Efficient, direct α-methylenation of carbonyls mediated by diisopropylammonium trifluoroacetate

Article abstract of DOI:10.1039/b924577d

A very efficient method for the direct α-methylenation of carbonyl compounds, with yields up to 99%, utilizing paraformaldehyde, diisopropylammonium trifluoroacetate, and catalytic acid or base, is presented.

Full text of DOI:10.1039/b924577d

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Efficient, direct a-methylenation of carbonyls mediated
by diisopropylammonium trifluoroacetatew
Alejandro Bugarin, Kyle D. Jones and Brian T. Connell*
Received (in College Park, MD, USA) 23rd November 2009, Accepted 7th January 2010
First published as an Advance Article on the web 25th January 2010
DOI: 10.1039/b924577d
A
very efficient method for the direct a-methylenation
of carbonyl compounds, with yields up to 99%, utilizing para-
formaldehyde, diisopropylammonium trifluoroacetate, and
catalytic acid or base, is presented.
Molecules containing the a,b-unsaturated carbonyl functionality
are commonly utilized as substrates for a range of chemical
transformations, including nucleophilic addition,1 Michael
addition,2 the Morita–Baylis–Hillman reaction,3 Diels–Alder
reaction,4 and several organo-catalytic reactions.5 The importance
of the a-methylene moiety is amplified by its presence in
numerous biologically active natural products.6 a-Methylenation
has attracted attention because it is generally an atom economical
method for conversion of simple carbonyl compounds to their
a,b-unsaturated derivatives.
Fig. 1 Amine salts used as catalysts.
from 92% to 95% (Table 1, entry 10). On the other hand,
addition of 10 mol% trifluoroacetic acid (TFA) raised the
yield to 499% (Table 1, entry 11).
We were pleased that by utilizing i-Pr2NHÁTFA, complete
conversion of the starting material to the a,b-unsaturated
carbonyl could be obtained in 8 h. The scope of this reaction
was next assessed with a representative selection of aldehydes,
ketones and esters.
Several methods have been developed for the a-methylenation
of carbonyls, but a practical approach has yet to be generalized
and optimized.7 Erkkila and Pihko recently reported an
¨
a-methylenation of aldehydes in aqueous isopropanol employing
catalytic pyrrolidine and propionic acid,8 but for the synthesis
of complex, functionalized a,b-unsaturated carbonyls, the
three step Mannich reaction–alkylation–elimination procedure
with dimethylmethylideneammonium iodide (Eschenmoser’s
salt) has been the most popular choice9 where the mild
reaction conditions are more important than the shortest
possible sequence.10,11 Gras had earlier reported a direct one
step a-methylenation of ketonic compounds using N-methyl-
anilinium trifluoroacetate as a catalyst with 1,3,5-trioxane in a
refluxing aprotic solvent (THF or 1,4-dioxane).12 This reaction
affords a,b-unsaturated carbonyls by way of a Mannich-type
reaction on a transiently formed methyleneammonium salt.
We were attracted to this simple method but needed a
more robust system with greater substrate scope and better
reproducibility to reliably deliver a wide range of unsaturated
substrates for an ongoing project.
As shown in Table 2, a wide variety of aliphatic and
aromatic ketones can be reliably converted to the corresponding
a,b-unsaturated ketones in good to excellent yields with
i-Pr2NHÁTFA. Also, cyclic symmetrical ketones are good
substrates for this transformation, affording exclusively
the mono-methylenated product in good yields (Table 2,
entries 4–6). Sterically demanding ketones are also tolerated
Table 1 Screening of ammonium salts as methylenation catalystsa
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
I
II
III
IV
V
VI
VII
VIII
VIII
VIII
VIII
82
5
In our initial study, we scanned a variety of ammonium salts
for the a-methylenation of acetophenone (Table 1, Fig. 1).
Diisopropylammonium trifluoroacetate (i-Pr2NHÁTFA, salt
VIII) was found to be the optimal mediator for a reaction
between acetophenone and paraformaldehyde in refluxing
THF, affording a 92% yield (Table 1, entry 9). Addition of
10 mol% i-Pr2NH to the catalytic system increased the yield
50
34
45
89
78
83
92
95
499
7
8c
9
10d
11e
Department of Chemistry, Texas A&M University, PO Box 30012,
College Station, TX 77842-3012, USA.
a
The reactions were performed with 1 mmol of acetophenone,
4 equiv. of paraformaldehyde (added in two portions), and 1 equiv.
of catalyst in 10 mL of THF at 67 1C for 8 h (see ESIw for details).
E-mail: connell@chem.tamu.edu; Tel: +1 979-218-9660
w Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of ammonium salts and a,b-unsaturated
carbonyls; copies of 1H and 13C NMR spectra of all compounds. See
DOI: 10.1039/b924577d
b
d
c
Determined by GC. Paraformaldehyde was added in one portion.
e
0.1 equiv. of i-Pr2NH was added. 0.1 equiv. of TFA was added.
ꢀc
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Table 2 Synthesis of a,b-unsaturated carbonyls from aldehydes,
Table 2 (continued )
ketones and estersa
Entry Substrate
Product
Yieldb (%)
15
16
17
18e
19
85
81
99
62
62
Entry Substrate
Product
Yieldb (%)
99
1
2
3
4
91
93
92
20d
96
92
21
(S)-Citronellal
5
84
a
Unless otherwise noted, the reactions were performed with 1 mmol of
carbonyl compound, 4 equiv. of paraformaldehyde added in two
portions, 1 equiv. of i-Pr2NHÁTFA, and 10 mol% TFA in 10 mL of
6
7
97
98
b
THF at 67 1C for 8 h. Isolated yield after purification by silica gel
c
chromatography. A 3 : 1 ratio of enol : methyl ketone is observed.
d
e
Ratio of i-Pr2NH : TFA (1.5 : 1). 2 equiv. of paraformaldehyde
was used, 2 h reaction time, ratio of i-Pr2NH : TFA (2 : 1).
as evidenced by the 84% yield of the desired product from
reaction of 2,2,5,5-tetramethylcyclohexanone (Table 2,
entry 5). Furthermore, no isomerization of the double bond could
be detected in any of these adducts by 1H NMR spectroscopy.
These reaction conditions are mild as evidenced by the
variety of functional groups which are compatible with this
system. For example, b-ketoester 7 reacted cleanly affording a
98% yield (Table 2, entry 7) of the desired product. Hydroxy
groups are also tolerated by these conditions. Interestingly,
2-hydroxyacetophenone underwent intramolecular conjugate
addition after initial a-methylenation to form 4-chromanone
which then underwent a second a-methylenation to afford
adduct 11 in 85% yield under our standard reaction conditions
(Table 2, entry 12).
8
9
83
88
10
11
91
94
a-Mono-substituted acyclic ketones appear slightly less
reactive than methyl ketones and cyclic ketones. For example,
1-phenylpropionone afforded adduct 8 in 83% yield (Table 2,
entry 8), versus 91% yield for adduct 10 (Table 2, entry 10) or
99% yield for adduct 1 (Table 2, entry 1). 1-Phenoxypropan-
2-one reacts regioselectively to give 3-phenoxybut-3-en-2-one
14 in 85% yield (Table 2, entry 15). Only inseparable traces of
1-phenoxybut-3-en-2-one were observed. Such regioselectivity
can be explained by the selective reaction of the
thermodynamic enol.
12
85
13
95
14d
84c
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Aldehydes are easily converted to acroleins using this
catalytic system. 3-Phenylpropional afforded a 95% yield
(Table 2, entry 13). The TBDPS protecting group is stable to
these reaction conditions (Table 2, entry 17).
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products when the reaction conditions were buffered with
additional i-Pr2NH instead of additional TFA (Table 1,
entry 9). For example, when the TES protected methyl
acetylene ketone (4-(triethylsilyl)but-3-yn-2-one)13 was treated
under our standard reaction conditions, no desired product
was observed. But, by adding 1 equiv. i-Pr2NH, the desired
adduct 17 was obtained in 2 h in 62% yield (Table 2, entry 18).
Additionally, the enol product 13 was produced in 85%
yield when 0.5 equiv. of i-Pr2NH was used instead of TFA
(Table 2, entry 14).
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As a final note, several reactions that we tried were
significantly slower when a catalytic amount (10–50 mol%)
of i-Pr2NHÁTFA was utilized. Given the modest cost and
convenience of this reagent, we have not further explored
the application of catalytic reaction conditions.
In conclusion, using the readily available diisopropylammonium
trifluoroacetate salt as a catalyst, the a-methylenation of
carbonyl compounds has been successfully accomplished
under mild reaction conditions in good to excellent yields
(62% to 99%, 19 of 21 examples above 80%) using various
aromatic and aliphatic ketones, aldehydes and esters at 67 1C
in 8 h. No isomerization of the double bond is detected, no
over alkylation or polymerization of any of the adducts
is detected and functional group tolerance is excellent. We
believe that this is the simplest and most straightforward
method currently available for the a-methylenation of carbonyl
compounds.
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The Norman Hackerman Advanced Research Program and
the Robert A. Welch Foundation (A-1623) are gratefully
acknowledged for support of this research. Dr Young Kim
performed the reaction described in Table 2, entry 18.
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ꢀc
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Chem. Commun., 2010, 46, 1715–1717 | 1717