A new strategy for the construction of α-amino acid esters via decarboxylation

Article abstract of DOI:10.1021/ol401139m

A new α-amino acid esters formation reaction has been developed via decarboxylation. The methodology is distinguished by its practical novelty in terms of the readily accessible starting materials, environmentally benign reaction conditions and waste streams, and wide substrate scope.

Full text of DOI:10.1021/ol401139m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A New Strategy for the Construction of
r‑Amino Acid Esters via Decarboxylation
Jie Zhang,† Jiewen Jiang,† Yuling Li,‡ Yun Zhao,† and Xiaobing Wan*,†
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, School of Chemistry and Chemical Engineering, Jiangsu Normal University,
Xuzhou 221116, P. R. China
wanxb@suda.edu.cn
Received April 24, 2013
ABSTRACT
A new r-amino acid esters formation reaction has been developed via decarboxylation. The methodology is distinguished by its practical
novelty in terms of the readily accessible starting materials, environmentally benign reaction conditions and waste streams, and wide
substrate scope.
The carboxyl group is one of the most common func-
tionalities in organic molecules and has a broad range
of applications in synthetic chemistry because of its high
activity and versatility.1 Carboxyl groups effectively acti-
vate the CÀH bonds of the sp3 carbon atoms to which they
are attached because of their strong electron-withdrawing
effect, and the R-functionalization of carboxyl groups has
been elegantly developed on the basis of this activation
mechanism to provide access to R-substituted carboxylic
acids.2 For example, the HellÀVolhardÀZelinsky reac-
tion,3 which is one of the oldest reactions in organic
chemistry, has been extensively used for the construc-
tion of R-halogenated carboxylic acids. Unfortunately,
however, there are several limitations to this particular
method, includingthe handlingof a stoichiometric amount
of a toxic halogenation reagent and the generation of
halogen-containing waste. In addition, during the course
of the past decade, transition metal catalyzed decarbox-
ylative coupling reactions have been developed as power-
ful tools for the formation of carbonÀcarbon and car-
bonÀheteroatom bonds. A variety of different research
groups, including those of Goossen,4 Myers,5 and Tunge,6
(4) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Rodrı
Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (c) Goossen, L. J.;
Rodrıguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248.
(d) Goossen, L. J.; Rodrıguez, N.; Lange, P. P.; Linder, C. Angew.
´
guez, N.; Melzer, B.; Linder, C.; Deng, G.;
´
´
Chem., Int. Ed. 2010, 49, 1111. (e) Bhadra, S.; Dzik, W. I.; Goossen, L. J.
J. Am. Chem. Soc. 2012, 134, 9938.
(5) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(c) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005,
127, 10323.
(6) (a) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002.
(b) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138.
(c) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 14860.
(d) Torregrosa, R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.; Tunge,
J. A. J. Am. Chem. Soc. 2010, 132, 9280. (e) Weaver, J. D.; Ka, B. J.;
Morris, D. K.; Thompson, W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132,
12179. (f) Jana, R.; Partridge, J. J.; Tunge, J. A. Angew. Chem., Int. Ed.
2011, 50, 5157.
† Soochow University
‡ Jiangsu Normal University
(1) Carey, F. A. Organic Chemistry, 4rd ed.; McGraw-Hill Higher
Education: New York, 2000, p 736.
(2) (a) Crawford, R. J. J. Org. Chem. 1983, 48, 1364. (b) Rozen, S.;
Hagooly, A.; Harduf, R. J. Org. Chem. 2001, 66, 7464. (c) Pfeffer, P. E.;
Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 1972, 37, 451. (d) Battersby,
A. R.; Westwood, S. W. J. Chem. Soc., Perkin Trans. 1 1987, 1679.
(e) Alliot, J.; Gravel, E.; Pillon, F.; Buisson, D.-A.; Nicolasb, M.; Doris,
E. Chem. Commun. 2012, 48, 8111.
(3) (a) Hell, C. Ber. Dtsch. Chem. Ges. 1881, 14, 891. (b) Zelinsky, N.
Ber. Dtsch. Chem. Ges. 1887, 20, 2026. (c) Volhard, J. Justus Liebigs Ann.
Chem. 1887, 242, 141.
r
10.1021/ol401139m
XXXX American Chemical Society

among others,7 have recently published pioneering and
systematic studies in this area.
a consecutive halogenation and decarboxylation process
would provide the basis for a new approach to the syn-
thesis of R-amino acid esters. R-Amino acids themselves
are important molecules in the chemical, biochemical,
and material sciences.10,11 Conventional routes to this
ubiquitous class of molecules include the nucleophilic
substitution of amines to R-halogenated esters.12 Unfor-
tunately, however, the involvement of a stoichiometric
quantity of halide constitutes a noticeable limitation
to this approach. Based on the general importance
of R-amino acids and shortcomings in existing synthetic
methodologies, we decided to develop an alternative
synthetic strategy to provide facile access to this group
of compounds.
Monomethyl malonate 1a and N-methylaniline 2a were
selected as model substrates to evaluate our strategy.
We recently developed an interest in green oxidation reac-
tions using tetrabutylammonium iodide (TBAI) as a cat-
alyst and tert-butyl hydroperoxide (TBHP) as a primary
oxidant.13cÀg It was envisaged that the use of the TBAI/
TBHP system would address several key issues associated
with our strategy, including (1) the in situ generation of
hypoiodite or iodine from TBAI and the subsequent
iodination of monomethyl malonate 1a; (2) the decarbox-
ylation to generate methyl iodoacetate; and (3) the nucleo-
philic substitution of N-methylaniline 2a to methyl
iodoacetate to deliver the desired R-amino acid esters.
Following a period of extensive screening, it was estab-
lished that the reaction of 1a and 2a in the presence of
20 mol % TBAI, 2.2 equiv of TBHP, and 2.0 equiv of
NaOAc in a mixture of H2O and MeCN at 90 °C for 8 h
furnished the desired product 3a in a high yield (84%).
Pleasingly, the stoichiometric addition of a halide was
therefore not required for this novel R-amino acid ester
forming reaction. Furthermore, in contrast to the transition
metal catalyzed versions of this particular transformation,4À7
this metal-free strategy had the advantage of not being
sensitive to moisture.
Scheme 1. Our Design to Construct R-Amino Acid Esters
Herein, we describe the successful sequential combina-
tion of the R-halogenation and decarboxylation reactions
of a series of malonates to generate the correspond-
ing electrophilic R-halogenated esters, which were subse-
quently reacted with an amine to form the R-amino acid
esters (Scheme 1).8 To minimize the amount of haloge-
nated waste generated by the process, the use of an
oxidant was investigated to regenerate the halogena-
tion reagent, with several different oxidants being eval-
uated. It is noteworthy that the decarboxylation of
malonates has found widespread application in synthetic
chemistry.9 For the current work, it was envisaged that
(7) For representative examples, see: (a) O’Brien, E. M.; Bercot,
E. A.; Rovis, T. J. Am. Chem. Soc. 2003, 125, 10498. (b) Voutchkova, A.;
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J. Org. Chem. 1987, 52, 616. (b) Augustine, J. K.; Naik, Y. A.; Mandal,
A. B.; Chowdappa, N.; Praveen, V. B. J. Org. Chem. 2007, 72, 9854.
(c) Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841.
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Chem. 2009, 74, 6190. (e) Sharma, A.; Sharma, N.; Kumar, R.; Shard,
A.; Sinha, A. K. Chem. Commun. 2010, 46, 3283.
(12) For representative examples, see: (a) Zhang, Y.; Gao, X.;
Hardcastle, K.; Wang, B. Chem.;Eur. J. 2006, 12, 1377. (b) Kumar,
V.; Kaushik, M. P.; Mazumdar, A. Eur. J. Org. Chem. 2008, 1910.
(c) Piao, X.; Zhang, X.; Mori, Y.; Koishi, M.; Nakaya, A.; Inoue, S.;
Aoki, I.; Otomo, A.; Yokoyama, S. J. Polym. Sci., Part A: Polym. Chem.
2011, 49, 47.
(10) For reviews on this topic, see: (a) Carey, F. A. Organic
Chemistry, 4rd ed., McGraw-Hill Higher Education: New York, 2000,
p 1051. (b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
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(13) Recently, we and others reported the oxidation reaction using
TBAI/TBHP, see: (a) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (b) Li,
Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (c) Chen, L.; Shi, E.;
Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem.;Eur. J.
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Commun. 2011, 47, 10827. (e) Chen, S.; Xu, Y.; Wan, X. Org. Lett.
2011, 13, 6152. (f) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X.
Angew. Chem., Int. Ed. 2012, 51, 3231. (g) Shi, E.; Shao, Y.; Chen, S.;
Hu, H.; Liu, Z.; Zhang, J.; Wan, X. Org. Lett. 2012, 14, 3384.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Investigations on the Active Speciesa
entry
catalyst
oxidant
base
yieldb
1
2
3
4
5
6
I2
TBHP
À
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
73
I2 (1.2 equiv)
NIS
13
TBHP
TBHP
TBHP
TBHP
72
IBr
72
Phl(OAc)2
IBX
N.D.c
N.D.
a 1.0 mmol of 1a, 0.5 mmol of 2a, 1.0 mmol of NaOAc, 20 mol % of
catalyst, 2.2 equiv of TBHP, 1.0 mL of MeCN, and 1.0 mL of H2O.
b Isolated yield. c Not detected.
The use of iodine as a catalyst provided the product 3a
in 73% yield (Table 1, entry 1). However, only a small
amount of product 3a was observed when stoichiometric
iodine was used in the absence of TBHP (Table 1, entry 2).
The use of catalytic iodine(I) reagents provided the desired
product 3a in good yields (Table 1, entries 3 and 4). In
sharp contrast, the use of hypervalent iodine reagents
halted the transformation (Table 1, entries 5 and 6).
Hypoiodite, which was generated in situ from iodide in
the presence of TBHP, was the active species in this
transformation and became the preferred choice for the
reaction. Relative to the well documented use of hyperva-
lent iodine,15 the use of hypoiodite has attracted much less
attention,16 likely because of its poor stability.
As well as the desired amino acid product 3a, a small
amount of the R-iodinated acid 4 was also obtained as a
byproduct in the model reaction. Notably, no β-amino
acid ester was observed, which indicated the addition of
enolate to imine was not involved in this reaction (eq 1).
Only a trace amount of methyl acetate 5 was detected when
the reaction was conducted in the absence of TBAI (eq 2),
suggesting the iodination event promoted the subsequent
decarboxylation process. It is noteworthy that no product
3a was observed when methyl acetate 5 was reacted with
N-methylaniline 2a in place of monomethyl malonate 1a,
which indicated that the iodination of methyl acetate 5
was not involved in the catalytic cycle (eq 3). Not surpris-
ingly, none of the corresponding product was detected
when monomethyl 2,2-dimethylmalonate was used as
the reaction partner (eq 4). Further control experiments
were carried out to elucidate the detailedmechanism of this
reaction. The use of methyl iodoacetate 6 as a catalyst
resulted in the desired product 3a in good yield (eq 5).
As expected, product 3a was isolated in 87% yield via the
direct nucleophilic substitution of amine 2a to methyl
iodoacetate 6 (eq 6). On the basis of these results, it was
concluded that the decarboxylation reaction in the current
reaction occurred following the initial halogenation of
the monomethyl malonate 1a, which is in sharp contrast
with the mechanism of the Hunsdiecker (decarboxylative
halogenation) reaction.14 When TEMPO (2,2,6,6-tetra-
methyl-1-piperidinyloxy), a well-known radical-trapping
reagent, was added to the reaction, product 3a was isolated
in good 64% yield (eq 7), thus suggesting that this R-amino
acid esters formation reaction was not a radical process.
Scheme 2. Proposed Catalytic Cycle
Based upon the results described above and in the
literature, a plausible catalytic cycle was proposed for the
transformation, as depicted in Scheme 2. The key fea-
tures of this cycle include (i) the in situ generation
of hypoiodite17 A from iodide in the presence of TBHP;
(ii) the iodination of malonate to give the intermediate B;18
(15) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(16) For representatilve examples, see: (a) Yamada, S.; Morizono,
D.; Yamamoto, K. Tetrahedron Lett. 1992, 33, 4329. (b) Courtneidge,
ꢀ
J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett. 1994, 35, 1003. (c) Wang,
D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387.
(d) Giri, R.; Wasa, M.; Breazzano, S. P.;Yu, J.-Q. Org. Lett. 2006, 8, 5685.
(17) See ref 13f and 13g.
(14) Johnson, R. G.; Ingham, R. K. Chem. Rev. 1956, 56, 219.
Org. Lett., Vol. XX, No. XX, XXXX
C

(iii) the decarboxylation of B to form iodoacetate C, and
(iv) the nucleophilic substitution of amine to C releasing
the desired amino acid ester D and iodide.
With the optimized conditions in hand, we proceeded to
explore the general scope of the reaction and investigated the
use of a variety of different amines (Figure 1). Aryl amines
(products 3bÀm and 3rÀv) and alkyl amines (products
3nÀq) both performed well in the reaction, providing the
desired amino acid esters in moderate to high yields. It is note-
worthy that primary anilines were also well tolerated under
the reaction conditions and transformed into the desired
products 3rÀv when reacted with monomethyl malonate 1a.
Figure 2. Scope of malonates. Reaction conditions: 1.0 mmol of 1,
0.5 mmol of 2a, 1.0 mmol of NaOAc, 20 mol % of TBAI, 2.2 equiv
of TBHP, 1.0 mL of MeCN, and 1.0 mL of H2O at 90 °C for 8 h.
Compound 8, a potential prodrug of metronidazole with
improved aqueous solubility and therapeutic efficacy,19 was
constructed in good yield under the optimized conditions
(eq 8). In sharp contrast to previous approaches for the
synthesis of this molecule, the key advantage of our method
is that this transformation is not sensitive to moisture and
does not require the stoichiometric addition of toxic halide
reagents.
In summary, a novel method for the construction of
R-amino acid esters has been developed, involving sequential
iodination, decarboxylation, and nucleophilic substitution
reactions. This work is of considerable interest in terms of the
readily accessible starting materials, environmentally benign
reaction conditions and waste streams, and wide substrate
scope. Further investigations focused on the use of nucleo-
philes other than amines and an asymmetric version of the
transformation are currently underway in our laboratory.
Figure 1. Scope of amines. Reaction conditions: 1.0 mmol of 1a,
0.5 mmol of 2, 1.0 mmol of NaOAc, 20 mol % of TBAI, 2.2 equiv
of TBHP, 1.0 mL of MeCN, and 1.0 mL of H2O at 90 °C for 8 h.
The scope of the current reaction was further expanded
to a variety of malonates 1 (Figure 2). Both aryl (product 7k)
and alkyl malonates reacted smoothly under the optimized
conditions to afford the corresponding products. Most
notably, R-substituted malonates could also be subjected
to the reaction conditions to afford the desired products
in moderate yields (products 7lÀp), thus uncovering the
potential of this methodology to prepare synthetically useful
amino acid derivatives.
Acknowledgment. A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Educa-
tion Institutions (PAPD) and NSFC (21072142, 21272165).
Prof. Dr. Y. Li is grateful to National Natural Science
Foundation of China (No. 21104064) and Natural Science
Foundation of Jiangsu Normal University (10XLR03).
Supporting Information Available. Experimental de-
tails, 1H, and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
To highlight the overall utility of this methodology, we
have designed one synthetic application for drug discovery.
(18) For iodination of ketones using hypoiodite, see: (a) Barluenga,
(19) Mahfouz, N. M.; Hassan, M. A. J. Pharm. Pharmacol. 2001, 53,
841.
ꢀ
ꢀ
J.; Marco-Arias, M.; Gonzalez-Bobes, F.; Ballesteros, A.; Gonzalez,
J. M. Chem. Commun. 2004, 2616. (b) Goswami, P.; Ali, S.; Khan,
M. M.; Khan, A. T. ARKIVOC 2007, 82. (c) Stavber, G.; Iskra, J.;
Zupana, M.; Stavber, S. Green Chem. 2009, 11, 1262.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX