A benzannulation protocol to prepare substituted aryl amines using a michael-aldol reaction of β-keto sulfones

Article abstract of DOI:10.1021/jo9017793

(Chemical Equation Presented) A practical benzannulation method to prepare variously substituted aryl amines and sulfides was developed. The approach involves a Michael-aldol reaction of β-keto sulfones with enones followed by a subsequent condensation of the initial adduct with various amines. The base-induced Michaelaldol cascade proceeds smoothly with a number of different β-keto sulfones, affording the adducts as single diastereomers. Heating the resulting Michael-aldol product with an amine in toluene at 120°C results in the formation of a transient enamine, which then undergoes loss of phenyl sulfenic acid to furnish the aromatized amine in good yield. A related reaction also occurred when the Michael-aldol product was heated with thiols or alcohols, giving rise to aryl-substituted sulfides or ethers.

Full text of DOI:10.1021/jo9017793

pubs.acs.org/joc
A Benzannulation Protocol To Prepare Substituted Aryl Amines Using a
Michael-Aldol Reaction of β-Keto Sulfones
Sezgin Kiren and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received August 17, 2009
A practical benzannulation method to prepare variously substituted aryl amines and sulfides was
developed. The approach involves a Michael-aldol reaction of β-keto sulfones with enones followed
by a subsequent condensation of the initial adduct with various amines. The base-induced Michael-
aldol cascade proceeds smoothly with a number of different β-keto sulfones, affording the adducts as
single diastereomers. Heating the resulting Michael-aldol product with an amine in toluene at 120 °C
results in the formation of a transient enamine, which then undergoes loss of phenyl sulfenic acid to
furnish the aromatized amine in good yield. A related reaction also occurred when the Michael-aldol
product was heated with thiols or alcohols, giving rise to aryl-substituted sulfides or ethers.
Introduction
reducible functionalities in a molecule is often a challenging
task. In addition, metal reduction of aromatic nitro com-
pounds frequently stops at an intermediate stage, producing
hydroxylamines, hydrazines, and azoarenes as side pro-
ducts.4 More recently, the metal-catalyzed C-N bond-form-
ing cross-coupling reaction of aryl halides has emerged as a
powerful protocol for preparing aryl amines.5-7 Amination
reactions employing nucleophiles as diverse as primary and
secondary aryl amines, carbamates, and hydrazones are
all known.8 Although great progress has been made in
Aromatic amines are useful intermediates in the prepara-
tion of dyes, pharmaceuticals, and agricultural chemicals.1
Therefore, the development of efficient methods to synthe-
size these compounds continues to be a topic of immense
importance. A wide variety of procedures to prepare aniline
derivatives are available and many involve the use of a
metal.2 Over the years an assortment of metals have been
used for the reduction of aromatic nitro compounds to aryl
amines, with the most traditional methods employing zinc,
tin, or iron in the presence of an acid.3 However, selective
metal reduction of a nitro group in the presence of other
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1051-1096. (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(c) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
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Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett.
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S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (f) Wolfe, J. P.; Buchwald, S. L.
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(1) (a) Negwer, M.; Scharmow, H. G. Organic-Chemical Drugs and their
Synonyms, 8th ed.; John Wiley and Sons: Chichester, U.K., 2001. (b) Lawrence,
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Chem. 2006, 71, 2196. (f) Shi, Q.; Lu, R.; Lu, L.; Fu, X.; Zhao, D. Adv. Synth.
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DOI: 10.1021/jo9017793
r
Published on Web 09/24/2009
J. Org. Chem. 2009, 74, 7781–7789 7781
2009 American Chemical Society

Kiren and Padwa
JOCArticle
SCHEME 1
SCHEME 2
noted that a related Robinson annelation of β-keto sulfoxi-
des with vinyl ketones had been reported by Boger
and Mullican as a method to prepare highly substituted
phenols.15
metal-catalyzed Ullmann-type N-arylation reactions, the
efficiency of the coupling is highly dependent on the involve-
ment of suitable ligands.9 Also, the need to address specific
mechanistic issues and in some cases the high cost of the
ligand detracts somewhat from the overall utility of the
amination reaction. Even though the aforementioned
methods are broadly used, there remains a need for alter-
native strategies for the synthesis of highly functionalized
arylamines as well as aryl thioethers.
In our laboratory, there has been an ongoing interest in
domino and multicomponent processes to prepare azapoly-
cyclic ring systems. As part of this program, we discovered
some years ago a conjugate addition-dipolar cycloaddition
cascade of 2,3-bis(phenylsulfonyl)-1,3-butadiene (1) with
various oximes as an approach for constructing functiona-
lized piperidone ring systems.10 The first step in the cascade
sequence was shown to involve conjugate addition of the
oxime with diene 1, and this was followed by proton transfer
to create a transient nitrone that undergoes a subsequent
1,3-dipolar cycloaddition with the tethered vinyl sulfone.11
The resulting cycloadduct can be cleaved reductively to
provide an azapolycyclic scaffold with a strategically placed
phenylsulfonyl functionality for further synthetic manipula-
tion.12 During our earlier studies, we found that treatment of
Results and Discussion
The 1,4-conjugate addition of stabilized anions to enones
is one of the most fundamental and efficient methods to form
C-C bonds.16 Although the Michael addition of R-thio-
esters,17 R-thioacetonitriles,18 sulfinyl or sulfonyl carban-
ions19 to activated π-bonds is well documented, the related
conjugated addition of β-keto sulfones with Michael accep-
tors has been much less studied.20-22 As a starting point for
our investigation, we first tested which base and solvent
system would work best for the Michael addition of
2-(phenylsulfonyl)-2,3-dihydro-1H-indene-1-one (6)23 with
methyl vinyl ketone (MVK). The reaction worked excep-
tionally well using either NaOMe or NEt3 as the base to give
the desired Michael addition product 7 in 94% yield
(Scheme 2). We next examined the reaction of dione 7 with
pyrrolidine (4.0 equiv) employing toluene as the solvent
together with a trace amount of p-TsOH at 110 °C. Under
these conditions, a 1:1 mixture of amide 9 and fluorenyl
pyrrolidine 10 was obtained in 84% yield. The distribution of
products was found to be markedly dependent on the con-
centration of pyrrolidine present in the solution. By using a
the resulting phenylsulfonyl-substituted piperidone
4
derived from the reduction of cycloadduct 3 with MVK in
the presence of pyrrolidine and acetic acid gave the unex-
pected benzo-isoquinolinone 5 in high yield (Scheme 1).13 As
a consequence of this observation, we became interested in
making further use of this operation for the synthesis of
various aryl amines. In this paper we describe the systematic
optimization of this benzoannulation reaction and the
applicability of the method for the preparation of variously
substituted aryl amines and aryl thioethers.14 It should be
(15) Boger, D.; Mullican, M. D. J. Org. Chem. 1980, 45, 5002.
(16) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series No. 9; Pergamon: Oxford, 1992. (b) Jung,
M. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, Chapter 1.1.
(17) Takasu, M.; Wakabayashi, H.; Furuta, K.; Yamamoto, H. Tetra-
hedron Lett. 1988, 29, 6943.
(18) Wang, N.-Y.; Su, S.-S.; Tsai, L.-Y. Tetrahedron Lett. 1979, 20, 1121.
(19) (a) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J. Am. Chem. Soc. 1988, 110, 5411. (b) Hirama, M.
Tetrahedron Lett. 1981, 22, 1905. (c) Casey, M.; Manage, A. C.; Nezhat, L.
Tetrahedron Lett. 1988, 29, 5821. (d) Hua,D. H.;Bharathi, S.N.;Takusagawa,
F.; Tsujimoto, A.; Panangadan, J. A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding,
A. M. J. Org. Chem. 1989, 54, 5659.
(20) Simpkins, N. S. Sulphones in Organic Synthesis; Tetrahedron
Organic Chemistry Series No. 10; Pergamon: Oxford, 1993.
(21) Marco, J. L. J. Org. Chem. 1997, 62, 6575.
(22) While there is only limited work on the use of β-ketosulfones as
Michael nucleophiles, related applications for inter- and intramolecular
additions of β-ketosulfoxides are known; see: (a) Marco, J. L.; Fernandez,
I.; Khiar, N.; Fernandez, P.; Romero, A. J. Org. Chem. 1997, 60, 6678. (b)
Marco, J. L. J. Org. Chem. 1997, 62, 6575. (c) Soucy, P.; L’Heureux, A.;
(9) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(10) (a) Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 2417. (b)
Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem. 1991, 56, 2154.
(11) (a) Grigg, R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978, 19,
2827. (b) Grigg, R. Chem. Soc. Rev. 1987, 16, 89. (c) Padwa, A.; Chiacchio,
U.; Dean, D. C.; Schoffstall, A.; Hassner, A.; Murthy, K. S. K. Tetrahedron
Lett. 1988, 29, 4169.
(12) (a) Flick, A. C.; Caballero, M. J. A.; Padwa, A. Org. Lett. 2008, 10,
1871. (b) Wilson, M. S.; Padwa, A. J. Org. Chem. 2008, 73, 9601.
(13) Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009, 74, 3491.
(14) For a related reaction to prepare aromatic amines by enamine
annulation, see: Wang, C.; Kohn, H. Org. Lett., 2000, 2, 1773.
ꢀ
Toro, A.; Deslongchamps, P. J. Org. Chem. 2003, 68, 9983.
(23) Bhat, V.; Cookson, R. C. J. Chem. Soc., Chem. Commun. 1981, 21,
1123.
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SCHEME 3
SCHEME 4
16-fold excess of pyrrolidine, the ratio of products 9:10
changed from 1:1 to 9:1. We assume that in the presence of
a large excess of base, a retro-Michael reaction occurred to
first regenerate β-keto sulfone 6, which then underwent
further reaction with pyrrolidine to give amide 9. A single-
crystal X-ray analysis of 9 unequivocally confirmed its
structure assignment. In support of the above mechanistic
suggestion, a control experiment showed that when β-keto
sulfone 6 was heated for short periods of time in toluene with
pyrrolidine, amide 9 was formed in 98% yield. We also found
that heating Michael adduct 7 with a trace of p-TsOH in
toluene furnished the Robinson annulated enone 8 in
49% yield. Further heating of 8 with pyrrolidine in the
presence of a trace amount of acid gave fluorenyl pyrrolidine
10 in 95% yield. More than likely this reaction proceeds
by formation of a transient enamine, which then under-
goes loss of phenyl sulfenic acid to afford the aromatic
pyrrolidine 10.
The generality of the benzannulation reaction was further
investigated using several different β-ketone sulfones. We
next observed that 2-(phenylsulfonyl)-3,4-dihydronaphtha-
lene-1(2H)-one (11) smoothly underwent 1,4-conjugate
addition with MVK to give the corresponding Michael
adduct 12 in 84% yield. Further reaction of 12 with pyrroli-
dine or morpholine furnished the corresponding aromatic
amines 13 and 14 in 40-60% yield. With this system the
byproduct that was also formed corresponded to β-keto
sulfone 11, and we believe that it is derived by a competitive
retro-Michael reaction from dione 12 (Scheme 3).
literature was assigned as the cis-stereoisomer.24 On the
other hand, when the reaction of 15 was carried out with
MVK using the weaker NEt3 as the base in CH2Cl2, only the
Michael addition product 17 was obtained in 94% yield.
Treatment of 17 with NaOMe in MeOH afforded the inter-
nal aldol product 16 in 75% yield. Heating a sample of 16 (or
17) with either a primary or secondary amine in toluene
furnished the aromatic tetrahydronaphthalene derivatives
18-22 in high yield. The entire reaction sequence proceeded
rapidly, affording the aromatized system directly without
isolation or detection of any reaction intermediates. A
related aromatization reaction also occurred upon heating
16 (or 17) with benzyl alcohol, methanol, or thiophenol,
producing the aromatized compounds 23-25 in comparable
yield (Scheme 4).
The Michael-aldol reaction also proceeded well with
acyclic β-keto sulfones such as 2-(phenylsulfonyl)aceto-
phenone (26). As indicated by the results described in
Scheme 5, the Michael reaction of 26 with MVK occurred
smoothly in CH2Cl2 with NEt3 as the base, affording dione
27 in 88% yield. Further treatment of 27 with NaOMe in
MeOH gave the cyclized aldol product 28 as a single diaster-
eomer in 98% yield. The same product was also obtained
from the reaction of 26 with MVK in MeOH with NaOMe as
the base in 80% yield. The intramolecular aldol reaction
product 28 has the large substituent groups in the equatorial
position, thereby resulting in the most stable diastereomer.
Condensation of pyrrolidine with either 27 or 28 followed by
loss of water and phenylsulfenic acid provided the aromatic
substituted amine 29 (Scheme 5). The generality of this
aromatic annulation protocol was further studied using
several secondary amines as well as thiols. The isolated yields
of the aromatized products are based on the starting ketone
and ranged from 34% to 98%.
We then turned our attention to the simpler β-keto
sulfonyl cyclohexanone system 15. The reaction of 15 with
MVK using NaOMe as the base in methanol gave rise to the
domino Michael-aldol reaction product 16. Only a single
diastereomer was obtained and from related results in the
(24) The domino Michael-aldol reaction encountered with this system is
related to the well-known proline-catalyzed Robinson annulation; see: (a)
Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
(b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Arai, T.;
Sasai, H.; Aoe, K.-I.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 104. (d) Bui, T.; Barbas, C. F. III Tetrahedron Lett.
2000, 41, 6951. (e) Dieckmann, W.; von Fischer, K. Ber. Dtsch. Chem. Ges.
1911, 44, 966. (f) Christoffers, J. J. Chem. Soc. Perkin Trans. 1 1997, 3141. (g)
Tanaka, F.; Thayumanavan, R.; Barbas, C. F. III J. Am. Chem. Soc. 2003,
125, 8523.
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SCHEME 5
SCHEME 7
SCHEME 6
SCHEME 8
Continuing with our systematic analysis of the structure-
reactivity relationship of the method, we next investigated
the reaction of β-keto sulfone 26 with ethyl vinyl ketone. As
before, this reaction occurred in the presence of NaOMe,
producing the Michael-aldol product 34 in 42% yield as a
single diastereomer together with the expected Michael
adduct formed in 28% yield. We assume that the stereo-
chemistry of 34 has all the large substituent groups in the
equatorial position as is typically found with related sys-
tems.25 Thermolysis of 34 with pyrrolidine gave aryl amine
35 in 64% yield, whereas heating 34 with thiophenol afforded
the aromatized sulfide 36 in 92% yield (Scheme 6).
Condensation of β-keto sulfone 26 with other R,β-unsa-
turated carbonyl compounds provides a convenient method
for accessing a variety of trisubstituted aryl amines. Several
different enones varying in structure were used to generate
the corresponding aromatic derivatives. For example, we
observed that 26 smoothly underwent the Michael-aldol
reaction with 3-penten-2-one to give the expected cyclized
product 37 as a single diastereomer. As was the case with the
earlier systems, the stereochemistry of 37 is assumed to have
all of the large substituents located in the equatorial position.
Heating 37 with either pyrrolidine or thiophenol produced
the 1,3,5-trisubstituted aromatized amine 38 and the related
sulfide 39. Attempts to improve the yield of 38 were un-
successful. Higher temperatures and longer reaction times
did not upgrade the yield, nor did the use of an excess amount
of pyrrolidine. Interestingly, we observed only the formation
of the Michael addition product 40 as a 1:1 mixture of
diastereomers when 26 was allowed to react with 3-methyl-
but-3-en-2-one using NaOMe as the base. Heating 40 with
pyrrolidine in the presence of catalytic p-TsOH gave the
1,2,5-trisubstituted aryl amine 41 in 57% yield. Similarly,
thermolysis of 40 with thiophenol afforded the related
aromatic sulfide 42 in 90% yield (Scheme 7).
When an aliphatic β-keto sulfone such as 2-(phenylsulfonyl)-
pentan-3-one (43) was used, the corresponding Michael addi-
tion product 44 was obtained as the exclusive product upon
treatment of β-keto sulfone 43 with MVK and NEt3. The
resulting dione 44 was then converted into the corresponding
1,4,5-trisubstituted aryl amine 45 in 60% yield by heating with
pyrrolidine in the presence of a trace of p-TsOH (Scheme 8).
(25) (a) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv.
Synth. Catal. 2004, 346, 1077. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2004, 43, 1272.
7784 J. Org. Chem. Vol. 74, No. 20, 2009

Kiren and Padwa
JOCArticle
In conclusion, we have found a useful benzoannulation
method that affords variously substituted aryl amines and
sulfides. The key steps consist of a Michael-aldol reaction of
β-keto sulfones with enones followed by a subsequent con-
densation of the initial adduct with an amine or thiol. The
Michael-aldol cascade proceeds with a number of β-keto
sulfones and enones, affording adducts as single diastereo-
mers. This remarkably simple and environmentally benign
method offers a practical route to substitued aryl amines and
sulfides.
heated at reflux for 1 h and was then cooled to room tempera-
ture. The solvent was removed under reduced pressure, and the
resulting residue was purified by silica gel chromatography to
provide 29 mg (42%) of 10 together with 43 mg (43%) of
(2-(2-phenylsulfonyl)ethyl)phenyl)-(pyrrolidin-1-yl)methanone
(9): mp 127-128 °C; IR (thin film) 3059, 2970, 1625, and 1448
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.76-1.90 (m, 4H), 2.95
(t, 2H, J=8.4 Hz), 3.05 (t, 2H, J=6.8 Hz), 3.42-3.47 (m, 4H),
7.12-7.28 (m, 4H), 7.53-7.63 (m, 2H), and 7.91-7.93 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 24.6, 26.2, 27.0, 45.5, 48.8, 57.2,
126.3, 127.4, 128.3, 129.4, 129.6, 130.1, 133.8, 134.0, 138.0,
139.1, and 169.0.
2-(3-Oxobutyl)-2-(phenylsulfonyl)-3,4-dihydronaphthalen-
1(2H)-one (12). A sample of 2-(phenylsulfonyl)-3,4-dihydro-
naphthalen-1(2H)-one23 (11) (0.6 g, 2.1 mmol) was dissolved
in 15 mL of CH2Cl2 and was treated with NEt3 (0.32 mL, 2.3
mmol). After 20 min of stirring at room temperature, methyl
vinyl ketone (0.19 mL, 2.3 mmol) was added to the mixture.
Stirring was continued for 2 days, and then an additional
quantity of NEt3 (0.1 mL, 0.8 mmol) and methyl vinyl ketone
(0.4 mL, 4.6 mmol) was added to the mixture. After stirring for
another 2 days, the mixture was quenched with a saturated
aqueous NH4Cl solution. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to furnish 0.62
g (84%) of the titled compound 12 as a yellow solid: mp 100-
102 °C; IR (thin film) 3066, 2936, 1716, 1675, and 1600 cm-1; 1H
NMR (400 MHz, CDCl3) δ 2.05-2.22 (m, 5H), 2.34-2.50 (m,
3H), 2.84 (dt, 1H, J=14.8 and 4.8 Hz), 2.98 (dt, 1H, J=16.8 and
4.8 Hz), 3.58-3.67 (m, 1H), 7.25 (d, 1H, J=7.6 Hz), 7.32 (t, 1H,
J=7.6 Hz), 7.49-55 (m, 3H), 7.65 (t, 1H, J=7.6 Hz), 7.78-7.81
(m, 2H), and 8.01 (d, 1H, J=8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 25.9, 27.1, 27.6, 30.1, 38.1, 72.8, 127.2, 128.3, 128.9,
129.1, 130.9, 132.1, 134.4, 134.6, 136.3, 143.8, 192.0, and 206.6.
HRMS calcd for [(C20H20O4S) þ H]þ: 357.1161. Found:
357.1156.
Experimental Section
2-(3-Oxobutyl)-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-
one (7). A sample of 2-(phenylsulfonyl)-2,3-dihydro-1H-inden-
1-one (6)23 (1.19 g, 4.4 mmol) was dissolved in 30 mL of CH2Cl2
and was treated with NEt3 (0.67 mL, 4.8 mmol). After 20 min of
stirring at room temperature, methyl vinyl ketone (0.39 mL,
4.8 mmol) was added to the solution. Stirring was continued for
14 h, and the mixture was quenched with a saturated aqueous
NH4Cl solution. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography to furnish 1.49 g (94%) of
the titled compound 7 as a white solid: mp 143-145 °C; IR (thin
film) 3064, 2934, 1720, 1607, 1589 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.05 (s, 3H), 2.27-2.47 (m, 1H), 3.20 (d, 1H, J=18.4
Hz), 4.05 (d, 1H, J=18.4 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.45-7.53
(m, 3H), 7.60-7.64 (m, 2H), 7.70 (d, 1H, J=8.0 Hz), and 7.82
(dd, 2H, J=8.0 and 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ
26.1, 30.2, 33.7, 37.8, 75.0, 125.0, 126.3, 128.5, 128.9, 130.9,
134.5, 135.0, 136.0, 136.3, 151.7, 198.4, and 206.2.
9a-(Phenylsulfonyl)-9,9a-dihydro-1H-fluoren-3(2H)-one (8).
A solution containing sulfone 7 (1.03 g, 3.0 mmol) in toluene
(20 mL) was treated with a catalytic amount of p-TsOH and was
heated at reflux for 24 h. After cooling to room temperature, the
reaction mixture was concentrated under reduced pressure, and
the residue was purified by silica gel chromatography to furnish
0.48 g (49%) of the titled compound 8 as a yellow solid: mp
138-139 °C; IR (thin film) 3064, 2924, 1660, 1632, 1604, and
1141 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.31-2.41 (m, 1H),
2.51-2.58 (m, 1H), 3.04 (d, 1H, J=18 Hz), 3.22-3.29 (m, 2H),
3.62 (d, 1H, J = 18 Hz), 6.58 (s, 1H), 6.83-6.86 (m, 1H),
7.10-7.13 (m, 2H), 7.19-7.23 (m, 2H), 7.34-7.41 (m, 2H),
and 7.59 (dd, 2H, J=8.0 and 1.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 29.8, 34.0, 41.8, 72.9, 122.5, 122.8, 124.9, 128.0, 128.5,
130.0, 132.0, 134.0, 135.7, 138.0, 144.4, 157.8, and 197.7. HRMS
calcd for [(C19H16O3S) þ H]þ: 325.0898. Found: 325.0894.
1-(9H-Fluoren-3-yl)pyrrolidine (10). A solution containing
0.05 g (0.18 mmol) of 2-(phenylsulfonyl)-2,3-dihydro-1H-
inden-1-one (6) in toluene (2 mL), pyrrolidine (0.046 mL, 0.54
mmol), and methyl vinyl ketone (0.046 mL, 0.54 mmol) was
treated with a catalytic amount of p-TsOH. The reaction
mixture was heated at reflux for 7 h and then cooled to room
temperature. The solution was concentrated under reduced
pressure, and the resulting residue was purified by silica gel
chromatography to provide 11 mg (26%) of the titled compound
10 as a clear oil: IR (thin film) 3049, 3016, 2964, 1619, and 1567
1-(9,10-Dihydrophenanthren-3-yl)pyrrolidine (13). A solution
containing 76 mg (0.21 mmol) of ketosulfone 12 in toluene
(2 mL) and pyrrolidine (0.09 mL, 1.1 mmol) was treated with a
catalytic amount of p-TsOH. The reaction mixture was heated at
reflux for 3 h and was then cooled to room temperature. The
solution was concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography to
provide 17 mg (39%) of 13 as clear oil: IR (thin film) 3057, 3021,
2964, 1615, and 1561 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.02-2.05 (m, 4H), 2.76-2.87 (m, 4H), 3.34-3.38 (m, 4H), 6.52
(dd, 1H, J=8.4 and 2.4 Hz), 7.10 (d, 1H, 2.4 Hz), 7.19-7.25 (m,
2H), 7.30 (dt, 1H, J=6.0 and 2.4 Hz), and 7.77 (d, 1H, J=7.2
Hz); 13C NMR (100 MHz, CDCl3) δ 25.7, 28.2, 29.9, 48.1, 107.2,
111.3, 123.8, 124.9, 126.8, 127.2, 128.3, 128.3, 135.0, 135.4,
138.2, and 147.5. HRMS calcd for [(C18H19N) þ H]þ:
250.1596. Found: 250.1589.
4-(9,10-Dihydrophenanthren-3-yl)morpholine (14). A solution
containing 0.05 g (0.13 mmol) of ketosulfone 12 in toluene
(1 mL) and morpholine (0.6 mL, 0.068 mmol) was treated with
a catalytic amount of p-TsOH. The reaction mixture was heated
at reflux for 2 h and then cooled to room temperature. The
solution was concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography to
provide 20 mg (56%) of the titled compound 14 as a colorless oil:
IR (thin film) 3058, 3031, 2957, 1611, and 1562 cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.78-2.88 (m, 4H), 3,21 (t, 4H, J=4.8 Hz),
3.91 (t, 4H, J=4.8 Hz), 6.84 (dd, 1H, J=8.4 and 2.4 Hz), 7.16 (d,
1H, J=8.4 Hz), 7.23-7.26 (m, 2H), 7.29-7.34 (m, 2H), and 7.74
(d, 1H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 28.3, 29.6,
50.2, 67.2, 111.8, 115.6, 123.7, 127.0, 127.5, 128.4, 128.9, 129.8,
13.9, 135.2, 137.9, and 150.8. HRMS calcd for [(C18H19NO) þ
H]þ: 266.1545. Found: 266.1541.
cm-1 1H NMR (400 MHz, CDCl3) δ 2.04-2.08 (m, 4H),
;
3.37-3.41 (m, 4H), 3.82 (s, 2H), 6.59 (dd, 1H, J=11.2 and 3.2
Hz), 7.00 (d, 1H, J=3.2 Hz), 7.26-7.32 (m, 1H), 7.35-7.41 (m,
2H), 7.53 (d, 1H, J=9.6 Hz), and 7.77 (d, 1H, J=9.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 25.7, 36.2, 48.3, 102.9, 111.4, 119.8,
125.1, 125.5, 126.5, 126.6, 130.5, 1422.5, 142.7, 144.7, and 147.8.
HRMS calcd for [(C17H17N) þ H]þ: 236.1439. Found: 236.1432.
A solution of ketosulfone 7 (0.1 g, 0.29 mmol) in toluene
(3 mL) was also treated with a catalytic amount of p-TsOH and
pyrrolidine (0.097 mL 1.17 mmol). The reaction mixture was
J. Org. Chem. Vol. 74, No. 20, 2009 7785

Kiren and Padwa
JOCArticle
8a-Hydroxy-4a-(phenylsulfonyl)octahydronaphthalen-2(1H)-
one (16). A sample of 2-(phenylsulfonyl)cyclohexanone (15)23
(0.25 g, 1.0 mmol) was dissolved in 4 mL of MeOH and 8 mL of
benzene and was treated with NaOMe (72 mg, 1.3 mmol). After
20 min of stirring at room temperature, methyl vinyl ketone
(0.12 mL, 1.5 mmol) was added to the reaction mixture. Stirring
was continued for 1 h, and then the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc and
washed with a saturated aqueous NH4Cl solution. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by silica gel chro-
matography to provide 0.21 g (65%) of the titled compound 16
as a white solid: mp 144-146 °C; IR (thin film) 3481, 3066, 2933,
1715, and 1446 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.13-1.39
(m, 4H), 1.51-1.75 (m, 3H), 1.92-1.99 (m, 1H), 2.03-2.13 (m,
1H), 2.20-2.32 (m, 2H), 2.40 (dd, 1H, J=14.4 and 1.6 Hz),
3.10-3.19 (m, 1H), 3.65 (d, 1H, J=14.4 Hz), 4.18 (d, 1H, J=1.2
Hz), 7.48-7.52 (m, 2H), and 7.82 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 19.9, 20.7, 25.5, 28.9, 37.0, 37.4, 54.4, 68.7, 74.9, 129.0,
130.5, 134.3, 136.2, and 208.3. HRMS calcd for [(C16H20O4S) þ
H - H2O)]þ: 291.1055. Found: 291.1053.
2-(3-Oxobutyl)-2-(phenylsulfonyl)cyclohexanone (17). A sam-
ple of 2-(phenylsulfonyl)cyclohexanone (15) (0.5 g, 2.1 mmol)
was dissolved in 15 mL of CH2Cl2 and was treated with NEt3
(0.32 mL, 2.3 mmol). After 20 min of stirring at room tempera-
ture, methyl vinyl ketone (0.19 mL, 2.3 mmol) was added to the
mixture. Stirring was continued for 2 days, and then an addi-
tional amount of NEt3 (0.1 mL, 0.8 mmol) and methyl vinyl
ketone (0.4 mL, 4.6 mmol) was added to the mixture. After
stirring for an additional 2 days, the reaction mixture was
quenched with a saturated aqueous NH4Cl solution. The or-
ganic layer was dried over Na2SO4 and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography to furnish 0.61 g (94%) of the titled compound
17 as a colorless oil: IR (thin film) 3065, 2948, 1712, 1584, and
1446 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.65-1.90 (m, 4H),
1.98-2.03 (m, 5H), 2.24-2.54 (m, 4H), 2.62-2.69 (m, 1H),
2.91-2.99 (m, 1H), 7.51 (t, 1H, J=8.0 Hz), 7.62-7.66 (m, 1H),
and 7.72 (dd, 1H, J=8.0 and 1.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.4, 25.4, 26.7, 30.1, 30.8, 38.0, 41.5, 129.0, 130.4,
134.4, 135.4, 205.3, and 206.8.
was purified by silica gel chromatography to provide 28 mg
(74%) of the titled compound 19 as a colorless oil: IR (thin film)
1
3411, 3027, 2925, 1615, and 1509 cm-1; H NMR (400 MHz,
CDCl3) δ 1.77-1.80 (m, 4H), 2.67-2.74 (m, 4H), 3.85 (brs, 1H),
4.32 s, 2H), 6.40 (d, 1H, J=2.4 Hz), 6.47 (dd, 1H, J=8.4 and 2.4
Hz), 6.92 (d, 1H, J=8.4 Hz), and 7.27-7.42 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 23.6, 23.8, 28.7, 29.9, 48.8, 111.3, 113.1,
126.6, 127.3, 127.7, 128.8, 130.0, 138.0, 140.0, and 146.2.
N,N-Dibenzyl-5,6,7,8-tetrahydronaphthalen-2-amine (20). A
40 mg (0.13 mmol) sample of ketosulfone 17 (or the cyclized
cyclohexanone derivative 16) and dibenzylamine (0.05 mL, 0.26
mmol) in toluene (1.5 mL) was treated with a catalytic amount
of p-TsOH. The reaction mixture was heated at reflux for 3 h and
then was cooled to room temperature. The solution was con-
centrated under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 38 mg (89%) of
the titled compound 20 as a colorless oil: IR (thin film) 3061,
3026, 2925, 1613, and 1510 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.73-1.80 (m, 4H), 2.25-2.71 (m, 4H), 4.64 (s, 4H), 6.52 (d, 1H,
J=2.8 Hz), 6.57 (dd, 1H, J=8.4 and 2.8 Hz), 6.91 (d, 1H, J=8.4
Hz), and 7.24-7.37 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
23.6, 23.8, 28.6, 30.1, 54.2, 110.8, 112.7, 125.7, 126.9, 128.8,
130.0, 138.0, 139.2, and 147.5.
N-Phenyl-5,6,7,8-tetrahydronaphthalen-2-amine (21). A solu-
tion containing 47 mg (0.15 mmol) of ketosulfone 17 (or the
cyclized cyclohexanone derivative 16) in toluene (1.5 mL) and
aniline (0.022 mL, 0.23 mmol) was treated with a catalytic
amount of p-TsOH. The reaction mixture was heated at reflux
for 4 h and then was cooled to room temperature. The solution
was concentrated under reduced pressure, and the resulting
residue was purified by silica gel chromatography to provide
10 mg (30%) of the titled compound 21 as a colorless oil: IR
1
(thin film) 3393, 3051, 3030, 2926, 1598, and 1497 cm-1; H
NMR (400 MHz, CDCl3) δ 1.76-1.81 (m, 4H), 2.70-2.77 (m,
4H), 6.82-6.91 (m, 3H), 6.98-7.05 (m, 3H), and 7.23-7.27 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 23.4, 23.6, 28.9, 29.8, 116.7,
117.1, 119.2, 120.4, 129.5, 130.0, 130.6, 138.3, and 140.4.
(S)-Methyl 2-(5,6,7,8-tetrahydronaphthalen-2-ylamino)-
3-phenylpropanoate (22). A 32 mg (0.10 mmol) sample of
ketosulfone 17 (or the cyclized cyclohexanone derivative 16),
NEt3 (0.018 mL, 0.135 mmol), and L-phenylalanine methyl ester
hydrochloride (29 mg, 0.14 mmol) in toluene (1 mL) was treated
with a catalytic amount of p-TsOH. The reaction mixture was
heated at reflux for 4 h and then was cooled to room tempera-
ture. The solvent was removed under reduced pressure, and the
resulting residue was purified by silica gel chromatography to
provide 23 mg (70%) of the titled compound 22 as a colorless oil:
IR (thin film) 3391, 3027, 2926, 1739, 1616, 1509 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.73-1.77 (m, 4H), 2.65-2.68 (m, 4H),
3.06-3.17 (m, 2H), 3.66 (s, 3H), 4.00 (brs, 1H), 3.66 (s, 3H), 4.33
(t, 1H), 6.33 (d, 1H, J=2.4 Hz), 6.40 (dd, 1H, J=2.4, 8.0 Hz),
6.89 (d, 1H, J=8.0 Hz), 7.17-7.32 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 23.5, 23.7, 28.7, 29.8, 39.0, 52.2, 58.2, 111.9,
114.0, 127.1, 127.5, 128.7, 129.4, 130.1, 136.7, 138.1, 144.3,
174.1.
6-(Benzyloxy)-1,2,3,4-tetrahydronaphthalene (23). A 55 mg
(0.18 mmol) sample of ketosulfone 17 (or the cyclized cyclohex-
anone derivative 16) and benzyl alcohol (0.04 mL, 0.36 mmol) in
toluene (2 mL) was treated with a catalytic amount of p-TsOH.
The reaction mixture was heated at reflux for 3 h and then was
cooled to room temperature. The solution was concentrated
under reduced pressure, and the resulting residue was purified
by silica gel chromatography to provide 38 mg (72%) of the
titled compound 23: IR (thin film) 3063, 3031, 2927, 1610, and
1501 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H),
2.70-80 (m, 4H), 5.05 (s, 2H), 6.73 (d, 1H, J=2.8 Hz), 6.77 (dd,
1H, J=8.4 and 2.8 Hz), 7.00 (d, 1H, J=8.4 Hz), and 7.32-7.47
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 23.4, 23.6, 28.8, 29.9,
Treatment of a sample of 17 with NaOMe in a benzene/
methanol mixture at 25 °C for 1 h afforded 8a-hydroxy-
4a-(phenylsulfonyl)octahydronaphthalen-2(1H)-one (16) in
75% yield.
1-(5,6,7,8-Tetrahydronaphthalen-2-yl)pyrrolidine (18). A 54
mg (0.17 mmol) sample of ketosulfone 17 (or the cyclized
cyclohexanone derivative 16) in toluene (2 mL) was treated with
a catalytic amount of p-TsOH and pyrrolidine (0.03 mL, 0.35
mmol). The reaction mixture was heated at reflux for 1 h and
was then cooled to room temperature. The solvent was removed
under reduced pressure, and the resulting residue was purified
by silica gel chromatography to provide 27 mg (80%) of the
titled compound 18 as a colorless oil: IR (thin film) 3051, 2925,
1616, ad 1513 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.76-1.79
(m, 4H), 1.97-2.00 (m, 4H), 2.65-2.79 (m, 4H), 3.23-3.27 (m,
4H), 6.30 (d, 1H, J=2.8 Hz), 6.41 (dd, 1H, J=8.0 and 2.8 Hz),
and 6.94 (d, 1H, J=8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
23.7, 24.0, 25.6, 28.6, 30.1, 48.0, 110.2, 112.0, 124.4, 129.9, 137.8,
and 146.4. HRMS calcd for [(C14H19N) þ H]þ: 202.1596.
Found: 202.1588.
N-Benzyl-5,6,7,8-tetrahydronaphthalen-2-amine (19). A 45
mg (0.13 mmol) sample of ketosulfone 17 (or the cyclized
cyclohexanone derivative 16) and benzylamine (0.03 mL, 0.29
mmol) in toluene (1.5 mL) was treated with a catalytic amount
of p-TsOH. The reaction mixture was heated at reflux for 20 min
and then was cooled to room temperature. The solution was
concentrated under reduced pressure, and the resulting residue
7786 J. Org. Chem. Vol. 74, No. 20, 2009

Kiren and Padwa
JOCArticle
70.2, 112.7, 115.0, 127.7, 128.0, 128.7, 129.8, 130.1, 137.6, 138.4,
and 156.8. HRMS calcd for [(C17H18O) þ H]þ: 239.1436.
Found: 239.1432.
same compound 28 was prepared by treating a sample of 27
under the above conditions.
1-(Biphenyl-3-yl)pyrrolidine (29). A solution containing dione
27 (or 28) (45 mg, 0.13 mmol) in toluene (1.3 mL) was treated
with a catalytic amount of p-TsOH and pyrrolidine (0.022 mL,
0.27 mmol). The reaction mixture was heated at reflux for 2 h
and was cooled to room temperature. The solvent was removed
under reduced pressure, and the resulting residue was purified
by silica gel chromatography to provide 16 mg (53%) of 29 as a
colorless oil: IR (thin film) 3055, 3030, 2963, 1597, 1568, 1484
6-Methoxy-1,2,3,4-tetrahydronaphthalene (24). A solution
containing 47 mg (0.15 mmol) of ketosulfone 17 (or the cyclized
cyclohexanone derivative 16) in toluene (1.5 mL) and methanol
(1.0 mL) was treated with a catalytic amount of p-TsOH. The
reaction mixture was heated at reflux for 1 h and then was cooled
to room temperature. The solution was concentrated under
reduced pressure, and the resulting residue was purified by silica
gel chromatography to provide 9 mg (35%) of the titled com-
pound 24 as a colorless oil: IR (thin film) 3059, 2927, 1610, 1501,
and 1253 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.76-1.80 (m,
4H), 2.68-2.78 (m, 4H), 3.75 (s, 3H), 6.61 (d, 1H, J=2.8 Hz),
6.68 (dd, 1H, J=8.4 and 2.8 Hz), and 6.98 (d, 1H, J=8.4 Hz).;
13C NMR (100 MHz, CDCl3) δ 23.3, 23.6, 28.7, 29.9, 55.4,
111.9, 113.8, 129.4, 130.1, 138.3, and 157.5.
cm-1
3.34-3.37 (m, 4H), 6.58 (dd, 1H, J=2.4, 8.4 Hz), 6.77 (s, 1H),
7.29-7.36 (m, 2H), 7.42-7.46 (m, 2H), 7.62-7.63 (m, 2H); 13
;
1H NMR (400 MHz, CDCl3) δ 2.02-2.05 (m, 4H),
C
NMR (100 MHz, CDCl3) δ 25.7, 47.9, 110.7, 110.9, 114.8, 127.2,
127.5, 128.7, 129.6, 142.5, and 148.4. HRMS calcd for
[(C16H17N) þ H]þ: 224.1439. Found: 224.1432.
N,N-Dibenzylbiphenyl-3-amine (30). A solution containing
dione 27 (or 28) (35 mg, 0.11 mmol) in toluene (1 mL) was
treated with a catalytic amount of p-TsOH and dibenzylamine
(0.04 mL, 0.21 mmol). The reaction mixture was heated at reflux
for 5 h and was cooled to room temperature. The solvent was
removed under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 36 mg (98%) of
the titled compound 30 as a colorless oil: IR (thin film) 3060,
Phenyl-(5,6,7,8-tetrahydronaphthalen-2-yl)sulfane (25). A so-
lution containing 24 mg (0.1 mmol) of 17 (or the cyclized
cyclohexanone derivative 16) in toluene (1 mL) and thiophenol
(0.1 mL, 1 mmol) was treated with a catalytic amount of
p-TsOH. The reaction mixture was heated at reflux for 2 h and
then was cooled to room temperature. The solution was concen-
trated under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 18 mg (98%) of
the titled compound 25 as a colorless oil: IR (thin film) 3058, 3008,
1
3028, 2924, 1597, 1569 cm-1; H NMR (400 MHz, CDCl3) δ
4.71 (s, 4H), 6.74 (dd, 1H, J=2.4, 8.0 Hz), 6.93-6.98 (m, 2H),
7.22-7.39 (m, 14H), and 7.46-7.48 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 54.4, 111.5, 111.7, 116.2, 126.9, 127.2, 127.3,
127.5, 128.8, 128.9, 129.8, 138.7, 142.2, 142.5, and 149.8.
(S)-Methyl-2-(biphenyl-3-ylamino)-3-phenylpropanoate (31).
A solution containing dione 27 (or 28) (35 mg, 0.11 mmol) in
toluene (1 mL) was treated with a catalytic amount of p-TsOH,
NEt3 (0.019 mL, 0.138 mmol) and L-phenylalanine methyl ester
hydrochloride (30 mg, 0.14 mmol). The mixture was heated at
reflux for 7 h and was then cooled to room temperature. The
solvent was removed under reduced pressure, and the resulting
residue was purified by silica gel chromatography to provide
12 mg (34%) of the titled compound 31 as a colorless oil: IR
(thin film) 3396, 3028, 2924, 1738, 1604, 1567 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.11-3.23 (m, 2H), 3.69 (s, 3H), 4.27 (brs,
1H), 4.44 (t, 1H, J=6.0 Hz), 6.60 (dd, 1H, J=8.4 and 2.4 Hz),
6.81 (s, 1H), 6.98 (d, 1H, J=8.0 Hz), 7.18-7.35 (m, 7H), 7.42 (t,
2H, J=8.0 Hz), and 7.54 (d, 2H, J=8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 29.9, 38.9, 52.4, 59.0, 112.6, 117.8, 127.2, 127.3,
127.4, 128.8, 128.8, 129.5, 129.5, 129.9, 136.4, 141.6, 142.7,
146.9, and 173.8.
2928, 1582, and 1477 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.77-1.80 (m, 4H), 2.70-2.77 (m, 4H), 7.02 (d, 1H, J=8.0 Hz),
and 7.11-7.14 (m, 2H), 7.16-7.20 (m, 1H), and 7.24-7.29 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 23.1, 23.2, 29.3, 29.4, 126.4,
129.2, 129.7, 129.8, 130.3, 131.0, 133.2, 137.2, 137.5, and 138.5.
1-Phenyl-2-(phenylsulfonyl)hexane-1,5-dione (27). A sample
of 2-(phenylsulfonyl)acetophenone (26)23 (0.5 g, 1.9 mmol) was
dissolved in 15 mL of CH2Cl2 and was treated with NEt3 (0.32
mL, 2.3 mmol). After 20 min of stirring at room temperature,
methyl vinyl ketone (0.21 mL, 2.5 mmol) was added to the
reaction mixture. Stirring was continued for 4 days, and the
mixture was quenched with a saturated aqueous NH4Cl solu-
tion. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography to furnish 0.56 g (88%) of the titled
compound 27 as a white solid: mp 105-106 °C; IR (thin film)
1
3065, 2934, 1714, 1679, and 1596 cm-1; H NMR (400 MHz,
CDCl3) δ 2.08 (s, 3H), 2.22-2.32 (m, 1H), 2.35-2.48 (m, 2H),
2.65-2.73 (m, 1H), 5.35-5.38 (m, 1H), 7.45-7.53 (m, 4H),
7.59-7.66 (m, 2H), 7.80 (dd, 2H, J=8.4 and 1.2 Hz), 7.94 (dd,
2H, J=8.4 and 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 22.3,
30.1, 39.6, 68.3, 129.0, 129.2, 129.8, 134.4, 134.5, 136.7, 136.9,
192.6, and 207.4.
Biphenyl-3-yl(phenyl)sulfane (32). A solution containing
dione 27 (or 28) (40 mg, 0.12 mmol) in toluene (1.2 mL) was
treated with a catalytic amount of p-TsOH and thiophenol (0.12
mL, 1.2 mmol). The reaction mixture was heated at reflux for 5 h
and was then cooled to room temperature. The solvent was
removed under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 32 mg (98%) of
the titled compound 32 as a colorless oil: IR (thin film) 3057,
3-Hydroxy-3-phenyl-4-(phenylsulfonyl)cyclohexanone (28). A
sample of 2-(phenylsulfonyl)acetophenone (26) (0.5 g, 1.9
mmol) was dissolved in 3 mL of MeOH and 12 mL of benzene
and was treated with NaOMe (0.12 g, 2.1 mmol). After 20 min of
stirring at room temperature, methyl vinyl ketone (0.2 mL, 2.5
mmol) was added to the reaction mixture. Stirring was contin-
ued for 16 h, and the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc and was washed
with a saturated aqueous NH4Cl solution. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
to provide 0.51 g (80%) of the titled compound 28 as a white
solid: mp 176-178 °C; IR (thin film) 3466, 3053, 2958, 1715, and
1445 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.49-2.77 (m, 6H),
4.12 (dd, 1H, J=10.4 and 2.8 Hz), 4.64 (d, 1H, J=2.8 Hz),
6.99-7.12 (m, 5H), 7.19-7.28 (m, 4H), and 7.40-7.44 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 21.8, 39.4, 55.6, 67.0, 125.0,
127.6, 127.8, 128.4, 129.1, 133.2, 140.0, 142.1, and 205.6. HRMS
calcd for [(C18H18O4S) þ H]þ: 331.1004. Found: 331.1003. The
1
2924, 1586, 1562, 1466 cm-1; H NMR (400 MHz, CDCl3) δ
7.26-7.29 (m,1H), 7.31-7.50 (m, 10H), 7.54-7.58 (m, 2H), and
7.62 (t, 1H, J=1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 126.1,
127.3, 127.8, 129.0, 129.5, 129.80, 129.83, 129.9, 131.3, 135.8,
136.6, 140.5, and 142.4.
Biphenyl-3-yl(butyl)sulfane (33). A solution containing dione
27 (or 28) (36 mg, 0.11 mmol) in toluene (1 mL) was treated with
a catalytic amount of p-TsOH and n-butylthiol (0.12 mL, 1.1
mmol). The reaction mixture was heated at reflux for 2 h and
was then cooled to room temperature. The solvent was removed
under reduced pressure, and resulting residue was purified by
silica gel chromatography to provide 26 mg (98%) of the titled
compound 33 as a colorless oil: IR (thin film) 3058, 3030, 2957,
1588, 1563, and 1465 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.94
J. Org. Chem. Vol. 74, No. 20, 2009 7787

Kiren and Padwa
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(t, 3H, J=7.2 Hz), 1.49 (sextet, 2H, J=7.2 Hz), 1.68 (p, 2H, J=
7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 7.29-7.41 (m, 4H), 7.43-7.48
(m, 2H), and 7.55-7.60 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
13.9, 22.2, 31.4, 33.4, 124.8, 127.3, 127.6, 129.0, 129.3, 137.8,
140.9, and 142.1.
20 min of stirring at room temperature, 3-penten-2-one (0.22
mL, 1.44 mmol) was added to the reaction mixture. Stirring was
continued for 2 days, and then the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc and
washed with a saturated aqueous NH4Cl solution. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by silica gel chro-
matography to provide 0.19 g (57%) of the titled compound 37
as a white solid: mp 186-187 °C; IR (thin film) 3346, 3066, 1712,
3-Hydroxy-2-methyl-3-phenyl-4-(phenylsulfonyl)cyclohexanone
(34). A sample of 2-(phenylsulfonyl)acetophenone (26) (0.4 g, 1.5
mmol) dissolved in 2 mL of MeOH and 8 mL of benzene was
treated with NaOMe (0.1 g, 1.8 mmol). After 20 min of stirring at
room temperature, ethyl vinyl ketone (0.24 mL, 2.3 mmol) was
added to the reaction mixture. Stirring was continued for 3 h, and
then the solution was concentrated under reduced pressure. The
residue was dissolved in EtOAc and washed with a saturated
aqueous NH4Cl solution. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to provide 0.2 g
(42%) of the titled compound 34 as white solid: mp 170-172 °C;
IR (thin film) 3468, 3069, 2981, 1710, 1638, and 1446 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.61 (d, 3H, J=6.8 Hz), 2.55-2.80
(m, 5H), 4.19 (dd, 1H, J = 12.4 and 4.0 Hz), 4.52 (brs, 1H),
6.92-7.16 (m, 4H), 7.18-7.26 (m, 5H), and 7.38-7.43 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 7.2, 22.1, 39.6, 55.0, 68.4, 80.1,
125.7, 127.5, 127.7, 128.3, 129.0, 133.0, 140.0, 140.8, and 207.1.
HRMS calcd for [(C19H20O4S) - H3O]þ: 327.1055. Found:
327.1051.
In addition to compound 34, 0.15 g (28%) of 1-phenyl-
2-(phenylsulfonyl)-heptane-1,5-dione was obtained as a white
solid: mp 120-122 °C; IR (thin film) 3067, 2977, 1713, 1678, and
1596 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J=7.2
Hz), 2.21-2.42 (m, 5H), 2.59-2.67 (m, 1H), 5.34-5.38 (m, 1H),
7.42-7.50 (m, 4H), 7.56-7.63 (m, 2H), 7.76-7.78 (m, 2H), and
7.90-7.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.8, 22.4,
36.1, 38.2, 68.3, 129.0, 129.1, 129.2, 129.8, 134.41, 134.48, 136.7,
136.9, 192.7, and 210.2. HRMS calcd for [(C19H20O4S) þ H]þ:
345.1161. Found: 345.1162.
1
1445, and 1146 cm-1; H NMR (400 MHz, CDCl3) δ 1.43 (d,
3H, (J = 7.2 Hz), 2.29-2.36 (m, 1H), 2.45-2.58 (m, 2H),
3.32-3.41 (m, 2H), 3.70 (d, 1H, J=6.0 Hz), 5.02 (d, 1H, J=
2.8 Hz), 7.00-7.10 (m, 5H), 7.19-7.26 (m, 4H), and 7.38-7.43
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.5, 27.4, 45.6, 54.0,
73.2, 76.5, 125.1, 127.5, 127.6, 128.4, 129.0, 133.1, 140.4, 142.8,
and 207.7.
1-(5-Methylbiphenyl-3-yl)pyrrolidine (38). A solution of the
above compound 37 (37 mg, 0.11 mmol) in toluene (1 mL) was
treated with a catalytic amount of p-TsOH and pyrrolidine
(0.018 mL, 0.21 mmol). The reaction mixture was heated at
reflux for 4 h and was cooled to room temperature. The solvent
was removed under reduced pressure and resulting residue was
purified by silica gel chromatography to provide 4.4 mg (17%)
of the titled compound 38 as a colorless oil: IR (thin film) 3057,
2959, 2924, 1598, and 1576 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.99-2.02 (m, 4H), 2.37 (s, 3H), 3.32-3.35 (m, 4H), 6.40 (s, 1H),
6.57 (s, 1H), 6.71 (s, 1H), 7.30-7.34 (m, 1H), 7.36-7.43 (m, 2H),
and 7.58-7.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.6,
29.9, 47.9, 108.1, 111.6, 115.9, 127.1, 127.5, 128.7, 139.3, 142.5,
142.6, and 148.5. HRMS calcd for [(C17H19N) þ H]þ:
238.1596. Found: 238.1591.
(5-Methylbiphenyl-3-yl)(phenyl)sulfane (39). A solution con-
taining 37 (30 mg, 0.087 mmol) in toluene (1 mL) was treated
with a catalytic amount of p-TsOH and thiophenol (0.089 mL,
0.89 mmol). The reaction mixture was heated at reflux for 2 h
and was then cooled to room temperature. The solvent was
removed under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 23 mg (96%) of
the titled compound 39 as a colorless oil: IR (thin film) 3058,
3035, 2922, 1570, and 1477 cm-1; 1H NMR (400 MHz, CDCl3) δ
2.38 (s, 3H), 7.16-7.19 (m, 1H), 7.23-7.27 (m, 1H), 7.30-7.42
(m, 9H), and 7.52-7.55 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
21.6, 127.2, 127.3, 127.7 128.9, 129.4, 130.8, 131.0, 136.0, 136.1,
139.6, 140.7, and 142.4.
1-(2-Methylbiphenyl-3-yl)pyrrolidine (35). A solution con-
taining 50 mg (0.145 mmol) of 34 in toluene (1.5 mL) was
treated with a catalytic amount of p-TsOH and pyrrolidine
(0.024 mL, 0.290 mmol). The reaction mixture was subjected
to microwave irradiation at 120 °C (150 W) with a maximum
internal pressure of 100 psi for 10 min. After the reaction
mixture cooled to rt, the solvent was removed under reduced
pressure, and the resulting residue was purified by silica gel
chromatography to provide 22 mg (64%) of the titled compound
35 as a clear oil: IR (thin film) 3056, 3027, 2963, 1600, 1561 cm-1
;
4-Methyl-1-phenyl-2-(phenylsulfonyl)hexane-1,5-dione (40).
A sample of 2-(phenylsulfonyl)acetophenone (26) (0.3 g, 1.15
mmol) was dissolved in 1.5 mL of MeOH and 6 mL of benzene
and was treated with NaOMe (0.08 g, 1.38 mmol). After 20 min
of stirring at room temperature, 3-methylbut-3-en-2-one (0.15 g,
1.4 mmol) was added to the reaction mixture. Stirring was
continued for 2 days, and the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc and
washed with a saturated aqueous NH4Cl solution. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by silica gel chro-
matography to provide 0.23 g (58%) of a 1:1 mixture of
diastereomers of dione 40 as a clear oil: IR (thin film) 3064,
2970, 2964, 1619, and 1567 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.08 (d, 3H, J=6.8 Hz), 1.11 (d, 3H, J=7.2 Hz), 1.94 (s, 3H),
2.13-2.20 (m, 5H), 2.27-2.44 (m, 3H), 2.85-2.94 (m, 1H), 5.20
(t, 1H, J =7.2 Hz), 5.26-5.29 (m, 1H), 7.41-7.63 (m, 12H),
7.73-7.79 (m, 4H), 7.84-7.93 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 17.0, 17.9, 28.1, 28.6, 29.9, 30.3, 30.5, 44.0, 44.2, 67.5,
67.7, 128.8, 129.0, 129.5, 129.7, 129.8, 134.3, 134.42, 134.48,
136.5, 136.8, 136.9, 137.1, 192.5, 192.6, 211.2, and 211.4.
1-(4-Methylbiphenyl-3-yl)pyrrolidine (41). A solution of dione
40 (60 mg, 0.17 mmol) in toluene (2 mL) was treated with
a catalytic amount of p-TsOH and pyrrolidine (0.029 mL,
1H NMR (400 MHz, CDCl3) δ 1.95-1.98 (m, 4H), 2.38 (s, 2H),
3.24-3.30 (m, 4H), 7.06-7.11 (m, 2H), 7.20 (d, 1H, J=8.0 Hz),
7.29-7.45 (m, 3H), and 7.57-7.62 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 20.6, 25.2, 51.2, 114.8, 119.1, 127.0, 127.3,
127.8, 128.8, 132.3, 139.6, 142.0, and 149.8. HRMS calcd for
[(C17H19N) þ H]þ: 238.1596. Found: 238.1591.
(2-Methylbiphenyl-3-yl)(phenyl)sulfane (36). A solution con-
taining 31 mg (0.09 mmol) of 34 in toluene (1 mL) was treated
with a catalytic amount of p-TsOH and thiophenol (0.09 mL, 0.9
mmol). The mixture was heated at reflux for 2 h and was then
cooled to room temperature. The solvent was removed under
reduced pressure, and the resulting residue was purified by silica
gel chromatography to provide 23 mg (92%) of the titled
compound 36 as a colorless oil: IR (thin film) 3057, 3027,
2923, 1582, and 1562 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.32 (s, 3H), 7.17-7.19 (m, 2H), 7.24-7.28 (m, 2H), 7.30-7.38
(m, 7H), and 7.41-7.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
18.4, 126.3, 126.9, 127.2, 128.3, 129.4, 130.7, 131.3, 135.6, 135.9,
136.8, 142.0, and 143.5.
3-Hydroxy-5-methyl-3-phenyl-4-(phenylsulfonyl)cyclohexanone
(37). A sample of 2-(phenylsulfonyl)acetophenone (26) (0.25 g,
0.96 mmol) was dissolved in 1.5 mL of MeOH and 6 mL of
benzene and was treated with NaOMe (0.07 g, 1.2 mmol). After
7788 J. Org. Chem. Vol. 74, No. 20, 2009

Kiren and Padwa
JOCArticle
0.34 mmol). The reaction mixture was heated at reflux for 15 h
and was cooled to room temperature. The solvent was removed
under reduced pressure, and resulting residue was purified by
silica gel chromatography to provide 23 mg (57%) of the titled
compound 41 as a colorless oil: IR (thin film) 3057, 3028, 2963,
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography to furnish 0.41
g (82%) of the titled compound 44 as a colorless oil: IR (thin
1
film) 3066, 2980, 1713, 1447, and 1303 cm-1; H NMR (400
MHz, CDCl3) δ 1.05 (t, 3H, J=7.8 Hz), 1.55 (s, 3H), 2.06-2.17
(m, 4H), 2.24-2.45 (m, 3H), 2.74-2.93 (m, 2H), 7.52-7.56 (m,
2H), 7.65-7.69 (m, 1H), and 7.72-7.75 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 8.1, 16.3, 26.8, 30.1, 34.0, 38.2, 75.7, 129.1,
130.4, 134.5, 135.0, 205.5, and 206.5.
1600, 1561, and 1484 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.95-1.99 (m, 4H), 2.39 (s, 3H), 3.25-3.30 (m, 4H), 7.08 (dd,
1H, J=8.0 and 1.6 Hz), 7.11 (d, 1H, J=1.6 Hz), 7.20 (d, J=8.0
Hz), 7.31-7.36 (m, 1H), 7.41-7.45 (m, 2H), 7.59-7.62 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 20.6, 25.2, 51.2, 114.8, 119.1,
127.0, 127.3, 127.8, 128.8, 132.3, 139.6, 142.1, 149.8. HRMS
calcd for [(C17H19N) þ H]þ: 238.1596. Found: 238.1592.
1-(3-Ethyl-4-methylphenyl)pyrrolidine (45). A solution of the
above compound 44 (34 mg, 0.12 mmol) in toluene (1 mL) was
treated with a catalytic amount of p-TsOH and pyrrolidine
(0.019 mL, 0.23 mmol). The mixture was heated at reflux for 4
h and was then cooled to room temperature. The solvent was
removed under reduced pressure, and the resulting residue was
purified by silica gel chromatography to provide 13 mg (60%) of
the titled compound 45 as a colorless oil: IR (thin film) 2963,
2927, 1616, 1511, and 1366 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.21 (t, 3H, J=8.0 Hz), 1.97-2.00 (m, 4H), 2.21 (s, 3H), 2.58 (q,
2H, J=8.0 Hz), 3.25-3.28 (m, 4H), 6.37 (dd, 1H, J=8.0 and 2.4
(4-Methylbiphenyl-3-yl)(phenyl)sulfane (42). A solution of of
dione 40 (58 mg, 0.17 mmol) in toluene (1 mL) was treated with a
catalytic amount of p-TsOH and thiophenol (0.086 mL, 0.84
mmol). The mixture was heated at reflux for 2 h and was then
cooled to room temperature. The reaction solvent was removed
under reduced pressure, and the resulting residue was purified
by silica gel chromatography to provide 41 mg (90%) of the
titled compound 42 as a colorless oil: IR (thin film) 3058, 3026,
2920, 1581, and 1553 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.43
(s, 3H), 7.19-7.35 (m, 7H), 7.39-7.43 (m, 2H), 7.48 (dd, 1H, J=
Hz), 6.42 (d, 1H, J=2.4 Hz), and 7.00 (d, 1H, J=8.0 Hz); 13
C
NMR (100 MHz, CDCl3) δ 14.9, 18.2, 25.6, 27.0, 48.0, 109.5,
111.9, 122.7, 130.8, 143.2, and 146.9. HRMS calcd for
[(C13H19N) þ H]þ: 190.1596. Found: 190.1588.
8.0 and 2.0 Hz), 7.51-7.54 (m, 2H), 7.60 (d, 1H, J=2.0 Hz); 13
C
NMR (100 MHz, CDCl3) δ 20.5, 126.6, 126.8, 127.1, 127.5,
129.0, 129.4, 129.6, 131.2, 131.9, 134.3, 136.3, 139.3, 139.9,
140.4.
Acknowledgment. Financial support provided by the
National Science Foundation (CHE-0742663) is greatly
appreciated.
5-Methyl-5-(phenylsulfonyl)octane-2,6-dione (44). A sample
of 2-(phenylsulfonyl)-pentan-3-one (43)26 (0.4 g, 1.8 mmol)
dissolved in 15 mL of CH2Cl2 was treated with NEt3 (0.34
mL, 2.4 mmol). After 20 min of stirring at room temperature,
methyl vinyl ketone (0.28 mL, 3.5 mmol) was added to the
reaction mixture. Stirring was continued for an additional 8
days, and the mixture was then quenched with a saturated
aqueous NH4Cl solution. The organic layer was dried over
Supporting Information Available: 1H and 13C NMR data
of various key compounds together with an ORTEP drawing for
compound 9, as well as the corresponding CIF file. Atomic
coordinates for compound 9 will be deposited with the
Cambridge Crystallographic Data Centre. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Xie, Y.-Y.; Chen, Z. C. Synth. Commun. 2001, 31, 3145.
J. Org. Chem. Vol. 74, No. 20, 2009 7789