Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to α-(Hetero)aryl Cyclohexanones

Article abstract of DOI:10.1021/acs.joc.6b01312

The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov cyclization have been disclosed. Using SnCl₄ as the catalyst, alkenyl cyclopropyl ketones undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 12:1. Regiospecific arylation occurs at the α-carbon of the oxyallyl cation due to polarization caused by the ester group.

Full text of DOI:10.1021/acs.joc.6b01312

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Article
Catalytic, Interrupted Formal Homo-Nazarov Cyclization with
(Hetero)arenes: Access to alpha-(Hetero)aryl Cyclohexanones
Corey W Williams, Raynold Shenje, and Stefan France
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01312 • Publication Date (Web): 16 Aug 2016
Downloaded from http://pubs.acs.org on August 18, 2016
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Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to
α-(Hetero)aryl Cyclohexanones
a,‡
a,‡
a,b,
Corey W. Williams , Raynold Shenje , and Stefan France *
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a
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia,
3
0332, United States
b
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta,
Georgia 30332, United States
‡
Theseꢀauthorsꢀcontributedꢀequally.
stefan.france@chemistry.gatech.edu
Abstract
The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov
4
cyclization have been disclosed. Using SnCl as the catalyst, alkenyl cyclopropyl ketones
undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent
intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes
provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural
products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 11.7:1.
Regiospecific arylation occurs at the α-carbon of the oxyallyl cation due to polarization caused
by the ester group.
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R5
R4
R6
R3
R4
R5
X
X
O
OH
O
O
(
10 equiv.)
R3
(10 equiv.)
O
OH
SnCl (20 mol %)
Me
SnCl (20 mol %)
4
4
MeO
MeO
MeO
Me
Me R6
CH Cl (0.1 M), rt
R1 R2
CH Cl (0.1 M), rt
R1 R2
2
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R1 R2
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up to 87% yield
up to 88% yield
8
examples
dr up to 4.3:1)
1
(
2 examples
dr up to 12:1)
(
INTRODUCTION
Functionalized α-aryl and heteroaryl cyclohexanones represent two structural
frameworks that are present at the core of a number of natural products and pharmaceutical
1
agents. Given their prevalence and importance, various approaches toward α-(hetero)aryl
cyclohexanones have been explored by synthetic chemists. Two common approaches involve the
2
direct α-arylation of cyclohexanones via transition metal catalyzed enol(ate) arylation or enolate
3
trapping with diaryl iodonium salts. Both of these approaches utilize aryl and/or heteroaryl
halides as electrophilic coupling partners for the enolates. Alternatively, an increasingly popular
approach to α-(hetero)aryl cyclohexanones involves the (hetero)arene as the nucleophile and an
4
in situ-generated oxyallyl cation as the electrophilic coupling partner in an umpolung fashion
5
6
(
via a Friedel-Crafts-type reaction). For instance, Chi and MacMillan demonstrated that base
(
Na CO or NEt ) promoted the reaction of indoles with α-halo- or α-tosyloxycyclohexanones to
2
3
3
form α-indolylcyclohexanones. Later, Tang reported the reaction of α-chlorocyclohexanone with
7
2
-naphthol. Finally, Kartika reported that 6-membered aryl-substituted α-hydroxy methylenol
ethers were readily converted to the corresponding oxyallyl cations and regioselectively trapped
8
by indoles. While each method is powerful in its own right, the classes of arenes employed
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(
indoles/naphthols) were limited, and the number of actual examples involving cyclohexanones
was small (<6 examples). Thus, the broader scope of these umpolung α-arylation reactions has
yet to be fully realized.
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Over the past five years, our group has explored the reactivity of oxyallyl cation
intermediates generated in the formal homo-Nazarov cyclization (ring-opening cyclization of
alkenyl cyclopropyl ketones) to access functionalized cyclohexanones, cyclohexenols, and
9
phenols. In addition, we recently disclosed the first example of a catalytic, interrupted formal
9
a
homo-Nazarov cyclization in the presence of allylsilanes. In that report, the oxyallyl cation
intermediate reacts with allyl TMS using catalytic SnCl to form α-allylcyclohexanones.
Additionally, hexahydrobenzofurans were preferentially obtained with stoichiometric SnCl and
4
4
allyl TBDPS via a formal [3+2] cycloaddition pathway. Given this success, we have now sought
to expand the interrupted formal homo-Nazarov cyclization to include other nucleophilic
trapping agents, with particular interest on arenes and heteroarenes.
Scheme 1. Arylative Interrupted Nazarov vs. Formal Homo-Nazarov Cyclization
A. Interrupted Nazarov Cyclization (West and others)
BF •Et O
3
2
(1.1 equiv.)
or
O
TMSOTf
(1.1 equiv.)
OLA
O
(
Het)Ar
(Het)Ar-H
R
R
R
R
R
R
R
R
R
R
R
R
B. Catalytic, Interrupted Formal Homo-Nazarov Cyclization (this work)
LA
O
O
OH
O
O
2
R3
cat. LA
(Het)Ar-H MeO2C
(Het)Ar
R3
R3
MeO
R1
3
5
MeO
1
6
3
4
5
R2
R1 R2
I
R1 R2
polarized
oxyallyl cation
regiospecific
arylation at C-3
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11
Toward this endeavor, we were inspired by seminal work from West and others on the
interrupted Nazarov cyclization. In these contributions, various examples of inter- and
intramolecular aryl trapping of the cyclopentyl oxyallyl cation were disclosed (Scheme 1A). We
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envisioned a homologous strategy to access functionalized α-(hetero)aryl cyclohexanones
involving the Friedel-Crafts-type reactions of various arenes and heteroarenes with the six-
membered, cyclic oxyallyl cations I generated through formal homo-Nazarov cyclizations
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(Scheme 1B). Lewis acid-activation of donor-acceptor-acceptor (D-A-A) cyclopropanes results
in a ring-opening cyclization to form an initial acyclic zwitterionic intermediate. Subsequent
intramolecular π-attack generates oxyallyl cations I which react with (hetero)arenes to provide
α-(hetero)aryl cyclohexanones. Most importantly, regiospecific arylation at C-3 of intermediate I
is expected due to the electron-withdrawing ester’s influence on the polarization of the oxyallyl
1
2
cation.
RESULTS AND DISCUSSION
Our reaction optimization began with cyclopropyl vinyl ketone 5a as the model substrate
with anisole (6a) as the aromatic nucleophile (Table 1). Fortuitously, our previously reported
4 2 2
allylsilane-trapping conditions (20 mol % SnCl , 10 equivalents of nucleophile, CH Cl , 25 ˚C),
proved ideal and the desired α-arylated homo-Nazarov product 7aa was obtained in 67% yield as
a complex keto-enol mixture of diastereomers. Consistent with reported and theoretical Friedel-
13
Crafts reactions of anisoles, only the 4-alkylated regioisomer was observed. Other catalysts
gave either decreased selectivity toward the arylated product or extended reaction times (entries
2-6). For instance, In(OTf)
3
favored the eliminative (untrapped) homo-Nazarov product 8a and
gave 69% yield but with reduced selectivity
gave only 11% yield of 7aa (entry 2), whereas InCl
3
and a longer reaction time (entry 3). Improved outcomes were not observed upon decreasing the
catalyst loading and/or the equivalents of anisole. Similarly, no improvement was seen by
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altering the reaction solvent or concentration (see Supporting Information). Attempts to shift the
keto-enol equilibrium toward either the keto or enol tautomer also failed to achieve any tenable
results.
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Table 1. Reaction Optimization
OMe
6
a
(10 equiv)
O
HO
O HO
O
O
Lewis acid
20 mol %) MeO
Me
OMe
Me
(
MeO
MeO
4-MeO-C6H4
CH Cl (0.1 M)
2
2
5a
rt
4-MeO-C H
7aa
4-MeO-C H 8a
6 4
6
4
7aa/8ab
yield of 7aa (%)c
entry
Lewis acid
time (h)
1
2
3
4
5
6
SnCl4
1
1
22.3:1
1:1.7
11.5:1
2.3:1
0:1
67
11
69
10
--d
63
In(OTf)3
InCl3
24
1
Sc(OTf)3
Al(OTf)3
Mg(OTf)2
72
27
5.7:1
a
Reactions were performed with 20 mol % Lewis acid, 10 equiv of anisole, and 1 equiv of
b
1
c
cyclopropane 5a in CH
2
Cl
2
(0.1 M) at 25 ˚C. Ratios determined by H NMR. Isolated yield of
d
keto/enol isomer mixture after column chromatography. Not determined.
Given the complex keto-enol mixture, we were unable to unequivocally determine the
absolute diastereoselectivity directly for 7aa. An estimate of the diastereoselectivity could be
1
inferred from the ratios of enol H’s using H NMR (11:1 dr, Figure 1A). However, an easily
exchangeable proton is usually not an ideal marker for determining ratios. This concern was
confirmed by subjecting 7aa to Krapcho decarbalkoxylation conditions and measuring the
1
diastereomeric ratio for product 9aa using H NMR of the crude reaction mixture (Figure 1B).
9
aa was obtained as a 7.7:1 diastereomeric mixture, which was later confirmed upon isolation.
Thus, although an initial estimate of diastereoselectivity could be made directly for 7aa, it did
not reflect the actual ratio (11:1 vs 7.7:1). Toward that end, for the remainder of the study, all
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diastereoselectivities were quantified and extrapolated to the keto-enol mixtures using the crude
Krapcho products. Nevertheless, in the cases where 7aa will be carried forward for further
1
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derivatization, the enol proton can still be used as a qualitative estimate.
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Figure 1. Determining Diastereoselectivity using H NMR
For 9aa, the major diastereomer had the two aryl substituents at C-2 and C-4 anti relative
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to one another (Scheme 2). This outcome can be rationalized using a modified cyclohexa-1,3-
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diene twist-chair conformation according to the Fürst-Plattner Rule. During the formation of
7aa, aryl attack on the Sn-oxyallyl cation complex II is expected to occur in an axial fashion in
order to achieve the preferred chair-like transition state (III). The anti orientation between the
1
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two aryl groups minimizes destabilizing 1,3-axial-pseudoaxial interactions upon aryl attack.
This destabilization is more pronounced in the formation of the minor diastereomer. This
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diastereoselectivity is consistent with our previous observations in the allylative, interrupted
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a
formal homo-Nazarov cyclization.
Scheme 2. Rationale for Stereochemical Outcome
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anti
orientation H
axial attack
preferred
H
OMe
O
R
Ar
III
Ar-H
Me
OMe
R
{Sn]
O
O
Me
O
[
Sn]
II
ꢀ
ꢀ
ꢀ
Next, the reactivity of anisole with various cyclopropanes under the optimized conditions
was examined (Table 2). Compared to 5a, phenyl cyclopropane 5b gave a reduced yield (44%)
of the expected arylated product 7ba with a 11.7:1 dr. 4-Fluorophenylcyclopropane 5c afforded
the desired product 7ca in 56% yield with a 10.5:1 dr. These product outcomes are consistent
1
8
with expected Hammett parameters for benzylic carbocation stability. The gem-disubstituted
methylphenyl cyclopropane 5d provided 7da in 44% yield with a 2.0:1 dr. This modest yield
was unanticipated as we expected 5d to perform better than 5b due to the added stabilization
from the gem-methyl group onto the benzylic carbocation intermediate. However, significant
product degradation was also observed. Good product yield (77%) and diastereoselectivity (8.3:1
dr) for 7ea was observed with the 2-naphthylcyclopropane 5e. Aryl-trapped product 7fa was
formed in 56% yield with a 5.5:1 dr from (2-thienyl)cyclopropane 5f.
Employing a non-aromatic cation-stabilizing donor on the cyclopropane (as in the
silylmethyl group in 5g) gave 57% yield of 7ga with good diastereoselectivity (11.2:1 dr).
Cyclopropanes 5h and 5i, respectively bearing an α-ethoxy or α-methylenesilyl substituent on
the alkene, both gave the undesired eliminative homo-Nazarov products and/or copious amounts
of indiscernible degradation products. The extra carbocation stabilization provided by the
heteroatom in 5h presumably reduces the electrophilicity of the oxyallyl cation thus hindering
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nucleophilic trapping, whereas the lability of the silyl group in 5i results in rapid formation of the
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2,19
eliminative product.
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Table 2.ꢀCatalytic, interrupted, formal homo-Nazarov cyclizations with anisole.
OMe
O
O
SnCl4
(20 mol %)
OMe
O
HO
R3
MeO
R1
MeO
Me
CH Cl (0.1 M)
2
2
R2
25 ˚C
5a-g
6
a
R1 R2
7
(10 equiv)
entrya
Cyclopropane
Product
yield (%)b
72 (63)
drc
OMe
O
O
O
OH
Me
Me
MeO2C
1
MeO
7.7:1
Me
Me
4
-MeO-C6H4
5a
4-MeO-C6H4
7aa
OMe
O
O
O
OH
MeO2C
2
MeO
44 (58)
12:1
Ph
5
5
b
c
Ph
7ba
OMe
O
O
O
O
OH
Me
Me
Me
Me
MeO2C
3
4
5
6
MeO
56 (57)
44 (61)
77 (77)
56 (76)
11:1
2.0:1
8.3:1
5.5:1
Me
Me
Me
Me
4-F-C6H4
4-F-C6H4
7ca
OMe
OH
MeO2C
MeO
Me
Ph
Me
Ph
5d
7da
OMe
O
OH
MeO2C
MeO2C
MeO
Np-2
5
5
e
2-Np
7ea
OMe
O
O
OH
MeO
2-thienyl
f
2-thienyl
7fa
OMe
O
OH
Me
MeO2C
7
8
MeO
TBDPS
57 (68)
11:1
Me
5
g
h
7ga
TBDPS
OMe
O
O
OH
OEt
MeO2C
--d
--e
MeO
-MeO-C6H4
OEt
4
5
5
4-MeO-C6H4
7ha
OMe
O
O
OH
MeO2C
--d
--e
9
MeO
-MeO-C6H4
TMS
4
TMS
i
4-MeO-C6H4
7ia
ꢀ
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a
4
Reactions were performed with cyclopropane 5 (1 equiv), arene 6 (10 equiv), and SnCl (20
b
mol %) in CH
2
Cl
2
(0.1 M) at 25 ˚C. Isolated yield after column chromatography. Numbers in
c
parentheses represent yields of Krapcho decarbalkoxylation products 9. Diastereomeric ratios
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1
d
e
determined by H NMR on the decarbalkoxylated products. No desired product formed Not
determined.
ꢀ
Other arenes were then employed to further probe the generality of the transformation
(Table 3). 1,2-Dimethoxybenzene (6b) is alkylated at its 4-position to give the expected product
7
ab in 72% yield with a 5.3:1 dr (entry 1). With 1,3-dimethoxybenzene (6c), two regioisomeric
products are possible; although only one product 7ac (alkylation at more sterically-accessible C-
) was obtained in 62% yield and a 6.8:1 dr (entry 2). Triphenylamine (6d) proved to be a
4
competent nucleophile providing 7ad in 71% yield and a 2.0:1 dr (entry 3). The 4-alkylated
product 7ae was isolated in 70% yield with a dr of 1.2:1 from the reaction with 1-
methoxynaphthalene (6e, entry 4). 4-Methylanisole (6f) gave a low yield (15%) of 7af (entry 5).
In this case, as compared to 7ac, steric hindrance presumably overrides any electronic preference
for reactivity. Less electron-rich arenes, such as benzene, toluene, halobenzenes, 3-bromoanisole,
and TMS benzene, failed to provide tractable amounts of α-arylated products (Figure 2). In these
cases, varying amounts of the eliminative homo-Nazarov product and a putative chloride-
trapping product were observed.
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Table 3. Reactions with various arenes.
R1
R2
R3
SnCl4
(20 mol %)
O
O
R2
OH
Me
R1
R3
R4
MeO
MeO2C
CH Cl (0.1 M)
Me R4
2
2
4-MeO-C6H4
25 ˚C
5
a
6b-f
(10 equiv)
7
4
-MeO-C6H4
entrya
Arene
Product
yield (%)b
drc
OMe
OMe
OH
OMe
OMe
MeO2C
1
72 (85)
88 (89)
71 (58)
70 (78)
5.3:1
Me
6
b
7ab
4-MeO-C6H4
OMe
OH
OMe
MeO2C
2
3
4
MeO
6.8:1
2.0:1
1.2:1
Me OMe
6
c
7ac
4-MeO-C6H4
NPh2
OH
NPh2
MeO2C
Me
6
d
7ad
4-MeO-C6H4
OMe
OH
OMe
MeO2C
Me
6
e
7ae
4-MeO-C6H4
Me
OH
OMe
MeO2C
15 (--)d
--e
5
Me OMe
Me
6
f
7af
4-MeO-C6H4
a
4
Reactions were performed with cyclopropane 5 (1 equiv), arene 6 (10 equiv), and SnCl (20
b
mol %) in CH
2
Cl
2
(0.1 M) at 25 ˚C. Isolated yield after column chromatography. Numbers in
c
parentheses represent yields of Krapcho decarbalkoxylation products 9. Diastereomeric ratios
1
d
determined by H NMR on the decarbalkoxylated products. No desired Krapcho product
e
isolated. Not determined.
ꢀ
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I
Br
F
Me
OMe
TMS
NMe2
Br
10
11
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Figure 2. Unsuccessful arene trapping agents
Given the success with arenes, we moved on to employing heteroarenes as the
nucleophiles under the same reaction conditions (Table 4). Furan (10a) and thiophene (10b) both
gave their expected 2-alkylated products 11aa and 11ab in 66% and 74% yield with dr’s of 1.8:1
and 4:3:1, respectively (entries 1 and 2). The observed regioselectivity is consistent with both the
2
0
10a
Friedel-Crafts reactivity of furan/thiophene and the observations by West for the interrupted
Nazarov cyclization. 2-Methoxythiophene (10c) afforded the 5-alkylated regioisomer 11ac in
7
5% yield and a 1.3:1 dr (entry 3). 2,5-Dimethylfuran (10d) and –thiophene (10e) provided their
respective products 11ad and 11ae in 46% and 87% yield (entries 4 and 5). Due to the instability
of 2,5-dimethylfuran in the presence of SnCl , the reaction was performed with InCl (10 mol %).
4
3
Benzothiophene (10f) was readily alkylated at the more nucleophilic C-3 position to form 11af in
73% yield and a 2.3:1 dr (entry 6). Similarly, N-tosyl indole (10h) afforded 11ah in 69% yield
and a 2.6:1 dr (entry 7). Blocking C-3 on N-tosyl indole with a methyl group (as in 10i) gave
only trace amount of product 11ai (entry 8). This outcome is most likely due to the combination
of the reduced nucleophilicity at C-2 and the steric influence of the methyl group. Finally, no
alkylated product was observed with N-tosyl- or N-methylpyrrole (entries 9 and 10).
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Table 4. Reactions using heteroarenes as nucleophiles
O
HO
X
O
O
SnCl4
(20 mol %)
Me
MeO
MeO
Me
X
CH Cl (0.1 M)
4-MeO-C6H4
2
2
5
a
10a-i
25 ˚C
4-MeO-C6H4
yield (%)b
11
drc
(10 equiv)
entrya
Heteroarene
X
Product
0
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9
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9
0
1
2
3
4
5
6
7
8
9
0
X
OH
MeO2C
Me
4-MeO-C6H4
1
2
10a (X = O)
10b (X = S)
11aa (X = O)
11ab (X = S)
66 (32)
74 (52)
1.8:1
4.3:1
OMe
S
OH
OMe
S
MeO2C
Me
3
75 (70)
1.3:1
4-MeO-C6H4
1
0c
11ac
Me
OH
X
Me
Me
MeO2C
X
Me
Me
4-MeO-C6H4
48d (42)
87 (71)
4
5
10d (X = O)
10e (X = S)
11ad (X = O)
11ae (X = S)
3.8:1
4.1:1
X
OH
X
MeO2C
Me
4-MeO-C6H4
6
7
10f (X = S)
10g (X = NTs)
11af (X = S)
11ag (X = NTs)
73 (62)
69 (78)
2.3:1
2.6:1
Me
OH
Me
MeO2C
NTs
Me
8
NTs
trace
--e
1
0h
4-MeO-C6H4
11ah
R
OH
N
MeO2C
NR
Me
4-MeO-C6H4
f
e
9
10
10i (R = Ts)
10j (R = Me)
11ai (R = Ts)
11aj (R = Me)
--
--
--
--
f
e
a
4
Reactions were performed with cyclopropane 5 (1 equiv), arene 10 (10 equiv), and SnCl (20
b
mol %) in CH
2
Cl
2
(0.1 M) at 25 ˚C. Isolated yield after column chromatography. Numbers in
c
parentheses represent yields of Krapcho decarbalkoxylated products 12. Diastereomeric ratios
1
d
determined by H NMR on the decarbalkoxylated products. Performed using 10 mol % InCl
3
e
f
instead of SnCl
4
. Not determined. No desired product formed.
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To showcase the utility of the α-(hetero)arylated products as synthetic building blocks,
we were inspired by the work of Padwa on intramolecular Diels-Alder reactions of alkylated
21
furans tethered to alkenes. Toward that end, we sought to initiate a subsequent intramolecular
10
11
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[
4+2] cycloaddition with furan product 11aa following α’-allylation. This sequence, if successful,
would form a functionalized tricycle that should allow access into the tetracyclic core of the
2
2
Swietenia mahagoni liminoids. When treated with NaH and allyl bromide, 11aa underwent
2
3
allylation in 53% yield to give 13 as a 7.1:3.6:3.1:1.0 mixture of diastereomers (Scheme 3). In
9a
agreement with our previous work, the major diastereomer from the allylation has the allyl and
furan groups syn to one another (i.e., 13A-α). 13A-α and the other syn diastereomer, 13A-β, are
both expected to undergo intramolecular cycloaddition, whereas the diastereomers with the allyl
and furan groups anti to one another (13B-α and 13B-β) will not react. When the mixture was
heated in xylenes at reflux, the desired [4+2] cycloadduct 14 was obtained in 46% yield (based
on 13A-α/β) as a 5.3:1 mixture of diastereomers. Full conversion was not achieved as some
unreacted 13A-α/β was recovered along with what appears to be some starting material/product
24
degradation.
Scheme 3. α’-Allylation and attempted intramolecular Diels-Alder cycloaddition of 11aa
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NaH
O
OH
O
O
Br
MeO2C
Me
2
MeO C
Me
THF
4
-MeO-C6H4
4
-MeO-C6H4
11aa
13A-α (25%); 13A-β (3.6%)
+ other
(
mixture of
diastereomers)
diastereomers 13B (24%)
O
0
1
2
3
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5
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7
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9
0
1
2
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0
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0
1
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8
9
0
[
4+2] xylenes, Δ
Me
O
H
O
O
R
O
Me
R
RO
Me Me
MeO2C
O
Me
Swietenia mahagoni
4
-MeO-C6H4
limonoids
1
4 (46%)
based on13A-α/β
In summary, we have developed a catalytic protocol for the interrupted, formal homo-
Nazarov cyclization using a range of electron-rich arenes and heteroarenes as nucleophiles for
trapping the six-membered oxyallyl cationic intermediate. The methodology provides facile
access to densely functionalized α-(hetero)aryl cyclohexanones in a single step from donor-
acceptor-acceptor cyclopropanes. α-(Hetero)arylated products are formed regiospecifically, and
in up to 88% yield and diastereoselectivities up to 12:1. A number of different cyclopropanes are
viable for reactivity. This cascade transformation represents the first example of a
(
hetero)arylative, interrupted homo-Nazarov cyclization. Further work on the intramolecular,
hetero)arylative capture of oxyallyl cations in the homo-Nazarov reaction is currently underway.
(
Application of the method toward specific bioactive natural product targets will be reported in
due course.
EXPERIMENTAL SECTION
General Information. Chromatographic purification was performed as flash chromatography
with silica gel (40-65µm) or preparative thin-layer chromatography (prep-TLC) using silica gel
F
254 (1000 µm) plates and solvents indicated as eluent with 0.1-0.5 bar pressure. For quantitative
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flash chromatography, technical grades solvents were utilized. Analytical thin-layer
chromatography (TLC) was performed on silica gel 60 µm F254 TLC glass plates. Visualization
was accomplished with UV light. Infrared (IR) spectra were obtained using FTIR with an ATR
attachment by attenuated total reflection through a diamond plate. The IR bands are
characterized as weak (w), medium (m), and strong (s). Proton and carbon nuclear magnetic
10
11
12
13
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1
13
resonance spectra ( H NMR and C NMR) were recorded on 300 MHz, 400 MHz, and 500 MHz
1
spectrometers with solvent resonances as the internal standard ( H NMR: CDCl
3
at 7.26 ppm;
1
3
19
C NMR: CDCl
spectrometers using PhCF
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets, dt
doublet of triplets, ddd = doublet of doublet of doublets, t = triplet, tt = triplet of triplets, m =
3
at 77.0 ppm). F NMR spectra were recorded on 400 and 500 MHz
1
13
19
3
as an external standard. H, C, and F NMR data are reported as
=
multiplet, br = broad), coupling constants (Hz), and integration. The accurate mass analyses were
run in EI mode on a double focusing magnetic sector mass spectrometer at a mass resolution of
1
0,000 using PFK (perfluorokerosene) as an internal calibrant or in ESI mode using a hybrid
linear ion trap/orbitrap tandem mass spectrometer. Uncorrected melting points were measured
with a digital melting point apparatus.
Reaction Optimizations Procedures.
Procedure for Catalyst Screening. To a dry flask charged with a stir bar and DCM was added the
Lewis acid (20 mol %) under nitrogen. Anisole (10.0 equiv) was added. Finally, cyclopropane 5a
(1.0 equiv, as a solution in DCM) was added, drop-wise, to mixture at the room temperature. The
volume of solvent used was such that the final concentration of cyclopropane in DCM was 0.1 M.
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4
4
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5
5
5
5
5
5
5
5
6
The reaction was monitored by TLC until complete conversion of cyclopropane was observed.
Upon reaching completion, the reaction was then quenched with distilled water (3 mL), and
extracted with DCM three times. The combined organic layers were concentrated under reduced
pressure and purified by silica gel flash chromatography using EtOAc/Hexane as the eluent.
Procedure for Optimization of Catalyst Loading. To a dry flask charged with a stir bar and DCM
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4 3
was added the applicable loading of SnCl or InCl under nitrogen. Anisole (10.0 equiv) was
added. Finally, cyclopropane 5a (1.0 equiv, as a solution in DCM) was added, drop-wise, to
mixture at the room temperature. The volume of solvent used was such that the final
concentration of cyclopropane in DCM was 0.1 M. The reaction was monitored by TLC until
complete conversion of cyclopropane was observed. Upon reaction completion, the reaction was
then quenched with distilled water (3 mL), and extracted with DCM three times. The combined
organic layers were concentrated under reduced pressure and purified by silica gel flash
chromatography using EtOAc/Hexanes as the eluent.
Procedure for Anisole Loading Screening. To a dry flask charged with a stir bar and DCM was
added the appropriate loading of anisole and SnCl
4
(20 mol %). Finally, cyclopropane 5a (1.0
equiv, as a solution in DCM) was added, dropwise, to the mixture at the room temperature. The
volume of solvent used was such that the final concentration of cyclopropane in DCM was 0.1 M.
The reaction was monitored by TLC until complete conversion of cyclopropane was observed.
Upon reaction completion, the reaction was then quenched with distilled water (3 mL), and
extracted with DCM three times. The combined organic layers were concentrated under reduced
pressure and purified by silica gel flash chromatography using EtOAc/Hexanes as the eluent.
Procedure for Temperature and Solvent Screening. To a dry flask charged with a stir bar and the
4
applicable solvent was added 20 mol% SnCl under nitrogen. Anisole (10.0 equiv) was added.
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Finally, cyclopropane 5a (1.0 equiv, as a solution in appropriate solvent) was added, drop-wise,
to the mixture at room temperature. In the temperature screening, DCM was used as the solvent.
The volume of solvent used was such that the final concentration of cyclopropane in the
appropriate solvent was 0.1 M. The reaction was monitored by TLC until complete conversion of
cyclopropane was observed. Upon reaching completion, the reaction was quenched with distilled
water (3 mL), and extracted with DCM three times. The combined organic layers were
concentrated under reduced pressure and purified by silica gel flash chromatography using
EtOAc/Hexanes as the eluent.
10
11
12
13
14
15
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Synthesis of Trapping Agents. 1-Methoxynaphthalene (6e) was prepared according to a
2
5
previously reported procedure.
2
6a
N-Tosyl indole (10g): Adapted from a reported procedure. Indole (500 mg, 4.26 mmol) as a
solution in THF (10 mL) was added to a suspension of NaH (256 mg as a 60% suspension in
mineral oil, 6.40 mmol) in THF (10 mL) and stirred for 30 min. Tosyl chloride (900 mg, 4.72
mmol) was added as a solution in THF (5 mL) and stirred overnight. Water was slowly added,
EtOAc added, and the organic layer was washed with sat. aq. NaHCO
Na SO , and concentrated. The residue was purified by flash column chromatography on silica
gel to give N-tosylindole (1.14 g, 98% yield). Characterization was consistent with that
3
, brine, and dried over
2
4
2
7
reported.
N-Tosyl-3-methylindole (10h): Adapted from a reported procedure. 3-methylindole (1.00 g,
.62 mmol) as a solution in THF (20 mL) was added to a suspension of NaH (666 mg as a 60%
suspension in mineral oil, 16.65 mmol) in THF (20 mL) and stirred for 30 min. Tosyl chloride
1.60 g, 8.38 mmol) was added as a solution in THF (10 mL) and stirred overnight. Water was
2
6a
7
(
3
slowly added, EtOAc added, and the organic layer was washed with sat. aq. NaHCO , brine, and
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4
4
4
4
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5
5
5
5
5
5
5
5
5
6
dried over Na
2
SO
4
, and concentrated. The residue was purified by flash column chromatography
on silica gel to give N-tosyl-3-methylindole (1.94 g, 89% yield). Characterization was consistent
2
6b
with that reported.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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0
2
8
N-Tosyl pyrrole (10i): Prepared using a modification of a patented procedure. Pyrrole (1.00 g,
15 mmol) as a solution in THF (4 mL) was added to a suspension of NaH (900 mg as a 60%
suspension in mineral oil, 22.5 mmol) in THF (4 mL) and stirred for 30 min. Tosyl chloride
(
2.84 g, 15 mmol) was added as a solution in THF (4 mL) and stirred for 3 h. Water was slowly
added, and the organic layer was separated, dried over Na SO , and concentrated. The residue
was purified by flash column chromatography on silica gel. Characterization was consistent with
2
4
2
8
that reported.
Synthesis of Cyclopropyl Malonates.
Dimethyl 2-((tert-butyldiphenylsilyl)methyl)cyclopropane-1,1-dicarboxylate (15g): Prepared
9
a
according to our previously reported conditions. Rh
2 2
esp (2 mg, 3 µmol) was dissolved in DCM
(2.05 mL) and allyl-TBDPS was added (1.18 mL, 4.11 mmol). After cooling to 0 ˚C,
diazodimethylmalonate (500 mg, 3.15 mmol) was added as a solution in DCM (2.05 mL). The
solution was allowed to warm to room temperature and stirred overnight. The reaction was
quenched with sat. aq. thiourea, extracted three times with DCM, and the organic layer was
washed with brine. The organic mixture was then dried over Na
The crude mixture was then purified by column chromatography on silica gel (10%
EtOAc/Hexane, R = 0.36) to give the cyclopropane 15g as a colorless oil (1.19 g, 92% yield).
2 4
SO , filtered, and concentrated.
f
2
9
All characterization was consistent with those previously published.
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Dimethyl 2-(thiophen-2-ylmethylene)malonate (16): Prepared using our previously reported
3
0
procedure. Dimethylmalonate (1.00 g, 7.57 mmol) was dissolved in benzene (15 mL).
Thiophene-2-carboxaldehyde (0.90 mL, 9.84 mmol), piperidine (0.15 mL, 1.51 mmol), and
acetic acid (0.22 mL, 3.78 mmol) were added. The reaction was heated to reflux with a Dean-
Stark apparatus for 4 h. The reaction was then concentrated. After water was added, the reaction
10
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14
15
16
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18
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was extracted three times with EtOAc, washed with 1M HCl, sat. aq. NaHCO
3
, and brine
sequentially, dried over Na SO , filtered, and concentrated. The mixture was purified by column
2
4
chromatography on silica gel (20% EtOAc/Hexanes, R
f
= 0.44) to give the unsaturated diester 16
) δ = 7.89 (d, J = 0.6 Hz, 1 H),
1
as a yellow oil (1.77g, >99% yield). H NMR (500MHz, CDCl
3
1
3
7.55 - 7.52 (m, 1 H), 7.38 - 7.36 (m, 1 H), 7.10 - 7.07 (m, 1 H), 3.93 (s, 3 H), 3.83 (s, 3 H). C
NMR (126MHz, CDCl ) δ = 166.6, 164.7, 135.9, 135.5, 134.7, 131.9, 127.8, 121.5, 52.8, 52.6.
3
-
1
+
10 4
IR: 2951 (w), 1719 (s), 1612 (s) cm . HRMS (EI) m/z: [M] Calcd. for C10H O S 226.0300;
Found 226.0302.
Dimethyl 2-(thiophen-2-yl)cyclopropane-1,1-dicarboxylate (15f): Prepared using a previously
3
1
reported procedure. Sodium hydride (195 mg as 60% suspension in mineral oil, 4.86 mmol)
was dissolved in DMSO (8.8 mL), and trimethylsulfoxonium iodide (1.07 g, 4.86 mmol) was
added in one portion at room temperature and stirred for 30 min. Compound 16 (1.00 g, 4.42
mmol) was added in one portion as a solution in DMSO (1.8 mL) at room temperature and
stirred for 30 min. The reaction was quenched with water at 0 ˚C, extracted five times with
diethyl ether, washed five times with water, dried over sodium sulfate, and concentrated. The
resulting mixture was purified by column chromatography on silica gel (20% EtOAc/Hexanes, R
f
1
=
0.52) to give the cyclopropane 15f as a yellow oil (591 mg, 56% yield). H NMR (300MHz,
CDCl
3
) δ = 7.18 - 7.14 (m, 1 H), 6.90 (dd, J = 3.5, 5.1 Hz, 1 H), 6.85 - 6.82 (m, 1 H), 3.78 (s, 3
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5
5
6
13
H), 3.48 (s, 3 H), 3.32 - 3.25 (m, 1 H), 2.17 - 2.12 (m, 1 H), 1.86 - 1.80 (m, 1 H). C NMR
(75MHz, CDCl ) δ = 169.7, 166.7, 138.0, 126.7, 126.2, 125.1, 52.9, 52.5, 37.8, 27.3, 21.0. IR:
12 4
951 (w), 1721 (s) cm . HRMS (EI) m/z: [M] Calcd. for C11H O S 240.0456; Found 240.0468.
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+
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0
Synthesis of Cyclopropyl Vinyl Ketones. Cyclopropyl vinyl ketones 5a-e, 5h, and 5i were
prepared according to our previously reported conditions. All characterizations were in
9
a,9c
agreement with those previously published.
Methyl
1-methacryloyl-2-(thiophen-2-yl)cyclopropane-1-carboxylate
(5f):
Prepared
9a,9c
according to our previously reported conditions.
Compound 15f (580 mg, 2.41 mmol)
dissolved in THF (6.2 mL) and isopropenylmagnesium bromide (5.8 mL as 0.5 M solution in
THF, 2.90 mmol) were stirred for 2 h at -78°C. The reaction was quenched with sat. aq. NH Cl,
extracted three times with EtOAc, acidified to pH=4 with HCl, and extracted a final time with
EtOAc. After drying with Na SO , filtering, and concentrating, the reaction was purified by flash
chromatography on silica gel (10% EtOAc/Hexanes, R
4
2
4
f
= 0.44) and 5f was given as a colorless
1
oil (398 mg, 65% yield). (Diastereomeric ratio = 2.7:1) H NMR (500MHz, CDCl
3
) δ = 7.15
(
dd, J = 1.1, 5.0 Hz, 0.37 H), 7.07 (dd, J = 1.1, 5.0 Hz, 1 H), 6.91 (dd, J = 3.7, 5.2 Hz, 0.41 H),
6
.89 - 6.87 (m, 0.41 H), 6.84 (dd, J = 3.5, 5.0 Hz, 1 H), 6.65 (td, J = 0.9, 3.7 Hz, 1 H), 5.91 (d, J
= 0.9 Hz, 0.37 H), 5.74 - 5.71 (m, 1.47 H), 5.64 - 5.62 (m, 1 H), 3.71 (s, 3 H), 3.50 - 3.45 (m,
.28 H), 3.44 - 3.39 (m, 0.41 H), 2.27 (dd, J = 4.7, 7.8 Hz, 0.41 H), 2.18 (dd, J = 5.0, 7.8 Hz, 1
H), 1.96 - 1.94 (m, 1.12 H), 1.76 (dd, J = 5.0, 9.3 Hz, 1 H), 1.74 (dd, J = 0.9, 1.5 Hz, 3 H), 1.61
2
1
3
(
dd, J = 4.9, 9.2 Hz, 0.47 H). C NMR (126MHz, CDCl
3
) δ = 195.7, 193.6, 171.2, 168.6, 144.3,
1
44.1, 138.3, 138.0, 126.8, 126.6, 126.6, 125.5, 125.2, 124.8, 124.4, 124.0, 52.6, 52.4, 42.3, 41.6,
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8.4, 24.9, 21.7, 20.4, 17.9, 17.4. IR: 2953 (w), 1724 (s), 1670 (s) cm . HRMS (EI) m/z: [M]
Calcd. for C13 S 250.0664; Found 250.0666.
1R,2S)/(1S,2R)-Methyl 2-((tert-butyldiphenylsilyl)methyl)-1-methacryloylcyclopropane-1-
14 3
H O
(
10
11
12
13
14
15
16
17
18
19
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21
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
a,9c
carboxylate (5g): Prepared according to our previously reported conditions.
Cyclopropane
15g (979 mg, 2.38 mmol) dissolved in THF (6.3 mL) and isopropenylmagnesium bromide (5.8
mL from 0.5 M solution in THF, 2.90 mmol) were stirred for 1 h at -78 ˚C. The reaction was
quenched with sat. aq. NH
4
Cl, extracted three times with EtOAc, acidified to pH=4 with HCl,
SO , filtering, and concentrating,
and extracted a final time with EtOAc. After drying with Na
2
4
the reaction was purified by flash chromatography on silica gel (10% EtOAc/Hexanes, R
f
= 0.47)
1
and 5g was given as a colorless oil (500 mg, 50% yield). H NMR (500MHz, CDCl
3
) δ = 7.64 -
7
.60 (m, 4 H), 7.42 - 7.32 (m, 6 H), 5.74 (s, 1 H), 5.60 - 5.59 (m, 1 H), 3.68 (s, 3 H), 2.04 - 1.96
(
m, 1 H), 1.85 (t, J = 1.1 Hz, 3 H), 1.50 (dd, J = 3.2, 14.8 Hz, 1 H), 1.28 - 1.24 (m, 1 H), 1.18 (dd,
1
3
J = 11.3, 15.0 Hz, 1 H), 1.06 (s, 9 H), 1.00 (dd, J = 4.6, 9.2 Hz, 1 H). C NMR (126MHz,
CDCl ) δ = 197.1, 170.7, 144.5, 136.1, 136.0, 134.3, 134.0, 129.2, 129.2, 127.7, 127.6, 127.5,
123.1, 77.3, 76.7, 52.2, 39.6, 27.8, 27.8, 24.1, 24.0, 18.1, 17.9, 8.4. IR: 2953 (w), 2929 (w), 2887
3
-
1
+
(
w), 2856 (w), 1728 (s), 1672 (s) cm . HRMS (ESI) m/z: [M+H] Calcd. for C26
33 3
H O Si
4
21.2193; Found 421.2185.
(1R,2R)/(1S,2S)-Methyl 2-((tert-butyldiphenylsilyl)methyl)-1-methacryloylcyclopropane-1-
9a,9c
carboxylate (epi-5g): Prepared according to our previously reported conditions.
Cyclopropane 15g (979 mg, 2.38 mmol) dissolved in THF (6.3 mL) and isopropenylmagnesium
bromide (5.8 mL from 0.5 M solution in THF, 2.90 mmol) were stirred for 1 h at -78 ˚C. The
4
reaction was quenched with sat. aq. NH Cl, extracted three times with EtOAc, acidified to pH=4
2 4
with HCl, and extracted a final time with EtOAc. After drying with Na SO , filtering, and
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5
5
6
concentrating, the reaction was purified by flash chromatography on silica gel (10%
1
EtOAc/Hexanes, R
NMR (500MHz, CDCl
.78 - 5.76 (m, 1 H), 3.59 (s, 3 H), 2.13 - 2.06 (m, 1 H), 1.97 (dd, J = 0.9, 1.5 Hz, 3 H), 1.49 (dd,
f
= 0.39) and epi-5g was given as a colorless oil (251 mg, 25% yield). H
3
) δ = 7.60 - 7.56 (m, 4 H), 7.42 - 7.33 (m, 6 H), 5.80 - 5.78 (m, 1 H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
J = 2.4, 14.6 Hz, 1 H), 1.19 (dd, J = 4.6, 7.6 Hz, 1 H), 1.04 - 1.01 (m, 10 H), 0.48 (dd, J = 12.2,
13
1
3
4.6 Hz, 1 H). C NMR (126MHz, CDCl ) δ = 196.3, 172.3, 145.7, 136.0, 135.9, 134.0, 133.9,
129.3, 127.7, 127.6, 124.3, 52.2, 38.6, 27.8, 26.2, 22.6, 18.1, 17.8, 9.8. IR: 2957 (w), 2928 (w),
-1
+
2
33 3
857 (w), 1726 (s), 1674 (s) cm . HRMS (ESI) m/z: [M+H] Calcd. for C26H O Si 421.2193;
Found 421.2185.
Synthesis of (Hetero)arylated Homo-Nazarov Products.
General Procedure: To a dry flask charged with a stir bar, 4 Å molecular sieves, and CH
added the appropriate arene or heteroarene (10 equiv.) and cyclopropane (1.0 equiv., as a
solution in CH Cl ). The final volume of CH Cl used was such that the concentration of
cyclopropane in CH Cl was 0.1 M. SnCl (20 mol %) was added dropwise or InCl (10 mol %)
2 2
Cl was
2
2
2
2
2
2
4
3
all at once and the reaction was stirred at room temperature (unless otherwise noted) until the
cyclopropane was consumed (as monitored by TLC). The reaction was quenched with water (3
2 2
mL) and extracted three times with CH Cl . The combined organic layers were dried over
Na SO and concentrated under reduced pressure. The resulting crude mixture was purified by
2
4
silica gel flash chromatography unless noted as being purified by preparatory thin-layer
chromatography using EtOAc/hexanes as the eluent.
Methyl 6'-hydroxy-4,4''-dimethoxy-1'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-terphenyl]-
5
'-carboxylate (7aa): Prepared following general procedure using cyclopropane 5a (100 mg,
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.37 mmol), anisole (0.40 mL, 3.65 mmol), and SnCl
stirred at room temperature for 1 h. After work-up and purification (10% EtOAc/Hexanes, R
.29), cyclohexenol 7aa was given as a colorless oil (94 mg, 67% yield). Complex mixture of
4 2 2
(9 µL, 0.07 mmol) in CH Cl (3.7 mL)
f
=
0
10
11
12
13
14
15
16
17
18
19
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
keto-enol tautomers and diastereomers. H NMR (300MHz, CDCl
3
) δ = 12.60 (s, 0.57 H), 7.30 -
7.23 (m, 2.23 H), 7.22 - 7.14 (m, 4.52 H), 7.07 - 7.01 (m, 1.65 H), 7.00 - 6.95 (m, 2.15 H), 6.91 -
6
2
.83 (m, 4.16 H), 6.83 - 6.77 (m, 1.72 H), 3.84 (s, 2.91 H), 3.81 - 3.79 (m, 8.20 H), 3.77 (d, J =
.8 Hz, 6.27 H), 3.27 - 3.15 (m, 1.26 H), 2.77 (dt, J = 3.3, 14.4 Hz, 1.11 H), 2.68 (dd, J = 1.7, 5.2
Hz, 0.35 H), 2.65 - 2.52 (m, 1.36 H), 2.37 - 2.15 (m, 3.02 H), 2.15 - 1.96 (m, 3.16 H), 1.61 (s,
1
3
2
.32 H), 1.29 (s, 3.00 H). C NMR (75MHz, CDCl
3
) δ = 208.4, 174.9, 173.3, 170.5, 158.5,
158.4, 157.9, 157.8, 138.2, 137.6, 135.7, 134.3, 127.6, 127.6, 127.5, 127.0, 114.8, 114.0, 113.7,
1
2
13.5, 98.7, 55.3, 55.2, 55.2, 54.1, 54.0, 52.0, 51.6, 46.4, 45.8, 45.0, 37.8, 37.1, 34.4, 32.0, 28.4,
-
1
7.1. IR: 2931 (w), 1746 (m), 1714 (m), 1653 (m), 1611 (m), 1512 (s) cm . HRMS (EI) m/z:
+
[
M] Calcd. for C23
H
26
O
5
382.1780; Found 382.1765.
Methyl
6'-hydroxy-4-methoxy-1'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-terphenyl]-5'-
carboxylate (7ba): Prepared following the general procedure using cyclopropane 5b (104 mg,
.42 mmol), anisole (0.44 mL, 4.09 mmol), and SnCl (9 µL, 0.07 mmol) in CH Cl (4.2 mL)
stirred at room temperature for 1 h. After work-up and purification by prepTLC (10%
0
4
2
2
EtOAc/Hexanes, R
f
= 0.48), cyclohexenol 7ba was given as a colorless oil (66 mg, 44% yield).
1
Complex mixture of keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl
3
) δ =
12.59 (s, 0.90 H), 12.36 (s, 0.14 H), 7.35 - 7.30 (m, 1.87 H), 7.28 - 7.21 (m, 7.89 H), 7.18 - 7.13
m, 2.85 H), 7.12 - 7.08 (m, 1.95 H), 6.98 - 6.94 (m, 1.67 H), 6.88 - 6.82 (m, 2.30 H), 3.82 (s,
.62 H), 3.79 - 3.77 (m, 6.49 H), 3.77 - 3.75 (m, 3.46 H), 3.74 (s, 0.23 H), 3.70 (s, 0.14 H), 3.23
(
2
(tt, J = 3.3, 12.7 Hz, 0.93 H), 3.12 - 2.99 (m, 0.24 H), 2.78 (dt, J = 3.2, 14.6 Hz, 1.01 H), 2.70 -
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5
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5
5
6
2
.59 (m, 2.04 H), 2.39 - 2.29 (m, 1.84 H), 2.26 - 2.18 (m, 1.02 H), 2.17 - 2.10 (m, 1.18 H), 2.09 -
1
3
1.99 (m, 2.21 H), 1.76 (s, 0.51 H), 1.59 (s, 3.00 H), 1.28 (s, 2.66 H), 1.25 - 1.19 (m, 0.84 H). C
NMR (126MHz, CDCl ) δ = 208.3, 174.9, 173.3, 170.5, 158.5, 157.9, 145.5, 143.6, 138.1, 134.2,
28.7, 128.4, 127.5, 127.0, 126.9, 126.8, 126.7, 126.7, 126.2, 114.9, 113.7, 113.6, 98.7, 55.3,
55.2, 54.1, 54.0, 52.0, 51.6, 46.1, 45.6, 45.0, 38.0, 37.5, 35.3, 31.8, 28.4, 27.1. IR: 2951 (w),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-1
+
1
746 (m), 1711 (m), 1651 (m), 1611 (m), 1512 (s) cm . HRMS (EI) m/z: [M] Calcd. for
C
22
H
24
O
4
352.1675; Found 352.1677.
Methyl
4''-fluoro-6'-hydroxy-4-methoxy-1'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-5'-carboxylate (7ca): Prepared following the general procedure using cyclopropane
5c (100 mg, 0.38 mmol), anisole (0.41 mL, 3.81 mmol), and SnCl (9 µL, 0.08 mmol) in CH Cl
3.8 mL) stirred at room temperature for 1.5 h. After work-up and purification (10%
4
2
2
(
EtOAc/Hexanes, R
f
= 0.33), cyclohexenol 7ca was given as a colorless oil (79 mg, 56% yield).
1
Complex mixture of keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl
3
) δ =
1
2.60 (s, 0.96 H), 12.38 (s, 0.10 H), 7.82 - 7.79 (m, 0.25 H), 7.37 - 7.33 (m, 0.28 H), 7.29 - 7.18
(m, 3.63 H), 7.17 - 7.15 (m, 0.57 H), 7.09 - 7.04 (m, 2.31 H), 7.04 - 6.96 (m, 1.31 H), 6.96 - 6.91
m, 2.17 H), 6.90 - 6.84 (m, 2.32 H), 3.84 (s, 0.90 H), 3.81 - 3.80 (m, 6.53 H), 3.79 - 3.77 (m,
.39 H), 3.28 - 3.20 (m, 0.39 H), 3.07 - 2.99 (m, 0.12 H), 2.80 - 2.73 (m, 0.43 H), 2.69 - 2.59 (m,
(
1
2.13 H), 2.45 (s, 0.39 H), 2.42 - 2.35 (m, 0.20 H), 2.35 - 2.26 (m, 1.36 H), 2.24 - 2.18 (m, 0.30
H), 2.13 - 2.08 (m, 1.09 H), 2.06 - 1.98 (m, 1.35 H), 1.77 (s, 0.33 H), 1.61 (s, 3.00 H), 1.29 (s,
1
3
0
.75 H). C NMR (126MHz, CDCl
44.0ꢀHz),ꢀ160.7,ꢀ158.6,ꢀ158.0, 157.9, 144.6, 141.1, 141.1, 139.3, 138.8, 138.0, 134.1, 129.8,
28.2, 128.1, 128.1, 128.1, 128.1, 127.8, 127.5, 127.3, 126.9, 115.6, 115.4, 115.2, 115.1, 115.1,
3
) δ = 208.1, 176.4, 174.9, 173.3, 170.4, 161.3ꢀ(d,ꢀ1JC-Fꢀ=ꢀ
2
1
115.0, 114.9, 113.8, 113.6, 98.6, 97.9, 66.8, 55.3, 55.2, 54.0, 54.0, 52.1, 51.7, 48.4, 46.3, 45.7,
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19
4
5.0, 45.0, 37.7, 37.3, 36.5, 34.6, 32.0, 31.9, 28.4, 27.0, 24.2, 21.6, 14.7. F NMR (471 MHz,
CDCl
3
) δ = -117.21 (quin, J = 6.0 Hz, 0.29 F), -118.01 - -118.07 (m, 0.14 F), -118.26 (quin, J =
-1
6
.0 Hz, 1.00 F). IR: 2928 (w), 1744 (w), 1715 (w), 1670 (s), 1653 (s), 1508 (s) cm . HRMS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(
EI) m/z: [M] Calcd. for C22
23 4
H O F 370.1580; Found 370.1570.
Methyl 6'-hydroxy-4-methoxy-1',3'-dimethyl-1',2',3',4'-tetrahydro-[1,1':3',1''-terphenyl]-
5
'-carboxylate (7da): Prepared following the general procedure using cyclopropane 5d (98 mg,
0
.39 mmol), anisole (0.42 mL, 3.87 mmol), and SnCl (9 µL, 0.08 mmol) in CH Cl (3.9 mL)
4
2
2
stirred at room temperature for 1 h. After work-up and purification (10% EtOAc/Hexanes, R
f
=
0
.38), cyclohexenol 7da was given as a colorless oil (61 mg, 44% yield). Complex mixture of
1
keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl
3
) δ = 12.53 (s, 0.90 H), 12.45
(
(
(
s, 0.44 H), 7.34 - 7.28 (m, 2.35 H), 7.25 - 7.18 (m, 1.91 H), 7.02 - 6.93 (m, 5.09 H), 6.88 - 6.84
m, 1.03 H), 6.78 - 6.73 (m, 2.07 H), 6.52 - 6.48 (m, 2.00 H), 3.92 - 3.89 (m, 4.31 H), 3.87 - 3.82
m, 0.98 H), 3.79 (s, 1.41 H), 3.70 (s, 2.90 H), 3.11 (dd, J = 2.3, 16.3 Hz, 0.50 H), 3.04 (dd, J =
1
.8, 16.2 Hz, 1.00 H), 2.51 - 2.43 (m, 2.50 H), 2.32 - 2.27 (m, 0.57 H), 2.23 - 2.18 (m, 0.50 H),
2.08 (d, J = 14.0 Hz, 0.97 H), 1.63 (s, 2.96 H), 1.30 - 1.25 (m, 3.70 H), 1.20 (s, 1.45 H), 1.03 (s,
13
1
1
5
1
3
.45 H). C NMR (126MHz, CDCl ) δ = 175.9, 175.7, 173.3, 173.1, 157.7, 156.9, 146.1, 140.3,
38.4, 128.2, 127.6, 127.2, 127.2, 126.3, 126.0, 125.9, 125.3, 113.6, 113.1, 97.7, 97.3, 55.2, 53.8,
2.7, 51.9, 51.8, 44.2, 43.9, 36.9, 36.5, 34.4, 34.2, 32.1, 31.9, 28.3, 25.3. IR: 2953 (w), 1653 (s),
-1
+
612 (s), 1510 (s) cm . HRMS (EI) m/z: [M] Calcd. for C23
2-hydroxy-4'-methoxy-1-methyl-5-(naphthalen-2-yl)-1,4,5,6-tetrahydro-[1,1'-
biphenyl]-3-carboxylate (7ea): Prepared following the general procedure using cyclopropane
e (100 mg, 0.35 mmol), anisole (0.38 mL, 3.52 mmol), and SnCl (8 µL, 0.07 mmol) in CH Cl
26 4
H O 366.1831; Found 366.1815.
Methyl
5
4
2
2
(
3.5 mL) stirred at room temperature for 1 h. After work-up and purification (10%
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EtOAc/Hexanes, R
f
= 0.36), cyclohexenol 7ea was given as a colorless oil (76 mg, 54% yield).
1
Complex mixture of keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl
3
) δ =
1
2.65 (s, 1.40 H), 12.42 (s, 0.21 H), 7.87 - 7.67 (m, 10.44 H), 7.56 (br. s., 1.50 H), 7.52 - 7.39 (m,
.51 H), 7.34 - 7.29 (m, 3.62 H), 7.27 - 7.25 (m, 2.26 H), 7.24 - 7.21 (m, 1.93 H), 7.04 - 7.00 (m,
1.90 H), 6.93 - 6.87 (m, 3.60 H), 3.86 (s, 3.13 H), 3.83 - 3.81 (m, 10.12 H), 3.81 - 3.80 (m, 3.45
H), 3.43 (tt, J = 3.3, 12.7 Hz, 1.00 H), 2.89 (dt, J = 3.2, 14.6 Hz, 1.26 H), 2.86 - 2.74 (m, 3.24 H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
2
1
.57 - 2.43 (m, 2.93 H), 2.37 - 2.29 (m, 1.27 H), 2.27 - 2.22 (m, 1.56 H), 2.20 - 2.13 (m, 2.51 H),
1
3
3
.83 (s, 0.71 H), 1.65 (s, 4.45 H), 1.41 (s, 0.42 H), 1.33 (s, 2.82 H). C NMR (126MHz, CDCl )
δ = 208.3, 175.0, 173.4, 173.1, 170.5, 158.6, 157.9, 142.9, 142.5, 141.0, 138.1, 134.2, 133.5,
133.5, 132.5, 132.2, 128.4, 127.9, 127.6, 127.6, 127.5, 127.5, 127.4, 127.0, 126.2, 126.0, 125.9,
1
5
2
25.8, 125.7, 125.7, 125.4, 125.3, 124.8, 124.8, 124.7, 114.9, 113.8, 113.6, 98.7, 55.3, 55.2, 54.1,
4.1, 52.1, 51.7, 46.2, 45.6, 45.1, 45.0, 38.0, 37.4, 37.3, 36.6, 35.4, 31.8, 31.6, 28.4, 27.1. IR:
-
1
+
928 (w), 1744 (m), 1713 (m), 1653 (m), 1611 (m), 1512 (s) cm . HRMS (EI) m/z: [M] Calcd.
for C26
H
26
O
4
402.1831; Found 402.1823.
Methyl
2-hydroxy-4'-methoxy-1-methyl-5-(thiophen-2-yl)-1,4,5,6-tetrahydro-[1,1'-
biphenyl]-3-carboxylate (7fa): Prepared following the general procedure using cyclopropane 5a
101 mg, 0.40 mmol), anisole (0.43 mL, 4.00 mmol), and SnCl (9 µL, 0.08 mmol) in CH Cl
(4.0 mL) stirred at room temperature for 1 h. After work-up and purification (10%
(
4
2
2
EtOAc/Hexanes, R
f
= 0.52), cyclohexenol 7fa was given as a colorless oil (81 mg, 56% yield).
1
Complex mixture of keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl3) δ =
1
7
2.60 (s, 0.96 H), 12.38 (s, 0.15 H), 7.32 - 7.24 (m, 3.42 H), 7.19 (dd, J = 1.1, 5.0 Hz, 0.45 H),
.18 - 7.13 (m, 1.13 H), 7.12 - 7.10 (m, 1.00 H), 6.99 - 6.95 (m, 1.47 H), 6.94 - 6.92 (m, 0.53 H),
6.91 - 6.84 (m, 4.55 H), 6.74 (dt, J = 1.1, 3.4 Hz, 1.00 H), 3.83 (s, 1.37 H), 3.82 (s, 3.55 H), 3.80
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(
s, 4.41 H), 3.78 - 3.77 (m, 1.33 H), 3.58 - 3.51 (m, 0.51 H), 2.99 - 2.90 (m, 1.77 H), 2.82 (ddd, J
= 1.8, 5.4, 15.9 Hz, 1.14 H), 2.50 - 2.44 (m, 0.33 H), 2.42 - 2.32 (m, 2.08 H), 2.28 (dt, J = 2.1,
2.9 Hz, 1.12 H), 2.18 - 2.07 (m, 0.85 H), 2.06 - 2.00 (m, 1.74 H), 1.77 (s, 0.54 H), 1.62 - 1.60
1
10
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53
54
55
56
57
58
59
60
1
3
(
m, 3.39 H), 1.40 (s, 0.32 H), 1.30 (s, 1.25 H). C NMR (126MHz, CDCl
3
) δ = 207.8, 174.8,
173.2, 158.6, 158.0, 149.6, 137.8, 129.4, 127.5, 127.4, 126.9, 126.8, 126.6, 126.5, 123.3, 122.9,
1
3
1
22.7, 122.6, 114.9, 113.8, 113.7, 98.3, 55.3, 55.2, 55.1, 53.9, 53.8, 52.1, 51.7, 47.4, 46.1, 44.9,
8.5, 36.6, 33.4, 32.5, 31.1, 28.3, 26.9. IR: 2951 (w), 2931 (w), 1744 (m), 1711 (m), 1653 (s),
-
1
+
611 (s), 1510 (s) cm . HRMS (EI) m/z: [M] Calcd. for C20
5-((tert-butyldiphenylsilyl)methyl)-2-hydroxy-4'-methoxy-1-methyl-1,4,5,6-
tetrahydro-[1,1'-biphenyl]-3-carboxylate (7ga): Prepared following the general procedure
using cyclopropane 5g (150 mg, 0.36 mmol), anisole (0.39 mL, 3.56 mmol), and SnCl (9 µL,
.07 mmol) in CH Cl (3.6 mL) stirred at room temperature for 27 h. After work-up and
purification (10% EtOAc/Hexanes, R
22 4
H O S 358.1239; Found 358.1236.
Methyl
4
0
2
2
f
= 0.62), cyclohexenol 7ga was given as a colorless oil
1
(
(
-
-
109 mg, 57% yield). Complex mixture of keto-enol tautomers and diastereomers. H NMR
3
500MHz, CDCl ) δ = 12.31 (s, 0.44 H), 12.28 - 12.27 (m, 0.03 H), 7.75 - 7.72 (m, 2.06 H), 7.71
7.68 (m, 2.08 H), 7.66 - 7.59 (m, 0.94 H), 7.48 - 7.39 (m, 9.69 H), 7.39 - 7.36 (m, 0.93 H), 7.36
7.32 (m, 1.45 H), 7.28 - 7.22 (m, 2.65 H), 6.90 - 6.86 (m, 1.10 H), 6.68 – 6.65 (m, 1.05 H), 6.63
- 6.59 (m, 2.01 H), 6.48 - 6.44 (m, 1.91 H), 3.78 (s, 1.61 H), 3.75 - 3.74 (m, 2.93 H), 3.70 - 3.68
m, 4.50 H), 3.34 (dd, J = 5.2, 13.4 Hz, 1.00 H), 2.32 (dt, J = 3.4, 14.3 Hz, 1.00 H), 2.21 (ddd, J
2.1, 5.0, 15.8 Hz, 0.59 H), 2.10 - 2.01 (m, 1.17 H), 1.98 - 1.92 (m, 1.23 H), 1.90 - 1.82 (m, 1.37
(
=
H), 1.79 - 1.68 (m, 1.66 H), 1.67 - 1.59 (m, 1.23 H), 1.59 - 1.54 (m, 0.50 H), 1.47 - 1.41 (m, 1.43
H), 1.40 (s, 0.67 H), 1.38 (s, 1.59 H), 1.32 (d, J = 5.2 Hz, 0.44 H), 1.28 (d, J = 4.9 Hz, 0.74 H),
1
.23 - 1.19 (m, 1.32 H), 1.18 – 1.15 (m, 0.78 H), 1.13 – 1.12 (m, 0.46 H), 1.08 (s, 0.70 H), 1.07 -
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13
1
.04 (m, 2.03 H), 1.02 (s, 4.10 H), 1.00 (s, 8.61 H), 0.91 - 0.89 (m, 4.55 H). C NMR (126MHz,
CDCl ) δ = 208.9, 174.8, 173.2, 170.6, 157.9, 157.5, 138.2, 136.2, 136.1, 136.0, 135.9, 134.8,
34.7, 134.5, 134.1, 133.9, 129.3, 128.8, 128.7, 127.8, 127.7, 127.4, 127.3, 127.3, 126.8, 114.4,
13.3, 98.8, 55.2, 55.1, 53.7, 53.4, 51.9, 51.4, 49.3, 47.3, 44.6, 40.9, 34.0, 28.2, 27.9, 27.8, 27.7,
3
1
1
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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8
9
0
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9
0
27.7, 26.6, 25.3, 24.8, 24.7, 23.3, 18.2, 18.0, 17.9, 16.8. IR: 2951 (w), 2857 (w), 1746 (s), 1711
-1
+
(
41 4
s), 1653 (m), 1611 (m), 1512 (s) cm . HRMS (ESI) m/z: [M+H] Calcd. for C33H O Si
5
29.2769; Found 529.2757.
Methyl
6'-hydroxy-3,4,4''-trimethoxy-1'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-5'-carboxylate (7ab): The general procedure was followed using cyclopropane 5a
(100 mg, 0.364 mmol), 1,2-dimethoxybenzene (0.47 mL, 3.65 mmol), SnCl (9 µL, 0.077 mmol)
and CH Cl (3.65 mL) at room temperature for 1 h. After work-up and purification (10%
EtOAc/hexane, R
4
2
2
f
= 0.450), cyclohexenol 7ab was afforded as a yellow oil (108 mg, 72% yield).
1
Complex mixture of keto-enol tautomers and diastereomers. H NMR (300 MHz, CDCl
3
) δ =
1
2.62 (s, 1.12 H), 12.40 (s, 0.29 H), 7.21 - 7.14 (m, 3.23 H), 7.07 - 7.01 (m, 3.20 H), 6.96 - 6.78
(m, 15.43 H), 6.69 (d, J = 2.2 Hz, 1 H), 3.92 - 3.85 (m, 19.30 H), 3.81 - 3.75 (m, 19.84 H), 3.30 -
3
1
.17 (m, 1.31 H), 3.07 - 2.94 (m, 0.42 H), 2.82 - 2.56 (m, 4.94 H), 2.44 - 2.28 (m, 2.92 H), 2.28 -
1
3
.95 (m, 6.91 H), 1.78 (s, 1.21 H), 1.61 (s, 4.32 H), 1.31 (s, 3 H). C NMR (75 MHz, CDCl
208.4, 174.7, 173.3, 170.4, 158.4, 157.9, 149.6, 148.6, 147.9, 147.4, 139.4, 138.6, 137.6, 137.1,
35.6, 134.7, 127.6, 127.6, 127.5, 119.0, 117.8, 114.1, 113.8, 113.7, 111.8, 110.7, 109.9, 109.2,
98.7, 98.0, 77.4, 76.6, 56.0, 55.9, 55.9, 55.9, 55.8, 55.2, 55.2, 55.2, 54.3, 54.2, 52.0, 51.6, 46.2,
3
) δ
=
1
-
1
4
5.9, 45.2, 37.6, 37.3, 36.3, 34.5, 32.0, 28.1, 27.2. IR: 3397 (m), 1648 (s) cm . HRMS (EI) m/z:
+
[M] Calcd. for C24
H
28
O
6
412.1886; Found 412.1887.
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Methyl
6'-hydroxy-2,4,4''-trimethoxy-1'-methyl-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-5'-carboxylate (7ac): Prepared following the general procedure using cyclopropane
a (77 mg, 0.28 mmol), 1,3-dimethoxybenzene (0.38 mL, 2.80 mmol), and SnCl (6 µL, 0.06
mmol) in CH Cl (2.8 mL) stirred at room temperature for 1 h. After work-up and purification
(20% EtOAc/Hexanes, R
5
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
2
f
= 0.44), cyclohexenol 7ac was given as a colorless oil (102 mg, 88%
1
yield). Complex mixture of keto-enol tautomers and diastereomers. H NMR (500MHz, CDCl
3
)
δ = 12.61 - 12.59 (m, 0.06 H), 12.48 (s, 0.21 H), 7.31 (d, J = 8.5 Hz, 1.00 H), 7.20 - 7.10 (m,
3
6
.91 H), 6.88 - 6.81 (m, 3.35 H), 6.60 (dd, J = 2.4, 8.5 Hz, 1.05 H), 6.51 (d, J = 2.7 Hz, 1.03 H),
.49 - 6.48 (m, 0.59 H), 6.46 – 6.44 (m, 0.39 H), 3.85 (s, 3.01 H), 3.84 (s, 0.81 H), 3.80 - 3.74 (m,
18.10 H), 3.74 - 3.69 (m, 1.86 H), 3.22 – 3.16 (m, 1.29 H), 3.08 - 3.00 (m, 0.28 H), 2.78 - 2.68
m, 1.36 H), 2.65 - 2.61 (m, 0.24 H), 2.52 - 2.41 (m, 0.80 H), 2.37 - 2.28 (m, 0.74 H), 2.25 (d, J
12.8 Hz, 1.04 H), 2.22 - 2.14 (m, 1.37 H), 1.90 (dd, J = 12.8, 14.3 Hz, 1.19 H), 1.84 - 1.79 (m,
.44 H), 1.75 (s, 0.77 H), 1.70 – 1.66 (m, 0.75 H), 1.63 - 1.61 (m, 0.82 H), 1.40 (s, 0.22 H), 1.30
(
=
0
1
3
(s, 0.40 H), 1.27 - 1.23 (m, 3.55 H). C NMR (126MHz, CDCl
3
) δ = 209.3, 207.1, 170.8, 170.7,
160.0, 157.3, 137.9, 136.5, 135.7, 127.7, 127.7, 127.7, 127.6, 127.6, 127.0, 126.3, 123.8, 114.0,
1
5
1
4
13.9, 113.7, 104.9, 103.9, 99.9, 98.9, 55.4, 55.4, 55.3, 55.2, 55.2, 55.0, 54.8, 52.9, 52.0, 51.8,
1.4, 47.5, 47.4, 38.8, 37.6, 37.1, 34.9, 25.5, 24.9, 24.6, 23.5. IR: 2936 (w), 1742 (s), 1715 (s),
-
1
+
28 6
611 (m), 1584 (m), 1512 (s) cm . HRMS (EI) m/z: [M] Calcd. for C24H O 412.1886; Found
12.1893.
Methyl
1,1':3',1''-terphenyl]-5'-carboxylate (7ad): Prepared following the general procedure using
cyclopropane 5a (100 mg, 0.37 mmol), triphenylamine (895 mg, 3.65 mmol), and SnCl (9 µL,
0.07 mmol) in CH Cl (3.7 mL) stirred at room temperature for 1 h. After work-up and
4-(diphenylamino)-6'-hydroxy-4''-methoxy-1'-methyl-1',2',3',4'-tetrahydro-
[
4
2
2
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