The first catalytic enantioselective aldol-type reaction of ethyl diazoacetate to ketones

Article abstract of DOI:10.1002/adsc.200900435

The aldol-type addition to ketones still represents a great challenge in asymmetric catalysis. Recently, the direct aldol reaction between the commercially available ethyl diazoacetate and aldehydes has attracted increasing attention. Ethyl diazoacetate i

Full text of DOI:10.1002/adsc.200900435

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DOI: 10.1002/adsc.200900435
The First Catalytic Enantioselective Aldol-Type Reaction of
Ethyl Diazoacetate to Ketones
Fides Benfatti,a Seda Yilmaz,a and Pier Giorgio Cozzia,*
a
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum, Universitꢀ di Bologna, Via Selmi 2, 40126 Bologna,
Italy
Fax : (+39)-051-209-9456; phone: (+39)-051-209-9511; e-mail: piergiorgio.cozzi@unibo.it
Received: June 24, 2009; Published online: July 31, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900435.
Abstract: The aldol-type addition to ketones still
represents a great challenge in asymmetric catalysis.
Recently, the direct aldol reaction between the
commercially available ethyl diazoacetate and alde-
hydes has attracted increasing attention. Ethyl
ic asymmetric aldol reactions through the use of par-
ticularly acidic nucleophiles.[10] It is well known that
the aldol reaction between commercially available a-
diazo esters and aldehydes has a valuable synthetic
utility and is also atom-economical. However, a-diazo
carbonyl compounds, despite their usefulness in the
preparation of amino alcohols and acids,[11] have only
in recent years been employed in direct aldol reac-
tions. Wang has recently developed a DBU-catalyzed
aldol-type condensation of aldehydes with ethyl
diazoACHTUNGTRENNUNGacetate is economical and allows further trans-
formation of the aldol adduct obtained. We present
a solution for the arduous, and not previously de-
scribed, addition of diazoacetate to ketones. Our
procedure employs commercially available nor-
ephedrine-derived ligands and dialkylzinc reagents
diazoACTHGNUTERNNUG
acetate.[12,13] Interesting examples of catalytic
[R2Zn: (diethylzinc, Et2Zn; dimethylzinc, Me2Zn)]
as starting materials, therefore the active catalyst is
prepared with a very straightforward methodology.
Remarkably, the reaction gives good enantiomeric
excesses with a-halo ketones, a class of compounds
that has not been commonly used in enolate addi-
tion.
asymmetric aldol condensation of ethyl diazoacetate
as nucleophile with aldehydes and imines have been
reported.[14,15] This year, a highly enantioselective
method for the catalytic direct aldol reaction of ethyl
diazoacetate with a broad range of aldehydes was de-
scribed by Trost.[16] Among all the procedures ac-
counted for in the literature, Et2Zn was also used to
deprotonate ethyl diazoacetate, and to promote the
corresponding reaction with aldehydes (Scheme 1).[17]
As the formation of a zinc enolate was probably in-
volved in these reactions, we conceived that the first
catalytic enantioselective addition of ethyl diazoace-
tate to ketones might be developed using ligands
active in catalytic enantioselective Reformatsky-type
Keywords: diazoacetates; dimethylzinc; enolates;
ketones; norephedrine
Enantioselective C C bond formation under catalytic reactions.[2,3] Herein, we report a practical catalytic
condition remains a challenging task in modern or- enantioselective addition of ethyl diazoacetate to ke-
ganic synthesis.[1] Recently, Feringa[2] and ourselves[3] tones promoted by inexpensive amino alcohols as
have described highly enantioselective variants of the chiral ligands.
Reformatsky reaction[4] with ketones, affording high
À
levels of enantiomeric excess.
However, these catalytic asymmetric processes rely
on the use of iodoacetate to successfully promote the
formation of the zinc enolate.[5] Considering the con-
venience of atom efficiency, it would be more desira-
ble to employ nucleophiles directly in catalytic asym-
metric aldol reactions with ketones.[6] Pioneering
work developed by Shibasaki,[7] Trost,[8] and Kobaya-
Scheme 1. Reaction of aldehydes in the presence of Et2Zn
shi[9] was directed towards the development of catalyt- as a base.
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Fides Benfatti et al.
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Many chiral amino alcohols were tested as ligands have found industrial application as chiral ligands in
in the model reaction with acetophenone (see Sup- the large scale synthesis of Efavirenz described by
porting Information).
Merck.[18] We have found two complementary proce-
Remarkably, the corresponding aldol product was dures for this enantioselective reaction. In the first
isolated with encouraging enantiomeric excesses. Cat- procedure, Et2Zn was used without additives, while in
alytic enantioselective addition of ethyl diazoacetate the other procedure, the less reactive Me2Zn was em-
to ketones was not yet described, thus we took the ployed in the presence of Ph3P=S as additive.[18] The
preliminary result obtained in the reaction of aceto- two procedures were applied to a series of ketones,
phenone in the presence of N-pyrrolidinylnorephe- and the results obtained are illustrated in Table 2.
drine 1 as the chiral ligand (67% ee, entry 5), and we
performed several experiments in order to improve minimize the effect of the background reaction. The
yields and enantiomeric excesses, some of these are il- two methods showed different selectivity in function
All the reactions were run at À258C in order to
lustrated in Table 1.
of the ketones employed, and they are complementa-
The background reaction is quite fast for the addi- ry. In general, with acetyl aromatic ketones the em-
tion of ethyl diazoacetate to ketones, and proceeds ployment of the more reactive Et2Zn is recommend-
without the need of a chiral ligand. The fast back- ed.
ground reaction imposed the use of a high percentage
However, in order to obtain good ees it is necessary
of the chiral ligand (25 mol%). However, substituted to stop the reaction after 48 h. Prolonged reaction
norephedrine derivatives are inexpensive, and they times are detrimental to enantioselectivity (Table 2).
For a-halo-substituted aromatic ketones, the use of
Me2Zn in combination with triphenylphosphine sul-
fide afforded good enantiomeric excesses and yields.
The reaction was quite sluggish at lower temperatures
without the admission of additives. It is worth adding
that a catalytic enantioselective addition of an enolate
to a-halo-substituted ketones is realized for the first
time, giving access to highly functionalized building
blocks. Transformation of the diazo adduct 2 to 3 was
used to establish the absolute configuration of prod-
ucts (Scheme 2). The reduction occurs in quantitative
yield using PtO2 as catalyst in 5 mol% with no race-
mization (see Supporting Information for details).
Tentatively we suggest for the reaction a mechanism
in which the diazoacetate is deprotonated by R2Zn. In
fact, the treatment of ethyl diazoacetate with Me2Zn
for two hours at room temperature, followed by
quenching with CD3OD, gave a-deuterated ethyl di-
azoacetate, which was detected by 13C NMR.[19]
We investigated some transformations of the ob-
tained diazo esters to demonstrate their synthetic util-
ity. Unfortunately, the adducts are quite sensitive to
basic conditions. It is well known that a-diazo-b-hy-
droxy esters are unstable under basic and acidic con-
ditions.[15] All attempts to protect the tertiary alcohol
in the presence of strong bases or amines gave start-
ing materials through a retro-aldol pathway. The re-
Table 1. Addition of diazoacetatate to acetophenone.
Entry[a] R2Z T [8C] t [h] Additive Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
Et
Et
Et
0
6
–
–
–
–
–
–
–
44
78
78
26
À25
48
24
24
3
48
24
72
72
25
25
70
40
37
À35
Me r.t.
Me
Me À25
Me
0
67
60
0
Ph3P=O 65
Ph3P=O 52
Ph3P=S 43
6[d]
54[d]
65[d]
Me À25
Me À25
[a]
All the reactions were performed in DCM at the indicat-
ed temperature. To a solution of R2Zn (2 equiv., R=Me,
Et) in CH2Cl2 (0.04M) the ligand was added
(0.25 equiv.), then the solution was stirred for 5 min at
room temperature. Acetophenone (1 equiv.) and ethyl di-
azoacetate (2 equiv.) were added by syringe at the indi- duction with DIBAL, LiAlH4 or different hindered
cated temperature. The reaction was quenched with
water after the indicated hours, and the product isolated
after usual work-up.
Isolated yield after chromatographic purification.
Enantiomeric excess was evaluated using a chiral HPLC
analysis (see supporting information for details). Abso-
lute (R) configuration was established by correlation
after reduction.
hydrides provided a complete reduction of ester and
diazo groups, in low yield. The adducts derived from
ketones are much more sensitive to a retro-aldol
pathway than the corresponding derivatives obtained
from aldehydes. In order to stabilize the adducts we
investigated the possibility of protecting the hindered
tertiary alcohols in several reactions. Remarkably,
working in excess of TMSOTf (trimethylsilyl triflate)
in the presence of imidazole as base (alternative
bases led to retro-aldolization of the products) the
[b]
[c]
[d]
30 mol% of additive were used. The additive was added
at room temperature to the reaction before the addition
of the diazoacetate and the ketone.
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The First Catalytic Enantioselective Aldol-Type Reaction
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Table 2. Addition of ethyl diazoacetate to aromatic and aliphatic ketones.
Entry[a]
Ketone
t [h]
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
4
5
C6H5COCH3
C6H5COCH3
C6H5COCH3
p-ClC6H5COCH2Br
p-ClC6H5COCH2Br
C6H5COCH2Br
C6H5COCH2Br
C6H5COCH2Cl
p-ClC6H5COCH2Cl
2-NaphthylCOCH3
m-CH3C6H5COCH2Cl
2-BenzofurylCOCH3
p-FC6H5COCH2Br
p-FC6H5COCH2Cl
p-BrC6H5COCH3
p-BrC6H5COCH3
p-FC6H5COCH3
p-FC6H5COCH3
o-ClC6H5COCH3
p-CH3C6H5COCH2Cl
i-PrCOCCH3
24
48
72
24
72
24
72
48
48
48
48
48
72
72
72
24
72
24
24
48
24
48
48
25
40
43
25
62
20
69
63
66
60
40
25
71
77
70
37
59
20
30
72
20
25
54
78
74
56
74
70
76
69
80
68
66
64
80
72
68
42
74
36
80
80
80
87
74
74
6
7
8
9
10[d]
11[d]
12[d]
13
14
15[d]
16[d]
17[d]
18[d]
19[d]
20
21[d]
22[d]
23[d]
i-PrCOCCH3
CyclohexylCOCH3
[a]
All the reactions were performed in DCM at À258C using the general procedure.
[b]
[c]
[d]
Isolated yield after chromatographic purification.
Enantiomeric excess was evaluated using a chiral HPLC analysis (see Supporting Information for details).
Performed with Et2Zn (2 equiv.) instead of Me2Zn at À258C without additives.
corresponding TMS ether 4 was isolated in high yield benzoylamide 5. Unfortunately, all attempts to per-
(Scheme 2, a). Reduction of the diazo group of 4 was form the reduction of 5 with SmI2 as described for the
carried out with LiEt3BH[20] or with phosphines,[21] diazo derivatives of aldehydes[20] gave complex mix-
À
and the derivative was isolated as a single diastereo- tures of products, in which the cleavage of the N N
isomer after reaction with benzoyl chloride. We found group was not observed. Treatment with Raney nickel
that the reductive cleavage of the diazo group can be gave extensive decomposition. Other tailored re-
carried out also by PEt3.[21] It is worth mentioning agents and reaction conditions in order to improve
that the unprotected 5 was quite unstable and showed yield and selectivity of this difficult transformation
traces of decomposition at À258C after a few hours. are currently under investigation in our laboratory.
The product is unstable towards mild acids and it was
In summary, we report the first enantioselective ad-
stabilized by the preparation of the corresponding dition of ethyl diazoacetate to ketones, that gives
Adv. Synth. Catal. 2009, 351, 1763 – 1767
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Fides Benfatti et al.
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Scheme 2. Transformation of the diazo adducts occurred with no racemization.
access to highly functionalized building blocks. For Acknowledgements
the first time, the addition of enolate to a-halo ke-
The European Commission through the project CATA-
FLU.OR, PRIN 2007 (Progetto Nazionale Stereoselezioni in
Chimica Organica: Metodologie ed Applicazioni) and Bolo-
gna University are acknowledged for financial support for
this research. S.Y. acknowledges the UE for summer research
fellowship grant.
tones is realized in a highly enantioselective manner.
Many opportunities are now opened up to explore
the facile generation of zinc enolates in the presence
of norephedrine derivatives for the controlled forma-
tion of quaternary stereogenic centres. These and
other options are under active investigation in our
laboratory.
References
[1] For reviews, see: a) M. Shibasaki, M. Kanai, Chem.
Rev. 2008, 108, 2853; b) P. G. Cozzi, R. Hilgraf, N. Zim-
mermann, Eur. J. Org. Chem. 2007, 5969.
[2] a) M. A. Fernꢂndez-IbꢂÇez, B. Maciꢂ, A. J. Minnaard,
B. L. Feringa, Chem. Commun. 2008, 2571; b) M. A.
Fernꢂndez-IbꢂÇez, B. Maciꢂ, A. J. Minnaard, B. L. Fer-
inga, Org. Lett. 2008, 10, 4041.
[3] a) P. G. Cozzi, Angew. Chem. 2006, 118, 3017; Angew.
Chem. Int. Ed. 2006, 45, 2951; b) P. G. Cozzi, P. Vicen-
nati, A. Mignogna, Adv. Synth. Catal. 2008, 350, 975;
for mechanistic studies, see: c) E. Mileo, F. Benfatti,
P. G. Cozzi, M. Lucarini, Chem. Commun. 2009, 469.
[4] P. G. Cozzi, Angew. Chem. 2007, 119, 2620; Angew.
Chem. Int. Ed. 2007, 46, 2568.
Experimental Section
General Procedure for the Addition to a-Halo
Ketones
To a solution of Me2Zn (2 equiv.) in dichloromethane
(DCM) at room temperature N-pyrrolidinylnorephedrine
(25 mol%) was added under nitrogen and the resulting solu-
tion was stirred for 5 min. The flask was cooled to À258C
and Ph3P=S (30 mol%) was added as solid, followed after
5 min by the ketones (1 equiv.) and diazoacetate (2 equiv.),
added by syringe. The flask was kept at À258C for the indi-
cated time without stirring then quenched with water. After
usual work-up the resulting oil was purified by chromatogra-
phy (n-hexane:acetone, 9:1).
[5] R. Ocampo, W. R. Dolbier, Jr., Tetrahedron 2004, 60,
9325.
[6] For pioneering studies in the aldol reaction with ke-
tones, see: S. E. Denmark, Y. Fan, J. Am. Chem. Soc.
2002, 124, 4233.
[7] a) S. Shibasaki, M. Kanai, K. Funabashi, Chem.
Commun. 2002, 1989; b) M. Shibasaki, N. Yoshikawa,
Chem. Rev. 2002, 102, 2187.
[8] a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122,
12033; b) B. M. Trost, H. Ito, E. R. Silcoff, J. Am.
Chem. Soc. 2000, 122, 12033.
[9] S. Saito, S. Kobayashi, J. Am. Chem. Soc. 2006, 128,
8704.
General Procedure for the Addition to Methyl
Ketones
To a solution of Et2Zn (2 equiv.) in DCM at room tempera-
tue N-pyrrolidinylnorephedrine (25 mol%) was added under
nitrogen and the resulting solution was stirred for 5 min.
The flask was cooled to À258C and the ketone (1 equiv.)
and the diazoacetate (2 equiv.) were added by syringe. The
flask was kept at À258C for the indicated time without stir-
ring then quenched with water. After usual work-up the re-
sulting oil was purified by chromatography (n-hexane:ace-
tone, 9:1).
[10] D. A. Alonso, S. Kitagaki, N. Utsumi, C. F. Barbas III,
Angew. Chem. 2008, 120, 4664; Angew. Chem. Int. Ed.
2008, 47, 4588.
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The First Catalytic Enantioselective Aldol-Type Reaction
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[11] Z. Zhang, J. Wang, Tetrahedron 2008, 64, 6577.
[12] N. Jiang, J. Wang, Tetrahedron Lett. 2002, 43, 1285.
[13] Condensation of diazoacetate with aldehydes was also
promoted by n-BuLi: a) U. Schçllkopf, H. Frasnelli,
Angew. Chem. 1970, 82, 291; Angew. Chem. Int. Ed.
Engl. 1970, 9, 301; LDA: b) R. Pellicciari, B. Natalini,
B. M. Sadeghpour, M. Marinozzi, J. P. Snyder, B. L.
Williamson, J. T. Kuethe, A. Padwa, J. Am. Chem. Soc.
1996, 118, 1; c) A. Padwa, Y. S. Kulkarni, Z. Zhang, J.
Org. Chem. 1990, 55, 4144; KOH: d) E. Wenkert, A. A.
Pherson, J. Am. Chem. Soc. 1972, 94, 8084; NaH: e) N.
Jiang, J. Wang, Org. Lett. 2001, 3, 2989; DBU: f) F.
Xiao, Y. Liu, J. Wang, Tetrahedron Lett. 2007, 48, 1147.
[14] a) Y. Zhao, Z. Ma, X. Zhang, Y. Zou, X. Jin, J. Wang,
Angew. Chem. 2004, 116, 6103; Angew. Chem. Int. Ed.
2004, 43, 5977; b) W. Yao, J. Wang, Org. Lett. 2003, 5,
1527.
1390; for Brønsted acid-mediated highly enantioselec-
tive addition of ethyl diazoacetate to imines, see: b) T.
Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2007, 129,
10054; c) D. Uraguchi, K. Sorimachi, J. Am. Chem.
Soc. 2005, 127, 9360.
[16] B. M. Trost, S. Malhotra, B. A. Fried, J. Am. Chem.
Soc. 2009, 131, 1674.
[17] C. J. Moody, C. N. Morfitt, Synthesis 1998, 1039. How-
ever, in the article is reported that ketones (cyclohexa-
none, acetone, pentan-2-one, pentan-3-one, acetophe-
none) failed to react.
[18] E. J. J. Grabowski, Chirality 2005, 17, S249.
[19] The deuteration was partial, probably due to incom-
plete deprotonation of the diazoacetate under the se-
lected conditions. See: L. D. Crombie, A. D. Heaven, J.
Chem. Soc. Perkin Trans. 1 1992, 1929.
[20] K. Hasegawa, S. Arai, A. Nishida, Tetrahedron 2006,
62, 1390.
[21] E. Yasui, M. Wada, N. Takamura, Chem. Pharm. Bull.
2007, 55, 1652.
[15] For the enantioselective asymmetric phase-transfer re-
action of ethyl diazoacetate with aldehydes, see: a) K.
Hasegawa, S. Arai, A. Nishida, Tetrahedron 2006, 62,
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