Organocatalytic hetero [4+2] cycloaddition reactions of 2-(1-alkynyl)-2-alkene-1-ones: Metal-free access to highly substituted 4H-pyrans

Article abstract of DOI:10.1039/c0ob00334d

Highly substituted 4H-pyrans can be smoothly synthesized from readily available 2-(1-alkynyl)-2-alkene-1-ones by DBU- or n-Bu₃P catalyzed hetero-[4+2] cycloaddition reactions, in which 2-(1-alkynyl)-2-alkene-1-ones act as both heterodiene and h

Full text of DOI:10.1039/c0ob00334d

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Organocatalytic hetero [4+2] cycloaddition reactions of 2-(1-alkynyl)-
2-alkene-1-ones: metal-free access to highly substituted 4H-pyrans†
Xiuzhao Yu,a Zhongyan Caoa and Junliang Zhang*a,b
Received 28th June 2010, Accepted 8th September 2010
DOI: 10.1039/c0ob00334d
Table 1 Screening reaction conditions for hetero-Diels–Alder reaction of
Highly substituted 4H-pyrans can be smoothly synthesized
from readily available 2-(1-alkynyl)-2-alkene-1-ones by DBU-
or n-Bu3P catalyzed hetero-[4+2] cycloaddition reactions, in
which 2-(1-alkynyl)-2-alkene-1-ones act as both heterodiene
and heterodinenophile.
1aa
The development of new tandem reactions for constructing highly
functionalized substituted pyrans from easily available acyclic
starting materials has been stimulated by their appearance in
many bioactive natural products and important pharmaceuticals
as well as useful building blocks in organic synthesis.1–3 Among
many strategies towards highly substituted pyrans,4 the hetero-
Diels–Alder reactions of a,b-unsaturated ketones (as heterodiene)
with electron-rich carbon–carbon unsaturated bonds (as hetero-
dienophiles) are considered as a straightforward method for the
synthesis of highly substituted 4H-pyrans.5 However, the alkynes
except ynamides6 are low reactive, which has limited their use
in the [4+2] cycloaddition reaction. In 2000, Trost reported a
ruthenium-catalyzed intramolecular [4+2] cycloaddition of yne-
enones leading to bicyclic 4H-pyrans.7 Very recently, Koyama
developed a nickel-catalyzed [4+2] cycloaddition of enones with
alkynes, which can provide highly substituted pyrans in good
yields.8 In the context of our ongoing effort to develop methods
towards heterocycles,9 we reported herein a novel organocatalytic
hetero-Diels–Alder of 2-(1-alkynyl)-2-alkene-1-ones10 leading to
full substituted multi-functionalized 4H-pyrans, in which the
enone moieties act as the heterodienes and the electron-deficient
alkyne moietes act as the heterodienophiles.
Entry
Base (mol%)c
Conditions
Yield (%)b
1
2
3
4
5
6
7
8
tBuOK (50)
K2CO3 (20)
KOH (20)
Et3N (20)
THF, 40 ◦C, 30 h
THF, 40 ◦C, 24 h
THF, 40 ◦C, 24 h
DMF, 40 ◦C, 24 h
DMF, 40 ◦C, 24 h
DMF, 40 ◦C, 48 h
DMF, 40 ◦C, 30 h
DMF, 40 ◦C, 6 h
DMF, 40 ◦C, 3 h
DMF, 0 ◦C, 11 h
DMF, 0 ◦C, 11 h
DMSO, 40 ◦C, 6 h
MeOH, 40 ◦C, 24 h
CH2Cl2, 40 ◦C, 48 h
Toluene, 40 ◦C, 12 h,
then 100 ◦C, 24 h
CH3CN, 40 ◦C, 9 h
DMA, 40 ◦C, 12 h
DMF, 100 ◦C, 24 h
48
Complicated
66
0
0
0
80
81
70
91
81
77
68
27
67
DABCO (20)
DMAP (20)
Cs2CO3 (20)
DBU (20)
DBU (50)
DBU (20)
DBU (10)
DBU (20)
DBU (20)
DBU (20)
DBU (20)
9
10
11
12
13
14
15
16
17
18
DBU (20)
DBU (20)
—
76
81
0
a The reactions were carried out by using 1a (0.5 mmol) in sol-
vent (2.5 mL). b Isolated yield. c DBU = 1.8-diazabicycl-[5.4.0]undec-
7-ene, DABCO = 1,4-diazabicyclo-[2.2.2.]-octane, DMAP = N, N-4-
dimethylaminopyridine.
During our study of the DBU-catalyzed nucleophilic addition
of nucleophiles to 2-(1-alkynyl)-2-alkene-1-ones,9f we happened
to find that poly-functionalized 4H-pyran 2a was formed when
occasionally mixing the base and electron-deficient 1,3-conjugated
yne-enone 1a without adding the nucleophiles. Then, a series of
reaction conditions were screened and the results were summarized
in Table 1. After some attempts, we were pleased to find that the
hetero-[4+2] cycloaddition reaction of 1a under DBU (20 mol%)
in DMF (2.5 mL) at 0 ◦C for 11 h afforded 91% yield of 2a
(Table 1, entry 10). Other inorganic bases such as tBuOK, K2CO3,
KOH and Cs2CO3 were tested and most of them except Cs2CO3
were less effective. No reaction occurred when Et3N, DABCO or
DMAP were used as catalyst (Table 1, entries 4–6). Solvent effect
was also studied (Table 1, entries 12–17). Lower catalyst loading
(10 mol%) results in a lower yield (Table 1, entry 11). The reaction
did not occur at 100 ◦C without the catalyst (Table 1, entry 18).
With the optimized conditions in hand, we determined the scope
of the electron-deficient conjugated yne-enones 1, and the results
were summarized in Table 2. Generally, introduction electron-
withdrawing groups to the conjugated yne-enones will increase
the reactivity and lead to high yields. For example, the reaction of
1c with an electron-withdrawing nitro group at para-position of
phenyl ring (R3) was consumed completely within 4 h to give 2c
in 91% yield, in contrast, only 60% yield of 2b could be obtained
from the corresponding 1b after 62 h (Table 2, entries 1 vs. 3).
The structure of 2b was further confirmed by single crystal X-ray
diffraction (Fig. 1).11 Introduction an electron-donating methoxy
group at para-position of R2 also decreased the reactivity, for
example, the cycloaddition of 1i gave 51% yield of 2i and 35% of
1i was recovered after 60 h under the catalysis of 20 mol% of DBU
(Table 2, entries 9 vs. 11). The reaction of aldehyde 1l was slow to
aShanghai Key Laboratory of Green Chemistry and Chemical Processes, De-
partment of Chemistry, East China Normal University, 3663 N, Zhongshan
Road, Shanghai 200062, P. R. China. E-mail: jlzhang@chem.ecnu.edu.cn;
Fax: (+86) 21-6223-5039
bState key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
† Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products. CCDC
reference numbers 738752. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00334d
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Table 2 Efficient synthesis of highly substituted functionalized 4H-
pyransa
Ketone 1
Entry
R1/R2/R3
Time/h
2 Yield (%)b
1
Ph/Ph/4-MeOC6H4 (1b)
1b
Ph/Ph/4-NO2Ph (1c)
Ph/Ph/n-C4H9 (1d)
4-ClC6H4/Ph/Ph (1e)
Me/Ph/Ph (1f)
Me/4-MeOC6H4/Ph (1g)
1g
Me/Ph/4-NO2C6H4 (1h)
Me/4-MeOC6H4/1-naphthyl (1i)
1i
62
22
4
2b (60)
2b (76)
2c (91)
2d (60)
2e (94)
2f (88)
2g (45d)
2g (82)
2h (80)
2i (51e)
2i (60)
2j (75)
2k (80)
2l (50)
2m (0)
2c
3
4c
4
5
2
15
38
60
22
1
60
22
60
3
6
7c
8
9
10c
11
12
13
14
Me/Ph/1-naphthyl (1j)
CO2Me/Ph/Ph(1k)
H/Ph/1-naphthyl (1l)
MeO/Ph/Ph (1m)
Scheme
1
Plausible mechanism of organocatalytic hetero [4+2]
60
96
cycloaddition.
a Unless otherwise specified, the reactions was carried out with enynes 1
(0.5 mmol) and DBU (20 mol%) at 0 ◦C in DMF (2.5–3 mL). b Isolated
yields. c 20 mol% of n-Bu3P was used instead of DBU and the reaction was
run at rt. d 37% of 1g was recovered. e 35% of 1i was recovered.
A plausible mechanism for this organocatalytic hetero-Diels–
Alder cycloaddition was depicted in Scheme 1. A nucleophlic
addition of the catalyst Nu (Nu = DBU or Bu3P) to conjugated
yne-enones 1 would produce zwitterionic intermediates with
three resonance structures, i.e., enolate A, propargylic carbanions
B and allenyl carbanions C. Subsequent Michael–addition of
allenyl carbanions C to another molecular of 1 would give new
zwitterionic intermediates also with three resonance structures,
i.e., allenyl carbanions D, propargylic carbanions E and enolates
F. Intramolecular nucleophlic substitutition (SN2¢) of interme-
diates F would produce the 4H-pyran products and regenerate
the catalyst.
give 2l in 50% yield. The ester 1m could not undergo hetero-[4+2]
reaction to give the corresponding cycloadduct. Interestingly, It
was found that n-Bu3P was a more effective catalyst than DBU
to give the corresponding products in higher yields. For example,
the reaction of 1g could not be complete after 60 h to give a 45%
yield under the catalysis of DBU (Table 2, entry 6), however, the
reaction proceeded smoothly to produce 2g in 82% yield in the
presence of 20 mol% of n-Bu3P (Table 2, entry 7).
Fig. 1 ORTEP representation of compound 2b.
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In conclusion, we have developed an organocatalytic hetero-
[4+2] cycloaddition reaction of readily available 2-(1-alkynyl)-2-
alkene-1-ones, which provided a general, efficient and metal-free
access to poly-functionalized 4H-pyrans in good yields under mild
conditions. The electron-deficient alkyne moiety of one molecular
of yne-enone plays the role of heterodinenophile component and
enone moiety of the other yne-enone plays the role of heterodiene
component. Studies on coupling of electron-deficient conjugated
yne-enones with other nucleophiles and electrophiles are ongoing
in this laboratory.
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Financial supports from the National Science Foundation
of China (20972054), the Ministry of Education of China
(20090076110007, NCET) and the Fundamental Research Funds
for the Central Universities are greatly appreciated.
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11 CCDC 738752 (2b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge form The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5059–5061 | 5061
©