Nucleophilic α-arylation and α-alkylation of ketones by polarity inversion of N-alkoxyenamines: Entry to the umpolung reaction at the α-carbon position of carbonyl compounds

Article abstract of DOI:10.1002/anie.201004374

A new aspect of enamine chemistry: The formation of N-alkoxyenamines from ketones has led to an efficient umpolung reaction. The alkylation of N-alkoxyenamines with trialkylaluminum compounds proceeded smoothly and gave α-alkylated ketones (see scheme). This reaction offers a simple transformation of ketones into α-substituted ketones without the need to isolate enamines and intermediary imines.

Full text of DOI:10.1002/anie.201004374

Communications
DOI: 10.1002/anie.201004374
Umpolung Reaction
Nucleophilic a-Arylation and a-Alkylation of Ketones by Polarity
Inversion of N-Alkoxyenamines: Entry to the Umpolung Reaction at
the a-Carbon Position of Carbonyl Compounds**
Tetsuya Miyoshi, Takayuki Miyakawa, Masafumi Ueda, and Okiko Miyata*
Umpolung reactions have been developed as unconventional
methods for the synthesis of biologically active target
molecules. Polarity inversions of the carbonyl group are
known in stoichiometric dithiane chemistry[1] and more
recently in catalytic NHC chemistry,[2] in which acyl anion
equivalents that are generated by the umpolung of reactivity
of the carbonyl carbon react with the electrophile. The
umpolung reaction of the a-carbon atom on the carbonyl
structure is an attractive reaction because it allows the direct
introduction of various types of substituents into the a posi-
tion through the use of nucleophiles. To the best of our
knowledge, less is known about the umpolung reaction at the
a position of the carbonyl group except for the use of
a-halogenated carbonyl compounds.[3] There are a few reports
Scheme 1. Umpolung strategy using an enamine intermediate. LA=Le-
wis acid, Nu=nucleophile.
of the umpolung reactions of enamine derivatives such as
vinyl azides,[4] N-sulfonylazoalkenes,[5] and enammonium salts
with an indolo[2,3-a]quinolizine structure.[6] Most umpolung
reaction of these enamine derivatives have been carried out
using nucleophilic alkylation reagents; however, the umpo-
lung arylation reactions of enamines have been much less
investigated.[7]
Our research group has developed a strategy for the
efficient umpolung a-alkylation and a-arylation of ketones
via enamine intermediates (Scheme 1). Generally, enamine 2
(X = alkyl) reacts with an electrophile to give a 2-substituted
ketone 3. We anticipated that enamine 2 carrying a heter-
oatom substituent (X = OR) would generate the correspond-
ing a-carbonyl carbocation equivalent B by coordination with
This method is remarkable in its ability to deliver a-aryl
ketones, which are normally difficult to prepare by using the
reaction of an enamine with electrophiles.[9] There have been
no reports of polarity reversal of N-alkoxyenamine and we
are aware of only one example of electrophilic alkylation of
N-alkoxyenamine which occurred much more slowly than the
corresponding pyrrolidine enamine.[10] Organoaluminum
reagents were chosen as the nucleophile because we expected
that the desired reaction with a nucleophile such as trialky-
laluminum, which has Lewis acidic character, could proceed
À
efficiently by sequential coordination, N O bond cleavage,
À
a Lewis acid followed by N X bond cleavage of the resulting
and addition of the nucleophile (complex C in Scheme 1).
With the optimal reaction conditions for the umpolung
reaction in hand (see entry 5 of Table S1 in the Supporting
Information), we investigated the umpolung alkylation of
various ketones with several commercially available trialky-
laluminum compounds (Table 1). At first, we evaluated the
reaction of cyclohexanone derivatives 1a–c. The expected
reaction of the N-cyclohexenylisoxazolidine intermediate
2a,[11] which was formed in situ, with Et3Al proceeded and
afforded 4a in 76% yield (Table 1, entry 1). Similarly, the
reaction of 2a with iBu3Al gave 4b in 69% yield (Table 1,
entry 2). The N-alkenylisoxazolidine 2b prepared from 1b,
successfully underwent the umpolung alkylation to provide
4c–e in more than 70% yield (Table 1, entries 3–5). In the
case of 2-methylcyclohexanone (1c), 2-ethyl-6-methylcyclo-
hexanone (4 f) was obtained as a result of regioselective
formation of trisubstituted N-alkoxyenamine 2c as an inter-
mediate. Next, we turned our attention to investigating the
umpolung reaction using acyclic ketones. The 5-nonanone
(1d) provided good yield of the corresponding ethylated
complex A. The subsequent desired reaction with a nucleo-
phile would occur at an electrophilic a-carbon atom to form
the imine which is unstable enough to undergo hydrolysis
upon aqueous work-up. Herein, we present the umpolung
a-alkylation and a-arylation of ketones via N-alkoxyen-
amines under mild reaction conditions.[8]
[*] T. Miyoshi, T. Miyakawa, Dr. M. Ueda, Prof. Dr. O. Miyata
Kobe Pharmaceutical University
Motoyamakita, Higashinada, Kobe 658-8558 (Japan)
Fax: (+81)78-441-7554
E-mail: miyata@kobepharma-u.ac.jp
[**] The Grant-in-Aid for Scientific Research from the Japan Society for
the Promotion of Science and the Science Research Promotion Fund
of the Japan Private School Promotion Foundation are gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004374.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 928 –931

Table 1: Umpolung alkylation of various ketones.
Entry
Substrate
Product: R
4a: Et
Yield [%][a]
76
1
2
4b: iBu 69
1a
1b
1c
3
4
5
4c: Me 72
(trans/cis=1:1)[b]
71
(trans/cis=1:1)[b]
4e: iBu 70
(trans/cis=1:3)[b]
4d: Et
Scheme 2. One-pot double nucleophilic reaction.
74
We first examined the arylation of 2a with various types of
triarylaluminum compounds.[13] The expected reaction using
Ph3Al proceeded smoothly and gave a-phenylated product 7a
in 60% yield (Table 2, entry 1). The scope of triarylaluminum
compounds used was expanded (Table 2, entries 2–5). The
electronic nature of the substituents on the benzene ring had
little effect on the reaction efficiency. The higher yields of
desired a-aryl ketone derivatives were observed when
N-alkoxyenamine 2d was subjected to the arylation reaction
(Table 2, entries 6–10). We next examined a-arylation of
various types of ketones with (4-MeOC6H4)3Al. The cyclo-
hexanone derivatives 1b and 1c gave the corresponding a-
arylated products 7k and 7l in a stereoselective manner in 68
and 60% yields, respectively (Table 2, entries 11 and 12). The
reaction of acyclic ketones 1h and 1i gave desired products
7m and 7n in good yields, respectively (Table 2, entries 13 and
14). However, the ketones 1e and 1g bearing a phenyl group
gave the products 7o and 7p in diminished yield (Table 2,
entries 15 and 16). Interestingly, unsymmetrical aliphatic
ketones 1j–l underwent regioselective a-arylation to yield
7q–s (Table 2, entries 17–19). Notably, functional groups such
as the alkenyl and cyano groups were tolerated during this
reaction (Table 2, entries 18 and 19).
Through further investigation, we identified a one-pot
umpolung arylation reaction involving enamine formation.
We expected that triarylaluminum would preferentially react
with N-alkoxyenamine over the ketone unit owing to the
steric hindrance caused by the bulky substituents of the
triarylaluminum reagent. We therefore examined a simple
one-pot procedure involving enamine formation without
MgSO4 and the umpolung arylation reaction (Scheme 3).
Pleasingly, treatment of 5-nonanone (1d) with both isoxazo-
lidine and triphenylaluminum in CH2Cl2 cleanly afforded the
desired product 7 f in 73% yield. Similar results were
obtained when triarylaluminum compounds such as p-tolyl,
4-methoxylphenyl and 4-fluorophenyl aluminum regents
were employed. This method is equivalent to direct umpolung
a-arylation of carbonyl compounds which proceeds smoothly
in the presence of isoxazolidine and it provides an efficient
alternative synthetic route to 2-aryl carbonyl compounds
using a simplified procedure.
6
4 f: Et
(trans/cis=5:2)[b]
7
1d
1e
1 f
1g
4g: Et
4h: Et
4i: Et
4j: Et
78
51
44
61
8
9
10
[a] Yield of isolated product. [b] The diastereomeric ratio was determined
by 1H NMR spectroscopy of the crude product.
product 4g (Table 1, entry 7). Similarly, acyclic ketones 1e
and 1 f gave 4h and 4i, respectively, in moderate yields
(Table 1, entries 8 and 9). In the case of ketone 1g, 4j was
obtained in a regioselective manner via a more stable
N-alkoxyenamine intermediate 2g (Table 1, entry 10).
To elucidate the reaction pathway, we investigated the
one-pot double nucleophilic alkylation of 2a (Scheme 2). The
treatment of 2a with Et3Al and subsequent reaction with
allylmagnesium bromide gave dialkylated amino alcohol 6 in
46% yield. This result indicates that this umpolung reaction
would proceed via intermediate imine 5. Finally, addition of
allylmagnesium bromide to imine 5 gave the amine 6. Instead
of allylation, the treatment of 5 with water during work-up
afforded 2-alkylated ketone 4a.
Encouraged by these results, this umpolung reaction was
extended to a-arylation (Table 2). We expected that this type
of umpolung reaction would be able to easily furnish a-aryl
ketone derivatives. The majority of recent progress in the
preparation of a-aryl ketone compounds has focused on the
development of transition-metal-catalyzed couplings of eno-
late species with aryl halides.[12] However, the two major
drawbacks of these reactions are that a high temperature is
required for a successful reaction and an expensive transition
metal reagent is needed.
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Communications
Table 2: Umpolung arylation of various ketones.
by mild reaction conditions and simple transformation of
ketones into a-substituted ketones without isolation of
enamine derivatives and intermediate imines. This method
provides an attractive alternative to chemistry involving
enolate and enamine species. Furthermore, this reaction
allows transition-metal-free a-arylation of ketones under
mild conditions. Further development of this umpolung
reaction is currently underway.
Entry
Substrate
Product: Ar
Yield
[%][a]
1
2
3
4
5
7a: Ph
7b: p-tolyl
7c: 4-MeOC6H4 68
7d: 4-FC6H4
7e: 4-ClC6H4
60
64
Received: July 17, 2010
Revised: October 4, 2010
Published online: November 23, 2010
1a
1d
60
61
Keywords: aluminum · enamines · ketones ·
.
nucleophilic addition · umpolung
6
7
8
9
7 f: Ph
7g: p-tolyl
7h: 4-MeOC6H4 83
7i: 4-FC6H4
83
74
75
85
10
7j: 4-tBuC6H4
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1
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