A NCS mediated oxidative C-H bond functionalization: Direct esterification between a C(sp3)-H bond and carboxylic acids

Article abstract of DOI:10.1039/c5cc02424b

A transition metal free oxidative C-H bond functionalization/esterification of α-alkoxy alkanes with acids is described in this report. This method is effectively mediated by NCS instead of traditional oxidants, like TBHP or its derivatives, and directly

Full text of DOI:10.1039/c5cc02424b

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A NCS mediated oxidative C‐H bond functionalization: direct
esterification between C(sp3)–H bond and carboxylic acids
Yang Zheng,a Jincheng Mao,*ab Guangwei Ronga and Xinfang Xu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
transition
metal
free
oxidative
C‐H
bond
functionalization/esterfication of α‐alkoxy alkanes with acids is
described in this report. This method is effectively mediated by
NCS instead of traditional oxidants, like TBHP or its derivatives,
and directly generates the esterification products in moderate to
high yield under mild conditions. This tranformation constitute a
practical and general approach toward various α‐acyloxy ethers
with broad substrates generality; alkyl‐, aryl‐, alkenyl‐ and alkynyl‐
carboxylic acids are all well tolerated.
Ester is an important motif and broad embodied in nature,1 beside
the traditional ester esterification process of alcohol with carboxylic
acid or their derivatives (acyl chlorides or anhydrides) promoted by
acid or base (Scheme 1, eq. 1),1,2 alternative effective
methodologies are reported: including direct esterification with
aldehydes catalyzed with NHC‐catalysts reported by Jiao and
Connon independently,3 oxidative esterification with alcohols by Lei
and others (eq. 2),4 C‐H activation/esterification5 and other
variants.6 All of these direct esterfication reactions provide a useful
and convenient approach toward the ester motifs, especially the
catalytic oxidative version of C(sp3)‐H bond with carboxylic acids
discovered by Li and other groups (eq. 3).7,8 However, oxidant is
ineluctable in all these reported researches, and most of them need
transition metal catalysts4‐7 or organo‐catalysts in some cases.3,8
Herein, we wish to report our recent discovery on the oxidative
coupling reaction:9 direct esterfication of carboxylic acid with
C(sp3)‐H bonds mediated by NCS (N‐chlorosuccinimide) in the
presence of base (eq. 4). This transformation constitutes a practical
and general access to form the corresponding ester under transition
metal free and oxidant free conditions.
Scheme 1 General methods for the esterfication.
used in synthetic organic chemistry,10‐12 for examples, NCS is typical
served as a halogenating reagent for chlorination10 or used to
generate the intermediates like the electrophilic N‐chloroamines11
and sulfenyl chloride.12 Very recently, Tang and co‐workers
reported an iron‐catalyzed NCS mediated radical oxidative cross‐
coupling reaction of 1,3‐dithiane with aryl olefins.13 In this report,
NCS was thought to be essentical to promote the reaction in the
pre‐activation step, by which, the intermidate 2‐chloro‐1,3‐dithiane
was generated, and followed by a radical oxidative process to give
the desired coupling product. Inspired by this work, we reasoned
that the NCS may also promote the oxidative coupling esterfication
of C(sp3)‐H bonds via similar initial radical step and followed by
trapping the corresponding intermediate with carboxylate.
N‐Chlorosuccinimide (NCS) is a versatile reagent, which is widely
Initially, we investigated the coupling reaction of phenylpropiolic
acid 1a with 1,4‐dioxane 2a in the presence of NCS and sodium
acetate under metal‐free condition (Table 1, entry 1). To our best
knowledge, direct esterfication of phenylpropiolic acid with C(sp3)‐H
bond have not been reported, although procedures for other
carboxylic acids have been well studied.7,8 To our delight, the
desired esterfication product 3a was obtained, albeit in low yield
(34%), and the generated α‐acyloxy ether motif is important and
useful in biological, medicinal and organic chemistry.14 Then
a.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou
215123, P. R. China, E-mail: xinfangxu@suda.edu.cn.
b.State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation,
Southwest Petroleum University, Chengdu, 610500, P. R. China, E‐mail:
jcmao@suda.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the reaction conditionsa
Table 2 Direct esterfication of 2a with various propiolic acid
derivativesa
Entry
1
2
3
4
5
6
7
8
Cat.
—
FeCl2∙4H2O
FeCl3
CuBr
—
—
—
Additive
NCS
NCS
NCS
NCS
—
NCS
NBS
NIS
TCCA
NCS
NCS
NCS
NCS
NCS
NCS
NCS
Base
K2CO3
K2CO3
K2CO3
NCS
Yieldb (%)
34
35
36
36
ND
ND
trace
ND
ND
27
30
33
46
ND
74
K2CO3
—
K2CO3
K2CO3
K2CO3
Na2CO3
t‐BuOK
K3PO4
NaOAc
Et3N
—
—
—
—
—
—
—
—
9
10
11
12
13
14
15 c
16d
NaOAc
NaOAc
—
64
a Reaction conditions: Propiolic acid derivatives (1, 0.30 mmol), 1,4-dioxane
(2a, 2.0 ml), NCS (0.51 mmol), NaOAc (0.51 mmol), 80 oC, 12 h.
a
Reaction conditions: Phenylpropiolic acid (1a, 0.30 mmol), catalyst (0.06
mmol), additive (0.36 mmol, 1.2 eq), base (0.36 mmol, 1.2 eq), 1,4-dioxane
(2a, 2.0 ml), 80 oC, 12 h. isolated yield. 1.7 eq of NCS and 1.7 eq of
NaOAc was used instead of 1.2 eq. d 2.0 eq of NCS and 2.0 eq of NaOAc was
used instead of 1.2 eq. TCCA = Trichloroisocyanuric acid.
b
c
Notably, 2‐furyl and 2‐naphthyl carboxylic acids also afford 4h and
4i in 74% and 71% yield, respectively. Besides, the alkyl ones,
including 3‐phenylpropionic acid and cinnamic acid derivatives
show good reactivity and produce the α‐acyloxy ethers in high yield
(60‐83%).
we proceeded to optimize the reaction conditions. Metal‐catalysts,
for examples, Fe(II),11a Fe(III)13 and Cu(I)11b,15 were tested, which
were used as catalysts in previous radical processes in associated
with NCS or NBS, and identical results were observed (entry 2‐4).
And the control reactions showed that no reaction occurs in the
absence of additive or base (Table 1, entry 5, 6). Further
optimization with various additives (entries 7‐9) and different bases
(entries 10‐14) turned out that the combination of NCS (1.2 equiv)
with sodium acetate (NaOAc, 1.2 equiv) was superior to others
(entry 13). Subsequently, the amount of NCS and NaOAc was
adjusted and 1.7 eq amounts gave the best isolated yield (entry 15,
74%).
Table 3 Direct esterfication of 2a with various carboxylic acidsa
With the optimized reaction conditions, the scope of this directly
oxidative coupling esterfication reaction was then examined by
using a series of phenylpropiolic acids 1 with 2a. As shown in Table
2, this transformation proceeds smoothly over a wide range of
substrates, providing the corresponding α‐acyloxy ethers in
moderate to high yield (55%‐83%). The substitutions on the ortho‐,
meta‐, and para‐ positions of the aryl ring, either with electronic
rich or deficient ones, marginally affect this reaction. Besides, 1‐
naphthyl and 2‐naphthyl propiolic acids also well tolerated under
this condition and to give the desired products in 63% and 55%
yield, respectively. It is worth mentioning that 2‐butynoic acid also
generates the corresponding product 3m in 62% yield.
The reaction could be extended to other carboxylic acids, and
only needs to switch the base with potassium carbonate (K2CO3) to
ensure high yield. As illustrated in Table 3, benzoic acids, either with
electronic rich or deficient substitutions, all work well under this
condition and to give the desired products in high yield (60‐94%).
a Reaction conditions: carboxylic acid (1, 0.30 mmol), 1,4-dioxane (2a, 2.0
ml), NCS (0.51 mmol), K2CO3 (0.51 mmol), 80 oC, 12 h.
2 | J. Name., 2012, 00, 1‐3
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Have demonstrated the scope of carboxylic acids, we then tested
the scope of ethers 2 by using phenylpropiolic acid 1a as the
coupling partner. Interestingly, the ethers containing only one
oxygen atom cannot afford the corresponding products, for
examples, THF or butyl ether. We are delighted to find out that 1,3‐
dioxolane 2b and 1,2‐dimethoxyethane 2c (DME) generate the
esterfication products in 30% and 72% yield, respectively, and the
regioselectivity of the later is about 1:1 (Scheme 2).
NaOAc
80 oC, 12 h
+
O
O
O
(5)
Ph
CO2H
+
O
O
O
2 ml
TEMPO (1.7 eq)
Ph
0.3 mmol
Not detected
NaOAc
O
O
O
80 oC, 12 h
(6)
NCS
0.51 mmol
O
+
+
O
N
H
A
Detected by
HRMS and 1H NMR
O
2 ml
D
Conclusions
In summary, we have developed a metal free oxidative coupling
esterfication of α-alkoxy alkanes with acids. This transformation is
effectively mediated by NCS instead of traditional oxidants under
mild conditions, and provides a direct and general approach toward
various α-acyloxy ethers in moderate to high yields with broad
substrates generality. Moreover, the developed oxidant free system
involving free radical process offers a practical alternate compared
to the other oxidative coupling esterfication, and the modified NCS
mediated system applies to other coupling reactions are undergoing
in our lab.
Scheme 2. Reaction of phenylpropiolic acid 1a with ethers.
We are grateful to the grants from the Priority Academic Program
Development of Jiangsu Higher Education Institutions, and the Key
Laboratory of Organic Synthesis of Jiangsu Province.
A possible mechanism for this NCS‐mediated oxidative coupling
esterfication reaction is proposed in Scheme 3. The reaction is
initiated by NCS via a free radical process,15 follows by the
formation of active cationic intermediate C via probably the radical
intermediate B, and generates the succinimide A as a by product,
which is detected by HRMS and proton NMR in the crude reaction
mixture.16 The control reaction in the present of the free
radical inhibitor TEMPO turn out to give no desired product at all,
which suggests that the transformation proceed through a radical
progress (eq. 5), although other pathways couldn’t be ruled out so
far. The final nucleophilic addition of the carboxylate to C leads to
the desired product 3, and this step is presented and studied by
Wan and others.7,8 It’s noteworthy that the existence of
intermediate C is further confirmed in our control reaction (eq. 6).
In the absence of phenylpropiolic acid 1a under standard conditions,
product D is detected by HRMS and proton NMR analysis,16 which is
believed to derivate from C via addition/elimination process.17
Notes and references
1
For selected reviews: (a) K. C. K. Swamy, N. N. B. Kumar, E.
Balaraman and K. V. P. P. Kumar, Chem. Rev., 2009, 109
,
,
2551; (b) P. Adams and F. A. Baron, Chem. Rev., 1965, 65
567; (c) W. Riemenschneider and H. M. Bolt, Esters, Organic.
Ullmann’s Encyclopedia of Industrial Chemistry, Wiley‐VCH,
Weinheim, 2005; (d) J. Otera and J. Nishikido, Esterification:
methods, reactions, and applications, Wiley‐VCH, Weinheim,
2010.
R. C. Larock, Comprehensive organic transformations: a
guide to functional group preparations, Wiley‐VCH, New
York, 1999.
(a) B. Zhang, P. Feng, Y. Cui and N. Jiao, Chem. Commun.,
2012, 48, 7280; (b) E. G. Delany, C.‐L. Fagan, S. Gundala, A.
Mari, T. Broja, K. Zeitler and S. J. Connon, Chem. Commun.,
2013, 49, 6510; (c) E. G. Delany, C.‐L. Fagan, S. Gundala, A.
Mari, T. Broja, K. Zeitler and S. J. Connon, Chem. Commun.,
2013, 49, 6513.
2
3
4
5
(a) X.‐F. Bai, F. Ye, L.‐S. Zheng, G.‐Q. Lai, C.‐G. Xia and L.‐W.
Xu, Chem. Commun., 2012, 48, 8592; (b) C. Liu, S. Tang and
A. Lei, Chem. Commun., 2013, 49, 1324; (c) L. Tang, X. Guo, Y.
Li, S. Zhang, Z. Zha and Z. Wang, Chem. Commun., 2013, 49
5213.
(a) A. R. Dick, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc.
,
,
2004, 126, 2300; (b) M. S. Chen, N. Prabagaran, N. A. Labenz,
and M. C. White, J. Am. Chem. Soc., 2005, 127, 6970; (c) D. J.
Covell and M. C. White, Angew. Chem. Int. Ed. 2008, 47
,
6448; (d) X. Chen, C. Zhu, X. Cui and Y. Wu, Chem. Commun.,
2013, 49, 6900.
6
(a) G. Majji, S. Guin, A. Gogoi, S. K. Rout, A. Behera and B. K.
Patel, Chem. Commun., 2014, 50, 12193; (b) J. Du, X. Zhang,
X. Sun and L. Wang, Chem. Commun., 2015, 51, 4372; (c) G.
Majji, S. Guin, A. Gogoi, S. K. Rout and B. K. Patel, Chem.
Commun., 2013, 49, 3031; (d) S. K. Rout, S. Guin, A. Banerjee,
Scheme 3. Possible reaction pathways.
N. Khatun, A. Gogoi and B. K. Patel, Org. Lett., 2013, 15
,
This journal is © The Royal Society of Chemistry 20xx
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4106; (e) S. K. Rout, S. Guin, K. K. Ghara, A. Banerjee and B. 17 (a) M. M. Kreilein, J. C. Eppich and L. A. Paquette, Organic
K. Patel, Org. Lett., 2013, 14, 3982.
Syntheses, 2005, 82, 99; (b) J. A. Molina de la Torre, P.
Espinet and A. C. Albéniz, Organometallics, 2013, 32, 5428; (c)
W. Yao, Y. Zhang, X. Jia and Z. Huang, Angew. Chem. Int. Ed.
2014, 53, 1390.
7
(a) C.‐Y. Wang, R.‐J. Song, W.‐T. Wei, J.‐H. Fan and J.‐H. Li,
Chem. Commun., 2015, 51, 2361; (b) J. Zhao, H. Fang, W.
Zhou, J. Han and Y. Pan, J. Org. Chem., 2014, 79, 3847; (c) S.
,
Priyadarshini, P. J. A. Joseph and M. L. Kantam, RSC Adv.
,
2013, , 18283; (d) W.‐T. Wei, R.‐J. Song and J.‐H. Li, Adv.
3
Synth. Catal., 2014, 356, 1703; (e) W.‐T. Wei, M.‐B. Zhou, J.‐H.
Fan, W. Liu, R.‐J. Song, Y. Liu, M. Hu, P. Xie and J.‐H. Li,
Angew. Chem. Int. Ed., 2013, 52, 3638; (f) Z. Cui, X. Shang, X.‐
F. Shao and Z.‐Q. Liu, Chem. Sci., 2012,
R.‐J. Song, X.‐H. Ouyang, Y. Li, H.‐B. Li and J.‐H. Li, Org. Chem.
Front., 2014, , 484; (h) Z.‐Q. Liu, L. Zhao, X. Shang and Z. Cui,
3, 2853; (g) W.‐T. Wei,
1
Org. Lett., 2012, 14, 3218; (i) Z. Li, Y. Zhang, L. Zhang and Z.‐Q.
Liu, Org. Lett., 2014, 16, 382.
8
9
(a) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X.
Wan, Chem. Eur. J., 2011, 17, 4085; (b) E. Shi, Y. Shao, S.
Chen, H. Hu, Z. Liu, J. Zhang and X. Wan, Org. Lett., 2012, 14
,
3384; (c) W.‐T. Wei, X.‐H. Yang, H.‐B. Li and J.‐H. Li, Adv.
Synth. Catal., 2015, 357, 59; (d) X.‐H. Yang, W.‐T. Wei, H.‐B.
Li, R.‐J. Song and J.‐H. Li, Chem. Commun., 2014, 50, 12867.
Our recent work on oxidative coupling reactions: (a) M. O.
Ratnikov, X. Xu and M. P. Doyle, J. Am. Chem. Soc., 2013,
135, 9475; (b) H. Yang, P. Sun, Y. Zhu, H.Yan, L. Lu, X. Qu, T. Li
and J. Mao, Chem. Commun., 2012, 48, 7847; (c) H. Yang, H.
Yan, P. Sun, Y. Zhu, L. Lu, D. Liu, G. Rong and J. Mao, Green
Chem., 2013, 15, 976
10 (a) G. K. S. Prakash, T. Mathew, D. Hoole, P. M. Esteves, Q.
Wang, G. Rasul and G. A. Olah J. Am. Chem. Soc. 2004, 126
15770; (b) D. Kalyani, A. R. Dick, W. Q. Anani and M. S.
.
,
,
Sanford, Org. Lett., 2006,
8
, 2523; (c) B. Chabaud and K
.
B.
B.
Sharpless, J. Org. Chem., 1979, 44, 4204; (d) T. Hori and K
.
Sharpless, J. Org. Chem., 1979, 44, 4208; (e) M. Yamanaka,
M. Arisawa, A. Nishida and M. Nakagawa, Tetrahedron Lett.,
2002, 43, 2403; (f) J. A. Tunge and S. R. Mellegaard Org. Lett.
,
2004, , 1205; (g) F. E. Michael and P. A. Sibbald, B. M.
6
Cochran, Org. Lett., 2008, 10, 793; (h) M. Jithunsa, M. Ueda
and O. Miyata, Org. Lett., 2011, 13, 518; (i) M. Sai and S.
Matsubara, Org. Lett., 2011, 13, 4676; (j) B. Wang, J. Zhang,
X. Wang, N. Liu, W. Chen and Y. Hu, J. Org. Chem., 2013, 78
,
10519.
11 (a) Z. Wang, Y. Zhang, H. Fu, Y. Jiang and Y. Zhao, Org. Lett.
,
2008, 10, 1863; (b) X. Liu and Y. Zhang, L. Wang, H. Fu, Y.
Jiang, Y. Zhao, J. Org. Chem., 2008, 73, 6207; (c) T. J. Barker
and E. R. Jarvo, Angew. Chem. Int. Ed., 2011, 50, 8325; (d) Z.
Niu, S. Lin, Z. Dong, H. Sun, F. Liang and J. Zhang, Org.
Biomol. Chem., 2013, 11, 2460.
12 (a) C. Ravi, D. C. Mohan and S. Adimurthy, Org.
Lett., 2014, 16, 2978; (b) J. S. Yadav, B. V. S. Reddy, R. Jain
and G. Baishya, Tetrahedron Lett., 2008, 49, 3015; (c) K. M.
Schlosser, A. P. Krasutsky, H. W. Hamilton, J. E. Reed and K.
Sexton, Org. Lett., 2004, 6, 819; (d) J.‐H. Cheng, C. Ramesh,
H.‐L. Kao, Y.‐J. Wang, C.‐C. Chan and C.‐F. Lee, J. Org. Chem.
2012, 77, 10369; (e) Y.‐C. Liu and C.‐F. Lee, Green Chem.
2014, 16, 357.
,
,
13 W. Du, L. Tian, J. Lai, X. Huo, X. Xie, X. She, S. Tang, Org. Lett.
,
2014, 16, 2470.
14 (a) J. E. Dalgard and S. D. Rychnovsky, J. Am. Chem. Soc.
,
2004, 126, 15662; (b) S. Chamberland and K. A. Woerpel,
Org. Lett., 2004,
6, 4739; (c) R. Jasti, J. Vitale and S. D.
Rychnovsky, J. Am. Chem. Soc., 2004, 126, 9904; (d) H.
Takamura, S. Kikuchi, Y. Nakamura, Y. Yamagami, T. Kishi, I.
Kadota and Y. Yamamoto, Org. Lett., 2009, 11, 2531; (e) X.
Su, D. S. Surry, R. J. Spandl and D. R. Spring, Org. Lett., 2008,
10, 2593.
15 M. Niu, Z. Yin, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem. 2008,
73, 3961.
16 See Supporting Information for details.
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A direct esterfication of α‐alkoxy alkanes with acids is reported under transition‐metal‐free conditions mediated by NCS with broad
substrates generality.
O
O
O
n
O
NCS, Base
80 oC, 12 h
RCO2H
+
n
O
R
O
R = Ar, Alkyl,
n = 1, 2
30-94% yield
30 examples
1. Transition Metal Free
2. Oxident Free
3. Broad Scope
Ar
R'
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