Copper-catalyzed intramolecular alkene carboetherification: Synthesis of fused-ring and bridged-ring tetrahydrofurans

Article abstract of DOI:10.1021/ja3034075

Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C-H functionalization provides the C-C bond. Mechanistic studies indicate a primary carbon radical intermediate is involved and radical addition to the aryl ring is the likely C-C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was also developed.

Full text of DOI:10.1021/ja3034075

Article
pubs.acs.org/JACS
Copper-Catalyzed Intramolecular Alkene Carboetherification:
Synthesis of Fused-Ring and Bridged-Ring Tetrahydrofurans
Yan Miller, Lei Miao, Azade S. Hosseini, and Sherry R. Chemler*
Department of Chemistry, The State University of New York at Buffalo, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a
number of natural products and biologically active compounds. A new copper-
catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic
tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intra-
molecular addition of alcohols to unactivated alkenes and subsequent aryl C−H
functionalization provides the C−C bond. Mechanistic studies indicate a primary
carbon radical intermediate is involved and radical addition to the aryl ring is the
likely C−C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide
evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic
enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly
enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was
also developed.
1. INTRODUCTION
Tetrahydrofurans are frequently found in bioactive com-
pounds.1 These structurally complex, oftentimes chiral
compounds are isolated from natural products, usually in
minute quantities, so de neuvo chemical synthesis of such
tetrahydrofurans has been actively pursued.2 Methods for
tetrahydrofuran synthesis include intramolecular SN2 reactions
involving alcohols and leaving groups, [3+2] dipolar cyclo-
additions, addition of alcohols to electrophile-activated alkenes,
addition of nucleophiles to Lewis acid-activated lactol
derivatives and hydrogenation of furans.2,3 This article reports
a new method for the formation of fused-ring and bridged-ring
bicyclic tetrahydrofurans via a copper-catalyzed doubly intra-
molecular alkene carboetherification/C−H functionalization of
aryl-substituted 4-pentenols (Scheme 1). Fused-ring and
Figure 1. Bioactive fused-ring and bridged-ring tetrahydrofurans.
Scheme 1. Copper-Facilitated Alkene Carboetherifications
annulations,6 [3+2] annulations,7 [5+2] annulations,8 ring-
expanding reactions9 and palladium-catalyzed doubly intra-
molecular alkene carboetherification/C−H functionalization.10
While these methods are synthetic advances, most are limited
in scope to either fused-ring or bridged-ring tetrahydrofuran
synthesis and few are enantioselective. The method reported
herein is general for both fused- and bridged-ring synthesis and
the potential for development of an efficient catalytic
enantioselective protocol is promising (vide infra).
The synthesis of tetrahydrofurans via transition metal-
catalyzed carboetherification, addition of alcohols and carbon
bridged-ring tetrahydrofurans analogous to the ones described
in this report can be found in a number of terpenoid natural
units to alkenes, represents an efficient transformation of two
products including those that possess antibiotic and anti-HIV
very common functional groups.3a,d Transition metal-catalyzed
activity (Figure 1).4
Previous syntheses of fused and bridged bicyclic tetrahy-
drofurans include tetrahydrofuran formation followed by
intramolecular electrophilic aromatic substitution,5 [4+3]
Received: April 16, 2012
Published: June 21, 2012
© 2012 American Chemical Society
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a
alkene carboetherification has been developed most extensively
with palladium catalysts10,11 and to a lesser extent with gold
catalysts.12 Similar transformations have also been reported to
occur under cobalt catalysis where carbon radical intermediates
are thought to be involved.13
Table 1. Optimization of Reaction Conditions
Few catalytic asymmetric examples of carboetherification
reactions of unactivated alkenes have been reported and all of
them occur under palladium catalysis.3a,14 A common limitation
of these methods is the potential for β-hydride elimination
which is either built into the method14c,d or avoided by use of
1,1-disubstituted alkene substrates.14a The racemic Pd-catalyzed
reactions most analogous to the reactions reported herein also
appear to require use of 1,1-disubstituted alkene substrates.10
Herein is reported the first copper-catalyzed intramolecular
alkene carboetherification. Notably, β-hydride elimination does
not occur in this reaction. This reaction likely occurs via a novel
cis-oxycupration and prognosis for its development into a
catalytic enantioselective protocol is promising (vide infra).
There are few reports of Cu-catalyzed additions of alcohols
to electronically unactivated alkenes. To date, such reactions
are limited to alkene hydration and the role of Cu in these
reactions is primarily as a controlled source of triflic acid [e.g.,
from Cu(OTf)2].15 In the presence of PhI(OAc)2, Cu(OTf)2
has also been shown to catalyze the diacetoxylation of
alkenes.16 A Cu-catalyzed intermolecular addition of alkenes
and anhydrides that forms γ-lactones (a net carboetherification)
has recently been reported, but is quite different with respect to
substrates and likely mechanism than the one reported
herein.17 Likewise, Cu-promoted cyclization−acetoxylation of
alkenes18 and Cu-catalyzed oxyalkylation of vinyl arenes19 have
been reported but these reaction involve initial addition of
carbon radicals to alkenes.
Our laboratory has reported the copper-catalyzed intra-
molecular addition of a variety of amines and carbon moieties
across alkenes (carboamination) for the synthesis of
pyrrolidines and to a lesser extent piperidines.20 Based on the
success of these substrates, we turned our attention to 4-
pentenols to ascertain if Cu(II) could promote intramolecular
addition of an alcohol to an unactivated alkene. Specifically, we
designed a doubly intramolecular carboetherification wherein a
projected carbon radical intermediate could add to a nearby aryl
ring, thereby resulting in a fused-ring or bridged-ring
tetrahydrofuran (vide supra, Scheme 1).
ligand
temp
yield
b
b
entry CuX2 (mol %)
(mol %)
oxidant
MnO2
(°C)
(%)
c
1
2
3
4
5
6
Cu(eh)2 (300)
Cu(eh)2 (150)
Cu(eh)2 (100)
Cu(eh)2 (20)
Cu(eh)2 (300)
120
120
120
120
120
120
>95
c
55
d
e
f
46
c
33
c
82
e
Cu(OTf)2
(20)
Bipy (25)
3 (25)
3 (25)
3 (25)
3 (19)
3 (25)
3 (25)
3 (25)
MnO2
MnO2
MnO2
MnO2
MnO2
trace
98
e
e
e
7
8
9
Cu(OTf)2
(20)
120
100
90
Cu(OTf)2
(20)
98
c
Cu(OTf)2
(20)
66
e
10
11
12
13
Cu(OTf)2
(15)
120
100
100
100
78
c
Cu(OTf)2
(20)
O2 (1 atm)
MnO2
20
e,f
Cu(OTf)2
(20)
95
f
c
Cu(OTf)2
(20)
O2 (1 atm)
20
c
14
15
Cu(eh)2 (20)
3 (25)
3 (25)
MnO2
MnO2
100
100
0
g
c
Cu(OTf)2
(20)
80
a
Reactions were run on 0.188 mmol scale of 1a in PhCF3 (0.1 M with
respect to 1a) with K2CO3 (1 equiv), CuX2, and the designated ligand
in a sealed pressure tube. For reactions using Cu(OTf)2, the Cu(OTf)2
was complexed with the ligand in CF3Ph for 1 h at 60 °C prior to
b
c
substrate addition. Yield of isolated product (>20:1 dr). Conversion
d
1
(%) based on crude H NMR. Alcohol 1a was treated with n-BuLi
(1.1 equiv) at 0 °C, the resulting solution was stirred at rt for 15 min,
then Cu(eh)2 was added and the mixture was stirred at rt for 1 h prior
e
f
to heating at 120 °C for 24 h. 300 mol % MnO2 was used. No K2CO3
g
was added in this reaction. Toluene was used instead of PhCF3. The
Cu catalyst appeared less soluble in this solvent. Cu(eh)2 = Cu(2-
ethylhexanoate)2, Bipy = 2,2′-bipyridine.
additional ligand also gave trace 2a (not shown).] Fortunately
bis(oxazoline) 3 complexed to Cu(OTf)2 (20 mol %) provided
98% yield of 2a using MnO2 (3 equiv) as oxidant at 120 °C in
CF3Ph (Table 1, entry 7).
2. RESULTS AND DISCUSSION
2.1. General Reaction Conditions and Optimization.
The intramolecular carboetherification of 3,3-dibenzyl-4-
penten-1-ol (1a) was evaluated using a number of Cu(II)
salts, ligands and reaction conditions (Table 1). The cis-fused
tetrahydronaphthofuran 2a was obtained with high diaster-
eoselectivity and variable yield depending upon the reaction
conditions. We first established the feasibility of the reaction by
treatment of 1a with excess of Cu(2-ethylhexanoate)2 [Cu-
(eh)2, 300 mol %] as the copper promoter (Table 1, entry 1).
Lowering the amount of Cu(eh)2 to 150 and 100 mol % using
either K2CO3 or n-BuLi as base led to roughly 50% conversion
(Table 1, entries 2 and 3). While this reaction (Table 1, entry
1) was efficient in providing the cyclized adduct 2a, we sought a
catalytic method. Use of MnO2 (3 equiv) as stoichiometric
oxidant and Cu(eh)2 (20 mol %) as catalyst provided only 33%
conversion (Table 1, entry 4). Changing to 2,2′-bipyridine-
complexed Cu(OTf)2 (20 mol %) provided only a trace
amount of 2a (Table 1, entry 6). [Use of Cu(OTf)2 without
The reaction temperature could be lowered to 100 °C
without affecting the yield (Table 1, entry 8), but lower
temperature and lower catalyst loading gave lower yields (Table
1, entries 9 and 10). Oxygen (1 atm, balloon) was not an
effective oxidant (Table 1, entry 11). It is also noteworthy that
K2CO3 as base is not necessary for reaction to occur but
provides a slightly higher yield in the reaction with Cu(eh)2
(Table 1, entries 1 and 5). K2CO3 in the Cu(OTf)2·bis-
(oxazoline)-catalyzed reactions does not appear necessary
(Table 1, compare entries 8 and 12) but was generally used
in subsequent reactions for simplicity. Use of oxygen as oxidant
was also attempted under neutral (no K2CO3) conditions but
again, no turnover occurred (Table 1, entry 13). When Cu(eh)2
was used in conjunction with ligand 3 under the otherwise
optimal reaction conditions (Table 1, entry 8) no conversion to
2a was observed, indicating the Cu(OTf)2·bis(oxazoline)
catalyst is more active (Table 1, entry 14). Finally, use of the
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more common solvent, toluene, was investigated. The desired
product was indeed obtained (Table 1, entry 15) but the
conversion was lower (80%), possible due to lower solubility of
the copper catalyst in this solvent.
Table 2. Scope of Fused-Ring Tetrahydrofuran Synthesis via
Alkene Carboetherification
a
2.2. Scope of Fused-Ring Synthesis. Variously sub-
stituted 3,3-dibenzyl-4-penten-1-ols were submitted to the
optimized reaction conditions (Table 1, entry 8). While the
electron-rich p-Me, p-OMe and p-SMe substrates provided
excellent yield under these conditions (Table 2, entries 1−3),
the more electron-deficient p-Br, p-Cl, p-F and p-CF3-
substituted substrates required heating to 110 or 120 °C for
complete conversion (Table 2, entries 4−7). All of the
reactions of the 3,3-disubstituted-4-pentenols were completely
selective for the cis-fused diastereomer. The cyclization reaction
forms two adjacent stereocenters where one is a quaternary
carbon.
Regioisomers were formed in cases where substrates had
ortho and meta-aryl substituents. The m-MeO substrate 4
produced a 1.9:1 mixture of ortho:para substituted regioisomers
5 and 6, respectively (Table 2, entry 8). This regioselectivity is
consistent with addition of a carbon radical to an aryl ring (vide
infra).20a,b,f,21
The o-Me and o-MeO-substituted substrates 7a and 7b
provided regioisomeric mixtures as well, where in products 9a
and 9b, the substituent had apparently moved over to the meta
position (Table 2, entries 9 and 10). This is consistent with
ipso addition of a carbon radical to the aryl ring followed by
alkyl migration/rearrangement to provide either product 8 or 9,
depending on which group migrates (Scheme 2).20f
Reaction of the mono-γ-substituted pentenol 10a required
heating to 120 °C and favored formation of the trans-fused
diastereomer 11a with modest selectivity under the Cu-
(OTf)2·3-catalyzed conditions (Table 2, entry 11). The
diastereoselectivity of the reaction could be improved with
use of Cu(eh)2 (20 mol %) as catalyst even though higher
temperature (140 °C) was required for good conversion (Table
2, entry 12). Two other monobenzyl substrates provided
analogous results (Table 2, entries 13 and 14). 3,3-Diphenyl-4-
penten-1-ol 13 provided the indanofuran 14 in 66% yield upon
Cu-catalyzed carboetherification (Table 2, entry 15). The
monophenyl analog of 13, 3-phenyl-4-penten-1-ol, however,
gave modest conversion (64%) of a 2:1 mixture of
carboetherification and hydroetherification products even with
higher Cu(OTf)2·3 loading (30 mol %) and longer reaction
time (48 h) (see Supporting Information for details). ( )-1-
Phenyl and 1-allyl-3,3-dibenzyl-4-penten-1-ols 15 underwent
the Cu(OTf)2·bis(oxazoline) 3-catalyzed reactions, providing
moderate diastereoselectivity for the 2,5-trans-tetrahydrofuran
diastereomers 16 (Table 3, entries 1 and 5). The
diastereoselectivity was improved when Cu(2-ethylhexanoate)2
was used to promote the reactions (Table 3, entries 2 and 6).
The diastereoselectivity further improved when the catalytic
conditions with Cu(eh)2 as catalyst were used (Table 3, entries
3, 4, 7−9). Although we have previously observed that choice
of Cu(II) ligands can affect diastereoselectivity of related alkene
aminooxygenation reactions,22 the oxidant contribution to
diastereoselectivity was unexpected. Addition of ligand 3 to the
Cu(eh)2-catalyzed reaction had little effect on the reaction
(compare entries 3 and 4, Table 3).
a
Reactions were run at 100 °C in CF3Ph with Cu(OTf)2 (20 mol %)
complexed with ligand 3 (25 mol %) in the presence of K2CO3 (1
equiv), and MnO2 (300 mol %) for 24 h. Ratio determined by
analysis of the H NMR spectra of the crude and flash chromato-
graphed product mixtures. Isolated yield after flash chromatography
b
1
c
2.3. Bridged-Ring Tetrahydrofuran Synthesis. A trans-
annular carboetherification for the formation of
oxabicyclo[3.2.1]octanes was next explored (Table 4). These
are rare examples of transannular additions of carbon radicals to
d
e
on SiO2. Reaction was run at 110 °C. Reaction was run at 120 °C.
f
Reaction was catalyzed by Cu(eh)2 instead of Cu(OTf)2·3 and was
run at 140 °C. All reactions were performed in duplicate.
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a
Scheme 2. Rationale for Regioisomer Formation
Table 4. Synthesis of Bridged Bicyclic Tetrahydrofurans
Table 3. Reactions of 1-Substituted 3,3-Dibenzyl-4-
a
pentenols
b
c
entry
1
substrate
CuX2·ligand
oxidant yield (%)
dr
15a, R = Ph
Cu(OTf)2·3
Cu(eh)2
MnO2
98
86
81
79
98
87
44
50
95
2.6:1
12:1
d
2
15a
3
4
5
15a
Cu(eh)2·3
Cu(eh)2
MnO2
MnO2
MnO2
>20:1
>20:1
2.5:1
15a
15b, R = Allyl
Cu(OTf)2·3
Cu(eh)2
d
6
15b
15b
15b
15b
5.5:1
7
8
Cu(eh)2·3
Cu(eh)2
MnO2
MnO2
MnO2
>20:1
>20:1
>20:1
e
9
Cu(eh)2
a
Same general reaction conditions as Table 2 unless otherwise noted.
b
c
Isolated yield after flash chromatography on SiO2. Ratio determined
1
by analysis of the H NMR spectra of the crude reaction mixture.
d
e
Reaction run with Cu(eh)2 (300 mol %). Reaction run at 120 °C for
48 h.
a
Reactions were run at 120 °C in CF3Ph (0.1 M with respect to
substrate) with Cu(OTf)2 (20 mol %) complexed with ligand 3 (25
arenes (vide infra). These reactions occurred best at 120 °C
using the Cu(OTf)2·bis(oxazoline) 3-catalyzed reaction con-
ditions. The oxabicyclo[3.2.1]octane 21 formed in entry 6
resembles the natural product bruguierol (Figure 1). We also
examined the reactivity of substrates with higher alkene
substitution in this carboetherification reaction (Table 4,
entries 7−9). 2,2-Diphenyl-4-methyl-4-penten-1-ol 22 under-
went the oxidative cyclization to afford the 2-methyl-
oxabicyclo[3.2.1]octane 23 in 87% yield. (E)-2,2-diphenyl-4-
hexen-1-ol 24a also underwent the cyclization efficiently,
producing adducts 25a as a 1:1 diastereomeric mixture. This
result was surprising as we have previously observed poor
reactivity with internal alkene substrates in copper-promoted
carboamination reactions.20b Substrate 24b, with phenyl
substitution on the terminal carbon of the alkene, reacted to
give a complex mixture that included aldehyde peaks in the
mol %) in the presence of K2CO3 (1 equiv) and MnO2 (300 mol %)
b
for 12 h unless otherwise noted. Isolated yield after flash
c
chromatography on SiO2. 18% of starting alcohol 20 was recovered.
analogous cyclic cis-oxycupration transition state (e.g., TS-B) in
the carboetherification reaction, this steric interaction is not
present, which could contribute to loss of enantioselectivity
(the enantiomeric TS-C may not be energetically very different
from TS-B).
We reasoned that increasing the steric demands of the
substrate near the alcohol region could render a cyclic
oxycupration step more enantioselective by increasing steric
interactions between the substrate and ligand. Thus, substrates
with mono and disubstitution at the hydroxyl-bearing carbon
were examined (Table 5). While 1-phenyl-3,3-dibenzyl-4-
pentenol 15a gave high diastereoselectivity for 16 with
Cu(eh)2·(R,R)-Ph-box as catalyst, the enantioselectivity was
<5%. Changing to the [Cu(R,R)-Ph-box](OTf)2 catalyst, we
obtained a 2:1 diastereomeric ratio of 16a to 17a where 16a
was formed in 30% ee and 17a was formed in 67% ee. This
reaction is likely a kinetic resolution of the racemic alcohol
substrate (absolute configurations tentatively assigned as
shown, vide infra). The analogous 1-phenyl-3,3-di(p-chloro-
benzyl)-4-pentenol 15c reacted with similar selectivity (Table
5, entry 3). The 1,1-diphenyl-3,3-dibenzyl-4-pentenol 15d
provided one carboetherification diastereomer in ca. 75% ee
(conservative estimate based on incompletely resolved
enantiomers) and its 1,1-diphenyl-3,3-di(p-chlorobenzyl)-4-
1
crude H NMR (Table 4, entry 9).
2.4. Catalytic Enantioselective Carboetherification.
Development of an enantioselective carboetherification proto-
col was next explored. The [Cu(R,R)-Ph-box](OTf)2 catalyst
was explored due to our previous success in rendering the
copper-catalyzed alkene carboamination reaction enantioselec-
tive (eq 1).20f Unfortunately 4-pentenols 1a and 18b provided
racemic carboetherification products using this catalyst (eqs 2
and 3).
We believe the enantioselectivity in the carboamination
reaction (eq 1) is due in large part to the steric interaction
between the substrate’s N-tosyl substituent and the phenyl
group on the ligand’s oxazoline ring (e.g., TS-A). Assuming an
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unfortunately. We have tentatively assigned the absolute
stereochemistry of the products as shown in Table 5 and eqs
4 and 5 (vide infra) by analogy to the enantioselective
carboamination products (e.g., eq 1 and see optical rotation
correlation discussion in the Supporting Information for 21,
vide infra).20f
2.6. Mechanistic Probes. We further explored the
enantioselective variant of the transannular carboetherification
of 4-pentenol 20. Although the reaction did not go to
completion at 100 °C, the bicyclic furan 21 was obtained in
50% ee (Scheme 3). We next introduced 1,4-cyclohexadiene to
a
Table 5. Catalytic Asymmetric Carboetherifications
Scheme 3. Enantioselective Transannular
Carboetherification and Hydroetherification
yield
dr
ee
b
c
entry
1
substrate
15a, R1 = Ph, R2 = H,
Ar = Ph
CuX2
(%) (16:17)
(%)
Cu(eh)2
62
>20:1
<5
2
3
15a
Cu(OTf)2
Cu(OTf)2
89
77
2:1
2:1
30, 67
32, 60
15c, R1 = Ph, R2 = H,
Ar = 4-Cl-C6H4
4
5
15d, R1 = Ph, R2 = Ph,
Cu(OTf)2
Cu(OTf)2
89
85
∼75
Ar = Ph
15e, R1 = Ph, R2 = Ph,
nd
Ar = 4-Cl-C6H4
a
Reaction conditions: CuX2 (0.376 mmol) and (R,R)-Ph-box (0.0470
mmol) were combined in PhCF3 (0.6 mL) and heated in a sealed tube
for 2 h. Alcohol 15 (0.188 mmol) in 0.9 mL of PhCF3, K2CO3, (0.188
mmol), and MnO2 (0.564 mmol) were added, and the reaction was
b
stirred at 100 °C in a sealed tube for 24 h. Substrates are racemic or
c
d
achiral. Isolated yield after flash chromatography on SiO2. Ratio
1
determined by analysis of the H NMR spectra of the crude reaction
c
mixture. Enantiomeric excess determined by chiral HPLC. nd = not
determined. Enantiomers could not be separated on chiral HPLC or
GC.
the reaction and obtained tetrahydrofuran 26 in 85% yield
(along with 10% unreacted alcohol 20, Scheme 3). Tetrahy-
drofuran 26 was obtained in 76% enantiomeric excess. Taken
together these reactions indicate (1) a carbon radical, one that
can perform H-atom abstraction, is a likely intermediate in the
reaction, (2) the H-atom abstraction is faster than transannular
C−C bond formation and (3) the carboetherification reaction
may suffer some ring-opening/unselective ring-closing prior to
C−C bond formation which could account for its diminished
enantioselectivity relative to the apparently less reversible
alkene hydroetherification involving H-atom abstraction. One
potential reversibility scenario is depicted in Scheme 3. This
pentenol derivative (15e) gave a product with a comparable
optical rotation (see Supporting Information), but the
enantiomers could not be separated for %ee determination.
The data in Table 5 clearly indicate that development of a
catalytic enantioselective copper-catalyzed alkene carboether-
ification is feasible. Mechanistically, the enantioselective
reactions provide strong support for the presence of Cu in
the alkene addition step.
2.5. Absolute Stereochemistry Assignment. X-ray
quality crystals of enantiomerically enriched heavy atom (Cl)-
containing carboetherification products could not be obtained,
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reversibility may be less prominent when addition to a more
proximal aryl ring, e.g. as in Table 5, occurs. Formation of the
favored cis-fused products, e.g. 16 and 17, may be faster than
furan ring-opening. In the case of α-substituted substrates 15a
and 15c−e, selectivity can be as high as 75% ee, which is
comparable to the hydroetherification reaction (Scheme 3).
The intermediacy of an sp2-hybridized carbon intermediate
(e.g., a carbon radical, see Schemes 1−3, was further probed by
the reaction of the isotopically labeled 3-p-methoxybenzyl-4-
penten-1-ol (10a-D). Carboetherification provided a 1.8:1 ratio
of trans-fused 11a-D and cis-fused 12a-D, both of which were
composed of a 1:1 diastereomeric mixture at the deuterated
carbon (eq 4). The presence of the carbon radical was further
confirmed by running the reaction in the presence of 1,4-
cyclohexadiene (eq 5). This hydroetherification reaction was
highly diastereoselective and produced the 2,3-trans-tetrahy-
drofuran 27 in 82% yield. No carboetherification products were
formed, indicating the H-atom transfer process is faster. This
relative rate data, in conjunction with the much higher trans-
diastereoselectivity for the hydroetherification, seems to
indicate again that addition to the alkene is less reversible in
the hydroetherification reaction. The 2,3-trans kinetic selectivity
can be rationalized by TS-D, which places the allylic substituent
in a pseudo-equatorial position in the cyclization transition
state. The 2,3-trans diastereomer should experience less sterics
in the H-atom abstraction step than its corresponding 2,3-cis
diastereomer, which can contribute to a highly trans-selective
hydroetherification (eq 5). Conversely, the C−C bond-forming
step of the corresponding carboetherification reaction (radical
addition to arene after O−C bond formation) in eq 4 should be
more facile for the minor 2,3-cis carbon radical intermediate
that leads to formation of the cis-fused diastereomer 12a-D,
than for the major 2,3-trans carbon radical to form the trans-
fused diastereomer 11a-D. The preference for cis-fused
cyclization is clear in the highly selective conversion of 1 to 2
(vide supra). Thus, the 2,3-trans carbon radical or organocopper
intermediate could suffer ring-opening and ring-closing prior to
C−C bond formation, resulting in a lower overall reaction
diastereoselectivity.
tion) to aromatic rings generally occurs at the less sterically
hindered para-position (e.g., eq 7).23
Our reaction provides a regioisomeric mixture where the
ortho-substituted product is formed as the major product
(Table 2, entry 8, ortho:para = 1.9:1). This regioselectivity is
most consistent with a carbon radical addition to the aromatic
ring.
2.7. Proposed Mechanism. A proposed catalytic cycle is
illustrated in Scheme 4. A cis-oxycupration transition state (TS-
Scheme 4. Proposed Carboetherification Catalytic Cycle
Based on the labeling and H-atom abstraction reactions, the
intermediacy of a primary carbon radical is reasonable. The C−
C bond-forming process in the aryl addition step of the
carboetherification could, however, still feasibly take place
either by a radical addition or an electrophilic aromatic
substitution mechanism. Aryl addition to an organocopper(III)
intermediate, either directly at carbon or via addition to
copper(III) followed by reductive elimination, could feasibly
lead to the carboetherification product. Analogous mechanisms
have been proposed for Pd- and Au-catalyzed reactions.23
(Carbon−carbon bond formation through a Friedel−Crafts-
type addition to a primary carbocation intermediate is less likely
as such an intermediate is expected to be very high energy and
unlikely to be formed under the reaction conditions.)
The stereochemistry of the deutero-alkene cannot be used in
our analysis since stereochemical information is lost due to the
presence of the carbon radical intermediate. Regiochemical
trends in electrophilic and radical aryl substitution reactions are
known, however, and can be used to infer the likely reaction
mechanism. It is known that radicals favor addition ortho to
substituents on aromatic rings, possibly due to electronic
stabilization of aryl radical intermediates (e.g., eq 6).21
Conversely, electrophilic addition of metals, electrophilic
organometallics or activated carbonyls (Friedel−Crafts acyla-
E) is proposed in analogy to related aminocuprations.20 For α-
substituted pentenols 15, the R group is placed in an equatorial
position in the cyclic transition state (TS-E) resulting in
formation of the major 2,5-trans-tetrahydrofuran diastereomer
16. The electronic effect observed in the substrate reactivity in
Table 1 seems to indicate that more electron-rich alkenes and/
or alcohols are more reactive. Homolysis of the unstable C−
Cu(II) bond of intermediate 28 results in the primary carbon
radical intermediate 29. Addition of the resulting carbon radical
to the nearest (cis) aryl ring produces the new C−C bond in
aryl radical 30, and aryl oxidation provides the product 16.
Oxidation of Cu(I) with MnO2 regenerates the Cu(II) catalyst.
We have observed that the reaction diastereoselectivity can
vary depending upon the nature of the copper(II) ligands, the
presence or absence of MnO2 and the presence or absence of
1,4-cyclohexadiene (Tables 2 and 3 and eqs 4 and 5). Reaction
reversibility due to a ring-opening and unselective ring-closing
process should be less prevalent if the subsequent step, reaction
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Article
termination by H atom abstraction or addition of the carbon
radical to the aromatic ring, is rapid. The Cu(eh)2 catalyst and
the presence of MnO2 increase reaction diastereoselectivity
which may indicate these reactions are also less reversible. This
is possibly due to an increase in stability of the primary carbon
radical intermediate by its reversible conversion to an
organocopper(III) species. This species can be formed by
direct oxidation of the organocopper(II) species (e.g., 28) or
addition of the primary carbon radical (e.g., 29) to Cu(II). Both
processes should be increased by greater concentration of
oxidizing species or greater propensity of the Cu(I) or Cu(II)
species to undergo oxidation. A ligand affect on copper
oxidation potential is feasible.24
The extent of the reversibility of the tetrahydrofuran ring
formation is also highly dependent upon the rate of the
subsequent C−C or C−H bond-forming step. As we observed
in our enantioselective reactions, 1-substituted-4-pentenol
substrates that are able to form cis-fused tetrahydronapthofuran
products, e.g. 16, and reactions involving C−H bond formation
via H-atom abstraction (e.g., formation of 26 in Scheme 3) give
the highest enantioselectivities (up to 76%). It can be inferred
with these substrates and reactions that the oxycupration step is
enantioselective and suffers little if any ring-opening/
unselective ring-closing.
Carbon−oxygen bond formation via trans-oxycupration is a
mechanistic alternative to the proposed cis-oxycupration shown
in Scheme 4. The product stereochemistry cannot be used to
differentiate the two mechanisms since stereochemical
information from the C−Cu bond formation is lost (vide
supra, eq 4). The cis-oxycupration mechanism requires
coordination of the alcohol to the copper center prior to
alkene addition. This seems likely due to the high affinity the
hard alcohol nucleophile should have for the hard Cu(II)
catalyst. The olefin, in comparison, is a softer nucleophile.
An alternative, oxygen radical alkene addition mechanism
(from homolysis of an O−Cu bond) can be ruled out since we
have observed that the ligand on Cu(II) can influence the
enantioselectivity of the reaction. A mechanism involving
internal charge transfer of the RO-Cu(II) intermediate to give
an RO·Cu(I) complex where both the metal and alkoxyradical
participate in the olefin addition step, in analogy to that
proposed for related Co-catalyzed reactions,13 cannot be ruled
out, but seems unlikely since such N to Cu charge transfer does
not appear to occur in the analogous aminocupration
reaction.25
will serve as the basis for the development of other alkene
oxidative difunctionalization reactions. We anticipate we can
broaden the scope of tetrahydrofurans formed through
carboetherification by introducing external alkene radical
acceptors20g to enable intermolecular C−C bond formation.
Application of this method in target-oriented synthesis,
optimization of the enantioselective protocol, and additional
product analysis for definitive absolute configuration determi-
nation are underway and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data, and crystallo-
graphic data for 11a and 16e (CIFs). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
schemler@buffalo.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Institute of General Medical Science
(GM078383) is gratefully acknowledged for support of this
research. We thank William W. Brennessel and the X-ray
Crystallographic Facility at the University of Rochester for the
X-ray structures of 11a and 16e. We thank Barbara Casavant,
Shulendu Kariakarte, and Timothy Liwosz for kind assistance in
the synthesis of five substrates.
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NOTE ADDED AFTER ASAP PUBLICATION
■
It has come to the authors' attention that a copper-promoted
carboetherification reaction involving endo cyclization of a
phenol onto a pendant alkene was reported recently. This work
is now cited as ref 27, and this paper reposted July 11, 2012.
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