Alkylation of active methylenes via benzhydryl cations

Article abstract of DOI:10.1055/s-2002-34884

The acid mediated reaction between active methylenes and benzhydryl alcohols, or their derivatives, is reported. Ethyl acetoacetate, acetylacetone, and N,N-dibenzyl-malonamic acid methyl ester are benzhydrylated in quantitative yields in the presence of molar amounts of BF₃·OEt₂ in CH₂Cl₂ at r.t. TMSOTf and H₂SO₄ appear to be equally efficient. Use of benzhydryl acetate in place of the starting free alcohol allows lowering of the Lewis acid to catalytic amounts. A general mechanism for this scarcely studied C-C bond formation is presented. Due to the easier availability of alcohols with respect to halides the method may favorably compare with the more classical halide-based basic conditions.

Full text of DOI:10.1055/s-2002-34884

LETTER
1823
Alkylation of Active Methylenes via Benzhydryl Cations
A
F
lkylation of
A
a
ctive Meth
b
ylenes via
B
r
enzhydr
i
yl
C
ati
c
ons e Bisaro, Guillaume Prestat, Maxime Vitale, Giovanni Poli*
Laboratoire de Chimie Organique, UMR 7611 CNRS, Université Pierre et Marie Curie, Tour 44-45, 4, Place Jussieu, Boîte 183,
5252, Paris, Cedex 05, France
7
Fax +33(1)44277567; E-mail: poli@ccr.jussieu.fr
Received 26 July 2002
ic study had been so far addressed. In this letter we report
our preliminary results on the study of such type of alkyl-
ation.
Abstract: The acid mediated reaction between active methylenes
and benzhydryl alcohols, or their derivatives, is reported. Ethyl
acetoacetate, acetylacetone, and N,N-dibenzyl-malonamic acid me-
thyl ester are benzhydrylated in quantitative yields in the presence
of molar amounts of BF OEt in CH Cl at r.t. TMSOTf and H SO
4
appear to be equally efficient. Use of benzhydryl acetate in place of
the starting free alcohol allows lowering of the Lewis acid to cata-
lytic amounts. A general mechanism for this scarcely studied C-C
bond formation is presented. Due to the easier availability of alco-
We first selected the simple alkylation of ethyl acetoace-
tate 4 with benzhydryl alcohol 5 as the model reaction.
Table 1 shows our results. Quantitative formation of the
3
2
2
2
2
5
monoalkylation product 6 was observed in the presence
of 1.2 or 2.5 molar equivalents of BF OEt (entries 1 and
3
2
hols with respect to halides the method may favorably compare with 2). On the other hand, sub-stoichiometric amounts of the
the more classical halide-based basic conditions.
same Lewis acid did not allow complete alkylation to take
Key words: boron, carbocations, enols, Lewis acids, benzhydryl- place (entries 3 and 4). TMSOTf and H SO appeared to
be as effective as BF OEt (entries 5 and 6). Other Lewis
2
4
ation
3
2
acids such as ZnBr , MgBr OEt , Ti(i-PrO) were com-
2
2
2
4
pletely ineffective.
In the course of our studies toward the synthesis of a lac-
tam analogue of the anticancer agent podophyllotoxin we
had to accomplish benzhydrylation of malonamide 1, so
as to obtain the alkylated product 2. Accordingly, alkyla-
Table 1 Acid-Promoted Alkylation of Ethyl Acetate 4 with Benz-
hydryl Alcohol 5
tion of the sodium enolate of 1 with benzhydryl bromide
1
3
a under conventional conditions was undertaken. Rath-
er surprisingly, compound 2 was obtained in a deceiving
6% yield. Further attempts to improve this result con-
1
Entry
Promoter
BF OEt
(mol equiv)
Time (h)
6 (%)
> 98
> 98
40
stantly met with failure. In the search for more advanta-
geous solutions we serendipitously found that the simple
reaction between malonamide 1 and the benzhydryl alco-
hol 3b in CH Cl at r.t. and in the presence of 2.0 molar
1
2
3
4
5
6
2.5
1.2
0.2
0.01
1.2
1
1
1
3
2
2
2
2
BF OEt
3
2
2
equivalents of BF OEt , smoothly gave the desired alky-
BF OEt
1
3
2
3
2
lated product 2 in quantitative yield (Scheme 1).
BF OEt
24
1
7
3
TMSOTf
H SO
> 98
> 98
1
2
4
Corollary experiments revealed that when the Lewis acid-
ic promoter was present in sub-stoichiometric amounts,
conversion of benzhydryl alcohol 5 into the symmetrical
6
ether 7 took place to a large extent (Scheme 2, a). As ex-
pected, such a transformation revealed to be independent
Scheme 1 a) X = Br, NaH, DMF, 0–60 °C, 16%; b) X = OH, of the presence of the active methylene (Scheme 2, b).
CH Cl , BF OEt 2.5 equiv, r.t., > 98%.
This result suggested that the symmetrical ether might
play a role in the C–C bond formation. Indeed, reaction
between ethyl acetoacetate 4 and the symmetrical ether 7
in the presence of either stoichiometric or catalytic
amounts of BF OEt gave rise to adduct 6 in quantitative
amounts (Scheme 2, c). Finally, a fourth experiment dem-
onstrated that the desired C–C bond formation could be
also obtained in the presence of sub-stoichiometric
2
2
3
2
A perusal into the literature surprisingly indicated that
acid-promoted alkylations, although known since a long
time, have been only scantly reported, and no systemat-
3
,4
3
2
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1823,1826,ftx,en;G20802ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1
824
F. Bisaro et al.
LETTER
amounts of the promoter by simply using benzhydryl ace- Further active methylenes were then tested for benzhydry-
tate (Scheme 2, d).
lation. Thus, submitting of acetylacetone 10a, or N,N-
dibenzyl-malonamic acid methyl ester 10b, and benzhy-
dryl alcohol 5 to the above described optimized reaction
conditions, furnished the corresponding alkylation prod-
ucts, again in quantitative yield (Table 3).
Table 3 BF OEt -Promoted Alkylation of Aactive Methylenes
3
2
a
with Benzhydryl Alcohol
Entry
Nucleo- R1
phile
R2
Product Time
(h)
Yield
(%)
1
2
4
Me
OEt
Me
6
3
3
> 98
> 98
> 98
Scheme 2
10a
10b
Me
11a
11b
Other differently functionalized benzhydryl alcohols de-
rivatives were next examined as electrophilic partners for
ethyl acetoacetate. Table 2 illustrates our results. Elec-
tron-rich aryl substituents allowed excellent yields in the
alkylation (entries 1 and 7). Conversely, aryl substitutions
3
Bn N
OMe
15
2
a
All reactions were performed using a 0.05 M concentration of ben-
zhydryl alcohol in CH Cl .
2
2
destabilizing benzhydryl cations were associated to lower On the other hand, some of the tested active methylenes
7
yields (entries 2 and 4). In these more difficult cases, high- did not afford the expected alkylation products. In these
er amounts of the Lewis acid allowed a considerable yield cases the active methylenes were either recovered unre-
improvement (entry 3). Halide o- or p-substitution on the acted or gave more complex uncharacterized material,
benzhydryl alcohol still allowed good coupling yields whereas the starting benzhydryl alcohol gave either the
(
entries 5 and 6) Finally, entry 8 indicates that benzyl-type symmetrical ether 7 or disproportionated to benzophe-
alcohols could also be used in the alkylation, albeit less none and diphenylmethane.8
efficiently.
The above results indicate that the reaction is highly de-
pendent on the nature of active methylenes, and not easily
rationalizable only on the basis of the nucleophile pK val-
ue.
a
Table 2 BF OEt -Promoted Benzhydrylation and Benzylation of
Ethyl Acetoacetate 4
3
2
9
a
The enol form of the nucleophile and the corresponding
benzhydryl cation are probably involved in the mecha-
nism of the C-C bond formation. However, the non-inno-
cent role of the Lewis acid on the active methylene must
also be taken into account. In order to obtain further infor-
1
Entry
R
BF OEt
Product
9a
Yield (%)
> 98
13
mation, the H NMR spectrum of ethyl acetoacetate 4 was
3
2
recorded in the absence and in the presence of BF OEt .
3
2
1
2
3
4
5
6
7
m-MeC H4
1.2 equiv
1.2 equiv
2.5 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
6
As expected, the initial spectrum of pure acetoacetate
showed a mixture of the carbonyl and the enol forms, the
former tautomer being strongly prevalent. Upon addition
of 1.0 molar equivalent of BF OEt , disappearance of the
former signals and concomitant generation of two new
sets of signals in a 60:40 ratio was detected. These latter
peaks have been assigned to the keto and the enol forms,
both coordinated to the Lewis acid.10
p-NO C H
9b
2
6
4
4
p-NO C H
9b
52
2
6
3
2
m-MeOC H4
9c
34
6
9d
90
6
o-Br-C H4
p-Cl-C H4
9e
90
6
The data so far collected led us to propose the general
mechanism shown in Scheme 3. The Lewis acid is expect-
ed to play the double role of generating the benzhydryl
-Naphthyl
Me
9f
> 98
58
8
9g
11
cation as well as of coordinating, and thereby probably
a
All reactions were performed at r.t. for 3 h using a 0.05 M concen-
tration of the benzhydryl alcohol in CH Cl .
12
activating, the nucleophile. The thus generated benzhy-
dryl cation A can then competitively interact either with
the benzhydryl alcohol, to give the symmetrical ether B,
2
2
Synlett 2002, No. 11, 1823–1826 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Alkylation of Active Methylenes via Benzhydryl Cations
1825
or with the (possibly Lewis acid-coordinated) enol form
of the active methylene Cenol, to give the alkylated product
D. Since etherification is a reversible process, irreversible
alkylation can be normally driven to completion. Howev-
er, when the rate of C-C bond formation becomes too
slow, possibly due to inefficient enolization, acid mediat-
ed dismutation to E may become the fastest irreversible
process, thereby diverting the transitory cation from alky-
lation.
Scheme 5
be possible, albeit less efficient. The ensemble of experi-
ments performed allowed us to propose a general mecha-
nism for such a scarcely studied C–C bond formation.
Owing to the simplicity of the experimental conditions
and to the easier availability of alcohols with respect to
halides, the method may favorably compare with the clas-
sical halide-based basic conditions. We believe that the
above results may be of interest for the constant develop-
ment of more and more efficient synthetic methods in or-
ganic chemistry.
Acknowledgement
We thank Professor Carsten Bolm and Mr. Jens Rudolph for a kind
gift of compound 12. Support from D24/0002/01 COST action is
gratefully acknowledged.
Scheme 3
Definitive proof for an S 1 type substitution mechanism
N
came from alkylation of acetylacetone with (R)-p-chloro-
1
3
References
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(
(
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5
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1
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Scheme 5).
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(
2
2
nitrogen was added BF OEt (217 L, 1.2 mmol) at r.t. The
3
2
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mixture was stirred for 1 hour before saturated NaHCO3
solution (10 mL) was added. The aqueous layer was
extracted with CH Cl (10 mL). The organic layers were
2 2
washed with brine (10 mL) dried (MgSO ) and concentrated
4
under reduced pressure. Short column chromatography
Synlett 2002, No. 11, 1823–1826 ISSN 0936-5214 © Thieme Stuttgart · New York

1
826
F. Bisaro et al.
LETTER
1
(
hexane/EtOAc = 8:2) afforded quantitatively ethyl 2-
(10) H NMR (CDCl , 400 MHz): coordinated keto form = 4.17
3
1
3
benzhydryl-3-oxo-butanoate. H NMR (CDCl , 400 MHz):
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3
3
3
(
ppm) 7.5–7.1 (m, 10 H, H), 4.81 (d, 1 H, J = 12.3 Hz),
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3
3
3
4
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1
3
3
(
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41.5, 141.2, 128.8–126.8, 65.2, 61.4, 50.8, 30.0, 13.7.
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1
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3
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(
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(
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Synlett 2002, No. 11, 1823–1826 ISSN 0936-5214 © Thieme Stuttgart · New York