Facile synthesis of aryl α-keto esters via the reaction of aryl diazoacetate with H2O and DEAD

Article abstract of DOI:10.1055/s-2006-950412

A facile synthesis of aryl aα-keto esters in high yields is reported involving the reaction of aryl diazoacetate with H₂O and diethyl azodicarboxylate (DEAD) catalyzed by dirhodium acetate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950412

2486
LETTER
Facile Synthesis of Aryl a-Keto Esters via the Reaction of Aryl Diazoacetate
with H2O and DEAD
S
a
ynthesis of
Ar
h
yl
a
-KetoEs
e
ters nqiu Guo,a,b Haoxi Huang,a,b Qingquan Fu,a,b Wenhao Hu*a
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85229250; E-mail: huwh@cioc.ac.cn
b
Graduate School of Chinese Academy of Sciences, Beijing, P. R. of China
Received 28 April 2006
Recently, we developed a novel method for aryl a-imino
esters via the ammonium ylide intermediate by the Rh(II)-
catalyzed reaction of aryl diazoacetates, DEAD, and aryl
amine12 (Scheme 1).
Abstract: A facile synthesis of aryl aa-keto esters in high yields is
reported involving the reaction of aryl diazoacetate with H2O and
diethyl azodicarboxylate (DEAD) catalyzed by dirhodium acetate.
Key words: a-keto ester, a-diazoacetate, oxonium ylide, fragmen-
tation
Ar''
DEAD, CH2Cl2
Rh2(OAc)4
N2
N
+
Ar''NH2
Ar'
COOR
Ar'
COOR
Aryl a-keto esters are important intermediates in the syn-
thesis of a-imino esters,1a succinates,1b furan derivatives,1c
a-oxiranyl esters,1d chiral a-hydroxy esters1e and tertiary-
a-hydroxy esters,1f chiral terminal 1,2-diols1g and 1,2-
Scheme 1 The three-component reaction for a-imino esters
formation
amino alcohols,1h optically active b-nitro-a-hydroxyesters Based on the mechanistic interpretation of a-imino esters
and b-amino-a-hydroxy esters,1i and numerous applica-
formation, we anticipated that this strategy would be
tions have been found in the asymmetric synthesis of bio-
similarly applicable to the oxonium ylide and azodi-
carboxylates to give aryl a-keto esters. A proposed
reaction mechanism for this reaction is given in Scheme 2.
We envisioned that the reaction would initially form an
oxonium ylide 3 from the aryl diazoacetates 1 and H2O
catalyzed by Rh2(OAc)4. The ylide would be trapped by
DEAD to give adduct 4. Fragmentation of 4 would afford
the a-keto esters.
logically active compounds, such as ritalin.2
Due to the importance of aryl a-keto esters and their
derivatives, various methods have been reported for the
synthesis of these compounds, such as the reaction of
Grignard reagent to oxalyl derivatives,3 direct oxidation
of aryl acetic esters,4 Friedel–Crafts acylation,5 the oxida-
tion of alkynyl derivatives,6 the rearrangement of aryl
cyanohydrin carbonate esters,7 oxidative cleavage of
cyano keto phosphoranes8 and aryl diazoacetate.9 Howe-
ver, some of these cases suffer from inherent drawbacks,
such as strict reaction conditions,3,7–9 the troublesome
preparation of oxidizing reagents8,9 and the limitation of
substrates.4,8 Thus the development of an efficient, eco-
nomical and environmentally friendly methodology for
the synthesis of aryl a-keto esters is still required.
Ar
+
H2O
–
N2
COOEt
Rh2(OAc)4
+
H2O
COOR
N
N
Ar
COOR
3
oxonium ylide
EtOOC
1
It is well known that metal–carbene complexes (or car-
benoids) react with heteroatoms to form onium ylides.
The chemistry of onium ylides is an area of continuing
interest. Phosphorus, sulfur, ammonium, carbonyl and
oxonium ylides have been widely utilized in organic syn-
thesis.10 We have explored the Rh(II)-catalyzed three-
component reaction of aryl diazoacetates, alcohols and al-
dehydes, in which alcoholic oxonium ylide was trapped
by aromatic aldehyde via a nucleophilic addition. Water
served as an ‘active alcohol’ to afford a,b-dihydroxyl
esters in moderate yields.11
H
O
N
H
N
Ar
COOEt
N
H
ROOC
EtOOC
Ar
COOEt
+
O
EtOOC
COOR
N
H
2
5
4
Scheme 2 The proposed mechanism for a-keto esters formation
Methyl phenyldiazoacetate was used as a substrate to test
the strategy. The reaction was carried out in CH2Cl2 or tol-
uene with different catalysts, and results are summarized
in Table 1. As we expected, reaction of methyl phenyl-
diazoacetate with H2O and DEAD in the presence of 1
mol% Rh2(OAc)4 gave methyl a-oxophenylacetate in
66% yield in CH2Cl2 (Table 1, entry 1). An increased
yield of 91% was obtained in refluxing toluene (Table 1,
SYNLETT 2006, No. 15, pp 2486–2488
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8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950412; Art ID: W08606ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Aryl a-Keto Esters
2487
entry 2). The higher yield was presumably due to easy Table 2 Synthesis of Aryl a-Keto Esters 2 by Rh2(OAc)4-Catalyzed
Reaction of Aryl Diazoacetates 1 with H2O and DEADa
fragmentation of 4 at elevated reaction temperature. Using
diisopropyl azodicarboxylate (DIAD) instead of DEAD
DEAD, toluene
N2
O
+
H2O
gave 89% yield of the a-keto ester. Similar yield was ob-
tained with Cu(OTf)2 catalyst (1 mol%, Table 1, entry 3).
With 1 mol% BF3·OEt2 Lewis acid was used as catalyst,
the reaction only gave a trace amount of methyl a-oxo-
phenylacetate (Table 1, entry 4). The O–H insertion prod-
uct methyl a-hydroxyphenylacetate was obtained with
Rh2(OAc)4 in the absence of DEAD.13 No reaction oc-
curred in the absence of catalyst and most phenyl diazo-
acetate was recovered (Table 1, entry 5).
Rh2(OAc)4
(1 mol%)
Ar
COOR
Ar
COOR
2
1
Entry Diazo 1
Product 2 Yield (%)b
1
2
1a, Ar = Ph, R = Me
1b, Ar = Ph, R = Bn
1c, Ar = Ph, R = i-Pr
2a
2b
2c
2d
2e
2f
91
88
93
96
97
98
90
80
85
77
70
86
76
72
65
90
3
4
1d, Ar = Ph, R = t-Bu
Table 1 Reaction of Methyl Phenyldiazoacetate with H2O and
DEAD with Different Catalysts and Solventsa
5
1e, Ar = p-MeOC6H4, R = Me
1f, Ar = o-MeC6H4, R = Me
1g, Ar = m-MeC6H4, R = Me
1h, Ar = p-FC6H4, R = Me
1i, Ar = o-ClC6H4, R = Me
1j, Ar = m-ClC6H4, R = Me
1k, Ar = p-ClC6H4, R = Me
1l, Ar = o-BrC6H4, R = Me
1m, Ar = m-BrC6H4, R = Me
1n, Ar = p-BrC6H4, R = Me
1o, Ar = p-NO2C6H4, R = Me
1p, Ar = 1-naphthyl, R = Me
N2
DEAD, solvent
cat. (1 mol%)
O
6
+
H2O
Ph
COOMe
Ph
COOMe
7
2g
2h
2i
Entry
Catalyst (1 mol%) Solvent
Yield (%)b
8
1
2
3
4
5
Rh2(OAc)4
Rh2(OAc)4
Cu(OTf)2
BF3·OEt2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
66
9
91c
10
11
12
13
14
15
16
2j
87
2k
2l
Traced
e
f
–
–
2m
2n
2o
2p
a Methyl phenyldiazoacetate (1.0 equiv), H2O (1.1 equiv), DEAD (1.1
equiv) in refluxing solvents for 4 h.
b Isolated yield after column chromatography purification.
c A yield of 89% was obtained using DIAD instead of DEAD.
d Determined by crude 1H NMR.
e No catalyst was used.
f No reaction and most phenyl diazoacetate was recovered.
a Aryl diazoacetate (1.0 equiv), H2O (1.1 equiv), DEAD (1.1 equiv) in
refluxing toluene for 4 h.
b Isolated yield after column chromatography purification.
Having established the preferred reaction conditions, we
have applied the synthetic strategy to a variety of aryl
diazoacetates to afford aryl a-keto esters in high yields14
(Table 2). Increased yields were obtained with the use of
diazoacetates bearing more bulky ester substitutions
(Table 2, entry 1–4). The aryl diazoacetates with the
ortho-position substituents gave higher yields than the
meta- and para-position substituents (Table 2, entry 6–7,
entry 9–11, entry 12–14). And the reaction proceeded well
with electron-donating substituents on the phenyl ring
(Table 2, entry 5–7). While using electron-withdrawing
substituents such as p-nitrophenyl diazoacetate, decreased
yield of a-keto ester was obtained (Table 2, entry 15).
To get more evidence to support the proposed reaction
mechanism shown in Scheme 2, reaction kinetics was fol-
lowed by 1H NMR in CDCl3 with methyl p-chlorophenyl-
diazoacetate as a substrate (Scheme 3). It was found that
the major process was the production of the ketoester 2k
H
O
O
N2
DEAD, CDCl3, r.t., 2 h
Cl
+
H2O
COOMe
ROOC
EtOOC
Rh2(OAc)4
(1 mol%)
+
COOMe
N
COOEt
Cl
N
H
Cl
1k
2k
4k
OH
+
COOMe
Cl
6k
Scheme 3
Synlett 2006, No. 15, 2486–2488 © Thieme Stuttgart · New York

2488
Z. Guo et al.
LETTER
(3) (a) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
through the intermediate 4k, while the oxidation of the
O–H insertion product 6k to 2k was also observed as a
minor process. We failed to isolate the intermediate 4k
because it was unstable during the isolation. However, we
were able to isolate its methyl ether derivative 7 by using
methanol instead of water as a starting material
(Scheme 4).15
Tetrahedron 1996, 52, 13513; and references cited therein.
(b) Nimitz, J.; Mosher, H. S. J. Org. Chem. 1981, 46, 211.
(c) de las Heras, M. A.; Vaquero, J. J.; Garcia-Navio, J. L.;
Alvarez-Builla, J. J. Org. Chem. 1996, 61, 9009.
(4) (a) Matsunaka, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 1999, 40, 2165. (b) Wentzel, B. B.;
Donners, M. P. J.; Alsters, P. L.; Feitersa, M. C.; Nolte, R. J.
M. Tetrahedron 2000, 56, 7797. (c) Velusamy, S.;
Punniyamurthy, T. Tetrahedron Lett. 2003, 44, 8955.
(5) Micetich, R. G. Org. Prep. Proced. Int. 1970, 2, 249.
(6) (a) Tatlock, J. H. J. Org. Chem. 1995, 60, 6221. (b) Li, L.-
S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427.
(7) Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.;
Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1019.
(8) (a) Wasserman, H. H.; Hot, W. B. J. Org. Chem. 1994, 59,
4364. (b) Wong, M.-K.; Yu, C.-W.; Yuen, W.-H.; Yang, D.
J. Org. Chem. 2001, 66, 3606.
Me
O
DEAD, toluene,
50 °C, 1 h
H3COOC
EtOOC
Ph
COOEt
N2
+
MeOH
N
Rh2(OAc)4
(1 mol%)
Ph
COOMe
N
H
7
66%
Scheme 4
(9) Ma, M.; Li, C.-K.; Peng, L.-L.; Xie, F.; Zhang, X.; Wang, J.-
B. Tetrahedron Lett. 2005, 46, 3927.
In summary, we have developed a new method for the
synthsis of aryl a-keto esters from aryl diazoacetates with
H2O and DEAD. The current method especially works
well with sterically hindered substrates and electron-
donating aryl functional groups. To some extend, this
method is complimentary to the traditional methods.
(10) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998. (b) Nitrogen, Oxygen and Sulfur
Ylide Chemistry; Clark, J. S., Ed.; Oxford University Press:
Oxford, 2002.
(11) Lu, C.-D.; Liu, H.; Chen, Z.-Y.; Hu, W.-H.; Mi, A.-Q. Org.
Lett. 2005, 7, 83.
(12) Huang, H.-X.; Wang, Y.-H.; Chen, Z.-Y.; Hu, W.-H. Synlett
2005, 2498.
Acknowledgment
(13) (a) BuiNguyen, M. H.; Dahn, H.; Mcgarrity, J. F. Helv.
Chim. Acta 1980, 63, 63. (b) Jones, J.; Kresge, A. J. J. Org.
Chem. 1993, 58, 2658.
We are grateful for financial support from National Natural Science
Foundation of China (Project 20472080, 20502025).
(14) Typical Procedure
To a refluxing toluene (20 mL) solution of Rh2 (OAc)4 (13.4
mg, 1 mol%), H2O (59.4 mL, 3.3 mmol) and DEAD (574.7
mg, 3.3 mmol) was added phenyl diazoacetate 1a (528.5 mg,
3 mmol) in 18 mL of toluene over 1 h via a syringe pump.
After stirring for additional 3 h, the reaction mixture was
cooled to r.t. and the solvent was removed. The crude
product was purified by flash chromatography on silica gel
by using 3% EtOAc–light PE as eluent to give an white oil
2a (448.2 mg, 2.73 mmol), yield 91%.
References and Notes
(1) For applications of aryl a-keto esters, see: (a) Boeykens,
M.; De Kimpe, N.; Tehrani, K. A. J. Org. Chem. 1994, 59,
6973. (b) Jacobson, I. C.; Prabhakar Reddy, G. Tetrahedron
Lett. 1996, 37, 8263. (c) Akiyama, T.; Suzuki, M. Chem.
Commun. 1997, 2357. (d) Petronijevic, F.; Hart, A. C.;
Paquette, L. A. Tetrahedron Lett. 2006, 47, 1741.
(e) Veeraraghavan Ramachandran, P.; Pitre, S.; Brown, H.
C. J. Org. Chem. 2002, 67, 5315. (f) Jiang, B.; Chen, Z.-L.;
Tang, X.-X. Org. Lett. 2002, 4, 3451. (g) Wang, G.-Y.; Hu,
J.-B.; Zhao, G. Tetrahedron: Asymmetry 2004, 15, 807.
(h) Periasamy, M.; Sivakumar, S.; Narsi Reddy, M.
Synthesis 2003, 1965. (i) Christensen, C.; Juhl, K.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875.
(2) Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. J. Org.
Chem. 1998, 63, 9628.
(15) Analytical data of 7: Rotamer ratio = 2.3:1; major rotamer:
1H NMR (300 MHz, CDCl3): d = 7.76–7.67 (m, 2 H), 7.38–
7.29 (m, 3 H), 6.24 (s, 1 H), 4.29–4.02 (m, 4 H), 3.88 (s, 3
H), 3.70 (s, 3 H), 1.32–1.13 (m, 6 H). 13C NMR (75 MHz,
CDCl3): d = 167.3, 156.0, 155.2, 136.8, 135.8, 128.2, 127.7,
127.2, 126.8, 92.8, 62.6, 61.6, 53.4, 52.2, 13.8, 13.7. HRMS:
m/z calcd for C16H22N2O7; 377.1319; found: 377.1321 [M +
Na]+.
Synlett 2006, No. 15, 2486–2488 © Thieme Stuttgart · New York