Pd(ii)-catalyzed formal [4+1] cycloaddition reactions of diazoacetates and aryl propargyl alcohols to form 2,5-dihydrofurans

Article abstract of DOI:10.1039/c5cc05000f

A Pd(ii)-catalyzed formal [4+1] cycloaddition of aryl diazoacetates and aryl propargyl alcohols is reported to afford 2,5-dihydrofuran derivatives as the dominant product over other traditional ones. The auto-tandem catalytic process is proposed to occur via Pd(ii)-catalyzed intermolecular oxonium ylide formation and subsequent intramolecular trapping of the ylide with Pd(ii)-activated alkynes.

Full text of DOI:10.1039/c5cc05000f

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Pd(II)-Catalyzed Formal [4+1] Cycloadditions of Diazoacetates and
Aryl Propargyl Alcohols to Form 2, 5-Dihydrofurans
Taoda Shi,†a Xin Guo,†a Shenghan Teng a and Wenhao Hu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A Pd(II)-catalyzed formal [4+1] cycloaddition of aryl diazoacetates stepwise Rh(II)-catalyzed O−H inserꢀon/ZnCl2-catalyzed Conia-
and aryl propargyl alcohols is reported to afford 2,5-dihydrofuran ene cyclization sequence.8 Up to now, electrophiles such as
derivatives as the dominant product over other traditional ones. imines, aldehydes, ketones, α, β-unsaturated ketoesters, and
The auto-tandem catalytic process is proposed to occur via Pd(II)- diazenes have been successfully utilized to trap protic oxonium
catalyzed intermolecular oxonium ylide formation and subsequent ylides.9 However, alkynes, as building blocks or versatile
intramolecular trapping of the ylide with Pd(II)-activated alkynes.
intermediates for compounds with value in biochemistry and
material sciences10 have not yet been explored to trap these
ylides. Inspired by the versatility of palladium catalyst in ylide
formation and alkyne activation, we hypothesized that the
trapping of oxonium ylide with alkynes would be realized with
diazoacetates and propargyl alcohols catalyzed by a proper
transition metal catalyst with both ylide-generating and π-
bond activating properties (Scheme 1). Herein we present our
findings.
The development of new chemical strategies for rapid access
to complex structures is an important goal for organic
chemists. Auto-tandem catalysis, in which two or more
mechanistically distinct reactions are promoted by a single
catalyst, has the advantages of atom economy, operational
simplicity, catalyst and process efficiency.1
Palladium is a versatile transition metal with intriguing
reactivity towards various functional groups. For example,
palladium(II) salts have been shown to efficiently activate
alkynes for the intramolecular addition of enolate-type
nucleophiles to construct carbo- or heterocycles.2 They have
also drawn growing attention in carbenoid chemistry such as
cross-coupling reactions3, X-H insertions4 and ylide-trapping
processes.5
N2
R1
CO2R2
R3
1
R1
MLn
CO2R2
MLn
R3
R1
R2O2C
+
O
O
H
R3
3
OH
2
Scheme 1 Concept of transition metal-catalyzed trapping of oxonium ylide with alkynes.
Transition metal-catalyzed reactions of diazo compounds
and propargyl alcohols or homopropargyl alcohols have been
studied by several groups (Scheme 1). Wood and co-workers
reported that diazoketones and propargyl alcohols underwent
[2, 3]- or [3, 3]-sigmatropic rearrangement depending on the
Rh(II) catalyst of choice.6 Davies et al. reported that
rhodium(II)-catalyzed reactions of tertiary propargyl alcohols
with methyl aryl/styryldiazoacetates result in tandem
reactions, consisting of oxonium ylide formation followed by
[2, 3]-sigmatropic rearrangement.7 Recently, Hatakeyama et al.
reported a formal [4+1]-cycloaddition of homopropargylic
alcohols with diazodicarbonyl compounds, which involves
Proof of principle studies were carried out with phenyl
diazoacetate 1a and phenyl propargyl alcohol 2a as substrates
for reactions in dichloromethane at room temperature. A
series of transition metal catalysts were screened. Besides the
traditional 2, 3-sigmatropic rearrangement product 4a6, 7, O-H
insertion product 5a, and cyclopropene 6a, a new 2, 5-
dihydrofuran derivative 3a, which was not reported before,
was also observed in most cases. The product distribution
varied with the use of different catalysts. The O−H inserꢀon
product 5a was the only product with Rh2(OAc)4 as the
catalyst, which is consistent with the results reported by
Davies (Table 1, Entry 1).7 When the reaction was catalyzed
with copper(I) salts with non-coordinating anions (Table 1,
Entry 2 and Entry 3), the ratio of the cycloaddition product 3a
and 2, 3-sigmatropic rearrangement product 4a increased.
However, 5a was dominant when the reaction was catalyzed
a.Institute of Drug Discovery and Development, East China Normal University,
Shanghai Engineering Research Centre for Molecular Therapeutics and New Drug
Development, Shanghai, 200062 (China).
b.Department of Chemistry, East China Normal University, Shanghai
，
200062.
† The authors contributed equally. Electronic Supplementary Information (ESI)
available: Experimental procedures and spectra data for compounds 3a 3t 4a
and . See DOI: 10.1039/x0xx00000x
-
,
- 6a
7- 9
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by CuCl or CuI (Table 1, Entries 4 and 5), which was used to catalyze
a
formal
Table 1 Development of transition metal-catalyzed [4+1] cycloaddition protocol.
Ph
N2
CO2Me
O
Ph
Ph
Ph
CO2Me
1a
O
Ph
CO2Me
3a
Ph
5a
Metal catalyst (x mol%)
DCM, rt
+
+
Ph CO2Me
OH
Ph
CO2Me
Ph OH
OH
Ph
2a
4a
6a
Entry
M (x mol%)
3a: 4a: 5a: 6aa
Conversiona(%)
Yield of 3ab(%)
1
2
[Rh2 (OAc) 4] (1)
Cu(OTf)2 (10)
0: 0: 100: 0
50: 30: 5: 15
32:36: 32: 0
11: 5: 84: 0
0: 0: 100: 0
-
100
100
100
100
100
<5
-
50
28
-
3
Cu(CH3CN)4PF6 (10)
CuCl (10)
4
5c
CuI (10)
-
6d
CuI(10)/phenanthroline(10)
AgOTf (10)
-
7
13: 12: 49:26
30: 8: 32: 30
-
100
100
<5
10
25
-
8
AgSbF6 (10)
9
AuCl3 (2)
10
11
12
13
14
15
16
17
18e
19f
20g
[{Ir(cod)Cl}2] (2)
PdCl2 (5)
-
<5
-
10: 10: 80: 0
-
100
<5
-
Pd(PPh3)2Cl2 (5)
Pd(CH3CN)2Cl2 (5)
Pd(OAc)2(5)
-
19: 72: 0: 9
13:50:38:0
0: 0: 100: 0
65: 5:30: 0
63: 6 :31: 0
79: 7 : 14: 0
0: 0: 100: 0
0: 0: 100: 0
100
100
32
15
9
Pd(OAc)2(10)/Et3N(50)
[{PdCl(ŋ3-C3H5)}2] (5)
[{PdCl(ŋ3-C3H5)}2] (2)
[{PdCl(ŋ3-C3H5)}2] (2)
[{PdCl(ŋ3-C3H5)}2] (2)
[{PdCl(ŋ3-C3H5)}2] (2)
-
100
100
100
100
100
60
60
70
-
-
a Determined by crude HNMR of the reaction mixture. b Isolated yield after column chromatography. c The reaction was performed in DCE at 90℃. d The reaction was
performed in DCE at 80℃. e 200mg of activated 4A molecular sieves was added. f The reaction was performed in DCM at 40℃. f The reaction was performed in DCE at
60 .
[4+1] cycloaddition between diazoacetates and α, β-acetylenic observed as the dominant product (Table 1, entrie 19 and 20).
ketones to form trisubstituted furans11. Catalyzed by Cu(I) or Hence, the optimal condition for the cyclization reactions was
Pd(II) complex with phenanthroline12, PPh3 or Et3N13 as ligands with 2 mol% of [PdCl(ŋ3-C3H5)]2 as catalyst, dichloromethane
or additives, only the dimer of 1a was observed (Table 1, Entry as solvent, and 4A molecular sieves as an additive.
6). Meanwhile, the 2, 3-sigmatropic rearrangement product 4a
With the optimized conditions, the substrate scope was
was more favoured when Pd(CH3CN)2Cl2 was used (Table 1, examined. As illustrated in Table 2, the aryl diazoacetates gave
Entry 13). In contrast, in Davies’s result, similar products were corresponding 2, 5-dihydrofurans in good yields (Table2,
only obtained with secondary and tertiary propargylic alcohols, entries 1-8). However, only dimers and O-H insertion products
indicating that Pd(CH3CN)2Cl2-associated oxonium ylide is more were observed with EDA and diazo ketones. Then, the scope of
electronically favourable for 2, 3-sigmatropic rearrangement substituted aryl propargyl alcohols was examined with the
than Rh(II)-associated oxonium ylide. The cyclopropenation reaction of diazoesters 1h (Table 2, entries 9-14) and 1a (Table
product 6a could be observed only in four cases with a lower 2, entries 15-20), and significant substitution effect was
ratio than the total amount of the other products (Table 1, observed. While the aryl propargyl alcohols bearing halides or
entries 2, 7, 8 and 9), indicating that the formation of the electron-donating substituents afforded moderate to good
oxonium ylide via reaction of the hydroxyl moiety with metal yields of the cyclization products (Table 2, entries 12-17), only
carbenes is more favourable.13 We were pleased to find that O-H insertion product was observed when aryl propargyl
[PdCl(ŋ3-C3H5)]2 turned out to be the optimal catalyst for the alcohols bearing an electron-withdrawing group such as NO2
formal [4+1] cycloaddition product 3a (Table 1, entry 16). The were used. Instead of cycloaddition products, O-H insertion
catalyst loading could be lowered to 2 mol% without products and dimers of the diazoesters were dominant for
decreased ratio of 3a (Table 1, entry 17), and the yield could propargyl alcohols (R3 = Methyl, H, CO2Bn), tertiary propargyl
be increased to 70% when 4A molecular sieves was added alcohols and homopropargyl alcohols.
(Table 1, entry 18). When the reaction was performed at
higher temperatures, the O-H insertion product 5a was
2 | J. Name., 2012, 00, 1-3
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Table 2 Substrate scope of the diazoacetates and propargyl alcohols.a
N2
AgSbF6(10 mol%)
Ph
CO2Me
1a
[PdCl(η3-C3H5)] 2 (2 mol%)
t-BuBox (4 mol%)
[Ir(COD)Cl]2 (5 mol%)
Ph
Ph CO2Me
R-BINAP (5 mol%)
R1
CO2R2
N2
R3
CO2Me
Ph OH
DCM, 4AMS, rt
+
DCM, 4AMS, rt
R3
OH
[Pd(Allyl)Cl]2(2mol%)
+
Ph
Ph
R1
CO2R2
O
OH
4a
OH
DCM, 4AMS, rt
6a
Yield=54%, ee=0
2a
2
1
3
Yield=70%, ee=0
EntEntry
R1
R2
R3
Yield
(%)b
Scheme 2 Control of the reaction of 1a and 2a towards 2,3-sigmatropic rearrangement
or cyclopropenation.
1
2
3
4
5
6
Ph
MeO
MeO
MeO
MeO
MeO
MeO
Ph
Ph
Ph
Ph
Ph
Ph
70
60
54
69
72
74
2, 5-Dihydrofurans are synthetically and biologically
interesting structural motif.14 To demonstrate the synthetic
value of the 2, 5-hydrofurans, 3a was easily transformed into
P-Br-C6H4
m-Cl-C6H4
P-Cl-C6H4
p-MeO-C6H4
3, 4-(MeO)2-
C6H3
the corresponding alcohol 7a, acid 8a and furan-2-ketone 9a15
,
with 54%, 89%, and 78% yield respectively (Scheme 3). The
structure of 8a was unambiguously confirmed by X-ray
crystallographic analysis (Figure 1).16
7
3, 4, 5-(MeO)3-
C6H2
MeO
Ph
78
Ph
Ph
Ph
8
9
Ph
BnO
Ph
59
58
PCC (2.0 eq)
KOAc (2.0 eq)
LiAlH4 (2.0 eq)
THF, reflux
Ph
3, 4, 5-(MeO)3-
C6H2
MeO
p-Br-C6H4
m-Br-C6H4
p-Me-C6H4
m-Me-C6H4
p-Cl-C6H4
Ph
CO2Me
Ph
OH
O
(CH2Cl)2, reflux
O
O
O
CO2Me
7a 54%
3a
9a 89%
10
11
12
13
14
3, 4, 5-(MeO)3-
C6H2
MeO
MeO
MeO
MeO
MeO
54
62
63
58
51
THF/H2O
= 1/1
LiOH (aq)
3, 4, 5-(MeO)3-
C6H2
3, 4, 5-(MeO)3-
C6H2
Ph
Ph
O
3, 4, 5-(MeO)3-
C6H2
CO2H
8a 78%
3, 4, 5-(MeO)3-
C6H2
3, 5-(Me)2-
C6H4
Scheme 3 Derivation of the [4+1] cycloaddition product 3a.
15
16
17
18
19
20
Ph
MeO
MeO
MeO
MeO
MeO
MeO
p-MeO-C6H4
p-Me-C6H4
m-Me-C6H4
p-Br-C6H4
p-Cl-C6H4
m-Br-C6H4
64
60
61
50
55
52
Ph
Ph
Ph
Ph
Ph
a Standard reaction conditions: 1 (0.3mmol, 1.5equiv) in dichloromethane (4 mL)
was added to a solution of 2(0.2mmol, 1.0 equiv), [PdCl(ŋ3-C3H5)]2 (0.004mmol,
2mol %) in dichloromethane (8 mL) over 1 h at rt. bIsolated yield after column
chromatography.
Fig 1 ORTEP illustration of 8a·H2O.
Ph
O
CO2Me
[Pd(Allyl)Cl]2(2mol%)
Ph
In our initial effort for asymmetric catalysis, we found that
the 2, 3-sigmatropic rearrangement product 4a was isolated as
the dominant product when the catalyst combination of
[PdCl(ŋ3-C3H5)]2 and t-BuBox was used, although no
enantioselectivity was observed. It’s complementary to Davies’
method, which is not effective for primary alcohols (Scheme 2).
However, the cyclopropenation product 6a was dominant
when the catalyst combination of [Ir(COD)Cl], AgSbF6 and
BINAP was used, indicating that the reaction of the Ir(I)
carbenoid with the internal alkyne moiety is more favourable
than with the hydroxy group in the ylide-forming process,
which is present in the other three reaction pathways. Thus,
control of chemoselectivity toward each of the four reaction
pathways could be realized with the choice of a specific
catalytic system.
Ph
Ph
CO2Me
O
X
DCM, 4AMS, rt
3a
Ph
5a
Ph CO2Me
[Pd(Allyl)Cl]2(2mol%)
CO2Me
Ph
Ph
X
OH
O
Ph
DCM, 4AMS, rt
3a
Ph
6a
Ph
[Pd(Allyl)Cl]2(2mol%)
CO2Me
X
CO2Me
O
DCM, 4AMS, rt
Ph OH
3a
4a
Scheme 4 Control reactions.
In order to investigate the reaction pathway of the Pd(II)-
catalyzed formal [4+1] cyclization, several control reactions
were conducted (Scheme 4). Compounds 4a, 5a, and 6a were
isolated and each subjected to the standard reaction
conditions catalyzed by [PdCl(ŋ3-C3H5)]2. As a result, the
cyclization product 3a was not detected, excluding the
formation of 3a from 4a, 5a or 6a. A plausible mechanism was
proposed as shown in Scheme 5. Diazoacetate 1a was
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decomposed by [PdCl(ŋ3-C3H5)]2, forming palladium carbenoid
A1. The palladium-associated oxonium ylide A2, which is in
equilibrium with palladium enolate A3, was formed in situ from
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W. C. MacMillan, Synlett 2007, 1477.
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G. Balme, D. Bouyssi and N. Monteiro, Palladium-
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A1 and propargyl alcohol 2a. A2 or A3 led to 3a via a proposed
migratory insertion of the activated C≡C triple bond into the
Pd(II)-C bond. 4a and 5a were also formed from oxonium ylide
A2 via 2, 3-σ-rearrangement and 1, 2-proton shift, while 6a was
formed from A1 and 2a via cyclopropenation. The formation of
A2 is more favourable than 6a due to the high electrophilic
character of the carbene carbon that favors the hydroxyl
attack.
3
Ph
Ph
N2
CO2Me
Ph
CO2Me
O
[{PdCl(allyl)}2]
1a
3a
Cl
Ph
Pd
Ph
Cl
Pd
CO2Me
Ph CO2Me
OH
Ph
CO2Me
Ph
A1
OH
4
OH
Ph
6a
cyclopropenation
2a
migratory insertion
Ph
Cl
O
Ph
Cl
Pd
Pd
Ph
MeO
Ph
5
6
7
O
H
MeO2C
O
A3
H
A2
Pd(II)-associated oxonium ylide
1, 2-H shift
Ph
Z. Li, V. Boyarskikh, J. H. Hansen, J. Autschbach, D. G.
Musaev and H. M. L. Davies, J. Am. Chem. Soc. 2012,
134, 15497.
F. Urabe, S. Miyamoto, K. Takahashi, J. Ishihara and S.
Hatakeyama, Org. Lett., 2014, 16, 1004.
X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427.
2,3 -σ-rearrangement
HO
Ph
8
9
Ph
CO2Me
O
Ph
CO2Me
10 F. Dénès, A. Pérez-Luna and F. Chemla, Chem. Rev.
2010, 110, 2366; X. Zeng, Chem. Rev., 2013, 113, 6864;
5a
4a
R. Chinchilla and C. Nájera, Chem. Rev. 2014, 114
1783.
,
Scheme 5 Proposed mechanism of the [4+1] cycloaddition.
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Liang, J. Org. Chem. 2007, 72, 10276.
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In conclusion, we have developed a Pd(II)-catalyzed formal
[4+1] cyclization of diazoacetates and aryl propargyl alcohols,
furnishing 2, 5-dihydrofuran derivatives as the dominant
product over those from other traditional reaction pathways.
This is the first example of trapping of oxonium ylides with
alkynes. In this auto-tandem catalytic process, the Pd(II)
catalyst not only catalyzed the formation of the protic
oxonium ylide, but also activated the alkyne moiety to trap the
highly active intermediate.
We are grateful for financial support from NSFC (21125209
and 21332003), the Ministry of Science and Technology
(MOST) of China (2011CB808600), STCSM of Shanghai
(12JC1403800).
16 CCDC
crystallographic data for 8a
obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1035999
contains
the
supplementary
.
These data can be
Notes and references
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1001; J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C.
,
,
,
4 | J. Name., 2012, 00, 1-3
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