Phosphine-catalyzed domino reaction for the synthesis of conjugated 2,3-dihydrofurans from allenoates and Nazarov reagents

Article abstract of DOI:10.1002/asia.201200140

A new domino reaction for Nazarov reagents: An efficient approach was developed for the construction of highly functionalized conjugated 2,3-dihydrofuran skeletons. Nazarov reagents were used for the first time in a phosphine-catalyzed domino reaction and successfully used to construct five-membered ring compounds using alcohol as the solvent. DFT calculations indicate that alcohol is essential for the catalysis of the [1,2]-proton transfer. Copyright

Full text of DOI:10.1002/asia.201200140

DOI: 10.1002/asia.201200140
Phosphine-Catalyzed Domino Reaction for the Synthesis of Conjugated 2,3-
Dihydrofurans from Allenoates and Nazarov Reagents
Peizhong Xie, Wenqing Lai, Zhishuai Geng, You Huang,* and Ruyu Chen[a]
The remarkable significance of 2,3-dihydrofurans and
their derivatives in chemical and biological research has mo-
tivated chemists to develop various approaches for their
construction.[1] In addition, functionalization of 2,3-dihydro-
furans often allows for further structural elaboration and
adornment.[1d] Recently, efforts have been made towards the
development of organocatalyzed domino processes,[2,3] such
as the [4+1],[2a–c] [3+2] annulation,[2d–h] multi-component
condensation.[2i,j] Nonetheless, a limited substrate scope, low
atom efficiency, and low diastereoselectivity often challenge
the above methods.[1,2a] Therefore, a facile new synthetic
method with high atom efficiency is still needed. In particu-
lar, methods for the synthesis of conjugated 2,3-dihydrofur-
ans, which constitute the core framework of an increasing
number of biologically active molecules (Scheme 1), have
rarely been reported.[4] These biologically active molecules
pose a significant synthetic challenge due to their structural
complexity and the need for a flexible and convergent
route.[5] Thus, the potential clinical significance of this scaf-
fold has led to a demand for efficient methods for their syn-
thesis. The presence of a C=C bond conjugated to an enol in
2,3-dihydrofurans increases the possibilities for their struc-
tural modulation and enhances their synthetic utility. There-
fore, a new synthetic method that allows an easy preparation
of such structures with high atom efficiency is highly desira-
ble.
The Nazarov reagent, which possesses nucleophilic carbon
and oxygen and an electronically poor C=C bond, has grad-
ually received attention from the organocatalytic community
for designing new domino processes.[6] A number of pioneer-
ing cycloaddition reactions involving the Nazarov reagent
have emerged (Scheme 2). Jørgensen and co-workers report-
Scheme 2. Comparison of organocatalyzed reactions with Nazarov re-
agents.
ed
a
tandem Michael/Morita–Baylis–Hillman reaction
(MBH) leading to the formation of cyclohexenone deriva-
tives.[6b] Gong et al. demonstrated that a C-5-substituted
Nazarov reagent was capable of directing the reaction to
a novel [3+3] cycloaddition.[6c] Recently, this group also re-
ported that, in the presence of a bifunctional catalyst, Naza-
rov reagents can be used for the construction of spiro[4-cy-
clohexeanone-1,3’-oxindoline] derivatives.[6a] The groups of
Deslongchamps and Takemoto independently incorporated
the Nazarov reagent into domino processes for the synthesis
of natural products.[6d–g] In recent years, phosphine-catalyzed
domino reactions[7] have become powerful tools for the
preparation of carbocycles and heterocycles.[8,9] However, so
Scheme 1. Natural products containing the conjugated 2,3-dihydrofuran
scaffold.
[a] P. Xie, W. Lai, Z. Geng, Prof. Dr. Y. Huang, Prof. Dr. R. Chen
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University
Tianjin 300071 (China)
Fax : (+86)22-23503627
E-mail: hyou@nankai.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200140.
Chem. Asian J. 2012, 00, 0 – 0
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Table 2. Scope of the domino reactions in the presence of phosphine.[a]
far phosphine-mediated reactions of Nazarov reagents have
not been reported. Based on the specific reactivity patterns
of the Nazarov reagent and our previous work on phos-
phine-catalyzed domino annulations,[10] we started to investi-
gate the reaction between allenoates and Nazarov reagents.
Herein, we report a phosphine-catalyzed domino reaction
for the efficient construction of conjugated 2,3-dihydrofuran
moieties.
We initiated our investigation by subjecting allenoate 2a
to Nazarov reagent 1a in the presence of PPh3 (100 mol%)
in toluene at room temperature. Only a trace amount of
product 3a was obtained (Table 1, entry 1). Screening of sol-
Entry
R1
R2
R3
R4
t [h]
Yield [%][b]
1
2
3
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Et
Et
Et
Et
Me
Et
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
24
24
25
19
15
24
10
29
20
15
24
32
32
30
24
24
86 (3a)
85 (3b)
59 (3c)
49 (3d)
60 (3e)
93 (3 f)
88 (3g)
76 (3h)
65 (3i)
63 (3j)
78 (3k)
62 (3l)
55 (3m)
36 (3n)
40 (3o)
56 (3p)
Me
Bn
Et
Me
Et
Me
Et
Me
Me
Me
Et
4[c]
5[c]
6
2-NO2C6H4 (1b)
2-NO2C6H4 (1b)
2,4-ClC6H3 (1c)
2,4-ClC6H3 (1c)
4-BrC6H4 (1d)
4-BrC6H4 (1d)
3-FC6H4 (1e)
4-MeC6H4 (1 f)
4-OMeC6H4 (1g)
4-OMeC6H4 (1g)
2,4-ClC6H3 (1c)
4-BrC6H4 (1d)
Me
7
8
9
Table 1. Screening of catalysts and conditions for the domino reaction.[a]
10[d]
11
12
13
14[e]
15[e]
16[f]
Bn
Et
Et
Entry
cat. [mol%]
Solvent
T [8C]
Yield [%][b]
Et
1
2
3
PPh3 (100)
PPh3 (100)
PPh3 (100)
PPh3 (100)
PPh3 (100)
PPh3 (100)
PPh3 (100)
PPh3 (50)
PPh3 (50)
PPh3 (30)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (15)
PPh3 (5)
Toluene
CH2Cl2
CH3CN
EtOH
EtOH
PriOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
rt
rt
rt
rt
rt
rt
rt
rt
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
trace
trace
trace
56
80
56
78
59
78
84
87
90
80
86
78
61
67
trace
[a] See the experimental section for details. [b] Isolated yields. [c] Z con-
figuration of the double bond in the Nazarov reagent. [d] Allenoate 2
was added dropwise to the solution over 1 h. [e] PACTHNUTRGNE(UNG p-ClC6H4)3 (20 mol%)
was used as catalyst. Trans/cis>95:5. [f] Hydroquinone (100 mol%) was
used as an additive, and PPh3 (20 mol%) was used as the catalyst.
4[c]
5
6
7
8
9
10
11
12[d]
13[e]
14[d]
15[d]
16[d]
17[d]
18[d]
Experiments that probed the generality of this domino re-
action were then performed under the optimized conditions.
As summarized in Table 2, this reaction displayed a broad
scope with regard to Nazarov reagents. The reaction had
a good tolerance of steric and electronic properties of sub-
stituents on the aromatic group. Even with the strong elec-
tron-withdrawing NO2 substituent (entries 4–5), the reaction
gave rise to the corresponding products in moderate yield.
By contrast, the steric property on allenoates 2 showed a re-
markable influence on the yield (entries 1–3). Notably, the
configuration of Nazarov reagents did not change during
this domino process (entries 4–5). In addition, the reaction
resulted in high stereoselectivity with slightly reduced yield
when g-substituted allenoates were used (entries 14–15)
which, due to their steric effect[8u–w] and versatile and lower
reactivity,[8,10a] have received less attention. Furthermore,
C5-methyl-substituted Nazarov reagents also delivered the
alkyl-substituted product 3p in moderate yield (entry 16).
This is particularly relevant to apply this strategy to the syn-
thesis of the aforementioned natural products.
To demonstrate the role of the solvent and gain insight
into the mechanism, a series of experiments were per-
formed. Our initial thought was that the transformation was
induced by H2O to catalyze the proton transfer.[8q,s,x] To ex-
plore this possibility, reactions in CD3OD and MeOH/D2O
(5:1) were carried out. In CD3OD, deuterated product 3a
was obtained in 67% yield with 60-90% incorporation of
deuterium at the a, b, and g-carbons (Scheme 3, top), while
only 19% of 3a was obtained (22% of 1a was recovered),
with 20-38% incorporation of deuterium at the a, b, and g-
PPh2Et (15)
PPhEt2 (15)
PBu3 (15)
[a] Reaction conditions: 1.0 equiv 1a (0.5 mmol), 1.5 equiv 2a in 2.0 mL
solvent. The reaction time was 24 h. [b] Isolated yields. [c] The reaction
time was 6 h. [d] Ratio of 1a/2a is 0.5. [e] Ratio of 1a/2a is 0.4.
vents revealed that the protic solvent EtOH worked best, af-
fording 3a in 80% yield (entry 5). The structure and stereo-
chemistry of 3 was determined by using NMR spectroscopy,
high-resolution mass spectrometry (HRMS), and single-crys-
tal X-ray analysis (3c).[11] When aprotic solvents such as
CH2Cl2 and CH3CN were used, no product or only traces of
product were observed (entries 2–3). The yield, to some
extent, was more sensitive to the temperature than the cata-
lyst loading. Increasing the reaction temperature resulted in
an improvement in yield (entries 8–9). Decreasing the
amounts of catalyst from 100 mol% to 15 mol% had little
effect on the yield (entries 10–14). Even with 5 mol% cata-
lyst loading, the reaction proceeded smoothly to give the de-
sired products (entry 15). The use of more nucleophilic
phosphines led to lower yields (entries 16–18), possibly be-
cause of a lower stability of the catalyst and polymerization
of the starting materials.
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Synthesis of Conjugated 2,3-Dihydrofurans from Allenoates and Nazarov Reagents
Scheme 3. Reactions performed to examine the role of the solvent.
carbons (Scheme 3, middle), when MeOH/D2O was used.
These results, to some extent, indicated that H2O inhibited
the reaction. In addition, as the pKa values of methanol
(pKa =15.5) and H2O (pKa =14) are similar, H–D exchange
between MeOH and H2O occurs, which could explain why
20–38% incorporation of deuterium took place in MeOH/
D2O. Furthermore, the conclusion that D2O disfavors the re-
action was supported by further experiments in which THF/
D2O (5:1) delivered trace amounts of 3a, while THF/
CH3OH (5:1) gave 3a in 16% yield (Scheme 3, bottom).
These results indicated that CD3OD is a better proton
donor than H2O in this reaction.
According to the experimental results and previous stud-
ies by Lu and co-workers,[12] we proposed the mechanism
outlined in Scheme 4a. To gain insight into the reaction
mechanism, the reaction was studied by means of DFT cal-
culations (Scheme 4b, see the Supporting Information for
details). All DFT calculations were performed with the
Gaussian 03 program package.[13a] The geometry optimiza-
tion of all the minima and transition states (TS) involved
Scheme 4. a) Possible mechanism. b) DFT computed surface energies of
were performed at the B3LYP levels of theory with the 6-
31+G(d) basis set used.[13b,c] The vibrational frequencies
were computed at the same level of theory to check whether
each optimized structure is an energy minimum or a transi-
tion state and to evaluate its zero-point vibrational energy
(ZPVE). In the proposed mechanism, the reaction is trig-
gered by nucleophilic addition of PPh3 to the allenoates,
producing the zwitterionic intermediate A.[7] Intermediate A
then deprotonates the Nazarov reagent 1a and this is fol-
lowed by umpolung addition[14] to generate zwitterionic in-
termediate B, which subsequently can be protonated to
form a new intermediate C. The intramolecular concerted
[1,2]-proton shift process (TS2’) is highly energy demanding
with a free energy of activation of 41.0 kcalmolÀ1. By con-
trast, protonation of ylide B (TS2) followed by ethanol-cata-
lyzed [1,2]-proton shift is much easier (20.7 kcalmolÀ1).
Though lower than that of the concerted [1,2]-proton shift,
the energy barrier is still so high that the reaction has to be
the main processes for the formation of 3 by a domino reaction.
conducted at a relatively high temperature (such as in etha-
nol under reflux conditions) and for a long reaction time.
After TS3 the ethanol-catalyzed [1,2]-proton shift is com-
pleted. Elimination of the catalyst from intermediate D
gives then umpolung adduct E.[14] Finally, a facile oxo-Mi-
chael addition affords the final product 3a. However, due to
the existence of an acidic proton (in the keto ester moiety)
in intermediate B, other potential reaction mechanisms
cannot be completely ruled out. For example, in alcohol as
the solvent, the intermediate B might be in rapid and rever-
sible equilibrium with the zwitterionic intermediate Bꢀ,
which can undergo SN2 substitution to give product 3a
(Scheme 5).
In summary, we have developed an efficient method for
the construction of highly substituted conjugated 2,3-dihy-
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You Huang et al.
COMMUNICATION
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Scheme 5. Another potential mechanism.
drofuran frameworks with high atom economy. Nazarov re-
agents were used for the first time in a phosphine-catalyzed
domino reaction and successfully used to construct five-
membered ring compounds. The DFT mechanistic study in-
dicates that the essential role of the alcohol is to catalyze
the [1,2]-proton transfer. Further efforts on the application
of this domino reaction in natural product synthesis and the
development of an asymmetric version are in progress.
Experimental Section
General information for the preparation of compounds 3: Nazarov re-
agent 1 (0.5 mmol, 1.00 equiv) and allenoate 2 (2.00 equiv) were dis-
solved in EtOH (2.0 mL). Subsequently, PPh3 (0.15 equiv) was added and
the reaction mixture was stirred at reflux. After complete conversion, as
indicated by TLC, all volatiles were removed in vacuo, and the residue
was purified by column chromatography (petroleum ether (60–90oC)/
ethyl acetate=10:1).
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Acknowledgements
This work was supported financially by the National Natural Science
Foundation of China (20972076, 21172115) and the Natural Science
Foundation of Tianjin (10JCYBJC04000). We also thank Prof. Jin Qu of
Nankai University for her help on the computation.
Keywords: allenoates · dihydrofurans · domino reactions ·
Nazarov reagent · phosphine
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Synthesis of Conjugated 2,3-Dihydrofurans from Allenoates and Nazarov Reagents
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[12] a) Y.-W. Sun, X.-Y. Guan, M. Shi, Org. Lett. 2010, 12, 5664; b) X. Y.
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[13] a) The DFT calculations were carried out by using the Gaussian 03
program (M. J. Frisch, et al. Gaussian 03, revision E.01, Gaussian,
Inc., Wallingford, CT, 2004). See Supporting Information for full ref-
erence; b) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; c) C. Lee, W.
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Sinisi, J. Sun, G. C. Fu, Proc. Natl. Acad. Sci. USA 2010, 107, 20652
and references therein.
[11] CCDC 819436 (3c) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Received: February 12, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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COMMUNICATION
Domino Reactions
Peizhong Xie, Wenqing Lai,
Zhishuai Geng, You Huang,*
Ruyu Chen
&&&& — &&&&
Phosphine-Catalyzed Domino Reac-
tion for the Synthesis of Conjugated
2,3-Dihydrofurans from Allenoates
and Nazarov Reagents
A new domino reaction for Nazarov
reagents: An efficient approach was
developed for the construction of
highly functionalized conjugated 2,3-
dihydrofuran skeletons. Nazarov
reagents were used for the first time in
a phosphine-catalyzed domino reaction
and successfully used to construct five-
membered ring compounds using alco-
hol as the solvent. DFT calculations
indicate that alcohol is essential for the
catalysis of the [1,2]-proton transfer.
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!