Migratory Aptitudes in Rearrangements of Destabilized Vinyl Cations

Article abstract of DOI:10.1021/acs.joc.9b02130

The Lewis acid-promoted generation of destabilized vinyl cations from β-hydroxy diazo ketones leads to an energetically favorable 1,2-shift across the alkene followed by an irreversible C-H insertion to give cyclopentenone products. This reaction sequence overcomes typical challenges of counter-ion trapping and rearrangement reversibility of vinyl cations and has been used to study the migratory aptitudes of nonequivalent substituents in an uncommon C(sp²) to C(sp) vinyl cation rearrangement. The migratory aptitude trends were consistent with those observed in other cationic rearrangements; the substituent that can best stabilize a cation more readily migrates. However, density functional theory calculations show that the situation is more complex. Selectivity in the formation of one conformational isomer of the vinyl cation and facial selective migration across the alkene due to an electrostatic interaction between the vinyl cation and the adjacent carbonyl oxygen work in concert to determine which group migrates. This study provides valuable insight into predicting migration preferences when applying this methodology to the synthesis of structurally complex cyclopentenones that are differentially substituted at the α and β positions.

Full text of DOI:10.1021/acs.joc.9b02130

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Migratory Aptitudes in Rearrangements of Destabilized Vinyl
Cations
Sarah E. Cleary,‡,§,∥ Magenta J. Hensinger,‡,§ Zhi-Xin Qin,† Xin Hong,*,† and Matthias Brewer*,‡
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: The Lewis acid-promoted generation of destabilized vinyl cations from β-hydroxy diazo ketones leads to an
energetically favorable 1,2-shift across the alkene followed by an irreversible C−H insertion to give cyclopentenone products.
This reaction sequence overcomes typical challenges of counter-ion trapping and rearrangement reversibility of vinyl cations
and has been used to study the migratory aptitudes of nonequivalent substituents in an uncommon C(sp2) to C(sp) vinyl cation
rearrangement. The migratory aptitude trends were consistent with those observed in other cationic rearrangements; the
substituent that can best stabilize a cation more readily migrates. However, density functional theory calculations show that the
situation is more complex. Selectivity in the formation of one conformational isomer of the vinyl cation and facial selective
migration across the alkene due to an electrostatic interaction between the vinyl cation and the adjacent carbonyl oxygen work
in concert to determine which group migrates. This study provides valuable insight into predicting migration preferences when
applying this methodology to the synthesis of structurally complex cyclopentenones that are differentially substituted at the α
and β positions.
spontaneously loses molecular nitrogen to yield exocyclic vinyl
cation 3. If an electron-releasing group is present in the γ-
position (e.g., 3, Y = OTBS), a Grob-like fragmentation
ensues, which leads to an aldehyde-tethered ynone (4).18
Compounds that lack an electron-releasing group do not
fragment but instead undergo a 1,2-shift across the alkene to
give a second vinyl cation (5). This rearrangement is
energetically favorable because the electron-withdrawing
carbonyl group destabilizes cation 3.4,16 Depending on the
structure of the ketone, vinyl cation 5 can then participate in
an intramolecular C−H insertion reaction to give a cyclo-
pentenone (6) or an electrophilic aromatic substitution
reaction to give an indenone (7).
Cyclopentenones, indanones, and their derivatives are
important motifs found in biologically active compounds and
natural products, which tend to be structurally complicated
molecules (Figure 1).19,20 In order for these vinyl cation
reaction sequences to be useful strategies for complex molecule
synthesis, it is important to be able to predict the migratory
aptitude of different groups in the 1,2-shift in systems that are
not symmetric (e.g., 3, Y = alkyl, aryl). While many studies
have looked at the migratory aptitudes of various groups in
cationic rearrangements that involve migrations from sp3
centers to sp3 centers, migrations across the alkene of vinyl
cations are unique in that they involve C(sp2) and C(sp)
INTRODUCTION
■
Although vinyl cations have been studied for over 60 years, a
lack of methods to generate these highly reactive intermediates
has hindered the development of general, synthetically useful
reactions.1,2 However, the recent realization of milder ways to
form vinyl cations has led to renewed interest in their
reactivity.3−10 For example, our group has taken advantage of
vinyl cations to develop a ring fragmentation reaction,11−14 as
well as methods to form cyclopentenones15,16 and indenones17
(Scheme 1). These reactions take advantage of Padwa and
Pellicciari’s finding that vinyl cations are formed when β-
hydroxy-α-diazo carbonyl compounds are treated with a Lewis
acid.4 As shown in Scheme 1, the Lewis acid facilitates the loss
of the β-hydroxy group to give vinyl diazonium 2, which
Scheme 1. Reactions of Vinyl Cations
Received: August 2, 2019
© XXXX American Chemical Society
A
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1
yields of the products or by H NMR of the crude reaction
mixtures using 1,3,5-trimethoxybenzene as an internal stand-
ard.
The initial vinyl cation precursor we targeted was β-hydroxy-
α-diazoketone 15a (Scheme 3), which we prepared by adding
lithiated 1-diazo-3,3-dimethylbutan-2-one to acetophenone.
Treating 15a with BCF gave the known23 regioisomeric
cyclopentenones 16a and 17a in 16 and 2% yield, respectively,
as determined by NMR spectroscopy of the crude reaction
mixture. The 8:1 product ratio favoring phenyl group
migration is consistent with the Baeyer−Villiger and
pinacol−pinacolone rearrangements and can be rationalized
by the intermediacy of a phenonium species.24 It is not clear
why the cyclopentenone products are formed in such low
yields in this case, but 1-phenyl-1-propyne (18a) was also
observed in the crude reaction mixture in 7% yield. This latter
product, which is fairly volatile and may have been produced in
higher quantities, could form from the vinyl cation
intermediate by bond fragmentation giving the alkyne and an
acylium ion, which is the reverse of the first step of the
Friedel−Crafts acylation of an alkyne. Cyclic systems, such as
those we have previously studied, are unlikely to suffer this side
reaction as it would lead to a highly strained cycloalkyne. Ethyl
analogue 15b gave phenyl migration product 16b in 30% yield,
with an additional 27% yield of alkyne 18b. The product of
ethyl migration (17b) was not identified in the crude reaction
mixture.
We next turned our attention to tetralone systems. The
Baeyer−Villiger oxidation of tetralone results in selective
migration of the aryl ring.25,26 However, Baeyer−Villiger
oxidation involves migration between adjacent sp3 centers,
whereas the vinyl cation rearrangement involves migration
from an sp2 center to an sp center. Because the vinyl cation is
coplanar with the migrating group, the stereoelectronic
arrangement is different than that of the Baeyer−Villiger
reaction; the tetralone aromatic π system would be nearly
perpendicular to the vacant p-orbital of the vinyl cation and a
phenonium intermediate should not form. As such, the
reaction would be a more direct comparison of the migratory
aptitude of an sp2 center versus an sp3 center.
Figure 1. Representative examples of biologically active cyclo-
pentenones and indanones.
centers and should show different stereoelectronic effects. To
date, the majority of studies involving vinyl cation rearrange-
ments have focused on the migratory aptitude of aryl rings,21
and few have involved destabilized vinyl cations such as 3.22
We recently reported density functional theory (DFT)
calculations of the energy profile of the transition metal-free
rearrangement and C−H insertion reaction of vinyl cations.16
As shown in Scheme 2, the energy barrier for the 1,2-shift of
vinyl cation 8 to vinyl cation 10 is only 1.8 kcal/mol and 10 is
6.1 kcal/mol lower in energy than 8. The subsequent C−H
insertion has an energy barrier of only 0.4 kcal/mol, leading to
a product that is 19.8 kcal/mol more stable. In view of these
low energy barriers, the rearrangement and insertion steps are
likely kinetically controlled and irreversible. As such, this
reaction sequence constitutes a good platform to study the
migratory aptitude of nonequivalent groups across the alkene
of destabilized vinyl cations. Herein, we report results of
experimental and computational studies that define the relative
migratory aptitudes of various alkyl and aryl groups in this
rearrangement step.
RESULTS AND DISCUSSION
■
We began our studies by comparing the migratory aptitude of
aryl rings to alkyl groups. In optimizing the conversion of diazo
ketones to cyclopentenones, we determined that treating the
diazo ketone with 1 equiv of tris(pentafluorophenyl)borane
(BCF; (C6F5)3B) in CH2Cl2 at 0 °C gave good results,15 and
these conditions were used for our present studies without
further attempts at optimization. Product ratios of the
regioisomeric cyclopentenones were determined from isolated
Scheme 2. Calculated Energy Profile of the Rearrangement and C−H Insertion of a Vinyl Cation
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Scheme 3. Migratory Competition between Phenyl and Alkyl Groups
a
1
Determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard. The group that migrated is colored red.
Adding a lithiated diazo ketone to tetralone was not trivial;
subjected to the standard C−H insertion conditions. In the
competition between methyl and a 1° alkyl chain (22, pentyl,
entry 1), migration of the alkyl chain was favored by 1.7−1 as
determined by the NMR spectrum of the crude reaction
mixture. However, cyclopentenone 23 proved difficult to
purify, and nearly equal quantities of 23 and 24 were isolated.
Increasing the substitution to a 2° alkyl group (25, cyclohexyl,
entry 2) led to an increase in relative migratory aptitude
compared with methyl. In this case, the product of cyclohexyl
migration (26) was formed in 16% yield while the product of
methyl migration (27) was formed in only trace amounts
(<5%). The major product of this reaction was prop-1-yn-1-
ylcyclohexane, which forms by fragmentation of the vinyl
cation similar to compounds 15a and 15b (Scheme 3). To
compare the relative migratory aptitude of 1 and 2° alkyl
groups, we prepared diazo 28 from 2-methylcyclohexanone
(entry 3). Treating this compound with BCF gave cyclo-
pentenone 29, formed by migration of the 2° alkyl group, in
50% yield with an additional 11% yield of a 1:1 mixture of 29
and 30 (entry 4). Attempts to isolate and characterize the
minor isomer (30) from this reaction failed. However, 30 was
isolated cleanly and fully characterized when SnCl4 was used as
the Lewis acid. With 30 being characterized, we were able to
determine by 1H NMR spectroscopy of the crude mixture that
(C6F5)3B gave 29 and 30 in a 4.4:1 ratio. All of these results
are consistent with other cationic 1,2-rearrangements, wherein
alkyl substituents that can best stabilize a positive charge in the
transition state have higher migratory aptitudes.
the standard reaction conditions gave no desired product. After
extensive optimization, we found that addition product 19a
could be isolated when lithiated 1-diazo-3-methylbutan-2-one
was added to tetralone in a 3.5:1 mixture of hexane and
tetrahydrofuran (THF) as the solvent. Interestingly, treating
this material with BCF gave exclusive migration of the alkyl
carbon to give cyclopentanone 20a as the major product in
27% yield as determined by NMR spectroscopy of the crude
complex reaction mixture. The regioisomeric product derived
from aryl ring migration (21a) was not observed. In migrations
to cationic centers, the group that can better stabilize a cation
tends to migrate more readily.27 In this case, preferential
migration of the methylene carbon may be rationalized by
considering the differing electronegativities of sp2- and sp3-
hybridized atoms. Centers that are sp2-hybridized are more
electronegative and unless they can form a stabilized
intermediate such as a phenonium ion, should be less likely
to migrate.
We continued these studies by preparing the substituted
tetralone derivatives shown in Scheme 4. In each case, Lewis
Scheme 4. Migratory Competition Studies of Tetralone-
Based Systems
With these results in mind, we would expect a 3° alkyl group
to migrate more readily than a 1° alkyl group. However, diazo
ketones 31 and 32 (entry 4), and the slightly less sterically
hindered 33 (entry 5), did not react with (C6F5)3B. As only
the starting material was obtained from these reactions, it
appears that steric crowding around the β-hydroxy group may
prevent Lewis acid coordination and vinyl cation formation.
Less bulky Lewis acids (SnCl4 and BF3·OEt2) were tested but
these also failed to promote a reaction.
a
1
Determined by H NMR spectroscopy using 1,3,5-trimethoxyben-
b
zene as an internal standard Isolated yield. The group that migrated
is colored red.
α-Chloro ketones are known to exhibit a strong preference
for migration of the nonhalogenated alkyl group in the
Baeyer−Villiger reaction. For example, 34 reacted with m-
CPBA to give α-chlorolactone 35 as the major product (87%,
Scheme 5a).28 To test if a similar trend holds for the
rearrangement of vinyl cations, γ-chloro-β-hydroxy-α-diazo
ketone 37 was prepared and treated with (C6F5)3B. In this
case, we were surprised to isolate dione 39 as the major
product (45% yield, Scheme 5b) in place of the expected
cyclopentenone products that would form by the C−H
insertion sequence. Diketone 39 could form directly from 37
by an acid-catalyzed rearrangement, but this seems unlikely as
we have only observed that type of reactivity when protic acids
are present.17 Alternatively, if diazo 37 reacts with BCF to give
the destabilized vinyl cation and the nonhalogenated carbon
acid treatment returned complex mixtures. Proton NMR
spectroscopy of the crude reaction mixtures revealed that the
tricyclic cyclopentenone compounds were the major products
formed, and the yields shown in Scheme 4 are isolated yields.
Not surprisingly, aryl rings with electron-withdrawing sub-
stituents gave only products of methylene migration (Scheme
4, 19b−d). However, an electron-donating methoxy group
para to the migrating atom promoted migration of the aryl
ring. Substrate 19e gave a 2.6 to 1 ratio of aryl to methylene
migration products, showing that electron-donating substitu-
ents can increase the migratory aptitude of sp2 centers.
We next focused on comparing the migratory aptitude of
various alkyl groups. The substrates shown in Table 1 were
prepared for these competition experiments and were
C
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Table 1. Migratory Competition between Alkyl Groups
a
1
Regiomeric ratio, determined from H NMR integrations of crude reaction. The group that migrated is colored red.
Scheme 5. Migratory Aptitude of a Chloro-Containing
Substituent
Figure 2. DFT-optimized structures of the vinyl cation conforma-
tional isomers 40 and 41. All hydrogens are omitted for clarity.
from an electrostatic interaction between the carbonyl oxygen
and the cationic carbon. From these intermediates, the
migration step could occur from the group that is either cis
or trans to the carbonyl or both. Importantly, for the
unsubstituted cyclohexane-based system, we observed that
the group that is cis to the carbonyl oxygen migrates
irreversibly across the alkene via TS1 (Figure 3), with an
energy barrier that is 6.9 kcal/mol lower than that for the
group trans to the carbonyl oxygen (TS2).
migrates as expected, then vinyl cation 38 would be formed.
This cation could be stabilized by the adjacent chlorine via a
chloronium-type intermediate, which should slow the C−H
insertion reaction and allow competitive addition of water to
give dione 39.
To gain a better understanding of what factors control the
selectivity of the migration step, we studied the reaction of
diazo ketone 28 computationally. The vinyl cation derived
from 28 can adopt two conformational isomers (40 and 41,
Figure 2) that have nearly identical energies and that benefit
This large energy difference, which is presumably due to the
electrostatic interaction, means that the vinyl cation isomers 40
and 41 would react to give different products; isomer 40 would
D
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vinyl cations is the rate-limiting step in these sequences.
Importantly, the energy barrier for N2 loss is 4.9 kcal/mol
lower for the (E)-isomer of the vinyl diazonium salt (44) than
(Z)-isomer 53 (TS45 vs TS54). This energy difference would
lead to the preferential formation of vinyl cation conforma-
tional isomer 40. Importantly, as shown in Scheme 8,
isomerization of 40 to 41 via TS61 has a higher energy
barrier (7.7 kcal/mol) than irreversible migration across the
alkene via TS46 (5.8 kcal/mol) to give vinyl cation 47. Once
47 is formed, it would undergo a fast insertion to give
cyclopentenone 29. The competing formation of the minor
product (30) suggests that a small portion of vinyl cation 40
isomerizes to 41, which would rearrange and insert. Thus,
cyclopentenone 29 is formed as the major product because
diazonium salt 44 loses nitrogen to give vinyl cation 40 more
easily than the alternative isomer that suffers from allylic 1,3-
strain. At this point, it is not clear if linear or tetralone-based
systems have similar control elements and further computa-
tional studies will be needed to clarify this point.
Figure 3. DFT-calculated transition states for migration across the
alkene in the cyclohexane-based system. All hydrogens are omitted for
clarity.
give 29 while isomer 41 would give 30. Our initial supposition
was that the isomerization between isomers 40 and 41 would
have a low energy barrier, and the outcome of the reaction
would be controlled by the energy barriers of the competitive
irreversible migrations. However, computational modeling
showed that the less substituted group migrates with a lower
energy barrier than the more substituted group (3.6 kcal/mol
for 41 to 56 and 5.8 kcal/mol for 40 to 47, Schemes 6 and 7).
The difference in energy is presumably because of a steric
interaction between the carbonyl oxygen and the bulkier
migrating group in TS46 (Scheme 6). Based on these results,
the major product of the reaction would be expected to be 30
rather than the observed 29. With this in mind, we performed a
more comprehensive computational study of the reaction paths
leading to cyclopentenones 29 and 30.
The initial step of this sequence, the Lewis acid mediated
loss of the β-hydroxy group from 42, leads to two
diastereomeric vinyl diazonium salts (44 and 53, Schemes 6
and 7), which cannot isomerize by direct rotation. However,
this dehydroxylation step is reversible and thus 44 and 53 are
in equilibrium. The (E)-isomer (44) is 1.9 kcal/mol lower in
energy than the (Z)-isomer (53). This difference in stability is
presumably because of allylic 1,3-strain between the linear
diazo group and the methyl in 53. Loss of nitrogen to form the
CONCLUSIONS
■
The relative migratory aptitudes of various alkyl and aryl
groups in the 1,2-shift across the alkene of destabilized vinyl
cations have been assessed. Qualitatively, the substituent that
best stabilizes the cation had the higher aptitude for migration.
However, DFT calculations show that in cyclohexanone-based
systems, the observed migratory aptitude is because of
conformational biases rather than transition-state stabilization.
An aryl ring migrated in preference to an alkyl group if a
phenonium intermediate could form. Conversely, in tetralone
systems that have electron neutral or electron poor aryl rings,
the alkyl group migrated in preference to the aryl ring. In these
cases, the vacant orbital of the vinyl cation is coplanar with the
migrating group, which prevents the formation of a phenonium
intermediate, and the less electronegative sp3-hybridized atom
migrated in preference to the more electronegative sp2 center.
However, incorporating an electron-releasing methoxy group
at the para position of the tetralone aryl ring increased the
Scheme 6. DFT-Computed Gibbs Free Energy Barriers for the Reaction Pathway Leading to the Major Product
E
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Scheme 7. DFT-Computed Gibbs Free Energy Barriers for the Reaction Pathway Leading to the Minor Product
EXPERIMENTAL SECTION
Scheme 8. DFT-Computed Gibbs Free Energy Barrier for
Interconversion of Vinyl Cation Isomers
■
General Information. All reactions were performed under an
atmosphere of nitrogen in flame-dried glassware. Solvents were
removed in vacuo using a rotary evaporator attached to a dry vacuum
pump. THF and dichloromethane (CH2Cl2) were dried via a solvent
dispensing system, hexane was distilled before use, and when used as a
reaction solvent it was also dried over 4 Å molecular sieves.
Diisopropylamine (iPr2NH) was freshly distilled from CaH2 prior to
use. 1-Diazo-3,3-dimetylbutan-2-one29 and 1-diazo-3-methylbutan-2-
one30 were prepared following known procedures. All other
commercially available reagents were used without further purifica-
tion. Flash column chromatography was performed on a CombiFlash
Rf 150 system using silica columns. Thin-layer chromatography
(TLC) analysis was carried out using silica on glass plates.
Visualization of TLC plates was achieved using ultraviolet light and
1
1
1
ceric ammonium molybdate. H, 13C{1H}, H−13C HMBC, and H
NOE NMR spectroscopic data were collected at room temperature
1
on a 500 MHz spectrometer in CDCl3. H NMR chemical shifts are
reported in ppm (δ units) downfield from tetramethylsilane, and
13C{1H} NMR spectra are referenced to the CDCl3 signal at 77.0
ppm. Exact mass analysis was performed on Waters Xevo G2-XS
LCMS-QTOF operated in positive ESI mode.
migratory aptitude of the aryl group, and in this case, both the
product of aryl migration and alkyl migration were isolable
with a preference for aryl migration. Further computational
studies will determine if steric interactions play a role in these
outcomes. In the migratory competition between two alkyl
groups, the more electron-rich group migrated with a higher
aptitude. For example, a 1 or 2° alkyl group migrated in
preference to methyl, and a 2° alkyl group migrated in
preference to a 1° alkyl group. Systems that contained a 3°
alkyl group adjacent to the β-hydroxy group failed to react,
presumably because of steric hindrance. Finally, incorporating
a halogen adjacent to the β-hydroxy group led to a dione
product. In this case, after migration of the unsubstituted side,
neighboring group participation may slow the C−H insertion
step, allowing water to capture the vinyl cation. Systems where
the product of rearrangement was an endocyclic vinyl cation
led to higher yields of insertion products. This is because of the
tendency of linear β-keto vinyl cations to fragment giving
alkyne products prior to insertion. These migratory aptitude
studies provide further insight into the reactivity of destabilized
vinyl cations and will facilitate the use of these electron-
deficient intermediates in more complex molecule synthesis.
General Procedure A: Preparation of β-Hydroxy-α-diazo
Ketones. A −78 °C solution of LDA (1.5 equiv) [prepared by adding
n-butyllithium in hexanes (1.5 equiv) to a solution of iPr2NH (1.7
equiv) in THF (3 mL per mmol of n-butyllithium)] was added
dropwise over 30 min down the inside wall of a chilled (−78 °C) flask
containing a solution of ketone (1 equiv) and α-diazo ketone (1.6
equiv) in THF (3 mL per mmol of ketone) under an atmosphere of
nitrogen. The mixture was maintained at −78 °C until complete
conversion was achieved as monitored by TLC (typically 30 min).
AcOH (0.5 M in THF, 1.6 equiv) was added, the reaction flask was
removed from the cold bath, and water (10 mL) was added. The
layers were separated, and the aqueous layer was extracted three times
with EtOAc (15 mL). The organic layers were combined, washed
with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), and
dried over anhydrous CaCl2. The solvent was removed in vacuo to
give an oily residue that was subjected to flash silica gel
chromatography to afford the desired β-hydroxy-α-diazo ketone.
General Procedure B: Preparation of β-Hydroxy-α-diazo
Ketones of Tetralone Derivatives. A −78 °C solution of LDA (1.5
equiv) [prepared by adding n-butyllithium in hexanes (1.5 equiv) to a
solution of iPr2NH (1.7 equiv) in dry hexanes (3 mL per mmol of n-
butyllithium)] was added dropwise over 10 min down the side of a
chilled flask containing a cold (−78 °C) solution of ketone (1 equiv)
F
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and α-diazo ketone (1.6 equiv) in dry hexanes (3 mL per mmol of n-
butyllithium) and dry THF (2.5 mL per mmol of ketone) under an
atmosphere of nitrogen. The mixture was maintained at −78 °C for
45 min. 1 equiv of AcOH in hexanes (16.4 mL per mmol AcOH) was
added to the dark red reaction at −78 °C under nitrogen at which
point the mixture became yellow. The reaction flask was removed
from the cold bath and allowed to warm to room temperature. The
reaction mixture was poured into a separatory funnel containing water
(50 mL), the layers were separated, and the aqueous layer was
extracted three times with EtOAc (15 mL). The organic layers were
combined, washed with saturated aqueous NaHCO3 (50 mL) and
brine (50 mL), and dried over anhydrous CaCl2. The solvent was
removed in vacuo to provide an oily residue that was subjected to
flash silica gel chromatography to afford the desired β-hydroxy-α-
diazo ketone.
(39% yield) of the title compound as a bright yellow solid: Rf = 0.29
(3.7:1 hexane/EtOAc); 1H NMR (500 MHz, CDCl3): δ 8.07 (dd, J =
8.7, 2.3 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H),
5.32 (s, 1H), 2.95−2.89 (m, 2H), 2.83 (hept, J = 6.8 Hz, 1H), 2.51
(ddd, J = 13.2, 6.6, 2.3 Hz, 1H), 2.13−2.02 (m, 2H), 1.83−1.72 (m,
1H), 1.17 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ
200.5, 147.7, 143.5, 139.4, 129.0, 124.2, 121.7, 73.5, 72.0, 36.9, 29.1,
19.9, 18.8, 18.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H17N3O4Na, 326.1117; found, 326.1119.
1-Diazo-1-(1-hydroxy-7-nitro-1,2,3,4-tetrahydronaphtha-
len-1-yl)-3-methylbutan-2-one (19c). Prepared from 7-nitro
tetralone (229 mg, 1.20 mmol) and 1-diazo-3-methyl-2-butanone
(216 mg, 1.93 mmol) following general procedure B. The crude
orange brown oil was purified using silica gel flash chromatography
(hexanes/CH2Cl2, gradient elution 0−90% CH2Cl2), the desired
compound was isolated, and then resubjected to silica gel flash
chromatography (hexanes/EtOAc, gradient elution 0−14% EtOAc)
to give 90.5 mg (25% yield) of the title compound as a bright yellow
solid: Rf = 0.28 (3.7:1 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3): δ 8.55 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.4, 2.3 Hz, 1H),
7.30 (d, J = 8.5 Hz, 1H), 5.34 (s, 1H), 2.94−2.89 (m, 2H), 2.84
(hept, J = 6.8 Hz, 1H), 2.51 (ddd, J = 13.1, 6.5, 2.5 Hz, 1H), 2.12−
2.02 (m, 2H), 1.82−1.72 (m, 1H), 1.17 (app t, J = 6.5 Hz, 6H);
13C{1H} NMR (125 MHz, CDCl3): δ 200.5, 147.1, 145.2, 138.5,
4-Diazo-5-hydroxy-2,2-dimethyl-5-phenylhexan-3-one
(15a). Prepared from acetophenone (80 μL, 0.69 mmol) and 1-diazo-
3,3-dimetylbutan-2-one (136 mg, 1.08 mmol) following general
procedure A with the modification that dry hexanes were used in
place of THF as the solvent. Unreacted acetophenone was removed
under high vacuum overnight. Further purification of the crude
material using silica gel flash column chromatography (hexanes/
EtOAc, gradient elution 0−10% EtOAc) afforded 53 mg (31% yield)
of the title compound as a yellow solid: Rf = 0.62 (4:1 hexanes/
1
EtOAc); H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.5 Hz, 2H),
130.4, 123.2, 73.4, 72.1, 36.9, 36.9, 29.2, 19.8, 18.9, 18.4. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C15H17N3O4Na, 326.1117; found,
326.1111.
7.33 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 5.24 (s, 1H), 1.61 (s,
3H), 1.22 (s, 9H); 13C{1H} (125 MHz, CDCl3): δ 202.1, 147.1,
128.4, 127.4, 124.3, 75.1, 69.4, 44.6, 28.9, 26.3. HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C14H18N2O2Na, 269.1266; found,
269.1263.
1-(6-Bromo-1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
1-diazo-3-methylbutan-2-one (19d). Prepared from 6-bromo
tetralone (90.9 mg, 0.40 mmol) and 1-diazo-3-methyl-2-butanone
(75.8 mg, 0.68 mmol) following general procedure B. The crude
orange solid was purified using silica gel flash chromatography
(hexanes/CH2Cl2, gradient elution 0 to 50 to 60% CH2Cl2) to give
67.8 mg (50% yield) of the title compound as a bright yellow solid: Rf
= 0.53 (100% CH2Cl2); 1H NMR (500 MHz, CDCl3): δ 7.53 (d, J =
8.4 Hz, 1H), 7.37 (dd, J = 8.5, 2.1 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H),
5.27 (s, 1H), 2.87−2.70 (m, 3H), 2.49−2.41 (m, 1H), 2.08−1.95 (m,
2H), 1.75−1.62 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H); 13C{1H} NMR
(125 MHz, CDCl3): δ 200.7, 139.8, 135.7, 132.0, 130.2, 129.4, 122.7,
73.8, 37.4, 36.9, 28.9, 20.3, 18.9, 18.5. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C15H17BrN2O2Na, 359.0371; found, 359.0365.
1-Diazo-1-(1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaph-
thalen-1-yl)-3-methylbutan-2-one (19e). Prepared from 6-
methoxy tetralone (150 mg, 0.85 mmol) and 1-diazo-3-methyl-2-
butanone (156 mg, 1.39 mmol) following general procedure B. The
crude orange brown oil was purified using silica gel flash
chromatography (hexanes/CH2Cl2, gradient elution 0−75%
CH2Cl2) to give 58.5 mg (24% yield) of the title compound as a
bright yellow solid: Rf = 0.42 (3.7:1 hexanes/EtOAc); 1H NMR (500
MHz, CDCl3): δ 7.56 (d, J = 8.7 Hz, 1H), 6.81 (dd, J = 8.8, 2.7 Hz,
1H), 6.60 (d, J = 2.4 Hz, 1H), 5.22 (s, 1H), 3.79 (s, 3H), 2.86−2.70
(m, 3H), 2.44 (ddd, J = 13.1, 6.5, 2.5 Hz, 1H), 2.05 (td, J = 12.6, 2.8
Hz, 1H), 2.02−1.93 (m, 1H), 1.74−1.63 (m, 1H), 1.16 (d, J = 6.8 Hz,
6H); 13C{1H} NMR (125 MHz, CDCl3): δ 200.6, 159.4, 139.1,
128.9, 113.3, 113.2, 73.9, 73.1, 55.3, 37.9, 36.8, 29.5, 20.6, 18.9, 18.4.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H20N2O3Na,
311.1372; found, 311.1370.
4-Diazo-5-hydoxy-2,2,5-trimethyldecan-3-one (22). Prepared
from 2-heptanone (110 μL, 0.79 mmol) and 1-diazo-3,3-dimetylbu-
tan-2-one (163 mg, 1.29 mmol) following general procedure A.
Purification of the crude material using silica gel flash column
chromatography (hexanes/EtOAc, gradient elution 0−15% EtOAc)
afforded 131 mg (69% yield) of the title compound as a yellow solid:
Rf = 0.58 (5:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3): δ 4.92
(s, 1H), 1.80 (ddd, J = 13.8, 11.1, 4.7 Hz, 1H), 1.69 (ddd, J = 13.8,
11.0, 4.8 Hz, 1H), 1.38 (s, 3H), 1.36−1.25 (m, 6H), 1.23 (s, 9H),
0.88 (t, J = 6.7 Hz, 3H); 13C{1H} (125 MHz, CDCl3): δ 202.8, 73.1,
67.5, 44.8, 41.4, 31.9, 26.5, 25.1, 24.2, 22.5, 14.0. HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C13H24N2O2Na, 263.1735; found,
263.1732.
4-Diazo-5-hydroxy-2,2-dimethyl-5-phenylheptan-3-one
(15b). Prepared from propiophenone (240 μL, 1.80 mmol) and 1-
diazo-3,3-dimethylbutan-2-one (363 mg, 2.88 mmol) following
general procedure A with the modification that the reaction was
quenched with 1 equiv of AcOH in THF (16.4 mL per mmol AcOH).
The crude yellow oil was purified using silica gel flash chromatog-
raphy (hexanes/EtOAc, gradient elution 0−15% EtOAc), the desired
compound was isolated, and then resubjected to silica gel flash
chromatography (hexanes/CH2Cl2, gradient elution 0−30% CH2Cl2)
to give 158 mg (34% yield) of the title compound as a bright yellow
oil which solidified upon standing in a freezer: Rf = 0.61 (4:1 hexanes/
EtOAc); 1H NMR (500 MHz, CDCl3): δ 7.41−7.37 (m, 2H), 7.35−
7.30 (m, 2H), 7.27−7.23 (m, 1H), 5.34 (s, 1H), 1.98 (dq, J = 14.7,
7.4 Hz, 1H), 1.77 (dqd, J = 14.8, 7.4, 1.2 Hz, 1H), 1.20 (s, 9H), 0.86
(t, J = 7.3 Hz, 3H); 13C {1H} NMR (125 MHz, CDCl3): δ 202.6
145.6, 128.2, 127.3, 125.0, 77.2, 69.4, 44.7, 33.4, 26.3, 7.6. HRMS
(ESI-TOF) m/z: [M + K]+ calcd for C15H20N2O2K, 299.1162; found,
299.1147.
1-Diazo-1-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
3-methylbutan-2-one (19a). Prepared from tetralone (150 μL,
1.13 mmol) and 1-diazo-3-methyl-2-butanone (203 mg, 1.81 mmol)
following general procedure B. The crude orange solid was purified
using silica gel flash chromatography (hexanes/EtOAc, gradient
elution 0−9% EtOAc), the desired compound was isolated, and then
resubjected to silica gel flash chromatography (hexanes/CH2Cl2,
gradient elution 0−100% CH2Cl2) to give 144 mg (43% yield) of the
title compound as a bright yellow solid: Rf = 0.50 (4:1 hexanes/
1
EtOAc); H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 7.8 Hz, 1H),
7.27−7.18 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 5.26 (s, 1H), 2.88−2.73
(m, 3H), 2.51−2.40 (m, 1H), 2.07 (td, J = 11.9, 2.8 Hz, 1H) 2.03−
1.93 (m, 1H), 1.77−1.64 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H); 13C{1H}
NMR (125 MHz, CDCl3): δ 200.6, 137.4, 136.4, 129.1, 128.5, 127.4,
126.8, 74.1, 72.9, 37.6, 36.7, 29.1, 20.4, 18.8, 18.4. HRMS (ESI-TOF)
m/z: [M + K]+ calcd for C15H18N2O2K, 297.1005; found, 297.0991.
1-Diazo-1-(1-hydroxy-6-nitro-1,2,3,4-tetrahydronaphtha-
len-1-yl)-3-methylbutan-2-one (19b). Prepared from 6-nitro
tetralone (262 mg, 1.37 mmol) and 1-diazo-3-methyl-2-butanone
(246 mg, 2.19 mmol) following general procedure B. The crude
orange solid was purified using silica gel flash chromatography
(hexanes/CH2Cl2, gradient elution 0−100% CH2Cl2) to give 161 mg
G
DOI: 10.1021/acs.joc.9b02130
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The Journal of Organic Chemistry
Article
5-Cyclohexyl-4-diazo-5-hydroxy-2,2-dimethylhexan-3-one
(25). Prepared from 1-cyclohexylethanone (140 μL, 1.00 mmol) and
1-diazo-3,3-dimetylbutan-2-one (243 mg, 1.64 mmol) following
general procedure A. Purification of the crude material using silica
gel flash column chromatography (hexanes/EtOAc, gradient elution
0−10% EtOAc) afforded 121 mg (48% yield) of the title compound
Hz, 1H), 1.54−1.50 (m, 1H), 1.39 (qt, J = 13.1, 4.1 Hz, 1H), 1.22 (s,
9H); 13C{1H} (125 MHz, CDCl3): δ 200.0, 72.9, 70.6, 64.9, 44.5,
35.1, 32.3, 26.5, 25.5, 20.6. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C12H19ClN2O2Na, 281.1033; found, 281.1029.
General Procedure C: Tris(pentafluorophenyl)borane-Pro-
moted Cyclopentenone Formation. A −15 °C solution of 0.1 M
diazo ketone (1 equiv) in CH2Cl2 was rapidly added to a −15 °C
solution of 0.1 M tris(pentafluorophenyl)borane (1 equiv) in CH2Cl2.
The reaction mixture was kept at −15 °C for 10 min as gas evolved
and the solution color diminished. Saturated aqueous NaHCO3 (20
mL) was added, and the biphasic layers were stirred for 30 min. The
mixture was transferred to a separatory funnel with the aid of CH2Cl2
(10 mL). The layers were separated, and the aqueous layer was
extracted three times with Et2O (10 mL). The organic layers were
combined, washed with water and brine, dried over MgSO4, and
filtered. If quantitative NMR was used to calculate yield, the internal
standard was added to the filtrate, and the solvent was removed under
vacuum that did not exceed 125 mmHg. An NMR of the crude
reaction mixture was taken, and the material was then purified by
silica gel flash column chromatography.
1
as a yellow solid: Rf = 0.63 (4:1 hexanes/EtOAc); H NMR (500
MHz, CDCl3): δ 4.99 (s, 1H), 1.92−1.85 (m, 1H), 1.78 (tt, J = 12.2,
3.3 Hz, 1H), 1.77−1.69 (m, 2H), 1.65−1.53 (m, 2H), 1.22 (s, 3H),
1.19 (s, 9H), 1.17−1.11 (m, 2H), 1.10−0.89 (m, 3H); 13C{1H} (125
MHz, CDCl3): δ 202.7, 75.8, 67.4, 47.9, 44.7, 28.6, 27.0, 26.6, 26.5,
26.42, 26.36, 20.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H25N2O2, 253.1916; found, 253.1923.
1-Diazo-1-(1-hydroxy-2-methylcyclohexyl)-3,3-dimethylbu-
tan-2-one (28). Prepared from 2-methylcyclohexanone (100 μL,
0.82 mmol) with 1-diazo-3,3-dimethyl-2-butanone (165 mg, 1.31
mmol) following general procedure A. Unreacted 2-methylcyclohex-
anone was removed under high vacuum to give the title compound in
33% yield as a yellow solid: Rf = 0.54 (5:1 hexanes/EtOAc); 1H NMR
(500 MHz, CDCl3): δ 5.00 (s, 1H), 2.06−2.01 (m, 1H), 1.73−1.64
(m, 2H), 1.59−1.47 (m, 5H), 1.23 (s, 9H), 1.28−1.18 (m, 1H), 0.93
(d, J = 6.0 Hz, 3H); 13C{1H} (125 MHz, CDCl3): δ 203.1, 74.1, 67.8,
44.9, 37.8, 37.7, 30.0, 26.5, 25.5, 21.5, 16.1. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C13H22N2O2Na, 261.1579; found, 261.1576.
1-Diazo-1-(1-hydroxy-2,2-dimethylcyclohexyl)-3,3-dime-
thylbutan-2-one (31). Prepared from 2,2-dimethylcyclohexanone3
(73 mg, 0.58 mmol) and 1-diazo-3,3-dimetylbutan-2-one (122 mg,
0.97 mmol) following general procedure A. Silica gel flash column
chromatography (hexanes/EtOAc, gradient elution 0−5% EtOAc)
afforded 28 mg (19% yield) of the title compound as a yellow oil: Rf =
General Procedure D: Tin(IV) Chloride-Promoted Cyclo-
pentenone Formation. A 1 M solution of SnCl4 in CH2Cl2 (1
equiv) was added quickly as a stream to a −20 °C solution of diazo
ketone (1 equiv) in CH2Cl2 (20 mL/mmol of diazo ketone). The
bright yellow reaction mixture was stirred at −20 °C for 10 min while
gas evolved and the solution color diminished. Saturated aqueous
NaHCO3 (20 mL) was added, and the mixture was transferred to a
separatory funnel with the aid of 10 mL CH2Cl2. The layers were
separated, and the aqueous layer was extracted three times with Et2O
(10 mL). The organic layers were combined, washed with water and
brine, dried over MgSO4, and filtered. If quantitative NMR was used
to calculate yield, a known quantity of the internal standard was added
to the filtrate, and the solvent was removed under a vacuum that did
not exceed 125 mmHg. An NMR of the crude reaction mixture was
taken, and the material was then purified by silica gel flash column
chromatography.
1
0.29 (5:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3): δ 6.53 (s,
1H), 1.86−1.62 (m, 4H), 1.53 (t, J = 17.6 Hz, 2H), 1.47−1.35 (m,
1H), 1.24 (s, 9H), 1.11 (d, J = 12.0 Hz, 1H), 0.95 (s, 3H), 0.85 (s,
3H); 13C{1H} (125 MHz, CDCl3): δ 203.9, 44.9, 43.2, 36.1, 32.1,
26.5, 23.3, 21.4, 20.7. HRMS (ESI-TOF) m/z: [M ]+ calcd for
C14H23O, 207.1749; found, 207.1755.
3,5,5-Trimethyl-2-phenylcyclopent-2-enone (16a),23 2,5,5-
Trimethyl-3-phenylcyclopen-2-enone (17a),23 and Prop-1-yn-
1-ylbenzene (18a).31 Prepared by subjecting diazo ketone 15a to 1
equiv of tris(pentafluorophenyl)borane following general procedure
C. Yields of the title compounds (16, 2, and 7%, respectively) were
determined using quantitative 1H NMR spectroscopy with 1,3,5-
1-Diazo-1-(1-hydroxy-2,2-dimethylcyclohexyl)-3-methylbu-
tan-2-one (32). Prepared from 2,2-dimethylcyclohexanone3 (81 mg,
0.64 mmol) and 1-diazo-3-methylbutan-2-one (108 mg, 0.96 mmol)
following general procedure A. Unreacted 2,2-dimethylcyclohexanone
was removed under high vacuum. Silica gel flash column
chromatography (hexanes/EtOAc, gradient elution 0−10% EtOAc)
afforded 26 mg (17% yield) of the title compound as a yellow oil: Rf =
1
trimethoxybenzene as an internal standard. H NMR values for 16a,
17a, and 18a matched those previously reported.23,31
1
0.59 (5:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3): δ 6.21 (s,
3-Ethyl-5,5-dimethyl-2-phenylcyclopent-2-en-1-one (16b)
and But-1-yn-1-ylbenzene (18b). Prepared by subjecting β-
hydroxy-α-diazo ketone 15b (64.8 mg, 0.25 mmol) to general
procedure C with the modification in which the aqueous layer was
extracted four times with CH2Cl2 (10 mL) instead of Et2O. The yield
1H), 2.86 (hept, J = 6.8 Hz, 1H), 1.87−1.65 (m, 5H), 1.58−1.48 (m,
2H), 1.48−1.35 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8
Hz, 3H), 0.96 (s, 3H), 0.89 (s, 3H); 13C{1H} (125 MHz, CDCl3):
202.1, 76.1, 68.8, 42.7, 36.5, 35.9, 32.3, 26.2, 23.3, 21.3, 20.6, 19.1,
18.2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H22N2O2Na,
261.1579; found, 261.1570.
4-Diazo-5-hydroxy-2,2,5,6,6-pentamethylheptan-3-one
(33). Prepared from pinacolone (210 μL, 1.68 mmol) and 1-diazo-
3,3-dimetylbutan-2-one (340 mg, 2.69 mmol) following general
procedure A. Purification of the crude material using silica gel flash
column chromatography (hexanes/EtOAc, gradient elution 0−10%
EtOAc) afforded 43 mg (11% yield) of the title compound as a yellow
oil: Rf = 0.14 (5:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3): δ
6.43 (s, 1H), 1.40 (s, 3H), 1.25 (s, 9H), 0.95 (s, 9H); 13C{1H} (125
MHz, CDCl3): δ 203.6, 78.1, 66.2, 45.0, 43.7, 26.6, 25.7, 21.9. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C12H23N2O2, 227.1760; found,
227.1768.
1
of the title compounds was determined using quantitative H NMR
spectroscopy with 1,3,5-trimethoxybenzene (41.8 mg, 0.25 mmol) as
an internal standard. Cyclopentenone 16b was formed in 30% yield,
and alkyne 18b was formed in 27% yield.
3-Ethyl-5,5-dimethyl-2-phenylcyclopent-2-en-1-one (16b).
1
Rf = 0.51 (4:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3): δ
7.39 (t, J = 7.6 HZ, 2H), 7.31 (tt, J = 7.4, 1.3 Hz, 1H), 7.28−7.26 (m,
2H), 2.55 (q, J = 7.6 Hz, 2H), 2.54 (s, 2H), 1.19 (s, 6H), 1.16 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 212.1, 173.4,
137.1, 132.4, 129.3, 128.3, 127.6, 45.9, 43.3, 25.5, 24.8, 12.4. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H19O, 215.1436; found,
215.1431.
But-1-yn-1-ylbenzene (18b). Rf = 0.76 (4:1 hexanes/EtOAc);
1-(2-Chloro-1-hydroxycyclohexyl)-1-diazo-3,3-dimethylbu-
tan-2-one (37). Prepared from 2-chlorocyclohexanone (95 mg, 0.70
mmol) and 1-diazo-3,3-dimetylbutan-2-one (143 mg, 1.13 mmol)
following general procedure A. Purification of the crude material using
silica gel flash column chromatography (hexanes/EtOAc, gradient
elution 0−10% EtOAc) afforded 143 mg (79% yield) of the title
1H NMR values matched those previously reported.32
2-Methyl-1,4,5,6-tetrahydrobenzo[e]azulen-3(2H)-one
(20a). Prepared by subjecting β-hydroxy-α-diazo ketone 19a (66.5
mg, 0.27 mmol) to general procedure C with the modification that 1.2
equiv of tris(pentafluorophenyl)borane was used, and the aqueous
layer was washed four times with CH2Cl2 (10 mL) instead of Et2O
during the workup. The yield of cyclopentenone 20a was 27% as
determined using quantitative 1H NMR spectroscopy with 1,3,5-
1
compound as a yellow solid: Rf = 0.45 (5:1 hexanes/EtOAc); H
NMR (500 MHz, CDCl3): δ 4.72 (dd, J = 11.9, 4.9 Hz, 1H), 3.36 (s,
1H), 2.10−1.94 (m, 4H), 1.79−1.72 (m, 1H), 1.68 (tt, J = 13.1, 4.0
H
DOI: 10.1021/acs.joc.9b02130
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
trimethoxybenzene (45.4 mg, 0.27 mmol) as an internal standard. In a
separate experiment, 20a was isolated by silica gel flash chromatog-
raphy (hexanes/EtOAc, gradient elution 0−10% EtOAc) to provide a
8-Methoxy-2-methyl-1,4,5,6-tetrahydrobenzo[e]azulen-
1
3(2H)-one (20e). Rf = 0.30 (3.7:1 hexane/EtOAc); H NMR (500
MHz, CDCl3): δ 7.52 (d, J = 8.7 Hz, 1H), 6.80 (dd, J = 8.7, 2.7 Hz,
1H), 6.74 (d, J = 2.7 Hz, 1H), 3.85 (s, 3H), 3.23−2.16 (m, 1H),
2.86−2.78 (m, 2H), 2.59−2.47 (m, 4 H), 2.07−1.89 (m, 2H), 1.26
(d, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 212.5,
162.1, 160.9, 146.4, 138.0, 129.6, 127.2, 115.5, 111.4, 55.4, 38.9, 38.7,
36.6, 27.2, 25.6, 17.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H19O2, 243.1385; found, 243.1384.
1
pale yellow solid: Rf = 0.53 (4:1 hexane/EtOAc); H NMR (500
MHz, CDCl3): δ 7.56 (dd, J = 6.9, 2.1 Hz, 1H), 7.34−7.27 (m, 2H),
7.21 (dd, J = 6.7, 2.3 Hz, 1H), 3.23 (ddt, J = 17.1, 6.9, 2.5 Hz, 1H),
2.87−2.76 (m, 2H), 2.59 (dq, J = 17.1, 2.6 Hz, 1H) 2.56−2.50 (m,
3H), 2.10−1.93 (m, 2H), 1.27 (d, J = 7.4, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 212.6, 162.5, 144.3, 140.0, 134.5, 130.0, 129.9,
127.7, 126.5, 39.1, 38.5, 36.0, 26.7, 26.4, 16.9. HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C15H17O, 213.1279; found, 213.1272.
8-Methoxy-2-methyl-3,4,5,6-tetrahydrobenzo[e]azulen-
1
1(2H)-one (21e). Rf = 0.20 (8:1 hexanes/EtOAc); H NMR (500
MHz, CDCl3): δ 7.84 (d, J = 8.7 Hz, 1H), 6.80 (dd, J = 8.6, 2.7 Hz,
1H), 6.71 (d, J = 2.8 Hz, 1H), 3.81 (s, 3H), 2.88 (dd, J = 18.5, 7.0 Hz,
1H), 2.65 (t, J = 5.5 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.53 (app pd, J
= 7.4, 2.8 Hz, 1H), 2.25 (dd, J = 18.5, 2.7 Hz, 1H), 2.16−2.05 (m,
2H) 1.25 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
210.7, 172.4, 158.9, 144.2, 135.7, 130.3, 123.6, 114.9, 110.7, 55.3,
40.6, 40.5, 34.4, 33.6, 28.8, 16.9. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H19O2, 243.1385; found, 243.1386.
2-Methyl-8-nitro-1,4,5,6-tetrahydrobenzo[e]azulen-3(2H)-
one (20b). Prepared by subjecting β-hydroxy-α-diazo ketone 19b
(65.8 mg, 0.22 mmol) to general procedure C with the modification
that 1.2 equiv of tris(pentafluorophenyl)borane was used, and the
reaction mixture was concentrated under vacuum without workup.
The crude oil was subjected to silica gel flash chromatography
(hexanes/CH2Cl2, gradient elution 0−100% CH2Cl2) to give 20.8 mg
(37% yield) of the title compound as a pale brown solid: Rf = 0.22
3,5,5-Trimethyl-2-pentylcyclopen-2-enone (23) and 2,5,5-
Trimethyl-3-pentylcyclopent-2-enone (24). Prepared by subject-
ing diazo ketone 22 (43 mg, 0.18 mmol) to general procedure C. 1H
NMR of the crude mixture showed a 1.7:1 ratio of 23 and 24.
Purification by silica gel flash column chromatography (hexanes/
Et2O, gradient elution 0−10% Et2O) returned 7.3 mg (21% yield) of
23 and 8.0 mg (23% yield) of 24 as oils: Rf = 0.25 and 0.19,
respectively (5:1 hexanes/EtOAc).
1
(3.7:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3): δ 8.13 (dd, J
= 8.5, 2.3 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H),
3.29−3.20 (m, 1H), 2.98−2.85 (m, 2H), 2.66−2.55 (m, 4H), 2.15−
1.97 (m, 2H), 1.30 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 211.8, 159.2, 147.9, 145.6, 143.2, 140.8, 128.4, 124.5,
121.5, 39.2, 38.5, 35.8, 26.7, 26.1, 16.7. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H16NO3, 258.1130; found, 258.1125.
2-Methyl-9-nitro-1,4,5,6-tetrahydrobenzo[e]azulen-3(2H)-
one (20c). Prepared by subjecting β-hydroxy-α-diazo ketone 19c
(60.5 mg, 0.20 mmol) to general procedure C with the modification
that 1.2 equiv of tris(pentafluorophenyl)borane was used, and the
reaction mixture was concentrated under vacuum without workup.
The crude oil was subjected to silica gel flash chromatography
(hexanes/CH2Cl2, gradient elution 0−94% CH2Cl2) to give 14.8 mg
(29% yield) of the title compound as a pale brown solid: Rf = 0.24
3,5,5-Trimethyl-2-pentylcyclopent-2-enone (23). 1H NMR
(500 MHz, CDCl3): δ 2.35 (s, 2H), 2.15 (t, J = 7.6 Hz, 2H), 2.01 (s,
3H), 1.37−1.20 (m, 6H), 1.07 (s, 6H), 0.87 (t, J = 7.0 Hz, 3H);
13C{1H} (125 MHz, CDCl3): δ 213.7, 166.3, 100.0, 48.7, 42.7, 31.7,
28.0, 25.1, 23.1, 22.5, 17.0, 14.0. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C13H23O, 195.1749; found, 195.1747.
2,5,5-Trimethyl-3-pentylcyclopent-2-enone (24). 1H NMR
(500 MHz, CDCl3): δ 2.38 (t, J = 8.1, 2H), 2.35 (s, 2H), 1.69 (s,
3H), 1.51 (p, J = 7.6, 2H), 1.40−1.25 (m, 4H), 1.08 (s, 6H), 0.90 (t, J
= 7.0, 3H); 13C{1H} (125 MHz, CDCl3): δ 214.3, 170.6, 133.2, 46.4,
42.7, 31.7, 30.9, 26.9, 25.2, 22.4, 14.0, 8.2. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C13H23O, 195.1749; found, 195.1747.
1
(4:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3): δ 8.41 (d, J =
2.3 Hz, 1H), 8.14, (dd, J = 8.3, 2.3 Hz, 1H), 7.38 (d, J = 8.4, 1H),
3.28 (ddt, J = 17.0, 7.0, 2.6 Hz, 1H), 3.01−2.86 (m, 2H), 2.67 (dq, J =
17.0, 2.8 Hz, 1H), 2.62−2.55 (m, 3H), 2.13−1.94 (m, 2H), 1.30 (d, J
= 7.4, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 212.0, 159.2, 151.3,
146.9, 142.1, 135.8, 130.9, 124.3, 122.6, 39.1, 38.5, 36.0, 26.9, 25.5,
16.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H16NO3,
258.1130; found, 258.1122.
8-Bromo-2-methyl-1,4,5,6-tetrahydrobenzo[e]azulen-
3(2H)-one (20d). Prepared by subjecting β-hydroxy-α-diazo ketone
19d (71.7 mg, 0.21 mmol) to general procedure C with the
modification that 1.2 equiv of tris(pentafluorophenyl)borane was
used, and the reaction mixture was concentrated under vacuum
without workup. The crude oil was subjected to silica gel flash
chromatography (hexanes/CH2Cl2, gradient elution 0−75% CH2Cl2),
and the desired compound was isolated with impurities and was
further purified by silica gel flash chromatography (8:1 hexanes/
EtOAc) to give 15.9 mg (26% yield) of the title compound as a
colorless solid: Rf = 0.50 (100% CH2Cl2); 1H NMR (500 MHz,
CDCl3): δ 7.43−7.39 (m, 2H), 7.37 (s, 1H), 3.22−3.14 (m, 1H),
2.84−2.72 (m, 2H), 2.59−2.43 (m, 4H), 2.09−1.89 (m, 2H), 1.27 (d,
J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 212.1, 161.0,
146.1, 140.5, 133.4, 132.7, 129.5, 129.1, 124.2, 39.0, 38.4, 35.8, 26.8,
25.9, 16.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H16BrO,
291.0385; found, 291.0385.
8-Methoxy-2-methyl-1,4,5,6-tetrahydrobenzo[e]azulen-
3(2H)-one (20e) and 8-Methoxy-2-methyl-3,4,5,6-
tetrahydrobenzo[e]azulen-1(2H)-one (21e). Prepared by sub-
jecting β-hydroxy-α-diazo ketone 19e (57.5 mg, 0.20 mmol) to
general procedure C with the modification that 1.2 equiv of
tris(pentafluorophenyl)borane was used, and the reaction mixture
was concentrated under vacuum without workup. The crude oil was
subjected to silica gel flash chromatography (hexanes/EtOAc,
gradient elution 0−11% EtOAc) to give 18.1 mg (37% yield) of
20e and 6.7 mg (14% yield) of 21e as pale orange solids.
2-Cyclohexyl-3,5,5-trimethylcyclopent-2-enone (26) and 3-
Cyclohexyl-2,5,5-trimethylcyclopent-2-enone (27). Prepared by
subjecting diazo ketone 25 (61.0 mg, 0.24 mmol) to 1 equiv of
tris(pentafluorophenyl)borane following general procedure C with
the modification that the aqueous layer was extracted four times with
CH2Cl2 (10 mL) instead of Et2O. Purification by centrifugal TLC
(2:1, hexanes/CH2Cl2) provided 8.2 mg (16% yield) of 26 and trace
quantities of 27. In a different run, 27 was isolated by gravity column
chromatography (19:1, pentane/Et2O) to afford a 1% yield: Rf = 0.60
and 0.27, respectively (100% CH2Cl2).
2-Cyclohexyl-3,5,5-trimethylcyclopent-2-enone (26). 1H
NMR (500 MHz, CDCl3): δ 2.40 (tt, J = 12.1, 3.7 Hz, 1H), 2.31
(s, 2H), 2.04 (s, 3H), 1.82−1.63 (m, 5H), 1.49−1.42 (m, 2H), 1.32−
1.20 (m, 3H), 1.04 (s, 6H); 13C{1H} (125 MHz, CDCl3): δ 213.7,
166.7, 141.3, 49.1, 42.6, 35.5, 30.1, 27.0, 26.2, 25.2, 17.6. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C14H23O, 207.1749; found, 207.1750.
3-Cyclohexyl-2,5,5-trimethylcyclopent-2-enone (27). 1H
NMR (500 MHz, CDCl3): δ 2.71−2.62 (m, 1H), 2.33 (s, 2H),
1.85−1.79 (m, 2H), 1.78−1.72 (m, 1H), 1.69 (s, 3H), 1.67−1.61 (m,
2H), 1.42−1.27 (m, 4H), 1.27−1.15 (m, 1H), 1.07 (s, 6H); 13C{1H}
(125 MHz, CDCl3): δ 214.7, 174.8, 132.0, 43.4, 42.5, 39.9, 30.5, 26.2,
26.1, 25.4, 8.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H23O,
207.1749; found, 207.1754.
2,2,8-Trimethyl-2,3,5,6,7,8-hexahydroazulen-1(4H)-one (29)
and 2,2,4-Trimethyl-2,3,5,6,7,8-hexahydroazulen-1(4H)-one
(30). Prepared by treating diazo ketone 28 (60 mg, 0.25 mmol)
with 1 equiv of tris(pentafluorophenyl)borane following general
1
procedure C. H NMR of the crude mixture showed a 4.4:1 ratio of
29 and 30. Purification by silica gel flash column chromatography
(hexanes/Et2O, gradient elution 0−5% Et2O) returned 24 mg (50%
yield) of pure 29 as an oil and 5 mg of a mixture of 29 and 30 (11%
I
DOI: 10.1021/acs.joc.9b02130
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
yield of both isomers). Alternatively, subjecting diazo ketone 28 to 1
equiv of SnCl4 following general procedure D gave 29 in 39% isolated
yield and 30 in 6% isolated yield: Rf = 0.32 and 0.26, respectively (9:1
hexanes/Et2O).
2,2,8-Trimethyl-2,3,5,6,7,8-hexahydroazulen-1(4H)-one
(29). 1H NMR (500 MHz, CDCl3): δ 2.93 (qt, J = 7.4, 3.8 Hz, 1H),
2.46 (dddd, J = 15.2, 12.1, 3.4, 1.4 Hz, 1H), 2.37 (td, J = 5.7, 5.0, 2.0
Hz, 1H), 2.35 (s, 1H), 2.34 (s, 1H), 1.93−1.86 (m, 1H), 1.85−1.71
(m, 3H), 1.55−1.46 (m, 1H), 1.44−1.34 (m, 1H), 1.08 (s, 3H), 1.05
(s, 3H), 1.00 (d, J = 7.2 Hz, 3H); 13C{1H} (125 MHz, CDCl3): δ
213.2, 171.1, 143.3, 49.3, 42.9, 33.1, 32.9, 28.0, 27.0, 25.2, 25.0, 24.8,
17.5. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H20ONa,
215.1412; found, 215.1413.
2,2,4-Trimethyl-2,3,5,6,7,8-hexahydroazulen-1(4H)-one
(30). 1H NMR (500 MHz, CDCl3): δ 2.65 (td, J = 7.4, 2.8 Hz, 1H),
2.43 (d, J = 18.4 Hz, 1H), 2.32 (d, J = 17.6 Hz, 1H), 2.36−2.24 (m,
2H), 1.93−1.86 (m, 1H), 1.78−1.66 (m, 2H), 1.61−1.44 (m, 3H),
1.15 (d, J = 7.2 Hz, 3H), 1.08 (s, 3H), 1.07 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 211.7, 177.0, 138.4, 46.6, 42.7, 37.3, 33.7, 27.6,
26.6, 25.3, 25.1, 23.3, 17.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C13H21O, 193.1592; found, 193.1588.
ORCID
Sarah E. Cleary: 0000-0001-8876-1696
Xin Hong: 0000-0003-4717-2814
Matthias Brewer: 0000-0003-4250-7195
Present Address
∥Department of Chemistry, University of Oxford, Inorganic
Chemistry Laboratory, South Parks Rd, Oxford, OX1 3QR,
UK.
Author Contributions
§S.E.C. and M.J.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation of the
USA (CHE-1665113, M.B.) the National Natural Science
Foundation of China (21702182, 21873081, X.H.), and the
Fundamental Research Funds for the Central Universities
(2019QNA3009, X.H.) is gratefully acknowledged. Mass
spectrometry data were acquired by Bruce O’Rourke with
support from the National Institutes of Health (NIH) grants
S10-OD018126 and P30-GM118228. Computations were
performed on the supercomputer cluster at the Department
of Chemistry, Zhejiang University.
2-Chloro-7-pivaloylcycloheptanone (39). Prepared by subject-
ing diazo ketone 37 (46 mg, 0.18 mmol) to general procedure C with
the modification that 30 mol % of tris(pentafluorophenyl)borane was
used. 1H NMR of the crude mixture showed 39 was the major
product. Silica gel flash column chromatography (hexanes/Et2O,
gradient elution 0−10% Et2O) provided 18 mg (45% yield, 92:8 dr)
of the title compound: Rf = 0.30 (9:1 hexanes/Et2O); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C12H19ClO2Na, 253.0971; found,
1
253.0967. Major diastereomer: H NMR (500 MHz, CDCl3): δ 4.80
(dd, J = 11.1, 3.7 Hz, 1H), 4.32 (dd, J = 10.5, 6.0 Hz, 1H), 2.32−2.24
(m, 1H), 2.00−2.09 (m, 1H), 1.99−1.78 (m, 4H), 1.58−1.44 (m,
1H), 1.38−1.27 (m, 1H), 1.17 (s, 9H); 13C{1H} (125 MHz, CDCl3):
δ 211.1, 202.2, 62.6, 57.8, 45.7, 35.9, 29.1, 27.3, 26.8, 25.9. Minor
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02130.
1
Copies of H and 13C{1H} NMR spectra for all new
compounds, 1H−13C HMBC spectra showing key
correlations for 23, 24, 26, and 29, and 1H NOE
spectrum of compound 20c (PDF)
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hxchem@zju.edu.cn (X.H.).
*E-mail: matthias.brewer@uvm.edu (M.B.).
J
DOI: 10.1021/acs.joc.9b02130
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