Highly selective synthesis of tetra-substituted furans and cyclopropenes: Copper(i)-catalyzed formal cycloadditions of internal aryl alkynes and diazoacetates

Article abstract of DOI:10.1039/c2ob26295a

A convenient Cu(i)-catalyzed cycloaddition of electron rich internal aryl alkynes and diazoacetates was discovered for the chemoselective and regioselective synthesis of tetra-substituted furans and cyclopropenes in moderate isolated yields (18-67%), and alkyne conversion (29-73%).

Full text of DOI:10.1039/c2ob26295a

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COMMUNICATION
Highly selective synthesis of tetra-substituted furans and cyclopropenes:
copper(I)-catalyzed formal cycloadditions of internal aryl alkynes and
diazoacetates†
Andrew K. Swenson,a Kate E. Higgins,a Matthew G. Brewer,a William W. Brennesselb and
Michael G. Coleman*a
Received 6th July 2012, Accepted 9th August 2012
DOI: 10.1039/c2ob26295a
group.15 It can be generalized, with some notable excep-
A convenient Cu(I)-catalyzed cycloaddition of electron rich
internal aryl alkynes and diazoacetates was discovered for
tions,4,9,16 that alkynes in the presence of highly electrophilic
diazoacetate compounds 1a undergo [3 + 2] cycloadditions to
yield tri-substituted furans 2a.1,2 On the other hand, alkynes and
highly selective donor–acceptor diazoacetate compounds 1b
exclusively undergo [2 + 1] cycloaddition reactions to afford
the chemoselective and regioselective synthesis of tetra-
substituted furans and cyclopropenes in moderate isolated
yields (18–67%), and alkyne conversion (29–73%).
1,3,3-trisubstituted
cyclopropene
compounds
2b
(Scheme 1).6,10,17
Unlike terminal alkynes, reports of internal alkynes indicate
that they are less reactive partners. Experimental and compu-
tational evidence suggests that internal alkynes are ineffective
substrates for rhodium-catalyzed cyclopropenation due to their
sterically hindered approach to the carbenoid center.6,10 The pio-
neering work of Davies and co-workers discovered that silver
carbenoids, which are more reactive than traditional rhodium
carbenoids, efficiently catalyzed the cyclopropenation of internal
alkynes in the presence of aryldiazoacetates 1b to form tetra-
substituted cyclopropene compounds 3 in excellent overall yields
(64–98%) (Scheme 2).8 This was the first research report where
internal alkyne substrates underwent a carbenoid cycloaddition
reaction. Furthermore, unlike Rh2(OAc)4, the AgSbF6-catalyzed
cyclopropanation of trans-substituted alkenes afford highly dia-
Introduction
Alkynes are a valuable class of hydrocarbons for transition
metal-catalyzed carbenoid cycloadditions due to their synthetic
versatility to undergo highly selective transformations into
furans,1–3 indenes,4 dihydroazulenes,5 cyclopentadienes,6,7 and
cyclopropene compounds.5,8–11 The diversity of these cyclo-
adducts contain structural features that are found in a wide range
of natural products, and therefore, are useful synthetic building
blocks in agricultural, pharmaceutical, and material science
applications.12,13 Despite the fact that many metal carbenoid
cycloaddition methods are known for terminal alkynes, the lack
of synthetic procedures developed for internal alkynes still
remains a significant limitation.
Several decades of transition-metal carbenoid research suggest
that the judicious choice of reactant partners is crucial for develo-
ping selective and efficient two-component cycloaddition reac-
tions.14 One major finding is that the divergence in
chemoselectivity of the cycloaddition of acetylenic compounds
depends largely on the electronic nature of the carbenoid struc-
ture. As a result, metal carbenoids are classified as (1) acceptor–
acceptor diazoacetates that contain two electron withdrawing
groups; (2) acceptor-only diazoacetates that contain a single elec-
tron-withdrawing group; and (3) donor–acceptor diazoacetates
that contain an electron-donating and electron-withdrawing
stereoselective cyclopropane
4 in high diastereoselectivity
(Scheme 2).18 Very recently, it was reported that chiral cationic
gold complexes, activated by silver metal, catalyzed the asym-
metric cyclopropenation of internal alkynes in high yields and
enantioselectivities.19
Still, steric and electronic influences on the metal carbenoid
are not the only consideration. The coupling partner also plays a
aDepartment of Chemistry, Rochester Institute of Technology, Rochester,
NY 14623, USA. E-mail: mgcsch@rit.edu
bDepartment of Chemistry, University of Rochester, Rochester, NY
14627, USA
†Electronic supplementary information (ESI) available. CCDC
889654–889658. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ob26295a
Scheme 1
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Table 1 Screen of transition-metal salts for the [3 + 2] metal carbenoid
cycloadditiona
Entry Catalyst
Solvent
Yieldb (%) Conversionc (%)
1
2
3
4
5
6
Pd(OAc)2
CuTHC
CuBr
Cu(CH3CN)4BF4 CH2Cl2
Cu(CH3CN)OTf
CuI
CuI
CuI
CuI
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
0
0
1.9
—
—
—
—
—
6.4
8.9
50
61
61
22
13
CH2Cl2
CH2Cl2
CH3CN 5.4
PhCH3
Neat
Neat
7d
8d
9e
10
11
12
47
50
48
17
5.9
Scheme 2
CuNHC
Rh2(OAc)2
—
Neat
Neat
significant role on the overall reactivity and selectivity of the car-
benoid cycloaddition. Electron-rich trans-1,2-disubstituted 5a,
and even tri-substituted alkenes 5b, in the presence of aryl-
diazoacetates 1b afforded highly chemo- and stereoselective
cyclopropane compounds 6a and 6b when catalyzed by the
sterically demanding Rh2(S-DOSP)4 catalyst (Scheme 2).20
Similar findings were observed for the Rh2(OAc)4-catalyzed
[3 + 2] cycloaddition of terminal alkynes, where increasing the
electron density of the alkyne, was credited for improving the
chemoselectivity from the formation of cyclopropene products to
exclusively tri-substituted furans.1 Chang and co-workers dis-
covered that electron-donating groups on phenyl acetylenes react
more readily with 1b, than the electron-deficient alkynes.4 In
this communication, we wish to report the copper(I)-catalyzed
cycloaddition of electron-rich internal alkynes for the chemo-
and regioselective construction of tetra-substituted furans and
cyclopropene compounds.
a Reaction conditions: 2.1 mmol (0.41 M) of 7 and 6.2 mmol (1.2 M) of
1a used in 5 mL of solvent. b Isolated yield. c Based on recovered 7.
d 16 mmol (3.1 M) of 1a, 48 h. e 13 mmol of 1a, 110 °C CuTHC: Cu(I)-
thiophene-2-carboxylate. CuNHC: chloro[1,3-bis(2,6-di-i-propylphenyl)-
imidazol-2-ylidene]Cu(I).
Results and discussion
To the best of our knowledge, there are no known reports illus-
trating the transition-metal catalyzed [3 + 2] cycloaddition of
internal alkynes and diazoacetate compounds for the formation
of tetra-substituted furans. We considered this to be an excellent
starting point to begin our investigation of electron-rich 1-(p-
CH3O)phenylprop-1-yne 7 and acceptor–acceptor diazoacetate
1a in the presence of various transition metals (Table 1).
We determined that palladium(II) and various copper(I) salts
were ineffective and 8a was not observed by H NMR (entries
1
Fig. 1 Crystal structure of 8a.
1–5). However, copper iodide indicated more effectiveness by
increasing the temperatures, equivalents of 1a, and reaction time
to afford 8a in low to modest yields (1.9%–47%, entries 6–8).
X-ray crystallographic analysis of 8a unambiguously confirmed
the structure (see ESI†) (Fig. 1).
Overall, the reaction is highly selective with no cyclopropene
or regioisomers observed by crude 1H NMR. In all instances, the
acetyl group of the diazoacetate 1a is responsible for ring
closure. Conducting the reaction neat reduced the equivalents of
diazoacetate needed without sacrificing the yield or selectivity
(entry 9). Equivalent findings were observed when the copper(I)
N-heterocyclic carbene chloride catalyst was used (48% yield,
entry 10). Dirhodium(II) acetate, a benchmark catalyst in metal
carbenoid chemistry, was found to be less effective (17% yield,
entry 11). In the absence of catalyst, a thermally induced back-
ground reaction was determined to be relatively low (5.9% yield,
entry 12).
With the best reaction conditions in hand, we then tested the
functional group tolerance of the newly developed Cu(I)-cata-
lyzed [3 + 2] cycloaddition of internal alkynes (Table 2).
First, electron neutral alkyne 9 was found to yield furan
product 16a as a 5 : 1 regioisomeric mixture in poor yield (8.5%,
7484 | Org. Biomol. Chem., 2012, 10, 7483–7486
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Table 2 Cu(I)-catalyzed [3 + 2] cycloaddition of internal alkynesa
Table 3 Role of the diazoacetate on the chemoselectivity of metal
carbenoid cycloadditions
Yieldb Conversionc
Product (%) (%)
Yielda Conversionb
Entry Alkyne R1
R2
Entry Diazo R1
R2
Ph
Product (%)
(%)
1d
2
3
9
10
11
H
CH3
16a
17a
9
19
38
n.d.
35
59
1
1b
1c
1d
1b
1b
CH3
23b
59
23
23
67
46
65
23
23
73
49
2-OCH3 CH3
2
OCH3 CO2CH3 23c
4-OCH3 CH2OSi(CH3)2- 18a
(t-Bu)
3
OCH3 CF3
CH3
CH3
23d
24b
24b
4c
5d
Ph
Ph
4
5
6
7
12
13
14
15
4-OCH3 CH2OCO2CH3 19a
24
19
19
39
35
29
32
58
4-OCH3 CH2O2CCH3
4-OCH3 Si(CH3)3
4-OPh CH3
20a
21a
22a
a Isolated yield. b Based on recovered alkyne. c Alkyne 10 was used.
d Alkyne 14 was used.
a Reaction conditions: 2.1 mmol of 7 and 13 mmol of 1a. b Isolated
yield. c Based on recovered alkyne. d 5 : 1 mixture of regioisomers
determined by 1H NMR. n.d = not determined.
Fig. 3 Crystal structure of 25b.
Fig. 2 X-ray structure of 21a.
In order to test the role of the diazoacetate on the chemoselec-
tivity of the metal carbenoid cycloaddition, 7 was subjected to
various diazoacetate compounds (Table 3).
entry 1). The crude reaction mixture was complex and no alkyne
was recovered. It is thought that the presence of the para-
methoxy group stabilizes the dipolar transition states. Reaction
with sterically demanding ortho-substituted alkyne 10 was also
an effective substrate albeit in low yield (19%, entry 2). The
scope of the Cu(I)-catalyzed [3 + 2] cycloaddition was further
explored with alkynes containing methylene site capable of C–H
insertion. In all cases, the internal alkynes 11–13 were converted
to the corresponding tetra-substituted furans (entries 3–5).
Internal alkyne containing a trimethylsilyl group 14 was also
effective for the synthesis of silyl-substituted furan product 21a
(19% yield, entry 6, Fig. 2). The former result is particularly
useful building block for organic synthesis due to the important
role of silicon in the substitution of furans.12 Diphenyl ether
methyl acetylene 15 was also an effective substrate for this
chemistry (39% yield, entry 7).
The copper(I)-catalyzed cyclopropenation of donor–acceptor
substituted diazoacetate 1b and internal alkyne 7 afforded cyclo-
propene 23b in good yield (59%). It well established that donor–
acceptor diazoacetates are highly chemoselective for cycloprope-
nation and no furan products were observed. The reaction of
acceptor–acceptor substituted diazomalonate 1c and 7 afforded
tetra-substituted furan 23c in 23% yield. Trifluoromethyl diazoa-
cetate 1d was equally effective yielding exclusively furan
product 23d as a single regioisomer (23%, entries 3). Moreover,
the copper(I)-catalyzed [2 + 1] cycloaddition of 1b in the pres-
ence of alkyne 10 gave the corresponding cyclopropene 24b in
67% yield, while alkyne 14 was converted to the 1-silylcyclo-
propene product 25b (46% yield, Fig. 3) (see ESI†).
1-Silylcyclopropene product 25b is an attractive building
block for organic synthesis.21 The analogous Ag(OTf)-catalyzed
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7483–7486 | 7485

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9 X. Cui, X. Xu, H. Lu, S. Zhu, L. Wojtas and X. P. Zhang, Enantioselec-
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cyclopropenation of 1-TMS-2-phenylethyne and 1b is ineffective
due to the formation of insoluble silver acetylide salts.8
In conclusion, we have demonstrated the first examples of
Cu(I)-catalyzed [3 + 2] cycloaddition reactions of internal
alkynes and acceptor–acceptor diazoacetates to afford highly
chemo- and regioselective tetra-substituted furan products. It was
also discovered that copper(I) iodide is an efficient catalyst for
the cyclopropenation of internal alkynes and donor–acceptor
diazoacetates. Although the overall conversion of the internal
alkynes to the corresponding cycloadduct products was relatively
modest (29–73%), it is thought that the simple recovery of
internal alkyne starting material, reduced reaction times, and
ease of purification suggests that this approach is promising.
Aims to increase the overall yields and expand the scope of elec-
tron-rich internal alkyne substrates are currently underway.
Acknowledgements
We would like to thank the Rochester Institute of Technology
Office of the Vice President of Research, College of Science,
and School of Chemistry and Materials Sciences for their gener-
ous financial support.
12 B. A. Keay, Synthesis of multi-substituted furan rings: the role of silicon,
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Org. Biomol. Chem., 2006, 4(11), 2076–2080; H. N. C. Wong,
X.-L. Hou, K.-S. Yeung and H. Huang, Five-membered heterocycles:
furan, Mod. Heterocycl. Chem., 2011, 1, 533–592; J. Salaun and
M. S. Baird, Biologically active cyclopropanes and cyclopropenes, Curr.
Med. Chem., 1995, 2(1), 511–542; J. W. Huffman and L. W. Padgett,
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14 M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic Methods for
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15 H. M. L. Davies and R. E. J. Beckwith, Catalytic enantioselective C–H
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16 F. Gonzalez-Bobes, M. D. B. Fenster, S. Kiau, L. Kolla, S. Kolotuchin
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