Regioselective addition of organometallic reagents to 2-(1-alkynyl)-2- alken-1-ones for an efficient synthesis of substituted 1,2-allenyl ketones

Article abstract of DOI:10.1002/adsc.201100009

Highly substituted 1,2-allenyl ketones can be easily and efficiently prepared from organometallic reagents and readily available 2-(1-alkynyl)-2- alken-1-ones. The synthetic application of 1,2-allenyl ketone products was also showcased by palladium-cataly

Full text of DOI:10.1002/adsc.201100009

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DOI: 10.1002/adsc.201100009
Regioselective Addition of Organometallic Reagents to 2-(1-Al-
kynyl)-2-alken-1-ones for an Efficient Synthesis of Substituted
1,2-Allenyl Ketones
Xiuzhao Yua and Junliang Zhanga,b,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-021-6223-5039; e-mail: jlzhang@chem.ecnu.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: January 5, 2011; Revised: March 26, 2011; Published online: May 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org./10.1002/adsc.201100009.
Abstract: Highly substituted 1,2-allenyl ketones can
be easily and efficiently prepared from organome-
tallic reagents and readily available 2-(1-alkynyl)-2-
alken-1-ones. The synthetic application of 1,2-allen-
yl ketone products was also showcased by palladi-
um-catalyzed further transformation.
methods based on functionalized alkynes, alkenes and
carbonyl compounds have been dedicated to the de-
velopment of efficient synthesis of allenes.[5,6] How-
AHCTUNGTREGeNNUN ver, the search for efficient and practical synthetic
methods for highly functionalized allenes from readily
available starting materials is still highly desirable.
Herein, we wish to report a regio- and chemoselective
conjugate addition of organozinc/copper reagents to
electron-deficient enynes 1,[7,8] leading to a facile ap-
proach to highly substituted 1,2-allenyl ketones.
Keywords: 2-(1-alkynyl)-2-alken-1-ones; 1,2-allenyl
ketones; organometallic reagents; regioselectivity
We recently developed a simple base-catalyzed nu-
cleophilic addition reaction of weak nucleophilic mal-
onates to electron-deficient 1,3-conjugated enynes,
Allenes are important molecules in modern organic leading to the quite special malonate substituted 1,2-
chemistry, and their unique chemical structure is allenyl ketones [Scheme 1, (a)].[8a] During this study,
found in many bioactive natural products and phar- we became interested in the nucleophilic addition re-
maceuticals.[1] Since the prediction of allenes by van’t action by using more reactive and commonly used or-
Hoff in 1875,[2a] and the first documented synthesis ganometallic reagents as nucleophiles which, if it
disclosed by Burton and von Pechmann in 1887,[2b] in- worked, would give a more general type of 1,2-allenyl
creasing attention has been paid to their interesting ketones [Scheme 1, (b)].
reactivities.[3,4] Throughout the past century, many
Scheme 1. The previous work (a) and our projected design (b).
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Xiuzhao Yu and Junliang Zhang
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Table 1. Screening of the reaction conditions for the reaction
of 1a and 2a.[a]
Table 2. Synthesis of multifunctionalized allenes 3.
Entry R (2) R1/R2/R3 (1)
Yield [%][a] of 3
Entry
Solvent
X-H
Yield[b] [%] of 3a (dr)
1
2
3
4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Me/Ph/Ph
94 (3a)
79 (3b)
72 (3c)
85 (3d)
65 (3e)
65 (3f)
65 (3g)
1[c]
2[c]
3[c]
4
5
6
THF
Et2O
CH2Cl2
toluene
toluene
toluene
NH4Cl
NH4Cl
NH4Cl
NH4Cl
PhCO2H
t-BuCO2H
33 (1.4:1)
35 (1.1:1)
55 (1:1)
97 (1:1)
88 (2.5:1)
94 (3:1)
Me/Ph/4-MeOC6H4
Me/Ph/1-naphthyl
Me/Ph/4-NO2C6H4
Me/Ph/n-C4H9
Me/Ph/cyclopropyl
Me/4-MeOC6H4/Ph
Me/4-MeOC6H4/1-naphthyl 72 (3h)
Me/4-MeOC6H4/4-MeOC6H4 64 (3i)
Me/n-C4H9/Ph
5
6
7[b]
8
[a]
9[b]
10
11
12
13
14
15
16
17
18
The reaction was carried out on a 0.5-mmol scale.
Isolated yield.
A trace amount of 4a was formed.
[b]
[c]
90 (3j)
99 (3k)
91 (3l)
86 (3m)
67 (3n)
93 (3o)
93 (3p)
78 (3q)
62 (3r)
Ph/Ph/Ph
Ph/Ph/4-MeOC6H4
Ph/4-MeOC6H4/Ph
Ph/Ph/n-C4H9
Ph/Ph/1-cyclohexenyl
4-ClC6H4/Ph/Ph
CO2Me/Ph/Ph
Me/Ph/Ph
Initially, we tested the reaction by using ketone 1a
and Et2Zn 2a as the model substrates (Table 1). Sub-
strate 2a was treated with the solution of 1a in THF
at À788C for 2 h and then the solution was slowly
warmed to room temperature. Gratifyingly, after the
reaction was quenched by the aqueous NH4Cl solu-
tion, the desired allenyl ketone 3a was obtained in
33% isolated yield (Table 1, entry 1), and a trace
amount of 4a was also detected. The screening of dif-
ferent solvents showed that the solvent has a signifi-
[a]
Isolated yield of 3, and if 4 exists, the yield is less than
5%.
CH2Cl2 was used as solvent instead of toluene.
[b]
cant influence on the reaction (Table 1, entries 1–4). to excellent yields; (v) gratifyingly, the reaction of
Toluene was found to be quite successful for this addi- Ph2Zn works also well to give the corresponding al-
ton reaction. During the processing, it is interesting to lenyl ketone product 3r in 62% yield (Table 2,
find that the acid, as the quencher, plays an important entry 18); (vi) the regioselectivity is pretty high and
role in affecting the diastereo- and regioslecticity. Fi- only a trace amount of the homo-alkynyl ketone can
nally, we were pleased to find that 3a could be isolat- be detected in a few cases.
ed in 94% yield with a 3:1 ratio of two diastereomers
using PivOH as the quencher (Table 1, entry 6).
We next turned to investigate the chemistry of the
organometallic reagent such as lithium organocuprate
With the optimal conditions in hand, we next exam- (prepared from RLi and CuI).[9] The additions of
ined the scope of this transformation by variation of
enynes 1 and the results are summarized in Table 2.
Table 3. Substrate scope of 1 and 5 in the reaction.
Several points are noteworthy: (i) in general, highly
substituted 1,2-allenyl ketones can be prepared in
good to excellent yields under the standard conditions
(Table 2); (ii) various substitutents (R1) on the ketone
such as aliphatic (Table 2, entries 1–10), aromatic
(Table 2, entries 11–16) and ester (Table 2, entry 17)
are compatible; (ii) the substituent on the alkene
Entry R1/R2/R3 (1)
R (5) Yield [%][a] of 3
moiety (R2) can be either an aromatic (Table 2, en-
tries 1–9, 11–17) or an aliphatic group (Table 2,
entry 10). For example, the reaction of an aliphatic
substituted enyne with Et2Zn affords the desired
allene 3j in 90% yield; (iv) substituents on the alkyne
moiety (R3) with aromatic (Table 2, entries 1–4, 7–13,
16, and 17) or aliphatic groups (Table 2, entries 5, 6,
14, and15) were also tolerated, and the reactions pro-
ceed smoothy to afford the disired allenes with good
1
2
3
4
5
6
7
Me/Ph/Ph
Me/Ph/1-naphthyl
Me/4-MeOC6H4/4-MeOC6H4 n-Bu 88 (3u)
Me/Ph/Ph
Me/Ph/Ph
Me/Ph/Ph
Me/Ph/Ph
n-Bu 94 (3s)
n-Bu 83 (3t)
Me
63 (3v)
i-Pr 75 (3w)
t-Bu 63 (3x)
Ph
64 (3r)
[a]
Isolated yield.
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Regioselective Addition of Organometallic Reagents to 2-(1-Alkynyl)-2-alken-1-ones
Scheme 3. Plausible mechanism to account for the addition
reaction.
Scheme 2. Synthetic applications of 3a and 3s.
R2CuLi to the ketones 1 proceed smoothly to afford highly substituted 1,2-allenyl ketones. Further studies
the expected products in good to excellent yields with including synthetic applications, the asymmetric catal-
excellent regioselevity (Table 3, entries 1–7). Gratify- ysis of this reaction are ongoing in this laboratory.
ingly, even the bulky (i-Pr)2CuLi and (t-Bu)2CuLi can
be used as the organometallic reagents to give the
corresponding products in good yields (Table 3, en- Experimental Section
tries 5 and 6). It is noteworthy that the reaction with
Ph2CuLi (Table 3, entry 7) also works well to give the Typical Procedure for the Synthesis of 1,2-Allenyl
same product as Ph2Zn (Table 2, entry 18).
Ketone 3 via R2Zn addition
The synthetic utilities of the allene product 3 were
demonstrated by transformations of two representa-
tive 1,2-allenyl ketones 3a and 3s (Scheme 2). The cy-
cloisomerization reaction of 3a in CH3CN at room
To a solution of 3-benzylidene-5-phenylpent-4-yn-2-one (1a)
(0.5 mmol, 123 mg) in 5 mL of anhydrous toluene at À788C
under N2 in a Schlenk tube was slowly added Et2Zn
(0.6 mmol, 1M in THF, 0.6 mL) by a syringe in 1 min. After
2 h, the reaction mixture was then warmed to room temper-
ature. After the enyne 1a had been consumed completely
determined by TLC analysis, PivOH (2.0 equiv.) was slowly
added to the reaction mixture. The reaction mixture was
then stirred at room temperature for another 0.5 h. After
routine work-up, the crude product was purified by column
chromatography on silica gel (hexanes:ethyl acetate=30:1)
to give 3a; yield: 130 mg (94%).
temperature under the catalysis of PdCl2ACTHNUTRGEN(UNG CH3CN)2
(5 mol%) for 72 h gives the 2,3,5-trisubstituted furan
6 in 87% isolated yield. The cross-coupling cyclization
reaction of 3a with allyl choride affords the tetrasub-
stituted furan 7 in 76% isolated yield after 72 h under
the catalysis of PdCl2ACTHNUTRGNEUNG
(CH3CN)2 (5 mol%).[10] Inter-
stingly, the reaction of 3s with PhI affords the tetra-
substituted allene 8[11a,b] via the direct cross-coupling
reaction at the g-position rather than the expected
tetrasubstituted furan[11c] under the catalysis of
PdACHTUNGTRENNUNG(PPh3)4 (5 mol%) and Ag2CO3 (5 mol%).
One plausible mechanism that accounts for this
highly regioselective addition reaction is depicted in
Typical Procedure for the Synthesis of 1,2-Allenyl
Ketone 3 via R2CuLi Addition
To a solution of CuI (0.6 mmol, 115 mg) in dried ether
Scheme 3. The 1,4-addition of nucleophile cuprates to (3 mL) at À308C in a Schlenk tube under N2, was added
BuLi (1.2 mmol, 2.5M in hexane, 0.48 mL). After the reac-
tion mixture had been stirred for 30 min, it was transferred
to a solution of 3-benzylidene-5-phenylpent-4-yn-2-one 1a
(0.5 mmol, 123 mg) in 5 mL of toluene (dried) at À788C
under N2 by a syringe in 1 min. After being stirred for an-
other 2 h, the reaction mixture was then warmed to room
temperature. After the enyne 1a had been consumed com-
pletely determined by TLC analysis, PivOH (2.0 equiv.) was
slowly added to the reaction mixture. The reaction mixture
was then stirred at room temperature for another 0.5 h.
enones 1 would afford intermediates A, which would
then undergo the cleavage of the copper-carbon bond
via intermediates B to produce enolates C. The disso-
ciation of RCu affords two convertible intermediates
– lithium enolate D and allenic lithium E – which in
turn upon protonation give the product.[12]
In summary, we have developed a highly regioselec-
tive addition of organometallic reagents to readily
available 2-(1-alkynyl)-2-alken-1-ones, which provides
a rapid and efficient approach to synthetically useful After routine work-up, the crude product was purified by
Adv. Synth. Catal. 2011, 353, 1265 – 1268
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Xiuzhao Yu and Junliang Zhang
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tate=30:1) to give 3s; yield: 143 mg (94%).
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Supporting Information
1
Experimental details and copies of H/13C NMR spectra of
all new compounds are available as Supporting Information.
Acknowledgements
Financial supports from National Natural Science Founda-
tion of China (20972054) and 973 program (2011CB808600),
Ministry of Education of PRC (NCET, 20090076110007) are
greatly appreciated.
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