An umpolung sulfoxide reagent for use as a functionalized benzyl carbanion equivalent

Article abstract of DOI:10.1016/j.tet.2011.05.033

N-Methyl ortho-carbamoylaryl benzyl sulfoxides can be used as synthetic equivalents for α-hydroxy, α-chloro, and α-acetammido benzyl carbanions by means of a two-step sequence involving highly diastereoselective α-C-alkylation with alkyl halides followed by displacement of the sulfinyl residue (which can be recovered and recycled) by a hydroxyl, a chlorine or an acetamido, respectively, under non-oxidative Pummerer conditions. The scope and limits of the method, including a stereoselective version of the reaction, as well as the mechanism of the process are discussed in detail.

Full text of DOI:10.1016/j.tet.2011.05.033

Tetrahedron 67 (2011) 5268e5281
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An umpolung sulfoxide reagent for use as a functionalized benzyl carbanion
equivalentq
Giovanni Pinna a, Maria Cristina Bellucci b, Luciana Malpezzi a, Laura Pisani c, Stefano Superchi c,
,
d
,
d,e,
*
Alessandro Volonterio a , Matteo Zanda
*
a Dipartimento di Chimica, Materiali e Ingegneria Chimica, Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy
Dipartimento di Scienze Molecolari Agroalimentari, Universita degli Studi di Milano, via Celoria 2, 20133, Milano, Italy
b
ꢀ
c
ꢀ
Dipartimento di Chimica, Universita della Basilicata, via dell’Ateneo Lucano 10, 85100 Potenza, Italy
d C.N.R.-I.C.R.M., via Mancinelli 7, 20131 Milano, Italy
e Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Methyl ortho-carbamoylaryl benzyl sulfoxides can be used as synthetic equivalents for
a-hydroxy,
Received 14 February 2011
Received in revised form 20 April 2011
Accepted 9 May 2011
a
-chloro, and
a
a
-acetammido benzyl carbanions by means of a two-step sequence involving highly dia-
-C-alkylation with alkyl halides followed by displacement of the sulfinyl residue (which
stereoselective
can be recovered and recycled) by a hydroxyl, a chlorine or an acetamido, respectively, under non-
oxidative Pummerer conditions. The scope and limits of the method, including a stereoselective ver-
sion of the reaction, as well as the mechanism of the process are discussed in detail.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 14 May 2011
Keywords:
Umpolung
Sulfoxide
Stereoselectivity
Pummerer reaction
1. Introduction
and its isotopes (Dꢀ and Tꢀ), by using a hexacoordinated dihy-
drophosphate as a key species,5 halogens by using halide sources
The methods for achieving umpolung reactivity of the natural
reactivity of functional groups, developed over the last four decades
has proved to be a significant enrichment in synthetic organic
chemistry.1 The problem owes the start of its vigorous research to
Corey and Seebach in the mid 1960s2 when they defined umpolung
as ‘any process by which donor and acceptor reactivity of an atom
are interchanged’.3 In their pioneering work, they reversed the
electrophilic character of an acyl carbon by creating a nucleophilic
acylating reagent by protecting the carbonyl group of an aldehyde
as dithioacetal. Since then, the concept of polarity inversion of
functional groups has considerably expanded the portfolio of useful
chemical transformations and has been consequently well used in
organic synthesis. Not only have many other different nucleophilic
acylating reagents been developed, such as unprotected acyl or
acyl-analogous derivatives, vinyl-ether type protected acyl anions,
and aldeydes hydrazones,4 but the concept has been applied to
reverse the polarity of atoms other than carbon, such as hydrogen
(Xꢀ) in combination with readily available oxidizing agents, thereby
affecting the in situ generation of Xþ equivalents,6 and nitrogen in
the addition to imine double bond in which the nitrogen acts as the
electrophilic center.7 Moreover, the umpolung concept has rou-
tinely been used in organometallic chemistry,8 and very recently,
has also been applied to aromatic chemistry by converting an
electron-rich aromatic ring (nucleophile) to the relatively highly
electrophilic quinone species,9 and to peptide chemistry by per-
forming the synthesis of amides using
a-halo nitroalkanes as acyl
donors for a variety of common amines.10
Sulfoxides constitute a family of organic compounds, which has
gained importance during the past decades. The intrinsic stereo-
genicity of the sulfinyl sulfur, as well as its configurational stability,
makes possible the synthesis of optically pure sulfoxides, which are
of importance in medicinal and pharmaceutical chemistry, and
have contributed to enhance the synthetic importance of sulfoxides
in the field of asymmetric synthesis.11 In this context,
a-sulfinyl
carbanions are useful chiral intermediates, which have been used
extensively to achieve stereoselective CeC bond-forming reactions
by alkylation with suitable electrophiles, Michael addition to
q
In memory of Prof. Carlo Rosini.
a,
b
-unsaturated systems, addition to C¼O bonds of aldehydes and
* Corresponding authors. Tel.: þ39 02 23993139; fax: þ39 02 23993180 (A.V.);
tel.: þ44 01224 555732; fax: þ44 01224 555844 (M.Z.); e-mail addresses: ales-
sandro.volonterio@polimi.it (A. Volonterio), m.zanda@abdn.ac.uk (M. Zanda).
ketones and addition to C¼N bonds of imines.12 In this context, we
recently demonstrated that enantiomerically pure a-Li sulfoxides
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.033

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5269
can be used as chiral
a
-hydroxy and
a
-chloro carbanion equivalents
NOCPR-like outcomes, namely the formation of the corresponding
alcohol 3 and chloride 4. Using Tf2O as a promoter of the Pummerer
reaction in some cases we observed the formation of products,
which very likely came from the intermediate formation of a ben-
zylic carbocation.20 Since Tf2O reacts with the sulfinyl oxygen
producing TfOꢀ, which is an extremely poor nucleophile, we argued
that the same reaction in the presence of a nucleophilic solvent,
such as acetonitrile could be used to form the corresponding
acetamides 5.
The process portrayed in Scheme 1 leads to the formation of
benzisothiazolone 6 as the co-product. However, 6 could be easily
recycled by a three-step synthetic sequence, namely regioselective
reduction of the NeS bond, alkylation of the corresponding thio-
phenol, and oxidation of the sulfide into sulfoxide 1. The possibility
to reconvert the co-product 6 into the starting sulfoxide 1 was
conceived as an advantage in terms of atom economy.
with alkyl and aryl imines,13 by means of a two-step procedure
based on: (1) CeC bond-forming reaction leading to
b-sulfinyl
amines, and (2) ‘non-oxidative’ Pummerer reaction (NOPR)14 or
chloro-Pummerer reaction (NOCPR),15 which allow for replacing
the sulfinyl auxiliary by an OH or a Cl atom, respectively, with an
SN2-like pathway (stereoinversion at carbon). This strategy was
exploited by us and others for the stereoselective synthesis of bi-
ologically important
trifluoromethyl (Tfm) analog,16 Tfm-analogs of ephedra alkaloids,17
several phenyl-glycinols,18 -chloro-amines and aziridines.15 As an
b
-amino-alcohols, such as statine,15 and its
b
extension of this synthetic concept, we commenced a project aimed
at developing sulfoxide reagents to be used as functionalized
carbanion equivalents of broader scope. For this purpose, we re-
cently demonstrated the usefulness of an arylsulfoxide reagent
bearing an ortho-N-methylformamide function, as umpolung
a
-hydroxy and
a
-chloro benzyl carbanion equivalents19 as well as
Since it has been demonstrated that NOPR and NOCPR per-
precursor for the synthesis of both aryl-tetralin and benzopyran
structural frameworks.20 In this paper, we provide a full account on
the scope and limits of this methodology as well as a discussion of
the mechanism. Of particular interest are (1) a new application of
such reagent as a-acetamido benzyl carbanion equivalent and (2)
the use of an optically enriched version of this sulfoxide reagent for
the synthesis of non-racemic products (Fig. 1).
formed on
to the formation of optically pure
b
-sulfinyl amines are stereoselective processes leading
a
-amino alcohols and -chlorides,
respectively, through an SN2-like pathway,14,15 we decided to pre-
pare enantiomerically enriched sulfoxides 1 in order to (1) in-
vestigate whether the reaction is stereoselective or rather takes
place through the formation of a carbocation intermediate and (2)
obtain non-racemic alcohols 3, chlorides 4, and acetamides 5.
Cl
Ar
2.1. Synthesis of sulfoxides 1
HO
H
Ar
H
The preparation of racemic sulfoxides (ꢁ)-1 started with S-al-
kylation of commercially available thiosalicylic acid with alkyl ha-
lides affording the ortho-carboxy sulfides 7, which were
transformed into amides 8 by coupling with CH3NH2 and (CH3)2NH,
and oxidized with MCPBA to (ꢁ)-1aeg in good overall yields
(Scheme 2, Table 1).
O
S
Ar
N
O
SH
S
R1
R1CH2X
R2NHCH3
TEA
dioxane
H
N
COOH
COOH
BOP-DIPEA
DMF
Ar
7
H
O
S
O
R1
S
R1
MCPBA
Fig. 1. The new chiral umpolung synthon.
NR2CH3
NR2CH3
CHCl3
0 °C
2. Results
(±)-1
8
O
O
In our strategy C-alkylation of racemic ortho-[(N-alkyl)carba-
moyl]phenyl sulfoxide 1 with an alkyl halide was planned to give
Scheme 2. Preparation of sulfoxides (ꢁ)-1.
the a-alkylsulfoxide 2. Next we expected that treatment of 2 under
Similarly, enantiomerically pure sulfoxides (þ)-1a and (ꢀ)-1a
were prepared by S-alkylation of thiosalycilic acid with benzyl
bromide and treatment of the resulting sulfide with enantiomeri-
Pummerer or chloro-Pummerer conditions, i.e., trifluoroacetic an-
hydride (TFAA) or oxalyl chloride, respectively, in the presence of
1 equiv of sym-collidine (TMP) in DCM, could give rise to NOPR- or
cally pure (þ)-2-b-naphthyl-ethylamine (Scheme 3). The following
1. TFFA, TMP,
DCM
OH
3
+
∗
R
R1
2. quench
O
S
O
S
R1
NHR2
1
1. Base
R1
∗
Cl
S
(COCl)2
4
N
R2
+
+
R
O
R
R1
∗
TMP, DCM
2. RX
6
O
1. Tf2O, TMP,
CH3CN
O
2
NHR2
NHAc
5
2. quench
R
R1
∗
Recycle
Scheme 1. Planned synthetic strategy.

5270
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
Table 1
Preparation of sulfoxides (ꢁ)-1
Entry
Prod.
X
R1
R2
Yielda (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Br
Br
Br
Br
Br
I
C6H5
4-MeOeC6H4
4CF3eC6H4
4NO2eC6H4
Et
H
Ph
H
H
H
H
H
H
Me
82
78
68
75
81
77
84
1g
Br
a
Overall isolated yield from thiosalicylic acid.
At first, oxidation of 8a was carried out using (R,R)-DPED as chiral
ligand and following the best standard conditions set up in previous
work.21a,b The reaction was then carried out at a temperature of 0 ꢂC
in CCl4, under N2 atmosphere, employing a reagent ratio sulfide/
DPED/Ti/H2O¼1.0:0.1:0.05:1.0 and 2 equiv of TBHP (70% in water) as
oxidant. Usually, these optimized conditions are the best compro-
mise in order to limit sulfone formation (<10%), to have a satisfac-
tory conversion, and good to high ees. However, under these
conditions the reaction of 8awas very slowand sulfoxide (ꢀ)-1awas
obtained in modest 46% ee and low28% yield after4 h. This result can
be ascribed to the very low solubility of 8a in CCl4. The long reaction
time can also explain the low ee obtained, because it has been
demonstrated that the Ti-DPED alcoholate, i.e., the chiral catalyst,
spontaneouslydecomposes aftersomehours.21a Wethenperformed
the oxidation at 0 ꢂC and with the same reagents ratio but in CH2Cl2,
where 8a is completely soluble. Also in these conditions, however,
a modest 46% ee was obtained, enriched to 60% ee by a single re-
crystallization fromhexane. Alsothereactionperformedin CH2Cl2 at
rt, with the aim to speed up the reaction, provided (ꢀ)-1a in the
same ee. Finally, the reaction was performed in CCl4 at rt. In these
conditions sulfide 8a slowly dissolves, giving rise to a homogeneous
solution after 5 h. The reaction was stopped after 20 h, recovering
sulfoxide (ꢀ)-1a in excellent 94% yield and satisfactory 70% ee. After
a single recrystallization from hexane sulfoxide (ꢀ)-1a was re-
covered in 80% ee and 85% overall yield.
1)
PhCH2Br
TEA
dioxane
S
Ph
SH
MCPBA
O
2) (R)-(+)-9,
BOP-DIPEA
DMF
CHCl3
0 °C
COOH
HN
10
O
S
O
Ph
S
Ph
+
O
O
NH2
HN
HN
(R)-(+)-9
(SS)-11
(RS)-11
1) KOH, EtOH
1) KOH, EtOH
2) CH3NH2
BOP-DIPEA
DMF
2) CH3NH2
BOP-DIPEA
DMF
O
S
O
Ph
S
Ph
O
O
NH
NH
α
α
(-)-1a [ ] =-258.3
(+)-1a [ ] = +256.8
ee > 98%
ee > 98%
Scheme 3. Preparation of enantiomerically pure sulfoxides (þ)- and (ꢀ)-1a.
In previous studies the use of (R,R)-DPED as chiral ligand for
sulfide oxidation always provided aryl benzyl sulfoxides of (S) ab-
solute configuration,21 therefore we could expect also in this case
the same stereochemical outcome. In order to obtain a reliable
assignment of the absolute configuration of (ꢀ)-1a analysis of its
circular dichroism (CD) spectrum (Fig. 2) was undertaken. An em-
pirical correlation between CD spectra and absolute configuration
of aryl alkyl sulfoxides was established by Mislow and co-workers
oxidation with MCPBA afforded an equimolar mixture of the two
diastereoisomers (SS)- and (RS)-11, which were easily separated by
flash-chromatography. After basic hydrolysis with KOH in refluxing
ethanol, followed by coupling of the resulting acid with CH3NH2 in
the same conditions described above we obtained the formation of
(þ)-1a and (ꢀ)-1a with ee >98%.
The preparation of enantiomerically enriched sulfoxide (ꢀ)-1a
was also attempted by Ti-catalyzed enantioselective oxidation of
sulfide 8a. Oxidation of 8a was then performed with tert-butyl
hydroperoxide (TBHP) in the presence of catalytic amounts of the Ti
alcoholate of enantiopure 1,2-diphenylethane-1,2-diol (DPED),
100
40
Δε
-3
x 10
ε
80
60
40
20
0
20
0
following
a procedure, which proved to be highly efficient
CD
and enantioselective in the oxidation of aryl benzyl sulfides
(Scheme 4).21
O
-20
S
Ph
S
Ph
(R,R)-DPED, Ti(i-PrO)4
UV
O
O
TBHP, H2O
solvent
-40
NH
8a
NH
200
250
300
350
/
nm
λ
(-)-1a
Scheme 4. Enantioselective oxidation of sulfide 8a.
Fig. 2. UV and CD spectra (CH3CN) of sulfoxide (ꢀ)-1a.

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5271
more than forty years ago,22 but only more recent nonempirical
analyses of their CD spectra provided suitable methods for a reli-
able absolute configuration assignment of these compounds.23 In
these recent studies it has been shown that in phenyl alkyl and
phenyl benzyl sulfoxides two main absorption bands appear at 220
and 250 nm allied, respectively, to the 1La benzene transition and
the S¼O transition. In correspondence to these two absorptions
oppositely signed Cotton effects (CEs) appear in the CD spectrum,
the longer wavelength one being negative for a (S) configured
sulfoxide. The presence of substituents on both the phenyl moieties
does not affect the main spectral features and only in the presence
of strong electron withdrawing substituents, like the nitro one,
a red shift was observed in both the UV and CD spectra. Very re-
cently, the CD spectra of aryl benzyl sulfoxides have also been
interpreted by means of computational methods, providing further
support to the previous qualitative approaches.24 The experimental
UV spectrum of (ꢀ)-1a in acetonitrile shows the main absorption
bands at 192 nm, followed by two shoulders at 228 and 250 nm. In
the CD spectrum five intense CEs are clearly visible: at 190 nm (D3
41.0), 212 nm (D3 8.4), 227 nm (D3 ꢀ13.9), 247 nm (D3 15.2), and
275 nm (D3 ꢀ17.7). Both the spectra then appear red shifted of
about 30 nm with respect to those of unsubstituted benzyl phenyl
sulfoxide,23,24 an effect that can be attributed to the presence of the
electron withdrawing carboxy amide group. In particular, in the CD
spectrum of (ꢀ)-1a CE allied to the S]O transition at 275 nm is
negative and, following previously established correlation,23 a (S)
absolute configuration shall be assigned to this enantiomer. In-
terestingly, the CD spectrum of (ꢀ)-1a appears in an almost mirror
image relationship with the one of the (R)-2-carboxyethyl benzyl
sulfoxide24 in which a very similar chromophoric system is present.
This qualitative comparison also provides further support to the
previous configurational assignment.
Since, in general, lithium amides (such as LDA) and alkyl lithium
reagents are the most used bases to remove the -proton of
a
a sulfoxide (although alkyl lithium compounds are less used be-
cause they can cleave the CeS bond by nucleophilic attack) we first
treated benzyl sulfoxide (ꢁ)-1a with 2.1 equiv of freshly prepared
LDA (the first equiv is quenched by the amidic hydrogen) before
adding the electrophile. However, in these conditions we recovered
almost quantitatively the unreacted starting sulfoxide (entry 1,
Table 2), whereas by using 1.05 equiv of LDA followed by 1.05 equiv
of less sterically hindered BuLi we obtained the formation of a small
amount of the products (11% yield) as an almost equimolar ratio of
the two diastereoisomers (entry 2, Table 2). These results demon-
strated that our system is very sensitive to the steric hindrance of
the base. In fact, by treating sulfoxide (ꢁ)-1a with 2.1 equiv of
n-BuLi26 we obtained the formation of the desired products (ꢁ)-2a,
again in an almost diastereoisomeric equimolar ratio, but with
higher yield (32%), even if still too low to have practical uses (entry
3, Table 2). Importantly, we did not detect any product arising from
the cleavage of the CeS bond, thus implying that n-BuLi could be
a suitable base. In order to improve the yield and, possibly, also the
diastereoselectivity, we tried the reaction in the presence of HMPA,
which is known to sequestrate the lithium cations from the solu-
tion thus rendering the C,N-bis-anion more reactive. Accordingly,
we were able to raise all at once the yields (55%) and the diaster-
eoselectivity (de 94%) by using 2.4 equiv of HMPA (entry 5, Table 2).
However, the co-solvent HMPA had to be added before n-BuLi
otherwise the yields dropped down to 19% while preserving the de
(entry 4, Table 2). Finally, by increasing the quantity of HMPA to
5 equiv we obtained the formation of (ꢁ)-2a in very high yields
(92%) and diastereoselectivity (94%, entry 7, Table 2). We then
turned our attention to studying the scope and limitations of the
reaction by applying the optimized conditions to the reaction of
ortho-[(N-alkyl)carbamoyl]phenyl sulfoxides with different alkyl
halides (Scheme 6). The results are summarized in Table 3.
2.2. Alkylation of sulfoxides 1
In order to optimize yield and diastereoselectivity for the al-
kylation of sulfoxides 1, we selected sulfoxide (ꢁ)-1a and 1-Br-3-
methylbutane as model reaction partners (Table 2), then different
reaction parameters, such as base, co-solvents and their equivalents
were systematically modified (Scheme 5).25
1. BuLi (2.1 equiv.)
HMPA (5.0 equiv.)
THF -60 °C
O
S
O
S
R1
R
R1
H
O
O
2. RX
from -60 °C to rt
N
N
R3
R2
R3
R2
Table 2
Alkylation of (ꢁ)-1a with 1-Br-3-methylbutane
Scheme 6. Alkylation of ortho-[(N-alkyl)carbamoyl]phenyl sulfoxide.
Entry
Base (equiv)
co-solvent (equiv)
dea (%)
Yieldb (%)
1
2
LDA (2.1)
LDA (1.05)
BuLi (1.05)
BuLi (2.1)
BuLi (2.1)
BuLi (2.1)
BuLi (2.1)
BuLi (2.1)
None
None
d
n.r.c
11
Highly reactive benzyl bromide and crotyl bromide reacted
smoothly with sulfoxide (ꢁ)-1a leading to the formation of the de-
sired products (ꢁ)-2b,c, respectively, with high yield and lower, al-
though still good, diastereoselectivities (entries 1 and 2, Table 3). Due
to the high reactivityand the low steric hindrance of the electrophile,
thereactionwithmethyliodideaffordedthedesiredsulfoxide(ꢁ)-2d
with low diastereocontrol together with the corresponding C,N-
dimethylated product (34%, entry 3, Table 3). However, this was the
only case where N-alkylation was observed. Less reactive bromides,
such as 1-Br-3-Ph-propane, 1-Br-4-pentene, and 1-Br-pentane pro-
duced alkylated sulfoxides (ꢁ)-2eeg, respectively, with high yields
and high diastereoselectivities (entries 4e6, Table 3). The stereo-
chemistryof the main diastereoisomer (ꢁ)-2g was assessed bysingle
crystal X-ray diffraction (Fig. 3), and the configurations of the other
main diastereoisomers were assigned on the basis of spectroscopic
and analytic analogies with (ꢁ)-2g.
<5
3
4
5
6
7
None
<5
94
94
d
32
HMPA (2.4)
HMPA (2.4)
TMEDA (2.4)
HMPA (5)
19d
55e
n.r.c,e
92e
94
Measured by HPLC/1H NMR.
Overall isolated yield.
No reaction occurred and the starting sulfoxide was almost completely
a
b
c
recovered.
d
HMPA was added after deprotonation with BuLi.
Co-solvent was added before BuLi.
e
O
O
S
1. Base (X equiv.)
THF\co-solvent
Ph
S
Ph
H
NHCH3
Interestingly, the two phenyl rings are nearly coplanar, the di-
hedral angle between them being of 8.1(2)ꢂ. Furthermore the
amidic carbonyl and the SeO bond are linearly arranged, with an
angle of 175.7(6)ꢂ. Finally, the amide group plane and the phenyl
ring show an interplanar angle of 11.1(2)ꢂ.
2. (CH3)2CH(CH2)2Br
CONHCH3
O
(±)-1a
(±)-2a
Scheme 5. Alkylation of (ꢁ)-1a with 1-Br-3-methylbutane.

5272
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
Table 3
Alkylation of ortho-[(N-alkyl)carbamoyl]phenyl sulfoxide
Entry
1
Substrate
R1
R2
R3
H
Alkyl halide
PhCH2Br
Product
dea
58
Yieldb
96
%
O
S
Ph
CH Ph
2
(ꢁ)-1a
Ph
Me
H
CONHCH
3
(±)-2b
O
Ph
S
2
3
(ꢁ)-1a
(ꢁ)-1a
Ph
Ph
Me
Me
H
H
(E)-CH3CH]CHCH2Br
66
50
79
H
CONHCH
3
(±)-2c
O
Ph
CH
S
48c
3
CH3I
H
CONHCH
3
(±)-2d
O
S
Ph
Ph
4
(ꢁ)-1a
Ph
Me
H
Ph(CH2)3Br
94
74
H
CONHCH
3
(±)-2e
O
S
Ph
5
6
(ꢁ)-1a
(ꢁ)-1a
Ph
Ph
Me
Me
H
H
CH27¼CH(CH2)3Br
92
88
95
69
H
CONHCH
(±)-2f
O
Ph
S
CH3(CH2)4Br
H
CONHCH
O
3
(±)-2g
Ph
S
7
8
9
(ꢁ)-1a
(ꢁ)-1a
(ꢁ)-1b
Ph
Me
Me
Me
H
H
H
CH3(CH2)4I
CH3(CH2)2I
Ph(CH2)3Br
86
92
86
65
74
78
H
CONHCH
3
(±)-2g
O
Ph
S
Ph
H
CONHCH
3
(±)-2h
OMe
O
S
4-MeOeC6H4
Ph
H
CONHCH
3
(±)-2i
OMe
OMe
OMe
OMe
O
S
10
11
(ꢁ)-1b
(ꢁ)-1c
4-MeOeC6H4
4-CF3eC6H4
Me
Me
H
H
(3,4,5-TriMeOeC6H2)eC6H2)e(CH2)3Br
96
78
88
51
H
CONHCH
(±)-2j
CF
3
O
S
Ph(CH2)3Br
Ph
H
CONHCH
3
(±)-2k
CF
3
O
S
12
13
14
(ꢁ)-1c
(ꢁ)-1d
(ꢁ)-1f
4CF3eC6H4
4NO2eC6H4
H
Me
Me
Me
H
H
H
Ph(CH2)3Br
42g
d
65d
n.r.e
62
Ph
H
CONHCH
3
Ph(CH2)3Br
d(±)-2k
O
S
OMe
(4-MeOeC6H4)CH2Cl
d
CONHCH
(±)-2l
O
S
Ph
15
16
(ꢁ)-1f
(ꢁ)-1e
H
Me
Me
H
H
Ph(CH2)3Br
d
85
70
CONHCH
(±)-2m
OMe
O
S
Et
(4-MeOeC6H4)CH2Cl
32
H
CONHCH
(±)-2n

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5273
Table 3 (continued )
Entry
Substrate
R1
Et
R2
R3
Alkyl halide
Product
dea
Yieldb
%
O
S
17
(ꢁ)-1e
Me
H
CH3(CH2)5Br
H
<5
60
CONHCH
3
(±)-2o
18
19
(ꢁ)-1g
(þ)-11
Ph
Ph
Me
Me
H
PhCH2Br
PhCH2Br
d
d
d
n.r.e
n.r.e
(S)-(1-C10H7)CH(CH3)
d
O
S
Ph
20
(S)(ꢀ)-1a
Ph
Me
H
(CH3)2CH(CH2)2Br
94
92f
H
CONHCH
(-)-2a
a
Measured by HPLC/1H NMR.
Overall isolated yield.
A 34% of the corresponding C,N-dimethylated product was recovered.
Reaction stopped after 330 min (ꢀ70 ꢂC/rt).
No reaction occurred.
b
c
d
e
f
No epimerization at sulfur occurred.
Reversal of diastereoselectivity was obtained.
g
independently of the reaction time (entry 11, Table 3). Quite sur-
prisingly, attempts of increasing the yield by warming the reaction
temperature to rt, produced an inversion of diastereoselectivity
(entry 12, Table 3).27 Finally, the even less nucleophilic p-NO2eBn
sulfoxide (ꢁ)-1d did not react at all with 1-Br-3-Ph-propane lead-
ing to the formation of a complex mixture of products when the
temperature was allowed to reach rt (entry 13, Table 3).
Then, we investigated the reactivity of alkyl sulfoxides, such as
methyl sulfoxide (ꢁ)-1f and propyl sulfoxide (ꢁ)-1e. Compound
(ꢁ)-1f reacted smoothly with both highly reactive p-MeOebenzyl
chloride and less reactive 1-Br-3-Ph-propane giving rise to the
formation of sulfoxides (ꢁ)-2l,m, respectively, in high yields (en-
tries 14 and 15, Table 3). Also
a-lithiated propyl sulfoxide (ꢁ)-1e
reacted with p-MeOebenzyl chloride affording derivative (ꢁ)-2n in
good yields but low diastereoselectivity (entry 16, Table 3). More-
over, with less reactive 1-Br-pentane we observed the formation of
an almost equimolar ratio of the two diastereoisomers (ꢁ)-2o
(entry 17, Table 3). These latter results suggest that the high dia-
stereoselection obtained with those sulfoxides having a benzyl
substituent likely arise from an interaction between the aromatic
Fig. 3. X-ray structure of 2g.
rings in the reaction transition state, possibly a
p-staking in-
teraction between the electron poor phenyl ring, bearing the sulf-
oxide and the carbamoyl substituents, and the aromatic ring of the
sulfoxide benzyl substituent.28 This hypothesis is corroborated by
(1) the higher stereocontrol obtained with electron-rich or -neutral
benzyl substituents, such as p-MeOebenzyl in (ꢁ)-1b and benzyl in
(ꢁ)-1a, as compared with the electron poor p-CF3ebenzyl sub-
stituent in (ꢁ)-1c, (2) by the fact that the reaction is highly de-
pendent on steric factors,29 and (3) the tendency of the phenyl rings
to adopt a planar conformation in the solid state, as evidenced by
the X-ray of (ꢁ)-2g (see above). Moreover, no reaction was ob-
served with the N,N-dimethylamide (ꢁ)-1f even with highly
reactive benzyl bromide (entry 18, Table 3), suggesting that the
ortho-lithiated amide function might play an important role in this
reaction. Further support for this hypothesis came from the ob-
servation that benzyl p-tolylsulfoxide was unreactive with 1-Br-
hexane under the same conditions (n-BuLi, HMPA), whereas using
LDA as base and HMPA as co-solvent afforded in modest yield and
no stereoselection both diastereoisomers of 1-phenyl-1-(p-tol-
ylsulfinyl)heptane.
The reactivity of alkyl iodides was very similar to that of the
corresponding bromides. Accordingly, 1-I-pentane reacted
smoothly with sulfoxide (ꢁ)-1a leading to the formation of the
corresponding sulfoxide (ꢁ)-2g with very similar yield and dia-
stereoselection as compared to 1-Br-pentane (entry 7, Table 3),
while with 1-I-propane we obtained the sulfoxide (ꢁ)-2h with
even higher de (entry 8, Table 3). Excellent results, both in terms of
yields and diastereoselectivities, were obtained with the electron
rich, and therefore highly nucleophilic,
a-lithiated p-MeOeBn
sulfoxide (ꢁ)-1b. In fact, with 1-Br-3-C6H4-propane we observed
the formation of (ꢁ)-2i with a 94% de (entry 9, Table 2), the same
result obtained with the unsubstituted benzyl sulfoxide (ꢁ)-1a.
Similar results were observed by using 1-Br-3-(3,4,5-triMeO)C6H2-
propane as electrophile (entry 10, Table 3). The reactivity of the less
nucleophilic
a
-lithiated p-CF3eBn sulfoxide (ꢁ)-1c proved to be
quite different. In fact, the reaction with 1-Br-3-Ph-propane at
ꢀ60 ꢂC gave the formation of the desired alkylated product (ꢁ)-2k
with high, albeit lower diastereocontrol, but in modest yield,

5274
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
Finally, reaction of enantiomerically pure sulfoxide (þ)-11 with
action of TFAA on the sulfinyl moiety of (ꢁ)-2a. The latter is trapped
by the nucleophilic solvent (CH3CN) leading to the formation of the
corresponding acetamide by hydrolysis occurring during the
reaction quenching. To render this mechanism useful for the syn-
thesis of acetamide (ꢁ)-5a we sought to identify reaction condi-
tions, which suppressed the formation of the corresponding
alcohol (ꢁ)-3a. We reasoned that replacing TFAA as a promoter of
the Pummerer reaction with Tf2O, which is known to react with the
sulfinyl oxygen producing TfOꢀ, which is an extremely poor nu-
cleophile, could maximize the formation of the target acetamide.
Rewardingly, by treating sulfoxide (ꢁ)-2a with Tf2O in CH3CN at
benzyl bromide did notaffordthe desired product probablyowingto
steric factors (entry 19, Table 3), while using enantiomerically pure
(þ)-1a with 1-Br-3-methylbutane we observed the formation of the
corresponding product (þ)-2a without loss of ee (entry 20, Table 3).
This result is very important because, in perspective, the high ster-
eoselectivity of the C-alkylation of enantiomerically pure sulfoxide
reagents, along with the preservation of the ee, may represent a key
factor for the development of an asymmetric version of the planned
methodology, whose success will also rely on the preparation of
alcohols, chloride, and acetamides in high enantiomeric purity.
0
ꢂC we obtained the formation of the acetamide (ꢁ)-5a in good
yield as the only product of the NOPR along with the heterocycle 6.
Concerning the NOCPR, racemic (ꢁ)-1a was already known to give
very good yields of benzyl chloride upon treatment with SOCl2.31 As
expected, we found that also the NOCPR conditions (oxalyl chlo-
ride, TMP, DCM, ꢀ50 ꢂC) worked well on substrate (ꢁ)-2a affording
the benzylic secondary chloride (ꢁ)-4a, together with 6, in very
good yield. In order to expand the scope of the reaction, we applied
the same conditions to the different racemic sulfoxides (ꢁ)-2 syn-
thesized as described before (Scheme 8). The results are listed in
Table 4.
2.3. Use of umpolung sulfoxide reagents 2
The first evidence that sulfoxide reagents 2 could undergo
Pummerer reactions under non-oxidative pathways was obtained
when we observed that benzylated sulfoxide (ꢁ)-2b spontaneously
decompose to (E)-stilbene and benzisothiazolone 6 after prolonged
storing at rt. Several authors reported that N-monosubstituted
ortho-carbamoylearylsulfoxides undergo an ‘interrupted’ Pum-
merer reaction30 upon treatment with certain electrophiles, pro-
viding the corresponding benzisothiazolones and esters (with
Ac2O/H2SO4 or trichloroacetic anhydride) or chlorides (with SOCl2,
diphosgene or AcCl) as co-products.31 Thus, we submitted de-
rivative (ꢁ)-2a to the classical conditions for the NOPR, namely
TFAA, TMP in CH3CN at 0 ꢂC followed by treatment in situ with
aqueous NaHCO3, and we obtained the formation of the desired
alcohol (ꢁ)-3a and benzisothiazolone 6 along with the acetamide
(ꢁ)-5a (23%, Scheme 7).
O
X
S
Ar
R
S
i or ii or iii
N
+
Ar
R
H
3 X = OH (i)
4 X = Cl (ii)
5 X = NHAc (iii)
CONHCH3
(±)-2
O
6
i. TFAA, TMP, DCM, 0 °C, then aq. NaHCO3; ii. (COCl)2, TMP,DCM -50 °C;
iii. Tf2O, TMP, CH3CN 0 °C
OH
Ph
Scheme 8. Synthesis of alcohols 3, chlorides 4, and acetamides 5.
1) TFAA, TMP
CH3CN, 0°C
S
(±)-3a (47%)
N
+
+
2) aq. NaHCO3
NHCOCH3
Table 4
6 (87%) O
Ph
Synthesis of alcohols 3, chlorides 4, and acetamide 5
(±)-5a (23%)
Subs.
Ar
R
Prod
X
Yielda (%)
(ꢁ)-2e Ph
Ph(CH2)3
CH2¼CH(CH2)3
(ꢁ)-3e OH
86
72
67
77
90
60
63
78
62
67
(ꢁ)-2f
(ꢁ)-2i
Ph
(ꢁ)-3f
(ꢁ)-3i
OH
OH
1) TFAA, TMP
CH2Cl2, 0°C
OH
S
4-MeOePh Ph(CH2)3
N
+
(ꢁ)-2k 4-CF3ePh
Ph(CH2)3
Ph(CH2)3
CH2¼CH(CH2)3
(ꢁ)-3k OH
Ph
(ꢁ)-2e Ph
(ꢁ)-4e Cl
2) aq. NaHCO3
O
S
(±)-3a (73%)
O
6 (92%)
(ꢁ)-2f
(ꢁ)-2i
Ph
(ꢁ)-4f
(ꢁ)-4i
Cl
Cl
Ph
4-MeOePh Ph(CH2)3
H
(ꢁ)-2k 4-CF3ePh
Ph(CH2)3
CH3(CH2)5
CH3(CH2)2
(ꢁ)-4k Cl
CONHCH3
(ꢁ)-2g Ph
(ꢁ)-5g NHAc
(ꢁ)-5h NHAc
(ꢁ)-2h Ph
(±)-2a
Cl
S
(COCl)2, TMP
CH2Cl2, -50 °C
(ꢁ)-2j
4-MeOePh 3,4,5-TriMeOePhe(CH2)3 (ꢁ)-5j
NHAc 48b
N
+
+
Ph
(ꢁ)-2k 4-CF3ePh
Ph(CH2)3
(ꢁ)-5k NHAc 57b
4a
(±)- (71%)
a
6 (90%) O
Overall isolated yield.
Formation of the corresponding tetralines as by-products was observed (see
b
Ref. 20).
NHCOCH3
S
Tf2O, TMP
N
The NOPR resulted to be quite general, working well with
neutral benzyl sulfoxides (ꢁ)-2e,f producing the corresponding
alcohols (ꢁ)-3e,f in good yields, with electron-rich benzyl sulfoxide
(ꢁ)-2i as well as with the electron poor benzyl alcohol (ꢁ)-2k,
which afforded the corresponding alcohols (ꢁ)-3i,k, respectively, in
good yields. Analogous results were achieved by performing the
NOCPR on the same starting sulfoxides, which afforded the chlo-
rides (ꢁ)-4e,f,i,k always in good yields.32
Ph
CH3CN, 0 °C
(±)-5a (73%)
6 (79%) O
Scheme 7. NOPR on sulfoxide (ꢁ)-2a.
By performing the reaction in DCM instead of acetonitrile, we
observed the exclusive formation of the alcohol (ꢁ)-3a along with
the benzisothiazolone co-product 6 in very good yield. These pre-
liminary experiments were very important because they provided
clear evidence that N-methyl ortho-carbamoylaryl sulfoxides are
Finally, when the R substituent did not contain an aromatic ring,
such as in sulfoxides (ꢁ)-2g,h the reaction worked well also with
Tf2O producing acetamides (ꢁ)-5g,h in good yield, while with
sulfoxides (ꢁ)-2j,k we obtained the corresponding acetamides
(ꢁ)-5j,k in lower yield due to the concomitant formation of the
tetraline derivatives as by-products.20
not only synthetic equivalents of
also be used as synthetic equivalents of an
a
-hydroxy carbanions, but can
-acetamido carbanion.
a
We reasoned that the formation of the acetamide (ꢁ)-5a probably
arose from a benzylic carbocationic intermediate originated by the

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5275
Unfortunately, non-benzylic sulfoxides failed to provide the
corresponding alcohols under NOPR conditions. In fact, using the
TFAA/TMP protocol unsubstituted (R2¼H) sulfoxide (ꢁ)-2l and
dialkyl sulfoxide (ꢁ)-2n gave moderate yields of two main prod-
ucts, which were tentatively identified as the benzo[1,3]thiazin-4-
In line with our synthetic plan, the co-product 6 was reduced
with an excess of NaBH4 to the thiol 13, which was reconverted to
the starting benzyl sulfides 8 by S-benzylation in ca. 80% overall
yields in all cases (Scheme 11).
ones 12a,b resulting from
(Scheme 9).
a
normal Pummerer mechanism
SCH2Ar
SH
S
ArCH2Br
TEA
NaBH4
N
CH3
CONHCH3
CONHCH3
O
13
8a, Ar = Ph (81%)
Ar = p-MeO-Ph (78%)
8c Ar = p-CF3-Ph (83%)
O
6
R1
S
R1
S
8b
TFAA, TMP
DCM
R2
R2
H
N
Scheme 11. Recycle of the co-product 6.
CONHCH3
O
(±)-2l (R1 = 4-MeO-Ph-CH2; R2 = H)
(±)-2n (R1 = 4-MeO-Ph-CH2; R2 = Et)
12a,b
In agreement with Uchida and Oae,31a and by considering our
experimental results, we suggest that benzyl sulfoxides 2 might
react according to the sequence shown in Scheme 12 for the model
substrate 2a.
Scheme 9. Reaction of non-benzylic sulfoxide under NOPR conditions.
Concerning the NOCPR with non-benzylic sulfoxides, the pro-
cess worked well with the homobenzylic sulfoxide (ꢁ)-2l pro-
ducing the corresponding 1-p-methoxyphenyl-3-Cl-propane in
80% yield, while it did not work at all with (ꢁ)-2l leading also in this
case to benzo[1,3]thiazin-4-one 12b.
Thus, with the aim of (1) synthesizing enantiomerically
enriched alcohols, chlorides, and acetamides and (2) having more
information about the mechanism of this intriguing process, we
performed the NOPR starting from the enantiomerically pure
sulfoxide (ꢀ)-2a using the same conditions described above
(Scheme 10).
X
TMP-H
+
O
S
X
S
Ph
H
CH3
Ph
TMP
S
2X
Ph
H
N
N CH3
H
CONHCH3
O
O
15
6
2a
TMP-H
14a X = CF3CO2; 14b X = Cl; 14c X = CF3SO3
Y
Y
S
N
CH3
+
Ph
Ph
1) TFAA, TMP
OH
CH2Cl2, 0°C
O
6
3a Y = OH; 4a Y = Cl; 5a Y = NHCOCH3
Ph
2) aq. NaHCO3
Scheme 12. Proposed mechanism for the Pummerer reactions.
(-)-3a
(75%)
α
]
ee 45%
[
D = -14.6 (c = 0.6; CHCl3)
O
Ph
S
34
Cl
Acylation of the sulfinyl oxygen by TFAA, (COCl)2 or Tf2O,
followed by capture of the transient sulfur cation by the ortho-
carbamoyl nitrogen provides the intermediate 14aec. The latter,
when the nucleophile Xꢀ is sufficiently strong, such as in the case of
Clꢀ, undergoes fragmentation (SeX and CeS bonds breaking
leading to 6) and recombination (formation of a new CleC bond)
through an SN2-like mechanism to afford benzyl chloride 4a with
complete inversion of configuration.35 When Xꢀ is a poor nucleo-
phile, such as in the case of TfOꢀ, this internal rearrangement
cannot occur and the fragmentation produces the intermediate
carbocation 15, which can be trapped by a sufficiently nucleophilic
solvent, i.e., CH3CN, to afford, after hydrolysis, the acetamide 5a
with complete epimerization. Probably, with TFAA the two mech-
anistic pathways are competitive and the alcohol 3a is formed with
partial loss of ee because the SN2-like mechanism is not exclusive.
This hypothesis is supported by the fact that better ee was obtained
when the reaction was promoted by TCAA, which generates
a stronger nucleophile (CCl3COOꢀ vs CF3COOꢀ). It is noteworthy
that the SN2-like mechanism proposed here is very similar to the
mechanism we propose previously for the NOPR and NOCPR in-
(COCl)2, TMP
H
Ph
CONHCH3
CH2Cl2, -50 °C
(83%)
4a
(-)-
]D = -66.7 (c = 0.4; CHCl3) ee > 98%
(SS,R)-2a
D = -45.1 (c = 0.8; CHCl3)
α
[
α
[
]
e.e > 98%
NHCOCH3
Tf2O, TMP
Ph
CH3CN, 0 °C
(64%)
(-)-5a
α
[ ]D = ca. 0.0 (c = 0.7; CHCl3) ee 0%
Scheme 10. Pummerer reactions on enantiomerically pure (SS,R)-2a.
As expected, the NOPR afforded the alcohol (ꢀ)-3a with in-
version of configuration at the benzylic stereocenter.33 However,
we observed partial loss of enantiomeric purity (ee 45% starting
from sulfoxide (SS,R)-2a with ee >98%), which evidenced that the
reaction did not occur exclusively through a SN2 mechanism as in
the case of b
-sulfinyl-amines.14 To enhance the enantioselectivity of
the reaction we explored the use of trichloroacetic anhydride
(TCAA), which produces the more nucleophilic CCl3COOꢀ anion
under Pummerer conditions. Gratifyingly, we obtained the forma-
tion of the corresponding alcohol with better enantioselectivity
volving b
-sulfinyl amines as substrates,14,15 with the notable dif-
ference that in the latter cases the sulfurane intermediate 14-like is
a highly reactive four membered ring that is exceptionally prone to
undergo ring opening even with poor nucleophile like CF3COOꢀ.
That is probably the driving force of the stereospecificity featured
by NOPR and NOCPR, whereas in the process discussed here the
sulfurane moiety in 14aec belongs to a very stable, condensed five
member ring and the nucleophilic attack to the electrophilic carbon
must take place in exo-cyclic manner, which is less favorable.
([a
]
D
ꢀ19.7, ee 61%). Even more satisfactorily, NOCPR on (SS,R)-2a
provided the corresponding chloride (ꢀ)-4a without any loss of ee
as evidenced by chiral HPLC. Finally, reaction with Tf2O in CH3CN
afforded the racemic acetamide 5a confirming that this reaction
probably takes place through the intermediate formation of
a carbocation.

5276
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
3. Conclusions
7.49 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 7.20 (m, 1H),
4.20 (s, 2H); 13C NMR (100.6 MHz, DMSO-d6)
167.6, 141.5, 136.8,
d
In conclusion we have developed a family of new umpolung
sulfoxide reagents for the synthesis of -benzyl alcohols, chlorides,
and acetamides. The synthesis of such reagents is very easy, highly
modular and allowed for the preparation of different reagents in
high yields and grams quantity. Such reagents could be considered
as synthetic equivalents of functionalized benzyl carbanions. In
132.6, 131.1, 129.4, 128.7, 127.8, 127.4, 125.9, 124.2, 35.9; MS (70 eV):
e/z (%): 244 (12) [Mþþ1], 91 (100); HRMS calcd for [C15H14O3S]
274.0664, found 244.0667.
a
4.2.2. 2-(4-Methoxybenzylthio)benzoic acid (7b). White solid,
Rf¼0.57 (CHCl3/MeOH¼95:5); mp 213e215 ꢂC (H2O); FTIR (micro-
fact, they can be easily converted to the corresponding
a-benzyl
scope) n d 7.84 (d,
3459, 1674 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
alcohols, chlorides, and acetamides through a two-step procedure,
namely a highly stereoselective alkylation of the sulfoxides fol-
lowed by ‘non-oxidative’ Pummerer reactions, which allow for the
replacement of the sulfinyl auxiliary by an hydroxy, a chloride, and
an acetamido group, respectively, in a very efficient manner both in
terms of yield and atom economy. The preparation of optically pure
or enantiomerically enriched sulfoxides, respectively, through di-
astereoisomeric synthesis and enantioselective oxidation of the
corresponding sulfides, led us to a proper understanding of the
mechanism of the non-oxidative Pummerer process, which could
arise (1) from a stereospecific SN2-like mechanism when the nu-
cleophile Xꢀ, which is formed after the reaction of the sulfoxide
with the electrophile, is sufficiently strong, such as in the case of
Clꢀ, leading to the synthesis of enantiomerically pure benzyl
chlorides, (2) through the formation of a benzylic carbocation,
which is trapped by the solvent, i.e., CH3CN, producing the corre-
sponding acetamides as racemates, when the nucleophile is very
poor, such as TfOꢀ, and (3) through both the mechanisms above
when the formed anion has an intermediate nucleophilic strength,
such as CF3COOꢀ leading to the final formation of enantiomerically
enriched benzylic alcohols. We are currently investigating the ap-
plication of such umpolung sulfoxide reagents to the synthesis of
more complex, biologically important structures.
J¼7.6 Hz, 1H), 7.44 (m, 2H), 7.33 (d, J¼8.6 Hz, 2H), 7.17 (m, 1H), 6.88
(d, J¼8.6 Hz, 2H), 4.12 (s, 2H), 3.73 (s, 3H); 13C NMR (100.6 MHz,
DMSO-d6) d 167.7,158.3,140.7,131.5,130.5,130.2,128.3,125.6,123.7,
113.8, 55.0, 35.2; EIMS (m/z) 274 [Mþ, (18)], 121 (100); HRMS calcd
for [C14H12O2S] 244.0558, found 244.0554.
4.2.3. 2-(4-(Trifluoromethyl)benzylthio)benzoic acid (7c). White
solid, Rf¼0.49 (CHCl3/MeOH¼95:5); FTIR (microscope)
n 2941,
7.87 (d, J¼7.6 Hz, 1H),
1690 cmꢀ1 1H NMR (400 MHz, DMSO-d6)
;
d
7.67 (m, 4H), 7.46 (m, 2H), 7.21 (m, 1H), 4.31 (s, 2H); 19F NMR
(235.4 MHz, DMSO-d6)
d6)
d
ꢀ61.0 (s, 3F); 13C NMR (100.6 MHz, DMSO-
d
167.6, 142.1, 140.5, 132.5, 131.1, 128.1, 127.6, 125.8, 125.4 (q,
J¼3.7 Hz), 124.4 (q, J¼271.9 Hz), 124.3, 122.2, 35.0; EIMS (m/z) 312
[Mþþ1, (26)], 159 (100), 153 (59); HRMS calcd for [C15H11F3O2S]
312.0432, found 312.0435.
4.2.4. 2-(4-Nitrobenzylthio)benzoic acid (7d). White solid, Rf¼0.59
(CHCl3/MeOH¼95:5); mp 205e206 ꢂC (MeOH); FTIR (microscope)
n
3460, 1682 cmꢀ1; 1H NMR (400 MHz, DMSO-d6)
d
8.18 (d, J¼8.6 Hz,
2H), 7.87 (d, J¼7.6 Hz, 1H), 7.71 (d, J¼8.6 Hz, 2H), 7.46 (m, 2H), 7.22
(m, 1H), 4.37 (s, 2H); 13C NMR (100.6 MHz, DMSO-d6)
d
167.3, 146.5,
145.3, 139.7, 132.2, 130.8, 130.2, 128.3, 126.0, 124.3, 123.5, 34.9; EIMS
(m/z) 289 [Mþ, (100)], 153 (81), 89 (77); HRMS calcd for
[C14H11NO4S] 289.0409, found 289.0411.
4. Experimental section
4.1. General method
4.2.5. 2-(Propylthio)benzoic acid (7e). White solid, Rf¼0.55 (hex-
ane/AcOEt 50:50); FTIR (film) 1734, 1681, 1252 cmꢀ1 1H NMR
;
(500 MHz, CD3OD)
d
7.88 (d, J¼7.5 Hz, 1H), 7.40 (m, 2H), 7.15 (m,1H),
Commercially available reagent-grade solvents were employed
without purification unless otherwise stated. Dry THF was distilled
from sodium while dry DCM was distilled from calcium hydride.
Melting points (mp) were obtained on a capillary apparatus. TLC
were run on silica gel 60 F254 Merck. Flash chromatographies (FC)
2.89 (t, J¼7.2 Hz, 2H), 1.69 (sextet, J¼7.2 Hz, 2H), 1.06 (t, J¼7.2 Hz,
3H); 13C NMR (100.6 MHz, CD3OD)
d 170.5, 142.3, 132.9, 132.0, 130.9,
127.3, 124.9, 35.0, 22.9, 13.9; MS (70 eV): e/z (%): 197 (34) [Mþþ1],
153 (100); HRMS calcd for [C10H12O2S] 196.0558, found 196.0555.
were performed with silica gel 60 (60e200
spectra were run on spectrometers 250, 400 or 500 MHz. Chemical
shifts are expressed in parts per million ( ), using tetramethylsilane
m
m, Merck). 1H NMR
4.3. General procedure for the synthesis of compounds 8
d
To a solution of crude 7 (17.9 mmol, 4.38 g) in DMF (0.1 M) were
added, respectively, solid BOP (1 equiv), the amine (1.1 equiv), and
DIPEA (2 equiv). The solution was stirred at rt over-night. The or-
ganic solvent was evaporated and the residue purified by flash-
chromatography.
(TMS) as internal standard for 1H and 13C nuclei (dH and dC¼0.00).
Absorption and CD spectra of compound (ꢀ)-1a were recorded on
a JASCO J815 spectropolarimeter at rt, in acetonitrile, using 0.1 mm
cells and concentrations of about 1ꢃ10ꢀ3 M. During the measure-
ment, the instrument was thoroughly purged with nitrogen. High-
resolution MS spectra were recorded with an FT-ICR (Fourier
Transform Ion Ciclotorn Resonance) instrument, equipped with an
ESI source, or a standard MS instrument, equipped with an EI source.
4.3.1. 2-(Benzylthio)-N-methylbenzamide (8a). White solid, Rf¼0.39
(hexane/AcOEt 50:50); mp 134e136 ꢂC (AcOEt); FTIR (film) 3250,
1630, 1405 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.59 (dd, J¼7.3 and
1.8 Hz, 1H), 7.40 (m, 1H), 7.30 (dt, J¼7.3 and 1.8 Hz, 1H), 7.28e7.21
4.2. General procedure for the synthesis of compounds 7
(m, 5H), 7.16 (m, 2H), 4.06 (s, 2H), 2.90 (d, J¼4.6 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3)
d 168.7, 138.2, 137.2, 133.0, 132.5, 130.4, 128.8,
To a cooled solution of thiosalicylic acid (1 equiv) and TEA
(2.1 equiv) in dioxane (0.1 M) benzyl bromide (1.1 equiv) was added
drop-wise at 0 ꢂC. After 10 min the organic solvent was evaporated,
the residue diluted in 1 N HCl aqueous solution and extracted with
AcOEt. The collected organic layers were dried on anhydrous
Na2SO4, filtered and the solvent evaporated in vacuo.
128.5, 127.3, 127.2, 40.3, 26.7; MS (70 eV): e/z (%): 257 (4) [Mþþ1],
166 (75), 91 (100); HRMS calcd for [C15H15NOS] 257.0874, found
257.0875.
4.3.2. 2-(4-Methoxybenzylthio)-N-methylbenzamide
solid, Rf¼0.57 (hexane/AcOEt¼80:20); FTIR (microscope)
1638, 1510 cmꢀ1 1H NMR (400 MHz, CD3OD)
(8b). White
3430,
7.39 (d, J¼7.7 Hz,
n
;
d
4.2.1. 2-(Benzylthio)benzoic acid (7a). White solid, Rf¼0.47 (hex-
ane/AcOEt 50:50); mp 180e182 ꢂC (MeOH); FTIR (film) 3440, 1639,
1H), 7.33 (m, 2H), 7.21 (m, 1H), 7.17 (d, J¼8.6 Hz, 2H), 6.79 (d,
J¼8.6 Hz, 2H), 4.06 (s, 2H), 3.73 (s, 3H), 2.84 (s, 3H); 13C NMR
1255 cmꢀ1
;
1H NMR (500 MHz, DMSO-d6)
d
7.88 (d, J¼7.8 Hz, 1H),
(100.6 MHz, CD3OD) d 171.9, 160.2, 139.0, 136.0, 131.7, 131.2, 131.1,

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5277
130.4, 128.6, 127.1, 114.8, 55.7, 39.3, 26.7; EIMS (m/z) 287 [Mþ,
(100)]; HRMS calcd for [C16H17NO2S] 287.0980, found 287.0984.
130.2, 126.6, 125.5, 122.7, 113.6, 62.2, 55.2, 26.8; EIMS (m/z) 303
(100) [Mþþ1]; HRMS calcd for [C16H17NO3S] 303.0929, found
303.0932.
4.3.3. N-Methyl-2-(4-(trifluoromethyl)benzylthio)benzamide
(8c). Yellowish oil, Rf¼0.49 (hexane/AcOEt¼50:50); FTIR (micro-
4.4.3. N-Methyl-2-(4-(trifluoromethyl)benzylsulfinyl)benzamide
(1c). White solid, Rf¼0.30 (AcOEt/hexane¼70:30); mp 204e205 ꢂC
scope) n d 7.53 (d,
3435,1643,1435 cmꢀ1; 1H NMR (400 MHz, CD3OD)
J¼8.2 Hz, 2H), 7.46 (d, J¼8.2 Hz, 2H), 7.37 (m, 2H), 7.30 (m, 1H), 7.23
(AcOEt/MeOH¼1:1); FTIR (microscope)
n
3282,1646, 1322 cmꢀ1; 1H
(m, 1H), 4.20 (s, 2H), 2.87 (s, 3H); 13C NMR (100.6 MHz, CD3OD)
NMR (400 MHz, CDCl3)
d
7.58 (m, 2H), 7.48 (d, J¼7.7 Hz, 2H), 7.43
d
171.9,143.6,139.7,135.1,132.1,131.2,130.6,130.1,128.8,127.6,126.2
(m, 2H), 7.24 (d, J¼7.7 Hz, 2H), 6.76 (br s,1H), 4.52 (d, J¼12.4 Hz,1H),
(q, J¼3.6 Hz), 125.6 (q, J¼271.4 Hz), 39.2, 26.7; EIMS (m/z) 325 [Mþ,
4.16 (d, J¼12.4 Hz, 1H), 2.98 (d, J¼4.6 Hz, 3H); 19F NMR (235.4 MHz,
(100)]; HRMS calcd for [C16H14F3NOS] 325.0748, found 325.0750.
CDCl3)
d
ꢀ63.6 (s, 3F); 13C NMR (100.6 MHz, CDCl3)
d 166.9, 144.7,
134.9, 132.0, 131.4, 130.9, 130.6, 126.4, 125.6, 124.9 (q, J¼3.6 Hz),
124.2 (q, J¼271.8 Hz), 62.2, 26.9; EIMS (m/z) 342 [Mþþ1, (39)], 182
(100), 159 (96); HRMS calcd for [C16H14F3NO2S] 341.0697, found
341.0700.
4.3.4. N-Methyl-2-(4-nitrobenzylthio)benzamide
oil; FTIR (microscope)
3427, 1636, 1518 cmꢀ1; 1H NMR (400 MHz,
CD3OD)
8.08 (d, J¼8.6 Hz, 2H), 7.48 (d, J¼8.6 Hz, 2H), 7.36 (m, 2H),
7.31 (m, 1H), 7.24 (m, 1H), 4.22 (s, 2H), 2.88 (s, 3H); 13C NMR
(8d). Yellowish
n
d
(100.6 MHz, CD3OD)
d
171.8, 148.3, 147.0, 139.9, 134.5, 132.5, 131.3,
4.4.4. N-Methyl-2-(4-nitrobenzylsulfinyl)benzamide
(1d). White
131.0, 128.8, 127.9, 124.4, 39.1, 26.7; EIMS (m/z) 302 [Mþ, (15)], 166
solid, Rf¼0.52 (AcOEt); mp 177e179 ꢂC (AcOEt/MeOH¼1:1); FTIR
(100); HRMS calcd for [C15H14N2O3S] 302.0725, found 302.0722.
(microscope) n ;
3296, 1646, 1519 cmꢀ1 1H NMR (400 MHz, CDCl3)
d
8.07 (d, J¼8.5 Hz, 2H), 7.59 (m, 2H), 7.46 (m, 2H), 7.27 (d, J¼8.5 Hz,
4.3.5. N-Methyl-2-(propylthio)benzamide
(8e). Yellowish
oil,
;
2H), 6.66 (br s, 1H), 4.56 (d, J¼12.4 Hz, 1H), 4.28 (d, J¼12.4 Hz, 1H),
Rf¼0.42 (hexane/AcOEt 50:50); FTIR (film) 3340, 1638, 1004 cmꢀ1
3.02 (d, J¼4.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
d 166.8, 147.7,
1H NMR (400 MHz, CDCl3)
d
7.49 (dd, J¼7.8 and 1.4 Hz, 1H), 7.33 (m,
144.5, 138.3, 131.9, 131.6, 131.4, 130.7, 126.3, 125.6, 123.1, 61.9, 26.9;
EIMS (m/z) 319 [Mþþ1, (10)], 182 (100); HRMS calcd for
[C15H14N2O4S] 318.0674, found 318.0677.
1H), 7.28 (m, 1H), 7.12 (dt, J¼7.8 and 1.4 Hz, 1H), 7.04 (br s, 1H), 2.90
(d, J¼4.9 Hz, 3H), 2.82 (t, J¼7.3 Hz, 2H), 1.61 (sextet, J¼7.3 Hz, 2H),
0.98 (t, J¼7.3 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
d 168.6, 136.3,
134.7,129.9, 129.4, 128.4, 125.4, 35.8, 26.2, 21.9, 13.4; MS (70 eV): e/z
(%): 210 (30) [Mþþ1], 152 (100); HRMS calcd for [C11H15NOS]
209.0874, found 209.0877.
4.4.5. N-Methyl-2-(propylsulfinyl)benzamide (1e). Yellowish oil,
Rf¼0.24 (AcOEt); FTIR (film) 3419, 1644, 998 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
8.07 (d, J¼7.8 Hz, 1H), 7.87 (br s, 1H), 7.75 (d,
J¼7.8 Hz, 1H), 7.62 (t, J¼7.8 Hz, 1H), 7.44 (t, J¼7.8 Hz, 1H), 3.26 (ddd,
J¼17.4, 12.8, and 6.4 Hz, 1H), 2.93 (d, J¼4.6 Hz, 3H), 2.71 (ddd,
J¼17.4, 12.8, and 5.0 Hz, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.02 (t,
4.3.6. 2-(Benzylthio)-N,N-dimethylbenzamide (8g). White solid,
Rf¼0.49 (hexane/AcOEt 50:50); FTIR (film) 3420, 1652, 947 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.30e7.16 (m, 9H), 4.10 (s, 2H), 3.09 (s,
J¼7.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
d 166.7, 145.7, 131.8,
3H), 2.70 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
d
169.8, 139.5, 137.2,
131.4, 130.0, 127.0, 124.4, 59.5, 26.6, 16.5, 12.9; MS (70 eV): e/z (%):
226 (25) [Mþþ1], 182 (46), 152 (100); HRMS calcd for [C11H15NO2S]
225.0823, found 225.0827.
132.1, 131.6, 128.8, 128.2, 127.0, 126.9, 126.4, 39.1, 38.0, 34.4; MS
(70 eV): e/z (%): 272 (24) [Mþþ1], 91 (100); HRMS calcd for
[C16H17NOS] 271.1031, found 271.1030.
4.4.6. N-Methyl-2-(propylsulfinyl)benzamide (1f). see Ref. 36
4.4. General procedure for the synthesis of compounds 1
4.4.7. 2-(Benzylsulfinyl)-N,N-dimethylbenzamide (1g). White solid,
Rf¼0.41 (AcOEt); mp 90e91 ꢂC (AcOEt); FTIR (film) 1626, 1397,
To a cooled solution of 8 (1 equiv) in CHCl3 (0.1 M) was added
drop-wise a 50% in weight solution of MCPA (1 equiv) in CHCl3
(0.1 M) at 0 ꢂC. After the addition was complete (ca. 30 min) the
solution was stirred for additional 20 min, quenched with a satu-
rated aqueous solution of NaHCO3, and the temperature was raised
to rt. The mixture was extracted with CHCl3, the collected organic
layers dried on anhydrous Na2SO4, filtered and the solvent evapo-
rated in vacuo. The residue was purified by flash-chromatography.
1032 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.51 (d, J¼7.8 Hz, 1H), 7.45
(t, J¼7.8 Hz, 1H), 7.38 (t, J¼7.8 Hz,1H), 7.31 (d, J¼7.8 Hz,1H), 7.23 (m,
3H), 7.12 (m, 2H), 4.42 (d, J¼12.8 Hz, 1H), 4.08 (d, J¼12.8 Hz, 1H),
3.13 (s, 3H), 2.89 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
d 168.0, 141.1,
133.2, 130.4, 130.3, 129.8, 129.4, 127.9, 127.8, 126.2, 125.4, 61.9, 38.9,
34.8; MS (70 eV): e/z (%): 287 (33) [Mþ], 196 (64), 91 (100); HRMS
calcd for [C16H17NO2S] 287.0980, found 287.0982.
4.4.1. (S)-2-(Benzylsulfinyl)-N-methylbenzamide ((S)-(ꢀ)-1a). White
4.5. General procedure for the synthesis of compounds 2
solid, Rf¼0.38 (CHCl3/MeOH¼95:05); mp 167e169 ꢂC (AcOEt/
20
D
MeOH); [
a]
ꢀ258.3 (c 1.1, CHCl3); FTIR (film) 3478, 1633,
To a cooled solution of 1 (1.83 mmol, 500 mg) and dry HMPA
(5 equiv) in dry THF (0.05 M) was added drop-wise, at ꢀ70 ꢂC and
under Ar atmosphere, a 2.5 M hexane solution of BuLi (1.2 equiv).
After 10 min, at ꢀ78 ꢂC 3-methyl-1-bromo-butane (1.2 equiv) was
added. After the reaction was complete (TLC monitoring), saturated
aqueous NH4Cl was added, the temperature raised to rt and the
solution extracted with AcOEt. The collected organic layers were
dried on anhydrous Na2SO4, filtered and the solvent evaporated in
vacuo. The residue was purified by flash-chromatography.
1027 cmꢀ1; 1H NMR (250 MHz, CDCl3)
d 7.60 (m, 2H), 7.38 (m, 3H),
7.21 (m, 3H), 7.10 (m, 2H), 4.48 (d, J¼12.4 Hz, 1H), 4.03 (d, J¼12.4 Hz,
1H), 2.89 (d, J¼4.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
d 166.9,
144.4, 132.1, 131.3, 130.7, 130.5, 130.4, 128.2, 128.0, 126.6, 125.7, 62.5,
26.9; MS (70 eV): e/z (%): 274 (41) [Mþþ1], 182 (83), 91 (100); HRMS
calcd for [C15H15NO2S] 273.0823, found 273.0821.
4.4.2. 2-(4-Methoxybenzylsulfinyl)-N-methylbenzamide (1b). White
solid, Rf¼0.20 (AcOEt/hexane¼80:20); mp 154e156 ꢂC (AcOEt/
MeOH¼1:1); FTIR (microscope)
n
3296, 1646, 1513 cmꢀ1
;
1H NMR
4.5.1. N-Methyl-2-(4-methyl-1-phenylpentylsulfinyl)benzamide
D
(400 MHz, CDCl3)
d
7.59 (m, 2H), 7.43 (m,1H), 7.37 (m, 1H), 7.10 (br s,
((SS,R)2a). White solid, Rf¼0.50 (AcOEt); [
a
]
23 ꢀ45.1 (c 0.8, CHCl3,
1H), 7.03 (d, J¼7.7 Hz, 2H), 6.74 (d, J¼7.7 Hz, 2H), 4.43 (d, J¼12.4 Hz,
ee 98%); mp 108e109 ꢂC (AcOEt); FTIR (film) 3383, 1653,
1000 cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.91 (d, J¼7.5 Hz, 1H), 7.62
(d, J¼7.5 Hz, 1H), 7.54 (t, J¼7.5 Hz, 1H), 7.44 (t, J¼7.5 Hz, 1H),
1H), 3.99 (d, J¼12.4 Hz, 1H), 3.74 (s, 3H), 2.92 (d, J¼3.5 Hz, 3H); 13C
d
NMR (100.6 MHz, CDCl3)
d 167.0, 159.5, 144.8, 132.1, 131.8, 131.1,

5278
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
7.37e7.22 (m, 5H), 6.82 (br s, 1H), 4.25 (dd, J¼11.3 and 3.8 Hz, 1H),
2.90 (d, J¼4.2 Hz, 3H), 2.05 (m, 1H), 1.80 (m, 1H), 1.39 (m, 1H), 0.89
(m, 2H), 0.70 (d, J¼6.3 Hz, 6H); 13C NMR (125.7 MHz, CDCl3)
(2) [Mþþ1], 136 (84), 117 (75), 91 (100); HRMS calcd for
[C20H25NO2S] 343.1606, found 343.1608.
d
166.9, 143.1, 136.5, 133.5, 130.8, 130.6, 129.1, 128.6, 128.0, 127.8,
4.5.7. N-Methyl-2-(1-phenylbutylsulfinyl)benzamide
(2h). Major
126.8, 68.8, 35.5, 27.8, 26.8, 22.7, 21.8; MS (70 eV): e/z (%): 344 (2)
[Mþþ1], 183 (91), 117 (100), 91 (100); HRMS calcd for
[C20H25NO2S] 343.1606, found 343.1610.
diast.: White solid, Rf¼0.25 (AcOEt); FTIR (film) 3285, 1653,
1016 cmꢀ1; mp 123e125 ꢂC (AcOEt); 1H NMR (400 MHz, CDCl3)
d
7.92 (d, J¼7.6 Hz, 1H), 7.62 (d, J¼7.6 Hz, 1H), 7.56 (dt, J¼7.6 and
1.2 Hz, 1H), 7.48 (dt, J¼7.6 and 1.2 Hz, 1H), 7.33e7.26 (m, 5H), 6.55
(br s, 1H), 4.30 (dd, J¼11.4 and 3.8 Hz, 1H), 2.95 (d, J¼5.0 Hz, 3H),
2.09 (m,1H),1.79 (m,1H),1.18 (m,1H),1.02 (m,1H), 0.76 (t, J¼7.3 Hz,
4.5.2. 2-(1,2-Diphenylethylsulfinyl)-N-methylbenzamide (2b). Major
diast.: Yellowish oil, Rf¼0.51 (AcOEt); 1H NMR (400 MHz, CDCl3)
d
8.23 (d, J¼7.8 Hz, 1H), 7.83e7.76 (m, 3H), 7.60e7.07 (m, 9H), 6.91
3H); 13C NMR (125.7 MHz, CDCl3)
d 167.0, 136.2, 134.0, 131.7, 131.0,
(m, 2H), 4.67 (dd, J¼11.4 and 3.9 Hz, 1H), 3.44 (dd, J¼14.2 and
11.4 Hz, 1H), 3.24 (dd, J¼14.2 and 3.9 Hz, 1H), 3.04 (d, J¼3.9 Hz,
3H); MS (70 eV): e/z (%), mixture of both diastereoisomers: 364
(12) [Mþþ1], 91 (100); HRMS calcd for [C22H21NO2S] 363.1293,
found 363.1294. Minor diast.: Rf¼0.51 (AcOEt); 1H NMR (400 MHz,
129.2, 128.6, 128.1, 127.4, 126.7, 125.5, 68.7, 27.6, 26.9, 19.9, 13.7; MS
(70 eV): e/z (%): 316 (34) [Mþþ1], 165 (88), 117 (77), 91 (100); HRMS
calcd for [C18H21NO2S] 315.1293, found 315.1296.
4.5.8. 2-(1-(4-Methoxyphenyl)-4-phenylbutylsulfinyl)-N-methyl-
benzamide (2i). Major diast.: Yellowish oil, Rf¼0.53 (AcOEt); FTIR
CDCl3)
d
8.12 (d, J¼7.8 Hz, 1H), 7.83e7.76 (m, 3H), 7.60e7.07 (m,
9H), 6.96 (m, 2H), 4.84 (dd, J¼9.6 and 6.2 Hz, 1H), 3.87 (dd, J¼14.2
and 6.2 Hz, 1H), 3.65 (dd, J¼14.2 and 9.6 Hz, 1H), 3.04 (d,
J¼3.9 Hz, 3H).
(microscope) n ;
3291, 1646, 1512 cmꢀ1 1H NMR (400 MHz, CDCl3)
d
7.90 (d, J¼7.7 Hz, 1H), 7.60 (d, J¼7.5 Hz, 1H), 7.52 (m, 1H), 7.41 (m,
1H), 7.28 (m, 2H), 7.12 (m, 3H), 6.93 (d, J¼8.5 Hz, 2H), 6.89 (br s, 1H),
6.85 (d, J¼8.5 Hz, 2H), 4.34 (dd, J¼11.4 and 3.6 Hz, 1H), 3.78 (s, 3H),
2.90 (d, J¼4.9 Hz, 3H), 2.43 (m, 2H), 2.07 (m, 1H), 1.71 (m, 1H), 1.46
4.5.3. (E)-N-Methyl-2-(1-phenylpent-3-enylsulfinyl)benzamide
(2c). Major diast.: Yellowish oil, Rf¼0.60 (AcOEt); 1H NMR
(m, 1H), 1.27 (8m, 1H); 13C NMR (100.6 MHz, CDCl3)
d 166.9, 159.5,
(500 MHz, CDCl3)
d
7.98 (d, J¼7.7 Hz, 1H), 7.64e6.75 (m, 9H), 5.28
143.1,141.7, 133.3,130.9, 130.6, 130.3, 128.4, 128.2, 128.1, 127.6, 126.7,
125.6, 114.1, 67.5, 55.2, 35.3, 28.1, 26.8, 24.1; ESI (m/z) 441 (MþþNa);
HRMS calcd for [C25H27NO3S] 421.1712, found 421.1709.
(m, 1H), 5.01 (m, 1H), 4.36 (dd, J¼11.5 and 4.4 Hz, 1H), 2.92 (d,
J¼4.9 Hz, 3H), 2.78 (m, 1H), 2.43 (m, 1H), 1.42 (d, J¼6.6 Hz, 3H); MS
(70 eV): e/z (%), mixture of both diastereoisomers: 327 (15) [Mþ], 91
(100). Minor diast.: Rf¼0.60 (AcOEt); 1H NMR (500 MHz, CDCl3)
4.5.9. 2-(1-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)bu-
tylsulfinyl)-N-methylbenzamide (2j). Major diast.: Yellowish oil,
d
8.05 (d, J¼8.2 Hz, 1H), 7.64e6.75 (m, 9H), 5.63 (m, 1H), 5.44 (m,
1H), 4.53 (dd, J¼8.8 and 7.1 Hz, 1H), 3.08 (m, 1H), 2.98 (d, J¼4.4 Hz,
3H), 2.91 (m, 1H), 1.60 (d, J¼6.6 Hz, 3H).
Rf¼0.22 (AcOEt); FTIR (microscope)
n ;
3316, 1663 cmꢀ1 1H NMR
7.90 (d, J¼7.7 Hz, 1H), 7.61 (m, 1H), 7.54 (m, 1H),
(400 MHz, CDCl3)
d
7.45 (m, 1H), 7.27 (m, 3H), 6.85 (d, J¼8.3 Hz, 2H), 6.69 (br d,
J¼3.6 Hz, 1H), 6.17 (s, 2H), 4.32 (dd, J¼11.6 and 3.9 Hz, 1H), 3.79 (s,
3H), 3.78 (s, 3H), 3.75 (s, 6H), 2.94 (d, J¼3.6 Hz, 3H), 2.41 (m, 2H),
2.10 (m, 1H),1.75 (m, 1H), 1.48 (m, 1H), 1.31 (m, 1H); 13C NMR
4.5.4. 2,2-(1,4-Diphenylbutylsulfinyl)-N-methylbenzamide
(2e). Major diast.: White solid, Rf¼0.59 (AcOEt); mp 130e131 ꢂC
(AcOEt); FTIR (film) 3451, 1661, 1019 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
7.92 (d, J¼7.9 Hz, 1H), 7.61 (d, J¼7.9 Hz, 1H), 7.53 (t,
(100.6 MHz, CDCl3) d 167.0, 159.6, 153.0, 131.8, 130.8, 130.6, 130.5,
J¼7.9 Hz, 1H), 7.42 (t, J¼7.9 Hz, 1H), 7.40e7.24 (m, 5H), 7.11 (m, 3H),
6.91 (m, 2H), 6.85 (br s, 1H), 4.35 (dd, J¼11.7 and 4.1 Hz,1H), 2.89 (d,
J¼4.1 Hz, 3H), 2.42 (m, 2H), 2.12 (m, 1H), 1.74 (m, 1H), 1.44 (m, 1H),
130.4, 129.0, 128.2, 128.0, 127.6, 127.0, 114.1, 105.4, 67.8, 60.8, 56.0,
55.3, 35.7, 28.0, 26.9, 24.3; ESI (m/z) 550 (MþþK), 534 (MþþNa);
HRMS calcd for [C28H33NO6S] 511.2029, found 511.2031.
1.29 (m, 1H); 13C NMR (125.7 MHz, CDCl3)
d 166.9, 143.2, 141.7,
136.4, 133.3, 130.9, 130.5, 129.2, 128.7, 128.2, 128.1, 128.0, 127.6,
126.8, 125.6, 68.3, 35.3, 28.1, 26.8, 24.1; MS (70 eV): e/z (%): 392 (2)
[Mþþ1], 332 (87), 165 (78), 117 (100); HRMS calcd for [C24H25NO2S]
391.1606, found 391.1608.
4.5.10. N-Methyl-2-(4-phenyl-1-(4-(trifluoromethyl)phenyl)bu-
tylsulfinyl)benzamide (2k). Major diast.: Yellowish oil, Rf¼0.50
(AcOEt/hexane¼70:30); FTIR (microscope)
n ;
3322, 1649 cmꢀ1 1H
NMR (400 MHz, CDCl3)
d
8.00 (d, J¼8.0 Hz, 1H), 7.67e7.05 (m, 5H),
6.90 (d, J¼7.2 Hz, 2H), 6.81 (br s, 1H), 4.48 (dd, J¼11.6 and 3.6 Hz,
4.5.5. 2N-Methyl-2-(1-phenylhex-5-enylsulfinyl)benzamide
(2f). Major diast.: Yellowish oil, Rf¼0.52 (AcOEt); FTIR (film) 3279,
1H), 2.94 (d, J¼3.6 Hz, 3H), 2.43 (m, 2H), 2.14 (m, 1H), 1.68 (m, 1H),
1.41 (m, 1H), 1.26 (m, 1H); 13C NMR (100.6 MHz, CDCl3)
d 166.6,
1639, 996 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼8.0 Hz, 1H),
143.1, 141.3, 141.1, 132.5, 131.3, 130.7, 129.6, 128.4, 128.3, 128.2,
127.2, 126.6, 125.8, 125.6 (q, J¼3.6 Hz), 67.6, 35.2, 27.9, 26.9, 23.4,
CF3 signal is obscured due to its low intensity; EIMS (m/z) 460
[Mþþ1, (2)], 276 (43), 165 (73), 104 (72), 91 (100); HRMS calcd for
[C25H24F3NO2S] 459.1480, found 459.1481.
7.63 (d, J¼8.0 Hz, 1H), 7.56 (t, J¼8.0 Hz, 1H), 7.45 (t, J¼8.0 Hz, 1H),
7.39e7.25 (m, 5H), 6.78 (br s, 1H), 5.57 (m, 1H), 4.81 (m, 2H), 4.31
(dd, J¼11.5 and 3.5 Hz, 1H), 2.93 (d, J¼3.5 Hz, 3H), 2.09 (m, 1H), 1.90
(m, 2H), 1.79 (m, 1H), 1.22 (m, 1H), 1.09 (m, 1H); 13C NMR
(100.6 MHz, CDCl3)
d 167.0, 140.2, 137.0, 134.1, 131.7, 130.7, 129.3,
128.7, 126.7, 126.1, 125.5, 120.3, 114.8, 69.0, 33.6, 33.3, 32.4, 26.0; MS
(70 eV): e/z (%): 342 (31) [Mþþ1], 166 (90), 117 (100); HRMS calcd
for [C20H23NO2S] 341.1449, found 341.1451.
4.5.11. 2-(4-Methoxyphenethylsulfinyl)-N-methylbenzamide
(2l). Yellowish oil, Rf¼0.43 (AcOEt/hexane¼70:30); 1H NMR
(400 MHz, CDCl3)
d 8.18 (m, 1H), 7.65 (m, 2H), 7.50 (m, 1H), 7.12 (d,
J¼8.2 Hz, 2H), 6.90 (br s, 1H), 6.78 (d, J¼8.2 Hz, 2H), 3.75 (s, 3H),
4.5.6. N-Methyl-2-(1-phenylhexylsulfinyl)benzamide
diast.: White solid, Rf¼0.56 (AcOEt); FTIR (film) 3290, 1643, 1554,
996 cmꢀ1; mp 110e111 ꢂC (AcOEt); 1H NMR (400 MHz, CDCl3)
7.91
(d, J¼7.7 Hz, 1H), 7.62 (d, J¼7.7 Hz, 1H), 7.50 (dt, J¼7.7 and 1.3 Hz,
1H), 7.47 (dt, J¼7.7 and 1.3 Hz, 1H), 7.35e7.24 (m, 5H), 6.64 (br s,
1H), 4.28 (dd, J¼11.6 and 4.1 Hz, 1H), 2.95 (d, J¼4.9 Hz, 3H), 2.08 (m,
1H), 1.82 (m, 1H), 1.35 (m, 6H), 0.74 (m, 3H); 13C NMR (125.7 MHz,
(2g). Major
3.20e2.95 (m, 4H), 2.98 (d, J¼4.8 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3)
d 167.8, 157.8, 143.0, 134.1, 133.2, 131.7, 131.2, 129.8, 128.4,
d
123.7, 114.2, 56.1, 55.8, 33.0, 26.7; HRMS calcd for [C17H19NO3S]
317.1086, found 317.1089.
4. 5.12. N-Methyl-2-(4-phenylbutylsulfinyl)benzamide
(2m). Yellowish oil; 1H NMR (500 MHz, CDCl3)
1H), 7.60 (m, 2H), 7.45 (m, 1H), 7.23 (m, 2H), 7.13 (m, 3H), 6.97 (br s,
d
8.10 (d, J¼8.1 Hz,
CDCl3)
d
167.0, 143.0, 136.3, 133.8, 130.9, 130.7, 129.2, 128.6, 128.0,
127.3, 68.9, 31.4, 26.9, 26.3, 25.3, 22.2, 13.9; MS (70 eV): e/z (%): 344
1H), 3.31 (m,1H), 2.93 (d, J¼4.6 Hz, 3H), 2.77 (m, 1H), 2.61 (m, 2H),

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5279
1.96 (m, 1H), 1.75 (m, 3H); MS (70 eV): e/z (%): 316 (4) [Mþþ1], 152
(75), 91 (100); HRMS calcd for [C17H19NO2S] 301.1136, found
301.1139.
d
7.26e7.13 (m, 7H), 6.87 (d, J¼8.6 Hz, 2H), 4.63 (t, J¼5.3 Hz, 1H),
3.80 (s, 3H), 2.62 (t, J¼7.1 Hz, 2H), 1.90e1.57 (m, 5H); 13C NMR
(100.6 MHz, CDCl3)
d 158.5, 142.0, 136.8, 128.1, 127.9, 126.8, 125.4,
113.4, 73.4, 54.8, 38.2, 35.4, 27.3; EIMS (m/z) 257 [Mþþ1, (100)];
4.5.13. 2-(1-(4-Methoxyphenyl)butan-2-ylsulfinyl)-N-methyl-
benzamide (2n). Yellowish oil, inseparable mixture of di-
astereoisomers, Rf¼0.63 (AcOEt/hexane¼70:30); 1H NMR (400 MHz,
HRMS calcd for [C17H20O2] 256.1463, found 256.1466.
4.6.5. 4-Phenyl-1-(4-(trifluoromethyl)phenyl)butan-1-ol
(3k). Yellowish oil, Rf¼0.68 (AcOEt/hexane¼60:40); 1H NMR
CDCl3) d 8.22 (m, 2H), 7.64 (m, 4H), 7.51 (m, 2H), 7.10 (m, 4H), 6.91 (br
s, 2H), 6.80 (m, 4H), 3.77 (s, 3H), 3.72 (s, 3H), 3.22e2.98 (m, 6H), 2.96
(m, 6H),1.63 (m, 4H), 0.98 (t, J¼7.5 Hz, 3H), 0.92 (t, J¼7.5 Hz, 3H); MS
(70 eV): e/z (%): 346 (19) [Mþþ1], 84 (100).
(400 MHz, CDCl3)
d
7.55 (d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 2H),
7.50e7.11 (m, 5H), 4.66 (br s, 1H), 2.60 (t, J¼6.8 Hz, 2H), 2.31 (br s,
1H), 1.81e1.52 (m, 4H); 13C NMR (100.6 MHz, CDCl3)
d
148.5, 141.9,
129.5 (q, J¼32.3 Hz), 128.3, 126.0, 125.8, 125.2 (q, J¼3.6 Hz), 125.1,
124.2 (q, J¼272.2 Hz), 73.6, 38.5, 35.5, 27.2; EIMS (m/z) 294 [Mþþ1,
(100)]; HRMS calcd for [C17H17F3O] 294.1231, found 294.1234.
4.5.14. N-Methyl-2-(nonan-3-ylsulfinyl)benzamide (2o). One dist.:
Yellowish oil, Rf¼0.41 (AcOEt); FTIR (film) 3298, 1651, 1550,
1000 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
8.03 (d, J¼7.5 Hz, 1H), 7.63
(m, 2H), 7.47 (m, 1H), 6.99 (br s, 1H), 3.00 (m, 1H), 2.96 (d, J¼6.6 Hz,
4.7. General procedure for the synthesis of compounds 4
3H), 1.78 (m, 2H), 1.47 (m, 2H), 1.31 (m, 11H), 0.71 (t, J¼7.5 Hz, 3H);
13C NMR (125.7 MHz, CDCl3)
d 166.8, 142.8, 131.1, 130.3, 128.6, 127.6,
To a cooled solution of 2 (1 equiv) and TMP (3 equiv) in dry DCM
(0.1 M) was added neat oxalyl chloride (1.2 equiv) at ꢀ50 ꢂC and
under Ar atmosphere. After complete disappearance of the starting
material (TLC), the reaction was quenched with 1 N HCl, the tem-
perature raised to rt and the mixture extracted with DCM. The
collected organic layers were dried on anhydrous Na2SO4, filtered
and the solvent evaporated in vacuo. The residue was purified by
flash-chromatography.
126.9, 64.4, 31.7, 29.6, 29.4, 26.8, 26.6, 22.6, 17.9, 14.0, 11.4; MS
(70 eV): e/z (%): 310 (17) [Mþ], 183 (25), 84 (100). Other diast.:
Rf¼0.33 (AcOEt); FTIR (film) 3298, 1651, 1550, 1000 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
8.03 (d, J¼7.5 Hz, 1H), 7.63 (m, 2H), 7.48 (m, 1H),
6.81 (br s, 1H), 3.01 (m, 1H), 2.97 (d, J¼4.9 Hz, 3H), 1.85 (m, 2H), 1.44
(m, 2H), 1.17 (t, J¼7.5 Hz, 3H), 1.14 (m, 4H), 1.06 (m, 4H), 0.79 (t,
J¼7.2 Hz, 3H); 13C NMR (125.7 MHz, CDCl3)
d 166.9, 143.4, 132.7,
131.0, 130.2, 127.3, 126.6, 64.2, 31.4, 29.0, 26.9, 23.9, 23.4, 22.4, 14.0,
11.3; MS (70 eV): e/z (%): 310 (17) [Mþ], 183 (25), 84 (100); HRMS
calcd for [C17H27NO2S] 309.1762, found 309.1764.
4.7.1. (1-Chloro-4-methylpentyl)benzene ((ꢀ)-4a). Yellowish oil;
D23
[a
]
ꢀ66.7 (c 0.4, CHCl3, ee >98%); FTIR (film) 1651, 1456,
1023 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.44e7.27 (m, 5H), 4.83
4.6. General procedure for the synthesis of compounds 3
(dd, J¼8.0 and 6.2 Hz, 1H), 2.10 (m, 2H), 1.59 (m, 1H), 1.40 (m, 1H),
1.20 (m, 1H), 0.90 (d, J¼7.1 Hz, 6H); 13C NMR (100.6 MHz, CDCl3)
To a cooled solution of 2 (1 equiv) and TMP (3 equiv) in dry DCM
(0.1 M) was added neat TFAA (5 equiv) at 0 ꢂC and under Ar at-
mosphere. The temperature was left to reach rt and the reaction
was stirred until complete disappearance of the starting material
was monitored (TLC). The organic solvent was evaporated, the
residue diluted with MeOH and water and an excess of solid K2CO3
was added until basic pH was reached. The mixture was extracted
with AcOEt, the collected organic layers dried on anhydrous
Na2SO4, filtered and the solvent evaporated in vacuo. The residue
was purified by flash-chromatography.
d
142.1, 128.6, 128.2, 126.9, 64.2, 38.0, 36.2, 27.7, 22.5, 22.4; MS
(70 eV): e/z (%): 198 (7) [Mþþ2], 196 (21) [Mþ], 125 (100), 91 (55);
HRMS calcd for [C12H17Cl] 196.1019, found 196.1017.
4.7.2. (1-Chloro-4-methylpentyl)benzene (4e). Yellowish oil, Rf¼0.67
(AcOEt/hexane¼90:10); 1H NMR (400 MHz, CDCl3)
d 7.35e7.11 (m,
10H), 4.84 (dd, J¼8.0 and 6.5 Hz, 1H), 2.63 (t, J¼7.7 Hz, 2H), 2.14 (m,
1H), 2.06 (m, 1H), 1.83 (m, 1H), 1.66 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) d 141.7, 128.6, 128.4, 128.2, 126.9, 125.9, 63.6, 39.4, 35.2, 28.7;
HRMS calcd for [C16H17Cl] 244.1019, found 244.1018.
4.6.1. 4-Methyl-1-phenylpentan-1-ol
((ꢀ)-3a). Yellowish
oil,
4.7.3. (1-Chloro-4-methylpentyl)benzene (4f). Yellowish oil, Rf¼0.70
23 ꢀ14.6 (c 0.6, CHCl3, ee 45%);
D
Rf¼0.66 (AcOEt/hexane¼70:30); [
a
]
1
(AcOEt/hexane¼90:10); H NMR (400 MHz, CDCl3)
d 7.20e7.05 (m,
1H NMR (400 MHz, CDCl3)
d
7.34e7.25 (m, 5H), 4.62 (t, J¼6.8 Hz,
5H), 5.75 (m, 1H), 4.93 (m, 2H), 4.81 (br s, 1H), 2.03 (m, 4H),
1H), 1.83e1.68 (m, 2H), 1.60e1.50 (m, 1H), 1.37e1.26 (m, 2H),
1.18e1.09 (m, 1H), 0.87 (d, J¼3.0 Hz, 3H), 0.86 (d, J¼3.0 Hz, 3H); 13C
1.59e1.41 (m 2H); 13C NMR (100.6 MHz, CDCl3)
d
141.9, 138.1, 128.6,
128.3, 126.9, 115.1, 63.7, 39.4, 33.1, 29.7, 26.3; HRMS calcd for
[C12H15Cl] 194.0862, found 194.0863.
NMR (100.6 MHz, CDCl3) d 144.9, 128.4, 127.5, 125.9, 75.0, 37.0, 34.9,
28.0, 22.6, 22.5; EIMS (m/z) 178 [Mþþ1, (100)].
4.6.2. 1,4-Diphenylbutan-1-ol (3e). Yellowish oil, Rf¼0.60 (AcOEt/
4.8. General procedure for the synthesis of compounds 5
hexane¼70:30); 1H NMR (400 MHz, CDCl3)
d 7.25e7.03 (m, 10H),
4.45 (t, J¼5.0 Hz, 1H), 2.75 (s, 1H), 2.51 (t, J¼7.0 Hz, 2H), 1.75e1.44
To a cooled solution of 2 (1 equiv) and TMP (3 equiv) in dry
CH3CN (0.1 M) was added neat Tf2O (5 equiv) at ꢀ50 ꢂC and under
Ar atmosphere. After complete disappearance of the starting ma-
terial (TLC), the reaction was quenched with 1 N HCl, the temper-
ature raised to rt and the mixture extracted with AcOEt. The
collected organic layers were dried on anhydrous Na2SO4, filtered
and the solvent evaporated in vacuo. The residue was purified by
flash-chromatography.
(m, 4H); 13C NMR (100.6 MHz, CDCl3)
d 144.5, 141.9, 128.1, 128.03,
127.97, 127.1, 125.6, 125.4, 74.0, 38.4, 35.6, 27.4; EIMS (m/z) 227
[Mþþ1, (100)]; HRMS calcd for [C16H18O] 226.1358, found 226.1360.
4.6.3. 1-Phenylhex-5-en-1-ol (3f). Yellowish oil, Rf¼0.70 (AcOEt/
hexane¼60:40); 1H NMR (400 MHz, CDCl3)
d 7.33e7.21 (m, 5H),
5.75 (m, 1H), 5.00e4.90 (m, 2H), 4.58 (m, 1H), 2.55 (br s, 1H),
1.32e2.07 (m, 6H); 13C NMR (100.6 MHz, CDCl3)
d 144.9, 128.5,
128.4, 127.6, 114.6, 74.7, 65.3, 38.4, 33.5; EIMS (m/z) 176 [Mþþ1,
4.8.1. N-(4-Methyl-1-phenylpentyl)acetamide (5a). Yellowish oil,
(100)]; HRMS calcd for [C12H16O] 176.1201, found 176.1199.
Rf¼0.34 (AcOEt/hexane¼60:40); 1H NMR (400 MHz, CDCl3)
d 7.45
(m, 5H), 5.63 (br s, 1H), 4.91 (br s, 1H), 2.03 (s, 3H),1.78 (m, 2H), 1.54
4.6.4. 1-(4-Methoxyphenyl)-4-phenylbutan-1-ol (3i). Yellowish oil,
Rf¼0.64 (AcOEt/hexane¼60:40); 1H NMR (400 MHz, CDCl3)
(m, 1H), 1.98 (m, 1H), 1.06 (m, 1H), 0.80 (m, 6H); 13C NMR
(100.6 MHz, CDCl3) d 142.5, 128.7, 127.3, 126.6, 53.8, 35.3, 34.0, 27.9,

5280
G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
23.5, 22.5, 22.4; MS (70 eV): e/z (%): 220 (21) [Mþ],106 (100); HRMS
References and notes
calcd for [C14H21NO] 219.1623, found 219.1621.
1. (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359e373; (b) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534e541; (c) Johnson, J. S. An-
gew. Chem., Int. Ed. 2004, 43, 1326e1328; (d) Smith, A. B.; Adams, C. M. Acc.
Chem. Res. 2004, 37, 365e377; (e) Kinson, C.; Meyer, N.; Opaz, T. Angew.
Chem., Int. Ed. 2005, 44, 5662e5664; (f) Setter, H.; Kuhlmann, H. Org. React.
1991, 40, 407e496; (g) Hase, T. A. Umpoled Synthons; Wiley: New York, NY,
1987.
4.8.2. N-(1-Phenylheptyl)acetamide (5g). White solid, Rf¼0.42
(AcOEt/hexane¼50:50); 1H NMR (400 MHz, CDCl3)
d 7.34e7.12
(m, 5H), 5.81 (br d, J¼7.8 Hz, 1H), 4.87 (dd, J¼8.0 Hz, both, 1H), 1.88
(s, 3H), 1.70 (m, 2H), 1.19 (m, 8H), 0.78 (t, J¼8.0 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 169.1,142.6,128.6, 127.2,126.6, 53.5, 36.2, 31.6,
2. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075e1077.
3. Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239e258.
29.0, 26.1, 23.3, 22.5, 13.9; MS (70 eV): e/z (%): 256 (100) [MþþNa];
4. For some reviews, see: (a) Seebach, D.; Kolb, M. Chem. Ind. (London) 1974,
687e692; (b) Lever, O. W., Jr. Tetrahedron 1976, 32, 1943e1971; (c) Braun, M.
Angew. Chem., Int. Ed. 1998, 37, 430e451; (d) Guan, H. R. Curr. Org. Chem. 2008,
12, 1406e1430; (e) Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J. M. Eur. J.
Org. Chem. 2007, 5629e5660 See also: (f) Denmark, S. E.; Wilson, T. W. Nat.
Chem. 2010, 2, 937e943.
5. Miyake, H.; Kano, N.; Kawashima, T. J. Am. Chem. Soc. 2009, 131, 16622e16623.
6. Akula, R.; Galligan, M.; Ibrahim, H. Chem. Commun. 2009, 6991e6993.
7. For a recent review, see: Dickstein, J. S.; Kozlowski, M. C. Chem. Rev. Soc. 2008,
37, 1166e1173.
HRMS calcd for [C15H23NO] 233.1780, found 233.1783.
4.8.3. 1-N-(1-Phenylbutyl)acetamide (5h). White solid, Rf¼0.29
(AcOEt/hexane¼50:50); 1H NMR (400 MHz, CDCl3)
d 7.39e7.18 (m,
5H), 5.80 (br s, 1H), 4.97 (dd, J¼8.0 Hz, both, 1H), 1.98 (s, 3H),
1.83e1.68 (m, 2H), 1.34 (m, 2H), 0.92 (t, J¼8.0 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3)
d 169.7, 142.4, 128.8, 127.5, 126.7, 38.4, 29.8,
23.5,19.6,13.9; MS (70 eV): e/z (%): 214 (100) [MþþNa]; HRMS calcd
8. For some reviews, see: (a) Tamaru, Y. J. Organomet. Chem. 1999, 576, 215e231;
(b) Marshall, J. A. Chem. Rev. 2000, 100, 3163e3185; (c) Zanoni, G.; Pontiroli, A.;
Marchetti, A.; Vidari, G. Eur. J. Org. Chem. 2007, 3599e3611.
for [C12H17NO] 191.1310, found 191.1313.
ꢁ
9. Guerard, K. C.; Sabot, C.; Beaulieu, M.-A.; Giroux, M.-A.; Canesi, S. Tetrahedron
4.9. Enantioselective oxidation of sulfide 8a
2010, 66, 5893e5901.
10. Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027e1032.
11. For a very recent book on this topic, see:Organosulfur Chemistry in Asymmetric
Synthesis; Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008.
12. For very recent reviews, see: (a) Pellissier, H. Tetrahedron 2006, 62, 5559e5601
and references therein; (b) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han,
Z.; Gallou, I. Aldrichimica Acta 2005, 38, 93e104; (c) Volonterio, A.; Zanda, M. In
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2008, Chapter 11.
13. Zanda, M.; Bravo, P.; Volonterio, A. In Asymmetric Fluoro-Organic Chemistry:
Synthesis, Applications, and Future Directions; Ramachandran, P. V., Ed.; ACS
Symposium Series 746; American Chemical Society: Washington, DC, 1999;
pp 127e141.
14. (a) Bravo, P.; Capelli, S.; Meilee, S. V.; Seresini, P.; Volonterio, A.; Zanda, M.
Tetrahedron: Asymmetry 1996, 7, 2321e2332; (b) Pesenti, C.; Bravo, P.; Corradi,
E.; Frigerio, M.; Maille, S. V.; Panzeri, W.; Viani, F.; Zanda, M. J. Org. Chem. 2001,
66, 5637e5640 For some recent reviews on Pummerer reaction, see: (c) Feld-
man, K. S. Tetrahedron 2006, 62, 5003e5034; (d) Akai, S.; Kita, Y. Top. Curr.
Chem. 2007, 274, 35e76; (e) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter,
D. J. Angew. Chem., Int. Ed. 2010, 49, 5832e5844.
To a suspension of (R,R)-DPED (8 mg, 0.038 mmol) in CCl4 or
CH2Cl2 (1.2 mL) were drop-wise added in sequence Ti(i-PrO)4 (5
mL,
0.018 mmol) and H2O (7 L, 0.39 mmol). To the resulting homo-
m
geneous solution was added 8a (100 mg, 0.38 mmol), stirring at rt
for 15 min. The solution was then cooled at 0 ꢂC and TBHP (70% in
water, 100 mL, 0.77 mmol) added. The mixture was left stirring at
the chosen temperature, then diluted with CH2Cl2, and dried over
Na2SO4 for a few minutes. After filtration and evaporation of sol-
vent the residue was immediately purified by column chromatog-
raphy (EtOAc) isolating sulfoxide (ꢀ)-1a.
Enantiomeric purity of 1a was determined by HPLC on chiral
stationary phase Chiralcel OD (hexane/isopropanol 90:10;
flow¼1.0 mL/min; ¼254 nm).
l
15. (a) Volonterio, A.; Bravo, P.; Pesenti, C.; Zanda, M. Tetrahedron Lett. 2001, 42,
3985e3988; (b) Volonterio, A.; Bravo, P.; Panzeri, W.; Pesenti, C.; Zanda, M. Eur.
J. Org. Chem. 2002, 3336e3340.
4.10. X-ray crystallographic study
16. Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.; Volonterio, A.; Zanda, M.
A colorless block shaped single crystal, of 0.2ꢃ0.3ꢃ0.6 mm, was
obtained by crystallization from hexane/AcOEt. Crystal data are as
follows: C20H25NO2S, Mr¼343.5; orthorhombic, space group
Pna2(1), a¼15.403(1), b¼9.818(1), c¼12.172(1), V¼1840.7(3) 3, Z¼4,
Tetrahedron: Asymmetry 1998, 9, 3731e3735.
17. Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille, S. V.; Soloshonok, V.
ꢀ
A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.; Zappala, C. J. Org. Chem. 1997, 62,
3424e3425.
18. (a) Garcia Ruano, J. L.; Alcudia, A.; del Prado, M.; Barros, D.; Maestro, M. C.;
Dc¼1.239 g cmꢀ3, F(000)¼736,
m
(Cu K
a
)¼1.644 mmꢀ1. Diffraction
ꢀ
Fernandez, I. J. Org. Chem. 2000, 65, 2856e2862; (b) Bravo, P.; Capelli, S.;
data were collected on a Siemens P4 diffractometer with graphite
Crucianelli, M.; Guidetti, M.; Markovsky, A. L.; Meille, S. V.; Soloshonok, V. A.;
Sorochinsky, A. E.; Viani, F.; Zanda, M. Tetrahedron 1999, 55, 3025e3040.
19. Volonterio, A.; Bravo, P.; Zanda, M. Tetrahedron Lett. 2002, 43, 6537e6540.
20. Volonterio, A.; Zanda, M. Tetrahedron Lett. 2005, 46, 8723e8726.
21. (a) Superchi, S.; Rosini, C. Tetrahedron: Asymmetry 1997, 8, 349e352; (b) Don-
noli, M. I.; Superchi, S.; Rosini, C. J. Org. Chem. 1998, 63, 9392e9395; (c) Su-
perchi, S.; Donnoli, M. I.; Rosini, C. Tetrahedron Lett. 1998, 39, 8541e8544; (d)
Donnoli, M. I.; Superchi, S.; Rosini, C. Enantiomer 2000, 5, 181e188; (e) Superchi,
S.; Scafato, P.; Restaino, L.; Rosini, C. Chirality 2008, 20, 592e596.
22. (a) Mislow, K.; Ternay, A. L., Jr.; Melillo, J. T. J. Am. Chem. Soc. 1963, 85,
2329e2330; (b) Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.; Simmons, T.;
Ternay, A. L., Jr. J. Am. Chem. Soc. 1965, 87, 1958e1976.
23. (a) Rosini, C.; Donnoli, M. I.; Superchi, S. Chem.dEur. J. 2001, 7, 72e79; (b)
Donnoli, M. I.; Giorgio, E.; Superchi, S.; Rosini, C. Org. Biomol. Chem. 2003, 1,
3444e3449.
24. Pescitelli, G.; Di Pietro, S.; Cardellicchio, C.; Capozzi, M. A. M.; Di Bari, L. J. Org.
Chem. 2010, 75, 1143e1154.
25. To our knowledge the a-C-alkylation of ortho-carbamoyl-aryl alkyl sulfoxides
monochromated (Cu K
technique. Unit cell parameters were determined using 44 re-
a
) radiation (
l
¼1.54179), using
q/2q scan
flections in the range 11.6ꢄ
q
ꢄ47.4ꢂ. A total of 2074 reflections
(1517unique, Rint¼0.039) were collected at rt in the range
2.88ꢂ< <60ꢂ (completeness to theta of 95.8%). Three standard re-
q
flections, monitored every 97 reflections, showed no intensity de-
cay during the data collection. The structure was solved by direct
methods (SIR97) and refined by full-matrix least-squares on F2
(SHELXL97) with anisotropic temperature factors for non-H atoms,
for 226 parameters. The H-atoms, with the exception of H1N, which
was freely refined, were placed geometrically and treated as riding
with isotropic temperature factors (1.2 or 1.5 times the temperature
factors of the attached atom). The final stage converged to
has not been reported previously. For some reviews on the alkylation of met-
allated sulfoxides, see: (a) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2000,
R¼0.0476 for 1398 observed reflections, with Iꢅ2
s(I), and
R¼0.0520 for all unique reflections after merging. Goodness of
fit¼1.059. The final difference map showed a maximum and
a minimum residual peaks of 0.488 and ꢀ0.327 eꢀ3, respectively.
CCDC deposition number: 245649.
ꢁ
€
835e871; (b) Solladie, G. In Houben-Weyl: Methods in Organic Synthesis; Muller,
E., Ed.; Thieme: Stuggart, 1995; Vol. E21b, pp 1793e1815.
26. In the previous communication (Ref. ) we claimed the need to use 2.6 equiv of
BuLi to run the reaction to completion. However, by careful titration the
commercial available solutions of BuLi according to the method reported in
literature ( Kofron, W. G.; Bablawski, L. M. J. Org. Chem. 1976, 41, 1979e1980 ),
we discovered that 2.1 equiv are enough.
27. The thermodynamic equilibration at rt arose only with more electron poor
p-CF3ebenzyl derivative, while with the corresponding benzyl and
p-MeOebenzyl sulfoxides we obtained the same de even leading the temper-
ature to raise rt.
Acknowledgements
Politecnico di Milano and CNR are gratefully acknowledged for
economic support.

G. Pinna et al. / Tetrahedron 67 (2011) 5268e5281
5281
28. For reaction of
involved a
a
-lithiated sulfoxide with electrophiles in which is presumably
the desired brominated product with the corresponding sulphide arising from
the reduction of the starting sulfoxide.
p
-stacking interaction in the transition state, see: Fustero, S.; Nav-
ꢁ
arro, A.; Pina, B.; Garcia Soler, J.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo, P.;
Fronza, G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621e2624.
29. Some alkyl halides, such as isobutyl-bromide and 2-bromomethyl-dioxolane
reacted very sluggishly with sulfoxides (ꢁ)-1a, b.
O
S
Br
Ph
Ph
S
(COBr) , TMP
2
+
H
30. Xia, M.; Chen, S.; Bates, D. K. J. Org. Chem. 1996, 61, 9289e9292 and references
cited therein.
H
DCM, - 50 °C
CONHCH
3
CONHCH
3
13 (47%)
14 (24%)
(±)-2a
31. (a) Uchida, Y.; Oae, S. Gazz. Chim. Ital. 1987, 117, 649e654 and references cited
therein; (b) Walter, W.; Krische, B. Liebigs Ann. Chem. 1980, 14e27; (c) Cipollina,
J. A.; Ruediger, E. H.; New, J. S.; Wire, M. E.; Shepherd, T. A.; Smith, D. W.; Yevich,
J. P. J. Med. Chem. 1991, 34, 3316e3328; (d) Wright, S. W.; Abelman, M. M.;
Bostrom, L. L.; Corbett, R. L. Tetrahedron Lett. 1992, 33, 153e156; (e) For a highly
33. The absolute configuration of alcohol (ꢀ)-3a was assessed by comparison of
the value of the optical rotation with that reported in literature: Onodera, G.;
Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed. 2006, 45, 3819e3822.
34. In this case, 1 equiv of both CO and CO2 are produced, in analogy with the
outcome of the Swern oxidation.
stereoselective lactonization with displacement of
Pummerer-type conditions, see: Casey, M.; Manage, A.; Murphy, P. J. Tetrahe-
dron Lett. 1992, 33, 965e968.
a sulfinyl group under
32. In order to be able to prepare also the brominated analogous of compounds 4,
we tried to perform the reaction on sulfoxide (ꢁ)-2a with commercially
available oxalyl bromide. However, probably due to the more nucleophilic
character of Brꢀ compared to Clꢀ, we obtained the formation of a mixture of
35. This hypothesis is supported by the fact that non-benzylic substrate, such as
sulfoxide (ꢁ)-2l undergo the chloro-Pummerer as well.
36. Kita, Y.; Tamura, O.; Shibata, N.; Miki, T. Chem. Pharm. Bull. 1990, 38, 1473e1478.