Nucleophilic β-alkenylation of N-alkoxyenamines: An umpolung strategy for the preparation of β,γ-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2016.04.033

An umpolung strategy has been developed for the synthesis of β,γ-unsaturated ketones utilizing nucleophilic β-alkenylation of N-alkoxyenamines, which are prepared in situ from ketones and isoxazolidine, with alkenyl aluminum reagents. Various β,γ-unsatura

Full text of DOI:10.1016/j.tetlet.2016.04.033

Accepted Manuscript
Nucleophilic β-alkenylation of N-alkoxyenamines: An umpolung strategy for
the preparation of β,γ-unsaturated ketones
Raj Kumar Nandi, Norihiko Takeda, Masafumi Ueda, Okiko Miyata
PII:
S0040-4039(16)30383-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.033
TETL 47533
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 February 2016
6 April 2016
12 April 2016
Please cite this article as: Nandi, R.K., Takeda, N., Ueda, M., Miyata, O., Nucleophilic β-alkenylation of N-
alkoxyenamines: An umpolung strategy for the preparation of β,γ-unsaturated ketones, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.033
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Tetrahedron Letters
Nucleophilic -alkenylation of N-alkoxyenamines: an umpolung strategy for the
preparation of ,-unsaturated ketones
Raj Kumar Nandi, Norihiko Takeda, Masafumi Ueda and Okiko Miyata
a Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An umpolung strategy has been developed for the synthesis of ,-unsaturated ketones utilizing
nucleophilic -alkenylation of N-alkoxyenamines, which are prepared in situ from ketones and
isoxazolidine, with alkenyl aluminum reagents. Various ,-unsaturated ketones have been
prepared following this simple procedure under mild conditions.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
,-Unsaturated ketone
N-Alkoxyenamine
Umpolung
Alkenyl aluminum reagent
Isoxazolidine
———
 Corresponding author. Tel.: +81-78-441-7554; fax: +81-78-441-7556; e-mail: miyata@kobepharma-u.ac.jp (O. Miyata).

2
Tetrahedron Letters
,-Unsaturated ketones are an important molecular scaffold
A reliable method for the synthesis of ,-unsaturated ketones
is widely known as a three-step synthesis and consists of a cross-
aldol reaction of different aldehydes, Wittig olefination of -
hydroxy aldehyde, and oxidation of homoallylic alcohol.1d
Several other methods have been developed for a convenient
straightforward synthesis of ,-unsaturated ketones from simple
ketones or -haloketones; these include: (i) Pd- or Ni-catalyzed
cross-coupling of ketone enolate with alkenyl halide under basic
conditions,6 (ii) nickel-catalyzed cross-coupling of -haloketone
with alkenyl zirconium reagent,7
because of their presence in biologically active and natural
compounds, including histone deacetylase (HDAC) inhibitor
trichostatin A,1 antitumor agent lactimidomycin,2 antifungal
agent khafrefungin,3 and anticancer drug taxol.4 In addition, ,-
unsaturated ketones also serve as versatile intermediates in
organic synthesis because of the well-studied chemistry of
carbonyls and olefins.5 Therefore, synthesis of ,-unsaturated
ketone scaffold has received considerable attention over the past
two decades.
Scheme 1. -Alkenylation of ketones via enamines.
Table 1. Optimization for nucleophilic -alkenylation using N-alkoxyenamine.
Entry
1
Alkenyl aluminum reagent 7a (equiv.)
Temperature (°C)
0
Time (h)
1
Yield of 8aa (%)a
Yield of 9 (%)a
3
62
NDb
2
3
4
2
1
3
0
0
−40
2
2
5
36
17
NDb
NDb
NDb
NDb
5
3
rt
1
24
28
a Yield after purification by preparative TLC.
b Not detected.
Scheme 2. Proposed reaction pathway.

(iii) copper-catalyzed 1,2-addition of -haloketone to alkyne at
elevated temperature,8 and (iv) base-promoted -alkenylation of
ketone with terminal alkyne at high temperature.9 In contrast, less
is known about the -alkenylation of ketones via enamine10 and
their derivative11 although the chemistry of enamine has widely
studied. There is an example for -alkenylation of simple ketones
via an enamine, where enamine 2 was converted to ,-
unsaturated ketone 4 via -lithiation of 2, Li/Zn transmetalation,
Negishi cross-coupling of 3 with alkenyl iodide, and protonolysis
(Scheme 1; Eq. 1).10 The scope and overall utility of this reaction,
however, are limited by the level of care required to conduct such
a complex and sequential procedure.
We are interested in developing alternative methods for the
efficient formation of ,-unsaturated ketones that would provide
facial access to these compounds and allow them to be used in
further synthetic applications. We recently reported the
development of a procedure for the umpolung -arylation of
carbonyls (aldehydes and ketones), which was triggered by the
reaction of N-alkoxyenamines with triarylaluminum reagents.12
As part of our program investigating the introduction of other
nucleophiles in the umpolung chemistry of N-alkoxyenamines,
we herein report our umpolung strategy for the synthesis of ,-
unsaturated ketones 8 utilizing nucleophilic -alkenylation of N-
alkoxyenamines 6, which were prepared from readily available
ketones 5 and isoxazolidine (Scheme 1; Eq. 2).
6a with alkenyl aluminum reagent 7a (3 equiv.) proceeded
smoothly at 0 °C to afford -alkenyl ketone 8aa in 62% yield
(Table 1, entry 1).14 Interestingly, none of -isobutyl ketone 9
was obtained under above reaction conditions. Either reduced
amount of alkenyl aluminum reagent or cooled reaction
temperature (−40 °C) led to a significant decrease in the yield of
-alkenyl ketone 8aa (Table 1, entries 2–4). When the reaction
was carried out at room temperature, desired 8aa was obtained in
24% yield, along with -isobutyl ketone 9 in 28% yield (Table 1,
entry 5). This result indicated that temperature control was
important for this reaction to suppress the formation of -
isobutyl ketone 9. On the basis on these results, the use of alkenyl
aluminum reagent 7a (3 equiv.) at 0 °C was considered necessary
to achieve good conversion and yield for this reaction.15
The plausible reaction pathway for the formation of ,-
unsaturated ketone 8aa from 2-hexanone (5a) can be rationalized
by the nucleophilic -alkenylation of N-alkoxyenamine 6a,
which is generated in situ by the condensation reaction of 5a and
isoxazolidine (Scheme 2). This umpolung reaction of 6a could
generate imine intermediate B by coordination with the alknenyl
aluminum reagent 7a, followed by N-O bond cleavage and
simultaneous nucleophilic attack of alkenyl aluminum reagent 7a
(C-position). Upon aqueous work-up, imine intermediate B
affords the ,-unsaturated ketone 8aa.
Having optimized the reaction conditions for the umpolung
reaction, we proceeded to evaluate the scope of this reaction by
investigating the introduction of various alkenyl aluminum
reagents to N-alkoxyenamine 6a (Table 2). Requisite alkenyl
aluminum reagents 7b–g were prepared in situ by
hydroalumination of commercially available terminal alkynes
with DIBAL-H according to literature procedures.13 The
umpolung reaction of 6a with sterically hindered (tert-butyl
group) alkenyl aluminum reagent 7b also proceeded to afford
We first optimized the umpolung -alkenylation of N-
alkoxyenamine 6a with regards to the amount of alkenyl
aluminum reagent 7a and the reaction temperature (Table 1),
where 6a was prepared in situ from 2-hexanone (5a) and
isoxazolidine. Alkenyl aluminum reagent 7a was prepared in situ
by hydroalumination of 1-pentyne with DIBAL-H.13 According
to our previous report,12a we first selected the stepwise operation
to form the N-alkoxyenamine 6a. After the formation of 6a from
5a and isoxazolidine in the presence of MgSO4, the reaction of
Table 2 Nucleophilic -alkenylation of N-alkoxyenamine using
,-unsaturated ketone 8ab in 59% yield (Table 2, entry 1).
Alkenyl aluminum reagents 7c (R = cPropyl) and 7d (R =
cHexyl), prepared by hydroalumination of cyclic alkyl alkynes
with DIBAL-H, gave the corresponding -alkenylated products
8ac and 8ad in moderate yields (Table 2, entries 2 and 3). The
use of alkenyl aluminum reagent 7e bearing a benzyl group (R =
CH2Ph) gave ,-unsaturated ketone 8ae in moderate yield (Table
2, entry 4). For the alkenyl aluminum reagents 7f and 7g carrying
extended alkyl chains, -alkenylated products 8af and 8ag were
obtained in low yield (Table 2, entries 5 and 6).16
various alkenyl aluminum reagents.a
The scope of different ketones in the synthetic protocol was
then explored using several alkenyl aluminum reagents (Table 3).
The reaction of acyclic ketones 5b and 5c, carrying terminal
alkene and nitrile, with 7a proceeded smoothly to afford the
corresponding ,-unsaturated ketones 8ba and 8ca in yields of
71% and 55%, respectively (Table 3, entries 1 and 2). Cyclic
ketones such as cyclohexanone (5d) and cyclododecanone (5e)
also gave the corresponding -alkenylated products 8da and 8ea
in moderate to good yields (Table 3, entries 3 and 4). We also
Entry
R
Product
8ab
8ac
8ad
8ae
Yield (%)b
1
2
3
4
5
6
tBu (7b)
cPr (7c)
cHexyl (7d)
CH2Ph (7e)
CH2CH2Ph (7f)
CH2CH2CH2CH2Cl (7g)
59
44
51
56
28
30
8af
8ag
a Reaction conditions: 2-hexanone (1 equiv.), isoxazolidine (2 equiv.), MgSO4
(250 mg), CH2Cl2 (5 mL), room temp., 16 h, then alkenyl aluminum reagent
(3 equiv.), 0 °C, 1–2 h.
b Yield after purification by preparative TLC.
Table 3 Nucleophilic -alkenylation of various N-alkoxyenamines using alkenyl aluminum reagents.a

4
Tetrahedron
Entry
1
Substrate
R3
Product
Yield (%)b
71
nPr (7a)
2
3
4
nPr (7a)
nPr (7a)
nPr (7a)
55
53
65
5
6
cHexyl (7d)
CH2Ph (7e)
58
60
5d
5e
a
Reaction conditions: ketone (1 equiv.), isoxazolidine (2 equiv.), MgSO4 (250 mg), CH2Cl2 (5 mL), room temp., 16 h, then alkenyl aluminum
reagent (3 equiv.), 0 °C, 1–2 h.
b Yield after purification by preparative TLC.
examined the use of cyclic ketones with two different alkenyl
aluminum reagents, which also afforded the corresponding
expected products 8dd and 8ee in moderate to good yields (Table
3, entries 5 and 6).
References and notes
1.
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K.; J. Antibiot. 1976, 29, 1-6; (b) Fleming, I.; Iqbal, J.; Krebs, E.-P.
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T.; Richer, J.; Hulett, T.; Schauer, D. J.; Wiest, O.; Helquist, P. Eur. J.
Org. Chem. 2013, 162-172.
We have developed
a procedure for nucleophilic -
alkenylation of N-alkoxyenamines with alkenyl aluminum
reagents under mild conditions that allowed the formation of ,-
unsaturated products without isomerization to ,-unsaturated
ketones. The advantages of this novel protocol include a
simplified procedure and milder reaction conditions when
compared with other -alkenylations of ketones. Efforts to
further expand the scope of this reaction and demonstrate the
synthetic utility of products are currently underway in our
laboratory.
2.
(a) Sugawara, K.; Nishiyama, Y.; Toda, S.; Komiyama, N.; Hatori, M.;
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This work was supported by Grant-in-Aid from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan
(MEXT), and the MEXT-Supported Program for the Strategic
Research Foundation at Private Universities.
Supplementary data
5.
Supplementary data associated with this article can be found, in
the online version, at http://---

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stirring at room temperature for 16 h, the reaction mixture was filtered
under Ar atmosphere. Alkenyl aluminum reagent 7a13 (0.60 M in n-
hexane, 3.0 mL, 1.5 mmol) was added dropwise to the filtrate at 0 °C.
After stirring at 0 °C for 1 h, the reaction was quenched with aqueous
Rochelle’s salt (1.3 M). The resulting suspension was extracted with
CHCl3. The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The residue
was purified by preparative thin-layer chromatography (n-hexane/Et2O
= 20:1) to give the ,-unsaturated ketone 8aa (52.2 mg, 62%) as a
colorless oil. IR (neat) max cm−1: 1716 (C=O). 1H NMR (300 MHz,
CDCl3): δ 0.88 (br t, J = 7.5 Hz, 6H), 1.14-1.50 (m, 5H), 1.62-1.72 (m,
1H), 1.88-2.12 (m, 2H), 2.13 (s, 3H), 3.02 (br dd, J = 15.0, 8.5 Hz,
1H), 5.28 (ddt, J = 15.0, 8.5, 1.0 Hz, 1H), 5.57 (br dt, J = 15.0, 7.0 Hz,
1H). 13C NMR (CDCl3, 75 MHz): δ 13.6, 13.9, 20.3, 22.4, 28.3, 3 3.1,
34.6, 57.2, 128.0, 134.4, 210.4. HRMS (ESI): calcd for C11H21O
[M+H]+ 169.1586, found 169.1587.
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15. The reaction of 5a with 7a (3 equiv.) in the presence of isoxazolidine
(2 equiv.) at 0 °C for 1 h gave ,-unsaturated ketone 8aa in 21% yield
(one-pot procedure).
16.
For the umpolung -alkenylation of N-alkoxyenamine 6a with
diisobutyl(styryl)aluminum [prepared in situ by Ni-catalyzed -
hydroalumination of phenylacetylene with DIBAL-H], -alkenylated
product carrying styryl group was obtained in 11% yield. When other
alkenyl aluminum reagent [prepared in situ by hydroalumination of 1-
phenyl-2-(trimethylsilyl)acetylene with DIBAL-H] was used, a trace
amount of -alkenylated product was detected.
14. Experimental procedure: To a solution of anhydrous MgSO4 (250 mg)
in dry CH2Cl2 (5.0 mL) were added isoxazolidine (73.0 mg, 1.0 mmol)
and 2-hexanone 5a (50.1 mg, 0.50 mmol) at room temperature. After
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6
Tetrahedron
<Highlights>

The synthesis of ,-unsaturated ketones by an
umpolung strategy.


A nucleophilic -alkenylation of N-alkoxyenamines.
The reaction features simple procedure.