Catalytic direct-type substitution reaction of α-alkyl enolates: A Pd/Bronsted base-catalysed approach to the decarboxylative allylation of sulfonylimidates

Article abstract of DOI:10.1039/b815845b

A mild and efficient process for the direct-type catalytic allylation of sulfonylimidates has been developed; this reaction represents the first example of Bronsted base-catalysed, in situ generation and use of α-alkyl enolates in substitution reactions; the success of this methodology stems from the tunable α-proton acidity and nucleophilicity of sulfonylimidates, which could be harnessed in the realization of a broader range of catalytic direct-type reactions using ester equivalents as nucleophiles. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b815845b

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Catalytic direct-type substitution reaction of a-alkyl enolates:
a Pd/Brønsted base-catalysed approach to the decarboxylative allylation
of sulfonylimidateswz
S. B. Jennifer Kan, Ryosuke Matsubara, Florian Berthiol and Shu¯ Kobayashi*
Received (in Cambridge, UK) 10th September 2008, Accepted 1st October 2008
First published as an Advance Article on the web 29th October 2008
DOI: 10.1039/b815845b
A mild and efficient process for the direct-type catalytic allyla-
tion of sulfonylimidates has been developed; this reaction repre-
sents the first example of Brønsted base-catalysed, in situ
generation and use of a-alkyl enolates in substitution reactions;
the success of this methodology stems from the tunable a-proton
acidity and nucleophilicity of sulfonylimidates, which could be
harnessed in the realization of a broader range of catalytic
direct-type reactions using ester equivalents as nucleophiles.
Scheme 1 Catalytic direct-type (a) addition and (b) substitution
reactions (X, Y = heteroatoms).
In response to the limited precedence for the use of a-alkyl
esters in catalytic direct-type reactions, our laboratory has
substitution is a well studied process for the functionalization
of carbonyl compounds such as malonates and b-ketoesters.4
For simple esters, however, the propensity of deprotonation is
inadequate to promote the reaction under neutral conditions.
In order to overcome this limitation, we proposed to introduce
a catalytic amount of external base to the system, and to
activate the carbonyl a-proton by electronic modification at
the nucleophile. These considerations, coupled with our recent
efforts to develop nitrogen analogues of carboxylic ester as
readily tunable nucleophiles, led us to investigate the substitu-
tion of allyl carbonates by sulfonylimidates. Our choice of
sulfonylimidates resides also on the ease to transform this
functionality1a to the corresponding amide, ester5 and alde-
hyde, and their applications in medicinal chemistry.6 Our
conceptual design is depicted in Scheme 2.
become interested in designing suitable nucleophiles and reac-
tion systems for the realization of this goal.1 Compared with
activated ester nucleophiles, such as those bearing a p system
or heteroatom adjacent to the ester functionality, the a-proton
pKa value of simple a-alkyl esters is markedly higher and
renders in situ catalytic enolate formation a formidable chal-
lenge. Recently, we and others have proposed solutions to this
problem in the context of catalytic carbonyl and Michael-type
addition reactions, through the use of a-alkyl ester equiva-
lents, including sulfonylimidates,1a (N-Boc)anisidides,1b,c and
trichloromethyl ketones2 as nucleophiles. Appropriate cataly-
tic systems were designed to complement these substrates, such
that a metal complex or simply a tertiary amine could be used
to promote proton transfer from the carbonyl nucleophile to
the addition adduct, and thereby effect carbon–carbon bond
formation under complete catalytic conditions (Scheme 1a).
Catalytic direct-type substitution reaction of a-alkyl esters/
ester equivalents, on the other hand, has not been realized to
date.3 Our strategy to implement this type of reaction is to use
the leaving group to serve as a proton sink in the catalytic
system. For this purpose, the leaving group would, despite its
good leaving group ability, need to be sufficiently basic. We
anticipated that a carbonate functionality would be suitable in
this regard, which upon nucleophilic substitution and sub-
sequent decarboxylation would generate an alkoxide anion
appropriate for Brønsted base regeneration (Scheme 1b).
External base-free, palladium-catalysed decarboxylative
Initial experiments showed that this strategy was feasible.
A combination of Pd(0) catalyst (10 mol%) and DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene, 20 mol%) effected the
direct allylation with good yield and regioselectivity upon
heating in toluene (Scheme 3). Importantly, double allylation
or tautomerisation of the mono-allylated product to the
corresponding enesulfonamide was not observed. The reaction
did not proceed in the absence of an external base, or when a
weaker amine base (Et3N) was used. Conducting the reaction
Department of Chemistry, School of Science and Graduate School of
Pharmaceutical Sciences, The University of Tokyo, The HFRE
Division, ERATO, Japan Science Technology Agency (JST), Hongo,
Bunkyo-ku, Tokyo, 113-0033, Japan.
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
w Electronic supplementary information (ESI) available: Experimental
details and physical data of the products. See DOI: 10.1039/b815845b
z This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Science (JSPS).
Scheme 2 Proposed Pd and Brønsted base-cocatalysed decarboxyla-
tive allylation of sulfonylimidate.
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of sulfonylimidate. Gratifyingly, when a para-nitrobenzene
ring was incorporated, which we believed should lower the
a-proton pKa value and stabilize the aza-enolate by an inductive
effect, remarkable rate acceleration was observed (Table 1). On
the other hand, the introduction of less electron-withdrawing
substituents (6 and 7) was not as effective. Interestingly, the use
of electron-rich imidate 8 also led to rapid allylation, presumably
fast nucleophilic attack could sufficiently drive the equilibrium
to favour enolate formation.
Scheme 3 Pd and DBU-catalysed allylation of sulfonylimidate with
cinnamyl carbonate.
Table
allylation reaction
1
Electronic effect of sulfonylimidate in decarboxylative
Armed with this information, we chose N-(p-nitrobenzene-
sulfonyl)imidate 5a to further improve our reaction system.
A weaker base, such as Et3N, also catalysed the reaction with
excellent yield and selectivity (Table 2, entry 2). Efficient
allylation was possible at room temperature using a somewhat
electron-deficient ligand,8 and the catalyst loading could be
reduced to 2.5 mol% Pd2dba3 and 10 mol% DBU (Table 2,
entry 6).
Entry
Ar
Time/h
Yield (%)
a : c
We next investigated the substrate scope of this reaction
(Table 3). Various substitutions in the a-position of sulfony-
limidate could be accommodated: methyl, ethyl, and the
sterically more demanding isopropyl group all gave compar-
able results with excellent yields. Allylation of stabilized a-aryl
sulfonylimidate 5d was hampered by a competing N-allylation
pathway, which was found to be irreversible under the reaction
conditions (entries 1–4). Linear aromatic, heteroaromatic and
aliphatic allyl carbonates with either E or Z olefin geometry
1
2
3
4
5
p-NO2C6H4 (5a)
p-CF3C6H4 (6)
m-CF3C6H4 (7)
Ph (8)
4
3
3
48
10
73
o31a
o24a
89
93 : 7
—
—
94 : 6
92 : 8
b
b
p-MeOC6H4 (8)
88
a
b
Conversion. Not determined.
in refluxing THF improved the regioselectivity (3a : 3c = 94 : 6,
89% yield), but an attempt to reduce the reaction temperature
further led to a marked decrease in reactivity.
Table 3 Catalytic direct-type allylation of sulfonylimidates (Ar =
p-NO2C6H4)
We reasoned that the relatively poor reactivity observed
might stem from the difficulty in generating an a-alkyl enolate
by catalytic deprotonation and the low concentration of such an
intermediate. The use of inorganic bases was thought to
stabilize the imidate enolate and improve reactivity via metal
enolate formation, but this approach was unsuccessful and no
inorganic base examined was found to be compatible with our
reaction system.7 Another solution to this problem would be to
modify the imidate sulfonyl-substituent and accordingly,
‘‘tune’’ the a-proton acidity, enolate stability and nucleophilicity
Entry Imidate Carbonateh a-Adducth Yield (%)a a : cb
1
2
3
4
5
6
5a
5b
5c
5d
5a
5a
5a
5a
5a
5a
5a
5a
5a
1b
1b
1b
1b
1a
1c
1d
1h
1e
1i
9ab
9bb
9cb
9db
9aa
9ac
9ab
9ad
9ae
9ai
99
99
95
74
83
82
72
70
87
99
73
93
98
—
—
—
—
Table 2 Pd and amine base-catalysed allylation of sulfonylimidate
with cinnamyl carbonate
95 : 5
91 : 9
96 : 4
94 : 6
97 : 3
—
7c
8c
9c
10d
11d
12f
13g
e
1j
1f
1g
9aj
9af
9ag
—
69 : 31
99 : 1
Entry
Ligandd
Base
Temp/1C
Yield (%)a
9aaa : 9aacb
1
2
3
4a
4a
4a
4b
4c
4c
DBU
Et3N
DBU
DBU
DBU
DBU
65
65
rt
rt
rt
73
94
59
75
79
83
93 : 7
94 : 6
96 : 4
91 : 9
95 : 5
95 : 5
a
b
c
Isolated yield. Determined by 1H NMR of crude products. At
d
e
f
30 1C. Ar = p-NMe2C6H4, at 65 1C. dr = 70 : 30. At 0 1C.
2.5 equiv. of carbonate was used.
g
4
h
5
6c
rt
a
b
c
Isolated yield. Determined by 1H NMR of crude products. The
reaction was performed using Pd2dba3 (2.5 mol%), ligand 4c (5 mol%)
and DBU (10 mol%).
d
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gave E-products exclusively with excellent regioselectivity
(entries 5–9). Branched and 1,3-disubstituted allyl carbonates
were found to be less reactive substrates, but the desired
products could be obtained in good to excellent yields when
an electron-rich sulfonylimidate was employed (entries 10–11).
Sensitive g-diene functionality could be incorporated into the
allylation product, albeit in moderate regioselectivity (entry 12).
The reaction conditions also accommodated the use of a
bifunctional electrophile and provided the desired a-allylation
product in a complete chemo- and regioselective manner
(entry 13).
Notes and references
1 (a) R. Matsubara, F. Berthiol and S. Kobayashi, J. Am. Chem. Soc.,
2008, 130, 1804; (b) S. Saito and S. Kobayashi, J. Am. Chem. Soc.,
2006, 128, 8704; (c) S. Saito, T. Tsubogo and S. Kobayashi, Chem.
Commun., 2007, 1236.
2 (a) H. Morimoto, S. H. Wiedemann, A. Yamaguchi, S. Harada,
Z. Chen, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed.,
2006, 45, 3146; (b) H. Morimoto, G. Lu, N. Aoyama, S. Matsunaga
and M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 9588.
3 Recently, an example of palladium-catalysed allylation of a-alkyl
amides using a stoichiometric amount of strong base was reported,
see: K. Zhang, Q. Peng, X.-L. Hou and Y.-D. Wu, Angew. Chem.,
Int. Ed., 2008, 47, 1741.
4 For pioneering work of the use of allyl carbonates in palladium-
catalysed allylation under neutral conditions, see: (a) J. Tsuji,
I. Shimizu, I. Minami and Y. Ohashi, Tetrahedron Lett., 1982, 23,
4809; (b) J. Tsuji, I. Shimizu, I. Minami, Y. Ohashi, T. Sugiura and
K. Takahashi, J. Org. Chem., 1985, 50, 1523; For a general review of
the Tsuji–Trost reaction, see: (c) B. M. Trost and D. L. Van
Vranken, Chem. Rev., 1996, 96, 395; (d) Z. Lu and S. Ma, Angew.
Chem., Int. Ed., 2008, 47, 258, and references cited therein.
5 An additional protocol for the conversion of sulfonylimidates to the
corresponding esters under mild hydrolysis conditions has been
developed in this work, see ESIz for details.
In summary, we have demonstrated a palladium/Brønsted
base-catalysed strategy to the decarboxylative allylation of
nitrogen analogues of carboxylic ester. This approach effected
carbon–carbon bond-forming substitution reactions under mild
and complete catalytic conditions, which would be appealing
for large scale syntheses and the preparation of molecules that
bear base-sensitive functionality or stereochemistry. This report
represents the first direct catalytic substitution reaction of
a-alkyl ester equivalents, the underlying concept of which could
be extended to other substitution reactions. Further studies in
developing asymmetric versions of this reaction, as well as
expanding the scope of using transition metal and Brønsted
base as cocatalysts and the utility of sulfonylimidates as
nucleophiles are now underway in our laboratory.
6 Sulfonylimidates as prodrug candidates: (a) H. Bundgaard and
J. D. Larsen, J. Med. Chem., 1988, 31, 2069; (b) J. D. Larsen and
H. Bundgaard, Int. J. Pharm., 1989, 51, 27.
7 The inorganic bases examined included NaOtBu, LiOtBu,
Mg(OtBu)2 and Cs2CO3.
8 The non-racemic version of this ligand gave only low enantio-
selectivity (see ESIw).
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This journal is The Royal Society of Chemistry 2008
6356 | Chem. Commun., 2008, 6354–6356