The insertion of arynes into the O-H bond of aliphatic carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2015.08.019

The insertion of arynes into the O-H bond of aliphatic carboxylic acids promoted by sodium carboxylates is described. The reactions led to the formation of aryl carboxylates in good yields with good chemoselectivities under mild conditions.

Full text of DOI:10.1016/j.tetlet.2015.08.019

Accepted Manuscript
The insertion of arynes into the O−H bond of aliphatic carboxylic acids
Chunxiao Wen, Qian Chen, Zhenwen He, Xinxing Yan, Changyuan Zhang,
Zhiyun Du, Kun Zhang
PII:
S0040-4039(15)01300-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.019
TETL 46603
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 June 2015
2 August 2015
10 August 2015
Please cite this article as: Wen, C., Chen, Q., He, Z., Yan, X., Zhang, C., Du, Z., Zhang, K., The insertion of arynes
into the O−H bond of aliphatic carboxylic acids, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.08.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
The insertion of arynes into the OH bond of aliphatic carboxylic acids
Chunxiao Wen, Qian Chen, Zhenwen He, Xinxing Yan, Changyuan Zhang, Zhiyun Du, Kun Zhang*
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, Guangdong 510006, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The insertion of arynes into the OH bond of aliphatic carboxylic acids promoted by sodium
carboxylates is described. The reactions led to the formation of aryl carboxylates in good yields
with good chemoselectivities under mild conditions.
© 2015 Published by Elsevier Ltd.
Available online
Keywords:
Arylation
Insertion
Aliphatic carboxylic acid
Aryne
Aryl esters have been found in a number of organic
compounds including biologically active and natural products.1 It
is obvious that the esterification reaction is one of the most
studied and frequently used organic processes, which has been
well documented.1 However, the direct esterification of phenols
by aliphatic or aromatic carboxylic acids, which is generally
promoted by strong acids, is limited to the synthesis of aryl
carboxylates due to the poor nucleophilicity of phenols.2 The
efficient preparation of aryl carboxylates from carboxylic acids
under mild conditions is still a demand to fulfill the modern
synthesis.
Aryne chemistry has been of particular interest due to its high
reactivity and broad applications in organic synthesis.3,4 The
insertion of arynes into C–C, C–N, C–O, C–S, C–P, C–Si, C–Sn,
C-Hal, C–H, O–H, N–H, S–H, N–S, N–Si, S–Sn, Si–Si and Sn–
Sn bonds leads to the formation of carbon–carbon and carbon–
heteroatom bonds.3a,3g,3h,4f,4j,4o In particular, Larock and co-
workers have reported an efficient O-arylation of aromatic
carboxylic acids through the insertion of arynes into the O–H
bond (Figure 1), whereas aliphatic carboxylic acids did not react
well under the same reaction conditions.5 The same group then
reported a different insertion of benzyne into the C–O bond of
aliphatic carboxylic acids (Figure 1).6 Most recently, Hoye and
co-workers achieved an efficient nucleophilic addition of acetic
acid to hexadehydro-Diels–Alder-generated benzyne to give aryl
acetate in high yield, while 56 equiv of acetic acid were used.7
Figure 1. Overview of the reactions of carboxylic acids with Kobayashi
aryne precursors.
With the above background and our recent investigations on
the behaviors of arynes,8 we became interested in studying the
insertion of arynes into the O–H bond of aliphatic carboxylic
acids. A variety of previous research described that some aryne
reactions required the promotion of an inorganic base (K2CO3 or
Cs2CO3).9 Most recently, Singh and co-workers reported a
coupling reaction of arynes with sulfinic acid salts to afford
biaryl sulfones.10 Thus, we envisioned that the addition of base
can accelerate the deprotonation of carboxylic acids, which
would enhance the nucleophilicity of acids. To test the
hypothesis, we first examined the reaction of Kobayashi benzyne
precursor 1a11 with NaOAc in the presence of CsF in CH3CN at
o
80 C. However, the desired phenyl acetate 3aa was obtained in
———
low yield with trace amount of C–O bond insertion product 4aa6
 Corresponding authors. Tel.: +86-20-3932-2231; fax: +86-20-3932-2235; E-mail addresses: qianchen@gdut.edu.cn (Q. Chen),
kzhang@gdut.edu.cn (K. Zhang).

2
Tetrahedron
(Table 1, entry 1). As a comparison, similar experimental
With the optimized conditions in hand (Table 1, entry 10), we
then set out to explore the generality of this method. The O-
phenylation of a variety of aliphatic carboxylic acids with
benzyne is summarized in Table 2. Acids 2a–2k were all
tolerated for the insertion of benzyne into their O–H bonds to
give esters 3 with trace amounts of 4 in 41–83% isolated yields.
It is noteworthy that this method also well tolerates ester, alkene,
and phenyl groups, and the corresponding products were isolated
in 68-79% yields (entries 9–11).
results were observed when the reaction was carried out with
HOAc (entry 2). We then turned to the use of a combination of
HOAc and NaOAc. To our delight, the desired products were
obtained in 72% yield with good chemoselectivity (3aa/4aa =
7.3/1) when both HOAc (2 equiv) and NaOAc (3 equiv) were
introduced (entry 3). We then carried out a brief optimization of
reaction conditions. Switching the carboxylate from NaOAc to
LiOAc, KOAc or CsOAc decreased the yield (entries 4–6). When
the reaction was carried out at 60 C, 40 oC or RT, the yield was
o
also decreased (entries 7–9). We then turned to the use of HOAc
(5 equiv) and NaOH (3 equiv) instead of HOAc/NaOAc (entry 3),
and the desired products were isolated in 70% yield (entry 10). It
is noteworthy that H2O produced by the neutralization of HOAc
and NaOH has no negative effect on this reaction. Thus, we
concluded that the optimized combination for the O-arylation
reaction was to use 5 equiv of HOAc, 3 equiv of NaOH, CsF as
the fluoride ion, CH3CN as the solvent, and the reaction was set
at 80 °C. For comparison, we examined the reaction of benzyne
with HOAc under Larock’s reaction conditions5, and the desired
phenyl acetate was obtained in only 30% yield, which further
demonstrated that the combination of carboxylic acid and sodium
carboxylate efficiently promoted O-arylation of aliphatic
carboxylic acids. These experimental results are in good
agreement with the previous research using the addition of base
in aryne reactions, which can accelerate the deprotonation of O–
H or N–H bonds and enhance the nucleophilicity of the
corresponding amides or phenols.9e-g
Table 2
O-phenylation of aliphatic carboxylic acids with benzynea
Table 1
O-phenylation of acetic acid with benzynea
2a
(equiv)
Additive
(equiv)
Yield (%)b
(3+4)
Ratioc
(3/4)
Entry
Temp.
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
60 oC
40 oC
RT
1
2
-
NaOAc (3)
-
35
34
9.0/1
12/1
7.3/1
7.0/1
9.4/1
9.0/1
10/1
10/1
20/1
7.3/1
2
2
2
2
2
2
2
2
5
3
NaOAc (3)
LiOAc (3)
KOAc (3)
CsOAc (3)
NaOAc (3)
NaOAc (3)
NaOAc (3)
NaOH (3)
72
4
32
5
51
6
15
7
32
8
16
9
5
80 oC
75 (70)d
a All reactions were carried out with 1a (0.68 mmol), 2 (3.4 mmol), NaOH
(2.0 mmol) and CsF (2.7 mmol) in CH3CN (4.0 mL) at 80 oC for 4 h.
b Isolated yield based on 1a.
10
a The reaction of 1a (0.34 mmol) and 2a was carried out in the presence of
CsF (1.4 mmol) in CH3CN (2.0 mL) for 4 h.
c Ratio was determined by 1H NMR analysis of crude products.
b
Yield based on 1a was determined by 1H NMR analysis of crude
products using an internal standard.
c Ratio was determined by 1H NMR analysis of crude products.
d Isolated yield on 0.68 mmol scale in parentheses.
Having succeeded in O-phenylation of aliphatic carboxylic
acids, we then turned to the O-arylation of butyric acid 2c with a
variety of arynes (Table 3). 4,5-Dimethyl-, 3,6-dimethyl-, 4,6-
dimethyl-,
4-methyl-,
4-tert-butyl-,
4-methoxy-,
4-

(trifluoromethoxy)-, and 4-fluoro-substituted aryne precursors
1b–1i afforded the desired products in 35–82% yields (entries 1–
8). For unsymmetrical arynes (entries 4–8), the product ratios of
meta- and para-position ranged from 2.3/1 to 1/2.3, which
suggested that these reactions involved an aryne mechanism.
Similarly, aryne precursor 1j for 1,2-didehydronaphthalene also
gave two isomers (α/β = 1/2.6) in good yield (entry 9).
of aryl carboxylates. This property of arynes should lead to new
and useful applications in organic synthesis. Further
investigations on the insertion of arynes into other σ-bonds are
ongoing and will be reported in due course.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (Project No. 21242002) and 100 Young
Talents Programme of Guangdong University of Technology
(Project No. 220413506).
Table 3
O-arylation of butyric acid with arynesa
Supplementary data
Supplementary data (these data include experimental details,
1
analytical data, H and 13C NMR spectra of all new compounds,
and 19F NMR spectrum of compounds 3hc and 3ic) associated
with this article can be found, in the online version, at http://...
References and notes
1.
(a) Ogliaruso, M. A.; Wolfe, J. F. The Chemistry of Carboxylic Acids
and Esters; Patai, S., Ed.; Interscience: London, 1991; (b) Evans, D. A.;
DeVries, K. M. In Glycopeptide Antibiotics, Drugs and the
Pharmaceutical Sciences; Nagarajan, R., Ed.; Marcel Decker, Inc.: New
York, 1994; Vol. 63, pp 63104; (c) Katritzky, A. R.; Meth-Cohn, C. O.;
Charles, W. R. Comprehensive Organic Functional Group
Transformations; Vol. 5, Cambridge University Press: Cambridge, 1995;
(d) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; 3rd ed.; John Wiley and Sons: New York, 1999; (e) Larock,
R. C. Comprehensive Organic Transformations: A Guide to Functional
Group Preparations, 2nd ed.; John Wiley & Sons: New York, 1999; (f)
Bauer, K.; Garbe, D.; Sturburg, H. Common Fragrance and Flavor
Materials: Preparation and Uses; 4th ed.; Wiley-VCH: Weinheim,
2001; (g) Otera, J. Esterification: Methods, Reactions and Applications;
Wiley VCH: Weinheim, 2003.
2.
3.
Beyer, H.; Walter, W. Handbook of Organic Chemistry; Prentice Hall
Europe: London, 1996; p 497.
For recent reviews, see: (a) , E. Angew.
Chem., Int. Ed. 2006, 45, 35793581; (b) Yoshida, H.; Ohshita, J.;
Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199219; (c) Bhojgude, S. S.;
Biju, A. T. Angew. Chem., Int. Ed. 2012, 51, 15201522; (d) Yoshida,
H.; Takaki, K. Synlett 2012, 23, 17251732; (e) Gampe, C. M.; Carreira,
E. M. Angew. Chem. 2012, 124, 38293842; Angew. Chem., Int. Ed.
2012, 51, 37663778; (f) Tadross, P. M.; Stoltz, B. M. Chem. Rev.
2012, 112, 35503577; (g) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem.
Soc. Rev. 2012, 41, 31403152; (h) Wu, C.; Shi, F. Asian J. Org. Chem.
2013, 2, 116125; (i) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C.
Org. Biomol. Chem. 2013, 11, 191218; (j) Hoffmann, R. W.; Suzuki,
K. Angew. Chem. 2013, 125, 27172718; Angew. Chem., Int. Ed. 2013,
52, 26552656; (k) , D.; , E. Eur. J. Org. Chem.
2013, 27, 59816013; (l) Holden, C.; Greaney, M. F. Angew. Chem., Int.
Ed. 2014, 53, 57465749.
4.
For recent examples, see: (a) Pirali, T.; Zhang, F.; Miller, A. H.; Head,
J. L.; McAusland, D.; Greaney, M. F. Angew. Chem. 2012, 124, 1030–
1033. Angew. Chem., Int. Ed. 2012, 51, 1006–1009; (b) Hamura, T.;
Chuda, Y.; Nakatsuji, Y.; Suzuki, K. Angew. Chem., Int. Ed. 2012, 51,
33683372; (c) Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A.
Angew. Chem., Int. Ed. 2013, 52, 29682971; (d) Li, R.; Wang, X.;
Wei, Z.; Wu, C.; Shi, F. Org. Lett. 2013, 15, 43664369; (e) Wang, Y.;
Yepremyan, A.; Ghorai, S.; Todd, R.; Aue, D. H.; Zhang, L. Angew.
Chem. 2013, 125, 79497953; (f) Rao, B.; Zeng, X. Org. Lett. 2014, 16,
314317; (g) Zhou, Y.; Chi, Y.; Zhao, Fei.; Zhang, W.-X.; Xi, Z. Chem.
Eur. J. 2014, 20, 24632468; (h) Dong, Y.; Liu, B.; Chen, P.; Liu, Q.;
Wang, M.; Angew. Chem., Int. Ed. 2014, 53, 34423446; (i) Peng, X.;
Wang, W.; Jiang, C.; Sun, D.; Xu, Z.; Tung, C.-H. Org. Lett. 2014, 16,
53545357; (j) Zeng, Y.; Hu, J. Chem. Eur. J. 2014, 20, 68666870; (k)
Schuler, B.; Collazos, S.; Gross, L.; Meyer, G.; Pérez, D.; Guitián, E.;
Peña, D. Angew. Chem. 2014, 126, 91509152; (l) Siyang, H. X.; Wu,
X. R.; Liu, H. L.; Wu, X. Y.; Liu, P. N. J. Org. Chem. 2014, 79,
15051510; (m) Thangaraj, M.; Bhojgude, S. S.; Bisht, R. H.; Gonnade,
R. G.; Biju, A. T. J. Org. Chem. 2014, 79, 47574762; (n) Pian, J.-X.;
He, L.; Du, G.-F.; Guo, H.; Dai, B. J. Org. Chem. 2014, 79, 58205826;
a All reactions were carried out with 1 (0.68 mmol), 2c (3.4 mmol), NaOH
(2.0 mmol) and CsF (2.7 mmol) in CH3CN (4.0 mL) at 80 oC for 4 h.
b Isolated yield based on 1.
c Ratio was determined by 1H NMR analysis of crude products.
d See the supplementary data for the structures of two isomers.
In summary, we have developed an efficient O-arylation of
aliphatic carboxylic acids through the insertion of arynes into the
O–H bond promoted by sodium carboxylates under mild
conditions, which provides a facile methodology for the synthesis

4
Tetrahedron
(o) Li, H.-Y.; Xing, L.-J.; Lou, M.-M; Wang, H.; Liu, R.-H.; Wang,
B. Org. Lett. 2015, 17, 10981101.
5.
(a) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99102; (b) Liu, Z.;
Larock, R. C. J. Org. Chem. 2006, 71, 31983209.
6.
7.
Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 31173119.
Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature
2012, 490, 208212.
8.
(a) Chen, Q.; Zhang, C.; Chen, L.; Wen, C.; Du, Z.; Chen, H.; Zhang,
K. Tetrahedron Lett. 2015, 56, 20942097; (b) Chen, L.; Zhang, C.;
Wen, C.; Zhang, K.; Liu, W.; Chen, Q. Catal. Commun. 2015, 65,
8184.
For selected examples, see: (a) Okuma, K.; Nojima, A.; Matsunaga, N.;
Shioji, K. Org. Lett. 2009, 11, 169–171; (b) Huang, X.; Zhang, T.
Tetrahedron Lett. 2009, 50, 208–211; (c) Rogness, D. C.; Larock, R. C.
Tetrahedron Lett. 2009, 50, 4003–4008; (d) Kivrak, A.; Larock, R. C. J.
Org. Chem. 2010, 75, 7381–7387; (e) Rogness, D. C.; Larock, R. C. J.
Org. Chem. 2011, 76, 4980–4986; (f) Lu, C.; Dubrovskiy, A. V.;
Larock, R. C. Tetrahedron Lett. 2012, 53, 2202–2205; (g) Shen, C.;
Yang, G.; Zhang, W. Org. Lett. 2013, 15, 5722–5725.
9.
10. Aithagani, S. K.; Yempalla, K. R.; Munagala, G.; Vishwakarma, R. A.;
Singh, P. P. RSC Adv. 2014, 4, 50208–50211.
11. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12,
12111214.

Leave this area blank for abstract info.
The insertion of arynes into the OH bond of
aliphatic carboxylic acids
Chunxiao Wen, Qian Chen, Zhenwen He, Xinxing Yan, Changyuan Zhang, Zhiyun Du, Kun Zhang