. C.;
Stoltz, B. M. Org. Lett. 2010, 12, 1612−1614. (o) Yoshida, H.;
Morishita, T.; Ohshita, J. Chem. Lett. 2010, 39, 508−509. (p) Rao, B.;
Tang, J.; Wei, Y.; Zeng, X. Chem. - Asian J. 2016, DOI: 10.1002/
asia.201600065.
(7) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340−5341. (b) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A.
Chem. Commun. 2005, 3292−3294. For selected early reports on the
insertion of arynes into C−C bonds, see: (c) Shair, M. D.; Yoon, T. Y.;
Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996,
118, 9509−9525. (d) Shair, M. D.; Yoon, T.-y.; Danishefsky, S. J.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1721−1723. (e) Danheiser, R.
L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471−9479.
(f) Guyot, M.; Molho, D. Tetrahedron Lett. 1973, 14, 3433−3436.
(8) (a) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron
Lett. 2005, 46, 6729−6731. (b) Yoshida, H.; Watanabe, M.; Morishita,
T.; Ohshita, J.; Kunai, A. Chem. Commun. 2007, 1505−1507. (c) Liu,
Y.-L.; Liang, Y.; Pi, S.-F.; Li, J.-H. J. Org. Chem. 2009, 74, 5691−5694.
(d) Zhang, T.; Huang, X.; Xue, J.; Sun, S. Tetrahedron Lett. 2009, 50,
1290−1294.
(9) Yoshida, H.; Kishida, T.; Watanabe, M.; Ohshita, J. Chem.
Commun. 2008, 5963−5965. (b) Yoshida, H.; Ito, Y.; Yoshikawa, Y.;
Ohshita, J.; Takaki, K. Chem. Commun. 2011, 47, 8664−8666.
(10) (a) Jiang, B.; Shi, D.; Cui, Y.; Guo, S. Arch. Pharm. 2012, 345,
444−453. (b) Wright, N. E.; ElSohly, A. M.; Snyder, S. A. Org. Lett.
2014, 16, 3644−3647. (c) Buchgraber, P.; Domostoj, M. M.; Scheiper,
B.; Wirtz, C.; Mynott, R.; Rust, J.; Furstner, A. Tetrahedron 2009, 65,
̈
6519−6534.
(11) (a) Hu, J.-Y.; Pu, Y.-J.; Satoh, F.; Kawata, S.; Katagiri, H.;
Sasabe, H.; Kido, J. Adv. Funct. Mater. 2014, 24, 2064−2071.
(b) Kuninobu, Y.; Tatsuzaki, T.; Matsuki, T.; Takai, K. J. Org. Chem.
2011, 76, 7005−7009.
(12) (a) Nishina, Y.; Kida, T.; Ureshino, T. Org. Lett. 2011, 13,
3960−3963. (b) Ohmura, T.; Kijima, A.; Suginome, M. Org. Lett.
2011, 13, 1238−1241. (c) Ohmura, T.; Kijima, A.; Suginome, M. J.
Am. Chem. Soc. 2009, 131, 6070−6071.
(13) (a) Chen, Q.; Zhang, C.; Chen, L.; Wen, C.; Du, Z.; Chen, H.
Tetrahedron Lett. 2015, 56, 2094−2097. (b) Mohanan, K.; Coquerel,
Y.; Rodriguez, J. Org. Lett. 2012, 14, 4686−4689.
(14) CCDC 1443328 (3af) contains the supplementary crystallo-
graphic data. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(15) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B.
M. Org. Lett. 2010, 12, 1224−1227.
D
DOI: 10.1021/acs.orglett.6b00578
Org. Lett. XXXX, XXX, XXX−XXX