Type 1 ring-opening reactions of cyclopropanated 7-oxabenzonorbornadienes with organocuprates

Article abstract of DOI:10.1021/ol5004737

For the first time, nucleophilic ring-openings of cyclopropanated 7-oxabenzonorbornadiene were investigated, providing a novel approach to the preparation of 2-methyl-1,2-dihydronaphthalen-1-ols. Satisfactory yields (up to 95%) were achieved using n-Bu₂CuCNLi₂ as the nucleophile and Et₂O as the solvent. The reaction demonstrated successful incorporation of primary, secondary, tertiary and aromatic nucleophiles, as well as ring-openings of substrates bearing arene substituents and C1-bridgehead substituents. A generalized mechanism for these transformations is also proposed.

Full text of DOI:10.1021/ol5004737

Letter
pubs.acs.org/OrgLett
Type 1 Ring-Opening Reactions of Cyclopropanated
7‑Oxabenzonorbornadienes with Organocuprates
Emily Carlson, Jamie Haner, Mary McKee, and William Tam*
Guelph−Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario, Canada N1G 2W1
S
* Supporting Information
ABSTRACT: For the first time, nucleophilic ring-openings of
cyclopropanated 7-oxabenzonorbornadiene were investigated,
providing a novel approach to the preparation of 2-methyl-1,2-
dihydronaphthalen-1-ols. Satisfactory yields (up to 95%) were
achieved using n-Bu2CuCNLi2 as the nucleophile and Et2O as the
solvent. The reaction demonstrated successful incorporation of
primary, secondary, tertiary and aromatic nucleophiles, as well as
ring-openings of substrates bearing arene substituents and C1-
bridgehead substituents. A generalized mechanism for these
transformations is also proposed.
eterobicyclic alkenes serve as valuable precursors for the
Hcreation of highly substituted cyclic and acyclic systems
alike.1 Most notably, ring-opening reactions of oxabicyclic
alkenes are well recognized for their ability to generate multiple
stereocenters in a single step.2 Nucleophilic ring-openings of 7-
oxabenzonorbornadiene 1 provide a diverse supply of 2-
substituted dihydronaphthalenol derivatives, depending on the
metal catalyst and nucleophile employed (Scheme 1).3
reductive openings of 1 with hydride nucleophiles have also
been achieved to provide the unsubstituted 6.11 The resulting
dihydronaphthalenols 2−6 and their variously substituted
analogues find broad application in the synthesis of biologically
active substances, such as arnottin I,12 as well as medicinal
compounds, such as sertraline.13
While nucleophilic ring-openings of olefin 1 have been
extensively studied, the similar chemical reactivities reported
between olefins and cyclopropanes14 drew our attention to
nucleophilic ring-opening reactions for cyclopropanated
analogues of 1. To begin our work, the substrates were
prepared by cyclopropanation of 7 using in situ generated
diazomethane, giving 8 in moderate to excellent yields (Scheme
2).15 For purposes of optimization, early trials focused on
reactions involving the unsubstituted parent compound 8a
(Scheme 3).
Scheme 1. Transition-Metal-Catalyzed Nucleophilic Ring-
Opening Reactions of 7-Oxabenzonorbornadiene 1
Three outcomes could be envisioned for nucleophilic ring-
opening reactions of 8a, based on the position of the attacking
nucleophile and the bond being broken (Scheme 3). The first
type of reaction would invoke nucleophilic attack at bridgehead
position C1 (Scheme 3), with simultaneous cleavage of the C−
Scheme 2. Recent Preparations of Cyclopropanated 7-
Oxabenzonorbornadienes
Syn-stereoisomeric products 2 or 3 are attained when
rhodium,4 palladium,5 or nickel6 are supplied with an arene
nucleophile and when palladium7 or nickel8 catalyzes the
addition of an alkyl nucleophile. In contrast, the anti-
diastereomers 4 or 5 are obtained when rhodium assists
addition of a heteroatomic nucleophile9 or when copper
catalyzes addition of an alkyl nucleophile.10 Furthermore,
Received: February 13, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
improvement seen with increased temperatures (Table 1,
entries 1 and 2). Using organolithium reagent,17a however, the
ring-opened product 10 was obtained as the sole product in
20% yield; again, no appreciable temperature dependence was
noted (entries 3 and 4). Other organometallic reagents
including in situ generated organocerium (entry 5)17b and
Lewis acidic monoorganocopper (entry 6)18 compounds were
less effective or showed no conversion at all. It was not until
subsequent trials involving organocuprates were attempted that
an increase in effectiveness was seen: Gilman reagents18,19
generated from copper(I) halide salts showed that chloride and
bromide derivatives were more effective than the iodide
derivative, giving 10 in moderate yields of >55% after 8 h
(entries 7−9). It was at this time that the formation of an
aromatic side product 13 was first noted. Higher-order
cuprates,20 when subjected to the reaction, also gave promising
yields of 10 with small proportions of 13 (entries 10 and 11).
Finally, a range of solvents was screened. The choice of diethyl
ether drastically improved the yield of 10 to near-quantitative
conversion (entry 12), while reactions in toluene, hexanes, and
dichloromethane proved to be unsuccessful (entries 13−15).
The structures of these compounds were determined by various
NMR experiments (1H, 13C, HSQC, and GOESY)21 and were
compared with the data of a structurally analogous syn-2-
methyl-1,2-dihydronaphthalen-1-ol (R = H) from the liter-
ature.22 With the optimization complete, the combination of
higher order cyanocuprate in diethyl ether was selected for
investigations toward the reaction scope.
Scheme 3. Proposed Types of Ring-Opening Reactions for
Cyclopropanated 7-Oxabenzonorbornadienes
O bond to give the ring-opened product 9. Early experiments,
however, showed that 9 was in fact not isolable, but further
undergoes ring-opening of the cyclopropane, leading to the
formation of dihydronaphthalenol 10 upon aqueous work up
(vide infra).16 This class of peculiar reactions which produced
10 was given the name Type 1 ring-opening reactions. To the
best of our knowledge, this paper describes the first account
where a cyclopropanated heterobicyclic molecule 8a has been
opened in this fashion. The second type of conceivable reaction
would result from nucleophilic attack on the cyclopropane at
position C3 (Scheme 3), leading to the ring-opened product
11. The third type of potential reaction would involve
nucleophilic attack at the cyclopropane position C2 (Scheme
3), producing cycloheptenol derivative 12 through ring
expansion.
The scope of the ring-opening reactions of 8a using various
higher order cyanocuprate nucleophiles is shown in Table 2.
Table 2. Effects of Various Organocuprate Nucleophiles on
Type 1 Ring-Opening Reactions of 8a
The effects of organometallic nucleophile, solvent, and
reaction time on Type 1 nucleophilic ring-openings of 8a are
summarized in Table 1. Initial attempts using Grignard reagent
as the organometallic nucleophile were futile, with no
Table 1. Organometallic Reagent and Solvent Effects on
Type 1 Ring-Opening Reactions of 8a
a
(%)
a
entry
nucleophile
time (h)
8a (%)
10
13
1
2
n-Bu
Me
Me
Et
8
160
48
2
40
16
48
49
15
35
0
95
59
64
50
10
10
40
18
45
12
23
2
0
b
3
19
2
a
(%)
4
16
a
5
Et
120
160
30
28
64
1
entry organometallic reagent
solvent
time (h) 8a (%)
10 13
6
Et
1
2
3
4
5
6
7
8
9
EtMgBr
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
toluene
hexanes
DCM
72
72
72
72
24
72
8
94
86
76
72
91
92
65
22
35
20
29
2
0
0
0
0
0
0
0
0
2
2
2
3
2
2
0
0
0
b
b
7
Hex
Hex
i-Pr
t-Bu
Ph
EtMgBr
8
140
40
77
47
20
0
n-BuLi
20
21
4
9
3
n-BuLi
10
11
30
37
60
n-BuCeCl2
48
n-BuCu·BF3
n-Bu2CuLi·LiI
n-Bu2CuLi·LiBr
n-Bu2CuLi·LiCl
n-Bu3CuLi2·LiCl
n-Bu2CuCNLi2
n-Bu2CuCNLi2
n-Bu2CuCNLi2
n-Bu2CuCNLi2
n-Bu2CuCNLi2
0
a
b
Isolated yield after column chromatography. 10 equiv of
30
67
58
71
69
95
0
organocuprate, heated to 65−75 °C.
8
8
10
11
12
13
14
15
8
Compared to n-Bu (entry 1), the methyl nucleophile (entry 2)
was particularly unreactive, resulting in a 40% recovery of 8a
after one week. This likely resulted from the low transferability
of a methyl ligand relative to an n-Bu ligand from the cuprate.23
When more forceful conditions of excess cuprate with heating
were employed, the reaction was driven further toward
completion (entry 3), with moderate yields of 10 and formation
of 13. Reactions with the ethyl nucleophile also manifested that
8
8
8
91
96
95
8
0
8
0
a
b
Isolated yield after column chromatography. Reaction was heated to
60−65 °C.
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Organic Letters
Letter
the longer the reaction was left, the greater the consumption of
starting material and formation of side product 13 (entries 4−
6). A similar observation was made for the hexyl nucleophile
(entries 7 and 8). It soon became evident that aromatization
proceeded readily in the sealed reaction vessel under reaction
conditions. Upon closer examination, it also became apparent
that 10 converts to 13 on standing at room temperature over
time.24 Finally, i-Pr and t-Bu nucleophiles showed relatively fast
conversion, although similar proportions of 10 and 13 were
recovered (entries 9 and 10), while surprisingly, the phenyl
nucleophile appeared to produce 10 without any recoverable
13 (entry 11).
comparable yields of 93% to that of the unsubstituted parent
substrate 8a (entry 12).
To account for the formation of 10 in Type 1 ring-opening
reactions, we propose a general mechanism (Scheme 4).
Scheme 4. Proposed Mechanism for Type 1 Ring Openings
The scope of the ring-opening reactions of derivatized
cyclopropanes 8, bearing various substituents on the arene as
well as at the bridgehead position, is summarized in Table 3.
Table 3. Effects of Substitution Pattern on the Substrate
toward Type 1 Ring-Opening Reactions
Following attack of an organometallic nucleophile at the
bridgehead position of 8a and cleavage of its C−O bond to give
14, a basic species present in the reaction medium removes a
bridgehead proton. This causes an internal rearrangement of
electrons in the framework which forces open the
cyclopropane, generating 15. Upon quenching, both anionic
C and O atoms of 15 would become protonated, giving rise to
the observed product, 10.
In summary, we have demonstrated the first examples of
Type 1 organocopper-mediated ring-opening reactions of
cyclopropanated 7-oxabenzonorbornadienes as a novel ap-
proach for the preparation of 2-methyl-1,2-dihydronaphthalen-
1-ols. This chemistry is applicable to the incorporation of
primary, secondary, tertiary and aromatic organic nucleophiles
as well as to substrates bearing para-arene substituents and C1-
bridgehead substituents. In addition, complete regioselectivity
was observed for reactions involving C1-substituted substrates.
Further investigations including mechanistic studies and
broadening of the reaction scope will continue in our
laboratories.
a
(%)
a
entry
X
Y
Z
time (h) 8 (%)
10
13
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
8
4
2
9
95
64
15
24
12
0
2
0
Me
OMe
OMe
OMe
H
H
H
1
78
53
31
96
35
9
7
H
20
14
51
0
H
48
OMe
H
H
160
48
H
Me
Me
Et
59
48
81
76
61
93
4
H
H
120
140
160
160
15
21
12
0
b
9
H
H
7
10
11
H
H
n-Bu
t-Bu
Br
20
22
5
H
H
0
c
12
H
H
0
a
b
Isolated yield after column chromatography. 5 equiv of
c
organocuprate. Z = H in 10.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Relative to the unsubstituted reaction of 8a (entry 1),
substrates bearing para-disubstituted arenes appeared to show
moderate reactivity toward ring-opening with surprisingly short
duration (entries 2 and 3). Once again, it was observed that
reactions left for longer periods experienced extensive
aromatization (entries 3−5). In contrast, the ortho-dimethoxy
derivative showed no signs of reacting (entry 6), which was not
surprising as we have previously observed similar differences in
reactivity between these ortho- and para-compounds in our
laboratories.25 C1-Alkyl-substituted substrates all showed good
reactivity and high regioselectivity but required longer reaction
times overall (entries 7−11). C1-Methyl-substituted 8 showed
moderate conversion after 48 h, although it was not until the
reaction was left for nearly a week that the consumption of 8
was near completion (entries 7 and 8). Ethyl and n-butyl
substituents gave >75% yields of 10 with minimal or
undetectable 13 after 140−160 h (entries 9 and 10). The
ring-opening also worked for the bulky C1-t-Bu substituent,
which gave no 13 (entry 11). Finally, when a C1-bromo-
substituted substrate was subjected to the ring-opening
reaction, the product did not contain the halogen, but instead
had a hydrogen in its place.26 Moreover, the reaction gave
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wtam@uoguelph.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC). J.H.
thanks the Ontario government for providing a postgraduate
scholarship (OGS).
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1
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