One-step deprotonation route to zinc amide and ester enolates for use in aldol reactions and Negishi couplings

Article abstract of DOI:10.1016/j.tetlet.2006.05.093

Simple amides and esters are conveniently deprotonated by Zn(tmp)₂ (tmp = 2,2,6,6-tetramethylpiperidinyl anion) to generate Zn enolates. Enolates formed by this method are suitable for use in aldol reactions that tolerate base-sensitive functional groups. Additionally, the Zn enolates are readily coupled with aryl bromides using typical Pd-catalyzed coupling methods.

Full text of DOI:10.1016/j.tetlet.2006.05.093

Tetrahedron Letters 47 (2006) 5049–5053
One-step deprotonation route to zinc amide and ester enolates
for use in aldol reactions and Negishi couplings
Mark L. Hlavinka and John R. Hagadorn*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA
Received 9 May 2006; revised 16 May 2006; accepted 16 May 2006
Available online 6 June 2006
Abstract—Simple amides and esters are conveniently deprotonated by Zn(tmp)2 (tmp = 2,2,6,6-tetramethylpiperidinyl anion) to
generate Zn enolates. Enolates formed by this method are suitable for use in aldol reactions that tolerate base-sensitive functional
groups. Additionally, the Zn enolates are readily coupled with aryl bromides using typical Pd-catalyzed coupling methods.
Ó 2006 Elsevier Ltd. All rights reserved.
Zinc amide and ester enolates (i.e. Reformatsky
reagents) are frequently used as mild carbon nucleophiles
in synthetic organic chemistry.1 Their uses include addi-
tion reactions with ketones, aldehydes, and activated
alkenes.2 They are also key reactants in some Pd-medi-
ated coupling reactions.3 The preparation of zinc amide
and ester enolates is generally achieved by one of two
methods.4 The first involves the insertion of activated
zinc metal into an a-halogenated amide or ester. Alter-
natively, deprotonation of a carboxy amide or ester with
a strong base (e.g. BuLi, LDA) followed by transmetal-
lation with ZnX2 (X = halide) is also frequently used. In
the interest of developing a more convenient route to Zn
enolates we have been exploring the use of simple Zn
species as bases for the deprotonation of amides and
esters. In this context, we recently reported the direct
formation of zinc amide enolates by reaction of carboxy
amides with a mixture of ZnPh2 and simple amines.5
The role of the amine in these reactions is to form an
intermediate zinc amido species (e.g. PhZnNR2) that is
competent for the deprotonation of the carboxy amide.6
To expand the usefulness and scope of this approach we
have investigated the use of zinc bis(amido) species for
the synthesis of amide and ester enolates. In this com-
munication, we report that Zn amide and ester enolates
can be conveniently prepared by the deprotonation
(tmp = 2,2,6,6-tetramethylpiperidinyl anion). This route
is highly tolerant of base-sensitive functionality, and the
resulting enolates can be effectively used in aldol and
Pd-catalyzed coupling reactions.
The deprotonation of simple amides and esters by Zn
amidos is essentially unexplored.8 We recently reported
that the equilibrium reaction of N,N-diethylacetamide
(DEA) with Zn[N(SiMe3)2]2 at 50 °C only led to the par-
tial formation of the Zn enolate and hexamethyldisilaz-
ane.5 The use of the more basic Zn(tmp)2 in place of
Zn[N(SiMe3)2]2 was anticipated to shift this equilibrium
to strongly favor the enolate product. This was found to
be the case when a C6D6 solution of Zn(tmp)2 was
reacted with 2.0 equiv of DEA at ambient temperature.
1H NMR spectroscopic data acquired after 30 min
indicated the complete consumption of Zn(tmp)2 and
the formation of tmp-H. The presence of
Zn[CH2C(O)NEt2]2 is implied by mass balance, but this
was not confirmed spectroscopically due to the broad-
ness and complexity of its NMR spectrum.
The reaction of Zn(tmp)2 with 2.05 equiv of DEA was
repeated in toluene solution over 2 h.9 To the in situ
prepared Zn[CH2C(O)NEt2]2 was added 1.5 equiv of
PhCHO (Table 1, Eq. 1). The reaction was stirred at
ambient temperature for 4 h and then quenched.
The expected aldol product was formed in 92% yield
(entry 1). The use of the more hindered amide N,N-di-
ethylpropionamide gave similar results, but it was
necessary to heat the Zn(tmp)2/amide mixture to 50 °C
for 24 h to completely form the zinc amide enolate
Zn[CH(Me)C(O)NEt2]2. This enolate was then reacted
7
of carboxy amides and esters with Zn(tmp)2
Keywords: Zinc; Amide enolate; Ester enolate; Reformatsky; Amido;
Aldol; Negishi coupling.
*
Corresponding author. Tel.: +1 303 492 5717; fax: +1 303 492
5894; e-mail: hagadorn@colorado.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.093

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M. L. Hlavinka, J. R. Hagadorn / Tetrahedron Letters 47 (2006) 5049–5053
Table 1. Reactions of in situ formed Zn amide enolates with aldehydesa
ð1Þ
Entry
1
Amide
DEA
Aldehyde
PhCHO
Product
O
Yield (%)b
OH
Ph
OH
Ph
92c
Et2N
O
O
2
3
PhCHO
PhCHO
85c,d
Et2N
Et2N
O
OH
Ph
O
99c,e
Ph
Et2N
Et2N
Ph
O
O
OH
OH
OH
OH
4
5
6
DEA
89
91
80f
Et2N
NO2
OMe
CN
O2N
MeO
NC
O
O
DEA
DEA
Et2N
O
O
Et2N
O
O
Et2N
7
DEA
85
OMe
MeO
O
O
O
O
O
OH
Et2N
8
9
DEA
DEA
93
86
O
O
O
OH
OH
Et2N
N
N
O
10
11
DEA
DEA
EtCHO
85
Et2N
Et
O
OH
tBu
tBuCHO
86f
Et2N
a General conditions: (i) 1 equiv (75.0 lmol) Zn(tmp)2, 2.05 equiv amide, PhMe (1.0 mL), 2 h, ambient temperature. (ii) 1.50 equiv of aldehyde, 4 h,
ambient temperature.
b Yields are for pure isolated material and are an average of two runs.
c Yield was determined by 1H NMR spectroscopy by comparison to an internal standard (1,3,5-trimethoxybenzene).
d Zinc metallation step performed at 50 °C for 24 h and the reaction with PhCHO was performed at ambient temperature for 12 h. syn:anti = 2:1.
e syn:anti = 1:1.4.
f 3.00 equiv of DEA were used.
with PhCHO at ambient temperature to form the addition
product in 85% overall yield (entry 2) and low diastereo-
selectivity (syn:anti = 2:1). The a-phenyl substituted
amide N,N-diethyl-2-phenylacetamide was also found
to be an acceptable substrate. It formed the expected
aldol product in 99% yield (entry 3) and low diastereo-
selectivity (anti:syn, 1.4:1).
The Zn(tmp)2-mediated aldol reaction can be performed
with aldehydes bearing a variety of common functional
groups. For example, in situ generated DEA enolate
reacted with para-substituted aryl aldehydes featuring
nitro, methoxy, cyano, and ester functionalities (entries
4–7) to form the expected aldol products in good yields.
Selective aldehyde addition can also be performed in the

M. L. Hlavinka, J. R. Hagadorn / Tetrahedron Letters 47 (2006) 5049–5053
5051
presence of ketones (entry 8). Lastly, both pyridyl-
substituted and aliphatic aldehydes were also found to
be suitable substrates (entries 9–11).
gave high yields when the reactions were performed at
ambient temperature. As was observed for the amide al-
dol reactions above, the ester aldol reactions can be per-
formed in the presence of many common funcitonalities
(entries 4–7) and by using aliphatic aldehyde substrates
(entries 8–11).
The use of Zn(tmp)2 was expanded to include ester aldol
production (Table 2, Eq. 2). For example, Zn(tmp)2 was
reacted with 2.05 equiv of ethyl acetate (EtOAc) at
5 °C for 1 h to generate the Zn ester enolate Zn[CH2C-
(O)OEt]2. The addition of 1.5 equiv of PhCHO to this
solution formed the aldol product in 81% yield (entry
2). Repeating the reaction at ambient temperature re-
sulted in a lower yield (61%). In contrast, reactions
involving the more hindered tert-butyl acetate (tBuOAc)
The use of Zn amide and ester enolates in Pd-catalyzed
coupling reactions is currently of significant interest.3
Our preliminary studies indicate that amide and ester
enolates generated via Zn(tmp)2 are highly effective in
this context (Table 3, Eq. 3). For example, Zn(tmp)2 re-
t
acted with 2.05 equiv of BuOAc over a couple of hours
Table 2. Reactions of in situ formed Zn ester enolates with aldehydesa
ð2Þ
Entry
Ester
Aldehyde
PhCHO
Product
Temperature (°C)
Yield (%)
61b
1
2
EtOAc
Ambient
5
O
OH
Ph
81b
EtO
O
OH
Ph
3
4
5
tBuOAc
EtOAc
EtOAc
PhCHO
Ambient
93b
82b
84c
tBuO
O
O
OH
5
5
EtO
MeO
O
OMe
O
OH
OH
OH
EtO
N
N
O
O
EtO
6
EtOAc
5
85b
O
O
O
O
EtO
7
8
9
EtOAc
EtOAc
EtOAc
5
5
5
89c
MeO
O
OMe
O
O
OH
EtCHO
42b,d
EtO
Et
O
OH
tBu
tBuCHO
64b,d
EtO
O
tBuO
O
OH
Et
OH
tBu
10
11
tBuOAc
tBuOAc
EtCHO
Ambient
Ambient
92b
95b
tBuCHO
tBuO
a General conditions: (i) 1 equiv (75 lmol) of Zn(tmp)2, 2.05 equiv ester, PhMe (1.0 mL), 1 h. (ii) 1.50 equiv of RCHO, 3 h, 5 °C.
b Yield was determined by 1H NMR spectroscopy by comparison to an internal standard (1,3,5-trimethoxybenzene).
c Yields are for pure isolated material and are an average of two runs.
d 3.00 equiv of the ester were used.

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M. L. Hlavinka, J. R. Hagadorn / Tetrahedron Letters 47 (2006) 5049–5053
Table 3. Pd-catalyzed coupling reactions of in situ formed Zn enolatesa
ð3Þ
Entry
1
Amide/ester
tBuOAc
Aryl halide
PhBr
Product
Yield (%)b
OtBu
96
O
OtBu
Br
2
3
tBuOAc
tBuOAc
75
74
O
OtBu
tBu
tBu
Br
O
Br
OtBu
4
5
6
tBuOAc
tBuOAc
tBuOAc
84
72
46
O
OMe
Br
OMe
OtBu
OtBu
O
N
N
Br
O
NO2
NO2
NEt2
7
8
DEA
DEA
PhBr
94
81
O
Br
NEt2
O
tBu
N
tBu
Br
NEt2
9
DEA
45
O
N
a General conditions: (i) 1 equiv (75 lmol) of Zn(tmp)2, 2.05 equiv ester/amide, PhMe (1.0 mL), 2 h. (ii) 2.00 equiv of aryl halide, 2% Pd2(dba)3, 4%
P(tBu)3, 24 h, ambient temperature.
b Yield was determined by 1H NMR spectroscopy by comparison to an internal standard (1,3,5-trimethoxybenzene). Reaction times and conditions
were not optimized.
to generate the expected ester enolate. Combining this
solution with 2 mol % Pd2(dba)3 (dba = trans,trans-di-
benzylideneacetone), 4 mol % P(tBu)3, and 2 equiv of
PhBr formed a purple solution that was stirred for
Pd-catalyzed coupling methods. The use of Zn(tmp)2
and other zinc amidos for the convenient deprotonation
of functionalized organics should allow for the
expanded use of Zn-based nucleophiles in organic
synthesis.
24 h. The reaction was then quenched with NH4Cl(aq)
.
1
Analysis of the crude product by H NMR against an
internal standard indicated that the expected a-phenyl-
ated product PhCH2C(O)OtBu was formed in 96% yield
(entry 1). Repeating the reaction using DEA in place of
the ester formed PhCH2C(O)NEt2 in 94% yield (entry
7). The use of several substituted (e.g. –OMe, –NO2,
pyridyl) aryl bromides in couplings with BuOAc and
DEA was also briefly examined. These afforded the
expected products in moderate to good yields.
Acknowledgements
We thank Professors Andy Phillips and Tarek Samma-
kia for many helpful discussions. We acknowledge the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for funding.
t
In summary, we have reported that amides and esters
are conveniently deprotonated using Zn(tmp)2 to gener-
ate Zn enolates. Enolates formed by this method are
suitable for use in aldol reactions that tolerate base-sen-
sitive functional groups. Additionally, the Zn enolates
are readily coupled with aryl bromides using typical
Supplementary data
Experimental details and characterization data are
presented as supplementary data. These can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.05.093.

M. L. Hlavinka, J. R. Hagadorn / Tetrahedron Letters 47 (2006) 5049–5053
5053
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2188; (b) Erdik, E. Organozinc reagents in organic synthesis;
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9. Full experimental details and characterization data are
presented as Supplementary data.