Deracemizing organocatalyzed Michael addition reactions of 2-(arylthio)cyclobutanones with β-nitrostyrenes

Article abstract of DOI:10.1039/c6ob00160b

Organocatalyzed Michael addition reactions of 2-(arylthio)cyclobutanones with trans-β-nitrostyrenes have been carried out using a bifunctional thiourea-primary amine catalyst, providing diastereoisomerically and enantiomerically enriched 2-alkyl-2-(arylthio)cyclobutanones having two contiguous stereocenters of which one is a chiral quaternary center. The absolute configuration of these novel adducts was assigned by X-ray diffraction analysis and a transition-state model is proposed to explain the observed stereoselectivities.

Full text of DOI:10.1039/c6ob00160b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: F. Secci, A.
Frongia, G. Sarais, D. J. Aitken, A. Luridiana and R. Guillot, Org. Biomol. Chem., 2016, DOI:
10.1039/C6OB00160B.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 10
View Article Online
DOI: 10.1039/C6OB00160B
Journal Name
ARTICLE
Deracemizing Organocatalyzed Michael Addition Reactions of
2-(Arylthio)cyclobutanones with β-Nitrostyrenes
Received 00th January 20xx,
Accepted 00th January 20xx
Alberto Luridiana,a Angelo Frongia,a David J. Aitken,b Regis Guillot,b Giorgia Sarais,c Francesco
Seccia*
DOI: 10.1039/x0xx00000x
Organocatalyzed Michael addition reactions of 2-(arylthio)cyclobutanones with trans-β-nitrostyrenes have been carried
www.rsc.org/
out using a bifunctional thiourea-primary amine catalyst, providing diastereoisomerically and enantiomerically enriched 2-
alkyl-2-(arylthio)cyclobutanones having two contiguous stereocenters of which one is a chiral quaternary center. The
absolute configuration of these novel adducts was assigned by X-ray diffraction analysis and a transition-state model is
proposed to explain the observed stereoselectivities.
Dedicated to Dr Jean Ollivier, a mentor and a friend, on the occasion of his retirement
Concerning organocatalyzed Michael addition reactions, Ley
and co-workers were the first to consider (unsubstituted)
Introduction
cyclobutanone in reactions with β-nitrostyrenes, employing L-
Cyclobutanones are a family of strained small-ring carbocyclic
molecules which are stable yet chemically reactive and are
recognised as powerful intermediates for the stereo- and
enantioselective synthesis of natural and/or biologically-active
products.1 The interest on this class of compounds arises from
proline derivatives as catalysts.16 Since then, however, little
development of this type of reaction has been reported. In one
significant result in the field, reported by Rodriguez and co-
workers, hydrogen bond-forming 2-carboxamide derivatives of
cyclobutanone were engaged successfully in straightforward
enantio- and diastereoselective Michael addition reactions
both the
α-proton acidity and the marked carbonyl group
electrophilicity.2 These intrinsic characteristics have been used
advantageously in synthesis, for the construction of highly
functionalized building blocks containing quaternary
stereogenic centres.3 Over the years, cyclobutanone
derivatives have been exploited in various synthetic
applications such as ring-opening,4 ring-expansion,5 and ring-
contraction reactions.6 while useful intramolecular cyclization
reactions7 and oxidation protocols8 have been established.
More recently, metal-catalyzed and organocatalytic
procedures have been developed in order to facilitate
controlled selective transformations of cyclobutanones,
with β
-nitrostyrenes using bifunctional organocatalysts.17 Our
own recent work in this area revealed that 3-substituted
cyclobutanones can be desymmetrized in Michael addition
reactions with nitroalkenes in mild organocatalyzed
conditions, yielding the corresponding
α-functionalized
adducts with high selectivity.18 However, reaction times were
long and many cyclobutanone derivatives are moisture and air
sensitive,19 so we considered that further exploration of
Michael reactions of cyclobutanones was warranted.
Our rationale for the developments described in this paper is
based on the added synthetic value of using cyclobutanones
including
of cyclobutanone itself; aldolization,12 nitrogen insertion,13 and
α
-alkylation,9 aldolization10 and Mannich reactions11
bearing an
compounds, we anticipated an enhanced reactivity of the
cyclobutanone -proton and an improved stability of the
intermediates during the enolization processes. Indeed, the
literature concerning -ketosulfides shows that the enolate of
-(phenylthio)cyclobutanone has pronounced pro-
α-sulfanyl group as substrates. With such
α
-amination14 of
2-hydroxycyclobutanone; and the aldol-
α
desymmetrization of prochiral 3-substituted cyclobutanones.15
β
α
a
nucleophilic character, comparable with ketoamides and 1,3-
dicarbonyl compounds (pKa (DMSO) = 16–19).20 It is also
known that
tendency to enolize in the presence of triethylamine/Ac2O,
generating the corresponding stable enolthioether.21 These
α-(phenylthio)cyclobutanones show a strong
β
-
ketosulfides, as well as their enolthioethers derivatives, have
been described in a number of synthetic applications22 but to
the best of our knowledge they have never been used in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 10
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Journal Name
enantioselective procedures. The chemical versatility of sulfur- diastereoselectivity for this compound. In toluene (entry 3) the
containing building blocks should also facilitate the use of such high selectivities observed using catalyst II were maintained
compounds in a wide number of subsequent transformations. but the conversion was diminished; the reaction failed to
For all of these reasons, we undertook a study of 2- proceed in dichloromethane (entry 4). The use of catalysts III-V
(arylthio)cyclobutanone derivatives as nucleophiles in new in DMSO (entries 5-7) progressed with lower conversions and
organocatalyzed Michael addition reactions with
nitrostyrenes.
β
-
reduced selectivities. While several aspects of this first-round
study were encouraging, unfortunately all of the isolated
samples of the main product iso-3a were close to racemic.
Likewise, HPLC analysis of the recovered unreacted
cyclobutanone 1a showed this material to be racemic
indicating no kinetic or dynamic resolution was operating.
Results and discussion
To begin, a catalyst screening was conducted. The catalysts
examined are illustrated in Figure 1 and fall into four
cat.I-V
O
Ph
O
20 mol %
O2N
+
categories: L-Proline derivatives I-V
, cinchona alkaloid
O
Ph
NO2
solvent, rt
derivatives VI-VII, thiourea–amine derivatives VIII-XII, and two
squaramide derivatives XIII-XIV. The model Michael addition
reaction between (±)-2-(phenylthio)cyclobutanone 1a23 and
SPh
PhS
3a
Ph
SPh
NO2
iso-3a
rac-1a
2a
trans-β-nitrostyrene 2a was selected to examine using each of
these catalysts in appropriate solvents at room temperature
Table 1. Michael addition reaction of cyclobutanone 1a with trans-β-
nitrostyrene 2a using catalysts I-V.a
for 2 days.
Entry Cat. Solvent Y(3a+i-3a)(%)b 3a:i-3ac i-3a d.r.c i-3a e.r.d
R
MeO
1
2
3
4
5
6
7
I
DMSO
44
62
25
17:83
2:98
4:96
9:91
2:98
4:96
57:43
55:45
53:47
HO
N
O
N
N
COOH
Ar
II DMSO
II toluene
II CH2Cl2
III DMSO
IV DMSO
N
N
H
N
HN
HN
S
N
H
H
O
O
I R= H
IV Ar = Ph
Ar = p-C6H4-n-C12H25
N
e
–
II R = OSiTBDP
III
VI
V
35
28
30
26:74 21:79
23:77 16:84
19:81 13:87
52:48
59:41
43:57
CF3
CF3
MeO
H2N
S
S
V
DMSO
N
F3C
N
F3C
N
N
H
N
H
a Reactions were carried out in a 5 mL vial with 1a (0.56 mmol), 2a (0.56 mmol), cat. I-V
(20 mol %) in the reported solvents (1.5 mL) at room temperature (48 h). b Yields were
H
H
N
N
IX
H2N
VII
VIII
c
determined by weight after chromatography. 3a:iso-3a ratios and iso-3a d.r. values
were determined by 1H NMR analysis (CDCl3) of the crude reaction mixtures. iso-3a
e.r. values were determined by chiral HPLC. e No reaction.
F3C
d
CF3
S
S
N
N
N
H
N
H
Bn
N
N
H
Bn
H
N
HN
HN
S
O
O
H2N
Unsatisfied with these results, we turned our attention to the
model reaction of 1a with 2a in the presence of 20 mol % of
the other catalysts VI-XIV; toluene was a more convenient
solvent for these reactions (Table 2). The cinchona-derived
catalysts VI and VII induced the formation of the quaternary
Michael adduct 3a (implicating reaction at the C2 center) in
low yields and diastereoselectivities (entries 1 and 2). When
the reaction was carried out in the presence of thiourea–
N
XI
XII
MeO
F3C
O
O
O
F3C
O
N
N
H
X
N
H
N
N
H
H
F3C
F3C
H2N
N
XIII
XIV
Figure 1. Catalysts I-XIV studied in this work.
tertiary amines VIII or
X (entries 3 and 5) the yields of 3a were
The first series of experiments was conducted in the presence
of 20 mol% of a proline derivative (Table 1). The use of
improved although diastereoselectivities remained low. The
related thiourea-primary amine IX performed less well,
L-proline I itself in DMSO (entry 1) led to the formation of two
providing 3a in
a lower yield and with a comparable
Michael adducts in a 10:1 ratio and a combined yield of 44%.
The major product was isolated and 1H NMR and NOESY
analysis revealed that its structure was iso-3a, obtained with a
diastereoselectivity; however, in contrast to its tertiary amine
congeners, IX provided sample of the major diastereomer of
3a with a more encouraging enantiomeric ratio, better than
4:1 (entry 4). Further improvements were obtained using
catalyst XI which gave 3a in 68% yield and a better than 7:1
diastereoselectivity; the diastereoselection in this case was in
favour of the syn-3a isomer (entry 6).25 The best result in this
series of test experiments was achieved using the thiourea–
primary amine catalyst XII, which afforded anti-3a, in 84%
yield, almost exclusively as a single diastereomer which had an
enantiomeric ratio of 99:1 (entry 7). The catalyst screening was
notable
10:1
diastereoselectivity.
The
quaternary
regioisomeric adduct 3a was identified as the minor product
(configuration not determined). Formation of this product is
rationalized by the hypothesis that the reaction proceeds
preferentially via the formation of the less-hindered enamine
(implicating the C4 center) due to the steric bulk of the PhS
group.24 Improved results were achieved using catalyst II in
DMSO (entry 2), which provided a higher conversion of 1a, an
excellent product selectivity in favour of iso-3a, and a very high
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 10
Journal Name
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
completed by examining the squaramide derivatives XIII and
XIV which gave disappointing results in terms of both product
yields and selectivities (entries 8 and 9). The anti configuration
observed for the major diastereoisomer in all these
experiments (with the exception of entry 6) is attributed here
on the basis of the x-ray diffraction analysis described later in
this manuscript. Anti- and syn-stereoisomers showed quite
similar 1H NMR spectra, although one of the four
1 n-hexane 20
2 EtOAc 20
3 m-xylene 20
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:3
3:1
1:6
1:10
168
48
48
36
72
48
48
48
120
48
48
48
48
48
48
27
20
19
1:99
1:99
7:93
10:90
10:90
–
e
4 CH2Cl2
5 CHCl3
20
20
13 13:87
29 10:90
22 28:72
20 21:79
80
48
72
71
81
49
63
28
13:87
9:91
e
–
6 dioxane 20
7 THF 20
22:78
1:99
3:97
2:98
2:98
2:98
4:96
3:97
7:93
8
9
toluene 20
toluene 10
1:99
4:96
1:99
2:98
1:99
4:96
2:98
8:92
10 toluene 15
11 toluene 30
12 toluene 15
13 toluene 15
14 toluene 15
15 toluene 15
cyclobutanone ring protons showed
a
configuration-
dependent chemical shift, appearing at 2.31 ppm in anti-3a
and at 1.95 ppm for syn-3a
.
cat.VI-XIV
20 mol %
O
O
O
+
Ph
NO2
Ph
NO2
a Reactions were carried out in a 5 mL vial with 1a (0.56 mmol), 2a (0.56 mmol), cat. XII
toluene, rt
SPh
Ph
PhS
PhS
b
(15-30 mol %) in the appropriate solvent (1.5 mL) at room temperature. Yields were
NO2
determined by weight after chromatography. 3a d.r. values were determined by 1H
c
rac-1a
NMR analysis (CDCl3) of the reaction crude mixtures. d anti-3a e.r. values determined by
2a
syn-3a
anti-3a
chiral HPLC. e Not determined.
Table 2. Michael addition reaction of cyclobutanone 1a with trans-β-nitro
styrene 2a using catalysts VI-XIV.a
Firstly, the effect of the solvent was assessed in reactions using
20 mol% catalyst and 1 equivalent each of 1a and 2a. In n-
hexane the diastereoselectivity was high but the reaction was
very slow and inefficient; after seven days, compound 3a was
obtained in only 27% yield (entry 1). Reactions remained
sluggish in several other solvents (entries 2-7) and in some
cases selectivity was compromised. We therefore returned to
toluene as the solvent of choice for the evaluation of the
reagent stoichiometry and catalyst loading parameters. Using
20 mol% catalyst and 1 equivalent each of 1a and 2a the
adduct 3a was obtained in 80% yield after 48 hours with
excellent diastereo- and enantioselectivity (entry 8). When the
catalyst loading was reduced to 10 mol%, the reaction was
considerably slower, giving 3a in 48% yield only after 5 days
(entry 9). On the other hand, an increased catalyst loading of
30 mol% did not provide any benefit in terms of yield or
selectivity (entry 11). A 72% yield of 3a with very high
selectivity was achieved in 2 days, when 15 mol% of catalyst
XII was employed (entry 10). The use of a 3-fold excess of the
cyclobutane substrate 1a reduced the yield of the adduct 3a
somewhat (entry 13), whereas the use of an 3-fold excess of
Entry
Cat.
Yield 3a (%)b syn:anti 3ac anti-3a e.r.d
1
2
3
4
5
6
7
8
9
VI
16
12
64
21
50
68
84
49
26
42:58
24:76
31:69
22:78
27:73
88:12
1:99
23:77
e
VII
VIII
IX
X
XI
XII
XIII
XIV
–
53:47
19:81
52:48
90:10f
1:99
14:86
20:80
8:92
18:82
a Reactions were carried out in a 5 mL vial with 1a (0.56 mmol), 2a (0.56 mmol), cat. VI-
XIII (20 mol %) in toluene (1.5 mL) at room temperature (48 h). b Yields were
determined by weight after chromatography. c 3a d.r. values were determined by 1
NMR analysis (CDCl3) of the reaction crude mixtures. d anti-3a e.r. values were
determined by chiral HPLC. e Not determined. f The value is given for the major syn-3a
H
adduct.
The pleasing results obtained using the thiourea–amine XII
inspired us to pursue studies with this catalyst and explore
different reaction conditions in which the solvent, the reagent
stoichiometry, the reaction time and the catalyst loading were
varied, with a view to optimization (Table 3).
trans-β-nitrostyrene 2a resulted in an increase of the yield of
cat. XII
10-30 mol %
3a to 81%, still characterized by high diastereo- and
enantioselectivities (entry 12) and considered by us the best
reaction condition for this transformation. Further increases in
the excess of the nitrostyrene did not improve on this result
(entries 14 and 15). The optimized protocol was therefore
O
O
Ph
+
NO2
Ph
NO2
solvent, rt
SPh
PhS
rac-1a
2a
anti-3a
Table 3. Michael addition reaction of cyclobutanone 1a with trans-β-nitro concluded as being the use of 15 mol% of catalyst XII in
styrene 2a using catalyst XII in different conditions.a
toluene at room temperature for 2 days with a 1:3 1a/2a ratio.
Entry Solv. Cat.(mol%) 1a:
2a time(h) 3a Y(%)b 3a d.rc 3a e.r.d
We then turned our attention to the XII-catalyzed Michael
addition reactions involving other 2-(arylthio)cyclobutanones
in order to establish the reaction scope and to evaluate the
electronic effects, if any, of substituents present on the
sulfanyl aromatic moiety. For these purposes, a panel of p-
substituted
derivatives
of
racemic
2-
(phenylthio)cyclobutanone 1b-g was prepared23 and each was
submitted to
a Michael addition reaction with trans-β-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 10
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Journal Name
nitrostyrene 2a to afford the corresponding C2 quaternary disubstituted trans-β-nitrostyrenes, 2i and 2j
, with only
cyclobutanone 3b-g (Table 4). In each case, the Michael adduct marginally lower yields and unaffected high stereoselectivities.
3b-g was obtained in good yield, with very high anti These observations gratifyingly illustrated a general tolerance
diastereoselectivity, and with high enantiomeric enrichment. of electronic and steric effects on the aryl moiety of the trans-
The major anti configuration was suggested by the uniformly β-nitrostyrene component.
low-field chemical shift values (>2.2 ppm) observed for the To probe the limits of the reaction scope, cyclobutanone 1a
cyclobutanone proton discussed above for 3a. Only marginal was placed with nitroalkenes 2k and 2l in the standard Michael
differences in the terms of yield and selectivity were observed addition conditions. The reaction failed to proceed with these
across the substrate panel, suggesting no significance of the substrates and almost complete recovery of the unchanged
electronic effects present in the arylthio moiety for either the starting materials was observed. This result is in line with
formation of the intermediate enamine or the progress of the comparable observations, reported previously by Wennemers
reaction.
and co-workers,26 of the low reactivity of α- or β-substituted β-
nitrostyrenes with sterically hindered nucleophiles in C–C
bond-forming reactions.
cat. XII
O
O
15 mol %
Ph
Ph
NO2
+
R
NO2
toluene, rt
S
S
R
cat. XII
O
O
R'
rac-1b-g
anti-3b-g
2a
15 mol %
R
R
+
NO2
toluene, rt
S
S
Table 4. Michael addition reactions of cyclobutanones 1b-g with trans-β-nitrostyrene
2a using catalyst XII in optimized conditions.a-d
NO2
R'
4b-l
2b-l
rac-1a
O
O
O
Table 5. Michael addition reactions of cyclobutanone 1a with trans-β-nitrostyrene
derivatives 2b-l using catalyst XII in optimized conditions. a-d
Ph
NO2
Ph
NO2
Ph
NO2
S
S
S
Cl
Br
F
Cl
Br
anti-3b
anti-3c
anti-3d
F
O
O
O
d.r. = 4:96
e.r. = 6:94
78% yield
d.r.= 2:98
e.r. = 8:92
71% yield
d.r. = 2:98
e.r. = 3:97
68% yield
S
S
S
NO2
NO2
NO2
O
O
O
anti-4c
anti-4d
d.r. 4:96
e.r. 3:97
anti-4b
d.r. = 2:98
e.r. = 5:95
62% yield
d.r. = 2:98
e.r. = 3:97
64% yield
Ph
NO2
Ph
NO2
Ph
NO2
S
S
S
75% yield
O2N
MeO
Me
anti-3e
anti-3f
anti-3g
OMe
Me
OBn
O
O
O
d.r. = 1:99
e.r. = 11:89
80% yield
d.r. = 2:98
e.r. = 4:96
82% yield
d.r. = 2:98
e.r. = 3:97
78% yield
S
S
S
NO2
NO2
NO2
a Reactions were carried out in a 5 mL vial with 1b-g (0.56 mmol), 2a (1.68 mmol),
anti-4e
anti-4f
anti-4g
d.r. = 2:98
e.r. = 2:98
75% yield
d.r. = 4:96
e.r. = 2:98
78% yield
d.r. = 2:98
e.r. = 2:98
57% yield
b
cat. XII (15 mol %) in toluene (1.5 mL), room temperature (48 h). d.r. values
were determined by 1H NMR analysis (CDCl3). c Yields were determined by weight
after chromatography. d e.r. values determined by chiral HPLC.
O
Cl
O
O
O
Cl
O
In the next series of experiments, we evaluated the scope of
the reaction and the significance, if any, of the electronic and
steric effects prevalent in the trans-β-nitrostyrene component.
S
S
S
Cl
NO2
NO2
F
NO2
For this purpose,
a
panel of differently substituted β-
anti-
4i
anti-4j
anti-4h
d.r. = 1:99
e.r. = 3:97
54% yield
d.r. = 1:99
e.r. = 1:99
47% yield
d.r. = 3:97
e.r. = 4:96
60% yield
nitrostyrene derivatives 2b-l was selected and each was
submitted to a Michael addition reaction with racemic 2-
(phenylthio)cyclobutanone 1a, using the optimized reaction
conditions established above, to afford the corresponding C2
quaternary cyclobutanones 4b-l (Table 5). Compound 1a
reacted smoothly with the p-substituted trans-β-nitrostyrene
derivatives 2b-g, bearing either an electron-donating or an
electron-withdrawing group, affording the corresponding anti
derivatives 4b-f (showing low-field chemical shift values for the
O
O
NO2
S
S
NO2
O2N
4k traces
4l traces
1
relevant cyclobutanone proton in H NMR spectra) with good
a Reactions were carried out in a 5 mL vial with 1a (0.56 mmol), nitrostyrene 2b-l
(1.68 mmol), cat. XII (15 mol %) in toluene (1.5 mL) at room temperature (48 h). b
d.r. values of compounds 4b-j were determined by 1H NMR analysis (CDCl3) of the
yields (57-78%) and with excellent diastereoselectivities and
e.r. values. The reaction with the m,p-methylenedioxy
derivative 2h to give 4h worked equally well, and the reaction
also proceeded with the o,p-disubstituted and o,o-
c
reaction crude mixtures.
Yields were determined by weight after
chromatography. d e.r. values determined by chiral HPLC.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 10
Journal Name
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Satisfied with the results obtained thus far in our investigation, Scheme 2. In this representation, cyclobutanone 1a interacts
we extended the methodology by applying it to other related with catalyst XII leading to the formation of an enamine
ketone substrates (Scheme 1). The α-sulfonyl cyclobutanone intermediate able to interact with the β-nitrostyrene 2a bound
(±)-
the presence of catalyst XII, yielding the quaternary Michael interactions.17,18 The geometrical alignment of the two reactive
adduct anti- in low yield as a single diastereoisomer. The α- entities in the transition state for the formation of the new C-C
sulfanyl cyclopentanone and cyclohexanone substrates, (±)- bond is therefore responsible for the observed
and (±)- , both reacted with trans-β-nitrostyrene 2a in the enantioselectivity of the reaction, leading to the isomer
standard conditions to provide the single diastereoisomeric (2R,1’S)-3a after hydrolytic liberation of the ketone from the
adducts anti- and anti-10, in 57 % (e.r. 4:96) and 52 % (e.r. catalyst manifold.
1:99) yields, respectively.
5 reacted only very slowly with trans-β-nitrostyrene 2a in to the thiourea moiety of the catalyst via hydrogen-bonding
8
6
7
9
cat. XII
15 mol %
O
S
O
Ph
2a, toluene, rt
SO2
O
O
NO2
rac-5
anti-8
d.r. = 1:99
e.r. = 1:99
18% yield
cat. XII
15 mol %
O
O
Ph
2a, toluene, rt
S
NO2
anti-9
S
rac-6
d.r. = 3:97
e.r. = 4:96
57% yield
cat. XII
15 mol %
O
O
Ph
2a, toluene, rt
S
NO2
anti-10
S
rac-7
Scheme 2. a) Plausible transition state (TS) model for the formation of cyclobutanone
3a. b) Oxidation of adduct 3a to sulfone 8 and ORTEP plot of the single crystal X-ray
structure of this compound (see the Supporting Information for details).
d.r. = 2:98
e.r. = 1:99
52% yield
Scheme 1. Reaction of other cyclic ketone substrates 5-7 with trans-β-nitrostyrene 2a
using catalyst XII in optimized conditions.
Conclusions
In order to establish the stereochemical profile of the Michael
addition reactions described in this work, the major
diastereoisomer of 3a (described in Table 2) was oxidized using
In summary, we have developed
a new, deracemizing
organocatalyzed Michael addition reaction between 2-
(arylthio)cyclobutanones and trans-β-nitrostyrenes which
m-CPBA in dichloromethane, to give sulfone 8, in 88% yield
provides access to
a selection of new C2 quaternary
(Scheme 2). This compound was spectroscopically identical
(superimposable 1H and 13C NMR spectra, same sign for
cyclobutanone derivatives in good yields and with excellent
regio-, diastereo- and enantio-selectivities. The extent of
substrate tolerance in both the electrophile and the
nucleophile, the successful preliminary extensions to other
cyclic ketone substrates, the reactivity potential embedded in
the highly-functionalized adducts, and the general simplicity
and feasibility of this C–C bond-forming reaction make it a
useful addition to the existing inventory of organocatalyzed
reactions currently available as tools for fine organic synthesis.
specific rotation) with the sample of
X-Ray diffraction analysis of a single crystal of the new sample
of revealed the anti diastereoisomeric structure with the R
8 obtained in Scheme 1.
8
configuration at the quaternary cyclobutanone C2 center and
the S configuration at the new exocyclic stereogenic center
(Scheme 2).27 This observation is in good agreement with our
previous work using catalyst XII for Michael addition reactions
of 3-substituted cyclobutanones with trans-β-nitrostyrenes,
which exhibited the same stereochemical selectivities at the
two above-mentioned sereocenters.18 On the basis of the
similarities in the 1H and 13C-NMR spectroscopic signatures it is
proposed by extension that the same configuration pattern
prevails for the major stereoisomer throughout the series of
Acknowledgements
The authors gratefully acknowledge R.A.S. “Sardinia Regional
Government” for financial support (P.O.R. Sardegna F.S.E.
Operational Programme of the Autonomous Region of
Sardinia, European Social Fund 2007-2013-Axis IV Human
Resources, Objective l.3, Line of Activity l.3.1) and
C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazionale di Ricerca
compounds 3a-g
, 4b-j, 8-10 prepared in this work.
A
plausible transition state model, which explains the
formation of the major anti-cyclobutanone adducts 3a-g and
4a-i with the attributed stereochemistry, is illustrated in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 10
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Journal Name
in Metodologie e Processi Innovativi di Sintesi). Funding by the General procedure for the organocatalyzed Michael
Université Paris-Sud, the CHARM3AT LabEx, and the Ile-de- reactions of ketones 1a-g and 5-7 with nitrostyrenes.
France Region (SESAME program 2012 N°12018501) for
In a 5 mL vial, a solution of the appropriate ketone (0.56
mmol), the appropriate nitrostyrene (1.68 mmol) and catalyst
Instrument resources is acknowledged.
XII (15 mol %), in dry toluene (1.5 mL) was stirred for 36 h at
room temperature. The reaction mixture was directly purified
Experimental section
by flash chromatography (hexanes:diethyl ether, gradient 95:5
to 50:50) to affording the corresponding pure product.
General information
(2R,1’S)-2-(2-nitro-1-phenylethyl)-2-(phenylthio)cyclobutanone
1H NMR spectra were recorded on 400 and 500 MHz Varian
anti-3a
.
Yellow
oil.
FTIR
(neat)
= +19.2 (
ν:
. 0.36,
spectrometers at 27 °C using CDCl3, DMFꢀd7, acetoneꢀd6 or
25
2952, 2342, 1790, 1566, 1051 cmꢀ1
;
[
α
]
c
D
DMSOꢀd6 as solvent. 13C NMR spectra were recorded at 100
and 125 MHz at 27 °C using CDCl3, DMFꢀd7 or DMSOꢀd6 as
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.51ꢀ7.48 (m, 2H),
7.39ꢀ7.34 (m, 1H), 7.32 (t,
6.2 Hz, 3H), 7.19ꢀ7.15 (m, 2H), 5.25 (dd,
4.88 (dd, = 13.3, 11.9 Hz, 1H), 3.89 (dd,
1H), 2.88 (ddd, = 17.9, 10.6, 7.3 Hz, 1H), 2.44 (ddd,
10.3, 5.6 Hz, 1H), 2.31 (ddd, = 12.3, 10.4, 7.4 Hz, 1H), 1.76
(ddd,
= 12.4, 10.7, 5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
J
= 7.2 Hz, 2H), 7.23 (dt,
= 13.4, 3.8 Hz, 1H),
= 11.8, 3.7 Hz,
= 17.9,
J = 6.9,
solvent. Chemical shifts (
δ) are given in ppm. Coupling
J
constants ( ) are reported in Hz. Infrared spectra were recorded
J
J
J
on a FTꢀIR Bruker spectrophotometer and are reported in
wavenumbers. High resolution mass spectra (HRMS) were
obtained using positive mode Electrospray ionization (ESI).
Optical rotation values were recorded with a PolAAr 32
instrument. Analytical thin layer chromatography was
performed using 0.25 mm silica gel 60ꢀF plates. Flash
chromatography was performed using 70ꢀ200 mesh silica gel.
Yields refer to chromatographically and spectroscopically pure
J
J
J
J
δ: 203.2, 136.2, 133.9, 130.1, 129.5, 129.2, 129.2, 129.0, 128.5,
75.0, 72.6, 45.2, 43.6, 21.2; HRMS (ESI): calcd for
C18H17NNaO3S: 350.0827 (M+Na+), found: 350.0829. HPLC
analysis (Phenomenex Luxꢀ1 column,
mL/min. = 254 nm, tR (major) = 20.78 min, tR (minor) =
18.44 min.
2-(2-nitro-1-phenylethyl)-2-(phenylthio)cyclobutanone syn
Colourless oil. FTIR (neat) ν: 2994, 2344, 1791, 1542, 1048
iꢀPrOH/Hexane 5:95, 1.0
λ
materials. Enantiomeric ratios
(e.r.) of Michael adduct
cyclobutanones reported in the text were determined by
analytical HPLC using a Diacel Chiralpak ADꢀH, a Chiracel
OJ, a Chiracel ASꢀH or a Phenomenex Lux Celluloseꢀ1
analytical column, with i-PrOH/Hexane as the moble phase.
Authentic racemic samples were used for reference
ꢀ
3a
25
cmꢀ1; [
CDCl3) δ: 7.50ꢀ7.47 (m, 2H), 7.40ꢀ7.32 (m, 3H), 7.27ꢀ7.19 (m,
3H), 7.08ꢀ7.04 (m, 2H), 5.27 (dd, = 13.3, 3.8 Hz, 1H), 5.06
(dd, = 13.2, 11.5 Hz, 1H), 3.79 (dd, = 11.4, 3.8 Hz, 1H),
2.85 (ddd, = 18.2, 10.5, 7.6 Hz, 1H), 2.39 (ddd, = 18.3, 10.2,
5.8 Hz, 1H), 1.95 (ddd, = 16.5, 10.7, 5.8 Hz, 1H), 1.87 (ddd,
α
]
= +19.2 (c
. 0.35, CHCl3); 1H NMR (500 MHz,
D
J
comparisons. All 2ꢀ(arylthio)cycloalkanones 1a-g, 6 and 7 were
J
J
prepared using the recent literature protocol.23 βꢀNitrostyrene
and its derivatives 2a-l were purchased from SigmaꢀAldrich or
AlfaꢀAesar and used without further purification. Catalyst XII
was purchased from SigmaꢀAldrich or prepared according to
J
J
J
J
= 12.4, 10.3, 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ:
205.8, 136.1, 135.7, 131.9, 129.9, 129.5, 129.1, 128.6, 128.5,
76.7, 73.7, 48.9, 43.7, 22.0; HRMS (ESI): calcd for
C18H17NNaO3S: 350.0827 (M+Na+), found: 350.0831. HPLC
the literature procedure 28
.
Synthesis of 2-(phenylsulfonyl)cyclobutanone 5.
To a stirred solution of cyclobutanone 1a (300 mg, 1.68 mmol)
analysis (chiral pack ADꢀH column,
mL/min. = 254 nm, tR (major) = 24.18 min, tR (minor) =
22.62 min.
(2 ,1’ )ꢀ2-(4-fluorophenylthio)-2-(2-nitro-1-phenylethyl)
cyclobutanone anti-3b. Yellow solid. Mp = 135ꢀ137 °C; FTIR
iꢀPrOH/Hexane 25:75, 1.0
λ
in CHCl3 (20 mL) cooled to –20 °C, commercial
mꢀCPBA
(70% pure; 752 mg, 3.36 mmol), was added portionꢀwise over
20 min. The reaction mixture was monitored by TLC and
stirred until the reaction was complete (5 h). The resulting
suspension was filtered through a pad of celite, which was
washed through with CHCl3. The organic layer was washed
successively with saturated aqueous NaHCO3 solution, water,
then brine. It was then dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by
flash chromatography (hexanes:diethyl ether, gradient 90:10 to
R
S
25
(KBr) ν: 2993, 2357, 1789, 1555, 1053 cmꢀ1
0.87, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.56 (dd,
5.3 Hz, 2H), 7.36ꢀ7.25 (m, 3H), 7.23 (d, = 7.7 Hz, 2H), 7.09
(t, = 8.5 Hz, 2H), 5.31 (dd, = 13.3, 3.7 Hz, 1H), 5.01ꢀ4.89
(m, 1H), 3.91 (dd, = 11.7, 3.7 Hz, 1H), 2.97 (ddd, = 17.7,
;
[
α
]
= +69.2 (c.
D
J
= 8.5,
J
J
J
J
J
10.6, 7.2 Hz, 1H), 2.56ꢀ2.47 (m, 1H), 2.44ꢀ2.35 (m, 1H), 1.87ꢀ
1.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 202.8, 165.2,
50:50) affording the pure product
5 as a pale yellow solid, in
138.4 (d,
J
= 8.5 Hz), 133.4 (d,
J = 29.0 Hz), 129.0, 128.9,
78% yield. Mp = 68ꢀ70 °C; 1H NMR (400 MHz, CDCl3) δ:
7.85ꢀ7.80 (m, 2H), 7.64ꢀ7.58 (m, 1H), 7.55ꢀ7.47 (m, 2H), 4.72ꢀ
128.4, 124.3, 116.5 (d,
J
= 21.9 Hz), 74.7, 72.4, 45.0, 43.5,
20.7; HRMS (ESI): calcd for C18H16FNNaO3S: 368.0727
(M+Na+), found: 368.0714. HPLC analysis (Phenomenex Luxꢀ
1 column, iꢀPrOH/Hexane 5:95, 1.0 mL/min. λ = 254 nm, tR
(major) = 21.51 min, tR (minor) = 23.97 min.
(2R,1’S)-2-(4-chlorophenylthio)-2-(2-nitro-1-
4.61 (m, 1H), 3.23 (dddd,
3.02 (m, 1H), 2.57 (ddt,
J
= 18.3, 11.1, 7.2, 2.8 Hz, 1H), 3.14ꢀ
J
= 12.8, 11.1, 6.4 Hz, 1H), 2.35 (dtd,
J
= 12.7, 9.8, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 195.0,
137.9, 134.2, 129.3, 128.5, 78.8, 47.6, 13.6. This compound
was prepared previously using a different method.29
phenylethyl)cyclobutanone anti-3c. Yellow solid. Mp = 91ꢀ94
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 10
Journal Name
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
22
°C; FTIR (KBr) ν: 2984, 2344, 1789, 1557, 1060 cmꢀ1
= +107.4 (
;
[
α
]
analysis (Phenomenex Luxꢀ1 column,
i
ꢀPrOH/Hexane 5:95, 1.0
D
c
. 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.50 mL/min.
J = 8.4 Hz, 2H), 7.42ꢀ7.35 (m, 2H), 7.34ꢀ7.27 (m, 3H), 7.24 25.75 min.
λ = 254 nm, tR (major) = 27.82 min, tR (minor) =
(d,
(t,
J
= 7.5 Hz, 2H), 5.29 (dd,
J
= 13.4, 3.7 Hz, 1H), 4.95 (t,
J
J
=
=
(2R,1’S)-2-(p-tolylthio)-2-(2-nitro-1-phenylethyl)cyclobutanone
anti-3g. White solid. Mp 83ꢀ85 °C; FTIR (ATR)
12.5 Hz, 1H), 3.93 (dd,
J
= 11.7, 3.6 Hz, 1H), 3.00 (ddd,
=
17.7, 10.5, 7.1 Hz, 1H), 2.60ꢀ2.46 (m, 1H), 2.45ꢀ2.34 (m, 1H), ν: 2989, 2354, 1790, 1585, 1440 cmꢀ1
;
[
α
]
= +71.0 (c. 1.07,
D
21
1.90ꢀ1.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 202.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.37 (d,
161.8, 137.3, 133.5, 129.6, 129.0, 128.9, 128.5, 127.6, 74.7, 2H), 7.26ꢀ7.20 (m, 3H), 7.20ꢀ7.14 (m, 2H), 7.12 (d,
J
J
= 8.0 Hz,
= 8.0 Hz,
72.4, 45.0, 43.5, 20.8; HRMS (ESI): calcd for 2H), 5.26 (dd,
C18H16ClNNaO3S: 384.0432 (M+Na+), found: 384.0415. HPLC Hz, 1H), 3.87 (dd,
analysis (Phenomenex Luxꢀ1 column, ꢀPrOH/Hexane 5:95, 1.0 10.5, 7.3 Hz, 1H), 2.43 (ddd,
mL/min. = 254 nm, tR (major) = 27.01 min, tR (minor) = (s, 1H), 2.30ꢀ2.24 (m, 1H), 1.75 (ddd,
J
= 13.4, 3.8 Hz, 1H), 4.88 (dd,
= 11.8, 3.7 Hz, 1H), 2.89 (ddd,
= 17.9, 10.3, 5.6 Hz, 1H), 2.31
= 12.4, 10.7, 5.6 Hz,
J
= 13.3, 12.0
J
J
= 17.9,
i
J
λ
J
24.15 min.
1H); 13C NMR (125 MHz, CDCl3) δ: 203.0, 140.4, 136.2,
133.9, 130.1, 129.0, 128.8, 128.3, 125.5, 74.9, 72.5, 45.0, 43.5,
(2R,1’S)-2-(4-bromophenylthio)-2-(2-nitro-1-
phenylethyl)cyclobutanone anti-3d. White solid. Mp = 132ꢀ133; 21.3, 20.9; HRMS (ESI): calcd for C19H19NNaO3S: 364.0978
20
FTIR (KBr) ν: 2949, 2350, 1790, 1563, 1064 cmꢀ1
+39.8 (
. 0.10, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.45 (d, 1 column,
= 8.5 Hz, 2H), 7.35 (d, = 8.5 Hz, 2H), 7.27ꢀ7.19 (m, 3H), (major) = 37.25 min, tR (minor) = 32.88 min.
;
[
α
]
=
(M+Na+), found: 364.0965. HPLC analysis (Phenomenex Luxꢀ
D
c
i
ꢀPrOH/Hexane 5:95, 1.0 mL/min. = 254 nm, tR
λ
J
J
7.17ꢀ7.14 (m, 2H), 5.21 (dd,
13.3, 11.8 Hz, 1H), 3.86 (dd,
J
J
= 13.4, 3.8 Hz, 1H), 4.87 (dd,
= 11.7, 3.7 Hz, 1H), 2.92 (ddd,
J
=
J
(2R,1’S)-2-(1-(4-fluorophenyl)-2-nitroethyl)-2-(phenylthio)
cyclobutanone anti-4b. Colourless oil. FTIR (neat) cmꢀ1
20
= 17.9, 10.6, 7.2 Hz, 1H), 2.45 (ddd,
1H), 2.33 (ddd, = 12.4, 10.4, 7.2 Hz, 1H), 1.75 (ddd,
10.6, 5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 202.8, Hz, 1H), 7.41ꢀ7.30 (m, 4H), 7.20ꢀ7.13 (m, 2H), 6.94 (dd,
137.6, 133.7, 133.7, 132.7, 129.1, 129.0, 128.6, 125.0, 74.6, 11.9, 5.2 Hz, 2H), 5.25 (dd, = 13.4, 3.7 Hz, 1H), 4.87ꢀ4.78
72.5, 45.1, 43.7, 21.0; HRMS (ESI): calcd for (m, 1H), 3.87 (dd, = 11.9, 3.6 Hz, 1H), 2.99ꢀ2.88 (m, 1H),
C18H16BrNNaO3S: 427.9926 (M+Na+), found: 427.9907. HPLC 2.53ꢀ2.43 (m, 1H), 2.31ꢀ2.19 (m, 1H), 1.78 (ddd,
= 12.5, 10.7,
analysis (Phenomenex Luxꢀ1 column,
ꢀPrOH/Hexane 5:95, 1.0 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 202.9, 162.5 (d,
mL/min. = 254 nm, tR (major) = 32.83 min, tR (minor) = = 248.3 Hz), 136.1, 130.7 (d, = 8.1 Hz), 130.1, 129.5, 129.4,
128.9, 115.9 (d, = 21.6 Hz), 74.9, 72.3, 44.5, 43.5, 20.9;
HRMS (ESI): calcd for C18H16FNNaO3S: 368.0727 (M+Na+),
J
= 18.0, 10.4, 5.7 Hz, ν: 2889, 2350, 1789, 1562, 1436, 1257 cmꢀ1
;
[
α
]
= +61.2 (c.
D
J
J J = 6.9
= 12.5, 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.49 (d,
J
=
J
J
J
i
J
λ
J
28.65 min.
J
(2R,1’S)-2-(4-nitrophenylthio)-2-(2-nitro-1-
phenylethyl)cyclobutanone anti-3e. Yellow oil. FTIR (neat) found: 368.0716. HPLC analysis (Phenomenex Luxꢀ1 column,
20
ν: 2997, 2340, 1790, 1576, 1478, 1242 cmꢀ1
;
[
α
]
= +31.7 (
c.
i
ꢀPrOH/Hexane 5:95, 1.0 mL/min.
= 8.5 17.63 min, tR (minor) = 18.64 min.
= 4.5 Hz, 3H), (2R,1’S)-2-(1-(4-chlorophenyl)-2-nitroethyl)-2-(phenylthio)
= 13.2, 4.2 Hz, 1H), 5.11ꢀ5.01 cyclobutanone anti-4c. Yellow oil. FTIR (neat)
= 10.7, 4.2 Hz, 1H), 3.18 (ddd, = +53.4 (
= 18.2, ν: 2967, 2340, 1789, 1558, 1442, 1378 cmꢀ1; [
10.4, 7.6 Hz, 1H), 2.73ꢀ2.61 (m, 1H), 2.29ꢀ2.15 (m, 1H), 2.14ꢀ 0.22, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.48ꢀ7.45 (m,
λ = 254 nm, tR (major) =
D
1
0.26, CHCl3); H NMR (400 MHz, CDCl3) δ: 8.24 (d,
J
Hz, 2H), 7.61 (d,
7.14–7.11 (m, 2H), 5.19 (dd,
(m, 1H), 3.97 (dd,
J = 8.5 Hz, 2H), 7.35 (d, J
J
25
J
J
α
]
c.
D
2.01 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 202.1, 139.0, 2H), 7.40ꢀ7.35 (m, 5H), 6.95 (d,
134.6, 133.7, 133.3, 129.3, 129.1, 128.7, 124.3, 74.8, 44.9, 13.4, 3.9 Hz, 1H), 5.00 (dd, = 13.3, 11.6 Hz, 1H), 3.76 (dd,
43.7, 22.7, 20.9; HRMS (ESI): calcd for C18H16N2NaO5S: = 11.5, 3.7 Hz, 1H), 2.92 (ddd,
395.0678 (M+Na+), found: 395.0683. HPLC analysis (ddd,
= 18.3, 10.1, 5.6 Hz, 1H), 1.96 (ddd,
(Phenomenex Luxꢀ1 column, ꢀPrOH/Hexane 5:95, 1.0 Hz, 1H), 1.86 (ddd,
= 12.5, 10.2, 7.8 Hz, 1H); 13C NMR (125
J
= 8.4 Hz, 2H), 5.23 (dd,
J
=
J
J
J
= 18.3, 10.5, 7.7 Hz, 1H), 2.45
= 12.4, 10.7, 5.6
J
J
i
J
mL/min.
41.57 min.
λ
= 254 nm, tR (major) = 35.90 min, tR (minor) = MHz, CDCl3) δ: 205.2, 136.1, 134.7, 132.3, 130.3, 130.0,
129.5, 129.3, 122.6, 76.4, 73.3, 48.1, 43.7, 21.9; HRMS (ESI):
(2R,1’S)-2-(4-methoxyphenylthio)-2-(2-nitro-1-phenylethyl)
cyclobutanone anti-3f. Colourless solid. Mp = 123ꢀ124 °C; 384.384.0426. HPLC analysis (Phenomenex Luxꢀ1 column,
calcd for C18H16ClNNaO3S: 384.0432 (M+Na+), found:
i
ꢀ
FTIR (ATR) ν: 2934, 2345, 1790, 1556, 1052 cmꢀ1
+68.5 (
. 1.342, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.22 25.41 min, tR (minor) = 21.935 min.
(ddt, = 18.5, 11.7, 4.2 Hz, 6H), 7.10ꢀ7.04 (m, 2H), 6.94ꢀ6.85 (2R,1’S)-2-(1-(4-bromophenyl)-2-nitroethyl)-2-(phenylthio)
(m, 1H), 5.24 (dd, = 13.4, 3.8 Hz, 1H), 4.87 (dd, = 13.2, cyclobutanone anti-4d. Yellow solid, Mp = 121ꢀ124 °C; FTIR
12.0 Hz, 1H), 3.92 (dd,
= 11.8, 3.8 Hz, 1H), 3.75 (s, 3H), 2.91 (ATR) ν: 2923, 2356, 1790, 1460, 1045 cmꢀ1
(ddd, = 17.7, 10.6, 7.2 Hz, 1H), 2.42 (ddd,
= 17.8, 10.3, 5.5 0.43, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.46 (m, 2H),
Hz, 1H), 2.30 (ddd, = 12.3, 10.4, 7.2 Hz, 1H), 1.75 (ddd,
12.3, 10.8, 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 203.2, 5.0, 10.0 Hz), 5.00 (dd,
;
[
α
]
=
PrOH/Hexane 5:95, 1.0 mL/min. λ = 254 nm, tR (major) =
20
D
c
J
J
J
26
J
; [α] D = +63.4 (c.
J
J
J
J
=
7.39ꢀ7.34 (m, 5H), 6.95 (d,
J
= 5.0 Hz, 2H), 5.23 (dd, 1H,
J
J
=
=
J
= 10.0, 15.0 Hz, 1H), 3.76 (dd,
130.2, 130.0, 129.0, 128.8, 128.4, 127.9, 120.4, 116.3, 74.8, 5.0, 15.0 Hz, 1H), 2.95ꢀ2.89 (m, 1H), 2.47ꢀ2.45 (m, 1H), 1.99ꢀ
72.3, 55.4, 44.9, 43.5, 20.9; HRMS (ESI): calcd for 1.93 (m, 1H), 1.91ꢀ1.85 (m, 1H); 13C NMR (125 MHz, CDCl3)
C19H19NNaO4S: 380.0927 (M+Na+), found: 380.0915. HPLC δ: 205.2, 136.1, 134.7, 132.3, 130.3, 130.0, 129.5, 129.3, 122.6,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 10
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Journal Name
76.4, 73.3, 48.1, 43.7, 21.9; HRMS (ESI): calcd for 5.90 (s, 2H), 5.23 (dd,
C18H16BrNNaO3S: 427.9926 (M+Na+), found: 427.9913. HPLC 12.1 Hz, 1H), 3.83 (dd,
analysis (Chiralpack ADꢀH column, ꢀPrOH/Hexane 10:90, 1.0 1H), 2.62ꢀ2.49 (m, 1H), 2.33 (ddd,
mL/min. = 254 nm, tR (major) = 43.98 min, tR (minor) = 1.81 (ddd,
= 12.4, 10.7, 5.7 Hz, 1H); 13C NMR (125 MHz,
J
= 13.3, 3.8 Hz, 1H), 4.81 (dd,
= 11.9, 3.8 Hz, 1H), 3.00ꢀ2.86 (m,
= 12.4, 10.3, 7.5 Hz, 1H),
J = 13.2,
J
i
J
λ
J
41.76 min.
CDCl3) δ: 203.2, 147.9, 147.6, 136.0, 129.9, 129.3, 129.1,
127.3, 122.5, 109.3, 108.4, 101.3, 75.1, 72.4, 44.9, 43.5, 21.1;
(2R,1’S)-2-(1-(4-methoxyphenyl)-2-nitroethyl)-2-(phenylthio)
cyclobutanone
anti-4e.
Yellow
oil.
FTIR
(neat) HRMS (ESI): calcd for C19H17NNaO5S: 394.0720 (M+Na+),
= +74.3 (c. 1.22, found: 394.0701. HPLC analysis (Phenomenex Luxꢀ1 column,
ν: 2996, 2354, 1790, 1554, 1033 cmꢀ1
;
[
α
]
21
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.52ꢀ7.48 (m, 2H),
i
ꢀPrOH/Hexane 5:95, 1.0 mL/min.
= 8.7 Hz, 2H), 6.77ꢀ6.73 (m, 2H), 16.99 min, tR (minor) = 26.84 min.
= 13.2, 3.9 Hz, 1H), 4.82 (dd, = 13.2, 12.0 Hz, (2R,1’S)-2-(1-(2,4-dichlorophenyl)-2-nitroethyl)-2-(phenylthio)
1H), 3.83 (dd, = 11.9, 3.8 Hz, 1H), 3.69 (s, 2H), 2.88 (ddd, cyclobutanone anti-4i. Yellow viscous oil. FTIR (neat)
= 18.0, 10.6, 7.3 Hz, 1H), 2.44 (ddd,
= 18.0, 10.3, 5.7 Hz, ν: 2996, 2360, 1788, 1436, 1058 cmꢀ1
1H), 2.29 (ddd, = 12.3, 10.3, 7.3 Hz, 1H), 1.75 (ddd,
= 12.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.64ꢀ7.55 (m, 2H),
10.6, 5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 203.5, 7.49ꢀ7.40 (m, 4H), 7.27ꢀ7.22 (m, 1H), 7.18 (d,
= 8.5 Hz, 1H),
159.6, 136.2, 130.3, 130.0, 129.4, 125.7, 114.4, 107.4, 75.2, 5.44 (dd, = 13.8, 3.9 Hz, 1H), 5.21 (dd, = 13.8, 11.4 Hz,
72.7, 55.3, 44.5, 43.6, 21.0; HRMS (ESI): calcd for 1H), 4.62 (dd, = 11.4, 3.9 Hz, 1H), 3.05 (ddd, = 18.4, 10.7,
C19H19NNaO4S: 380.0927 (M+Na+), found: 380.0925. HPLC 7.7 Hz, 1H), 2.51 (ddd,
= 18.2, 10.2, 5.6 Hz, 1H), 2.16ꢀ2.08
analysis (Phenomenex Luxꢀ1 column, ꢀPrOH/Hexane 2:98, 1.0 (m, 1H), 1.79 (ddd,
= 12.5, 10.2, 7.9 Hz, 1H); 13C NMR (125
λ = 254 nm, tR (major) =
7.38ꢀ7.29 (m, 3H), 7.09 (d,
5.22 (dd,
J
J
J
J
J
26
J
;
[
α
]
= +47.4 (c. 0.33,
D
J
J
J
J
J
J
J
J
i
J
mL/min.
39.23 min.
λ
= 254 nm, tR (major) = 43.07 min, tR (minor) = MHz, CDCl3) δ: 205.0, 136.8, 136.3, 135.0, 132.4, 130.4,
130.3, 129.7, 129.3, 128.8, 128.1, 107.5, 75.6, 73.5, 44.1, 43.9,
(2R,1’S)-2-(2-nitro-1-p-tolylethyl)-2-(phenylthio)cyclobutanone 22.1; HRMS (ESI): calcd for C18H15Cl2NNaO3S: 418.0042
anti-4f. Yellow solid, Mp
=
92ꢀ95 °C; FTIR (ATR) (M+Na+), found: 418.0025. HPLC analysis (Phenomenex Luxꢀ
27
ν: 2899, 2348, 1790, 1380, 1061 cmꢀ1
;
[
α
]
= +26.5 (c. 0.62, 1 column, iꢀPrOH/Hexane 3:97, 1.0 mL/min. λ = 254 nm, tR
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.59ꢀ7.48 (m, 1H), (major) = 30.23 min, tR (minor) = 40.38 min.
7.38 (ddd,
13.3, 3.8 Hz, 1H), 4.89 (dd,
= 11.8, 3.8 Hz, 1H), 2.91 (ddd,
(ddd,
2H), 1.79 (ddd,
6.5, 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 203.4, 138.3, 7.17 (dd,
136.2, 130.8, 130.0, 129.7, 129.4, 129.0, 75.1, 72.6, 44.8, 43.6, (dd, = 11.4, 8.2 Hz, 1H), 5.27 (dd,
21.2, 21.1; HRMS (ESI): calcd for C19H19NNaO3S: 364.0983 (t, = 11.5 Hz, 1H), 4.65 (dd, = 10.8, 4.3 Hz, 1H), 3.34ꢀ3.23
(M+Na+), found: 364.1035. HPLC analysis (Phenomenex Luxꢀ (m, 1H), 2.80 (dd,
= 10.2, 5.4 Hz, 1H), 2.76ꢀ2.67 (m, 1H),
1 column, ꢀPrOH/Hexane 5:95, 1.0 mL/min.
= 254 nm, tR 1.93ꢀ1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 200.5,
(major) = 23.38 min, tR (minor) = 20.80 min. 163.0, 160.5, 136.7, 130.2, 130.1, 129.2, 126.6, 120.6 (d,
(2R,1’S)-2-(1-(4-(benzyloxy)phenyl)-2-nitroethyl)-2- 16.1 Hz), 115.1 (d, = 24.6 Hz), 73.5 (d, = 8.6 Hz), 72.4,
(phenylthio) cyclobutanone anti-4g. White solid. Mp = 62ꢀ63 43.5, 39.8, 21.1 (d, = 9.4 Hz); HRMS (ESI): calcd for
C18H15ClFNNaO3S: 402.0337 (M+Na+), found: 402.0324.
. 0.71, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.47 (d, HPLC analysis (Chiralpack OJ column,
ꢀPrOH/Hexane 5:95,
= 6.4 Hz, 2H), 7.38ꢀ7.24 (m, 8H), 6.98 (d, = 8.6 Hz, 2H), 1.0 mL/min. = 254 nm, tR (major) = 20.78 min, tR (minor) =
6.84 (d, = 8.6 Hz, 2H), 5.25 (dd, = 13.2, 3.8 Hz, 1H), 5.01 18.44 min.
(dd, = 22.2, 9.2 Hz, 1H), 4.93 (s, 2H), 3.74 (dd, = 11.5, 3.8 (2R,1’S)-2-(2-nitro-1-phenylethyl)-2-
Hz, 1H), 2.82 (ddd, = 18.2, 10.2, 7.9 Hz, 1H), 2.39 (ddd, (phenylsulfonyl)cyclobutanone anti-8. White solid, Mp = 160ꢀ
18.3, 9.9, 6.2 Hz, 1H), 2.00ꢀ1.84 (m, 2H); 13C NMR (100 MHz, 162 °C; FTIR (ATR) ν: 3000, 1790, 1480, 1440 cmꢀ1
CDCl3) δ: 206.3, 158.9, 136.7, 136.2, 130.0, 129.9, 129.7, +51.4 (
. 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 8.00 (d,
129.6, 128.7, 128.2, 127.8, 127.6, 115.4, 76.8, 73.9, 70.2, 48.3, = 7.5 Hz, 2H), 7.82 (t, = 7.5 Hz, 1H), 7.70 (t, = 7.8 Hz,
43.8, 22.1; HRMS (ESI): calcd for C25H23NNaO4S: 456.1240 2H), 7.28 (d, = 1.5 Hz, 1H), 7.27 (d, = 1.7 Hz, 2H), 7.09
= 6.5, 2.8 Hz, 2H), 5.42 (dd, = 13.7, 3.7 Hz, 1H), 4.99
= 13.6, 12.0 Hz, 1H), 4.07 (dd, = 11.9, 3.7 Hz, 1H),
J
= 10.6, 6.4, 2.2 Hz, 2H), 7.08 (s, 2H), 5.26 (dd,
J
=
(2R,1’S)-2-(1-(2-chloro-6-fluorophenyl)-2-nitroethyl)-2-
J
= 13.3, 11.9 Hz, 1H), 3.88 (dd,
J
J
(phenylthio) cyclobutanone anti-4j. Yellow oil. FTIR (neat)
24
= 17.7, 10.6, 7.2 Hz, 1H), 2.47 ν: 2999, 2355, 1789, 1484, 1258 cmꢀ1
;
[
α
]
= +38.2 (
c
. 0.22,
= 7.8 Hz,
= 7.5 Hz, 2H),
= 7.8 Hz, 1H), 6.97
J = 13.2, 4.3 Hz, 1H), 5.19
D
1
J
= 17.8, 10.3, 5.6 Hz, 1H), 2.39ꢀ2.30 (m, 1H), 2.26 (s, CHCl3); H NMR (500 MHz, CDCl3) δ: 7.62 (d,
J
J
= 12.4, 10.6, 5.6 Hz, 1H), 0.86 (ddt,
J
= 10.3, 2H), 7.45 (dd,
J = 10.7, 3.8 Hz, 1H), 7.40 (t, J
= 11.2, 4.9 Hz, 1H), 7.13 (t,
J
J
J
J
J
J
i
λ
J
=
J
J
J
27
°C; FTIR (ATR) ν: 2964, 1791, 1586, 1253 cmꢀ1
+31.2 (
;
[
α]
=
D
c
i
J
J
λ
J
J
J
J
J
J =
23
;
[
α
]
=
D
c
J
J
J
J
J
(M+Na+), found: 456.1286. HPLC analysis (chiralpackꢀOJ (dd,
column, ꢀPrOH/Hexane 25:75, 1.0 mL/min. = 254 nm, tR (dd,
(major) = 31.18 min, tR (minor) = 46.53 min.
(2R,1’S)-2-(1-(benzo[d][1,3]dioxol-6-yl)-2-nitroethyl)-2-
J
J
J
i
λ
J
3.08ꢀ2.99 (m, 1H), 2.99ꢀ2.90 (m, 1H), 2.61ꢀ2.52 (m, 1H), 2.48ꢀ
2.38 (m, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.4, 135.1,
(phenylthio) cyclobutanone anti-4h. Yellow oil. FTIR (neat) 134.7, 132.3, 130.3, 129.5, 129.2, 129.0, 128.7, 88.9, 74.3,
24
ν: 2994, 1791, 1378, 1256 cmꢀ1
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.52 (dd,
Hz, 1H), 7.40ꢀ7.31 (m, 2H), 7.04 (dd, = 8.0, 1.5 Hz, 1H), 6.96 (Chiralpack ADꢀH column,
(d, = 1.6 Hz, 1H), 6.83 (d, = 8.0 Hz, 1H), 6.71ꢀ6.65 (m, 2H),
;
[
α
]
=
+78.6
(
c
.
0.54, 46.8, 42.9, 15.3; HRMS (ESI): calcd for C18H17NNaO5S:
= 7.5, 6.0 382.0725 (M+Na+), found: 382.0718; HPLC analysis
ꢀPrOH/Hexane 5:95, 1.0 mL/min.
D
J
J
i
J
J
λ
= 254 nm, tR (major) = 22.35 min, tR (minor) = 19.57 min.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 10
View Article Online
DOI: 10.1039/C6OB00160B
Journal Name
ARTICLE
7
8
(a) G. Alberti, A. M. Bernard, A. Frongia, P. P. Piras, F. Secci
and M. Spiga, Synlett, 2006, 2241; (b) A. M. Bernard, E.
Cadoni, A. Frongia, P. P. Piras and F. Secci, Org. Lett., 2002, 4,
2565; (c) A. M Bernard, C. Floris, A. Frongia, P. P Piras and F.
Secci, Tetrahedron, 2004, 60, 449.
(a) N. Sasakura, K. Nakano, Y. Ichikawa and H. Kotsuki, RSC
(2R,1’S)-2-(2-nitro-1-phenylethyl)-2-(phenylthio)
cyclopentanone
anti-9.
Yellow
oil.
=
FTIR (neat)
+42.3 (c. 0.12,
27
ν: 2998, 1747, 1485, 1254 cmꢀ1
;
[
α
]
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.51ꢀ7.46 (m, 2H),
7.42 (d,
3.4 Hz, 1H), 4.99 (t,
Hz, 1H), 2.44 (dd,
2.17ꢀ2.05 (m, 1H), 1.86 (dd,
13.6, 8.6 Hz, 1H), 1.72 (dd,
J
= 7.5 Hz, 2H), 7.26ꢀ7.15 (m, 5H), 5.71 (dd,
= 12.8 Hz, 1H), 4.04 (dd, = 12.4, 3.3
= 18.3, 8.3 Hz, 1H), 2.37ꢀ2.29 (m, 1H),
= 13.6, 6.7 Hz, 1H), 1.79 (dd,
= 18.9, 9.2 Hz, 1H); 13C NMR
J = 13.2,
Adv., 2012, 2, 6135; (b) Y. Imada, H. Iida, S.-I. Murahashi and
J
J
T. Naota, Angew. Chem., Int. Ed., 2005, 44, 1704; (c) S.-I.
Murahashi, S. Ono and Y. Imada, Angew. Chem., Int. Ed.,
2002, 41, 2366; (d) S. Xu, Z. Wang, X. Zhang, X. Zhang and K.
Ding, Angew. Chem., Int. Ed., 2008, 47, 2840.
J
J
J
J =
(125 MHz, CDCl3) δ: 204.9, 135.0, 131.8, 128.3, 128.0, 127.1,
126.3, 125.9, 109.9, 74.0, 60.8, 43.0, 34.0, 28.7, 16.0; HRMS
(ESI): calcd for C19H19NNaO3S: 364.0978 (M+Na+), found:
9
(a) A. Mastracchio, A. A. Warkentin, A. M. Walji and D. W. C.
MacMillan, Proc. Nat. Acad. Sci. USA, 2010, 107, 20648; (b) L.
Zhang, L. Cui, X. Li, J. Li, S. Luo and J.-P. Cheng, Chem. Eur. J.,
2010, 16, 2045; (b) C. M. Reeves, C. Eidamshaus, J. Kim and
B. M. Stoltz, Angew. Chem., Int. Ed., 2013, 52, 6718.
364.0969. HPLC analysis (Chiralpack ADꢀH column,
iꢀ
PrOH/Hexane 5:95, 1.0 mL/min.
30.50 min, tR (minor) = 24.96 min.
λ = 254 nm, tR (major) =
10 (a) X. Ma, C.-S. Da, L. Yi, Y.-N. Jia, Q.-P. Guo, L.-P. Che, F.-C.
Wu, J.-R. Wang and W.-P. Li, Tetrahedron: Asymmetry, 2009,
20, 1419; (b) P. Kotrusz, I. Kmenttová, B. Gotov, Š. Toma and
E. Solčániová, Chem. Commun., 2002, 2510; (c) B. Alcaide, P.
Almendros and A. Luna, Tetrahedron, 2007, 63, 3102.
(2R,1’S)-2-(2-nitro-1-phenylethyl)-2-(phenylthio)
cyclohexanone anti-10. White solid. Mp = 92ꢀ94 °C; FTIR
27
(ATR) ν: 2964, 1732, 1556, 1261 cmꢀ1; [
α] D = +37.8 (c. 0.30,
11 (a) E. Veverková, J. Štrasserová, R. Šebesta and Š. Toma,
Tetrahedron: Asymmetry, 2010, 21, 58; (b) E. Alza, C.
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.41ꢀ7.29 (m, 4H),
7.25ꢀ7.06 (m, 6H), 5.49 (dd,
J
= 13.0, 3.2 Hz, 1H), 4.84 (t,
J
J
=
=
Rodríguez-Escrich, S. Sayalero, A. Bastero and M. A. Pericàs,
Chem. Eur. J., 2009, 15, 10167; (c) A. J. A. Cobb, D. M. Shaw
and S. V. Ley, Synlett, 2004, 558.
12.7 Hz, 1H), 4.16 (dd, = 12.4, 3.1 Hz, 1H), 2.99 (ddd,
J
15.8, 13.9, 6.3 Hz, 1H), 2.31ꢀ2.19 (m, 1H), 2.18ꢀ2.10 (m, 1H),
2.06ꢀ1.93 (m, 1H), 1.87 (ddd, = 25.0, 11.0, 2.7 Hz, 1H), 1.70ꢀ
1.61 (m, 2H), 1.39ꢀ1.25 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ: 201.5, 135.8, 134.8, 131.8, 130.9, 130.2, 129.4, 128.1, 127.7,
64.6, 56.4, 46.3, 37.8, 32.5, 25.0, 20.7; HRMS (ESI): calcd for
C20H21NNaO3S: 378.1134 (M+Na+), found: 378.1172. HPLC
12 (a) D. J. Aitken, F. Capitta, A. Frongia, J. Ollivier, P. P. Piras
and F. Secci, Synlett, 2012, 727; (b) D. J. Aitken, F. Capitta, A.
Frongia, D. Gori, R. Guillot, J. Ollivier, P. P. Piras, F. Secci and
M. Spiga, Synlett, 2011, 712.
13 F. Capitta, A. Frongia, J. Ollivier, P. P. Piras and F. Secci,
Synlett, 2011, 89.
14 (a) D. J. Aitken, P. Caboni, H. Eijsberg, A. Frongia, R. Guillot, J.
J
analysis (Chiralpack ADꢀH column,
mL/min. = 254 nm, tR (major) = 20.61 min, tR (minor) =
19.18 min.
iꢀPrOH/Hexane 5:95, 1.0
Ollivier, P. P. Piras and F. Secci, Adv. Synth. Catal., 2014, 356
,
λ
941; (b) N. Melis, L. Ghisu, R. Guillot, P. Caboni, F. Secci, D. J.
Aitken and A. Frongia, Eur. J. Org. Chem., 2015, 4358; (c) N.
Melis, F. Secci, T. Boddaert, D. J. Aitken and A. Frongia,
Chem. Commun., 2015, 51, 15272.
15 D. J. Aitken, A. M. Bernard, F. Capitta, A. Frongia, R. Guillot, J.
Ollivier, P. P. Piras, F. Secci and M. Spiga, Org. Biomol. Chem.,
2012, 10, 5045.
16 A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold and S.
V. Ley, Org. Biomol. Chem., 2005, 3, 84.
Notes and references
1
(a) J. C. Namyslo and D. E. Kaufmann, Chem. Rev., 2003, 103,
1485; (b) E., Lee-Ruff and G. Mladenova, Chem. Rev., 2003,
103, 1449.
2
3
The Chemistry of Cyclobutanes, ed. Z. Rappoport and J. F.
Liebman, John Wiley & Sons, Chichester, 2005.
17 D. Mailhol, M. del Mar Sanchez Duque, W. Raimondi, D.
Bonne, T. Constantieux, Y. Coquerel and J. Rodriguez, Adv.
Synth. Catal., 2012, 354, 3523.
(a) F. Secci, A. Frongia and P. P. Piras, Molecules, 2013, 18
,
15541; (b) A. M. Bernard, A. Frongia, F. Secci and P. P. Piras,
Chem. Commun., 2005, 3853; (c) F. Secci, A. Frongia, J.
Ollivier and P. P. Piras, Synthesis, 2007, 999; (d) A. Frongia, C.
Girard, J. Ollivier, P. P. Piras and F. Secci, Synlett, 2008, 2823;
(e) F. Secci, A. Frongia, M. G. Rubanu, M. L. Sechi, G. Sarais,
M. Arca and P. P. Piras, Eur. J. Org. Chem., 2014, 6659.
(a) R. D. Miller and D. R. McKean, Tetrahedron. Lett., 20,
1979, 1003; (b) X. Zhang and Z. W. Li, Synth. Commun., 2006,
36, 249.
18 F. Capitta, A. Frongia, J. Ollivier, D. J. Aitken, F. Secci, P. P.
Piras and R. Guillot, Synlett, 2015, 26, 123.
19 Mechanisms of Atmospheric Oxidation of the Oxygenates, J.
G. Calvert, A. Mellouki, J. J. Orlando, M. J. Pilling and T. J.
Wallington, Oxford University Press, New York, 2011.
20 (a) The Proton in Chemistry, R. P. Bell, Cornell University
Press, Ithica, 1959; (b) F. G. Bordwell, X. Zhang and M. S.
Alnajjar, J. Am. Chem. Soc., 1992, 114, 7623; (c) F. G.
Bordwell, H. E. Fried, D. L. Hughes, T. Y. Lynch, A. V. Satish
and Y. E. Whang, J. Org. Chem., 1990, 55, 3330.
4
5
(a) M. Murakami, K. Takahashi, H. Amii and Y. Ito, J. Am.
Chem. Soc., 1997, 119, 9307; (b) Z. Chai and T. J. Rainey, J.
Am. Chem. Soc., 2012, 134, 3615; (c) E. Zhang, C. A. Fan, Y. Q.
21 B. M. Trost, W. C. Vladuchick and A. J. Bridges, J. Am. Chem.
Soc., 1980, 102, 3548.
Tu, F. M. Zhang and Y. L. Song, J. Am. Chem. Soc., 2009, 131
,
22 (a) P. Leiverend and C. Huard, Sulfur Lett., 1990, 11, 219; (b)
A. Bury, H. A. Earl and C. J. M. Stirling, J. Chem. Soc. Perkin
Trans II, 1987, 9, 1281; (c) T. Wakanatsu, N. Miyachi, F. Ozuki
and Y. Ban, Heterocycles, 1987, 26, 1445; (d) M. D. Lawlor, T.
W. Lee and R. L. Danheiser, J. Org. Chem., 2000, 65, 4375.
23 A. F. Vaquer, A. Frongia, F. Secci, E. Tuveri, RSC Adv., 2015, 5,
14626; (d) D. C. Moebius and J. S. Kingsbury, J. Am. Chem.
Soc., 2009, 131, 878; (e) J. A. Dabrowski, D. C. Moebius, A. J.
Wommack, A. F. Kornahrens and J. S. Kingsbury, Org. Lett.,
2010, 12, 3598; (f) M. Yoshida, H. Nemoto and M. Ihara,
Tetrahedron Lett., 1999, 40, 8583.
6
(a) J. M. Conia and M. J. Robson, Angew. Chem., Int. Ed.,
1975, 14, 473; (b) Cleavage of Carbon-Carbon Single Bonds
by Transition Metals, M. Murakami and N. Chatani, Wiley-
VCH, Weinheim, 2015.
96695.
24 A. M. Bernard, A. Frongia, P. P. Piras, F. Secci and M. Spiga,
Tetrahedron Lett., 2008, 49, 3037.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C6OB00160B
ARTICLE
Journal Name
25 The predominant formation of the syn adduct of 3a using the
tertiary amine catalyst XI is an indication that a different
catalytic mechanism is probably operating, as would be
expected since formation of an enamine intermediate (as
suggested in Scheme 2 for catalyst XII) is precluded.
S
S
N
N
H
N
N
H
H
H
O
O
O
N
N
O
O
H
H
N
N
N
N
O
S
S
Ts2
Ts3
O
O
S
S
NO2
NO2
syn-3a
anti-3a
Scheme 3. Hypothetic transition states evoked for the formation of anti-3a (Ts2) and
syn-3a (Ts3) using catalyst XI.
26 J. Duschmal and H. Wennemers, Chem. Eur. J., 2012, 18
1111.
27 Details of the x-ray diffraction study of
,
8 are given in the SI
document. CCDC 1442520 contains the crystallographic data
for compound ; these data can be obtained free of charge
8
from the Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/Community/Requestastructure.
28 A. G. Wenzel and E. N. Jacobsen, J. Am. Chem. Soc., 2002,
124, 12964.
29 J. J. Eisch, J. E. Galle and L. E. Hallenbeck, J. Org. Chem., 1982,
47, 1608.
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins