Stereochemical investigation of conjugate additions of carbon- and heteronucleophiles to ring-substituted nitrosocyclohexenes

Article abstract of DOI:10.1016/j.tet.2011.08.054

Intermolecular Michael-type conjugate additions of some in situ-generated ring-substituted nitrosocyclohexenes with both carbon- and heteronucleophiles have been found to be highly stereoselective, leading predominantly (or exclusively) to products result

Full text of DOI:10.1016/j.tet.2011.08.054

Tetrahedron 67 (2011) 8229e8234
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereochemical investigation of conjugate additions of carbon- and
heteronucleophiles to ring-substituted nitrosocyclohexenes
*
Ritobroto Sengupta, Jason A. Witek, Steven M. Weinreb
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2011
Received in revised form 19 August 2011
Accepted 22 August 2011
Available online 28 August 2011
Intermolecular Michael-type conjugate additions of some in situ-generated ring-substituted nitro-
socyclohexenes with both carbon- and heteronucleophiles have been found to be highly stereoselective,
leading predominantly (or exclusively) to products resulting from axial attack on a half-chair confor-
mation of the nitrosoalkene substrate.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselectivity
Michael-type additions
Enolonium ion equivalents
Organocuprate additions
1. Introduction and background
treatment of the a-chlorooxime 1, formed from a ring-substituted
a
-chlorocyclohexanone, with 2.3 equiv of the potassium salt of
We have recently been involved in exploring synthetic meth-
odology based on inter-1 and intramolecular2 conjugate additions
of nucleophiles to highly reactive, transient nitrosoalkenes.3 In
particular, we have been interested in using this type of trans-
formation to evaluate the synthetic potential of nitrosoalkenes as
enolonium ion equivalents.4 At the outset of these investigations it
became evident to us that there are a number of fundamental
stereochemical issues relevant to this type of conjugate addition
that have never been addressed. For example, in a recent publica-
tion we described stereochemical studies on nucleophilic additions
the nucleophile in THF at ꢀ78 ꢁC (Method A) and (2) the Denmark
procedure6 involving treatment of an
a-chloro-O-silyloxime 2 with
tetrabutylammonium fluoride in THF in the presence of 1.2 equiv of
the potassium salt of the nucleophile (Method B).
to acyclic nitrosoalkenes bearing a g-stereogenic center, a process
found to be highly diastereoselective, leading exclusively to the anti
adducts.5 We now report some new stereochemical investigations
of conjugate additions of various carbon- and heteronucleophiles to
cyclic systems.
2. Results and discussion
Scheme 1. Addition of nucleophiles to substituted nitrosocyclohexenes.
Our current studies focussed on probing the stereochemical
outcome of nucleophilic additions to substituted nitro-
socyclohexenes 3 to form a-substituted oxime products 4 (Scheme
1). For comparison purposes in the exploratory stages of this in-
vestigation, the requisite nitrosoalkenes 3 were generated and
reacted with the nucleophile via two different procedures: (1)
Initial experiments involved examining the addition of various
malonate ester enolates to in situ-produced 4-tert-butylni-
trosocyclohexene. Thus, the known6a,7 racemic cis-
a-chloro-4-tert-
butylcyclohexanone oxime 5a and the corresponding trans-isomer
5b were combined with the potassium enolate of diethyl malonate
(6a) under the conditions of Method A (see Experimental section
for details) to afford exclusively trans-adduct 8a (R0¼H) in good
* Corresponding author. E-mail address: smw@chem.psu.edu (S.M. Weinreb).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.054

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R. Sengupta et al. / Tetrahedron 67 (2011) 8229e8234
yields (Table 1, >20:1 8/9 estimated by 1H NMR). In both experi-
ments only one oxime geometric isomer of 8a was produced. Al-
though we cannot definitively assign geometry in this case, the fact
that we have generally observed formation of the (E)-oximes as the
exclusive (or predominant) product in other examples (vide infra)
has led us to tentatively propose this geometry for adduct 8a. The
configuration and chair conformation of 8a, as shown in Scheme 2,
surprising since Allinger has reported that trans-1,3-di-tert-butyl-
cyclohexane exists in this conformation.10
Addition of the potassium enolate of a-ethyl diethyl malonate
(6c) to the nitrosocycloalkene derived from the three oxime de-
rivatives 5aec as was done with malonates 6a and 6b also afforded
a single trans-adduct 8c with the (E)-oxime configuration. As was
the case with 8b, NMR analysis indicated that this system exists in
a twist boat conformation (Scheme 2).
were established by NMR analysis.8 Exposure of cis-
a-chloro-O-
silyloxime 5c6a to the Denmark conditions in the presence of
diethyl malonate potassium enolate (Method B) also afforded
a comparable yield of the same trans-adduct 8a as the sole product.
It seems reasonable that adduct 8a is formed in all three cases via
preferred axial attack9 on the half-chair conformation of 4-tert-
butylnitrosocyclohexene (7). These experiments also indicated that
the stereoselectivity and yield of the addition products are in-
dependent of the precursor and method of generation of the
nitrosoalkene.6a
Finally, addition of a-allyl diethyl malonate (6d) to a-chloroox-
imes 5a via Method A and 5c via Method B led to an inseparable
9.1:1 mixture of (E)-trans-adduct 8d and (E)-cis-compound 9d. It
was possible in this case to crystallize the major (E)-trans isomer 8d
from the mixture, and X-ray analysis of this compound showed it
indeed to exist in a twist boat conformation and confirmed the (E)-
oxime geometry.11
It is also possible to add heteronucleophiles to vinylnitroso
compound 7 with a high degree of stereoselectivity. Therefore,
N-methyl-p-toluenesulfonamide undergoes smooth axial addition
to the nitrosoalkene formed from
a-chloro-O-TBS-oxime 5c
under the conditions of Method B to afford exclusively the trans-
(E)-oxime product 10 (Scheme 3). The structure and stereochem-
istry of this adduct were firmly established by X-ray analysis.
Scheme 2. Configurations and conformations of malonate adducts of 4-tert-
butylnitrosocyclohexene.
Table 1
Malonate additions to 4-tert-butylnitrosocyclohexene
Scheme 3. Addition of heteronucleophiles to 4-tert-butylnitrosocyclohexene.
Similarly, potassium thiophenoxide undergoes highly axial-
stereoselective addition to the nitrosoalkene derived from
a-
chlorooxime 5a via Method A, as well as using the Denmark pro-
cedure from O-silyloxime 5c (Method B).12 Both procedures led to
a chromatographically separable w19:1 mixture of the (E)-trans-
product 11 and the (E)-cis isomer 12 in high yields. The structure of
the minor product 12 was confirmed by X-ray analysis.
We have also investigated the stereochemistry of the addition
of organocuprates to 4-tert-butylnitrosocyclohexene (7). For ex-
ample, treatment of
thylcopper lithium afforded a chromatographically separable 4:1
mixture of trans -methyl product 13a derived from axial attack
a-chlorooxime 5a with 2 equiv of dime-
a
Further studies were subsequently carried out with
substituted malonate nucleophiles. It was found that repeating the
above experiments with oxime derivatives 5aec using -methyl
a-alkyl-
on nitrosoalkene 7, and the corresponding cis isomer 14a in ex-
cellent total yield (Scheme 4). A small amount (w10%) of the re-
ductive dechlorination product of starting oxime 5a was also
formed in this reaction. In addition, the major isomer 13a was
found to be an inseparable 1:1 mixture of (E/Z)-oxime geometric
isomers,8 whereas the minor product 14a was exclusively (E) as
determined by X-ray analysis. Similar but improved stereo-
selectivity was observed in the conjugate addition reactions with
aryl cuprates. Therefore, the phenyl cuprate addition gave a 12:1
mixture of trans-13b and cis-14b in high overall yield, whereas the
p-tolyl cuprate cleanly afforded a 9:1 mixture of 13c and 14c. It
should also be noted that in the aryl cuprate additions
a
diethyl malonate (6b) in most runs afforded an inseparable 6.2:1
mixture of adducts (E)-trans-8b and (E)-cis-9b in good total yield.
However, in one reaction conducted with oxime 5a, only the trans-
product 8b was formed, thereby providing a pure sample of this
material. Interestingly, the major trans-product 8b apparently ex-
ists in the twist boat conformation shown in Scheme 2 as de-
termined by 2D NMR NOE analysis of the pure isomer. We have
again assumed the oxime geometry to be (E) in this system since
the stereochemistry could not be determined unambiguously by
spectral methods. The fact that 8b is a twist boat is not too

R. Sengupta et al. / Tetrahedron 67 (2011) 8229e8234
8231
generally favored by varying degrees using a wide variety of car-
bon- and heteronucleophiles. It should be noted that due to the
high electrophilicity of nitrosoalkenes, as well as the methods of
generation of these species, we are limited to use of non-
nucleophilic solvents, such as THF.
The studies outlined here further demonstrate the potential for
stereospecific alkylation and arylation of nitrosoalkenes, which can
act as effective enolonium ion equivalents. The product
a-
substituted oximes can be converted back to the parent carbonyl
compounds via a plethora of methods.16 Alternatively, these oximes
could potentially be reduced to the corresponding amines or sub-
jected to Beckmann rearrangements to afford ring-expanded lac-
tams. We are continuing to investigate the potential of
nitrosoalkenes in organic synthesis.
Scheme 4. Addition of cuprates to 4-tert-butylnitrosocyclohexene.
diastereomer and (E/Z)-oxime ratios were observed to be quite
variable from run to run, probably due to equilibration during
workup and/or purification. However, we have been unable to
determine if similar isomerizations occurred in the malonate re-
actions (cf. Table 1).
4. Experimental
Finally, we have briefly investigated the stereochemistry of the
addition of diethyl malonate to some other nitrosocyclohexenes.
4.1. General methods
For example, treatment of
from the corresponding known
a
-chloro-O-TBS-oxime 15b, prepared
-chloroketone 15a (mixture of
All non-aqueous reactions were carried out under an inert
argon atmosphere in flame dried glassware. Liquid reagents
sensitive to air were added via a dry syringe. All solvents and
reagents were obtained from commercial sources and used
without further purification. EM Science silica gel 60
(230e400 mesh) was used for flash column chromatography, and
silica gel 60 PF254 plates were used for analytical and preparative
thin layer chromatography. 1H and 13C NMR experiments were
performed on Bruker CDPX 300, DRX 400 or AV-III-600 MHz
a
isomers),13 with the potassium salt of diethyl malonate, followed by
TBAF led to a single diastereomeric adduct 17 (yield unoptimized)
(Scheme 5). This product, which is a 5:1 (E/Z) mixture of oxime
isomers, has the cis-stereochemistry and conformation as shown
based upon NMR analysis. The adduct 17 probably arises via axial
attack by the malonate enolate on the half-chair vinylnitroso in-
termediate 16.
Scheme 5. Addition of diethyl malonate to ring-substituted nitrosocyclohexenes.
Similarly, addition of malonate anion to the nitrosoalkene de-
rived from known
spectrometers. All high and low resolution mass spectral data
were obtained using a Waters LCT Premier time of flight mass
spectrometer (Waters Corporation, Micromass Ltd., Manchester,
UK). IR spectra were measured on a PerkineElmer 1600 Series
FTIR.
a
-chloro-O-silyloxime 186c led to the trans-
product 20 as an 11:1 (E/Z) oxime mixture. It seems reasonable that
this adduct is formed via axial attack on the preferred (due to A1,2
-
strain)14 quasi-axial-ethyl half-chair nitrosoalkene 19.
3. Conclusion
4.2. Synthesis and characterization
Analogous to the work described here, a number of studies have
appeared probing the stereochemistry of Michael additions to
cyclohexenes bearing electron-withdrawing groups, such as cyano,
phenylazo, acetyl, carboxylate, etc.15 Interestingly, with many of
these Michael acceptors the preference for axial or equatorial attack
varies widely depending on the particular nucleophile, solvent, and
reaction conditions, as well as steric factors. In the case of the
nitrosocyclohexene systems described here, axial attack is
4.2.1. General procedures for intermolecular Michael additions of
nucleophiles to in situ-generated 4-tert-butylnitrosocyclohex-
ene. Method A: Addition of malonate and thiophenoxide nucleophiles
to 4-tert-butylnitrosocyclohexene generated from a-chlorooximes 5a
and 5b. A flame dried 25 mL round-bottomed flask containing
a stirring bar was purged with Ar. The flask was cooled to ꢀ78 ꢁC
and charged with dry THF (3 mL). At this temperature, KHMDS
(0.5 M in PhMe, 0.9 mL, 0.45 mmol) was added, followed by the

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R. Sengupta et al. / Tetrahedron 67 (2011) 8229e8234
nucleophile (0.44 mmol). The mixture was stirred at ꢀ78 ꢁC for
1114, 1026, 955 cmꢀ1; HRMS-ES [MþH]þ calcd for C19H34NO5:
45 min. A solution of the
a
-chlorooxime 5a or 5b (39 mg,
356.2437, found: 356.2444.
0.19 mmol) in THF (1 mL) was added slowly and the mixture was
stirred at ꢀ78 ꢁC for 20 min. The reaction was quenched with
saturated NH4Cl solution and was extracted with Et2O. The com-
bined organics were dried over anhydrous MgSO4. The residue
obtained after solvent removal under reduced pressure was puri-
fied by flash column chromatography on silica gel (gradient elution
using 10e20% ethyl acetate in hexanes).
4.2.1.4. 2-Allyl-2-(5-tert-butyl-2-hydroxyiminocyclohexyl)-ma-
lonic acid diethyl ester (8d). Method A: cis-5a (yield: 89%). Method
B: cis-5c (yield: 72%). Product was isolated as an inseparable 9.1:1
mixture of 8d/9d. X-ray quality crystals of the major trans isomer 8d
were obtained from the mixture by slow evaporation from acetone/
ethyl acetate. 1H NMR (400 MHz, CDCl3, cis isomer 9d)
d 7.44 (br s,
Method B: Addition of malonate, sulfonamide, and thiophenoxide
1H), 5.99e5.89 (m, 1H), 5.05 (br d, J¼8.3 Hz, 1H), 5.03 (br s, 1H),
4.30e4.12 (m, 4H), 3.42 (br d, J¼13.2 Hz, 1H), 2.97 (dd, J¼5.8,
14.0 Hz,1H), 2.91e2.65 (m, 3H), 2.09 (br d, J¼12.4 Hz,1H),1.91 (br d,
J¼10.5 Hz, 1H), 1.65e1.54 (m, 1H), 1.30e1.18 (m, 8H), 0.88 (s, 9H). 1H
nucleophiles to 4-tert-butylnitrosocyclohexene generated from
a-
chloro-O-TBS-oxime 5c. A flame dried 25 mL round-bottomed
flask containing a stirring bar was purged with Ar. The flask was
cooled to ꢀ78 ꢁC and charged with dry THF (2 mL), followed by
KHMDS (0.5 M in PhMe, 0.45 mL, 0.23 mmol). The nucleophile
(0.22 mmol) was added and the mixture was stirred at ꢀ78 ꢁC for
NMR (400 MHz, CDCl3, trans isomer 8d) d 7.52 (br s, 1H), 5.99e5.89
(m, 1H), 5.05 (br d, J¼8.3 Hz, 1H), 5.03 (br s, 1H), 4.30e4.12 (m, 4H),
3.16 (t, J¼7.4 Hz, 1H), 2.91e2.65 (m, 3H), 2.29e2.17 (m, 2H),
1.75e1.57 (m, 2H), 1.30e1.18 (m, 8H), 0.87(s, 9H); 13C NMR
45 min. A solution of the
a-chloro-O-TBS-oxime 5c (57 mg,
0.18 mmol) in THF (1 mL) was added slowly to the reaction
mixture at ꢀ78 ꢁC, followed by the dropwise addition of TBAF
(1.0 M in THF, 0.56 mL, 0.56 mmol) at this temperature. The
temperature of the reaction bath was raised to ꢀ60 ꢁC and
maintained there for 20 min. The reaction was quenched with
saturated NH4Cl solution at ꢀ60 ꢁC, removed from the cold bath,
and allowed to warm to rt. The reaction mixture was extracted
with Et2O and the combined organics were dried over anhydrous
MgSO4. The residue obtained after solvent removal under re-
duced pressure was purified by flash column chromatography on
silica gel (gradient elution using 10e20% ethyl acetate in
hexanes).
(100 MHz, CDCl3, trans isomer 8d) d 171.7, 171.0, 160.3, 134.5, 118.6,
61.6, 61.5, 59.8, 43.7, 42.6, 39.8, 33.3, 27.8, 27.5, 24.6, 23.1, 14.5, 14.4;
IR (thin film, 8d/9d mixture) 3448, 2954, 2873, 1725, 1655, 1249,
1167, 1108, 1020, 930 cmꢀ1; HRMS-ES [MþH]þ (8d/9d mixture)
calcd for C20H34NO5: 368.2437, found: 368.2422.
4.2.1.5. N-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-4,N-dime-
thylbenzenesulfonamide (10). Method B: cis-5c (yield: 83%). X-ray
quality crystals were obtained by slow evaporation from acetone/
ethyl acetate. 1H NMR (300 MHz, CDCl3)
d 8.59 (s, 1H), 7.72 (d,
J¼8.1 Hz, 2H), 7.31 (d, J¼8.1 Hz, 2H), 4.11 (t, J¼6.0 Hz, 1H), 3.05 (dq,
J¼2.2, 15.5 Hz, 1H), 2.75 (s, 3H), 2.42 (s, 3H), 2.34e2.22 (m, 1H),
2.15e2.07 (m, 1H), 1.85 (d, J¼10.7 Hz, 1H), 1.65e1.52 (m, 1H),
1.50e1.40 (m, 1H), 1.35e1.21 (m, 1H), 0.86 (s, 9H); 13C NMR
4.2.1.1. 2-(5-tert-Butyl-2-hydroximinocyclohexyl)-malonic acid
diethyl ester (8a). Method A: cis-5a (yield: 85%), trans-5b (yield:
93%). Method B: cis-5c (yield: 86%). 1H NMR (300 MHz, CDCl3)
(100 MHz, CDCl3)
d 160.9, 143.8, 135.0, 130.0, 128.3, 57.7, 42.4, 33.2,
33.0, 31.1, 27.5, 24.1, 23.7, 22.0; IR (thin film) 3460, 3284, 2954, 2872,
1655, 1337, 961 cmꢀ1; HRMS-ES [MþH]þ calcd for C18H29N2O3S:
353.1899, found: 353.1890.
d
7.95 (br s, 1H), 4.28e4.13 (m, 4H), 3.77 (d, J¼11.5 Hz, 1H), 3.26 (dt,
J¼4.7, 11.5 Hz, 1H), 3.15 (dq, J¼2.1, 15.6 Hz, 1H), 2.07e1.75 (m, 3H),
1.53e1.18 (m, 9H), 0.87 (s, 9H); 13C NMR (75 MHz, CDCl3)
168.4,
d
168.3, 160.2, 62.0, 53.7, 42.6, 40.3, 32.9, 30.0, 27.7, 25.5, 22.5, 14.6,
14.4; IR (thin film) 3460, 3307, 2954, 2872, 1731, 1655, 1249, 1179,
1149, 1102, 1032, 926 cmꢀ1; HRMS-ES [MþH]þ calcd for C17H30NO5:
328.2124, found: 328.2127.
4.2.1.6. trans-4-tert-Butyl-2-phenylsulfanylcyclohexanone oxime
(11). Method A: cis-5a (isolated yield: 87%). Method B: cis-5c
(isolated yield: 89%). 1H NMR (400 MHz, CDCl3)
d 8.05 (br s, 1H),
7.43 (d, J¼7.0 Hz, 2H), 7.31e7.23 (m, 3H), 4.05 (br s, 1H), 3.25 (br d,
J¼14.6 Hz, 1H), 2.32e2.19 (m, 2H), 2.01e1.97 (m, 1H), 1.79 (br t,
J¼12.4 Hz, 1H) 1.70 (dq, J¼4.5, 12.7 Hz, 1H), 1.20 (qd, J¼4.2, 13.0 Hz,
4.2.1.2. 2-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-2-
methylmalonic acid diethyl ester (8b). Method A: cis-5a (yield: 89%),
trans-5b (yield: 85%). Method: B: cis-5c (yield: 81%). Product was
isolated as an inseparable 6.2:1 mixture of trans-8b/cis-9b. 1H NMR
1H), 0.90 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 160.0, 134.8, 133.1,
129.3, 127.8, 50.4, 42.5, 33.9, 32.6, 27.8, 26.9, 20.8; IR (thin film)
3248, 3070, 2954, 2860, 1708, 926 cmꢀ1; HRMS-ES [MþH]þ calcd
for C16H24NOS: 278.1579, found: 278.1571.
(300 MHz, CDCl3, cis isomer 9b) d 7.38 (br s, 1H), 4.25e4.07 (m, 4H),
3.41 (dm, J¼15.6 Hz, 1H), 3.17 (dd, J¼3.3, 12.4 Hz, 1H), 1.93e1.58 (m,
4H), 1.54 (s, 3H), 1.43e1.16 (m, 8H), 0.85 (s, 9H). 1H NMR (300 MHz,
4.2.1.7. cis-4-tert-Butyl-2-phenylsulfanylcyclohexanone
oxime
CDCl3, trans isomer 8b)
d
7.60 (br s, 1H), 4.25e4.07 (m, 4H), 3.33 (t,
(12). Method A: cis-5a (isolated yield: 5%). Method B: cis-5c (iso-
lated yield: 5%). X-ray quality crystals were obtained by slow evap-
oration from dichloromethane/acetone, mp 142e144 ꢁC. 1H NMR
J¼8.2 Hz, 1H), 2.71 (dm, J¼17.4 Hz, 1H), 2.33e2.20 (m, 1H),
1.83e1.57 (m, 3H), 1.52 (s, 3H), 1.43e1.16 (m, 8H), 0.85 (s, 9H); 13C
NMR (100 MHz, CDCl3, trans isomer 8b)
d
172.0, 171.9, 160.2, 61.8,
(600 MHz, CDCl3)
d
7.88 (br s, 1H), 7.39 (d, J¼7.5 Hz, 2H), 7.27 (t,
61.7, 56.2, 43.8, 42.1, 33.5, 27.4, 26.4, 25.1, 22.0, 18.0, 14.4, 14.3; IR
(thin film) 3448, 2954, 2872, 1725, 1655, 1296, 1243, 1179, 1108,
1020, 932 cmꢀ1; HRMS-ES [MþH]þ calcd for C18H32NO5: 342.2280,
found: 342.2281.
J¼7.4 Hz, 2H), 7.27 (t, J¼7.4 Hz,1H), 3.77 (dd, J¼4.4,11.7 Hz,1H), 3.47
(dt, J¼3.9,14.7 Hz,1H), 2.25e2.22 (m,1H),1.93e1.90 (m,1H),1.76 (td,
J¼5.64, 13.3 Hz, 1H), 1.58e1.19 (m, 3H), 0.82 (s, 9H); 13C NMR
(150 MHz, CDCl3)
d 159.0, 134.8, 131.6, 128.8, 126.8, 49.8, 47.6, 36.0,
32.6, 27.4, 26.1, 24.6; IR (thin film) 3260, 2943, 2872, 932 cmꢀ1
;
4.2.1.3. 2-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-2-
ethylmalonic acid diethyl ester (8c). Method A: cis-5a (yield: 76%),
trans-5b (yield: 88%). Method B, cis-5c (yield: 72%). 1H NMR
HRMS-ES [MþH]þ calcd for C16H24NOS: 278.1579, found: 278.1571.
4.2.2. Addition of organocuprates to 4-tert-butylnitrosocyclohexene
(300 MHz, CDCl3)
d
7.44 (br s, 1H), 4.31e4.14 (m, 4H), 3.20 (t,
generated from cis-a-chlorooxime 5a. CuI powder (75 mg,
J¼6.6 Hz, 1H), 2.89 (br d, J¼14.5 Hz, 1H), 2.24e2.06 (m, 3H),
0.40 mmol) in a round-bottomed flask was dried by heating at
150 ꢁC for 2 h under vacuum. The heating was discontinued and
the flask was allowed to cool to rt under Ar. The flask was then
transferred to an ice bath and charged with dry THF (1 mL). The
1.97e1.85 (m, 1H), 1.79e1.76 (m, 1H), 1.69e1.61 (m, 1H), 1.32e1.22
(m, 8H), 0.96e0.87 (m, 12H); 13C NMR (100 MHz, CDCl3)
d 172.1,
171.2, 160.3, 61.2, 59.7, 43.0, 42.3, 32.9, 28.3, 28.0, 27.3, 23.8, 14.2,
14.0, 9.5; IR (thin film) 3460, 2954, 2872, 1725, 1655, 1296, 1232,
mixture was maintained at 0 a solution of the
ꢁC and

R. Sengupta et al. / Tetrahedron 67 (2011) 8229e8234
8233
organolithium reagent (0.80 mmol) was added slowly. A turbid
green coloration was observed after addition of the first equivalent
of the organolithium reagent, but the mixture turned transparent
or clear tan after the addition of the second equivalent. The
mixture was stirred at this temperature for 2 min and then the
reaction flask was transferred to an acetone/dry-ice bath at
4.2.2.5. trans-4-tert-Butyl-2-p-tolylcyclohexanone oxime (13c).
Isolated yield: 85% as an inseparable 5.5:1 mixture of oxime E/Z
isomers. 1H NMR (400 MHz, CDCl3, Z isomer)
8.77 (br s, 1H),
d
7.19e7.14 (m, 4H), 4.84 (br s, 1H), 2.51e2.47 (m, 1H), 2.41 (dm,
J¼14.2 Hz, 1H), 2.34 (s, 3H), 2.16 (td, J¼4.8, 13.9 Hz, 1H), 1.87e1.20
(m, 4H), 0.91 (s, 9H). 1H NMR (400 MHz, CDCl3, E isomer)
d 8.77 (br
ꢀ78 ꢁC. A solution of the
a
-chlorooxime cis-5a (41 mg, 0.20 mmol)
s, 1H), 7.19e7.14 (m, 4H), 3.80 (br s, 1H), 3.29 (br d, J¼14.4 Hz, 1H),
2.55 (dm, J¼13.7 Hz, 1H), 2.34 (s, 3H), 1.87e1.73 (m, 2H), 1.66 (td,
J¼5.1, 12.2 Hz, 1H), 1.51e1.40 (m, 1H), 1.27 (td, J¼4.4, 12.5 Hz, 1H),
in THF (2 mL) was added slowly to this mixture at ꢀ78 ꢁC whereby
the solution turned bright yellow. The reaction mixture was stir-
red for 30 min at ꢀ78 ꢁC and quenched with concentrated HCl
(12.1 M, 1 mL, 12.1 mmol) at this temperature. The dry-ice bath
was removed and ethylenediamine (3 mL, 45 mmol) was added to
the cold mixture followed by the addition of ice-cold water
(10 mL). The addition of ethylenediamine was exothermic and the
flask was properly vented to prevent the buildup of pressure. The
reaction mixture turned turbid blue on the initial addition of
ethylenediamine and later changed to clear Prussian blue on the
addition of water. Stirring was discontinued after 2 min and the
organic layer was extracted with ether, dried over anhydrous
MgSO4 and the solvent was removed under vacuum. The product
was purified by flash column chromatography on silica gel eluting
with dichloromethane (100%) followed by ethyl acetate/hexanes
(gradient, 10%e20% ethyl acetate in hexanes).
0.91 (s, 9H); 13C NMR (100 MHz, CDCl3, E isomer)
d 162.8, 137.9,
136.1,129.8,127.5, 43.9, 42.2, 32.9, 31.2, 27.8, 27.0, 22.4, 21.4; IR (thin
film) 3237, 3107, 2942, 2872, 1655, 932 cmꢀ1; HRMS-ES [MþH]þ
calcd for C17H26NO: 260.2014, found: 260.2011.
4.2.2.6. cis-4-tert-Butyl-2-p-tolylcyclohexanone oxime (14c).
Isolated yield: 9%. 1H NMR (400 MHz, THF-d8)
d 10.82 (s, 1H), 7.01
(dd, J¼7.9, 9.2 Hz, 4H), 3.49 (br d, J¼14.4 Hz, 1H), 3.30 (dd, J¼4.05,
12.8 Hz, 1H), 2.26 (s, 3H), 2.00e1.89 (m, 2H), 1.69e1.64 (m, 1H), 1.56
(t, J¼12.0 Hz, 1H), 1.48e1.42 (m, 1H), 1.25e1.21 (m, 1H), 0.91 (s, 9H);
13C NMR (100 MHz, THF-d8, compound has extremely low solubility
leading to reduced signal intensity and therefore the oxime carbon
peak could not be observed)
d 140.8, 136.2, 130.3, 129.4, 50.6, 49.4,
37.7, 33.7, 31.2, 28.5, 28.1, 21.7; IR (thin film) 3232, 2954, 2922, 2859,
1664, 930 cmꢀ1; HRMS-ES [MþH]þ calcd for C17H26NO: 260.2014,
found: 260.2011.
4.2.2.1. trans-4-tert-Butyl-2-methylcyclohexanone oxime (13a).
Isolated yield: 71%. 1H NMR (300 MHz, CDCl3, inseparable w1:1
mixture of oxime Z/E isomers)
d
8.75 (br s, 1H), 3.65e3.61 (m, 0.5H,
4.2.2.7. 2-Chloro-5-methylcyclohexanone O-(tert-butyldimethyl-
Z), 3.15 (br d, J¼8.7 Hz, 0.5H), 2.67e2.64 (m, 0.5H, E), 2.34e2.22 (m,
1H), 1.95e1.85 (m, 1.5H), 1.67e1.63 (m, 1H), 1.49e1.36 (m, 2H),
1.20e1.11 (m, 4H), 0.86 (s, 9H); 13C NMR (100 MHz, CDCl3, in-
silyl) oxime (15b). To a stirred solution of the a-chloroketone 15a
ꢀ
(3.41 mmol) in CH2Cl2 (7 mL) and a spatula of 4 A molecular sieves
were added H2NOTBS (529 mg, 3.41 mmol) and PPTS (spatula tip
full). The reaction mixture was stirred at rt for 12 h and then filtered
through a pad of Celite. The solution was concentrated in vacuo and
the residue was purified by flash column chromatography on silica
gel eluting with a mixture of ethyl acetate in hexanes (5e30%) to
provide the product 15b as a clear oil (632 mg) in 67% yield as
a mixture of (E/Z)-isomers and diastereomers: 1H NMR (360 MHz,
separable w1:1 mixture of oxime Z/E isomers)
d 164.7, 164.6, 41.9,
41.8, 34.8, 34.0, 33.2, 32.7, 32.6, 29.0, 28.1, 27.9, 27.8, 27.0, 26.3, 21.5,
19.0,17.2; IR (thin film) 3237, 2954, 2872,1660, 944 cmꢀ1; HRMS-ES
[MþH]þ calcd for C11H22NO: 184.1701, found: 184.1709.
4.2.2.2. cis-4-tert-Butyl-2-methylcyclohexanone oxime (14a).
Isolated yield: 18%. X-ray quality crystals were obtained by slow
evaporation from chloroform/ethyl acetate, mp 143e145 ꢁC.1H NMR
CDCl3) d 5.64 (br s, 0.4H), 5.50 (br s, 0.1H), 4.72 (br s, 0.4H), 4.57 (br
s, 0.1H), 3.31 (t, J¼5.7 Hz, 1H), 2.40e2.30 (m, 1H), 2.23e2.18 (m, 1H),
2.10e2.05 (m, 1H), 1.94e1.76 (m, 3H), 1.69e1.45 (m, 5H), 1.11e1.04
(m, 6H), 0.96e0.94 (m, 18H), 0.22e0.19 (m, 12H); 13C NMR (90 MHz,
(300 MHz, CDCl3)
d
9.62 (br, s,1H), 3.44 (dm, J¼14.0 Hz,1H), 2.25 (m,
1H), 1.92 (dm, J¼12.3 Hz, 2H), 1.62 (td, J¼5.1, 14.0 Hz, 1H), 1.30 (tt,
J¼2.9, 12.0 Hz, 1H), 1.25e1.10 (m, 4H), 1.01 (q, J¼9.4 Hz, 1H), 0.87 (s,
CDCl3)
d 162.7, 161.9, 160.7, 159.3, 66.3, 59.1, 54.5, 49.3, 47.4, 47.0,
9H); 13C NMR (100 MHz, CDCl3)
d
163.5, 47.8, 37.9, 37.7, 32.8, 28.0,
38.7, 37.1, 35.4, 34.9, 33.6, 33.5, 32.4, 31.4, 31.3, 31.2, 29.7, 29.0, 28.4,
28.2, 27.6, 27.5, 26.6, 26.1, 25.8, 24.5, 23.5, 22.4, 22.1, 21.9, 21.2, 19.9,
18.9, 18.8, 18.2, 16.8; IR (thin film) 2955, 2858, 1744, 1461, 1252,
945 cmꢀ1; LRMS-ESþ m/z (relative intensity) 276 (MHþ, 10); HRMS-
ES [MþH]þ calcd for C13H27NOSCl: 276.1550, found: 276.1543.
27.3, 24.8, 17.0; IR (thin film) 3260, 2943, 2872, 1660, 932 cmꢀ1
HRMS-ES [MþH]þ calcd for C11H22NO: 184.1701, found: 184.1708.
;
4.2.2.3. trans-4-tert-Butyl-2-phenylcyclohexanone oxime (13b).
Isolated yield: 85% as an inseparable 36:1 mixture of oxime E/Z
diastereomers. 1H NMR (300 MHz, CDCl3, Z isomer)
d
8.92 (br s, 1H),
4.2.3. General procedure for conjugate additions to ring-substituted
nitrosoalkenes 16 and 19. To a stirred solution of diethyl malo-
nate (6a, 3 mmol, 481 mg) in THF (6.5 mL) was added KHMDS
(6 mL, 0.5 M in PhMe, 3 mmol) at ꢀ78 ꢁC. The resulting solution
was then stirred for 45 min at that temperature. The O-TBS oxime
7.40e7.24 (m, 5H), 4.93 (br s, 1H), 2.58e2.53 (m, 1H), 2.45 (br d,
J¼14.0 Hz, 1H), 1.92e1.21 (m, 5H), 0.94 (s, 9H). 1H NMR (300 MHz,
CDCl3, E isomer) d 8.92 (br s, 1H), 7.40e7.24 (m, 5H), 3.88 (br s, 1H),
3.33 (dm, J¼12.2 Hz,1H), 2.60 (dm, J¼13.7 Hz,1H), 1.92e1.6 (m, 3H),
1.50 (tm, J¼9.3 Hz, 1H), 1.36e1.21 (m, 1H), 0.94 (s, 9H); 13C NMR
(15b or 18, 1 mmol) dissolved in THF (600 mL) was added slowly
(75 MHz, CDCl3, E isomer)
d
162.7, 141.0, 129.0, 127.7, 126.6, 44.3,
over 1 min, followed by dropwise addition of TBAF (2 mL, 1.0 M
in THF, 2 mmol) over 3 min. The resulting solution was imme-
diately transferred to an ice bath and stirred for an additional 2 h.
The reaction mixture was diluted with concentrated aqueous
NH4Cl and EtOAc. The organic layer was separated and the
aqueous layer was extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo to give
a residue, which was purified by flash column chromatography
on silica gel eluting with a mixture of ethyl acetate in hexanes
(25e40%).
42.3, 32.9, 31.2, 27.8, 27.0, 22.5; IR (thin film) 3260, 2954, 2872,
1666, 932 cmꢀ1; HRMS-ES [MþH]þ calcd for C16H24NO: 246.1858,
found: 246.1855.
4.2.2.4. cis-4-tert-Butyl-2-phenylcyclohexanone oxime (14b).
Isolated yield: 7%. 1H NMR (400 MHz, CDCl3)
d 7.36e7.21 (m, 5H),
3.50 (dm, J¼13.2 Hz, 1H), 3.40 (dd, J¼4.1, 12.9 Hz, 1H), 2.12e1.98 (m,
2H), 1.79 (td, J¼5.4, 13.9 Hz, 1H), 1.64 (q, J¼12.4 Hz, 1H), 1.49e1.43
(m, 1H), 1.37e1.22 (m, 2H), 0.92 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
162.9, 141.3, 129.1, 128.7, 127.1, 49.8, 48.1, 36.1, 33.0, 28.0, 26.9,
24.9; IR (thin film) 3247, 2950, 2868, 1668, 928 cmꢀ1; HRMS-ES
[MþH]þ calcd for C16H24NO: 246.1858, found: 246.1855.
4.2.3.1. Diethyl 2-(2-(hydroxyimino)-4-methylcyclohexyl)malo-
nate (17). The product 17 was obtained as a clear oil (47 mg,

8234
R. Sengupta et al. / Tetrahedron 67 (2011) 8229e8234
45% yield) as a 5:1 mixture of (E/Z) oxime isomers: 1H NMR
(360 MHz, CDCl3) 8.00e7.50 (br s, 1H), 4.23e4.10 (m, 4H), 3.79
Supplementary data
d
(d, J¼10.0 Hz, 0.2H), 3.71 (d, J¼10.9 Hz), 3.20e3.13 (m, 0.3H),
3.11e3.04 (m, 1H), 2.86e2.72 (m, 0.3H), 2.56 (dd, J¼14.1, 4.7 Hz,
1H), 2.33 (dd, J¼14.0, 7.8 Hz, 1H), 1.93e1.74 (m, 2H), 1.72e1.61
(m, 4H), 1.44e1.37 (m, 2H), 1.30e1.19 (m, 6H), 1.01 (d, J¼7.5 Hz,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.054.
References and notes
1H), 0.96 (d, J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3)
d 168.7,
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168.6, 159.3, 158.8, 61.9, 60.8, 53.8, 53.5, 41.4, 33.9, 32.0, 31.4,
30.7, 29.5, 27.7, 23.1, 23.0, 21.5, 20.6, 14.6, 14.5, 14.4, 11.8; IR
(thin film) 3279, 2931, 2871, 1732, 1455, 1292, 1178, 1033,
947 cmꢀ1; LRMS-ESþ m/z (relative intensity) 286 (MHþ, 36);
HRMS-ES [MþH]þ calcd for C14H25NO5: 286.1654, found:
286.1649.
4.2.3.2. Diethyl 2-(2-ethyl-6-(hydroxyimino)cyclohexyl)malonate
(20). The product 20 was obtained as a clear oil (18 mg, 34% yield)
as a w11:1 mixture of (E/Z) oxime isomers: 1H NMR (300 MHz,
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d 8.31 (s, 1H), 8.10 (s, 0.1H), 4.27e4.05 (m, 4H), 3.83 (d,
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Data Centre via www.ccdc.cam.ac.uk/data_request/cif. CCDC 833440¼8d; CCDC
833441¼10; CCDC 833442¼12; CCDC 833443¼14a.
J¼8.5 Hz, 1H), 3.72 (d, J¼8.1 Hz, 0.09H), 3.13 (d, J¼10.6 Hz, 1H),
3.01 (d, J¼8.5 Hz, 1H), 2.01e1.92 (m, 1H), 1.81e1.74 (m, 1H),
1.73e1.61 (m, 3H), 1.60e1.49 (m, 2H), 1.48e1.39 (m, 1H), 1.36e1.21
(m, 8H), 0.92 (t, J¼5.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 168.3,
159.0, 158.6, 62.0, 61.9, 54.0, 53.5, 45.4, 39.7, 25.4, 25.3, 21.8, 20.5,
14.4, 12.1, 12.0, 11.7; IR (thin film) 3278, 2960, 2874, 1732, 1456,
1262, 1034, 951 cmꢀ1; LRMS-ESþ m/z (relative intensity) 300
(MHþ, 26); HRMS-ES [MþH]þ calcd for C15H26NO5: 300.1811,
found: 300.1799.
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Acknowledgements
We are grateful to the National Institutes of Health (GM-087733)
and the National Science Foundation (CHE-0806807) for financial
support of this research. We also thank Dr. H. Yennawar (Penn State
Small Molecule X-Ray Cystallographic Facility) for the X-ray crystal
structure determinations.