Alkynyl group as activating group: Base-catalyzed diastereoselective domino reactions of electron-deficient enynes

Article abstract of DOI:10.1002/adsc.200900633

This paper describes a base-catalyzed domino reaction of electron-deficient enynes with malonate-derived a,b-unsaturated esters and ketones, which provides a rapid, stereoselective access to multi-functionalized cyclopentanes and inden-5-(6 H)-ones in hig

Full text of DOI:10.1002/adsc.200900633

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DOI: 10.1002/adsc.200900633
Alkynyl Group as Activating Group: Base-Catalyzed Diastereo-
selective Domino Reactions of Electron-Deficient Enynes
Wenbo Li,a Yuanjing Xiao,a 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: September 11, 2009; Revised: November 9, 2009; Published online: December 8, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900633.
Abstract: This paper describes a base-catalyzed
domino reaction of electron-deficient enynes with
malonate-derived a,b-unsaturated esters and ke-
tones, which provides a rapid, stereoselective access
to multi-functionalized cyclopentanes and inden-5-
ACHTUNGTRENNUNG(6H)-ones in high yields. In this reaction, the alkyn-
yl group of the enyne acts as an activating group
rather than a reacting group.
Keywords: alkynes; cyclohexanes; cyclopentanes;
domino reactions; Michael reaction; stereoselectiv-
ity
Scheme 1. Reaction design.
Domino reactions take an important place in synthet- (2 equiv.) under the catalysis of PdCl2ACTHNUTRGNEU(GN CH3CN)2. To
ic chemistry, since they provide a rapid and efficient our surprise, the products were cyclopentane 3a and
access to architecturally complex molecules from rela- its diastereomer 4a via a tandem double Michael ad-
tively simple starting materials by combination of sev- dition reaction rather than a 5,6-bicyclic furan. Fur-
eral transformations into one-step.[1] Recently, tandem ther studies showed that this reaction could proceed
reactions triggered by Michael addition have attracted in the presence of only a catalytic amount of base
interest of many chemists.[1g–j,2] In the context of our (Table 1). After some attempts, we were pleased to
ongoing efforts to develop novel chemistry of elec- find that the reaction proceeded smoothly under the
tron-deficient enynes,[3,4] we report herein a novel catalysis of 10 mol% of DBU in acetone at room tem-
base-catalyzed domino reaction consisting of double perature (entry 6, conditions A) to give the products
Michael additions of electron-deficient enynes for the 3a/4a in combined 95% isolated yield but the diaste-
rapid construction of highly functionalized cyclopen- reoselectivity is only 1/1.9, while a much better selec-
tanes[5] and hexahydro-1H-inden-4(2H)-ones.
Recently, we described palladium-catalyzed ed yield under the catalysis of t-BuOK in THF
tivity (1/7.8) of 3a/4a could be obtained in 88% isolat-
a
tandem reaction of 2-(1-alkynyl)-2-alkene-1-ones with (entry 8, conditions B). The structures of 3a and 4a
2-allylmalonate in the presence of allylic chloride to were confirmed by X-ray crystallographic analysis
produce 5,6-bicyclic furans (Scheme 1). We envisaged (Figure 1).[6] Considering that there are three stereo-
that a bicyclic furan might be formed if crotonate-de- genic centers in the product, the diastereoselectivity is
rived malonate 2a was used instead of a 2-allylmalo- quite good.
nate under the same conditions.[3c]
With the optimal reaction conditions in hand, we
Initially, we examined the reaction of 1a and 2a in next turned our attention to studying the scope of
the presence of allyl chloride (3 equiv.) and K2CO3 enyne 1 (Table 2). Generally, the reaction proceeded
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Table 1. Screening conditions for tandem reaction of 1a with
2a.
Table 2. Synthesis of mutifunctionalized cyclopentanes.
Entry[a] R1/R2/R3 (Enyne 1)
Time Isolated yields
Entry[a]
Base (10 mol%)
Solvent
Isolated yields
of 3a/4a [%]
[h]
of 3, 4 [%]
1
2
Me/Ph/Ph (1a)
Ph/Ph/Ph (1b)
4
3a (10),
4a(78)[b]
3b (11), 4b
(66)[b]
1
NaH
DBU
DBU
DBU
DBU
DBU
K2CO3
t-BuOK
Cs2CO3
THF
THF
14/54
4/21
2[b]
3
48
DMSO
CH2Cl2
toluene
CH3COCH3
CH3COCH3
THF
11/58
12/19
15/24
33/62
11/72
10/78
11/79
4
5
6
3
MeO/Ph/Ph (1c)
96
12
14
10
6
14
3.5
4
3c (8), 4c (76)
4d (84)[b]
4e (65)[e]
4f (73)[e]
4g (36)[e]
4h (70)[b]
4i (79)[e]
4j (92)[e]
4
5
Me/Ph/4-MeOC6H4 (1d)
Me/n-Bu/Ph (1e)
7[b]
8[b]
9[b]
6
Me/1-naphthyl/Ph (1f)
Me/4-NO2C6H4/Ph (1g)
Me/4-MeOC6H4/Ph (1h)
Me/Ph/n-Bu (1i)
7[c]
8
THF
9
[a]
All the reactions were carried out using 1a (0.33 mmol),
2a (0.3 mmol) and 10 mol% of base at room temperature
for 2–12 h.
10
Me/4-MeOC6H4/4-
MeOC6H4 (1j)
11
Ph/4-MeOC6H4/Ph (1k)
Ph/Ph/4-MeOC6H4 (1l)
4-ClC6H4/Ph/Ph (1m)
12
12
2
3k (9), 4k (68)
3l (8), 4l (61)
3m (27), 4m
(64)
[b]
A trace amount of another diastereomer was detected by
12
1H NMR analysis of the crude product.
13[d]
smoothly to afford the corresponding products in
moderate to excellent yields in high diastereoselectiv-
ity. It is interesting to find that the reactions of
enynes 1e–1g and 1i–1j gave only one diastereomer
(>20:1) (entries 5–7, 9–10). It is also noteworthy that
the reaction of enyne 1c with an ester group could
[a]
Unless specified, all the reactions were carried out at
room temperature in 0.3 mmol scale under conditions B.
[b]
[c]
A
trace amount of diastereomer was detected by
1H NMR analysis of the crude product.
The solution of 1g was added by syringe pump through
1h and then stirred for another 5 h, a significant amount
of by-product from the dimerization of 1g was isolated.
The reaction was run under conditions A.
[d]
[e]
No other diastereomer was formed.
Figure 1. X-ray structures of 3a (left) and 4a (right).
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Alkynyl Group as Activating Group: Base-Catalyzed Diastereoselective Domino Reactions
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Table 3. Product control in tandem reactions of enyne 1 with
8.
also give the desired product 4c in high yield (76%)
with 8% yield of its diastereomer 3c (entry 3).
The reaction of a cyclic yne-enone 1n with 2a pro-
duced the desired fused 5,6-bicyclic product 5 in 63%
yield after stirring the reaction mixture for 0.5 h
under conditions B [Eq. (1)]. Enyne 1o with a phenyl-
sulfonyl moiety as the electron-withdrawing group re-
acted with 2a under condtions B to give the corre-
sponding product 6 in 81% yield [Eq. (2)]. Multi-
functionalized cyclohexanes could be obtained in
63% yield from the reaction of 1a with substrate 2b
[Eq. (3)].
Entry[a] R1/R2/R3 (Enyne 1)
Time Isolated yields
[hj
of 9, 10 [%][b]
1
2
3
4
5
6
Me/Ph/Ph (1a)
Ph/Ph/Ph (1b)
4
9a (–), 10a (59/
28)
2
9b (62)[c], 10b
(20)
1b
12
12
12
6
9b (9)[c], 10b
(68)
9g (16), 10g
(66/4)
9h (8), 10h (67/
25)
9j (20), 10j (58/
14)
9l (49), 10l (32)
9l (10), 10l (73)
9p (48/9), 10p
(37)
Me/4-NO2C6H4/Ph (1g)
Me/4-MeOC6H4/Ph (1h)
Me/4-MeOC6H4/4-
MeOC6H4 (1j)
Ph/Ph/4-MeOC6H4 (1l)
1l
7
8
9
5
12
16
Ph/n-Bu/Ph (1p)
[a]
[b]
[c]
All the reactions were carried out at room temperature
in 0.3 mmol scale.
Numbers in parenthesis are the isolated yields of the cor-
responding diastereoismers.
We next examined the domino reaction of yne-
enone 1a with malonate-derived a,b-unsaturated
ketone 8 and the results are summarized in Table 3. It
is interesting to find that the reaction of 1a with 8
proceeded smoothly to give a multi-functionalized bi-
cyclic hexahydro-1H-inden- 4(2H)-one 10a as two
Trace amount of another diastereomer was formed.
separable diastereomers in 87% total yield after 4 h ones 10b, 10l and 10p as a single diastereomer, respec-
via novel tandem double Michael additions and aldol tively (entries 3, 8 and 9).
reaction (entry 1), The relative stereochemistry of the
Interestingly, the reaction of 2a with a mixture of
minor diastereomer of 10a was further confirmed by yne-enone 1a and enone 11 only gave cycloadducts 3a
X-ray crystallographic analysis (Figure 2)[6]. Multi- and 4a, in which no any cycloadducts of 11 with 2a
functionalized cyclopentanes 9 could be also obtained were detected [Eq. (4)]. This result indicates that the
by running the reaction for a shorter time. For exam- alkynyl group acts as an activating group by lowering
ple, the reaction of 1b with 8 gave cyclopentane 9b in the LUMO level to make yne-enone 1a more active
62% yield along with 20% of bicyclic inden-5 (6H)- than the correponding enone 11
one 10b after reacting for 2 h. In contrast, only 9%
yield of 9b along with a higher yield of 10b were ob-
tained after 12 h, indicating that 9b could convert into
10b slowly under the reaction conditions (entries 2
and 3). It is noteworthy that those R1 =Ph substrates
such as 1b, 1l, 1p could give the desired inden-5 (6H)-
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Figure 2. X-ray structures of the minor isomer of 10a (left) and 12 (right).
The synthetic utilities of compounds 9 were show-
cased by selective transformation of a representative
product 9b.[7] Compound 9b could be converted into
functionalized hexahydropentalene 12 in 96% yield
by a gold(I)-catalyzed regioselective intramolecular
alkyne-ketone metathesis [Eq. (5)].[8] The structure of
compound 12 was confirmed by X-ray crystallograph-
ic analysis (Figure 2).[6]
Pleasingly, an asymmetric version of the tandem re-
action was achieved by application of a chiral phase- enolate B/B’. Subsquent intramolecular Michael addi-
transfer catalyst. For example, the reaction of yne- tion of the enolate carboanion to the enone would
enone 1a and 2a in the present of 25 mol% Cs2CO3 give a new enolate intermediate C. It is possible that
and 10 mol% cinchonidine-derived salt 13 in toluene sterically less hindered alkynyl groups result in a “cis”
at room temperature could give 4a, b in 75% and orientation for the substituent R3.[9] Protonation of
82% ee, respectively [Eq. (6)]. These results would the resulting intermediate C would produce cyclopen-
male this reaction even more attractive.
tanes 9 and regenerate intermediate A. The intramo-
One plausible mechanism for this base-catalyzed lecular aldol reactions would produce the bicyclic
domino reaction of electron-deficient enynes with inden-5 (6H)-ones 10.
malonate-derived ketone is depicted in Scheme 2.
In summary, we have developed a base-catalyzed
Treatment of the malonate-derived a,b-unsaturated domino reaction of electron-deficient enynes with
ketone 8 with the base produced stablized carboanoin malonate-derived a,b-unsaturated esters or ketones,
intermediate A, which would undergo an intermolec- which provides a rapid, efficient and stereoselective
ular Michael addition to the yne-enone 1 to afford access to multifunctionalized cyclopentanes, cyclohex-
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Alkynyl Group as Activating Group: Base-Catalyzed Diastereoselective Domino Reactions
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Scheme 2. Plausible mechanism.
anes and hexahydro-1H-inden-4(2H)-ones. It is note- Committee of Science and Technology (08dj1400101) are
greatly appreciated. This work was also supported by Shang-
hai Shuguang Program (07SG27).
worthy that the alkynyl group acts as an activating
group to accelerate this domino transformation. Syn-
thetic applications of this domino reaction are ongo-
ing in this laboratory and will be reported in due
course.
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Experimental Section
General Procedure for the Synthesis of
Multifunctionalized Cyclopentanes and Cyclohexanes
Synthesis of 3a and 4a under conditions A: To a dry
Schlenk tube, 2a (69.0 mg, 0.3 mmol), 1a (81.2 mg,
0.33 mmol), and DBU (4.6 mg, 10 mol%, 0.03 mmol) in ace-
tone (2.5 mL) were added sequentially. The reaction mixture
was allowed to stir under a nitrogen atmosphere at room
temperature. The reaction progress was monitored by TLC.
The solvent was removed under vacuum, and the residue
was purified by flash column (hexanes/ethyl acetate=5:1) to
afford compound 3a (yield: 47.1 mg, 33%) and 4a (yield:
88.5 mg, 62%), respectively.
Synthesis of 4j under conditions B: To a dry Schlenk
tube, 2a (69.0 mg, 0.3 mmol), 1j (101.0 mg, 0.33 mmol), and
t-BuOK (3.5 mg, 10 mol%, 0.03 mmol) in dry THF (2.5 mL)
were added sequentially. The reaction mixture was allowed
to stir under a nitrogen atmosphere at room temperature.
The reaction progress was monitored by TLC. The solvent
was removed under vacuum, and the residue was purified by
flash column (hexanes/ethyl acetate=5:1) to afford 4j;
yield: 148 mg (92%).
Supporting Information
Experimental details and copies of H/13C NMR spectra of
1
all new compounds are available as supporting information.
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