Further studies of intramolecular michael reactions of nitrosoalkenes for construction of functionalized bridged ring systems

Article abstract of DOI:10.1021/jo1024392

A wide variety of stabilized carbanions have been found to participate as nucleophiles in intramolecular Michael-type conjugate additions to in situ generated nitrosoalkenes to form bridged carbocyclic systems. The vinylnitroso platforms for these cyclizations have been prepared via two key steps involving ring-closing metathesis of vinyl chlorides and regioselective conversion of vinyl chlorides to α-chloroketones with sodium hypochlorite in glacial acetic acid/acetone. An alternative approach to preparation of some cyclization substrates has involved use of more reactive enol ethers as precursors to the requisite α-chloroketones. A sulfonamide anion has also been found to be an effective nucleophile in this type of reaction, leading to formation of a 6-azabicyclo[3.2.1]octane.

Full text of DOI:10.1021/jo1024392

ARTICLE
pubs.acs.org/joc
Further Studies of Intramolecular Michael Reactions of Nitrosoalkenes
for Construction of Functionalized Bridged Ring Systems
Praveen Kumar, Puhui Li, Ilia Korboukh, Tony L. Wang, Hemant Yennawar,† and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S Supporting Information
b
ABSTRACT: A wide variety of stabilized carbanions have been found to
participate as nucleophiles in intramolecular Michael-type conjugate
additions to in situ generated nitrosoalkenes to form bridged carbocyclic
systems. The vinylnitroso platforms for these cyclizations have been
prepared via two key steps involving ring-closing metathesis of vinyl
chlorides and regioselective conversion of vinyl chlorides to R-chlor-
oketones with sodium hypochlorite in glacial acetic acid/acetone. An
alternative approach to preparation of some cyclization substrates has
involved use of more reactive enol ethers as precursors to the requisite R-chloroketones. A sulfonamide anion has also been found to
be an effective nucleophile in this type of reaction, leading to formation of a 6-azabicyclo[3.2.1]octane.
’ INTRODUCTION AND BACKGROUND
primarily with a series of substrates using malonate anions as the
nucleophile. For example, malonate 5 was first deprotonated,
followed by exposure of the R-chloro-O-silyloxime moiety to
tetrabutylammonium fluoride in THF to generate the vinylni-
troso intermediate 6, which then cyclized to afford bicyclo-
[2.2.2]octane 7 as a single (E)-oxime isomer (Scheme 2). Cycli-
zation substrates such as 5 were easily prepared via two reactions
developed in these laboratories: ring-closing metathesis of vinyl
chlorides9 and regioselective conversion of vinyl chlorides to R-
chloroketones with sodium hypochlorite/glacial acetic acid (vide
infra).10 In view of our success in carrying out these cyclizations,
we became interested in exploring the possibility of effecting
related transformations using a range of soft nucleophiles other
than malonates, and these recent studies are the subject of
this paper.
Although vinylnitroso compounds 3 were first postulated as
transient, highly reactive intermediates over 100 years ago,1,2 the
first isolable member of this class of unstable electron-deficient
alkenes was not reported until 1960.3 Two primary modes of
reactivity have been described for nitrosoalkenes over the years.
It has been observed that species such as 3 can act as a
heterodiene in [4 þ 2]-cycloadditions with electron-rich alkenes
to form 5,6-dihydro-4H-1,2-oxazines. Both inter- and intramo-
lecular versions of this process have been effected.2b Vinylnitroso
compounds 3 are also known to act as Michael acceptors in con-
jugate addition reactions with a variety of carbon and heteroatom
nucleophiles to afford adducts 4, but little in the way of sys-
tematic study of this type of transformation currently exists
(Scheme 1).2,4
The two most commonly used methods for producing nitro-
soalkenes utilize oximes of R-chloro aldehydes and ketones. The
large preponderance of examples in the literature of generation of
vinylnitroso compounds has involved base-promoted dehydro-
halogenation of R-halooximes 1.2 However, for effecting con-
jugate additions, this process usually involves the use of 2 equiv of
a nucleophile, one of which acts as a base. In the 1980s, Denmark
and co-workers developed a useful and more efficient alternative
procedure based on the fluoride-induced cleavage of easily
prepared R-chloro-O-silyloximes 2 to give a nitrosoalkene 3.5
We have recently been engaged in expanding the utility of
nitrosoalkenes as enolonium ion equivalents and in applying this
chemistry to total syntheses of some natural product targets.4,6
During the course of these studies, we decided to explore the
feasibility of effecting intramolecular conjugate additions of
nitrosoalkenes to produce bridged and fused ring systems since
such methodology had not previously been reported.7 In a brief
preliminary communication,8 we have demonstrated that such
cyclizations are indeed easily effected. This initial work was done
’ RESULTS AND DISCUSSION
Our initial experiments were directed toward synthesis of the
requisite cyclization substrates for these expanded studies. It was
decided to first explore a platform leading to various bicyclo-
[2.2.1]heptane ring systems, and thus readily prepared iodide 8
was chosen as a precursor (see the Supporting Information).
Alkylation of malononitrile anion in DMSO with this iodide led
to vinyl chloride 9, which upon treatment with sodium hypo-
chlorite in acetone/glacial acetic acid10 afforded R-chloroketone
10 as a mixture of diastereomers (Scheme 3). The O-silyloxime
11 was then prepared (complex mixture of diastereomers and
geometrical isomers) from ketone 10 using commercially avail-
able O-TBS-hydroxylamine. Using a similar protocol as for the
malonate systems,8 malononitrile 11 was deprotonated with
potassium hexamethyldisilazide in THF at -78 °C, followed
Received: December 9, 2010
Published: February 28, 2011
r
2011 American Chemical Society
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ARTICLE
Scheme 1. Formation and Conjugate Additions of
Nitrosoalkenes
Scheme 3. Formation of a Dicyanobicyclo[2.2.1]heptane
Scheme 2. Intramolecular Nitrosoalkene Conjugate
Addition
Scheme 4. Synthesis of Various Cyclization Substrates
by addition of TBAF and slow warming to room temperature to
generate the transient nitrosoalkene intermediate 12, which then
cyclized to bicyclic dinitrile 13 in good yield. Compound 13 is a
single oxime isomer we have tentatively assigned the (E)-geom-
etry as shown. It might also be noted that with several of the
substrates described in this paper, it was found that yields of
cyclization products were slightly improved by using potassium
hexamethyldisilazide rather than the corresponding sodium base
(cf. Scheme 2).
Since iodide 8 proved rather difficult to manipulate due to its
volatility, we therefore opted to prepare other substrates via a
modified strategy. Thus, the sequence shown in Scheme 4 was
used to synthesize a diverse array of cyclization precursors
bearing various groups to be tested as nucleophiles (yields unop-
timized; see the Supporting Information for detailed experimen-
tal procedures). Diene iodide 14, which we have previously
described,8 is more easily handled than 8 and could be combined
with a number of active methylene compounds to produce
alkylated products 15a-g. These dienes all underwent successful
ring-closing metathesis using the second-generation Grubbs
catalyst to afford cyclic vinyl chlorides 16a-g.9 Using our sodium
hypochlorite methodology,10 vinyl chlorides 16a-g were then
converted to the corresponding R-chloroketones 17a-g, respec-
tively, in moderate yields. Finally, these R-chloroketones were
transformed into the requisite R-chloro-O-TBS-oxime cycliza-
tion substrates 18a-g.
Cyclization studies were then conducted on the 1,3-diketone
18a and the bis-phenylsulfone 18b (Scheme 5). Using our
standard protocol, O-silyloxime substrates 18a and 18b were
first deprotonated using potassium hexamethyldisilazide, fol-
lowed by treatment with TBAF to generate the vinylnitroso
intermediate, leading to bicyclo[2.2.1]heptanes 19 and 20,
respectively. Both of these compounds were found to be single
oxime geometric isomers, once again presumed to have the (E)-
stereochemistry.
Another system to be examined was the phenylsulfone methyl
ester 18d, which upon cyclization under the usual reaction
conditions led to a single stereoisomeric product 22a in high
yield (Scheme 6). Since we could not establish the configuration
of 22a directly by NMR methods due to peak overlap, we
attempted to effect a Beckmann rearrangement to afford the
azabicyclo[3.2.1]octane 23 which we hoped might be more easily
analyzed. However, treatment of 22a with tosyl chloride/triethy-
lamine/DMAP11 instead led to the stable crystalline oxime
tosylate 22b. 2D NMR studies on tosylate 22b established its
configuration to be as shown, primarily due to an NOE enhance-
ment between the methyl group of the ester and an aromatic
proton ortho to the sulfonyl group of the tosyl moiety. In addi-
tion, we observe an upfield shift for the 1H NMR resonances of
the O-methyl group of 22a and 22b (0.17 and 0.49 ppm,
respectively) relative to the corresponding uncyclized precursors
15d-18d. Further confirmation of this structure, along with the
(E)-geometry of the oxime, came from an X-ray analysis of 22b
(see the Supporting Information). In the crystal, the methyl ester
moiety of 22b is disposed above the face of the aromatic ring of
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Scheme 5. Formation of Bicyclo[2.2.1]heptanes
Scheme 7. Cyclizations of Additional Unsymmetrical
Substrates
Scheme 6. Stereoselective Formation of Oxime 22a
Scheme 8. Substrate Preparation via an Enol Ether and
Stereoselective Cyclization to a Bicyclo[3.2.1]octane
the tosyl group, thus lending support to the NMR upfield shift
argument. Thus, the cyclization apparently occurs via an ester
enolate conformation like 21. At this point, it is not clear if the
preference for formation of the product having the ester group
syn to the oxime is a result of steric factors, or if there is some type
of dipole effect controlling the stereochemical outcome.
Several other cyclizations involving unsymmetrical substrates
are shown in Scheme 7. The nitro ester 18e also was stereo-
selective and provided a single cyclization product 24. Surpris-
ingly, treatment of oxime 24 with tosyl choride, as was done with
oxime 22a, gave no reaction even upon heating. However, based
upon the fact that the -OCH2- group of the ethyl ester of 24 is
not shifted upfield relative to precursors 15e-18e, we have
tentatively assigned the configuration of this compound as having
the oxime and ester anti as shown.
The β-ketoester substrate 18c also could be successfully
cyclized, but in this case an inseparable 2.2:1 mixture of epimeric
products 25 was produced. Similarly, phosphonate ester 18f also
cyclized in good yield, but with this system an inseparable 1:1
mixture of epimers 26 was obtained. Finally, with phenylsulfone
nitrile substrate 18g a 10:1 epimeric mixture of bicycloheptanes
27 was generated, which again was inseparable by chromatogra-
phy. In each of the above three examples, the products all
appeared to be single oxime geometric isomers assumed to be
(E), although the configuration of the products at the quaternary
carbon was not determined due to our inability to obtain pure
compounds. At present, it is unclear why there is so much var-
iation in the stereochemical outcomes of these cyclizations with
different functional groups.
One difficulty encountered during the course of these studies
is that the hypochlorite-induced halogenation of vinyl chlorides
often leads to a variety of undesired side products, including
competitive chlorination of the active methine portion of the
substrate, thereby lowering the yield of the desired R-chloroke-
tones (Cf Scheme 4).10b It is believed that some of these problems
are probably due in part to the electron-deficient nature of the
olefinic double bond of vinyl chlorides, thus leading to relatively
slow conversion to the respective R-chloroketones. We therefore
considered the possibility of using more electron rich enol ethers
as alternative precursors to R-chloroketones in order to accel-
erate the halogenation and possibly obviate some of these pro-
blems. Moreover, we anticipated that such a strategy should
provide greater flexibility in preparation of various precursors for
the nitrosoalkene conjugate addition methodology.
To test this idea, the known enol ether alcohol 28, prepared via
the Diels-Alder reaction of 2-methoxybutadiene12 with ethyl
acrylate followed by ester reduction with lithium aluminum
hydride,13 was converted to tosylate 29 (Scheme 8). Alkylation
of methyl R-phenylsulfonylacetate with this tosylate then led to
30 as a mixture of diastereomers in 53% yield based on alcohol
28. Using the halogenation conditions described by Cha et al.,14
enol ether 30 was transformed to R-chloroketone 31 with N-
chlorosuccinimide in 64% yield. Conversion of this R-chloroke-
tone to O-TBS-oxime 32, followed by cyclization under the usual
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Scheme 9. Cyclization with a Sulfonamide Nucleophile
conditions afforded the bicyclo[3.2.1]octane 33a as a single
diastereomer. The configuration and (E)-oxime geometry of this
product was established by conversion to the oxime tosylate 33b,
which was analyzed by X-ray crystallography. Therefore, the
outcome of this cyclization is the same as that observed in the
bicyclo[2.2.1]heptane series 22 where the ester group is syn to
the oxime in the product (cf. Scheme 6).
aza-heterocyclic ring system.20 We are currently investigating
further extensions and variations of this methodology, along with
applications to the synthesis of some natural products.
’ EXPERIMENTAL SECTION
2-(3-Chlorocyclopent-3-enylmethyl)malononitrile (9). A
suspension of NaH (60% dispersion in mineral oil, 180 mg, 4.5 mmol)
in DMSO (2 mL) was heated at 70 °C for 1 h and cooled to rt. To the
resulting mixture was added a solution of malononitrile (298 mg, 4.5
mmol) in DMSO (2 mL) at rt. After the mixture was stirred for 5 min, a
solution of iodide 8 (545 mg, 2.25 mmol) in DMSO (1 mL) was added,
and the mixture was stirred for 12 h at 65 °C. Saturated aqueous NH4Cl
and ether were added. The organic layer was separated, and the aqueous
layer was extracted with ether. The combined ether layer was washed
with water and brine. The organic layer was dried over Na2SO4, and the
solvent was removed under reduced pressure. The residue was purified
by flash chromatography (30% ether/pentane) to afford the vinyl
We have also explored the possibility of effecting intramole-
cular nitrosoalkene conjugate additions using nitrogen nucleo-
philes to form bridged azaheterocycles. Thus, Diels-Alder
cycloaddition of 2-methoxybutadiene12 with acrylonitrile as
reported by Katritzky and co-workers15 gave an 8:1 mixture of
the desired adduct 34 along with its regioisomer, which was not
easily separated (Scheme 9). Therefore, the mixture was reduced
to the corresponding amine 35,16 followed by treatment of the
crude material with tosyl chloride to afford sulfonamide 36,
which could be purified by chromatography. We were pleased to
find that under the Cha reaction conditions14 enol ether 36 was
cleanly transformed to R-chloroketone 37 in high yield. It should
be added that we have observed that halogenation of some vinyl
chloride systems related to enol ether 36 using our sodium
hypochlorite method led to significantly lower yields of the
respective R-chloroketones and also produced varying amounts
of products resulting from N-chlorination of the sulfonamide.17
Subsequent reaction of compound 37 with O-TBS-hydroxy-
lamine produced the required R-chloro-O-silyloxime 38. Inter-
estingly, it was discovered that TBAF is a sufficiently strong base
to deprotonate the sulfonamide for the cyclization onto the
derived nitrosoalkene. Thus, exposure of substrate 38 to 2 equiv
of TBAF in acetonitrile at 0 °C led directly to formation of the
desired 6-azabicyclo[3.2.1]octane in good total yield as a 5:1
oxime geometric isomer mixture. The major isomer of 39 was
determined by X-ray crystallography to have the (E)-geometry as
shown. For further characterization, the oxime mixture could be
oxidatively cleaved to afford the bridged ketone 40 in 76% yield.18
1
chloride 6 as a colorless oil (203 mg, 50%): H NMR (300 MHz,
CDCl3) δ 5.47-5.46 (m, 1H), 3.59 (t, J = 7.4 Hz, 1H), 2.67-2.46 (m,
3H), 2.17-2.09 (m, 1H), 2.03-1.91 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 130.2, 124.5, 112.1, 42.1, 36.5, 35.8, 34.4, 20.9; no molecular
ion was detected by HRMS.
2-(3-Chloro-4-oxocyclopentylmethyl)malononitrile (10).
To a solution of vinyl chloride 9 (39 mg, 0.22 mmol), acetone
(2.1 mL), and glacial acetic acid (0.9 mL) at 0 °C was added dropwise
sodium hypochlorite (0.18 mL of 10% solution, 0.22 mmol) via syringe.
The reaction mixture was stirred at 0 °C for 30 min and quenched by
addition of saturated aqueous NaHCO3 solution. The mixture was then
extracted with dichloromethane. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by flash chroma-
tography (80% ether/pentane) affording the R-chloroketone 10 as a
1
clear oil (20 mg, 47%): H NMR (300 MHz, CDCl3, diastereomer
mixture) δ 4.21-4.11 (m, 1H), 3.79-3.72 (m, 1H), 2.88-2.66 (m,
2H), 2.48-2.40 (m, 1H), 2.23-2.15 (m, 2H), 2.12-1.89 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 207.3, 207.1, 112.3, 112.2, 58.3, 56.6, 41.4,
41.3, 39.5, 39.2, 36.3, 36.1, 31.9, 31.0, 21.8, 21.6; HRMS-AP [M þ
NH4]þ calcd for C9H13ClN3O 214.0747, found 214.0748.
’ CONCLUSION
In summary, we have found that intramolecular conjugate
additions of nitrosoalkenes, generated in situ via the Denmark R-
chloro-O-silyloxime methodology,5 can be effected using a wide
variety of soft carbon nucleophiles to produce bridged ring
systems.19 Some of these cyclizations were found to proceed
with high stereoselectivity, although the factors controlling the
product configurations are not yet well understood. Similarly, use
of a sulfonamide nucleophile leads to the formation of a bridged
2-(3-Chloro-4-tert-butyldimethylsilyloxyiminocyclopen-
tylmethyl)malononitrile (11). To a solution of R-chloroketone
10 (17 mg, 0.086 mmol) in dichloromethane (3 mL) were added
O-(tert-butyldimethylsilyl)hydroxylamine (16.5 mg, 0.11 mmol), 4 Å
molecular sieves (crushed), and a catalytic amount of PPTS. The mix-
ture was stirred at rt for 24 h and then filtered through a pad of Celite.
The solvent was removed under reduced pressure, and the residue was
purified by flash chromatography (30% ether/hexanes) to afford the
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R-chloro-O-silylketoxime 10 as a colorless oil (18 mg, 64%): 1H NMR
(300 MHz, CDCl3, complex mixture of diastereomers including oxime
geometric isomers) δ 4.88-4.54 (m, 1H), 3.63-3.57 (m, 1H), 2.86-
2.42 (m, 2H), 2.24-1.89 (m, 4H), 1.76-1.61 (m, 1H), 0.77-0.70
(m, 9H), 0.01-0.00 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 165.5,
165.0, 164.5, 164.1, 112.6, 112.5, 58.4, 56.0, 50.7, 42.3, 41.2, 36.7, 36.1,
35.8, 33.4, 32.1, 31.9, 26.4, 26.3, 26.3, 22.0, 21.9, 18.5, 18.5, -4.8, -
4.8; HRMS-AP [M þ H]þ calcd for C15H25ClN3OSi 326.1455, found
326.1459.
6-Hydroxyimino-2-(4-methoxybenzoyl)bicyclo[2.2.1]he-
ptane-2-carboxylic acid ethyl ester (25): 66% (16.2 mg, pre-
pared from 39 mg (0.081 mmol) of 18c); 1H NMR (300 MHz, CDCl3,
inseparable ∼2.2:1 mixture of isomers) δ 7.96-7.92 (m, 2H, major),
7.88-7.84 (m, 2H, minor), 7.04 (br s, 1H, minor), 6.91 (d, J = 6.6 Hz,
2H, major and minor), 6.71 (br s, 1H, major), 4.12-4.04 (m, 2H, major
and minor), 3.87 (s, 3H, major and minor), 3.70 (s, 1H, major), 3.66 (s,
1H, minor), 2.88 (dd, J = 2.1, 9.8 Hz, 1H, major), 2.71 (dd, J = 1.8,
9.7 Hz, 1H, minor), 2.59 (s, 1H, major and minor), 2.43-2.30
(m, 1H, major and minor), 2.19-2.11 (m, 1H, major and minor),
1.92-1.86 (m, 1H, major and minor), 1.75-1.64 (m, 2H, major and
minor), 1.07-1.01 (m, 3H, major and minor); 13C NMR (75 MHz,
CDCl3) δ 193.4, 192.5, 173.6, 172.3, 163.8, 163.8, 163.7, 162.8, 131.6,
131.3, 129.2, 127.4, 114.2, 64.1, 63.5, 62.4, 61.9, 55.8, 55.8, 50.5, 50.1,
40.5, 40.2, 38.7, 37.8, 36.1, 34.9, 34.0, 33.3, 14.2, 14.1; HRMS-ES [M þ
H]þ calcd for C18H22NO5 332.1498, found 332.1512.
Typical Intramolecular Nitrosoalkene Cyclization: 6-Hydr-
oxyiminobicyclo[2.2.1]heptane-2,2-dicarbonitrile (13). To a
stirred solution of O-silyloxime 11 (16.3 mg, 0.05 mmol) in THF (3 mL)
at -78 °C was added dropwise KHMDS (0.5 M in toluene, 0.12 mL,
0.06 mmol) via syringe, and the reaction mixture was stirred at -78 °C
for 1 h. TBAF (1 M in THF, 0.05 mL, 0.05 mmol) was added dropwise
via syringe, and the mixture was warmed to rt over 3 h. Saturated
aqueous NH4Cl was then added. The mixture was extracted with ether,
and the combined extracts were dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by flash
chromatography (75% ether/pentane) to afford the bridged bicyclic
oxime 13 as a single geometric isomer (7.1 mg, 82%): 1H NMR (300 MHz,
CDCl3) δ 7.94 (br s, 1H), 3.37 (d, J = 1.2 Hz, 1H), 2.70-2.66 (m, 1H),
2.47-2.31 (m, 2H), 2.14 (dd, J = 3.3, 17.9 Hz, 1H), 2.02 (dd, J = 2.5,
13.4 Hz, 1H), 1.90-1.84 (m, 1H), 1.79-1.67 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 156.7, 114.5, 113.5, 50.9, 42.2, 36.9, 34.4, 32.8,
32.5; HRMS-EI [M]þ calcd for C9H9N3O 175.0746, found 175.0759.
6,6-Dibenzoylbicyclo[2.2.1]heptan-2-one oxime (19): 78%
(8 mg, prepared from 15 mg (0.031 mmol) of 18a); 1H NMR (300 MHz,
CDCl3) δ 7.80-7.76 (m, 2H), 7.71-7.68 (m, 2H), 7.35-7.28 (m, 2H),
7.23-7.17 (m, 4H), 6.60 (br s, 1H), 3.89 (d, J = 0.9 Hz, 1H), 3.08 (dd, J =
2.6, 12.8 Hz, 1H), 2.53 (s, 1H), 2.33-2.16 (m, 2H), 1.93-1.85 (m, 2H),
1.64-1.60 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 197.9, 197.2, 163.4,
137.2, 135.3, 133.7, 133.5, 129.7, 129.5, 129.0, 128.9, 70.1, 51.2, 40.5, 38.6,
35.8, 33.6; HRMS-ES [M þ H]þ calcd for C21H20NO3 334.1443, found
334.1447.
2-(Diethoxyphosphoryl)-6-hydroxyiminobicyclo[2.2.1]-
heptane-2-carboxylic acid ethyl ester (26): 75% (5.4 mg,
prepared from 10.5 mg (0.022 mmol) of 18f); 1H NMR (300 MHz,
CDCl3, inseparable ∼1:1 mixture of isomers) δ 7.83 (br s, 1H),
4.26-4.00 (m, 6H), 3.40-3.34 (m, 1H), 2.60 (s, 1H), 2.46-1.95
(m, 6H), 1.39-1.23 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 169.9,
169.9, 163.1, 162.9, 63.1, 63.0, 63.0, 62.9, 61.8, 55.3, 53.5, 48.8, 38.4,
35.5, 35.4, 33.7, 33.6, 33.5, 16.4, 16.4, 16.3, 16.3, 13.9; HRMS-ES
[M þ H]þ calcd for C14H25NO6P 334.1420, found 334.1426.
2-Benzenesulfonyl-6-hydroxyiminobicyclo[2.2.1]hept-
ane-2-carbonitrile (27). 85% (7 mg, prepared from 12.5 mg
1
(0.028 mmol) of 18g); H NMR (300 MHz, CDCl3, inseparable
∼10:1 mixture of isomers) δ 7.98 (d, J = 7.5 Hz, 2H, minor), 7.89
(d, J = 7.5 Hz, 2H, major), 7.62 (t, J = 7.3 Hz, 1H, major and minor),
7.49 (t, J = 7.7 Hz, 2H, major and minor), 7.33 (br s, 1H, minor), 7.22
(br s, 1H, major), 3.21 (s, 1H, major), 2.99 (s, 1H, minor), 2.67-2.60
(m, 2H, major and minor), 2.40-2.26 (m, 2H, major and minor), 2.06
(dd, J = 3.5, 18.1 Hz, 1H, major and minor), 1.90 (dd, J = 2.6, 13.1 Hz,
1H, major and minor), 1.51 (d, J = 10.4 Hz, 1H, major and minor); 13C
NMR (75 MHz, CDCl3) δ 160.3, 159.8, 135.8, 135.6, 135.0, 130.9,
129.9, 129.7, 118.5, 117.7, 67.1, 65.7, 50.1, 40.6, 39.3, 37.6, 37.2,
36.0, 35.6, 33.6, 33.5; HRMS-ES [M þ H]þ calcd for C14H15N2O3S,
291.0803; found, 291.0800.
2-Benzenesulfonyl-6-(p-toluenesulfonyloxyimino)bicy-
clo[2.2.1]heptane-2-carboxylic Acid Methyl Ester (22b).
To a stirred mixture of p-toluenesulfonyl chloride (23.4 mg, 0.123
mmol), triethylamine (0.017 mL, 0.123 mmol), and a catalytic
amount of 4-dimethylaminopyridine in dichloromethane (1 mL)
was added a solution of oxime 22a (15.7 mg, 0.049 mmol) in
dichloromethane (2 mL) at rt. The resulting mixture was stirred for
2 h at rt. Dichloromethane was then added, and the organic layer was
washed with water and brine. The organic layer was dried over
MgSO,4 and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (30% ethyl acetate/
hexanes) to afford the bicyclic O-tosyl oxime 22b as a white solid
(19.0 mg, 82%). A sample of 22b was recrystallized for X-ray analysis
from CH2Cl2/EtOAc: mp 121-125 °C; 1H NMR (300 MHz,
CDCl3) δ 7.77-7.69 (m, 4H), 7.65-7.59 (m, 1H), 7.48 (t, J = 7.6
Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 3.46 (s, 1H), 3.14 (s, 3H), 2.78-
2.69 (m, 2H), 2.54-2.49 (m, 1H), 2.42-2.30 (m, 5H), 2.15 (dd, J =
3.8, 18.4 Hz, 1H), 1.50 (d, J = 9.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 170.7, 167.0, 145.4, 137.4, 134.9, 133.0, 130.1, 130.0,
129.4, 129.2, 78.5, 53.1, 50.8, 38.3, 35.9, 35.8, 33.9, 22.0; HRMS-ES
[M þ H]þ calcd for C22H24NO7S2 478.0994, found 478.0989.
Methyl 3-(4-Methoxycyclohex-3-enyl)-2-(phenylsulfonyl)-
propanoate (30). To a solution of alcohol 28 (230 mg, 1.62 mmol) in
pyridine (10 mL) was added tosyl chloride (617 mg, 3.24 mmol). The
mixture was stirred at rt for 18 h and washed with saturated NaHCO3. The
6,6-Bis-benzenesulfonylbicyclo[2.2.1]heptan-2-one oxime
(20): 61% (5.7 mg, prepared from 13 mg (0.023 mmol) of 18b); H
1
NMR (300 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.64-7.61
(m, 2H), 7.56-7.49 (m, 2H), 7.44-7.34 (m, 4H), 6.98 (br s, 1H),
3.25 (s, 1H), 2.66-2.60 (m, 2H), 2.45-2.34 (m, 3H), 2.24 (dd, J = 3.5,
17.3 Hz, 1H), 1.47-1.34 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 162.3, 139.6, 137.1, 135.0, 134.6, 131.0, 131.0, 129.3, 129.0, 95.5,
50.8, 40.8, 35.9, 35.1, 33.5; HRMS-ES [M þ H]þ calcd for
C19H20NO5S2 406.0783, found 406.0774.
2-Benzenesulfonyl-6-hydroxyiminobicyclo[2.2.1]heptane2-
carboxylic acid methyl ester (22a): 96% (17 mg, prepared from 26
mg (0.055 mmol) of 18d); 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J =
7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 3.41 (s, 3H),
3.26 (s, 1H), 2.76-2.65 (m, 2H), 2.46-2.41 (m, 1H), 2.33-2.15 (m, 2H),
1.98 (dd, J = 3.4, 17.8 Hz, 1H), 1.44 (d, J = 10.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 167.7, 161.9, 137.7, 134.7, 130.1, 129.3, 79.2, 53.3,
50.4, 38.2, 36.0, 34.0, 34.0; HRMS-ES [M þ H]þ calcd for C15H18NO5S
324.0906, found 324.0901.
6-Hydroxyimino-2-nitrobicyclo[2.2.1]heptane-2-carboxylic
Acid Ethyl Ester (24). In this case, the reaction mixture was warmed
to 0 °C after the TBAF addition: 70% (6.4 mg, prepared from 15 mg
(0.038 mmol) of 18e); 1H NMR (300 MHz, CDCl3) δ 7.22
(br s, 1H), 4.38-4.22 (m, 2H), 3.74 (d, J = 1.0 Hz, 1H), 2.80-2.71
(m, 2H), 2.55-2.47 (m, 1H), 2.37 (dd, J = 3.3, 17.8 Hz, 1H), 2.27-2.17
(m, 1H), 2.00-1.95 (m, 1H), 1.86-1.81 (m, 1H), 1.31 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 166.2, 159.8, 97.3, 63.1, 51.4, 40.0,
38.3, 34.8, 33.2, 13.8; HRMS-ES [M þ H]þ calcd for C10H15N2O5
243.0981, found 243.0979.
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organic layer was removed, and the aqueous layer was extracted with EtOAc.
The combined organic extracts were dried over Na2SO4, and the solvent was
removed under reduced pressure to give the tosylate 29 as a yellow oil.
The compound was used for the next step without purification: 1H NMR
(300 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H),
4.434 (br s, 1H), 3.84 (d, J = 6.8 Hz, 2H), 3.40 (s, 3H), 2.34 (s, 3H), 2.11-
1.66 (m, 7H).
stirred for 1 h at -78 °C, TBAF (1 M in THF, 0.13 mL, 0.12 mmol) was
added, and the reaction mixture was stirred at 0 °C for 3 h. Saturated
NH4Cl was added, and the mixture was extracted with EtOAc. The
combined organic layers were dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel (2:1 EtOAc/hexanes) to afford the
title compound 33a as a white solid (23 mg, 83%): 1H NMR
(300 MHz, CDCl3) δ 7.71-7.67 (m, 2H), 7.56-7.50 (m, 1H),
7.43-7.38 (m, 2H), 3.40 (s, 3H), 3.38-3.29 (m, 1H), 2.97-2.87 (m,
Methyl phenylsulfonylacetate (0.29 mL, 1.62 mmol) was added to a
stirred solution of sodium hydride (77 mg, 1.94 mmol, 60% dispersion in
mineral oil) in DMF (8 mL) at 0 °C. The reaction mixture was warmed
to rt and stirred for 1 h. A solution of crude tosylate 29 in DMF (2 mL)
and NaI (98 mg, 0.65 mmol) was added at rt. The resulting mixture was
heated at 65 °C for 18 h and then cooled to rt. The mixture was washed
with brine, the organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were dried over
Na2SO4. The solvent was removed under reduced pressure to give a
residue purified by flash column chromatography on silica gel (1:3:0.01
EtOAc/hexanes/triethylamine) to afford the title compound 30 as a
clear oil containing a mixture of diastereomers in an 1:1 ratio (290 mg,
53% for two steps): 1H NMR (300 MHz, CDCl3) δ 7.89-7.81
(m, 2H), 7.68-7.62 (m, 1H), 7.60-7.51 (m, 2H), 4.47 (br s, 1H),
4.08-3.98 (m, 1H), 3.61-3.61 (m, 3H), 3.46-3.42 (m, 3H), 2.12-
1.95 (m, 6H), 1.94-1.66 (m, 4H), 1.661.21 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.9, 165.9, 154.4, 154.2, 136.3. 136.2, 133.6,
128.6, 128.4, 90.9, 90.5, 68.6, 68.4. 53.3, 52.3, 52.3, 32.0, 31.2, 30.8, 30.2,
29.3, 28.6, 28.2, 27.0, 26.4, 26.2; HRMS-ES [M þ H]þ calcd for
C17H23O5S 339.1266, found 339.1259.
2H), 2.58-2.39 (m, 3H), 1.63-1.42 (m, 4H), 1.21-1.04 (m, 1H); 13
C
NMR (75 MHz, CDCl3) δ168.0, 158.8, 137.0, 134.7, 130.4, 129.3, 83.0,
53.3, 49.6, 37.5, 35.0, 33.4, 30.5, 18.5; HRMS-ES [M þ H]þ calcd for
C16H20NO5S 338.1062, found 338.1061.
Synthesis of Oxime Tosylate 33b. To a stirred mixture of
triethylamine (0.02 mL, 0.11 mmol), tosyl chloride (20 mg, 0.11 mmol),
and a catalytic amount of 4-dimethylaminopyridine in CH2Cl2 (1 mL)
was added a solution of oxime 33a (12 mg, 0.036 mmol) in CH2Cl2
(2 mL) at rt. The resulting mixture was stirred at rt for 2 h and washed
with saturated NaHCO3. The organic layer was removed, and the
aqueous layer was extracted with EtOAc. The combined organic extracts
were dried over Na2SO4, and the solvent was removed under reduced
pressure to give a residue purified by flash column chromatography on
silica gel (1:2 EtOAc/hexanes) to afford compound 33b as a white solid
(11 mg, 63%). A sample was crystallized from MeOH/CH2Cl2 for X-ray
analysis: mp 120-124 °C; 1H NMR (300 MHz, CDCl3) δ 7.77-7.71
(m, 4H), 7.71-7.65 (m, 1H), 7.60-7.47 (m, 2H), 7.28-2.25 (m, 2H),
3.61 (d, J = 4.8 Hz, 1H), 3.19 (s, 3H), 3.06-2.92 (m, 2H), 2.70-2.58
(m, 2H), 2.42 (s, 3H), 1.76-1.51 (m, 4H), 1.55-1.15 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 166.3, 166.2, 143.8, 135.5, 133.4, 131.6,
128.8, 128.4, 128.0, 81.1, 51.8, 47.2, 36.3, 33.0, 32.6, 29.2, 20.66, 19.3;
HRMS-ES [M þ H]þ calcd for C23H26NO7S2 492.1151, found
492.1134.
4-Methoxycyclohex-3-ene Carbonitrile (34) and 3-Meth-
oxycyclohex-3-ene Carbonitrile.15. To a pressure flask containing
2-methoxy-1,3-butadiene12 (3.21 g, 38.2 mmol) in toluene (12 mL) was
added acrylonitrile (2.75 mL, 42.0 mmol). The flask was sealed tightly,
and the mixture was stirred for 16 h at 145 °C. The solvent was removed
under reduced pressure, and the residue was purified by flash column
chromatography on silica gel (1:1 EtOAc/hexanes) to afford the adducts
as a clear oil containing a mixture of regioisomers in an 8:1 ratio (2.93 g,
56%): 1H NMR (300 MHz, CDCl3) δ 4.60 (t, J = 3.9 Hz, 0.11H), 4.49
(t, J = 12.9 Hz, 0.88H), 3.44 (s, 3H), 2.72-2.69 (m, 0.88H), 2.38-2.35
(m, 0.11H), 2.35-2.18 (m, 2H), 2.18-2.11 (m, 1H), 2.11-1.96 (m,
1H), 1.96-1.74 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.1, 152.0,
122.7, 93.2, 90.2, 54.5, 30.9, 27.3, 26.0, 25.9, 25.7, 25.3, 21.6; HRMS-EI
[M þ H]þ calcd for C8H12NO 138.0919, found 138.0921.
Methyl 3-(3-Chloro-4-oxocyclohexyl)-2-(phenylsulfonyl)-
propanoate (31). To a solution of enol ether 30 (110 mg,
0.33 mmol) in THF/H2O (4:3, 3 mL) were added NaOAc (29 mg,
0.36 mmol) and N-chlorosuccinimide (48 mg, 0.36 mmol). The reaction
mixture was stirred at 0 °C for 5 h and then extracted with EtOAc. The
combined organic extracts were dried over Na2SO4. The solvent was
removed under reduced pressure to give a residue purified by flash
column chromatography on silica gel (1:3 EtOAc/hexanes) to afford the
1
title compound 31 as a clear oil (74 mg, 64%): H NMR (300 MHz,
CDCl3) (complex diastereomer mixture) δ 7.89-7.82 (m. 2H), 7.71-
7.66 (m, 1H), 7.58-7.54 (m, 2H), 4.16 (br s, 1H), 3.98 (dd, J = 11.0, 4.2
Hz, 1H), 3.65-5.60 (m, 3H), 3.13-2.84 (m, 1H), 2.29-2.12 (m, 3H),
2.07-1.97 (m, 3H), 1.89-1.75 (m, 1H), 1.48-1.30 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 207.4, 204.0, 203.9, 166.7, 166.6, 137.2, 137.1,
135.0, 129.7, 129.7, 129.6, 69.3, 69.2, 59.6, 59.3, 53.9, 53.7, 53.6, 41.3,
40.1, 35.7, 35.5, 32.9, 31.8, 31.7, 31.7, 31.3, 29.2, 29.1.
O-Silyloximes 32. To a solution of R-chloroketones 31 (19 mg,
0.05 mmol) in CH2Cl2 (5 mL) were added O-(tert-butyldimethylsi-
lyl)hydroxylamine (16 mg, 0.11 mmol), 4 Å molecular sieves (crushed),
and a catalytic amount of PPTS. The mixture was stirred at rt for 84 h
and then filtered through a pad of Celite which was washed with EtOAc.
The filtrate was evaporated under reduced pressure to give a residue
purified by flash column chromatography on silica gel (1:3 EtOAc/
hexanes) to afford compound 32 as a clear oil containing a complex
mixture of diastereomers including oxime geometric isomers (17 mg,
66%): 1H NMR (300 MHz, CDCl3) δ 7.89-7.82 (m, 2H), 7.73-7.64
(m, 1H), 7.62-7.52 (m, 2H), 5.60-4.70 (m, 1H), 4.07-3.97 (m, 1H),
3.63-3.60 (m, 3H), 3.28-1.83 (m, 7H), 1.84-1.03 (m, 2H), 0.92-
0.87 (m, 9H), 0.13-0.03 (m, 6H); 13C NMR (75 MHz, CDCl3) δ166.9,
166.8, 161.0, 159.7, 137.2, 134.8, 129.8, 129.7, 129.5, 69.3, 69.1, 59.0,
58.9, 53.6, 53.5, 47.0, 46.8, 41.9, 40.7, 32.7, 32.7, 32.6, 31.8, 30.8, 30.0,
29.7, 27.1, 26.4, 20.0, 19.8, 18.6, -4.9; HRMS-ES [M þ H]þ calcd for
C22H35ClNO5SSi 488.1694, found 488.1691.
N-(4-Methoxycyclohex-3-enylmethyl)-4-methylbenzene-
sulfonamide (36). To a stirred suspension of LiAlH4 (276 mg, 7.29
mmol) in THF (10 mL) at 0 °C was added the mixture of the above
nitriles (500 mg, 3.64 mmol) in THF (2 mL) dropwise, and the mixture
was stirred at rt for 2 h. The reaction was quenched by slow addition of a
5:1 mixture of THF/H2O at 0 °C, followed by addition of 1 M NaOH
with stirring. The solids were filtered off and washed with EtOAc. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organics were dried over Na2SO4, and the
solvent was removed under reduced pressure to afford a yellow oil.
The mixture of amines was used for the next step without purification.
1
Data for major regioisomer 35: H NMR (300 MHz, CDCl3) δ 4.51
(br s, 1H), 3.44 (s, 3H), 2.56 (d, J = 6.5 Hz, 2H), 2.15-1.92 (m, 5H),
1.76-1.64 (m, 2H), 1.64-1.36 (m, 1H), 1.36-1.06 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 155.7, 92.3, 54.4, 47.8, 37.6, 28.1, 27.7, 26.9;
HRMS-EI [M þ H]þ calcd for C8H16NO 142.1232, found 142.1240.
To a solution of the above crude amines (513 mg, 3.64 mmol) in
CH2Cl2 (12 mL) were added triethylamine (0.5 mL, 3.59 mmol), tosyl
Methyl 4-(Hydroxyimino)-6-(phenylsulfonyl)bicyclo[3.2.1]-
octane-6-carboxylate (33a). To a stirred solution of oxime 32
(40 mg, 0.08 mmol) in THF (2 mL) at -78 °C was added KHMDS
(0.5 M in toluene, 0.24 mL, 0.12 mmol) dropwise. After the mixture was
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The Journal of Organic Chemistry
ARTICLE
chloride (2 g, 10.5 mmol), and a catalytic amount of 4-(dimethy-
lamino)pyridine. The mixture was stirred at rt for 18 h and washed
with saturated NaHCO3. The organic layer was removed, and the
aqueous layer was extracted with EtOAc. The combined organic extracts
were dried over Na2SO4, and the solvent was removed under reduced
pressure to give a residue which was purified by flash column chroma-
tography on silica gel (1:4 EtOAc/hexanes) to afford the title compound
36 as a white solid (617 mg, 57% for two steps): 1H NMR (300 MHz,
CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H) 7.23 (d, J = 8.0 Hz, 2H), 4.90 (t, J =
10.7 Hz, 1H), 4.42 (br s, 1H), 3.40 (s, 3H), 2.77 (t, J = 6.0 Hz, 2H), 2.35
(s, 3H), 2.07-1.90 (m, 3H), 1.73-1.55 (m, 3 H), 1.25-1.16 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 155.4, 143.8, 137.4, 130.1, 127.5, 112.1,
109.6, 91.8, 54.4, 48.5, 34.4, 27.8, 27.2, 26.6, 22.0; HRMS-EI [M þ H]þ
calcd for C15H22NO3S 296.1320, found 296.1316.
N-(3-Chloro-4-oxocyclohexylmethyl)-4-methylbenzene-
sulfonamide (37). To a solution of sulfonamide enol ether 36
(950 mg, 3.22 mmol) in THF/H2O (4:3, 35 mL) were added NaOAc
(26 mg, 0.32 mmol) and N-chlorosuccinimide (475 mg, 3.54 mmol).
The reaction mixture was stirred at rt for 1 h and then extracted with
EtOAc. The combined organic extracts were dried over Na2SO4. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (1:2 EtOAc/
hexanes) to afford the R-chloroketone 37 as a mixture of two dia-
stereomers (935 mg, 92%). A sample of the isomers was separated
by chromatography for characterization purposes. Less polar major
diastereomer of 37: 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J =
8.3 Hz, 2H) 7.25 (d, J = 7.9 Hz, 2H), 5.35 (t, J = 6.6 Hz, 1H), 4.14-
4.11 (m, 1H), 2.86-2.76 (m, 3H), 2.36 (s, 3H), 2.25-2.16 (m, 3H),
1.98-1.93 (m, 1H), 1.82-1.74 (m, 1H), 1.35 -1.13 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 204.6, 144.2, 137.1, 130.3, 127.4, 59.7, 47.5,
38.6, 35.5, 31.5, 30.1, 22.0. More polar minor diastereomer of 37: 1H
NMR (300 MHz, CDCl3) δ 7.68 (d, J = 10 Hz, 2H) 7.26 (d, J = 8.2 Hz,
2H), 5.38 (t, J = 6.6 Hz, 1H), 4.44-4.39 (m, 1H), 2.82-2.77 (m, 2H),
2.51-2.48 (m, 1H), 2.36 (s, 3H), 2.33-2.00 (m, 3H), 2.02-1.98
(m, 1H), 1.60-1.48 (m, 1H), 1.36-1.28 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 202.3, 144.3, 137.0, 130.3, 127.4, 63.2, 47.6,
42.1, 39.9, 37.8, 30.7, 22.0.
X-ray analysis. Data for mixture: 1H NMR (300 MHz, CDCl3)
δ 7.69-7.57 (m, 2H), 7.19 (d, J = 8 Hz, 2H), 5.38 (d, J = 5.8 Hz,
0.17H), 4.42 (d, J = 5.6 Hz, 0.83H), 3.41-3.33 (m, 1H), 3.22 (d, J =
9.5 Hz, 0.17H), 3.06 (d, J = 13.2 Hz, 0.83H), 2.82 (dd, J = 16.5,
6.6 Hz, 1H), 2.45 (br s, 1H), 2.3 (s, 3H), 1.73-1.40 (m, 4H), 1.47-
1.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ157.1, 142.7, 142.6,
134.8, 134.8, 128.9, 128.8, 128.6,126.9, 126.4, 126.2, 59.6, 51.9,
50.8, 50.4, 49.3, 48.5, 36.7, 36.3, 34.2, 33.4, 29.7, 27.8, 25.6, 24.3,
20.7, 17.0; HRMS-EI [M þ H]þ calcd for C14H19N2O3S 295.1116,
found 295.1107.
6-(Toluene-4-sulfonyl)-6-azabicyclo[3.2.1]octan-4-one
(40). To a stirred solution of oximes 39 (40 mg, 0.14 mmol) in 2:1
acetonitrile/H2O (4 mL) was added KMnO4 (43 mg, 0.272 mmol). The
mixture was refluxed for 2.5 h and then cooled to rt. The mixture was
extracted with CH2Cl2, and the aqueous layer was washed with CH2Cl2.
The combined organic extracts were dried over Na2SO4, and the solvent
was removed under reduced pressure to give a residue which was
purified by flash column chromatography on silica gel (1:1 EtOAc/
hexanes) to afford the ketone 40 as a white solid (29 mg, 76%): 1H NMR
(300 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H),
4.07 (d, J = 6.0 Hz, 1H), 3.51-3.46 (m, 1H) 3.39 (d, J = 9.7 Hz, 1H),
2.54 (m, 1H), 2.36 (s, 3H), 2.30-2.21 (m, 1H), 2.13-2.05 (m, 1H),
1.91-1.79 (m, 2H), 1.72-1.51 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 207.3, 144.2, 136.0, 130.3, 127.4, 66.2, 52.3, 37.9, 34.8, 34.7, 30.7, 22.0;
HRMS-EI [M þ H]þ calcd for C14H18NO3S 280.1007, found 280.0984.
’ ASSOCIATED CONTENT
S
Supporting Information. Proton and carbon NMR spec-
b
tra of new compounds and experimental procedures for some
sequences. X-ray data for compounds 22b, 33b, and (E)-39
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
O-Silylketoximes 38. To a solution of R-chloroketones 37
(128 mg, 0.41 mmol) in CH2Cl2 (5 mL) were added O-(tert-butyldi-
methylsilyl)hydroxylamine (66 mg, 0.45 mmol), 4 Å molecular sieves
(crushed), and a catalytic amount of PPTS. The mixture was stirred at rt
for 48 h and then filtered through a pad of Celite which was washed with
EtOAc. The filtrate was evaporated under reduced pressure to give a
residue which was purified by flash column chromatography on silica gel
(1:3 EtOAc/hexanes) to afford compound 38 as a clear oil which was an
inseparable complex mixture of diastereomers and silyloxime geometric
isomers (121 mg, 67%): 1H NMR (300 MHz, CDCl3) δ 7.60
(d, J = 8.3 Hz, 2H) 7.16 (d, J = 8 Hz, 2H), 5.55-4.48 (m, 2H),
4.00-3.11, (m, 1H), 2.66-2.29 (m, 2H), 2.21 (s, 3H), 2.08-1.94 (m,
3H), 1.89-1.08 (m, 2H), 0.91-0.78 (m, 1H), 0.78-0.69 (m, 9H),
0.04-0.00 (m, 6H); HRMS-EI [M þ H]þ calcd for C20H34N2O3SSiCl
445.1748, found 445.1751.
6-(Toluene-4-sulfonyl)-6-azabicyclo[3.2.1]octan-4-one
Oxime (39). To a solution of O-silyloxime 38 (190 mg, 0.43 mmol)
in acetonitrile (5 mL) was added TBAF (1 M in THF, 1.07 mL, 1.07
mmol) dropwise at 0 °C, and the mixture was stirred at that
temperature for 1 h. Saturated NH4Cl was added, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over Na2SO4, and the solvent was removed under reduced
pressure to give a residue which was purified by flash column
chromatography on silica gel (1:1 EtOAc/hexanes) to afford the
title compound 39 as a white solid (106 mg, 84%) containing a mix-
ture of E/Z oxime isomers in a 5:1 ratio. The solid was recrystallized
from chloroform to afford colorless crystals of the (E)-isomer suitable for
Corresponding Author
*E-mail: smw@chem.psu.edu.
Notes
†Author for inquiries concerning X-ray data.
’ ACKNOWLEDGMENT
We are grateful to the National Institutes of Health (GM-
087733) and the National Science Foundation (CHE-0806807)
for financial support of this research.
’ REFERENCES
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