Transition metal free oxidative esterification of alcohols with toluene

Article abstract of DOI:10.1016/j.tetlet.2013.07.114

Using Bu₄NI as the catalyst and tert-butyl hydroperoxide as the oxidant, direct esterification of alcohols with toluene derivatives was achieved. Mechanistic investigations indicate that the alcohols are sequentially oxidized to aldehydes, carboxylic acids, and then to benzyl esters. Bu ₄N⁺ functions as a phasetransfer reagent and iodide catalyzes the reaction.

Full text of DOI:10.1016/j.tetlet.2013.07.114

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition metal free oxidative esterification of alcohols
with toluene
⇑
Lianghui Liu, Lin Yun, Zikuan Wang, Xuefeng Fu , Chun-hua Yan
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Using Bu4NI as the catalyst and tert-butyl hydroperoxide as the oxidant, direct esterification of alcohols
with toluene derivatives was achieved. Mechanistic investigations indicate that the alcohols are sequen-
tially oxidized to aldehydes, carboxylic acids, and then to benzyl esters. Bu4N+ functions as a phasetrans-
fer reagent and iodide catalyzes the reaction.
Received 20 June 2013
Accepted 22 July 2013
Available online xxxx
Ó 2013 Published by Elsevier Ltd.
Keywords:
Oxidative esterification
Transition metal free
Bu4NI
Alcohol oxidation
Toluene
Carboxylic acid esters are not only among the most abundant
chemicals in nature but also serve as important building blocks
in organic transformations and chemical industry. They are tradi-
tionally prepared by a reaction of alcohols with carboxylic acids
or activated carboxylic acid derivatives (Scheme 1, a1) which re-
quires multiple procedures and produces unwanted by-products.1
Direct selective esterification of alcohols,2 aldehydes,3 (Scheme 1,
a2) or CO with hydrocarbons4 (Scheme 1, a3) by homogeneous or
heterogeneous catalysts provides a promising alternative and
many efforts have been devoted to achieve this transformation.
Recently, several groups have reported fine works on oxidative
esterification of carboxylic acids (Scheme 1, b1)5 with hydrocar-
bons via C–H bond activation. As is the same concern, it will be
more attractive yet challenging to start with aldehydes,6 alcohols,
or hydrocarbons7 (Scheme 1, b2–b3).
On the other hand, after the pioneering work reported by Ishi-
hara’s group,8 where quaternary ammonium iodide was used as
a highly active catalyst for oxidative cycloetherification of ketoph-
enols, Bu4NI catalyst combined with green oxidants (H2O2 or
tBuOOH) has attracted extensive attention9 for the construction
of C–O,10 C–N,11 and C–C12 bonds through cross-dehydrogenation
coupling (CDC) reaction.13 Herein we report on the synthesis of
benzyl esters by oxidative esterification of alcohols with benzylic
C–H bonds using Bu4NI as the catalyst.
a1
b1
R'H
R'H
R'H
RCOOH
RCOX
R'OH
R'OH
R'OH
(X = OH, Cl)
O
a2
a3
b2
b3
R'
b
RCH2OH / RCHO
RCHO / RCH3
O
R
a
this work
R-H
CO
RCH2OH
Scheme 1. Pathways for synthesis of esters.
1-naphthoate (1c, Table 1, entry 1). Obviously, ester 1c was
generated from the oxidative cross-coupling reaction between
the alcohol substrate 1-naphthalenemethanol and toluene solvent.
No reaction occurred under one bar of oxygen and only 2% yield of
1-naphthaldehyde was observed using di-tert-butyl peroxide
(DTBP) as the oxidant (Table 1, entries 2 and 3). The yield of the
esterification product dramatically increased to 60% by adding
1.2 equiv of NaH2PO4 (Table 1, entry 4) and 68% yield was obtained
when acetonitrile was used as the solvent (Table 1, entry 5).
Prolonging the reaction time to 36 h led to a decent yield (79%;
Table 1, entries 6 and 7). However, only 1–11% yields of ester 1c
were formed if Bu4NI was replaced by Bu4NBr or KI (Table 1, en-
tries 8 and 9) and 1c was not observed when iodine was used
(Table 1, entry 10). In order to explore the potential application
of this method, a scale-up experiment was performed and 83% iso-
lated yield was obtained using 5 mmol of 1-naphthalenemethanol
where the ester product was one gram scale (Table 1, entry 11).
The oxidative esterification of various primary alcohols under
optimum conditions is listed in Table 2. A variety of substituted
benzyl alcohol derivatives were observed to form benzyl esters in
toluene with good to excellent yields. Electronic effects associated
Heating a mixture of 1-naphthalenemethanol, six equivalents of
oxidant tert-butyl hydroperoxide (TBHP, 70% aqueous solution)
and 20 mol % of Bu4NI in toluene gave 43% yield of benzyl
⇑
Corresponding author. Tel.: +86 10 6275 6035; fax: +86 10 6275 1708.
E-mail address: fuxf@pku.edu.cn (X. Fu).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.07.114
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2
L. Liu et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Oxidation of 1-naphthalenemethanola
[O]
COOH
O
1a
OH
O
O
1c
H3C
1b
Entry
Catalyst (mol %)
Oxidant (equiv)
Additive (equiv)
Convb (%)
Yieldb (%)
(1a)
(1b)
(1c)
1
2
3
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NBr (20)
KI (20)
TBHP (6)
O2 (1 bar)
DTBP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
—
—
—
100
0
2
100
100
100
100
91
1
—
2
1
1
1
1
7
9
17
—
—
7
8
4
43
—
—
60
68
76
79
1
4
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
NaH2PO4 (1.2)
5c
6c,d
7c,e
8c,e
9c,e
10c,e
11f
5
51
41
6
83
29
100
11
0
I2 (10)
Bu4NI (20)
23
1
2
83g
a
b
c
d
e
f
Reaction conditions: 1-naphthalenemethanol (0.50 mmol), toluene (10 mmol), under air atmosphere, 80 °C, 12 h.
GC results.
CH3CN (2 mL).
24 h.
36 h.
1-Naphthalenemethanol (5.0 mmol), toluene (100 mmol), CH3CN (20 mL), 36 h.
Isolated yield.
g
Table 2
Scope of alcoholsa
R
OH
RCOOBn (Bn = benzyl)
COOBn
COOBn
COOBn
COOBn
O
2a, 85%
2b, 71%
2c, 78%
COOBn
2d, 74%
COOBn
COOBn
I
COOBn
COOBn
Br
Cl
F
2e, 79%
2f, 84%
2g, 82%
COOBn
2h, 77%
COOBn
COOBn
F3C
NC
O2N
2i, 86%
S
2j, 89% (87%)b
2k, 86%
2l, 80%
COOBn
2m, 86%
a
Reaction conditions: alcohol (0.50 mmol), toluene (10 mmol), NaH2PO4 (0.60 mmol, anhydrous), Bu4NI
(0.10 mmol), TBHP (3.0 mmol, 70% aqueous solution), MeCN (2 mL), air atmosphere, 80 °C, 36 h. GC results.
b
Isolated yield.
with electron donating and electron withdrawing substituents on
the phenyl ring showed little effect on the efficiency of the oxida-
tion reaction. Esters 2a–2d were formed in good yields without
over oxidation of the methoxy and methyl groups. Halide groups
were well tolerated in the system (2e–2h). 4-(Trifluoro-
methyl)benzyl alcohol, 4-cyanobenzyl alcohol, and 4-nitrobenzyl
alcohol were all converted to esters 2i–2k with excellent yields
and 2-biphenylmethanol also showed pretty good yield (2l). The
yield of 2-thiophenemethanol was 86%, indicating good tolerance
of heteroatoms (2m).
Encouraged by the results of Table 2, the scope of hydrocarbons
was also examined (Table 3). Mesitylene and xylenes were all
converted to esters 3a–3d in moderate to good yields without
formation of multi-esters. Halogenated toluenes including 2-iodo-
toluene, 4-bromotoluene, 4-chlorotoluene, and 4-fluorotoluene all
gave good yields of about 85% (3e–3h). Toluenes with strong
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L. Liu et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 3
Scope of hydrocarbonsa
HO
R
H
R
OOCPh
OOCPh
OOCPh
OOCPh
OOCPh
OOCPh
OOCPh
OOCPh
3a, 50%
3e, 83%
3b, 72%
3f, 84%
3c, 75%
3g, 85%
3d, 65%
3h, 84%
OOCPh
OOCPh
I
Br
Cl
F
Et
OOCPh
OOCPh
NC
O2N
3i, 57%
3j, 58%
3k, 48%
a
Reaction conditions: benzyl alcohol (0.50 mmol), hydrocarbon (10 mmol), NaH2PO4 (0.60 mmol,
anhydrous), Bu4NI (0.10 mmol), TBHP (3.0 mmol, 70% aqueous solution), MeCN (2 mL), air atmosphere,
80 °C, 36 h. GC results.
electron withdrawing groups on the phenyl ring also provided
good performance that both 4-cyanotoluene and 4-nitrotoluene
formed esters 3i–3j in moderate yields of about 60%. Propylben-
zene showed a synthetically useful yield (48%; 3k).
pathway that toluene was firstly oxidized to benzyl alcohol and
then esterified to 1c was ruled out. Under the optimum conditions,
the reaction of sodium benzoate in 4-chlorotoluene also produced
66% yield of 4-chlorobenzyl benzoate (Scheme 2S, b), which sug-
gested that the ester product may be formed through nucleophilic
attack by carboxylic anion. Moreover, the nucleophilic displace-
ment between sodium benzoate and benzyliodide gave high yield
of benzyl benzoate (Scheme 2S, c). Thus it is likely that toluene is
converted to benzyliodide first followed by a reaction with carbox-
ylic anions to form the esters.
As for the transformation of the catalyst Bu4NI, Wan and co-
workers proposed an I2/IÀ redox process.5g,10a,b,11g For our system,
when Bu4NI was replaced by KI (Table 1, entry 9), the yield of ben-
zyl 1-naphthoate (1c) was as low as 11%. However, addition of a
phasetransfer reagent benzo-18-crown-6 resulted in 74% yield of
1c (Scheme 3, a). Although no ester product was observed using
I2 as the catalyst (Table 1, entry 10), 84% yield of 1c was formed
by adding a catalytic amount of Bu4NBr (Scheme 3, b). On the other
hand, employment of Bu4NBr led to a dramatic decrease of the
yield of 1c (Table 1, entry 8). In addition, using Bu4NI as the
To probe the details of the mechanism, a series of control exper-
iments were designed and performed. When using 1-naphthalde-
hyde or 1-naphthoic acid as the substrate, the yield of benzyl
1-naphthoate increased to 82–90% (Scheme 2, a–b). Applying a
strong radical inhibitor butylated hydroxytoluene (BHT) com-
pletely inhibited the reaction (Scheme 1S). If adding two equiva-
lents of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the
reaction mixture, 2,2,6,6-tetramethylpiperidin-1-yl 1-naphthoate
(1d) was formed with 60% isolated yield (Scheme 2, c). These
observations suggested that the esterification reaction occurred
through a sequential oxidation involving: (1) radical initiated oxi-
dation of alcohol to aldehyde; (2) oxidation of aldehyde to carbox-
ylic acid via a carbonyl radical intermediate; (3) oxidative coupling
of carboxylic acid and toluene to form benzyl ester.
Benzyl 1-naphthoate (1c) was not observed from the reaction of
1-naphthoic acid with benzyl alcohol (Scheme 2S, a). Thus, the
Standard conditions
Standard conditions
(a)
(a)
No Bu4NI
KI (20 mol%)
CH2OH
0.5 mmol
COOBn
74%
CHO
0.5 mmol
COOBn
82%
Benzo-18-crown-6 (20 mol%)
Standard conditions
Standard conditions
(b)
(c)
(b)
(c)
No Bu4NI
I
2 (10 mol%)
CH2OH
0.5 mmol
COOBn
84%
Bu4NBr (20 mol%)
COOH
0.5 mmol
COOBn
90%
tBuOOH
tBuO + OH-
Standard conditions
TEMPO (2 equiv)
I-
I
-
3/2
1/2
3
CH2OH
0.5 mmol
Scheme 2. Investigation of the reaction intermediate.
N
O
O
H2O + tBuOO
tBuOOH + OH-
60% (isolated)
1d
Scheme 3. Investigation on the role of Bu4NI.
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4
L. Liu et al. / Tetrahedron Letters xxx (2013) xxx–xxx
catalyst, I2 was isolated from the brown reaction mixture.14 Thus,
Bu4N+ must function as a phasetranser reagent and IÀ is probably
in a redox equilibrium with I3 (Scheme 3, c). Phasetransfer re-
L.; Lai, G.; Xia, C.; Xu, L. Chem. Commun. 2012, 8592–8594; (h) Liu, C.; Tang, S.;
Lei, A. Chem. Commun. 2013, 1324–1326.
3. (a) Gopinath, R.; Patel, B. K. Org. Lett. 2000, 2, 577–579; (b) Kiyooka, S.; Ueno,
M.; Ishii, E. Tetrahedron Lett. 2005, 46, 4639–4642; (c) Lerebours, R.; Wolf, C. J.
Am. Chem. Soc. 2006, 128, 13052–13053; (d) Yoo, W.; Li, C. J. Org. Chem. 2006,
71, 6266–6268; (e) Ekoue-Kovi, K.; Wolf, C. Chem. Eur. J. 2008, 14, 6302–6315;
(f) Marsden, C.; Taarning, E.; Hansen, D.; Johansen, L.; Klitgaard, S. K.; Egeblad,
K.; Christensen, C. H. Green Chem. 2008, 10, 168–170; (g) Hashmi, A. S. K.;
Lothschütz, C.; Ackermann, M.; Doepp, R.; Anantharaman, S.; Marchetti, B.;
Bertagnolli, H.; Rominger, F. Chem. Eur. J. 2010, 16, 8012–8019; (h) Liu, C.; Tang,
S.; Zheng, L.; Liu, D.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 5662–
5666; (i) Tschaen, B. A.; Schmink, J. R.; Molander, G. A. Org. Lett. 2013, 15, 500–
503.
À
agent and iodine are two key factors in the oxidation process.
Therefore, we propose the reaction mechanism is as follows:
tert-butoxyl and tert-butylperoxyl radicals which are formed
through interaction of TBHP with the I3À/IÀ redox couple
(Scheme 3, c), initiate the oxidation reaction by abstracting hydro-
gen atoms of C–H bonds adjacent to the oxygen atoms of 1-naph-
thalenemethanol to produce 1-naphthaldehyde. Subsequently,
1-naphthaldehyde undergoes a similar hydrogen abstraction reac-
tion to form acyl radical which is then oxidized by TBHP to 1-naph-
thoic acid. After deprotonation, 1-naphthoic acid reacts with
benzyliodide to form benzyl 1-naphthoate.15 Benzyliodide is
generated from the iodization of toluene with I3À under the oxida-
tion conditions.16
In summary, we developed a Bu4NI-catalyzed system for the
synthesis of benzyl esters directly from alcohols and toluene deriv-
atives. The sequential oxidation of alcohols to aldehydes, to car-
boxylic acid, and to benzyl esters is accomplished in one-pot. The
direct oxyacylation of benzyl C–H bond under transition metal free
conditions also provides a new strategy for the rational design of
methods for the functionalization of sp3 C–H bonds.
4. (a) Brennführer, A.; Neumann, H.; Beller, M. ChemCatChem 2009, 1, 28–41; (b)
Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 10788–10799; (c) Xie,
P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134,
9902–9905.
5. (a) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc.
2005, 127, 6970–6971; (b) Lee, J. M.; Chang, S. Tetrahedron Lett. 2006, 47, 1375–
1379; (c) Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448–6451;
(d) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010,
132, 15116–15119; (e) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew.
Chem., Int. Ed. 2011, 50, 5331–5334; (f) Feng, J.; Liang, S.; Chen, S.; Zhang, J.; Fu,
S.; Yu, X. Adv. Synth. Catal. 2012, 354, 1287–1292; (g) Shi, E.; Shao, Y.; Chen, S.;
Hu, H.; Liu, Z.; Zhang, J.; Wan, X. Org. Lett. 2012, 14, 3384–3387.
6. (a) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2012, 14,
3982–3985; (b) Huang, J.; Li, L.; Li, H.; Husan, E.; Wang, P.; Wang, B. Chem.
Commun. 2012, 10204–10206.
7. Majji, G.; Guin, S.; Gogoi, A.; Rout, S. K.; Patel, B. K. Chem. Commun. 2013, 3031–
3033.
8. Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376–1379.
9. For recent reviews: (a) Uyanik, M.; Ishihara, K. ChemCatChem 2012, 4, 177–185;
(b) Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979–999.
10. (a) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J.
2011, 17, 4085–4089; (b) Wei, W.; Zhang, C.; Xu, Y.; Wan, X. Chem. Commun.
2011, 10827–10829; (c) Tan, B.; Toda, N.; Barbas, C. F., III Angew. Chem., Int. Ed.
2012, 51, 12538–12541.
Acknowledgment
This research was supported by the NSFC (21171012 and
J1034013).
11. (a) Zhu, C.; Wei, Y. ChemSusChem 2011, 4, 1082–1086; (b) Froehr, T.; Sindlinger,
C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. Org. Lett. 2011, 13, 3754–
3757; (c) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem. Commun. 2011, 11333–11335;
(d) Kloeckner, U.; Weckenmann, N. M.; Nachtsheim, B. J. Synlett 2012, 23, 97–
100; (e) Chen, S.; Xu, Y.; Wan, X. Org. Lett. 2011, 13, 6152–6155; (f) Xie, J.; Jiang,
H.; Cheng, Y.; Zhu, C. Chem. Commun. 2012, 979–981; (g) Liu, Z.; Zhang, J.;
Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed. 2012, 51, 3231–3235; (h)
Mai, W.; Wang, H.; Li, Z.; Yuan, J.; Xiao, Y.; Yang, L.; Mao, P.; Qu, L. Chem.
Commun. 2012, 10117–10119; (i) Li, H.; Xie, J.; Xue, Q.; Cheng, Y.; Zhu, C.
Tetrahedron Lett. 2012, 53, 6479–6482.
Supplementary data
Supplementary data (experimental details and characterization
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.07.114.
References and notes
12. (a) Rodríguez, A.; Moran, W. J. Org. Lett. 2011, 13, 2220–2223; (b) Li, L.; Huang,
J.; Li, H.; Wen, L.; Wang, P.; Wang, B. Chem. Commun. 2012, 5187–5189.
13. For reviews on CDC reactions: (a) Li, C. Acc. Chem. Res. 2009, 42, 335–344; (b)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292.
1. (a) Otera, J.; Nishikido, J. Esterification: Methods, Reactions, and Applications;
WILEY-VCH: Weinheim, 2003; (b) Luo, F.; Pan, C.; Cheng, J. Synlett 2012, 357–
366.
2. (a) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127,
10840–10841; (b) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Chem. Commun.
2008, 624–625; (c) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem.
Soc. 2009, 131, 3146–3147; (d) Miyamura, H.; Yasukawa, T.; Kobayashi, S. Green
Chem. 2010, 12, 776–778; (e) Gowrisankar, S.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 5139–5143; (f) Liu, C.; Wang, J.; Meng, L.; Deng, Y.; Li,
Y.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144–5148; (g) Bai, X.; Ye, F.; Zheng,
14. After heated for 10 hrs under the optinum conditions, the solvents were
removed under vacuum.
A purple eluent was isolated from the reaction
mixture by silica gel column chromatography. The potassium iodide-starch
test strips turned dark blue when contacting with the isolated purple species,
indicated that I2 was formed.
15. See Supplementary data for more mechanistic studies.
16. Montoro, R.; Wirth, T. Org. Lett. 2003, 5, 4729–4731.
Please cite this article in press as: Liu, L.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.07.114