Cobalt-Catalyzed Decarboxylative Acetoxylation of Amino Acids and Arylacetic Acids

Article abstract of DOI:10.1021/acs.orglett.5b02142

The first cobalt-catalyzed decarboxylative acetoxylation reaction was accomplished. This methodology is applicable to a wide range of amino acids and arylacetic acids.

Full text of DOI:10.1021/acs.orglett.5b02142

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed Decarboxylative Acetoxylation of Amino Acids and
Arylacetic Acids
Kun Xu,*,† Zhiqiang Wang,† Jinjin Zhang,† Lintao Yu,† and Jiajing Tan*,‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061 P. R. China
‡Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: The first cobalt-catalyzed decarboxylative ace-
toxylation reaction was accomplished. This methodology is
applicable to a wide range of amino acids and arylacetic acids.
a
ransition-metal-catalyzed decarboxylative couplings have
emerged as a versatile approach in organic synthesis.1 This
Table 1. Optimization of the Reaction Conditions
T
method employs inexpensive and benchtop stable carboxylic
acids as substrate, without the need for preformed organo-
metallic reagents, thus providing an attractive alternative to
traditional cross-couplings. Moreover, the decarboxylative
coupling strategy is likely promising for regiospecific function-
alization and only provides nontoxic carbon dioxide as a
byproduct.
b
entry
Mn+
solvent
temp (°C)
yield (%)
1
Co(OAc)2·4H2O
CoCl2·6H2O
Co(acac)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
Tol
120
120
120
120
120
120
120
120
120
120
120
120
130
100
86
51
Until now, transition-metal-catalyzed decarboxylative cou-
plings have relied heavily on using late and noble transition
metals including palladium,2 silver,3 and rhodium complexes.4
Although naturally abundant first-row transition metals, such as
Cu5 and Ni,6 have recently witnessed considerable attention,
the development of a low cost, low toxicity catalyst system for
decarboxylative coupling still represents a challenging task.
Whereas significant progress has been made toward the
decarboxylative C−C bond formations, the decarboxylative
C−O couplings are rather limited.7 Given the fact that C−O
moieties are ubiquitous in both natural products and
pharmaceuticals, developing efficient decarboxylative strategies
for construction of a C−O bond is highly desired.8 Herein, we
report our recent efforts on cobalt-catalyzed decarboxylative
acetoxylation of amino acids and arylacetic acids.9 This method
represents a new type of decarboxylative coupling reaction
catalyzed by earth-abundant, inexpensive first-row transition
metals.10
Our investigation began with the reaction of phthalimide
protected phenylglycine 1a and iodosobenzene diacetate 2 in
the presence of a catalytic amount of cobalt complexes (Table
1). A screen of catalysts was first conducted with 1,2-
dicholoroethane (DCE) as the solvent. The results showed
that Co(OAc)2·4H2O was the most effective catalyst for this
reaction, whereas CoCl2·6H2O, Co(acac)2, and CoC2O4 all
gave lower yields (entries 1 vs 2−4); other Lewis acids such as
FeCl3, Cu(OTf)2, and Ag2CO3 gave inferior results (entries 5−
7). Control experiment revealed that the cobalt catalyst was
essential for this transformation as only 13% yield was obtained
without cobalt salts (entry 8). Further assessment of the solvent
effect indicated that DCE was the best solvent for this reaction,
2
3
74
4
CoC2O4·2H2O
FeCl3
35
5
14
6
Cu(OTf)2
16
7
Ag2CO3
21
8
13
9
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
67
10
11
12
13
14
37
dioxane
EtOH
DCE
DCE
trace
23
79
83
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), catalyst (0.05
b
mmol), solvent (2 mL), 8 h. Isolated yield.
providing higher yield than other commonly used solvents
(entry 1 vs 9−12). Both increasing and decreasing the
temperature resulted in lower yields (entries 13 and 14).
Under the optimized conditions, the substrate scope of
amino acid was investigated. As shown in Figure 1, this
protocol is successful with a large variety of phthalimide-
protected amino acids. The electron-withdrawn group on the
aromatic ring led to a slightly lower yield (3a vs 3b−e).
Compared with the substrate with para-substituents, those with
meta-substituents on the aromatic ring gave better yields (3d vs
3b, 3e vs 3c). Substrates with an alkyl substituent group were
Received: July 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalyst, diaryl-substituted acids could give excellent yields
(5a,b); however, only moderate yield was obtained when 2-
phenylbutyric acid and 1,4-benzodioxane-2-carboxylic acid were
employed as the substrates (5c,d). It is noteworthy that primary
carboxylic acid, such as 4-methylphenylacetic acid, was also well
tolerated in this transformation, thus affording the correspond-
ing product 5e in 64% yield.11 However, n-hexanoic acid, pivalic
acid, and phenylpropionic acid were unreactive.
To probe the nature of this decarboxylative coupling, the
radical-trapping reagent (TEMPO) was added into the reaction
of 1a and 2 (Scheme 1). It was shown that the formation of
product 3a was completely prohibited, suggesting a radical
process was involved.12
Scheme 1. Control Experiment
On the basis of the control experiment, a plausible reaction
mechanism was proposed as shown in Scheme 2. Initially,
Scheme 2. Plausible Mechanism for This Reaction
Figure 1. Substrate scope of N-protected amino acids. (a) Reaction
conditions: 1 (0.5 mmol), 2 (0.75 mmol), Co(OAc)2·4H2O (0.05
mmol), DCE (2 mL), 10 h. (b) The reaction temperature was 120 °C,
8 h.
also tolerable where the steric hindrance had a profound effect.
While linear groups provided the desired products with similar
level of yields, the bulky alkyl groups led to a sharp decrease of
the yields (3h−j vs 3k−m). Finally, N-phthaloylglycine was
successfully employed as the substrate, giving the correspond-
ing acetate 3g in 72% yield.
To further establish the general utility of this transformation,
we next sought to examine other types of aliphatic carboxylic
acids. As shown in Figure 2, a series of primary and secondary
acids were all good reaction partners with a minor modification
of the standard reaction conditions. With CoCl2·6H2O as the
amino acid 1a coordinated with Co(OAc)2 to give cobalt
carboxylate 6, which could then be oxidized by PhI(OAc)2 to
form radical 7 and one molecule of Co(OAc)3. Next, radical 7
could be converted into intermediate 8 with the extrusion of
CO2. Under the catalysis of Co(OAc)3, radical 8 undergoes an
oxidation process to give cation 9 while releasing one molecule
of acetate anion. Finally, nucleophilic attack of cation 9 by
acetate anion affords the desired product 3a.
In conclusion, we have developed the first example of a
cobalt-catalyzed decarboxylative C−O bond-forming reaction.
The reaction is tolerable to a wide range of amino acids and
arylacetic acids, giving the corresponding acetates in moderate
to good yields. The ready availability and low cost of the
catalyst and the mild reaction conditions render this method of
practical value in the construction of C−O bonds. Efforts to
expand the synthetic applications, as well as further mechanistic
studies, are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02142.
Figure 2. Substrate scope of other types of aliphatic carboxylic acids.
(a) Reaction conditions: 4 (0.5 mmol), 2 (0.75 mmol), CoCl2·6H2O
(0.05 mmol), DCE (2 mL), 10 h.
B
DOI: 10.1021/acs.orglett.5b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, characterization data, copies of
Letter
(7) (a) Bhadra, S.; Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc. 2012,
134, 9938. (b) Kiyokawa, K.; Yahata, S.; Kojima, T.; Minakata, S. Org.
Lett. 2014, 16, 4646.
1H NMR and 13C NMR of new compounds (PDF)
(8) For selected examples of PhI(OAc)2- and I2-promoted
decarboxylative C−O bond formation, see: (a) Francisco, C. G.;
AUTHOR INFORMATION
■
Gonzal
A.; Hernan
(c) Boto, A.; Hernan
2495. (d) Boto, A.; Hernan
4930.
́
ez, C. C.; Suar
dez, R.; Suar
dez, R.; Suar
dez, R.; Suar
́
ez, E. Tetrahedron Lett. 1997, 38, 4141. (b) Boto,
Corresponding Authors
́
́
ez, E. Tetrahedron Lett. 1999, 40, 5945.
ez, E. Tetrahedron Lett. 2000, 41,
ez, E. J. Org. Chem. 2000, 65,
́
́
*E-mail: xukun@nynu.edu.cn.
*E-mail: jiajing.tan@foxmail.com.
́
́
(9) For selected examples on the decarboxylation of amino acids, see:
(a) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889.
(b) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798. (c) Wang,
Q.; Zhang, S.; Guo, F.; Zhang, B.; Hu, P.; Wang, Z. Y. J. Org. Chem.
2012, 77, 11161.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) For selected recent examples catalyzed by first-row transition
metals, such as Co and Fe, see: (a) Ilies, L.; Chen, Q.; Zeng, X.;
Nakamura, E. J. Am. Chem. Soc. 2011, 133, 5221. (b) Li, B.; Wu, Z.-H.;
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2011, 50, 1109. (c) Ding, Z.; Yoshikai, N. Angew. Chem., Int. Ed. 2013,
52, 8574. (d) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am.
Chem. Soc. 2013, 135, 6030. (e) Zhao, D.; Kim, J. H.; Stegemann, L.;
Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508.
(f) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490.
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(11) For the electron-withdrawing arylacetic acids, the yield
decreased dramatically. For example, when nitro-substituted arylacetic
acid was employed as the substrate, the decarboxylative acetoxylation
reaction did not occur.
Financial support from the Foundation of He’nan Educational
Committee (15A150067) and Nanyang Normal University
(ZX2015010) is greatly acknowledged.
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DOI: 10.1021/acs.orglett.5b02142
Org. Lett. XXXX, XXX, XXX−XXX