Synthesis of α-Arylated Cycloalkanones from Congested Trisubstituted Spiro-epoxides: Application of the House-Meinwald Rearrangement for Ring Expansion

Article abstract of DOI:10.1021/acs.joc.8b01448

A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging cycloheptanones is reported. First, an efficient one-pot synthesis of β,β'-disubstituted benzylidene cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available feedstock chemicals is described. Furthermore, an epoxidation followed by the House-Meinwald rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated cycloalkanones upon ring expansion. Reactions catalyzed by bismuth triflate underwent quasi-exclusively ring expansion for all substrates (electronically poor and rich), with yields ranging from 15% to 95%, thus demonstrating the difficulty of achieving ring enlargement for electron-deficient spiro-epoxides. On the other hand, by means of catalysis with aluminum trichloride, the rearrangement of spiro-epoxides proceeded typically in high yields and with remarkable regioselectivity on a broader substrate scope. In this case, a switch of regioselectivity was achieved for spiro-epoxides with electron-withdrawing substituents which enable the method to be successfully extended to some chemospecific arene shifts and the synthesis of aldehydes bearing a α-quaternary carbon. While the HMR has been extensively studied for smaller ring enlargement, we are pleased to report herein that larger cyclohexanones and cycloheptanones can be obtained efficiently from more sterically demanding trisubstituted spiro-epoxides bearing electron-releasing and electron-neutral arene substituents.

Full text of DOI:10.1021/acs.joc.8b01448

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Featured Article
Synthesis of #-Arylated Cycloalkanones from Congested
Trisubstituted Spiro-Epoxides: Application of the
House-Meinwald Rearrangement for Ring Expansion
Nagalakshmi Jeedimalla, Camille Jacquet, Diana Bahneva,
Jean-Jacques Youte Tendoung, and Stephane P. Roche
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01448 • Publication Date (Web): 08 Aug 2018
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The Journal of Organic Chemistry
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Synthesis of α-Arylated Cycloalkanones from Congested
Trisubstituted Spiro-Epoxides: Application of the House-
Meinwald Rearrangement for Ring Expansion.
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Nagalakshmi Jeedimalla, Camille Jacquet, Diana Bahneva, Jean-Jacques Youte Tendoung,
Stéphane P. Roche*
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida
33431.
*sroche2@fau.edu.
Dedicated to the memory of Professor Jerrold Meinwald (1927-2018), 2014 winner of the National
Medal of Science (USA)
TOC/Abstract Graphic
catalyst
AlCl3
Regioselective HMR
EDG
R
Regio- and chemoselective
EWG
House-Meinwald rearrangement (HMR)
1. epoxidation
2. HMR
1. epoxidation
2. HMR
Access to synthetically challenging
O
α
CHO
-arylated cycloheptanones
14 cycloalkanones synthesized
n
n
n
n = 0,1
Obtained by a
Barluenga coupling
(up to 95% yield)
Vs AlCl catalysts
up to
95% yield
up to
Bi(OTf)3
3
90% yield
catalyst
Bi(OTf)3
Exclusively
ABSTRACT:
A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging
cycloheptanones is reported. First, an efficient one-pot synthesis of β,β’-disubstituted benzylidene
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cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available
feedstock chemicals is described. Furthermore an epoxidation followed by the House-Meinwald
rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated
cycloalkanones upon ring expansion. Reactions catalyzed by bismuth triflate underwent quasi-
exclusively ring expansion for all substrates (electronically poor and rich), with yields ranging from
15% to 95% thus demonstrating the difficulty to achieve the ring enlargement for electron deficient
spiro-epoxides. On the other hand, by means of catalysis with aluminium trichloride, the
rearrangement of spiro-epoxides proceeded typically in high yields and with remarkable
regioselectivity on a broader substrate scope. In this case, a switch of regioselectivity was
achieved for spiro-epoxides with electron-withdrawing substituents which enable the method to
be successfully extended to some chemospecific arene shifts and the synthesis of aldehydes
bearing a α-quaternary carbon. While the HMR has been extensively studied for smaller ring
enlargement, we are pleased to report herein that larger cyclohexanones and cycloheptanones
can be obtained efficiently from more sterically demanding trisubstituted spiro-epoxides bearing
electron-releasing and electron-neutral arene substituents.
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Keywords: Aryl halides; Barluenga cross-coupling; β,β’-Disubstituted styrenes; Spiro-epoxide
rearrangement; House–Meinwald rearrangement (HMR); Lewis acid catalysis; α-arylated
cycloalkanones, ring enlargement.
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1. Introduction
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Styrenes are ubiquitous building blocks for the synthesis of polymers and also pertain to
several architecturally complex natural products (e.g. 1-5, Figure 1A).
Figure 1. Styrenes functionality embedded in natural products
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R1
Given their inherent reactivity as π-
Me
OH
O
R2
O
OH
OH
A
O
nucleophiles, styrenes are not only unique
functionalities in natural products, but are also
important building blocks for the construction
Me
HO
* Me
8
OH
OH
H
1
wiedendiol B (
-Me, R
)
Me
3
Me
(C8:
= R = Me)
aigialomycin D ( )
β
1
2
−
2
( )-siphonodictyal B ( )
-Me, R1
= CHO, R = H)
α
O
(C8:
2
H
O
O
of
more
elaborated
such
molecules
and
Me
HN
N
H
N
OMe
H
H
Me
O
Me
O
H
macromolecules
as
polymers.1
N
Me
H
OH
α
4
-codeimethine (
5
canthiumine (
)
)
Recently, an interesting biosynthetic proposal
for the transformation of the natural product (–
)-siphonodictyal B (2) to (+)-liphagal (9)
through a sequence of epoxidation and
skeletal rearrangement (ring expansion),2
caught the attention of several research
groups (Figure 1B).3 This straightforward
approach to a highly functionalized medium-
sized ring has been proposed to occur via the
OH
HO
OH
B
HO
CHO
Me
CHO
Me
Me
Me
epoxidation
Me
OH
Me
OH
H
H
H
H
O
H
H
6
Me
Me
−
(
not isolated
2
)-siphonodictyal B ( )
House-Meinwald
rearrangement (HMR)
OHC
HO
OH
OH
HO
CHO
Me
Me
Me
OH
Me
Me
O
O
H
H
H
Me
Me
H
H
O
H
8
7
Me
HO
CHO
HO
Me
Me
O
H
Me
Me
(+)-liphagal ( )
H
9
regio- and stereoselective rearrangement of a styrenyl epoxide intermediate 6. Indeed, spiro-
epoxide 6 was proposed to rearrange via a non-trivial ring enlargement reaction known as
the House–Meinwald rearrangement (HMR) to deliver the α-arylated cycloheptanone
skeleton 8.4 While the George group reported their elegant stereoselective total synthesis of
(+)-liphagal (9) by the intermediacy of a biomimetic diastereoselective HMR and the
stereochemical revision of 2,3b our group was already engaged in similar biomimetic studies
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and decided to focus on studying the pivotal HMR reaction to better understand the
stereoelectronic factors governing the HMR reaction of spiro-epoxides.
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8
9
Scheme 1. Possible access to six and seven-membered
cyclic ketones by means of a catalyzed HMR.
Even though the HMR reaction of acyclic
for some stereoselective ring enlargements
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Precedent by Shi
of cyclobutyl spiro-epoxides
epoxides has been extensively studied,5
O
O
Et2AlCl
R
H
R
the rearrangement of carbocyclic fused6
and spirocyclic epoxides7,8 remains largely
unexplored. Given the high propensity of
strained cyclopropanes and cyclobutanes
to rearrange to larger four and five-
membered rings respectively, it is not
11
10
R = EDG or EWG ( 90% ee)
>
up to xx% yield (80-95% ee)
for R = EDG: Et2AlCl (25 mol%)
for R = EWG: Et2AlCl (100 mol%)
: Lewis acid catalyzed regioselective ring enlargements
This work
of cyclopentyl and cyclohexyl spiro-epoxides
O
2. HMR
catalyzed
1. epoxidation
R
O
n
R
R
n
14
13
12
n
stepwise rearrangement
SN1-like mechanism
R = EDG or EWG
n = 0 or 1
surprising that only few examples of HMR ring expansion of larger spiro-epoxides have been
reported.8 Certainly one of the most impressive example of HMR ring-enlargement was
reported by Shi with the highly regio- and stereoselective rearrangement of cyclobutenyl
spiro-epoxides 10 into the corresponding cyclopentanones 11 (Scheme 1).7c In this report,
the most challenging rearrangement reactions of spiro-epoxides bearing electron-deficient
benzene appendages (σ+ < 0.15) were outlined by the need of spending stoichiometric
amounts of Lewis acid (e.g. Et2AlCl). Collectively, these previous reports on the HMR support
that the rearrangement of sterically-demanding trisubstituted (spiro)epoxides 13 remains a
synthetic challenge.7,8 Herein, we report results for some unprecedented catalyzed HMRs of
larger cyclopentyl and cyclohexyl spiro-epoxides 13 that further expand the initial reaction
scope reported by Shi to prepare the corresponding α-arylated cyclopentanones and
cycloheptanones 14. This study also reveals the importance of both stereo- and electronic
effects on the innate reactivity of the spiro-epoxides and on the regioselectivity path taken
during the rearrangement.
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2. Results and Discussion
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2.1. High Yielding Access to β,β’-Disubstituted Styrenyl Substrates.
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9
In order to develop a useful methodology toward several ring size of α-arylated cyclic ketones,
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we intuitively decided to mimic the HMR reaction
[Method A]
TsNHNH2
O
Ar-X, LnPd0
base
NNHTs
highlighted in the synthesis of liphagal (9) from the
styrenyl precursor 2 (Figure 1B). Therefore, a
straightforward and potentially high yielding sequence of
three steps was planned with 1) the synthesis of β,β’-
disubstituted styrenes, followed by 2) epoxidation and
concluded by 3) a catalyzed HMR.
R1
R3
R2
16
R3
R3
Ar
TsNHNH
LnPd0
2, Ar-X
R1 R2
R1 R2
, base
15
17
[Method B]
OMe
MeO
OMe
21b
21a
: 39% yield
: 36% yield
A
A
Scheme 2. Comparison of a two-step (Method A) vs one-
pot (Method B) palladium-catalyzed styrene synthesis a
Styrenes are most commonly produced synthetically by metathesis,9 Wittig10 and palladium cross-
coupling reactions.11 In 2007, Barluenga reported a new type of palladium-catalyzed cross-
coupling reaction, a versatile and efficient transformation for the synthesis of mono- and
polysubstituted styrenes as well as β,β’-disubstituted styrenes 17 from a carbonyl functional group
15 via the intermediacy of tosylhydrazone 16 (Scheme 2; Method A).12 Soon thereafter, the same
research group reported the direct coupling of an aldehyde or a ketone with aryl halides in a
multicomponent fashion13 through the in situ transient formation of a diazonium intermediate from
a tosylhydrazone (Scheme 1 Method B).14
Unfortunately, the Barluenga coupling of electron-rich electrophilic arene partners is a delicate
reaction due to the difficult oxidative addition of the palladium(0) catalyst. Indeed, the syntheses
of the electron-rich cyclopentyl-derived styrenes in two steps (Method A) were hampered by the
lack of reactivity of the corresponding hydrazones leading to the isolation of 21a and 21b in the
modest yields of 39% and 36% yields respectively.
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Table 1. One-pot Barluenga cross-coupling reaction (Method B)a-c
4
5
,
OMe
TsNHNH2
(2 mol%),
OMe
O
Pd
2(dba)3
Not only the formation of the tosylhydrazone
from the cyclopentane carboxaldehyde
proved to be difficult (< 47% yield), but the
efficiency of the cross-coupling under the
typical conditions reported by Barluenga was
moderate (50% conversion, see Supporting
Information).
6
7
8
9
Xphos (4 mol%),
n
LiOt-Bu,
Br
,
,
dioxane, reflux
n
n=0
n=1
21a,
22a,
n=0
n=1
19
20
19/20
(eq.)a
18a
LiOt-Bu
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19
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Conv.
(%)b
Yield
(%)c
Reaction Time
(hours)
Entry
(eq.)
3.5
1
2
20
28
28
50
< 55
22a
(1.0)
(1.7)
(45)
(38)
20
20
2.3
22a
22a
3
4
5
4.0
4.0
4.0
2.5
2.5
2.5
80
(1.7)
(2.0)
(2.0)
(62)
20
19
100
100
22a
21a
(74)
(82)
a Aldehyde and TsNHNH
1:1 ratio; b Conversions were determined
2 are used in
by 1H NMR of the crude reaction mixture; c Isolated yields are reported.
Scheme 3. Scope for the synthesis of β,β’-disubstituted styrenes 21-22a
R
In this context, a one-pot Barluenga
multicomponent reaction strategy (Method
B) was evaluated to achieve a quick access
to electron rich β,β’-disubstituted styrenes.
Reaction conditions were screened to
optimize the Pd(0)-catalyzed cross-coupling
reaction in a multicomponent fashion for an
electron-rich aryl bromide 18a with both
O
R
TsNHNH2
LiOt-Bu
n
Br
18a-m
Pd
2(dba)3
, Xphos
,
,
,
,
n = 0
n = 1
19
20
n
n = 0
n = 1
21a-m
22a-m
OMe
MeO
MeO
OMe
MeO
OMe
OMe
OMe
n
n
n
n
21b
21a
22a
, 83% yield
, 71% yield
21c
22c
21d
, 82% yield
, 74% yield
, 80% yield
, 78% yield
, 94% yield
22d
, 94% yield
22b
OMe
OMe
CHO
MeO
Me
OMe
n
n
n
66% yield
70% yield
n
cyclopentane
and
cyclohexane
21h,
22h,
21f,
22f
71% yield
, 84% yield
21g
22g
, 79% yield
, 56% yield
22e
, 25% yield
CN
F
CF3
Cl
carboxaldehyde 19-20 (Table 1).
Upon the typical reaction conditions
reported by Barluenga (Entries 1-2),
conversions to the desired styrene 22a
n
n
n
n
21m
22m,
21l,
, 50% yield
58% yield
21j
22j,
21k,
22k
41% yield
21i,
22i
40% yield
52% yield
, 54% yield
, 60% yield
32% yield
, 65% yield
(1 eq.) with aldehyes
or
19 20
a
18a-m
Reactions carried on a 0.5 mmol scale of aryl bromides
(2 eq.), TsNHNH (2 eq.), LiOtBu (4 eq.), Pd
2
2
(dba)3 (2 mol%), and Xphos (4 mol%) in dioxane
[0.1 M] for 2-5 hours. Isolated yields are reported.
remained low (< 55%). Forcing reaction conditions with an excess of aldehyde 20 to facilitate the
in situ hydrazone formation and a larger excess of base to promote the decomposition towards
the reactive carbene led to drastic improvements in conversion and isolated yields 62% and 74%
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yields respectively (Entries 3-4). As shown in entry 5, the cyclopentyl styrene 21a was synthesized
in 82% yields through the optimized protocol. With this optimized protocol in hand, 24 styrenes
21/22 with five and six membered rings bearing electron–donating and electron–withdrawing
groups have been synthesized (Scheme 3) in one-step with moderate to good yields (25-94%
yields). The styrenes were freshly prepared and purified on silica gel to avoid polymerization and
decomposition (most styrenes were stored and found stable for only up to two weeks at -78 °C).
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2.2. Optimization of the catalyzed House–Meinwald Rearrangement (HMR) of spirocyclic
epoxides.
Having established some optimized reaction conditions for the palladocatalyzed Barluenga cross-
coupling and the synthesis of styrenes 21/22, we turned our attention to evaluate the scope of the
pivotal HMR step.
Table 2. Derivatization of styrenes through the epoxidation and
House–Meinwald rearrangement sequence.a-d
R
R
R
To this aim, we were pleased to see that typical
conditions for the epoxidation of trisubstituted
alkenes with oxone can be utilized in a general
manner to efficiently obtain the spirocyclic
epoxides.15 Under the optimized conditions for
styrene epoxidation, spiro-epoxides 23a/24a
and 23h/24h were prepared in 75-90% yields.
Higher loadings of oxone and longer reaction
times were required in case of electron poor
styrene to achieve full conversions and high
yielding epoxidations. Importantly, we noticed
that epoxides can be purified on neutralized
alumina, kept for months in a freezer, and
R
H
H
H
O
O
O
[epoxidation] a
[HMR] b
n
n
n
n
27a
25a
25h
26a
26h
21a
, n=0, R= OMe
23a
(99% yield)
(80% yield)
(87% yield)
(75% yield)
27h
28a
28h
21h,
22a
22h,
n=0, R= H
23h
24a
24h
, n=1, R= OMe
n=1, R= H
ketone:aldehyde
ratioc
Catalyst
(10 mol%)
Time
(min)
Isolated yield
( % )
Entry
Epoxide
(98)
1d
2d
3
23a
23a
23a
2
2 days
60
25a
Et2AlCl
Me3Al
1:0
1:0
1:0
(75)
25a
(85)
MABR
AlCl3
25a
(92)
< 2
4
5
23a
23a
25a
1:0
1:0
(79)
< 10
25a
Bi(OTf)3
Et2AlCl
AlCl3
(85)
< 2
24a
26a
6
1:0
1:0
(90)
< 2
60
300
10
5
7
24a
24a
23h
23h
23h
26a
(75)
26a
8
Bi(OTf)3
Et2AlCl
1:0
-
9
NR
(15)
10
11
25h
Bi(OTf)3
AlCl3
1:0
0:1
(90)
27h
(20)
24h
24h
26h
12
13
15
5
Bi(OTf)3
AlCl3
25:1
1:8
(78)
28h
a Reaction conditions: styrene (1.0 mmol), oxone (1.0 eq.), acetone [0.03 M], sat.
[0.05 M] in H b Reaction conditions: catalyst (10 mol%) in
NaHCO3
2O [0.09 M].
DCE [0.05 M] at -20 °C unless otherwise stated. c Ratios of structural isomers and
1H NMR of the crude reaction mixture with mesitylene
yields were determined by
as internal standard. d
Reactions carried at -78 °C (entry 1) and at 60 °C (entry 2).
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were more stable than their styrene counterparts. These epoxides were therefore engaged in the
rearrangement reaction to evaluate the scope of the HMR reaction and optimize conditions for
the catalysis.16 Numerous catalysts have been previously reported to efficiently promote the HMR
of acyclic epoxides.5 From an extensive screening of solvents and over twenty catalysts
encompassing Lewis and BrØnsted acids,16 the aluminium–based catalysts and bismuth triflate
Bi(OTf)3 were identified to promote efficient rearrangement in dichloroethane (DCE) as shown by
the best results reported in Table 2. From this initial screening, two stereoelectronic trends have
also emerged. Firstly, although Bi(OTf)3 was found to be an efficient catalysts for the HMR,
aluminium-based catalysts appeared to be more suitable to promote catalysis and enable epoxide
opening and ring enlargement via a carbon–carbon bond 1,2-shift (Entries 1-5). Our current
explanation lays on the fact that a cohesive catalyst for the HMR reaction must trigger both ring-
opening (Lewis acid nature) which might operate from both epoxide lone pairs and also release
electron density from the zwitterionic intermediate to promote the σ-bond 1,2-shift (Figure 2).
Therefore a fine tune between Lewis acidity and the oxophilic nature of the catalyst must be
consider to optimize the HMR reaction. Indeed the five-to-six membered ring enlargement of the
electronically rich spiro-epoxide 23a (EDG, R = p-methoxy; σ+ value of -0.78)17 was efficiently
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catalyzed by Et2AlCl and AlCl3 leading to the corresponding α-aryl cyclohexanone 25a in 98%
and 92% yields respectively (Entries 1 & 4). We were also pleased that similar conditions enabled
the six-to-seven membered ring expansion to proceed smoothly and delivered the α-aryl
cycloheptanone 26a in 85% and 90% yields respectively (Entries 6-7). In this case, Bi(OTf)3 was
found to similarly catalyze the HMR and produce 26a in 75% yield. The second trend in the HMR
reaction unraveled upon evaluating the rearrangement of several electronically deficient spiro-
epoxides.16 As shown in Table 2 (Entries 9-13) and on the proposed mechanism schematic for
the HMR regioselectivity (Figure 2), electron deficient spiro-epoxide underwent a different bond-
breaking reaction. In the case of spiro-epoxides 23h and 24h (R = H; σ+ value of 0),17 the reaction
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did not proceed with the Et2AlCl catalyst at lower temperature (Table 2, entry 9) and resulted in
decomposition under forced conditions while reactions catalyzed by Bi(OTf)3 afforded the desired
enlarged cycloalkanones 25h and 26h in only 15% and 20% yields respectively.
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Figure 2. Regioselectivity outcome for the HMR reaction of spiro-epoxides 23/24
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catalyzed by Bi(OTf)3 versus AlCl3
R
These modest yields for electron poor
A
AlCl3
H
EDG
+ < 0
O
H
σ
O
R:
substrates (EWG, σ+ value > 0) might
be explained by considering that the
rate determining carbocation formation
could not be enhanced by the Lewis
acidity of the bismuth catalyst. On the
other hand, catalyzed rearrangements
of the same epoxides 23h and 24h
proceeded efficiently and rapidly with
AlCl3 to afford the corresponding α-
arylated aldehydes 27h and 28h in
AlCl3
O
R
n
n
25-26
H
R
n
Al
Cl3
H
H
EWG
23-24
O
R
0
O
σ
≥
+
R:
one enantiomer
n
presented for clarity
n
27-28
R
B
90% and 78% yields respectively. These results suggest that not only the stereoelectronic nature
of the catalysts is crucial for the rearrangement to proceed, but more importantly that the
regioselectivity originates mainly from the substrate. An overview of the HMR regioselectivity
outcome is presented in Figure 2A. Regio-isomeric ratios and NMR yields reported were obtained
from crude reaction mixtures (integrations average from 2-3 peaks/compound) using mesitylene
as internal standard (Figure 2B). In the case of aluminium trichloride, the catalyst demonstrated
high efficiency presumably by facilitating the formation of carbocations either at the benzylic
position (e.g. rearrangement of 23a, 24a, 23f and 23g) or at the tertiary position in the case of
23h, 24h and 24k. As previously suggested by Yamamoto, the Lewis acid catalyst might well
discriminate the two lone pairs of epoxides to chelate preferentially on the less hindered side
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(Figure 2A).7g After ring opening, the carbocation may endure a σ-bond shift concomitant to the
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π-bond formation of the carbonyl, therefore forcing the group antiperiplanar to the Lewis acid to
specifically migrate. Given the number of precedents that support a highly chemoselective shift in
the HMR,5b our observation of a specific arene shift suggest that the migratory aptitude is less
relevant than the Lewis acid positioning on the spiro-epoxide substrates. Even in this case of an
electron deficient arene in epoxide 24k (EWG, R = p-CF3; σ+ value of 0.61), the hydride migration
is not observed, instead the unexpected trifluoromethylbenzene migration occurred to deliver the
cyclohexyl carboxaldehyde 28k bearing a α-quaternary center with high yield and in a
chemospecific manner. Having in hand two efficient catalysts for the ring expansion reaction or
the regioisomeric hydride shift, the reaction scope was evaluated (Scheme 4).
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Scheme 4. Scope of the ring enlargement strategy for the synthesis of α-arylated
cycloalkanones 25/26 and cycloalkyl carboxaldehydes 27/28. a,b
R
R
R
H
Overall, eleven electronically rich
or neutral substrates (σ+ ≤ 0, 25a-
c, 25f-g, 25m, 26a-b, 26f-g and
26m) have been synthesized and
rearranged with ring-expansion in
good to high yield and with
excellent chemoselectivity without
observing any major differences in
efficiency between the reactions
carried with either the bismuth or
the aluminium catalysts. To our
Lewis acida,b
(10 mol%)
H
H
O
O
O
DCE [0.05 M]
-20 °C
n
n
27a-m
28a-m
23a-m
24a-m,
, n = 0
n = 1
25a-m
26a-m
n
OMe
OMe
Me
OMe
O
MeO
MeO
O
MeO
O
O
O
n
n
n
n
n
70% yielda
a
a
a
25a,
25b,
25c,
25f,
79% yield
92% yieldb
95% yield
93% yieldb
90% yielda
86% yieldb
76% yield
25g,
26g,
71% yieldb
77% yieldb
66% yielda
69% yieldb
26a, 75% yielda
26b,
26f, 75% yielda
a
87% yield
90% yieldb
90% yieldb
73% yieldb
R
CF3
F
O
H
H
H
n
O
O
O
O
n
n
O
n
n
n
80% yieldb
b
b
b
b
25m, 75% yielda
25h, R= H, 15% yielda
26h, R= H, 20% yielda
27k,
28k, 75% yieldb
27i,
28i,
27h,
28h,
45% yield
36% yield
90% yield
78% yield
a
26m,
66% yield
25i,
R= F, 11% yieldb
or b AlCl Isolated yields are reported (2 steps).
3.
a Bi(OTf)3
HMR reactions carried out with 10 mol% of:
delight, six α-aryl cycloheptanones have been synthesized in moderate to good yields (up to 95%
yield) and some dimeric structures 25m/26m have been also obtained in high yields through two
rearrangements occurring in the same pot. On the other end, 25h/27h, 26h/28h, 27i, 28i, 27k
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and 28k with electron neutral or deficient substituents (σ+ > 0) have been synthesized and were
only obtained through the aluminium trichloride catalysis. Overall these results from this study
tend to demonstrate that aluminium trichloride is the most general catalyst amenable to efficiently
rearrange a broad range of substrates with high chemoselectivity.
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3. Conclusion
In summary, we reported a general strategy for a three-step sequence that enable a rapid access
to α-arylated cyclohexanones and cycloheptanones from commercially inexpensive starting
materials. The sequence comprised of a Barluenga cross-coupling and epoxidation enabled a
rapid and straightforward access to spiro-epoxides in high yields. The targeted α-arylated
cycloalkanones which are challenging building blocks to synthesize by previous methods7, have
been readily obtained from a Lewis acid-catalyzed House-Meinwald rearrangement (HMR). The
reactions presented have been optimized to deliver a series of six and seven-membered ring α-
arylated cycloalkanones in good yields. Bismuth triflate and aluminium trichloride have emerged
from this study to be the most efficient and complementary catalysts to promote the HMR on a
broad substrate scope (20 compounds with up to 95% yield and high regioselectivity). This study
demonstrates that the rearrangement’ regioselectivity is essentially governed by electronic factors
inherent to the spiro-epoxides. The scope for the ring expansion reaction catalyzed by aluminium
trichloride encompasses spiropentyl- and spirohexyl-epoxides with electron-releasing and
electron-neutral substituents. A regioselectivity switch was observed for spiro-epoxides with
electron withdrawing substituents which enable the method to be successfully applied to a
chemospecific 1,2-shift of arenes for the synthesis of aldehydes bearing a α-quaternary carbon.
Finally, this study revealed that the innate regioselectivity in spiro-epoxide opening could not be
overcome by any of the BrØnsted and Lewis acid catalysts evaluated, yet aluminium trichloride
was found a be the most efficient and suitable catalyst to achieve this rearrangement. Given the
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significance of ring enlargements in complex natural products,2,3 we anticipate that the efficiency
of HMR catalyzed by aluminium trichloride will be applicable by others in the context of challenging
medium-sized ring enlargement. Ongoing studies are aimed at developing an asymmetric variant
of this ring enlargement transformation from enantioenriched spiro-epoxides.
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4. Experimental Section
Reactions were performed in flame-dried glassware under a positive pressure of argon. Yields
refer to spectroscopically pure compounds. Analytical TLC was performed on 0.25 mm glass
backed 60Å F-254 TLC plates (Silicycle, Inc.). The plates were visualized by exposure to UV light
(254 nm) and developed by a solution of vanillin in ethanol/sulfuric acid or cerium-ammonium-
molybdate in water/sulfuric acid and heat. Flash chromatography was performed using 200-400
mesh silica gels (Silicycle, Inc.). Infrared spectra were recorded on a Nicolet IS5 FT-IR
spectrophotometer. 1H NMR spectra were recorded on Varian Mercury400 and Bruker
biospinGmbH (400 MHz) spectrometers and are reported in ppm using solvent as an internal
standard (CDCl3 at 7.26 ppm or CD3CN at 1.96 ppm). NMR spectra were performed using
standard parameter and data are reported as: (b = broad, s = singlet, d = doublet, t = triplet, q =
13
quartet, m = multiplet; coupling constant(s) in Hz, integration). C NMR spectra were recorded
on Varian Mercury400 (100 MHz) spectrometer. Chemical shifts are reported in ppm, with solvent
resonance employed as the internal standard (CDCl3 at 77.2 ppm or CD3CN at 1.3 and 118.3
ppm). Melting points were determined using Digimelt digital melting point apparatus. The GC-MS
(gas chromatography –mass spectroscopy) analysis was performed using Perkin Elmer auto
system XL with Turbo mass. Electron ionization (EI) source was used and Restek (Rtx®-5)
capillary column with 30 m length, 1.25 mm internal diameter and 0.1μm film thickness. Accurate
mass (High resolution HRMS) was obtained from University of Florida using Agilent 6220 TOF
and Bruker Daltonics, Impact II QTOF instrument.
General Procedure A for the Barluenga coupling reaction using preformed
tosylhydrazone and an electron-rich aryl bromide.
A two neck round bottom flask under argon equipped with a condenser was charged with N'-
(cyclopentylmethylene)-4-methylbenzenesulfonohydrazide (200 mg, 0.75 mmol, 1.5 equiv.) or N'-
(cyclohexylmethylene)-4-methylbenzenesulfonohydrazide (210 mg, 0.75 mmol, 1.5 equiv.),
tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] (9 mg, 0.01 mmol,
2
mol %),
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dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (XPhos) (9 mg, 0.02 mmol, 4 mol %), followed
by LiOt-Bu (140 mg, 1.75 mmol, 3.5 equiv.), 1,4-dioxane (5.0 mL, [0.1 M]) and the desired aryl
bromide 18a-m (0.5 mmol, 1.0 equiv.). The heterogeneous solution was then stirred at reflux for
24 hours. After completion of the reaction (judged by TLC), the reaction mixture was directly
filtered through a pad of celite and washed with n-hexanes (10 x 5 mL). Solvent was evaporated
under reduced pressure and the residue was purified by flash chromatography on silica gel using
an isocratic solvent system of 100% n-hexanes.
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General Procedure
B
for the one-pot Barluenga coupling reaction of
cyclohexanecarboxaldehyde and aryl bromide.
A two-neck round bottom flask equipped with a condenser was charged under argon with Xphos
(9 mg, 0.02 mmol, 4 mol %), [Pd2(dba)3] (9 mg, 0.01 mmol, 2 mol %), LiOt-Bu (160 mg, 2 mmol,
4
equiv.), cyclopentanecarboxaldehyde 19 (98 mg,
1
mmol,
2
equiv.) or
cyclohexanecarboxaldehyde 20 (112 mg, 1 mmol, 2 equiv.), tosylhydrazine (186 mg, 1 mmol, 2
equiv.) and 1,4-dioxane (5.0 mL, [0.1 M]). After 1 minute, the desired aryl halide 18a-m (0.5 mmol,
1.0 equiv.) was added. The reaction mixture was stirred under reflux and monitored by TLC until
completion (x hours). When the reaction was completed the crude reaction mixture was allowed
to cool down to room temperature, taken up into n-hexanes (5 mL) and filtered through a pad of
celite. The celite pad was further washed with n-hexanes (10 x 5 mL). Solvent was evaporated
under reduced pressure and the residue was purified by flash chromatography on silica gel using
n-hexanes as solvent.
General Procedure C for the epoxidation of styrenes.
A one neck round bottom flask under argon was charged with styrene 21a-m or 22a-m (1.0 mmol,
1.0 equiv.) which was dissolved in acetone (33 mL, [0.03 M]) and cooled down to 0 °C. A saturated
°
sodium bicarbonate solution (20 mL, [0.05 M]) was added to the solution at 0 C. A solution of
oxone (x mmol) in water (10 mL, [0.1 M]) was then added dropwise for 5 min. The reaction was
°
stirred until the completion while carefully maintaining the reaction temperature at 0 C. The
reaction progress was monitored using neutralized TLC plate (platepretreated with 5% Et3N). The
reaction mixture was diluted with n-hexanes (10 mL) and water (10 mL) to facilitate phase
separation. The two layers were separated and the aqueous phase was extracted at least 7 times
using n-hexanes (7 X 10 mL). Combined organic layers were washed with a saturated brine
solution (5 mL) and then dried over Na2SO4. The solvent was evaporated under vacuum and the
product was purified by flash chromatography on neutralized silica gel (silica gel pretreated with
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5% Et3N ). Caution: The epoxides described below are sensitive to long exposure to non-
neutralized silica gel leading to decomposition and some epoxide rearrangement.
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General Procedure D for the catalyzed House-Meinwald rearrangement reaction.
A flame dried one neck round bottom flask under argon was charged with the desired spiro-
epoxides 23a-m or 24a-m (0.1 mmol, 1.0 equiv.) in dichloroethane (DCE) (2.0 mL, [0.05 M]) at -
20 °C. Lewis acids such as Bi(OTf)3 (7 mg, 10 mol %) or AlCl3 (1 mg, 10 mol %), were added and
the reaction mixture was stirred at -20 °C until the reaction completion. The reaction mixture was
diluted with dichloromethane (DCM) (2 mL) and allowed to room temperature. The reaction is
quenched with water (5 mL) under a strong agitation. The two layers were separated and product
was extracted from the aqueous layer using DCM (3 x 2 mL). Combined organic layers were
washed with a saturated brine solution (2 mL) and then dried over Na2SO4. The solvent was
evaporated under vacuum and the product was purified by flash chromatography using an
isocratic eluent of ethyl acetate in n-hexanes (5:95).
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Compounds Characterization
The syntheses and characterizations of compounds 21a,18a 21f-g,18b 21h,18a 21i-j,18c 21k,18a
22a,18a 22g-h,18d 22j,18e 23h,19 24h,19 25a-b,20a 25c,20b 25f,20c 25g,20d 25h,20e 25i,20f 26a,20g 26b,20h
26f,20i 26g-h,20j 27h,21a 27i,21b 27k,21c 28h,21d 28i,21e 28k,21f were previously reported.
1-(cyclopentylidenemethyl)-4-methoxybenzene 21a:
Compound 21a was synthesized and purified accordingly to general procedure
OMe
A from 1-bromo-4-methoxybenzene 18a (94 mg, 0.5 mmol, 1.0 equiv.) and
obtained in pure form as a yellow oil 21a (73 mg, 0.39 mmol, 77% yield).
21a
Compound 21a was also synthesized from aryl bromide 18a (94 mg, 0.5 mmol,
H
C13 16O
MW: 188.27 g.mol-1
1.0 equiv.) under reflux for 2.5 hours and purified accordingly to general
procedure B to obtain pure material 21a (77 mg, 0.41 mmol, 82% yield). Rf = 0.47 (Et2O/n-
1
hexanes 1:9). IRνmax (neat): 2938, 1599, 1500, 1185, 830 cm-1. H NMR (400 MHz, CDCl3) δ
(ppm) 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.32-6.28 (m, 1H), 3.81 (s, 3H), 2.54 –
13
2.45 (m, 4H), 1.80 – 1.75 (m, 2H), 1.69 – 1.55 (m, 2H). C NMR (100 MHz, CD3CN) δ (ppm)
158.6, 145.5, 132.6, 130.0 (2C), 120.9, 114.5 (2C), 55.8, 36.5, 31.6, 27.9, 26.4. Spectral data for
compound 21a were consistent with the data previously reported in the literature.18a SMILES:
COC1=CC=C(/C=C2CCCC/2)C=C1
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1-(cyclopentylidenemethyl)-2,4-dimethoxybenzene 21b:
Compound 21b was synthesized and purified accordingly to general procedure
OMe
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8
9
A using 1-bromo-2,4-dimethoxybenzene 18b (109 mg, 0.5 mmol, 1.0 equiv.)
and obtained in pure form as a yellow oil (89 mg, 0.41 mmol, 82% yield).
Compound 21b was also synthesized from aryl bromide 18b (109 mg, 0.5
mmol, 1.0 equiv.) under reflux for 3 hours and purified accordingly to general
MeO
21b
H
C14 18O2
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MW: 218.30 g.mol-1
procedure B to obtain pure material 21b (92 mg, 0.42 mmol, 83% yield). Rf = 0.28 (Et2O/n-
hexanes 1:99). IRνmax (neat): 2950, 1606, 1500, 1205, 1153, 1035, 832 cm-1. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.33 – 7.23 (m, 1H), 6.60 – 6.40 (m, 3H), 3.81 (s, 6H), 2.48 (dd, J = 16.9, 8.0 Hz,
4H), 1.74 (dt, J = 13.7, 6.8 Hz, 2H), 1.66 (dt, J = 13.8, 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
(ppm) 159.0, 157.5, 145.2, 129.1, 120.9, 114.3, 103.9, 98.3, 55.4, 55.3, 35.3, 31.0, 27.0, 25.6.
⋅
GCMS (EI) m/z: [M+ ] Calcd for C14H18O2 218; Found 218.
SMILES: COC1=CC=C(/C=C2CCCC/2)C(OC)=C1
2-(cyclopentylidenemethyl)-1,4-dimethoxybenzene 21c:
Compound 21c was synthesized from 2-bromo-1,4-dimethoxybenzene 18c
OMe
(109 mg, 0.5 mmol, 1.0 equiv.) under reflux for 3 hours and purified accordingly
MeO
21c
to general procedure B to obtain pure material as a yellow oil (87 mg, 0.40
H
C14 18O2
MW: 218.30 g.mol-1
mmol, 80% yield). Rf = 0.28 (Et2O/n-hexanes 1:99). IRνmax (neat): 2950,
1606, 1500, 1205, 1153, 1035, 832 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 6.95 (d, J = 3.0 Hz,
1H), 6.78 (d, J = 8.9 Hz, 1H), 6.70 (dd, J = 8.9, 3.0 Hz, 1H), 6.57 – 6.55 (m, 1H), 3.79 (s, 3H),
3.78 (s, 3H), 2.55 – 2.48 (m, 4H), 1.79 – 1.71 (m, 2H), 1.71 – 1.65 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ (ppm). 153.4, 151.1, 147.8, 129.0, 115.1, 114.9, 111.5, 111.4, 56.3, 55.9, 35.6, 31.3,
⋅
27.1, 25.7. GCMS (EI) m/z: [M+ ] Calcd for C14H18O2 218; Found 218.
SMILES: COC1=CC=C(OC)C=C1/C=C2CCCC/2
1-(cyclopentylidenemethyl)-2,4,5-trimethoxybenzene 21d:
Compound 21d was synthesized from 1-bromo-2,4,5-trimethoxybenzene 18d
OMe
OMe
(124 mg, 0.5 mmol, 1.0 equiv.) under reflux for 12 hours and purified accordingly
MeO
to general procedure B to obtain pure material as a yellow oil (117 mg, 0.47
21d
mmol, 94% yield). Rf = 0.41 (EtOAc/n-hexanes 5:95). IRνmax (neat): 2950,
H
C15 20O3
MW: 248.32 g.mol-1
1
1606, 1500, 1205, 1153, 1035, 832 cm-1. H NMR (400 MHz, CDCl3) δ (ppm)
6.96 (s, 1H), 6.51 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 2.50 (td, J = 7.2, 2.0 Hz, 4H),
1.77 – 1.72 (m, 2H), 1.68 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 151.2, 148.0,
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145.5, 142.8, 120.1, 114.6, 113.0, 97.8, 56.7(2C), 56.3, 35.6, 31.2, 27.2, 25.8. GCMS (EI) m/z:
⋅
[M+ ] Calcd for C15H20O3 248, Found 248. SMILES: COC1=CC(OC)=C(OC)C=C1/C=C2CCCCC/2
7
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1-(cyclopentylidenemethyl)-2-methoxybenzene 21f:
9
Compound 21f was synthesized from 1-bromo-2-methoxybenzene 18f (94 mg,
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MeO
0.5 mmol, 1.0 equiv.) under reflux for 4 hours and purified accordingly to general
21f
procedure B to obtain pure material as a clear oil (67 mg, 0.36 mmol, 71% yield).
H
C13 16O
MW: 188.27 g.mol-1
Rf = 0.30 (n-hexanes). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J = 7.7 Hz,
1H), 7.16 (t, J = 7.7 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 3.84
(s, 3H), 2.50 (dd, J = 14.5, 7.3 Hz, 4H), 1.74 (dd, J = 13.9, 7.0 Hz, 2H), 1.70 – 1.63 (m, 2H).
Spectral data for compound 21f were consistent with the data previously reported in the
literature.18b SMILES: COC1=CC=CC=C1/C=C2CCCC/2
1-(cyclopentylidenemethyl)-4-methylbenzene 21g:
Compound 21g was synthesized from 1-bromo-4-methylbenzene 18g (86 mg,
Me
0.5 mmol, 1.0 equiv.) under reflux for 4 hours and purified accordingly to general
procedure B to obtain pure material as a clear oil (68 mg, 0.40 mmol, 79% yield).
21g
Rf = 0.64 (n-hexanes). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.21 (d, J = 8.0 Hz,
H16
C13
MW: 172.27 g.mol-1
2H), 7.13 (d, J = 8.0 Hz, 2H), 6.35-6.31 (m, 1H), 2.54 56-2.50 (t, J = 7.0 Hz, 2H),
2.48 (t, J = 7.0 Hz, 2H), 2.34 (s, 3H), 1.81 – 1.75 (m, 2H), 1.70 – 1.63 (m, 2H). Spectral data for
compound 21g were consistent with the data previously reported in the literature.18b SMILES:
CC1=CC=C(/C=C2CCCC/2)C=C1
Cyclopentylidenemethyl benzene 21h:
Compound 21h was synthesized from bromobenzene 18h (79 mg, 0.5 mmol, 1.0
equiv.) under reflux for 5 hours and purified accordingly to general procedure B
21h
to obtain pure material as a clear oil (52 mg, 0.33 mmol, 66% yield). Rf = 0.50 (n-
H14
C12
hexanes). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.33-7.14 (m, 5H), 6.38 – 6.34 (m,
MW: 158.24 g.mol-1
1H), 2.59 – 2.53 (m, 2H), 2.52 – 2.46 (m, 2H), 1.82-1.75 (m, 2H), 1.70-1.63 (m, 2H). Spectral data
for compound 21h were consistent with the data previously reported in the literature.18a SMILES:
[H]C1=CC=C(/C=C2CCCC/2)C=C1
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1-(cyclopentylidenemethyl)-4-fluorobenzene 21i:
F
Compound 21i was synthesized from 1-bromo-4-fluorobenzene 18i (88 mg, 0.5
mmol, 1.0 equiv.) under reflux for 4 hours and purified accordingly to general
procedure B to obtain pure material as a clear oil (46 mg, 0.26 mmol, 52% yield).
Rf = 0.77 (n-hexanes). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.26 – 7.08 (m, 2H),
21i
H
13F
C12
MW: 176.23 g.mol-1
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7.00 (t, J = 8.9 Hz, 2H), 6.34-6.30 (m, 1H), 2.49 (dt, J = 10.9, 7.2 Hz, 4H), 1.79 (p, J = 7.0 Hz,
2H), 1.67 (p, J = 7.3 Hz, 2H). Spectral data for compound 21i were consistent with the data
previously reported in the literature.18c SMILES: FC1=CC=C(/C=C2CCCC/2)C=C1
1-chloro-4-(cyclopentylidenemethyl)benzene 21j:
Cl
Compound 21j was synthesized from 1-bromo-4-chlorobenzene 18j (96 mg, 0.5
mmol, 1.0 equiv.) at 90 °C for 3 hours and purified accordingly to general
procedure B to obtain pure material white needles (46 mg, 0.26 mmol, 52% yield).
21j
H
1
C12 13Cl
Rf = 0.50 (n-hexanes). H NMR (400 MHz, CDCl3) δ (ppm) 7.28 (d, J = 8.6 Hz,
MW: 192.69 g.mol-1
2H), 7.23 (d, J = 8.6 Hz, 2H), 6.32-6.30 (m, 1H), 2.53-2.47 (m, 4H), 1.86 – 1.73
(m, 2H), 1.73 – 1.59 (m, 2H).13C NMR (100 MHz, CDCl3) δ (ppm) 148.2, 137.4, 131.2, 129.2 (2C),
128.4 (2C), 119.8, 36.1, 31.3, 27.3, 25.8. Spectral data for compound 21j were consistent with
the data previously reported in the literature.18c SMILES: ClC1=CC=C(/C=C2CCCC/2)C=C1
1-(cyclopentylidenemethyl)-4-(trifluoromethyl)benzene 21k:
Compound 21k was synthesized from 1-bromo-4-(trifluoromethyl)benzene 18k
CF3
(113 mg, 0.5 mmol, 1.0 equiv.) under reflux for 7 hours and purified accordingly
to general procedure B to obtain pure material as a clear oil (45 mg, 0.2 mmol,
21k
1
40% yield). Rf = 0.48 (EtOAc/n-hexanes 4:96). H NMR (400 MHz, CDCl3) δ
H13F3
C13
MW: 226.24 g.mol-1
(ppm) 7.56 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.40 – 6.37 (m, 1H),
2.58-2.51 (m, 4H), 1.85 – 1.78 (m, 2H), 1.73 – 1.64 (m, 2H). Spectral data for compound 21k
were consistent with the data previously reported in the literature.18a SMILES:
FC(C1=CC=C(/C=C2CCCC/2)C=C1)(F)F
4-(cyclopentylidenemethyl)benzonitrile 21l:
Compound 21l was synthesized from 4-bromobenzonitrile 18l (91 mg, 0.5 mmol,
CN
1.0 equiv.) under reflux for 5 hours and purified accordingly to general procedure
B to obtain pure material as white needles (38 mg, 0.21 mmol, 41% yield). Rf =
21l
H13N
1
0.59 (n-hexanes). IRνmax (neat): 2955, 2228, 1705, 1272, 831 cm-1. H NMR
C13
MW: 183.25 g.mol-1
(400 MHz, CDCl3) δ (ppm) 7.56 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.40
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– 6.37 (m, 1H), 2.55-2.50 (m, 4H), 1.84-1.77 (m, 2H), 1.72– 1.65 (m, 2H). C NMR (100 MHz,
CDCl3) δ (ppm) 152.3, 143.4, 132.1 (2C), 128.3 (2C), 119.9, 119.4, 108.7, 36.5, 31.7, 27.3, 25.6.
SMILES: N#CC1=CC=C(/C=C2CCCC/2)C=C1
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1,4-bis(cyclopentylidenemethyl)benzene 21m:
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Compound 21m was synthesized from 1,4-dibromo benzene 18m (118 mg, 0.5
mmol, 1.0 equiv.) under reflux for 10 hours and purified accordingly to the
protocol adopted from general procedure B to obtain pure material as white
crystals (60 mg, 0.3 mmol, 50% yield). The optimized reaction condition for this
21m
adopted general procedure B includes cyclopentane-carboxaldehyde 19 (246
H22
C18
MW: 238.37 g.mol-1
mg, 2.5 mmol, 5 equiv.), tosylhydrazine (466 mg, 2.5 mmol, 5 equiv.), Pd2(dba)3
(18 mg, 0.02 mmol, 4 mol %), XPhos (18 mg, 0.04 mmol, 8 mol %), LiOt-Bu (319 mg, 3.5 mmol,
7 equiv.), 1,4-dioxane (5.0 mL, [0.1 M]). Rf = 0.59 (n-hexanes). IRνmax (neat): 2923, 2850, 1650,
933, 760 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.26 (d, J = 1.1 Hz, 2H), 6.36 – 6.29 (m, 1H),
13
2.58-2.53 (m, 2H), 2.50-2.46 (m, 2H), 1.84 – 1.73 (m, 2H), 1.71 – 1.61 (m, 2H). C NMR (100
MHz, CDCl3) δ (ppm) 146.8 (2C), 136.4 (2C), 127.9 (4C), 120.8 (2C), 36.2 (2C), 31.4 (2C), 27.4
⋅
(2C), 25.8 (2C). GCMS (EI) m/z: [M+ ] Calcd for C18H22 238; Found 238.
SMILES: C1(/CCCC1)=C/C2=CC=C(/C=C3CCCC/3)C=C2
1-(cyclohexylidenemethyl)-4-methoxybenzene 22a:
Compound 22a was synthesized from 1-bromo-4-methoxybenzene 18a (94 mg,
OMe
0.5 mmol, 1.0 equiv.) under reflux for 2.5 hours and purified accordingly to
general procedure B to obtain pure material as clear oil (75 mg, 0.37 mmol, 74%
22a
H
C14 18O
yield). Rf = 0.47 (Et2O/n-hexanes 1:9). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.13
MW: 202.3 g.mol-1
(d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H), 3.76 (s, 3H), 2.36 –
2.32 (m, 2H), 2.25 – 2.21 (m, 2H), 1.64-1.57 (m, 4H), 1.56-1.50 (m, 2H). 13C NMR (100 MHz,
CD3CN) δ (ppm) 158.8, 143.0, 131.6, 130.8 (2C), 122.1, 114.4 (2C), 55.8, 38.2, 30.0, 29.5, 28.6,
27.4. Spectral data for compound 22a were consistent with the data previously reported in the
literature.18a SMILES: COC1=CC=C(/C=C2CCCCC/2)C=C1
1-(cyclohexylidenemethyl)-2,4-dimethoxybenzene 22b:
Compound 22b was synthesized from 1-bromo-2,4-dimethoxybenzene 18b (109 mg, 0.5 mmol,
1.0 equiv.) under reflux for 5 hours and purified accordingly to general procedure B to obtain pure
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material as clear oil (95 mg, 0.41 mmol, 82% yield). Rf = 0.47 (Et2O/n-hexanes
OMe
1
1:9). IRνmax (neat): 2923, 2850, 1606, 1500, 1205, 1035, 832 cm-1. H NMR
MeO
22b
(400 MHz, CDCl3) δ (ppm) 7.05 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.45
(dd, J = 8.3, 2.4 Hz, 1H), 6.14 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.30-2.26 (m,
4H), 1.64 – 1.56 (m, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.5, 158.3,
H
C15 20O2
MW: 232.32 g.mol-1
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142.5, 131.0, 120.1, 117.0, 103.9, 98.5, 55.6, 55.5, 37.7, 30.0, 28.8, 28.1, 26.9. HRMS
(ESI/QTOF) m/z: [M+H]+ Calcd for C15H21O2 233.1536; Found 233.1536 (0 ppm). SMILES:
COC1=CC=C(/C=C2CCCCC/2)C(OC)=C1
2-(cyclohexylidenemethyl)-1,4-dimethoxybenzene 22c:
OMe
Compound 22c was synthesized from 2-bromo-1,4-dimethoxybenzene 18c (109
MeO
mg, 0.5 mmol, 1.0 equiv.) under reflux for 5 hours and purified accordingly to
general procedure B to obtain pure material as a yellow oil (91 mg, 0.39 mmol,
78% yield). Rf = 0.23 (n-hexanes). IRνmax (neat): 2924, 2851, 1582, 1490, 1216,
1047, 799 cm-1. 1H NMR (400 MHz, CD3CN) δ (ppm) 6.85 (d, J = 8.9, 1H), 6.75
22c
H
C15 20O2
MW: 232.32 g.mol-1
(dd, J = 8.9, 3.1 Hz, 1H), 6.68 (d, J = 3.1 Hz, 1H), 6.15 (s, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.30 –
13
2.24 (m, 4H), 1.63 – 1.58 (m, 4H), 1.56 – 1.51 (m, 2H). C NMR (100 MHz, CD3CN) δ (ppm)
154.0, 152.4, 144.1, 128.6, 118.5, 117.3, 112.6, 112.4, 56.4, 56.1, 38.1, 30.4, 29.4, 28.6, 27.3.
HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C15H21O2 233.1536; Found 233.1536 (0 ppm). SMILES:
COC1=CC=C(OC)C=C1/C=C2CCCCC/2
1-(cyclohexylidenemethyl)-2,4,5-trimethoxybenzene 22d:
Compound 22d was synthesized from 1-bromo-2,4,5-trimethoxybenzene 18d
OMe
OMe
(124 mg, 0.5 mmol, 1.0 equiv.) under reflux for 12 hours and purified accordingly
MeO
to general procedure B to obtain pure material as a yellow oil (123 mg, 0.47
22d
mmol, 94% yield). Rf = 0.41 (EtOAc/n-hexanes 5:95). IRνmax (neat): 2950,
H
C16 22O3
MW: 262.35 g.mol-1
1
1606, 1500, 1205, 1153, 1035, 832 cm-1. H NMR (400 MHz, CDCl3) δ (ppm)
6.71 (s, 1H), 6.52 (s, 1H), 6.16 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 2.31-2.27 (m, 5H),
13
1.66-1.63 (s, 2H), 1.58-1.56 (s, 3H). C NMR (100 MHz, CD3CN) δ (ppm) 152.7, 149.7, 143.5,
142.9, 119.3, 116.2 (2C), 99.1, 57.2, 56.8, 56.6, 38.1, 30.5, 29.5, 28.6, 27.4. HRMS (ESI/QTOF)
m/z: [M+H]+ Calcd for C16H23O3 263.1642; Found 263.1644 (0.8 ppm). SMILES:
COC1=CC(OC)=C(OC)C=C1/C=C2CCCCC/2
3-(cyclohexylidenemethyl)-2,5,6-trimethoxybenzaldehyde 22e:
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Compound 22e was synthesized from 3-bromo-2,5,6-trimethoxybenzaldehyde
18e (34 mg, 0.13 mmol, 1.0 equiv.) under reflux for 12 hours and purified
accordingly to general procedure B to obtain pure material as a clear oil (9 mg,
0.03 mmol, 25% yield). Rf = 0.49 (EtOAc/n-hexanes 5:95). IRνmax (neat): 2929,
1696, 1477, 1230, 1128, 1008 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 10.41
O
OMe
OMe
H
MeO
22e
H
C17 22O4
MW: 290.36 g.mol-1
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(s, 1H), 6.92 (s, 1H), 6.18 (s, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 2.28 25 (dt, J = 11.8,
5.7 Hz, 4H), 1.66-1.62 (m, 3H), 1.59-1.57 (m, 1H), 1.55-1.51 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 190.2, 152.9, 149.9, 148.8, 145.1, 128.3, 124.0, 120.6, 116.6, 62.3, 62.2, 56.6, 37.5, 30.2,
28.7, 27.9, 26.7. HRMS (ESI/TOF) m/z: [M+H]+ Calcd for C17H23O4 291.1591; Found 291.1594
(1.0 ppm).
SMILES: [H]C(C1=C(OC)C(/C=C2CCCCC/2)=CC(OC)=C1OC)=O.
1-(cyclohexylidenemethyl)-2-methoxybenzene 22f:
Compound 22f was synthesized from 1-bromo-2-methoxybenzene 18f (94 mg,
0.5 mmol, 1.0 equiv.) under reflux for 7 hours and purified accordingly to general
MeO
procedure B to obtain pure material as a clear oil (85 mg, 0.42 mmol, 84% yield).
22f
H
C14 18O
Rf = 0.30 (n-hexanes). IRνmax (neat): 2945, 1609, 1504, 1201, 1037, 820 cm-1.
MW: 202.30 g.mol-1
1H NMR (400 MHz, CDCl3) δ (ppm) 7.36 (dd, J = 7.5, 1.1 Hz, 1H), 7.17 (td, J = 7.5, 1.5 Hz, 1H),
6.93 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.61-6.57 (m, 1H), 3.83 (s, 3H), 2.32 – 2.29 (m,
4H), 1.68-1.62 (m, 2H), 1.61-1.55 (m, 4H). 13C NMR (100 MHz, CDCl3) δ (ppm) 157.3, 143.5,
⋅
130.7, 127.5, 127.3, 120.1, 117.5, 110.5, 55.6, 37.8, 30.0, 28.8, 28.1, 26.9. GCMS (EI) m/z: [M+ ]
Calcd for C14H18O 202; Found 202. SMILES: COC1=CC=CC=C1/C=C2CCCCC/2
1-(cyclohexylidenemethyl)-4-methylbenzene 22g:
Me
Compound 22g was synthesized from 1-bromo-4-methylbenzene 18g (86 mg,
0.5 mmol, 1.0 equiv.) under reflux for 6 hours and purified accordingly to general
procedure B to obtain pure material as a clear oil (52 mg, 0.28 mmol, 56% yield).
22g
H18
C14
1
Rf = 0.72 (n-hexanes). H NMR (400 MHz, CDCl3) δ (ppm) 7.12 (d, J = 8.2 Hz,
MW: 186.30 g.mol-1
2H), 7.12 (d, J = 8.2 Hz, 2H), 6.19 (s, 1H), 2.40 – 2.34 (m, 2H), 2.33 (s, 3H), 2.27 – 2.21 (m, 2H),
1.68 – 1.57 (m, 4H), 1.55 (t, J = 6.4 Hz, 2H). Spectral data for compound 22g were consistent
with the data previously reported in the literature.18d SMILES: CC1=CC=C(/C=C2CCCCC/2)C=C1
(cyclohexylidenemethyl)benzene 22h:
Compound 22h was synthesized from bromobenzene 18h (79 mg, 0.5 mmol, 1.0 equiv.) under
reflux for 6 hours and purified accordingly to general procedure B to obtain pure material as a
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clear oil (60 mg, 0.35 mmol, 70% yield). Rf = 0.70 (n-hexanes). H NMR (400
MHz, CDCl3) δ (ppm) 7.41 – 7.27 (m, 5H), 3.87 (s, 1H), 1.87-1.81 (m, 1H), 1.77 –
1.59 (m, 3H), 1.54 – 1.39 (m, 4H), 1.33 – 1.24 (m, 2H). Spectral data for
compound 22h were consistent with the data previously reported in the
22h
H16
C13
MW: 172.27 g.mol-1
literature.18d SMILES: C1(/C=C2CCCCC/2)=CC=CC=C1.
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1-(cyclohexylidenemethyl)-4-fluorobenzene 22i:
Compound 22i was synthesized from 1-bromo-4-fluorobenzene 18i (88 mg, 0.5
F
mmol, 1.0 equiv.) under reflux for 5 hours and purified accordingly to general
procedure B to obtain pure material as a clear oil (51 mg, 0.27 mmol, 54% yield).
Rf = 0.77 (n-hexanes). IRνmax (neat): 2925, 2853, 1505, 1219, 1156, 864, 849,
22i
H15
F
C13
1
762 cm-1. H NMR (400 MHz, CDCl3) δ (ppm) 7.16-7.12 (m, 2H), 7.01-6.96 (m,
MW: 190.26 g.mol-1
2H), 6.17 (s, 1H), 2.34-2.31 (m, 2H), 2.26 – 2.23 (m, 2H), 1.64-1.62 (m, 4H), 1.57-1.51 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm) 161.3 (d, J = 244.7 Hz), 143.6, 134.5 (d, J = 3.1 Hz), 130.5
(d, J = 7.6 Hz, 2C), 121.0, 114.94 (d, J = 21.2 Hz, 2C), 37.7, 29.5, 28.7, 28.0, 26.8. GCMS (EI)
⋅
m/z: [M+ ] Calcd for C13H15F 190; Found 190. SMILES: FC1=CC=C(/C=C2CCCCC/2)C=C1.
1-chloro-4-(cyclohexylidenemethyl)benzene 22j:
Compound 22j was synthesized from 1-bromo-4-chlorobenzene 18j (96 mg, 0.5
Cl
mmol, 1.0 equiv.) under stirred at 90 °C for 3 hours and purified accordingly to
general procedure B to obtain pure material as white needles (33 mg, 0.16 mmol,
22j
32% yield). Rf = 0.81 (n-hexanes). 1H NMR (400 MHz, CD3CN) δ (ppm) 7.34 –
H
C13 15Cl
MW: 206.71 g.mol-1
7.29 (m, 2H), 7.19 (dd, J = 6.4, 4.2 Hz, 2H), 6.20 (s, 1H), 2.37 – 2.31 (m, 2H),
2.26-2.24 (m, 2H), 1.66 – 1.59 (m, 4H), 1.56-1.53 (m, 2H). Spectral data for compound 22j were
consistent with the data previously reported in the literature.18e SMILES:
ClC1=CC=C(/C=C2CCCCC/2)C=C1.
1-(cyclohexylidenemethyl)-4-(trifluoromethyl)benzene 22k:
CF3
Compound 22k was synthesized from 1-bromo-4-(trifluoromethyl)benzene 18k
(113 mg, 0.5 mmol, 1.0 equiv.) under reflux for 7 hours and purified accordingly
to general procedure B to obtain pure material as white needles (78 mg, 0.33
22k
H15F3
C14
MW: 240.27 g.mol-1
mmol, 65% yield). Rf = 0.81 (n-hexanes). IRνmax (neat): 2929, 2855, 1321,
1120, 851 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.55 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.8 Hz,
2H), 6.24 (s, 1H), 2.47 – 2.32 (m, 2H), 2.32 – 2.24 (m, 2H), 1.71 – 1.59 (m, 4H), 1.59-1.56 (m,
2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 146.2, 142.6, 129.6 (3C), 124.9 (q, J = 272.0 Hz), 125.4
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⋅
(q, J = 3.0 Hz, 2C), 121.4, 38.2, 30.0, 29.1, 28.3, 27.1. GCMS (EI) m/z: [M+ ⋅] Calcd for C14H15F3
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240; Found 240. SMILES: FC(C1=CC=C(/C=C2CCCCC/2)C=C1)(F)F.
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1,4-bis(cyclohexylidenemethyl)benzene 22m:
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Compound 22m was synthesized from 1,4-dibromo benzene 18m (118 mg, 0.5 mmol, 1.0 equiv.)
under reflux for 10 hours and purified accordingly to the protocol adopted from general procedure
B to obtain pure material as white crystals (77 mg, 0.29 mmol, 58% yield). The
optimized reaction condition for this adopted general procedure B includes
cyclohexanecarboxaldehyde 20 (224 mg, 2.0 mmol, 4.0 equiv.), tosylhydrazine
(372 mg, 2.0 mmol, 5.0 equiv.), Pd2(dba)3 (18 mg, 0.02 mmol, 4 mol %), XPhos
22m
(18 mg, 0.04 mmol, 8 mol %), LiOt-Bu (319 mg, 3.5 mmol, 7.0 equiv.), 1,4-
H26
C20
MW: 266.43 g.mol-1
dioxane (5 mL, [0.1 M]). Rf = 0.83 (n-hexanes). IRνmax (neat): 2922, 2850,
1650, 933, 751 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.14 (s, 4H), 6.20 (s, 2H), 2.42 – 2.39
(m, 4H), 2.27 – 2.24 (m, 4H), 1.66 – 1.60 (m, 7H), 1.59 – 1.53 (m, 5H).13C NMR (100 MHz, CDCl3)
δ (ppm) 143.3 (2C), 136.1 (2C), 128.7 (4C), 122.0 (2C), 37.9 (2C), 29.7 (2C), 28.8 (2C), 28.0 (2C),
⋅
26.9 (2C). GCMS (EI) m/z: [M+ ] Calcd for C20H26 266; Found 266. SMILES:
C1(/C=C2CCCCC/2)=CC=C(/C=C3CCCCC/3)C=C1
2-(4-methoxyphenyl)-1-oxaspiro[2.4]heptane 23a.
Compound 23a was synthesized from styrene 21a (188 mg, 1.0 mmol, 1.0
MeO
equiv.) and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 °C for 1 hour and purified
O
accordingly to general procedure C to obtain pure material as a clear oil (192
23a
H
mg, 0.94mmol, 94% yield). Rf = 0.54 (n-hexanes). IRνmax (neat): 2920, 1613,
C13 16O2
MW: 204.27 g.mol-1
1
1513, 1446, 1245, 1035 cm-1. H NMR (400 MHz, CDCl3) δ (ppm) 7.18(d, J =
8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 3.96 (s, 1H), 3.81 (s, 3H), 2.02-1.97 (m, 1H), 1.85-1.76 (m,
4H), 1.68-1.43 (m, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.2, 129.3, 127.5 (2C), 113.7 (2C),
72.6, 63.2, 55.4, 34.1, 28.5, 25.4, 25.3. HRMS (ESI/TOF) m/z: [M+H]+ Calcd for C13H17O2
205.1223; Found 205.1225 (1.0 ppm). SMILES: COC1=CC=C(C2C3(O2)CCCC3)C=C1
2-(2,4-dimethoxyphenyl)-1-oxaspiro[2.4]heptane 23b.
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Compound 23b was synthesized from styrene 21b (218 mg, 1.0 mmol, 1.0
equiv.) and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 °C for 1 hour and purified
accordingly to general procedure C to obtain pure material as a clear oil (194
mg, 0.83 mmol, 83% yield). Rf = 0.48 (n-hexanes). IRνmax (neat): 2950, 1606,
1500, 1205, 1153, 1035, 832 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.06 (d,
OMe
O
MeO
23b
H
C14 18O3
MW: 234.30 g.mol-1
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J = 8.4 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.48 (dd, J = 8.4 , 2.3 Hz, 1H), 4.13 (s, 1H), 3.80 (s, 3H),
3.82 (s, 3H), 2.07-2.01 (m, 2H), 1.86-1.80 (m, 3H), 1.75 – 1.70 (m, 2H), 1.69-1.66 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 159.0, 127.2, 118.7, 118.5, 103.9, 98.3, 72.3, 59.8, 55.6, 55.5,
33.7, 28.7, 25.3, 25.2. HRMS (ESI/QTOF) m/z: [M+Na]+ Calcd for C14H18O3Na 257.1148; Found
257.1152 (1.5 ppm). SMILES: COC1=CC(OC)=C(C2C3(O2)CCCC3)C=C1
2-(2-methoxyphenyl)-1-oxaspiro[2.4]heptane 23f.
Compound 23f was prepared from styrene 21f (188 mg, 1.0 mmol, 1.0 equiv.) and oxone (615
OMe
mg, 1.0 mmol, 1.0 equiv.) at 0 °C for 1.5 hour and purified accordingly to general
O
procedure C to obtain pure material as a clear oil (168 mg, 0.82 mmol, 82% yield).
Rf = 0.23 (n-hexanes). IRνmax (neat): 2957, 1493, 1241, 1026, 752cm-1. 1H NMR
23f
H
C13 16O2
MW: 204.27 g.mol-1
(400 MHz, CDCl3) δ (ppm) 7.23 (td, J = 1.2, 7.9 Hz, 1H), 7.18 (dd, J = 7.5, 1.4 Hz,
1H), 6.94 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 4.20 (s, 1H), 3.85 (s, 3H), 2.12-2.04 (m,
1H), 1.87-1.80 (m, 2H), 1.76 – 1.64 (m, 2H), 1.57 – 1.50 (m, 2H), 1.42 – 1.35 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 157.9, 128.3, 126.5, 125.9, 120.3, 110.0, 72.3, 59.9, 55.5, 33.7, 28.7,
25.3, 25.1. SMILES: COC1=C(C2C3(O2)CCCC3)C=CC=C1
2-(p-tolyl)-1-oxaspiro[2.4]heptane 23g.
Compound 23g was synthesized from styrene 21g (172 mg, 1.0 mmol, 1.0
equiv.) and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 °C for 3 hour and purified
Me
O
accordingly to general procedure C to obtain pure material as a clear liquid at
23g
room temperature and white solid at 4-5 °C (168 mg, 0.89 mmol, 89% yield). Rf
H
C13 16O
MW: 188.27 g.mol-1
1
= 0.31 (n-hexanes). IRνmax (neat): 2957, 1515, 1193, 787, 755 cm-1. H NMR
(400 MHz, CDCl3) δ (ppm) 7.15 (s, 4H), 3.98 (s, 1H), 2.35 (s, 3H), 2.03 – 1.98 (m, 1H), 1.88 –
1.78 (m, 3H), 1.68 – 1.60 (m, 2H), 1.57 – 1.44 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 137.2,
134.3, 128.9 (2C), 126.3 (2C), 72.6, 63.4, 34.1, 28.5, 25.4, 25.3, 21.3. SMILES:
CC1=CC=C(C2C3(O2)CCCC3)C=C1
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2-phenyl-1-oxaspiro[2.4]heptane 23h.
Compound 23h was synthesized from styrene 21h (158 mg, 1.0 mmol, 1.0
equiv.), acetone (66 mL, [0.02 M]), sat. NaHCO3 solution (40 mL, [0.03 M]), oxone
(1.84 g, 3.0 mmol, 3.0 equiv.) and water (20 mL, [0.05 M]) at 0 °C for 5 hour and
purified accordingly to general procedure C to obtain pure material as a clear oil
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23h
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H
C12 14O
MW: 174.24 g.mol-1
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(152 mg, 0.87 mmol, 87% yield). Rf = 0.31 (EtOAc/n-hexanes 3:97). IRνmax (neat): 2957, 1496,
1454, 745, 698 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37 – 7.25 (m, 5H), 4.01 (s, 1H), 2.09
– 1.99 (m, 1H), 1.85 – 1.79 (m, 3H), 1.71 – 1.57 (m, 2H), 1.50 – 1.43 (m, 2H). Spectral data for
compound 23h were consistent with the data previously reported in the literature.19 SMILES:
C1(C2C3(O2)CCCC3)=CC=CC=C1
2-(4-fluorophenyl)-1-oxaspiro[2.4]heptane 23i.
Compound 23i was synthesized from styrene 21i (176 mg, 1.0 mmol, 1.0 equiv.), acetone (66
mL, [0.02 M]), Sat. NaHCO3 solution (40 mL, [0.03 M]), oxone (1.84 g, 3.0 mmol, 3.0 equiv.) and
water (20 mL, [0.05 M]) at room temperature for 2 hours and purified accordingly to general
procedure C to obtain pure material as a white solid (150 mg, 0.78 mmol, 78% yield). Rf = 0.11
F
1
(n-hexanes). IRνmax (neat): 2959, 1510, 1222, 840, 764 cm-1. H NMR (400
O
MHz, CDCl3) δ (ppm) 7.38 – 7.35 (m, 2H), 7.02 (t, J = 8.1 Hz, 2H), 4.58 (s, 1H),
1.81-1.73 (m, 4H), 1.62-1.58 (m, 3H), 1.30 – 1.25 (m, 1H). 13C NMR (100 MHz,
23i
H13FO
MW: 192.23 g.mol-1
C12
CDCl3) δ (ppm) 162.5 (d, J = 246.5 Hz), 137.0, 129.1(d, J = 8.0 Hz, 2C), 115.1
(d, J = 21.2 Hz, 2C), 84.9, 79.1, 37.9, 36.1, 23.8, 23.7. HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for
C12H14FO 193.1023; Found 193.1024 (0.5 ppm). SMILES: FC1=CC=C(C2C3(O2)CCCC3)C=C1
2-(4-(trifluoromethyl)phenyl)-1-oxaspiro[2.4]heptane 23k.
Compound 23k was synthesized from styrene 21k (226 mg, 1.0 mmol, 1.0
equiv.), acetone (66 mL, [0.02 M]), sat. NaHCO3 solution (40 mL, [0.03 M]),
oxone (1.84 g, 3.0 mmol, 3.0 equiv.) and water (20 mL, [0.05 M]) at room
temperature for 2 hours and purified accordingly to general procedure C to obtain
pure material as a white solid (189 mg, 0.78 mmol, 78% yield). Rf = 0.60 (Et2O/n-
F
3C
O
23k
H13
F
C13
3O
MW: 242.24 g.mol-1
hexanes 15:85). IRνmax (neat): 2959, 1510, 1222, 840, 764 cm-1. 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.62 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 4.08 (s, 1H), 2.15 – 1.99 (m, 1H), 1.94 –
1.52
(m,
5H),
1.47-1.43
(m,
1H),
1.31-1.29
(m,
1H).
SMILES:
FC(C1=CC=C(C2C3(O2)CCCC3)C=C1)(F)F
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1,4-di(1-oxaspiro[2.4]heptan-2-yl)benzene 23m.
Compound 23m was synthesized from styrene 21m (238 mg, 1.0 mmol, 1.0
equiv.), acetone (132 mL, [8 mM]), sat. NaHCO3 solution (80 mL, [10 mM]),
oxone (3.69 g, 6.0 mmol, 6.0 equiv.) and water (40 mL, [30 mM]) at room
temperature for 4 hours and purified accordingly to general procedure C to
obtain pure material as a white solid (200 mg, 0.74 mmol, 74% yield). Rf = 0.23
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23m
H
C18 22O2
MW: 270.37 g.mol-1
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(n-hexanes). IRνmax (neat): 2926, 1451, 910, 773, 709 cm-1. H NMR (400
MHz, CDCl3) δ (ppm) 7.23 (s, 4H), 4.00 (d, J = 1.1 Hz, 2H), 2.05 – 1.96 (m, 2H), 1.87 – 1.74 (m,
7H), 1.71 – 1.60 (m, 5H), 1.59 – 1.52 (m, 2H), 1.50 – 1.42 (m, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm) 136.6 (2C), 126.1 (4C), 72.7 (2C), 63.2 (2C), 31.4 (2C), 28.5 (2C), 25.4 (2C), 25.3 (2C).
HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C18H23O2 271.1693; Found 271.1688 (1.8 ppm); m/z:
[M+NH4]+ Calcd for C18H26NO2 288.1958; Found 288.1954 (1.4 ppm). SMILES:
C1(C2C3(O2)CCCC3)=CC=C(C4C5(CCCC5)O4)C=C1
2-(4-methoxyphenyl)-1-oxaspiro[2.5]octane 24a.
MeO
Compound 24a was synthesized from styrene 22a (202 mg, 1.0 mmol, 1.0
equiv.) and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 °C for 2 hours and purified
O
24a
accordingly to general procedure C to obtain pure material as a clear oil (203
H
C14 18O2
mg, 0.93mmol, 93% yield). Rf = 0.70 (EtOAc/n-hexanes 5:95). IRνmax (neat):
MW: 218.13 g.mol-1
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2931, 1512, 1243, 1169, 1063, 806 cm-1. H NMR (400 MHz, CDCl3) δ (ppm)
7.22 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 3.80 (s, 1H), 3.77 (s, 3H), 1.78-1.74 (m, 1H),
1.64-1.56 (m, 2H), 1.55-1.46 (m, 2H), 1.45-1.33 (m, 2H), 1.29-1.16 (m, 3 H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 159.0, 128.6, 127.6 (2C), 113.6 (2C), 65.6, 64.5, 55.4, 35.5, 28.5, 25.7, 25.5,
24.7. HRMS (ESI/TOF) m/z: [M+H]+ Calcd for C14H19O2 219.1380; Found 219.1384 (1.8 ppm).
SMILES: COC1=CC=C(C2C3(CCCCC3)O2)C=C1
2-(2,4-dimethoxyphenyl)-1-oxaspiro[2.5]octane 24b.
MeO
OMe Compound 24b was synthesized from styrene 22b (232 mg, 1.0 mmol, 1.0 equiv.)
°
and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 C for 3 hours and purified
O
accordingly to general procedure C to obtain pure material as a clear oil (176 mg,
24b
H
C15 20O3
0.71 mmol, 71% yield). Rf = 0.35 (n-hexanes). IRνmax (neat): 2949, 1606, 1505,
1211, 1038, 836 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.12 (dd, J = 8.5, 0.8
MW: 248.32 g.mol-1
Hz, 1H), 6.48 – 6.43 (m, 2H), 3.86 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 1.77 – 1.71 (m, 2H), 1.66 –
1.60 (m, 4H), 1.55 – 1.51 (m, 2H), 1.40 – 1.35 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.2,
158.8, 128.1, 117.8, 103.6, 98.2, 65.4, 61.9, 55.5, 55.4, 35.5, 28.9, 25.8, 25.4, 24.8.
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SMILES: COC1=C(C2C3(CCCCC3)O2)C=CC(OC)=C1
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2-(2,5-dimethoxyphenyl)-1-oxaspiro[2.5]octane 24c.
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OMe
Compound 24c was synthesized from styrene 22c (232 mg, 1.0 mmol, 1.0 equiv.)
°
MeO
24c
and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 C for 3 hours and purified
O
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accordingly to general procedure C to obtain pure material as a clear oil (194 mg,
H
C15 20O3
0.78 mmol, 78% yield). Rf = 0.35 (n-hexanes). IRνmax (neat): 2950, 1606, 1500,
MW: 248.32 g.mol-1
1485, 1223, 1153, 1035, 832 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 6.83 (d, J = 2.0 Hz, 1H),
6.88 (d, J = 4.0 Hz, 1H), 6.70(d, J = 3.1 Hz, 1H), 3.91 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 1.82-1.73
(m, 2H),1.71-1.63 (m, 2H), 1.53-1.50 (m, 2H), 1.39-1.37 (m, 2H), 1.29-1.21 (m, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 153.4, 151.9, 126.3, 113.3, 112.9, 110.8, 65.5, 61.9, 55.9, 55.8, 35.5,
28.8, 25.7, 25.2, 24.7. SMILES: COC1=C(C2C3(CCCCC3)O2)C=C(OC)C=C1
2-(2-methoxyphenyl)-1-oxaspiro[2.5]octane 24f.
Compound 24f was synthesized from styrene 22f (202 mg, 1.0 mmol, 1.0 equiv.)
°
and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 C for 2 hours and purified
O
OMe
accordingly to general procedure C to obtain pure material as a white solid (153
24f
mg, 0.70 mmol, 70% yield). Rf = 0.68 (EtOAc/n-hexanes 1:9). IRνmax (neat):
H
C14 18O2
MW: 218.30 g.mol-1
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2929, 1494, 1241, 1026, 752 cm-1. H NMR (400 MHz, CDCl3) δ (ppm) 7.25 –
7.23 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 3.93 (s, 1H), 3.86 (s, 3H), 1.83-
1.74 (m, 2H), 1.70 – 1.65 (m, 2H), 1.55 – 1.53 (m, 2H), 1.42 – 1.34 (m, 2H), 1.29 – 1.19 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm) 157.8, 128.3, 127.6, 125.3, 120.2, 109.8, 65.5, 62.1, 55.4,
35.6, 29.0, 25.8, 25.4, 24.8. HRMS (ESI/TOF) m/z: [M+H]+ Calcd for C14H19O2 219.1380; Found
219.1385 (2.3 ppm). SMILES: COC1=C(C2C3(CCCCC3)O2)C=CC=C1
2-(p-tolyl)-1-oxaspiro[2.5]octane 24g.
Compound 24g was synthesized from styrene 22g (186 mg, 1.0 mmol, 1.0 equiv.)
Me
°
and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 C for 3 hours and purified
O
accordingly to general procedure C to obtain pure material as a clear oil (170 mg,
24g
H
C14 18O
0.84 mmol, 84% yield). Rf = 0.81 (EtOAc/n-hexanes 1:9). IRνmax (neat): 2927,
1447, 915, 802, 794 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.19 (d, J = 8.0 Hz,
MW: 202.30 g.mol-1
2H), 7.14 (d, J = 8.1 Hz, 2H), 3.83 (s, 1H), 2.35 (s, 3H), 1.85 – 1.80 (m, 1H), 1.77 – 1.68 (m, 1H),
1.68 – 1.56 (m, 3H), 1.51 – 1.36 (m, 3H), 1.32 – 1.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm)
137.2, 134.3, 128.9 (2C), 126.6 (2C), 72.5, 63.4 (2C), 34.1, 28.5, 25.4, 25.3, 21.3. HRMS
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(ESI/TOF) m/z: [M+H]+ Calcd for C14H19O 203.1430; Found 203.1434 (1.8 ppm). SMILES:
CC1=CC=C(C2C3(CCCCC3)O2)C=C1
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2-phenyl-1-oxaspiro[2. 5]octane 24h.
Compound 24h was synthesized from styrene 22h (172 mg, 1.0 mmol, 1.0 equiv.)
°
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O
and oxone (615 mg, 1.0 mmol, 1.0 equiv.) at 0 C for 5 hours and purified
24h
accordingly to general procedure C to obtain pure material as a white solid (151
H
C13 16O
MW: 188.27 g.mol-1
mg, 0.80 mmol, 80% yield). Rf = 0.12 (n-hexanes). IRνmax (neat): 2930, 1452,
910, 751, 701 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.38 – 7.27 (m, 5H), 3.87 (s, 1H), 1.89 –
1.57 (m, 5H), 1.52 – 1.37 (m, 3H), 1.33 – 1.24 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 136.5,
128.1 (2C), 127.4, 126.5 (2C), 65.6, 64.7, 35.6, 28.5, 25.6, 25.5, 24.7. Spectral data for compound
24h were consistent with the data previously reported in the literature.19 SMILES:
C1(C2C3(CCCCC3)O2)=CC=CC=C1
2-(4-fluorophenyl)-1-oxaspiro[2.5]octane 24i.
Compound 24i was synthesized from styrene 22i (190 mg, 1.0 mmol, 1.0 equiv.),
F
acetone (66 mL, [0.02 M]), sat. NaHCO3 solution (40 mL, [0.03 M]), oxone (1.84
O
g, 3.0 mmol, 3.0 equiv.) and water (20 mL, [0.05 M]) at room temperature for 3.5
24i
H15FO
C13
MW: 206.26 g.mol-1
hours and purified accordingly to general procedure C to obtain pure material as
a white solid (153 mg, 0.74 mmol, 74% yield). Rf = 0.77 (n-hexanes). IRνmax
(neat): 2931, 1510, 1215, 814, 767 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.30 – 7.24 (m, 2H),
7.02 (t, J = 8.7 Hz, 2H), 3.82 (s, 1H), 1.83-1.80 (m, 1H), 1.73 – 1.69 (m, 1H), 1.66 – 1.54 (m, 5H),
13
1.46 – 1.39 (m, 3H). C NMR (100 MHz, CDCl3) δ (ppm) 162.2 (d, J = 245.2 Hz), 132.2, 128.0
(d, J = 8.8 Hz, 2C), 115.0 (d, J = 22.1 Hz, 2C), 65.7, 64.1, 35.4, 28.4, 25.5, 25.4, 24.6. HRMS
(ESI/QTOF) m/z: [M+H]+ Calcd for C13H16FO 207.1181; Found 207.1176 (1.8 ppm). SMILES:
FC1=CC=C(C2C3(CCCCC3)O2)C=C1
2-(4-(trifluoromethyl)phenyl)-1-oxaspiro[2.5]octane 24k.
Compound 24k was synthesized from styrene 22k (240 mg, 1.0 mmol, 1.0
F
3C
O
equiv.), acetone (66 mL, [0.02 M]), sat. NaHCO3 solution (40 mL, [0.03 M]), oxone
(1.84 g, 3.0 mmol, 3.0 equiv.) and water (20 mL, [0.05 M]) at room temperature
for 7 hours and purified accordingly to general procedure C to obtain pure material
as a clear liquid (236 mg, 0.92 mmol, 92% yield). Rf = 0.17 (n-hexanes); IRνmax
24k
H15
F
C14
3O
MW: 256.27 g.mol-1
(neat): 2934, 1321, 1121, 1065 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.60 (d, J = 8.1 Hz, 2H),
7.43 (d, J = 8.1 Hz, 2H), 3.89 (s, 1H), 1.83 (s, 1H), 1.78 – 1.59 (m, 4H), 1.51 – 1.35 (m, 3H), 1.30
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– 1.20 (m, 2H). C NMR (100 MHz, CDCl3) δ (ppm) 140.7, 129.6 (q, J = 32.3 Hz), 126.8 (2C),
125.1 (q, J = 3.7 Hz, 2C), 124.3 (q, J = 271.9 Hz, 1C), 66.1, 64.0, 35.5, 28.5, 25.5, 25.4, 24.6.
HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C14H16F3O 257.1148; Found 257.1142 (2.3 ppm).
SMILES: FC(C1=CC=C(C2C3(CCCCC3)O2)C=C1)(F)F
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1,4-di(1-oxaspiro[2.5]octan-2-yl)benzene 24m.
Compound 24m was synthesized from styrene 22m (266 mg, 1.0 mmol, 1.0
equiv.), acetone (132 mL, [8 mM]), sat. NaHCO3 solution (80 mL, [10 mM]),
O
oxone (3.69 g, 6.0 mmol, 6.0 equiv.) and water (40 mL, [30 mM]) at room
O
temperature for 5 hours and purified accordingly to general procedure C to obtain
24m
H
C20 26O2
pure material as a white solid (269 mg, 0.9 mmol, 90% yield). Rf = 0.8 (EtOAc/n-
hexanes 85:15). IRνmax (neat): 2922, 1455, 910, 773, 710 cm-1. 1H NMR (400
MW: 298.43 g.mol-1
MHz, CDCl3) δ (ppm) 7.27 (s, 4H), 3.84 (s, 2H), 1.85 – 1.78 (m, 2H), 1.76 – 1.59 (m, 8H), 1.51 –
1.38 (m, 6H), 1.33 – 1.21 (m, 4H). 13C NMR (100 MHz, CDCl3) δ (ppm) 135.5 (2C), 126.1 (4C),
65.7 (2C), 64.6 (2C), 35.5 (2C), 28.5 (2C), 25.6 (2C), 25.4 (2C), 24.6 (2C). HRMS (ESI/QTOF)
m/z: [M+H]+ Calcd for C20H27O2 299.2006; Found 299.2002 (1.3 ppm).
SMILES: C1(C2C3(CCCCC3)O2)=CC=C(C4C5(CCCCC5)O4)C=C1
2-(4-methoxyphenyl)cyclohexan-1-one 25a.
Compound 25a was synthesized from styrene oxide 23a (20 mg, 0.1 mmol, 1
OMe
equiv.) and purified accordingly to general procedure D to obtain pure material as
a white powder (16 mg, 0.079mmol, 79% yield) using Bi(OTf)3 and (18 mg,
O
0.09mmol, 92 % yield) using AlCl3. Rf = 0.40 (Et2O/n-hexanes 2:8). 1H NMR (400
25a
MHz, CDCl3) δ (ppm) 7.06 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 3.80 (s,
H
C13 16O2
MW: 204.27 g.mol-1
3H), 3.57 (dd, J = 12.2, 5.5 Hz 1H), 2.55 – 2.41 (m, 2H), 2.28 – 2.24 (m, 1H), 2.18
13
– 2.11 (m, 1H), 2.05 – 1.95 (m, 2H), 1.88 – 1.77 (m, 2H). C NMR (100 MHz, CDCl3) δ (ppm)
210.9, 158.5, 130.9, 129.5 (2C), 113.9 (2C), 56.7, 55.3, 42.3, 35.4, 27.9, 25.5. Spectral data for
compound 25a were consistent with the data previously reported in the literature.20a SMILES:
O=C1CCCCC1C2=CC=C(OC)C=C2
2-(2,4-dimethoxyphenyl)cyclohexan-1-one 25b.
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Compound 25b was synthesized from styrene oxide 23b (30 mg, 0.13 mmol, 1 equiv.) and purified
accordingly to general procedure D to obtain pure material as a white powder (29
OMe
6
7
8
9
mg, 0.12 mmol, 95% yield) using Bi(OTf)3 and (28 mg, 0.12 mmol, 93% yield)
using AlCl3. Rf = 0.35 (Et2O/n-hexanes 2:8). 1H NMR (400 MHz, CDCl3) δ (ppm)
MeO
O
7.01 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.2, 2.5 Hz, 1H),
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25b
3.85 (dd, J = 12.8, 5.7 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.53 – 2.43 (m, 1H),
H
C14 18O3
MW: 234.30 g.mol-1
2.35 – 2.32 (m, 1H), 2.14 – 2.08 (m, 3H), 1.86 – 1.67 (m, 3H). Spectral data for
compound 25b were consistent with the data previously reported in the literature.20a
SMILES: O=C1CCCCC1C2=C(OC)C=C(OC)C=C2
2-(2,5-dimethoxyphenyl)cyclohexan-1-one 25c.
Compound 25c was synthesized from styrene oxide 23c (20 mg, 0.1 mmol, 1
OMe
equiv.) and purified accordingly to general procedure D to obtain pure material
MeO
O
as a white powder (18 mg, 0.08 mmol, 90% yield) using Bi(OTf)3 and (17 mg,
0.07 mmol, 86% yield) using AlCl3. Rf = 0.40 (Et2O/n-hexanes 2:8). IRνmax
25c
H
C14 18O3
1
(neat): 2937, 1713, 1452, 1050, 803 cm-1. H NMR (400 MHz, CDCl3) δ (ppm)
MW: 234.30 g.mol-1
6.86-6.75 (m, 3H), 3.93 (dd, J = 10.3, 5.3 Hz 1H), 3.77 (s, 3H), 3.73 (s, 3H), 2.89 – 2.85 (m, 2H),
2.07 – 1.96 (m, 4H), 1.72 – 1.69 (m, 1H), 1.56 – 1.44 (m, 2H). Spectral data for compound 25c
were consistent with the data previously reported in the literature.20b SMILES:
O=C1CCCCC1C2=CC(OC)=CC=C2OC
2-(2-methoxyphenyl)cyclohexan-1-one 25f.
Compound 25f was synthesized from styrene oxide 23f (50 mg, 0.25 mmol, 1
equiv.) and purified accordingly to general procedure D to obtain pure material as
MeO
O
a white powder (38 mg, 0.19 mmol, 76% yield) using Bi(OTf)3 and (39 mg, 0.07
1
mmol, 77% yield) using AlCl3. Rf = 0.35 (EtOAc/n-hexanes 2:8). H NMR (400
25f
H
C13 16O2
MHz, CDCl3) δ (ppm) 7.23 (dd, J = 7.0, 1.2 Hz, 1H), 7.11 (dd, J = 7.5, 1.7 Hz, 1H),
MW: 204.27 g.mol-1
6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.88 (dd, J = 8.2, 0.9 Hz, 1H), 3.93 (dd, J = 12.7, 5.4 Hz, 1H), 3.77
(s, 3H), 2.57 – 2.44 (m, 2H), 2.24 – 2.13 (m, 2H), 2.09 – 1.97 (m, 2H), 1.89 – 1.74 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 209.9, 157.1, 128.9, 128.1, 120.7 (2C), 110.8, 55.6, 51.2, 42.4,
33.6, 27.7, 25.8. Spectral data for compound 25f were consistent with the data previously reported
in the literature.20c SMILES: O=C1CCCCC1C2=C(OC)C=CC=C2
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