3-Trimethylsilylcycloalkylidenes. γ-Silyl vs γ-Hydrogen Migration to Carbene Centers

Article abstract of DOI:10.1021/acs.joc.5b01955

A series of γ-trimethylsilyl-substituted carbenes have been studied experimentally and by computational methods. In an acyclic system, 1,3-trimethylsilyl migration successfully competes with 1,3-hydrogen migration to the carbene center. The behavior of cy

Full text of DOI:10.1021/acs.joc.5b01955

Article
pubs.acs.org/joc
3‑Trimethylsilylcycloalkylidenes. γ‑Silyl vs γ‑Hydrogen Migration to
Carbene Centers
Xavier Creary*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: A series of γ-trimethylsilyl-substituted carbenes
have been studied experimentally and by computational
methods. In an acyclic system, 1,3-trimethylsilyl migration
successfully competes with 1,3-hydrogen migration to the
carbene center. The behavior of cyclic 3-trimethylsilyl-
substituted carbenes contrasts with that of the acyclic system.
Only 1,2-hydrogen migration processes are observed in the
five-membered ring due to the high barrier to 1,3-hydrogen
migration. In the cyclohexyl system, a small amount of a
cyclopropane derived from 1,3-hydrogen migration occurs, as
shown by a labeling study. In the cycloheptyl carbene system, a labeling study again showed that 1,3-hydrogen migration to the
carbene center leads to the major product. Computational studies suggest that the cyclic carbenes all have lower energy
conformations where the trimethylsilyl group is in a pseudo equatorial conformation where it cannot migrate to the carbene
center. Computational studies also suggest that cyclohexyl and cycloheptyl carbene systems are slightly stabilized by a rear lobe
interaction of the Si−C bond with the carbene center.
INTRODUCTION
■
A number of years ago, we became interested in the effect of
the trimethylsilyl group on carbenes. This was an outgrowth of
the remarkable stabilizing effect of β-silyl groups on
isoelectronic carbocations.1 β-silyl carbocations can form up
to 1011 times faster than unsilylated analogs,2 and they are
calculated to be stabilized by up to 35 kcal/mol relative to β-H
analogs.3 The effect of β- and γ-silyl groups on carbenes has
been studied in our laboratory.4 The β-trimethylsilyl group
migrates readily to the carbene center of 1,4a while both the β-
trimethylsilyl group and the β-hydrogen migrate to the carbene
center in 3.4a The bicyclic carbenes 6 and 8 reveal both the
propensity for γ-trimethylsilyl groups to migrate to carbene
centers as well as the ability of trimethylsilyl groups to enhance
the migratory aptitude of adjacent hydrogen to carbenic
centers.4b A labeling study shows that 1,3-hydrogen migration
occurs in carbene 10 and not 1,3-silyl migration.4f These
carbene reactions of 1, 3, and 6 suggest that trimethylsilyl
groups migrate very efficiently to carbene centers. They also
suggest that trimethylsilyl groups in 3, 8, and 10 increase the
propensity for hydrogen to migrate to carbene centers.
In view of the reactions of the β-silyl carbenes 1 and 3 as well
as the reactions of γ-silyl carbenes 6, 8, and 10 (Scheme 1), we
were interested in the chemistry of other γ-trimethylsilyl-
substituted carbenes. How will the behavior of less rigid
carbenes compare with that of carbenes 6, 8, and 10? What
group(s) (TMS or H) will migrate to the carbene center in less
rigid systems? Reported here are studies on γ-trimethylsilyl-
substituted carbenes 12−15.
RESULTS AND DISCUSSION
■
The first carbene to be generated was the acyclic system 12,
where the possibility of 1,2-hydrogen migration has been
excluded by the presence of methyl groups, and 1,3-migration
processes should dominate. The synthetic precursor to this
carbene was the diazo compound 20, which was prepared
starting with isobutyronitrile, 16 (Scheme 2). Deprotonation of
16 followed by alkylation with chloromethyltrimethylsilane
gave 17, which was converted to ketone 18 by reaction with
phenylmagnesium bromide. This relatively hindered ketone 18
was converted to the tosylhydrazone 19 by an acid-catalyzed
reaction with tosylhydrazine. Deprotonation of 19 followed by
vacuum pyrolysis of the dry salt5 gave diazo compound 20 as a
relatively stable distillable liquid.
Carbene 12 is generated by thermal decomposition of a
solution of 20 in cyclohexane in a sealed tube at 100 °C.
Thermal generation of this carbene and subsequent rearrange-
ments likely proceed from the singlet state.6 A complex product
mixture is formed that includes five cyclopropane products
(Scheme 3), whose structures were all confirmed by
independent syntheses. The major product 21 (57%) and a
minor product 22 (5%) are both derived from 1,3-hydrogen
Received: August 21, 2015
Published: October 26, 2015
© 2015 American Chemical Society
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Scheme 1. Rearrangements of Trimethylsilyl-Substituted
Carbenes
Scheme 3. Generation and Rearrangement of Carbene 12
trimethylsilylcyclopentanone, 26 (Scheme 4). The products
formed are the alkenes 27 and 28 that are derived from 1,2-
Scheme 4. Generation and Pyrolysis of Tosylhydrazone Salt
26
migration to the carbene center. The cyclopropane 23 (26%) is
derived from trimethylsilyl migration. Also formed are small
amounts (12%) of the isomeric cyclopropanes 24 derived from
carbene insertion into the CH3 groups of 12. There are trace
amounts of two minor alkene products that can be removed
from the product mixture by ozonolysis, whose structures were
not proven. This experimental study shows that in the
unconstrained carbene 12, although 1,3-hydrogen migration is
preferred, 1,3-trimethylsilyl migration is still an important
process. A computational study at the B3LYP/6-311+G** level
also suggests that 1,3-hydrogen migration and 1,3-trimethylsilyl
migration should be competitive.7
hydrogen migration to the carbene center. There is no trace of
the bicyclopentane 30 that would be derived from 1,3-
migration processes. This observation stands in contrast to
the behavior of the analogous 3-trimethylsilylcyclobutylcarbene
10, where 1,3-hydrogen migration predominates to give the
bicyclobutane product 11.
Computational studies8 were used to better understand the
lack of 1,3-migration processes in carbene 13. Two
conformations, 13a and 13b, were located at the M062X/6-
311+G** computational level, with conformation 13a being 0.7
kcal/mol lower than 13b. Scheme 5 shows selected calculated
Attention was next turned to the more rigid cyclic carbene
13. This carbene was generated by vacuum pyrolysis of the
sodium salt of the tosylyhydrazone5 derived from 3-
Scheme 2. Preparation of Diazo Compound 20
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Scheme 5. M062X/6-311+G** Calculated Barriers for Rearrangement of Carbene 13
rearrangement barriers for these carbenes. The barrier to 1,3-
hydrogen migration in 13a is quite large (18.4 kcal/mol), and
the corresponding 1,3-trimethylsilyl migration barrier in 13b is
also very large (13.5 kcal/mol). Two factors could contribute to
the large barrier to 1,3-hydrogen migration. The first is the large
ring stain in formation of the potential bicyclopentane product
30, which has an estimated strain energy of 56 kcal/mol.9
However, bicyclobutane 11 also has a large ring strain,9 and,
nonetheless, it is produced by a 1,3-hydrogen migration process
(ΔE⧧ = 10.4 kcal/mol) from carbene 10. Another factor is the
geometry of carbenes 10 and 13b as shown in Figure 1. The
Scheme 6. Generation and Pyrolysis of Tosylhydrazone Salt
35
major products are 1,2-hydrogen migration products 36 and 37,
the 13% of product 38 is derived from 1,3-migration to the
carbene center. The behavior of carbene 14 therefore contrasts
with that of the parent cyclohexylidene, which rearranges only
to cyclohexene and gives no bicyclo[3.1.0]hexane.10
Figure 1. M062X/6-311+G** calculated structures of carbenes 10 and
13a.
It was necessary to determine the origin of the 1,3-migration
product 38. Is this product derived from 1,3-hydrogen
migration or from 1,3-trimethylsilyl migration to the carbene
center? Previously a carbon-12 labeling experiment was used to
determine which group migrated in carbene 10.4f While an
analogous approach would be feasible (but expensive) with
carbene 14, a different labeling approach was used. 3-
Trimethylsilylcyclohexanone was deuterated by treatment
with Na2CO3 in D2O/CH3OD. The 2,2,6,6-tetradeutero-3-
trimethylsilylcyclohexanone was then converted to the
tosylhydrazone salt 35-d4 (Scheme 7), which was then
subjected to vacuum pyrolysis. The cyclopropane product was
isolated, and its structure was determined using 13C NMR
spectroscopy.
migrating hydrogen in 10 is only 2.156 Å from the carbene
center, but 2.935 Å from the carbene center in 13a. This greater
distance could contribute to the significantly larger 1,3-
hydrogen migration barrier in 13a. On the other hand, the
1,2-hydrogen migration processes leading to the observed
products 27 and 28 are calculated to be much more facile
processes. 1,2-Hydrogen migration processes in the less stable
carbene 13b are also facile processes with comparable barriers.
Also, the hydrogens cis and trans to the TMS group all migrate
with comparable small barriers.
The approach to carbene 14 (Scheme 6) also utilized
pyrolysis of a tosylhydrazone salt. In this case, vacuum pyrolysis
of the sodium salt 35 gave three products 36−38. Although the
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Scheme 7. Generation and Rearrangement of Labeled
Carbene 14-d4
Scheme 8. Synthesis of 2,2,5-Trideutero-1-
trimethylsilylbicyclo[3.1.0]hexane, 38-d3
The basis for the structural assignment was the lack of a
signal at δ 28.1 and the presence of a signal at δ 29.0 in the
cyclopropane product as seen in Figure 2. To aid in the 13C
barrier in 14a (2.0 kcal/mol) and the 1,3-trimethylsilyl
migration barrier in 14b (2.4 kcal/mol) are quite small. The
transition state for interconversion of these two conformations
via ring inversion could not be located computationally, but it is
presumed to be significant.11 This calculated energy diagram in
Figure 3 accounts for H-migration as the predominant 1,3-
migration process. However, it should be pointed out that
calculated energy barriers for formation of alkenes 36 and 37
from carbene 14a are 2.9 and 4.0 kcal/mol, respectively. These
values are inconsistent with the fact that 38 is only the minor
product formed in Scheme 6.
A question concerns potential stabilization of carbene 14a.
What is the stabilizing effect of the trimethylsilyl group? The
isodesmic calculation in Scheme 9 suggests that carbene 14a is
more stable than cyclohexylidene, 44, by 1.8 kcal/mol at
M062X/6-311+G** level. While this stabilization energy is
rather small, an analysis of the structure of carbene 14a (Figure
4) offers some insight. There is a slight tilt of the carbene center
toward C3 (relative to the parent carbene 44). The C1−C3
bond distance shrinks from 2.369 Å in 44 to 2.324 Å in 14a. At
the same time, the C2−C3 bond length increases from 1.568 to
1.581 Å, while C1−C2 shrinks from 1.478 to1.471 Å. These
trends all suggest a weak stabilizing interaction of the carbene
center in 14a with the C2−C3 bond and with the rear lobe of
the C3−Si bond. This interaction is far less than in the
corresponding 3-trimethylsilylcyclohexyl cation, where the
calculated stabilization has a much more substantial value of
19.2 kcal/mol. However, the small stabilization in 14a appears
to be real and more significant than in carbene 13a, where the
calculated stabilization energy is an insignificant value of 0.4
kcal/mol.
The final carbene to be studied was 3-trimethylsilycyclo-
heptylidene, 15. The approach to this system was similar to the
generation of carbene 14 (Scheme 10). Conjugate addition of
trimethylsilyllithium to cycloheptenone gave 48, which was
converted to the corresponding tosylhydrazone salt 49 by
standard methods. Pyrolysis of 49 in dry diglyme12 gave the
carbene derived products 50−52 in a 9:14:77 ratio.
An analogous deuterium labeling study was used to discern
the origin of the major cyclopropane product 52. Conversion of
the labeled ketone 48-d4 to the tosylhydrazone salt and
pyrolysis of this salt generated the deuterium labeled carbene
15-d4. The structure of the cyclopropane rearrangement
product was again determined by 13C NMR spectroscopy
Figure 2. Partial 13C NMR spectra of 38 and the products of pyrolysis
of salt 35-d4.
NMR assignments, an authentic sample of deuterated cyclo-
propane 38-d3 was prepared (Scheme 8). 2,2,5,5-Cyclo-
pentanone-d4, 39, was converted to the tosylhydrazone 40,
and silylation of the vinyl anion derived from 40 gave the
vinylsilane 41. Cyclopropanation using a modified Simmons−
Smith reaction gave cyclopropane 38-d3, which showed no 13
C
NMR signal at δ 29.0 (C2) and a signal at δ 28.0 (C4). The
signal at δ 29.0 in the pyrolysis product from 35-d4 (Figure 2)
is therefore due to C2, and the lack of a signal at δ 28.0 is due
to the presence of deuterium at C4. The carbene rearrangement
product was therefore 38a-d4, a product of hydrogen migration
to the carbene center. The alternative product 38b-d4, derived
from trimethylsilyl migration, was not observed.
Computational studies at the M062X/6-311+G** level were
again used to gain insight into the preferential H-migration in
carbene 14 (Figure3). There are two conformations of carbene
14, with conformation 14a being 1.1 kcal/mol lower in energy
than conformation 14b. Both the 1,3-hydrogen migration
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Figure 3. M062X/6-311+G** calculated energy diagram for conversion of carbenes 14a and 14b to 38.
Scheme 9. Isodesmic Reaction of Carbene 14a with
Cyclohexane
Scheme 10. Generation and Pyrolysis of Tosylhydrazone Salt
49
shift, and C5 appears at δ 23.9. The structure of the pyrolysis
product is assigned as 52-d4 due to the lack of a 13C signal at δ
23.9. Hence 52 arises from 1,3-hydrogen migration to the
carbene center in 15. Trimethylsilyl migration to the carbene
center of 15-d4 is not an important process.
Computational studies on carbene 15 are complicated by the
existence of a number of conformational energy minima. Two
pseudoequatorial energy minima have been located for carbene
15 at the M062X/6-311+G** level (Figure 6). The lowest
energy is 15a, which is 3.0 kcal/mol below 15b. There is also
one pseudoaxial energy minimum, 15c, which is 3.2 kcal/mol
above 15a. The transition state for 1,3-hydrogen migration in
15a is only 1.0 kcal/mol above 15a. Barriers for 1,2-hydrogen
migration in 15a are much higher (7.1 and 6.9 kcal/mol). The
Figure 4. M062X/6-311+G** calculated structures of carbene 14a
and cyclohexylidene, 44.
(Figure 5). But first it was necessary to unambiguously assign
the 13C signals in the unlabeled product 52. This was
accomplished by a combination of proton coupled 13C NMR,
COSY, HSQC, and HMBC methods. These assignments are
shown in Scheme 11. As expected, C2 appears furthest
downfield at δ 25.7 due to the silicon β-effect on chemical
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Figure 6. M062X/6-311+G** calculated structures of carbenes 15 and
cycloheptylidene, 53.
Figure 5. Partial 13C NMR spectra of 52 and the pyrolysis product 52-
d4.
Scheme 12. Isodesmic Reaction of Carbene 15a with
Cycloheptane
transition state for 1,3-trimethylsilyl migration in 15c has not
been located at the M062X/6-311+G** level, although at the
B3LYP/6-31G* level, the migration barrier is only 0.2 kcal/
mol.
The computational behavior of carbene 15a parallels that of
14a. The analogous isodesmic reaction of 15a with cyclo-
heptane (Scheme 12) suggests stabilization of 15a by the small
value of 1.9 kcal/mol relative to cycloheptylidene, 53. The
carbene center of 15a is closer to C3 (2.256 Å) than in the
unsubstituted cycloheptylidene, 53 (2.354 Å). The C1−C2−C3
bond angle in 15a is only 95°. The comparable angle in the
parent carbene 53 is 101°. These features, as well as the C1−
C2 and C2−C3 bond lengths, are consistent with a small
stabilizing interaction between the carbene vacant orbital and
the C2−C3 bond, as well as the rear lobe of the C3−Si bond.
Only 1,2-H migration processes are observed. There are no 1,3-
migration products, and this is consistent with computational
studies that show relatively high barriers to 1,3-migration
processes. The behavior of 13 therefore contrasts greatly with
that of the cyclobutyl analog, 10. While 1,2-H migration
processes also predominate in the cyclohexyl system 14, a small
amount of 1,3-H migration occurs, as confirmed by a labeling
study. In the cycloheptyl system 15, the major product is the
cyclopropane 52, and a labeling study again showed that this
product is derived from 1,3-H migration to the carbene center.
CONCLUSIONS
■
The chemistry of the acyclic carbene 12 is dominated by 1,3
migration processes, with 1,3-H migration being slightly
favored over 1,3-silyl migration. The behavior of the cyclic
carbene 13 stands in contrast to the other carbenes studied.
Scheme 11. Generation and Rearrangement of Labeled Carbene 15-d4
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NaOCH3 in methanol (0.917 mmol) was added via syringe. The
mixture was stirred at room temperature until the tosylhydrazone
dissolved, and the methanol was then removed using a rotary
evaporator. The solid salt that formed was further evacuated at
aspirator pressure for 2 h.
These experimental studies, as well as computational studies,
suggest that, although trimethylsilyl migration processes are
quite facile, they may not predominate due to conformational
factors. The cyclic carbenes 10, 13, 14, and 15 all have lower
energy conformations where the trimethylsilyl group cannot
migrate. Computational studies suggest that carbenes 14 and
15 are slightly stabilized by an interaction of the carbene center
with the rear lobe of the Si−C bond.
The solid salt was broken up with a spatula, and a short path
distillation head with a receiver flask was attached. The pressure was
reduced to <0.1 mm using a vacuum pump, and the salt was then
heated using an oil bath. At about 85 °C a purple/red color began to
appear, and the receiver flask was cooled in a dry ice bath. The
temperature in the oil bath was slowly increased to 165 °C as the
distillation head was warmed gently with a heat gun. No
decomposition of the diazo compound was detected during the
course of the pyrolysis. The diazo compound 20, contaminated with a
trace of methanol, collected in the cold receiver flask with the aid of a
heat gun. The receiver flask was disconnected, and the deep red diazo
compound was redistilled using a short path distillation head to give
179 mg of 20 (88% yield), bp ∼70 °C (0.05 mm). Neat diazo
compound 20, which decomposes on standing at room temperature,
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded on a 600 MHz spectrometer.
HRMS measurements were carried out using a spectrometer with an
electrospray ionization source with time-of-flight mass analyzer.
Preparation of 1-Trimethylsilyl-2-cyano-2-methylpropane, 17. A
solution of 3.76 g (37.3 mmol) of diisopropylamine in 30 mL of dry
tetrahydrofuran under argon was cooled to −78 °C, and 22.5 mL of
1.6 M n-BuLi in hexanes (36.0 mmol) was added dropwise. The
solution was warmed to 0 °C and then recooled to −78 °C. A solution
of 2.37 g of isobutyronitrile (34.3 mmol) in 10 mL of THF was then
added dropwise, and the solution was allowed to warm to −20 °C.
The solution was then cooled to −78 °C, and 4.18 g of ClCH2SiMe3
(34.1 mmol) was added. The mixture was then warmed to room
temperature and stirred for 8 h. The mixture was then quenched with
water and transferred to a separatory funnel using ether. The ether
extract was washed with water, saturated NaCl solution, and dried over
a mixture of Na2SO4 and MgSO4. After filtration, the solvents were
removed using a rotary evaporator. The residue was distilled to give
4.69 g of 17 (89% yield), bp 80−83 °C (15 mm). 1H NMR (CDCl3) δ
1.40 (s, 6 H), 1.00 (s, 2 H), 0.14 (s, 9 H). 13C NMR (CDCl3) δ 126.3,
30.7, 30.25, 30.20, −0.06. IR (neat) 2233, 1252, 839 cm−1. Exact mass
(ESI)(M + Na+) calcd for C8H17NNaSi: 178.1022. Found: 178.1026.
Preparation of 2,2-Dimethyl-1-phenyl-3-(trimethylsilyl)propan-1-
one, 18. A solution of 30 mL of 0.90 M PhMgBr in ether (27 mmol)
was stirred as 2.72 g of nitrile 17 (17.6 mmol) in 5 mL of ether was
added dropwise. The solution was then refluxed for 3 h and then
cooled in an ice bath. The solution was carefully quenched with
aqueous NH4Cl solution and transferred to a separatory funnel. The
ether phase was washed with water, saturated NaCl solution, and dried
over a mixture of Na2SO4 and MgSO4. After filtration, the solvents
were removed using a rotary evaporator, and the residue was distilled
to give 3.08 g (75% yield) of ketone 18, bp 104−106 °C (0.2 mm)
which was contaminated with a small amount of biphenyl. A pure
sample of ketone 18 was isolated by chromatography on silica gel
using increasing amounts of ether in pentane. The biphenyl impurity
eluted with pure pentane and ketone 18 eluted as an oil with 3−4%
1
gave no parent ion in the mass spectrometer. H NMR (CDCl3) δ
7.32 (m, 2 H), 7.14 (m, 2 H), 7.05 (m, 1 H), 140 (s, 6 H), 1.24 (s, 2
H), −0.01 (s, 9 H). 13C NMR (CDCl3) δ 131.7, 128.7, 124.3, 123.6,
32.6, 31.7, 31.2, 0.2. IR (neat) 2027, 1248, 835 cm−1.
Pyrolysis of Diazo Compound 20. Diazocompound 20 (26 mg)
was dissolved in 3.6 mL of cyclohexane, and the solution was sealed in
a pyrex tube under argon. The mixture was heated at 100 °C for 8.5 h.
The color gradually disappeared with a half-life of approximately 1 h.
The tube was opened, and the cyclohexane was removed using a rotary
evaporator. The residue was chromatographed on 0.6 g of silica gel in a
pipet and 19.4 mg of products (84% yield) eluted with pentane. NMR
spectra of the product mixture are shown as Supporting Information.
The products 21−24 were identified by NMR spectral comparison
and gas chromatographic retention time comparison with authentic
samples prepared as described below.
Preparation of Cyclopropanes 21 and 22. Phenyldiazomethane5c
(53 mg) was dissolved in 1.73 g of 2-methyl-1-trimethylsilylpropene,13
and the solution was sealed in a pyrex tube under argon. The solution
was irradiated for 72 min with a Hanovia 450 W lamp. The tube was
opened, and the excess 2-methyl-1-trimethylsilylpropene was removed
by distillation using a short path distillation head at 15 mm pressure.
The residue was chromatographed on 2.6 g of silica gel, and the
fraction that eluted immediately with pentane was collected. After
removal of the pentane, the residue (which contained 21 and 22 along
with some alkene byproducts) was dissolved in 4 mL of methanol. The
solution was cooled to −78 °C, and ozone was bubbled through the
solution until the methanol solution became light blue in color. The
mixture was warmed to about −30 °C, and a small amount of NaBH4
was added. The mixture was then warmed to room temperature, and
an aqueous workup followed using pentane extraction. The pentane
extract was washed with water and then dried over Na2SO4. After
removal of the pentane solvent using a rotary evaporator, the residue
was chromatographed on 0.7 g of silica gel in a pipet using pentane to
elute. A mixture of cyclopropanes 21 and 22 (37 mg; 38% yield) in a
63:37 ratio eluted as an oil with pure pentane. 1H NMR of 21
(CDCl3) δ 7.29−7.22 (m, 3 H), 7.19−7.14 (m, 2 H), 1.92 (d, J = 7.8
Hz, 1 H), 1.251 (s, 3 H), 0.829 (s, 3 H), 0.105 (s, 9 H), 0.027 (d, J =
7.8 Hz, 1 H). 13C NMR of 21 (CDCl3) δ 141.2, 129.0, 127.8, 125.5,
34.7, 25.2, 24.2, 23.7, 17.7, −0.10. Exact mass calcd for C14H22Si:
218.1491. Found: 218.1485. 1H NMR of 22 (CDCl3) δ 7.29−7.22 (m,
3 H), 7.19−7.14 (m, 2 H), 2.22 (d, J = 10.4 Hz, 1 H), 1.300 (s, 3 H),
1.104 (s, 3 H), −0.059 (d, J = 10.4 Hz, 1 H), −0.064 (s, 9 H). 13C
NMR of 22 (CDCl3) δ 140.2, 130.8, 127.7, 125.8, 34.3, 31.1, 21.4,
20.4, 20.0, 0.9. IR (neat) 1247, 832 cm−1. Exact mass calcd for
C14H22Si: 218.1491. Found: 218.1503.
1
ether in pentane. H NMR (CDCl3) δ 7.72 (m, 2 H), 7.45 (m, 1 H),
7.39 (m, 2 H), 1.38 (s, 6 H), 1.20 (s, 2 H), 0.00 (s, 9 H). 13C NMR
(CDCl3) δ 209.0, 138.6, 130.8, 128.3, 128.0, 46.8, 30.3, 29.1, 0.6. IR
(neat) 1672, 1248, 832 cm−1. Exact mass (ESI)(M + Na+) calcd for
C14H22NaOSi: 257.1332. Found: 257.1315.
Preparation of Tosylhydrazone 19. A mixture of 302 mg of ketone
18 (1.313 mmol) and 262 mg of NH2NHTs (1.409 mmol) in 3.0 mL
of CH3OH in a vial was stirred as 26 mg of TsOH·H2O was added.
The mixture was heated in an oil bath at 42−48 °C °C for 18 h. The
methanol solvent was then removed using a rotary evaporator. The
residue was taken up into 6 mL of HCCl3 and filtered through a cotton
plug in a pipet. The HCCl3 was then removed using a rotary
evaporator, and the residue was slurried with about 3 mL of pentane,
cooled to 0 °C, and the pentane was decanted. After removal of the
last traces of pentane under aspirator pressure, the solid tosylhy-
1
drazone, mp 84−86 °C was collected (483 mg; 93% yield). H NMR
(CDCl3) δ 7.78 (m, 2 H), 7.45−7.40 (m, 3 H), 7.32 (m, 2 H), 6.85
(m, 3 H), 2.45 (s, 3 H), 1.09 (s, 6 H), 0.84 (s, 2 H), −0.04 (s, 9 H).
13C NMR (CDCl3) δ 165,6, 143.9, 135.6, 131.9, 129.40, 129.34,
129.21, 128.1, 127.7, 41.2, 29.7, 28.8, 21.6, 0.7. IR 1339, 1245, 1166,
833, 555 cm−1. Exact mass (ESI)(M + H+) calcd for C21H31N2O2SSi:
403.1870. Found: 403.1891.
Preparation of Cyclopropane 23. A solution of 198 mg of 1-
bromo-2,2-dimethyl-1-phenylcyclopropane14 (0.880 mmol) in 2 mL of
THF was cooled to −78 °C, and 1.2 mL of 1.5 M t-BuLi in pentane
(1.800 mmol) was added via syringe. After 30 min at −78 °C, 200 mg
of chlorotrimethylsilane (1.843 mmol) was added. The mixture was
warmed to room temperature. After 3 h, water was added, and the
Preparation of Diazo Compound 20. Tosylhydrazone 19 (334
mg; 0.830 mmol) was placed in a 10 mL flask and 1.92 mL of 0.478 M
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mixture was transferred to a separatory funnel using ether. The organic
phase was washed with water, saturated NaCl solution, and then dried
over MgSO4. After filtration, the solvents were removed using a rotary
evaporator, and the residue was distilled using a short path distillation
head. After a forerun containing 2,2-dimethyl-1-phenylcyclopropane,
dry tosylhydrazone salt formed, and it was broken up with a spatula. A
short path distillation head was attached, and the pressure was lowered
to 0.2 mm. The flask was gradually heated to 140 °C as the receiver
flask was cooled to −78 °C in a dry ice/acetone bath. A liquid (93 mg,
59% yield) collected in the receiver flask. NMR analysis (see
Supporting Information) of the distillate showed a mixture of 36,16
37,16 and 38 in a 50:37:13 ratio. 1H NMR of 38 (CDCl3) δ 1.81 (m, 1
H), 1.66−1.46 (m, 4 H), 1.24−1.09 (m, 2 H), 0.28−0.19 (m, 2 H),
−0.06 (s, 9 H). 13C NMR of 38 (CDCl3) δ 29.0, 28.1, 21.9, 20.4, 13.5,
8.9, −2.9. IR (neat) 1247, 830 cm−1. Exact mass calcd for C9H18Si:
154.1178. Found: 154.1181.
Preparation and Pyrolysis of Tosylhydrazone Salt 35-d4. 3-
Trimethylsilylcyclohexanone, 34, (440 mg) was placed in a flask, and
6.8 mL of D2O was added along with 110 mg of K2CO3. The mixture
was refluxed for 4 h and then extracted with 15 mL of pentane. The
pentane extract was dried over Na2SO4, and the solvent was removed
using a rotary evaporator. NMR analysis showed a high level of
deuterium incorporation. The reaction product was recycled using an
additional 6.8 mL of D2O and 110 mg of Na2CO3. After refluxing for
an additional 3 h and extraction with pentane, 411 mg (91% yield) of
2,2,6,6-tetradeutero-3-trimethylsilylcyclohexanone was recovered.
NMR analysis (see Supporting Information) showed >96% deuterium
incorporation.
Reaction of tosylhydrazine (453 mg) with 2,2,6,6-tetradeutero-3-
trimethylsilylcyclohexanone (411 mg) in 2 mL of CH3OD as solvent
was completely analogous to reaction of undeuterated 34. The
tosylhydrazone salt 35-d4 was prepared in an analogous fashion to the
preparation of 35 using 445 mg of tosylhydrazone and 2.60 mL of
0.557 M NaOCH3 in CH3OD. The vacuum pyrolysis of 35-d4 was also
completely analogous to the pyrolysis of 35.
Preparation of 2,2,5-Trideutero-1-trimethylsilylbicyclo[3.1.0]-
hexane, 38-d3. Tosylhydrazine (2.191 g) was placed in a flask, and
6.0 mL of CH3OD was added. A solution of 988 mg of 2,2,5,5-
tetradeuterocyclopentanone in 2.5 mL of CH3OD was added, and the
mixture was warmed slightly to dissolve the tosylhydrazine. After 20 h,
the flask was cooled in ice, and the product was collected in a Buchner
funnel, washed with cold ether, and dried under vacuum. The yield of
cyclopentanone-d4 tosylhydrazone, 40, was 2.762 g (96% yield).
Conversion of tosylhydrazone 40 to 41 followed the same procedure
as used to convert undeuterated cyclopentanone tosylhydrazone to 1-
trimethylsilylcyclopentene.18
1
127 mg of 23 (66% yield) was collected, bp 70−73 °C (2 mm). H
NMR of 23 (CDCl3) δ 7.21 (m, 2 H), 7.14−7.07 (m, 2 H), 6.98 (m, 1
H), 1.31 (s, 3 H), 0.94 (d, J = 4 Hz, 1 H), 0.83 (d, J = 4 Hz, 1 H), 0.76
(s, 3 H), −0.06 (s, 9 H). 13C NMR of 23 (CDCl3) δ 145.3, 130.5,
129.6, 128.0, 127.3, 124.5, 26.9, 25.5, 24.9, 24.5, 22.0, −0.1. IR (neat)
1247, 832 cm−1. Exact mass calcd for C14H22Si: 218.1491. Found:
218.1486.
Preparation of Cyclopropanes 24. A solution of 25 mg of
phenyldiazomethane in 4 mL of 2-methyl-3-trimethylsilylprop-1-ene15
was sealed in a Pyrex tube under argon. The solution was irradiated for
45 min with a Hanovia 450 W lamp. The tube was opened, and the
excess 2-methyl-3-trimethylsilylprop-1-ene was removed by distillation
at aspirator pressure. The residue was passed through 0.6 g of silica gel
in a pipet with pentane elution. The cyclopropanes 24 (20 mg; 43%
yield) eluted as an oil in a 1.1:1 mixture of isomers with pure pentane.
1H NMR of 24 (CDCl3) δ 7.30−7.11 (m, 5 H), 1.86 (d of d, J = 8.5,
6.0 Hz, 0.52 H), 1.81 (d of d, J = 8.5, 6.0 Hz, 0.48 H), 1.24 (s, 1.5 H),
0.7−0.74 (m, 5 H), 0.49 (m, 0.48 H), 0.09 (s, 4.7 H), −0.03 (s, 4.3 H).
13C NMR of 24 (CDCl3) δ 140.44, 140.41, 129.0, 128.8, 127.84,
127.81, 125.384, 125.379, 30.86, 30.79, 27.9, 21.6, 21.2, 21.0, 20.3,
19.8, 18.6, 0.04, −0.05. IR (neat) 1247, 834 cm−1. Exact mass calcd for
C14H22Si: 218.1491. Found: 218.1498.
Preparation and Pyrolysis of Tosylhydrazone Salt 26. Tosylhy-
drazine (247 mg; 1.328 mmol) was placed in a vial and stirred, and 2
mL was of methanol was added. 3-Trimethylsilylcyclopentanone16
(204 mg; 1.308 mmol) was added, and the mixture was stirred for 4 h.
The mixture was stored in the freezer overnight, and some
tosylhydrazone crystallized. Most of the methanol was then removed
using a rotary evaporator, and the crude residue was slurried with 2 mL
of 20% ether in pentane. After cooling to −20 °C, the solvent was
decanted from the solid product. The last traces of solvent were
removed using a rotary evaporator. The yield of tosylhydrazone was
1
396 mg (93% yield). H NMR and 13C NMR spectra (Supporting
Information) showed a mixture of two isomers.
The tosylhydrazone (299 mg; 0.923 mmol) prepared above was
placed in a 15 mL flask, and 1.70 mL of 0.579 M NaOCH3 (0.984
mmol) in methanol was added. The mixture was swirled for 10 min to
dissolve the tosylhydrazone. The methanol was then removed using a
rotary evaporator, and the residue was evacuated at 15 mm pressure
for 5 h. The solid dry tosylhydrazone salt 26 was then broken up with
a spatula, a short path distillation head with a receiver flask was
attached, and the pressure was lowered to 0.2 mm. The flask was
gradually heated to 130 °C as the receiver flask was cooled to −78 °C
in a dry ice/acetone bath. At about 120 °C the pressure rose slightly,
and there was a large pressure increase at about 130 °C. A liquid
collected in the cooled receiver flask. At the end of the pyrolysis, the
pressure dropped to about 0.2 mm. The distillate (60 mg) showed
2716 and 2816 in a 67:33 ratio as determined by NMR. See Supporting
Information.
Ethylzinc iodide (2.0 mL of 1.0 M in ether) was placed in a flask
under argon and 330 mg of CH2I2 was added. The mixture was
refluxed for 5 min, and then a solution of about 58 mg of alkene 41 in
a small amount of ether was added. The mixture was refluxed for 8 h.
More ether was added to the mixture, which was then quenched with
NaOH in water. Pentane was added, and the organic extract was
separated and dried over MgSO4. After filtration the solvent was
removed using a rotary evaporator. The crude residue was distilled at
15 mm pressure using a short path distillation head, and a receiver
1
flask cooled in an ice bath to prevent loss of the volatile 38-d3. H
NMR of 38-d3 (CDCl3) δ 1.80 (m, 1 H), 1.60 (m, 1 H), 1.49 (m, 1
H), 1.17 (m, 1 H), 0.25−0.19 (m, 2 H), −0.06 (s, 9 H). 13C NMR of
38-d3 (CDCl3) δ 28.0, 20.2, 13.3, 8.7, −2.9.
Preparation of 3-Trimethylsilycycloheptanone, 48. In order to
prevent significant formation of 3-(SiMe2SiMe3)cycloheptanone, the
modified procedure for generation of TMSLi developed by Hudrlik17b
was used. A magnetically stirred solution of 1.252 g of Me3Si-SiMe3
(8.575 mmol) in 3.5 mL of HMPA under argon was cooled to −78 °C.
The mixture became solid and stirring stopped. Halide-free
methyllithium (4.3 mL of 1.6 M, 6.880 mmol) in ether was added
dropwise to the frozen mixture. On completion of the addition, 10 mL
of dry THF was slowly added to the frozen mixture. The −78 °C bath
was then replaced with an ice bath and stirring started after a few
minutes as the mixture began to melt. The mixture was then stirred for
10 min in the ice bath, and the solution became dark red/orange. The
mixture was recooled to −78 °C, and an additional 5 mL of THF was
slowly added. A solution of 583 mg of cycloheptenone (5.300 mmol)
in 2.5 mL of THF was next added dropwise at −78 °C. The mixture
was warmed to about −40 °C and then quenched with water. The
Preparation and Pyrolysis of Tosylhydrazone Salt 35. Tosylhy-
drazine (386 mg; 2.075 mmol) was placed in a vial, and 2.5 mL was of
methanol was added. 3-Trimethylsilylcyclohexanone16,17 (344 mg;
2.024 mmol) was added, and the mixture was stirred. Tosylhydrazone
product crystallized after a few hours, and about 80% of the methanol
was removed using a rotary evaporator. The crude residue was slurried
with 2 mL of 20% ether in pentane. After cooling to −20 °C, the
solvent was decanted from the solid product. The last traces of solvent
were removed using a rotary evaporator. The yield of tosylhydrazone
1
product was 605 mg (88% yield). H NMR and 13C NMR spectra
(Supporting Information) showed a mixture of two isomers.
The tosylhydrazone above (347 mg; 1.027 mmol) was placed in a
15 mL flask, and 1.88 mL of 0.579 M NaOCH3 in methanol (1.089
mmol) was added. The mixture was swirled for 10 min to dissolve the
tosylhydrazone. The methanol was then removed using a rotary
evaporator, and the residue was evacuated at 15 mm for 5 h. The solid
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mixture was then transferred to a separatory funnel using 60 mL of
pentane. The organic phase was washed with 3 portions of water. The
aqueous extracts were collected for later destruction of the toxic
HMPA. The pentane extract was dried over MgSO4 and filtered, and
the solvent was removed using a rotary evaporator. The residue was
distilled to give 836 mg (86% yield) of 48, bp 108−110 °C (15 mm).
1H NMR of 48 (CDCl3) δ 2.56 (m, 1 H), 2.49 (m, 1 H), 2.42 (m, 1
H), 2.35 (d of d, J = 14.6, 12 Hz, 1 H), 2.05 (m, 1 H), 2.00−1.86 (m, 2
H), 1.54 (m, 1 H), 1.31 (m, 1 H), 1.17 (m, 1 H), 0.82 (m, 1 H), −0.01
(s, 9 H). 13C NMR of 48 (CDCl3) δ 215.7, 44.5, 43.5, 31.9, 31.1, 24.4,
23.7, −3.5. IR (neat) 1698, 1247, 832 cm−1. Exact mass calcd for
C10H20 OSi: 184.1283. Found: 184.1280.
Preparation and Pyrolysis of Tosylhydrazone Salt 49. Tosylhy-
drazine (90 mg; 0.484 mmol) was placed in a flask, and 0.5 mL of
CH3OH was added. 3-Trimethylsilylcycloheptanone, 48 (82 mg; 0.446
mmol) in 0.5 mL of CH3OH was then added. The mixture was stirred
at room temperature for 18 h, and then 1.10 mL of 0.478 M NaOCH3
in methanol (0.526 mmol) was added. The methanol solvent was
removed using a rotary evaporator, and the flask was then evacuated at
15 mm for 8 h. The solid was then dissolved in 7 mL of dry diglyme. A
condenser was attached, and the solution (under argon) was slowly
warmed in an oil bath from room temperature to 155 °C. The flask
was then cooled to room temperature, and the mixture was transferred
to a separatory funnel using 20 mL of pentane and 25 mL of water.
The pentane extract was washed with 3 portions of water, and after
drying over Na2SO4, the solvent was removed using a rotary
evaporator. The crude residue was chromatographed on 0.6 g of
silica gel in a pipet and eluted with pentane. The yield of
chromatographed products was 31.0 mg (41% yield). NMR analysis
(Supporting Information) showed 50, 51,19 and 5220 in a 9:14:77
ratio.
AUTHOR INFORMATION
Corresponding Author
*E-mail: creary.1@nd.edu.
Notes
■
The authors declare no competing financial interest.
REFERENCES
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Preparation and Pyrolysis of Tosylhydrazone Salt 49-d4. 3-
Trimethylsilylcycloheptanone, 48, was converted to 48-d4 by reaction
in D2O with Na2CO3 as a catalyst using a procedure analogous to the
exchange reaction of 3-trimethylsilylcyclohexanone, 34. The reflux
time for each exchange was 24 h, and three exchanges were carried out.
Procedures for conversion of 48-d4 to the corresponding tosylhy-
drazone salt 49-d4 (reaction with NH2NHTs in CH3OD followed by
reaction with NaOCH3 in CH3OD) and solution pyrolysis of this salt
in diglyme were completely analogous to the procedures used for the
undeuterated 48. NMR analysis (see Supporting Information) of the
products after chromatography showed a mixture of 50-d4, 51-d4, and
52-d4 in a 5:10:85 ratio.
Computational Studies. Ab initio molecular orbital calculations
were performed using the Gaussian 09 series of programs.8 Structures
were characterized as energy minima via frequency calculations that
showed no negative frequencies or as transition states that showed one
negative frequency.
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migration to give 23 is 1.4 kcal/mol. The corresponding energy
diagram is shown as Supporting Information.
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significant..
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01955.
Complete ref 8, the M062X/6-311+G** calculated
structures, energies, and Cartesian coordinates of 13a,
13b, 14a, 14b, 15a, 15b, 15c, 29, 31, 32, 33, 42, 43, 44,
45, 46, 53, 54, and 55, the B3LYP/6-311+G** calculated
(12) As in the case of the salt of cycloheptanone tosylhydrazone,10a
vacuum pyrolysis gave a very poor yield of products. Pyrolysis was
therefore carried out in dry diglyme, where the yield is higher.
(13) Soderquist, J. A.; Lee, S.-J. H. Tetrahedron 1988, 44, 4033.
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1977, 132, 301.
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1
energy diagram for conversion of 12 to 21 and 23, H
and 13C NMR spectra of 17, 18, 19, 20, 21 and 22, 23,
24, 38, 38-d3, 48, the tosylhydrazone mixtures derived
from 25 and 34, the pyrolysis products derived from 26,
35, 35-d4, 49 and 49d4, and 2,2,6,6-tetradeutero-3-
trimethylsilylcyclohexanone as well as IR spectra for 17,
18, 19, 20, 21 and 22, 23, 24, 38, and 48 (PDF)
Waugh, M. A.; Hudrlik, A. M. J. Organomet. Chem. 1984, 271, 69.
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