Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular C-H Insertion Reactions of α-Diazo-β-oxosulfones

Article abstract of DOI:10.1021/acs.joc.8b03160

Effective desymmetrization in copper-catalyzed intramolecular C-H insertion reactions of α-diazo-β-oxosulfones in the formation of fused thiopyran dioxides is described for the first time. The use of a copper-bis(oxazoline)-NaBARF catalyst complex system leads to formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee. The effect of varying the bis(oxazoline) ligand, copper salt, and site of C-H insertion on both diastereo- and enantioselectivities of these intramolecular C-H insertion reactions has been investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to date in a copper-mediated desymmetrization through C-H insertion.

Full text of DOI:10.1021/acs.joc.8b03160

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Featured Article
Desymmetrization by Asymmetric Copper-Catalyzed
Intramolecular C–H Insertion Reactions of #-Diazo-#-oxosulfones
Thomas A. Brouder, Catherine N. Slattery, Alan Ford, U. B. Rao Khandavilli, Eliska
Skorepova, Kevin S. Eccles, Matteo Lusi, Simon E. Lawrence, and Anita R. Maguire
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03160 • Publication Date (Web): 04 Mar 2019
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Desymmetrization
Intramolecular C–H Insertion Reactions of α-Diazo-β-oxosulfones
by
Asymmetric
Copper-Catalyzed
†
†
†
†
Thomas A. Brouder, Catherine N. Slattery, Alan Ford, U. B. Rao Khandavilli, Eliška
†
†
‡
†
*,§
Shořepová, Kevin S. Eccles, Matteo Lusi, Simon E. Lawrence, and Anita R. Maguire
1
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†School of Chemistry, Analytical and Biological Chemistry Research Facility, University College
Cork, Cork T12 K8AF, Ireland
‡Department of Chemical & Environmental Sciences, University of Limerick, Limerick V94 T9PX,
Ireland
§School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research
Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF,
Ireland
Abstract
CuCl2
O
O
H
O O
S
O O
S
(
4R)-Ph bis(oxazoline)
OMe
OMe
NaBARF
N2
CH Cl , 
2
2
H
78%
dr 98:2
98% ee
Effective desymmetrization in copper catalyzed intramolecular C–H insertion reactions of α-
diazo-β-oxosulfones in the formation of fused thiopyran dioxides is described for the first
time. The use of a copper–bis(oxazoline)–NaBARF catalyst complex system leads to
formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee.
The effect of varying the bis(oxazoline) ligand, copper salt, and site of C–H insertion on both
diastereo- and enantioselectivities of these intramolecular C–H insertion reactions has been
investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone
proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to
date in a copper mediated desymmetrization through C–H insertion.
Introduction
Transition metal mediated C–H insertion reactions of α-diazocarbonyl compounds are
versatile transformations in organic synthesis, allowing formation of a variety of heterocycles
and carbocycles.1-4 The utilization of intramolecular catalytic asymmetric C–H insertion has
facilitated the formation of new C–C bonds with high diastereoselectivity and
5
enantioselectivity. While formation of five-membered rings is the most common outcome, in
some instances electronic and/or conformational effects can promote the formation of other
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ring sizes. Acceptor-acceptor α-diazo compounds have been the most widely explored
precursors to exploit these transformations, as the highly selective electrophilic metal
carbenoid generated in-situ is well-suited to intramolecular C–H insertion.
Early studies of intermolecular reactions using terminal diazocarbonyl compounds and
copper(I) chloride as a catalyst showed poor efficiency for C–H insertion and a high
0
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percentage of dimerization. Teyssié’s pioneering work highlighted that rhodium mediated
7
C–H insertion could be synthetically useful, as evidenced by Wenkert in forming a
8
cyclopentanone in good yield from an α-diazoketone using rhodium acetate. In the
subsequent decade Taber explored this methodology extensively as a general synthetic route
to cyclopentanones.9-11 Since the first rhodium catalyzed enantioselective intramolecular C–H
insertion was reported by McKervey,12 significant developments were made by Doyle13-16
and Hashimoto17-19 in the intramolecular asymmetric synthesis of heterocycles and
carbocycles using diverse rhodium carboxylate and carboxamidate catalysts with excellent
enantiocontrol in many instances, through judicious selection of catalyst/substrate pairs.
Rhodium mediated C–H insertion has been used to advantage in the total synthesis of
2
0
21
22
compounds such as enterolactone, baclofen, and imperanene.
Building on the identification of effective rhodium carboxylates and carboxamidates for
enantioselective C–H insertion, the groups of Doyle,23-27 Hashimoto,28 and Kan29 have
demonstrated desymmetrization through selective insertion processes in prochiral or meso
systems; some examples are illustrated in Figure 1 (a) and (b). Doyle and co-workers showed
the use of the carboxamidate Rh (4S-MACIM) to form the cis fused bicyclic lactone (2) with
2
4
an enantiomeric excess of 97% ee, in 99:1 ratio over the trans fused isomer (3) which was
formed with 65% ee. Using a rhodium carboxylate catalyst, Hashimoto and co-workers
synthesized a cis fused 5 membered carbocycle (5) in 82% yield and 99% ee, by treating the
α-diazoester (4) with Rh (S-PTTL) in toluene at −78 °C. One of the earliest reported
2
4
examples of copper mediated intramolecular C–H insertion involved a desymmetrization,
where a Cu(OTf)–bis(oxazoline) catalyst system resulted in poor diastereocontrol, but modest
enantiocontrol, as reported by Sulikowski and co-workers (Figure 1 (c)).30-31 More recently,
Chiu reported up to 44% ee in a copper mediated desymmetrization in the formation of a cis
3
2
fused bicyclic cyclopentanone 10 (Figure 1 (d)). To date we are not aware of any reported
example of highly enantioselective copper catalyzed desymmetrization through C–H
insertion.
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Rhodium Catalyzed Desymmetrization
Doyle, 1994 (ref. 23)
O
O
O
Rh (4S-MACIM)4
2
O
(0.5 mol%)
O
O
(a)
N2
H
H
+
H
H
1
1
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1
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0
CH Cl , 
2
2
1
2 (97% ee)
3 (65% ee)
7
0%, 99:1 2:3
Hashimoto, 2016 (ref. 28)
CO Me
2
CO Me
2
Rh (S-PTTL)4
2
N2
H
H
(1 mol%)
(b)
O
toluene, –78 °C
O
O
O
4
5 (99% ee)
2%
8
Copper Catalyzed Desymmetrization
Sulikowski, 1997 (ref. 31)
CO Me
2
CO Me
CO Me
2
2
Cu(OTf)
ligand L6
N
N2
N
N
H
H
O
+
(c)
O
CHCl3
MS 4Å
O
O
O
O
6
7
8
dr 66:33
dr 57:43
26% ee
51% ee
9
0–94%, 3:1 7:8
Chiu, 2011 (ref. 32)
O
O
Cu(OTf)
ligand L5
OTES
OTES
N2
(d)
H
3
CHCl3
O
O
9
10
1%, 44% ee
Figure 1: Rhodium and copper catalyzed desymmetrization of α-diazocarbonyl compounds
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In recent years, Du Bois33-36 and Novikov37-39 have demonstrated that through the
incorporation of a sulfone moiety into the framework, 6-membered rings including thiopyran
dioxides (hereafter reported as thiopyrans for convenience), δ-sultones or oxathiazinanes are
formed preferentially due to the geometry surrounding the sulfone fragment.
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Within our group, excellent enantioselectivity in the intramolecular C–H insertion process
has been achieved in sulfone containing substrates when utilizing the copper–bis(oxazoline)–
NaBARF catalyst system (Figure 2 (a–c)). Thiopyrans (11), cyclopentanones (12) and γ-
4
0
41
lactams (13) have been synthesized with enantioselectivities of up to 98% ee, 91% ee, and
4
2
8
2% ee, respectively. The additive, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl)]borate,
NaBARF, has been shown to be essential for inducing high levels of enantiocontrol.
Investigation of the role of the additive suggest that it functions by supplying a sodium cation
which sequesters the chloride anion to form the active catalyst. Fraile has conducted
theoretical calculations on copper-catalyzed cyclopropanation, highlighting the influence of
the coordinating chloride counter-anion on the transition state geometry and the effect of this
on enantiocontrol.43
CuCl2
Bis(oxazoline)
NaBARF
O
O O
S
O
O O
S
OMe
(a)
OMe
N2
Ph
CH Cl , 
2
2
Ph
11
47%, 98% ee
CuCl2
Bis(oxazoline)
NaBARF
O
O O
S
O
O O
S
(b)
N2
CH Cl , 
2
2
Ph
Ph
12
64%, 91% ee
CuCl2
Bis(oxazoline)
NaBARF
O
O
O O
S
O O
S
N
N
(c)
N2
CH Cl , 
2
2
13
61%, 82% ee
Figure 2: Highly enantioselective intramolecular C–H insertion using the copper–
bis(oxazoline)–NaBARF catalyst system
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Herein we report the extension of the copper–bis(oxazoline)–NaBARF catalyst system to
highly enantioselective desymmetrization of prochiral α-diazo-β-oxosulfones, leading to the
formation of fused thiopyrans, and cyclopentanones. Previously reported examples of
successful desymmetrization through C–H insertion have focused exclusively on five
membered ring formation and, to the best of our knowledge, this is the first report of
desymmetrization in the formation of a six membered heterocycle.
1
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Results and Discussion
Thiopyran Precursors
Cyclopentanone Precursors
O
O
O
O
O
O O
S
O O
S
O O
S
O O
S
O O
S
R
Ph
Ph
Ph
Ph
N2
N2
N2
N2
N2
1
1
4 R = OMe
5 R = Ph
16
17
18
19
Figure 3: α-Diazo-β-oxosulfones designed for desymmetrization investigation
Six novel -diazo--oxosulfones (14–19) (Figure 3) were designed for this investigation to
enable exploration of the impact of conformational effects (insertion into a cyclohexyl,
cyclopentyl or freely rotating alkyl chain), electronic effects (-diazoester or -diazoketone),
catalyst effects through various bis(oxazoline) ligands (Figure 4), in addition to variation of
the copper source. Substrates 14–17 enable investigation of desymmetrization in the
formation of thiopyrans while 18 & 19 enable a similar investigation in the formation of
cyclopentanones.
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O
O
O
O
Ph
Ph
N
N
N
N
Ph
Ph
R
R
L1: (4R)-Ph
L2: (4R)-Bn
L3: (4R,5S)-diPh
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O
O
O
O
N
N
N
N
R
R
L4: (3S,8R)-Ind
L5: (4S)-t-Bu
L6: (4S)-ipr
Figure 4: Commercially available bis(oxazoline) ligands
Scheme 1: Synthesis of β-oxosulfones 20–23, 27 & 28
O
O
O
HS
O O
S
Br
OMe
mCPBA
S
(
a)
OMe
OMe
acetone, 
2
CH Cl2
Yield
89%
2
0
i) NaH, THF, 0°C
ii) n-BuLi, 0°C
O
O
O O
S
O O
S
(
b)
R
Ph
iii) 24, 25 or 26
iv) reflux
Ph
Yield
38%
50%
68%
2
1 R = cyclohexylmethyl
22 R = cyclopentylmethyl
23 R = 2-propylpentyl
I
I
I
24
25
26
i) n-BuLi (2 eqv.)
O
O O
S
O O
S
O
THF
(c)
R1
R1
Ph
Ph
+
MeO
ii) aq. NH Cl
4
Yield
4%
64%
1
27 R = cyclohexylmethyl
4
1
28 R = 4-heptyl
The novel sulfonyl ester 20, outlined in Scheme 1 (a), was readily accessed through alkylation
of methyl thioglycolate with (2-bromoethyl)cyclohexane followed by oxidation with m-CPBA
(
89% over two steps). The sulfonyl ketones 21–23 were prepared in modest yields through
alkylation of the dianion of methylsulfonylacetophenone, generated using NaH and n-BuLi, with
the appropriate alkyl iodide (24–26) in each instance, providing sufficient material for the
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subsequent investigations without further optimization (Scheme 1, b). The sulfone precursors 27
& 28 were generated from dilithiated methyl phenyl sulfone by reaction with the appropriate
ester in modest yields (Scheme 1, c). Following the purification and isolation of all six novel
sulfone precursors, the α-diazo--oxosulfones 14–19 were readily prepared by diazo transfer to
the corresponding -sulfonyl ester or ketone using p-acetamidobenzenesulfonyl azide (p-ABSA)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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5
5
5
5
5
6
0
1
2
3
4
5
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8
9
0
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2
3
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8
9
0
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2
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8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
(
or tosyl azide in the case of 19) and K CO in acetonitrile (Table 1). The -diazo--oxosulfones
2
3
14–19 were isolated in good yields following column chromatography, and could be stored in
the freezer without difficulty.
Table 1: Synthesis of α-diazo-β-oxosulfones (14–19)
p-ABSA
K CO
2 3
O
O O
S
O
O O
S
R
R1
R1
R
MeCN
N2
1419
2023, 2728
R1
Yield (%)a
Entry
Sulfone
Diazo
R
1
20
14
OMe
79
2
3
21
22
15
16
Ph
Ph
75
71
4
5
23
27
28
17
18
Ph
84
80
77
Ph
Ph
6b
19
a
b
Isolated yield after chromatography. p-TsN
3
was the diazo transfer agent used in the synthesis of 19.
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Thiopyran formation
O
O O O
S
O
O O
S
O
S
H
H
H
O
O O
S
O
H
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OMe
OMe
OMe
OMe
and/or
and/or
N2
14
Figure 5: Possible reaction pathways with α-diazo-β-oxosulfone 14
Initial catalyst investigations focused on the -diazoester 14 which can undergo C–H
insertion to form six-, five-, or four-membered ring products (Figure 5) along with by-
products such as chlorine abstraction from the reaction solvent, diazo reduction and hydride
abstraction. As a result of the two equivalent 2° positions on the cyclohexyl ring, four fused
thiopyran diastereoisomers may be formed. In practise, however, only three products are
1
observed; the ratio is determined by integration of the H NMR spectra of the crude product.
Rhodium acetate catalyzed C–H insertion of 14 proved to be very efficient, with 14 being
consumed within 1 h under reflux in DCM. The trans fused, 1,8a trans substituted thiopyran
2
2
9b was formed as the major product, while the trans fused, 1,8a cis substituted thiopyran
9a and sulfolane 30 were observed as minor products (Table 2, entry 1). On utilizing copper
triflate or copper chloride, C–H insertion proved much slower for 14 and while providing the
same insertion products 29a, 29b and 30, the selectivity was strongly catalyst-dependent with
substantially increased formation of thiopyran 29a using Cu(OTf) , and sulfolane 30 when
2
CuCl was employed (Table 2, entry 2 & 3). Addition of NaBARF to the CuCl catalyst led
2
2
to improved selectivities and an improved yield of 29a (Table 2, entry 4).
Significantly, use of the copper chloride (5 mol%), bis(oxazoline) (6 mol%), and NaBARF
6 mol%) catalyst system, led to faster reaction times and substantially enhanced selectivities,
(
relative to any of the achiral copper catalysts, with up to 98:2 dr and yields of up to 82% for
the major thiopyran 29a and enantioselectivities of up to 98% ee with the (4R)-Ph
bis(oxazoline) ligand L1 (Table 2, entry 5–9). Interestingly, while the presence of the
bis(oxazoline) ligand had an enormous impact on the outcome, variation of the ligand had
little impact on the product ratios, and, while the enantioselectivity was ligand sensitive (85–
9
8% ee), this variability was notably less in these transformations than in our earlier studies
4
4
of insertions into freely rotating alkyl chains. There was no evidence of formation of cis-
fused thiopyran products.
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Table 2: Transition metal catalyzed C–H insertion of α-diazo-β-oxosulfone 14
O
O O
S
O
H
O
H
O O
S
O O
S
O O
S
Catalyst, Ligand,
Additive
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
OMe
OMe
OMe
N2
CH Cl , Reflux,
2
2
H
H
N2
14
29a
29b
30
Yieldb,c
9a (%) 29b (%) 30 (%)
Yieldb
Yieldb
Time
29a eed
(%)
Entry
Catalyst
Ligand Additive
29a : 29b : 30a
(h)
2
1
2
3
4
5e
6
7
8
9
Rh
2
(OAc)
4
-
-
1
1 : 10.0 : 0.90
1 : 0.51 : 0.74
1 : 0.44 : 1.20
1 : 0.12 : 0.34
1 : 0.02 : 0.09
1 : 0.03 : 0.12
1 : 0.07 : 0.17
1 : 0.04 : 0.13
1 : 0.04 : 0.12
1
57
6
0
9
0
0
Cu(OTf)
2
-
-
48
144
120
16
23
31
62
73
62
60
82
57
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
-
-
7
19
13
4
0
-
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
4
0
L1
L2
L3
L4
L5
1
98 f
20
<1
3
1
85 f
95 f
32
4
30
<1
<1
5
88 g
90 g
20
3
a
Ratios of products were calculated from 1H NMR spectra of the crude product mixture. bIsolated yield after
c
chromatography. Difficult to isolate 30 pure due to co-elution with 29a, reduction product, and hydride abstraction product.
dThe enantiomeric excess was measured by chiral phase HPLC analysis (for full details see the Supporting Information).
eWhen the reaction was carried out on a 1 mmol scale, the reaction was complete after 8 hours and 29a had an isolated yield
f
g
of 78% in 98:2 dr and 98% ee. The major enantiomer has a 1S,4aS,8aR configuration. The major enantiomer has a
1R,4aR,8aS configuration.
The desymmetrization of α-diazoester 14 is very effective, providing the trans fused, 1,8a cis
substituted thiopyran 29a in excellent diastereo- and enantiocontrol in the copper mediated
transformation. The single crystal X-ray structure of 29a (product isolated from Table 2,
entry 7) confirmed the stereochemistry of the product as 1S,4aS,8aR when the (4R,5S)-diPh
ligand L3 is used; this aligns exactly with the stereoselectivity observed in our original study
of thiopyran formation, in which L3 leads to the formation of the 2S,3S thiopyran.40 The
enantiomeric series was confirmed by chiral phase HPLC of the single crystal used for
crystallographic determination.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In addition, the optimum enantioselectivity is achieved with the (4R)-Ph bis(oxazoline) ligand
L1 in line with our initial report, highlighting that the key ligand-substrate interactions which
determine the stereochemical outcomes of the insertion are the same in the asymmetric
insertion and the desymmetrization process. Preferential formation of 29a with the copper
catalysts and 29b using rhodium acetate is consistent with our previous observations of
formation of cis thiopyrans using copper catalysts,40, 44 and the rhodium-catalyzed trans
thiopyran formation reported by Novikov.37, 39
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In order to probe reaction parameters, various solvents and copper salts were investigated
with the best performing ligand L1 as summarized in Table 3. Increasing the reaction
temperature resulted in a slight decrease in regio- and diastereoselectivity (formation of 29b
and 30 slightly enhanced) albeit with no noticeable impact on enantioselectivity in the
formation of 29a (Table 3, entry 2 & 3). Alteration of the copper salt from CuCl to
2
Cu(CH CN) PF or Cu(OTf) resulted in decreased reaction times with no impact on regio-
3
4
6
2
or stereoselectivity or yields of the major thiopyran 29a which from a practical perspective is
advantageous (Table 3, entry 4 & 5).
Table 3: Solvent and copper source effects on copper catalyzed C–H insertion reaction
of α-diazo-β-oxosulfone 14
Time
(h)
Yieldc
Yieldc
Yieldc,d 29a eee
Catalysta
29a : 29b : 30b
Entry
Solvent
29a (%) 29b (%) 30 (%)
(%)
1f
2
3
4
5
CuCl
CuCl
CuCl
DCM
DCE
16
5
1 : 0.02 : 0.08
1 : 0.05 : 0.13
1 : 0.04 : 0.15
1 : 0.03 : 0.09
1 : 0.04 : 0.10
73
52
74
72
73
1
1
4
6
7
4
4
98 g
2
2
2
96 g
98 g
CHCl
3
18
5
2
Cu(CH
3
CN)
4
PF
6
DCM
DCM
1
98 g
Cu(OTf)
2
4
<1
98 g
a
b
1
All reactions were carried out using the (4R)-Ph ligand L1 and NaBARF. Ratios of products were calculated from H NMR
c
d
spectra of the crude product mixture. Isolated yield after chromatography. Difficult to isolate 30 pure due to co-elution
e
with 29a. The enantiomeric excess was measured by chiral phase HPLC analysis (for full details see the Supporting
f
g
Information). Data from Table 2, Entry 5. The major enantiomer is 1S,4aS,8aR.
Encouraged by the positive outcome in the formation of the trans fused, 1,8a cis substituted
thiopyran 29a in 73 % yield and 98% ee, the study was extended to the α-diazo-β-
oxosulfones 15–17. The results obtained with α-diazoketone 15 were compared to those using
the α-diazoester 14, enabling insight into electronic effects with regards to desymmetrization.
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As observed with the α-diazoester 14, when substrate 15 was cyclized with rhodium acetate
in dichloromethane, preferential formation of the trans fused, 1,8a trans substituted product
was observed, and 31b was isolated with a comparable 56% yield (Table 4, entry 1). Again,
when changing from the rhodium catalyst to a copper catalyst system, a switch to the trans
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
fused, 1,8a cis substituted diastereomer was observed (Table 4). The use of Cu(OTf) on its
2
own as a catalyst showed poor selectivity, as observed previously with 14, and once again the
copper–bis(oxazoline)–NaBARF catalyst complex led to high efficiency and selectivity, in
fact, higher isolated yields were obtained for 31a (70–94%) compared to those seen for 29a
(57–82%). Most importantly, when comparing the selectivity of the α-diazoester 14 and the
α-diazoketone 15, the levels of regioselectivity and diastereoselectivity remain relatively
unchanged for the formation of the fused thiopyran system highlighting its insensitivity
towards alteration from ester to ketone functionality. A slight decrease in enantioselectivity is
observed across the series when changing from the methyl ester to the phenyl ketone
substrate; the best performing ligand, the (4R)-Ph L1, recorded 94% ee with the same
absolute stereochemistry seen with 29a, however the use of (4R)-Bn L2 and (3S,8R)-Ind L4
resulted in reduced enantioselectivity, affording 78% and 70% ee respectively (Table 4, entry
3–7). Notably, the (4S)-t-Bu ligand L5 produced 31a in 91% ee and 98:2 dr in an isolated
yield of 94%. The absolute stereochemistry of 31a, was confirmed by single crystal X-ray
analysis of the isolated product from the reaction using the (4R)-Ph ligand L1 (Table 4, entry
3
). The minor amounts of 31b isolated after column chromatograph showed an enantiomeric
excess ranging from 64% to 75% ee, with the 3S,8R-Ind ligand L4 producing the highest
level of enantioselectivity (Table 4, entry 6).
Table 4: Transition metal catalyzed C–H insertion of α-diazo-β-oxosulfone 15 and 16
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Rh (OAc) /Cu(OTf)
2
4
2
or
O
O O
S
O
H
O
H
n
O
H
n
O O
S
O O
S
O O
S
O O
S
O
CuCl , Ligand,
2
Ph
NaBARF
Ph
Ph
Ph
Ph
N2
CH Cl , Reflux,
2
2
N2
H
H
H
n
n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n
n = 2, 15
n = 1, 16
n = 2, 31a
n = 1, 33a
n = 2, 31b
n = 1, 33b
n = 2, 31c
n = 1, 33c
n = 2, 32
n = 1, 34
O
O O
S
Ph
35
Yieldb
Yieldb
Yieldb
Yieldb,c
31b eed
Time
h)
31a eed
(%)
Diazo Entry
Ligand
31a : 31b : 31c : 32a
31c (%)
(
3
1a (%) 31b (%)
32 (%)
(%)
15
1
2
3
4
5
6
7
Rh
2
(OAc)
4
24
17
17
29
18
30
27
1 : 7.14 : 0.00 : 0.14
1 : 0.52 : 0.00 : 0.20
1 : 0.03 : 0.00 : 0.06
1 : 0.07 : 0.00 : 0.16
1 : 0.03 : 0.00 : 0.04
1 : 0.06 : 0.00 : 0.14
1 : 0.02 : 0.00 : 0.05
4
56
13
0
2
0
0
0
0
Cu(OTf)
L1
2
16
87
70
85
87
94
0
1
1
0
3
94 e
64 f
78 e
68 f
L2
1
0
8
L3
<1
0
3
6
93 e
70 g
91 g
65 f
75 h
71 h
L4
<1
0
0
L5
<1
2
Yieldb
Yieldb
3c (%)
Yieldb,i
34 (%)
33c eed
(%)
Yieldb
33a eed,j
3a : 33b : 33c : 34a
3
3
3
3b (%)
(%)
3
3a (%)
16
8k
9l
Rh
2
(OAc)
4
3
1 : 3.57 : 2.29 : 5.71
1 : 0.00 : 0.75 : 2.13m
1 : 0.03 : 0.42 : 1.74
1 : 0.06 : 0.35 : 2.81
1 : 0.03 : 0.24 : 1.12
1 : 0.07 : 0.27 : 1.64
1 : 0.01 : 0.10 : 0.27
<1
0
10
0
8
0
13
3
-
-
0
-
Cu(OTf)
2
18
20
19
20
55
21
1
1
1
0
1
2
L1
23
20
34
11
61
0
12
6
46
52
35
18
19
94 n
83 o
L2
0
74 n
34 o
93 n
79 o
L3
<1
<1
0
7
13p
L4
5
51 q
91 q
16 r
49 r
1
4
L5
8
a
Ratios of products were calculated from signals in the crude H NMR spectra. bIsolated yield after chromatography.
1
c
d
D
i
f
f
i
c
u
l
t
t
o
i
s
o
l
a
t
e
3
2
p
u
r
e
d
u
e
t
o
c
o
-
e
l
u
t
i
o
n
w
i
t
h
3
1
a
,
r
e
d
u
c
t
i
o
n
p
r
o
d
u
c
t
,
a
n
d
h
y
d
r
i
d
e
a
b
s
t
r
a
c
t
i
o
n
p
r
o
d
u
c
t
.
T
h
e
e
enantiomeric excess was measured by chiral phase HPLC analysis (for full details see the Supporting Information). The
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9
f
major enantiomer is 1S,4aS,8aR. Major enantiomer with unassigned configuration. Specific rotation of 31b was positive.
g
h
The major enantiomer is 1R,4aR,8aS. Major enantiomer with unassigned configuration. Specific rotation of 31b was
i
j
negative. Difficult to isolate 34 pure due to co-elution with 33a, reduction product, and hydride abstraction product. Chiral
phase HPLC conditions for 33a developed from 14% yield of 33a isolated from reaction using; CuCl
2
(10 mol%), NaBARF
k
(
12 mol%), (4R)-Ph bis(oxazoline) ligand L1 (6 mol%) and (4S)-Ph bis(oxazoline) ligand (6 mol%) in DCM at reflux. 27%
l
of the β-hydride by-product 35 was isolated. Only trace amount of the thiopyrans 33a and 33c, and sulfolane 34 were
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
observed in the H NMR of the crude product mixture. The β-hydride by-product 35 was the major product and had an
m
n
isolated yield of 21%. Ratio calculated from the trace quantity observed in the crude products. The major enantiomer is
o
p
1
S,4aS,7aR. Major enantiomer with unassigned configuration. Specific rotation of 33c was negative. 5% of the β-hydride
q
r
by-product 35 was isolated. The major enantiomer is 1R,4aR,7aS. Major enantiomer with unassigned configuration.
Specific rotation of 33c was positive.
In order to investigate conformational effects, the insertion into a cyclopentyl ring was
examined, using the α-diazo-β-oxosulfone 16. When employing the achiral catalysts, rhodium
acetate and copper triflate, β-hydride abstraction product 35 was observed as the major
product, in particular with Cu(OTf) (Table 4, entry 8 & 9). After column chromatography of
2
the crude product obtained from the Cu(OTf) catalyzed reaction, no thiopyran 33 was
2
isolated and only 3% sulfolane 34. The use of the copper–bis(oxazoline)–NaBARF system
led to a shift in regioselectivity, affording predominantly the sulfolane 34 due to insertion
into the 3° C–H bond, and lesser amounts of the thiopyran 33. The (4R)-Ph ligand L1 which
proved very selective and efficient with substrates 14 and 15 in the synthesis of the trans
fused, 1,8a cis substituted thiopyran, showed greatly reduced selectivity, affording 23% yield
for 33a (Table 4, entry 10). It is worthy to note that the (4S)-t-Bu ligand L5 showed
significantly improved selectivity, with the highest isolated yield of 61% for 33a while still
retaining a 91% ee (Table 4, entry 14). The (4S)-t-Bu ligand L5 appears as the most
consistently selective bis(oxazoline) ligand across the α-diazo-β-oxosulfone substrates 14–16
in the formation of the trans fused, cis substituted thiopyran. The isolated product 33a from
the reaction using the (4S)-t-Bu ligand (Table 4, entry 14) was used to determine the absolute
stereochemistry by single crystal X-ray analysis.
Interestingly, for the first time, the cis fused, 1,7a trans substituted thiopyran 33c (relative
1
stereochemistry confirmed by single crystal X-ray crystallography), was observed in the H
NMR of the crude product mixture and isolated in 12% yield, in addition to the 46% yield of
the major sulfolane 34, when using the (4R)-Ph ligand L1 (Table 4, entry 10). While reduced
levels of regio- and diastereoselectivity were observed, the enantiomeric excess of 33a (94%
ee) was comparable to that observed for the formation of 31a (also 94% ee) using the (4R)-Ph
ligand L1. Low diastereoselectivity was observed across the bis(oxazoline) ligand series for
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
6, with 33c being isolated in all instances with varying levels of enantioselectivity ranging
from 16% ee to 83% ee (Table 4, entry 10–14).
Until now, the study of copper catalyzed intramolecular desymmetrization of α-diazo-β-
oxosulfones has focused on insertion into a 2° C–H bond restrained within a ring system,
however in order to evaluate the importance of the ring system with regards to
desymmetrization, the acyclic α-diazo-β-oxosulfones substrate 17 was designed for
comparison. In contrast to insertion into a cyclic structure (14–16) which has given relatively
consistent levels of desymmetrization, a greater level of variability in selectivity was
observed for asymmetric intramolecular C–H insertion into the freely rotating alkyl chain of
substrate 17 (Table 5). The achiral catalyst, rhodium acetate, preferentially formed the 6-
membered thiopyran, 36, after 4 hours (Table 5, entry 1). Due to increased conformational
flexibility, the C–H insertion reaction of 17 leads to the formation of four diastereoisomers
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
6a–d, and the regioisomer 37, all observed in the crude product mixture, reflecting
decreased levels of regio- and diastereocontrol in comparison to substrates 14–16. The
diastereoisomer 36b, was isolated in 9% yield which indicates much lower selectivity in
comparison to the major 29b and 31b, with the same relative stereochemistry, isolated when
using rhodium acetate. Interestingly in this case, diastereoisomer 36a was isolated in a higher
yield (Table 5, entry 1).
The achiral copper triflate once more showed poor efficiency for C–H insertion with very low
yields (Table 5, entry 2), however, a distinct improvement in isolated product yields was
observed when the copper–bis(oxazoline)–NaBARF catalyst system was applied (Table 5,
entry 3–7). Once again, the 6-membered thiopyran 36 was the predominant C–H insertion
product formed, although significant amounts of the 5-membered sulfolane 37 were also
evident in the crude product mixtures. Notably, the diastereocontrol in the C–H insertion of
17 to form 36a–d differed from that of the earlier substrates, favoring the all cis isomer 36d
(23–29%) and affording less 36a, in contrast to the dominance of 29a, 31a, 33a.
Table 5: Transition metal catalyzed C–H insertion of α-diazo-β-oxosulfone 17
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3
4
Rh (OAc) /Cu(OTf)
2
4
2
O
O
O
O
O O
S
O O
S
O O
S
O O
S
O
or
O O O
S
O O
S
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CuCl2, Ligand,
NaBARF
Ph
Ph
Ph
Ph
Ph
Ph
N2
CH Cl , Reflux,
2
2
N2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
36a
36b
36c
36d
37
Yieldb
36a %
Yieldb
36b %
Yieldb
36c %
Yieldb,d
36d %
Yieldb,e
37 %
Time
36a : 36b : 36c : 36d : 37a
Entry
Ligand
(h)
ee %)c
(ee %)c
(ee %)c
(ee %)c
(ee %)c
(
1
4
9
(0)
3
0
(-)
0
11
(0)
0
9
(0)
1
2
3
4
5
6
7
Rh
2
(OAc)
4
4
1 : 1.96 : 0.16 : 2.18 : 0.91
1 : 0.89 : 0.29 : 1.86 : 2.17
1 : 0.39 : 0.34 : 1.08 : 1.32
1 : 1.25 : 0.27 : 3.44 : 3.46
1 : 0.61 : 0.43 : 1.17 : 1.36
1 : 0.72 : 0.23 : 2.27 : 1.13
1 : 0.57 : 0.60 : 2.15 : 1.94
(
0)
4
8
Cu(OTf)
2
20
14
6
(0)
(0)
7
(-)
0
(-)
(0)
2
1
29
27
L1
90) f
(
(33)
11
(-)
0
(31)
29
(31)
30
1
1
L2
(69) f
(59)
9
(-)
0
(24)
26
(35)
23
1
8
L3
5
(
87) f
(38)
10
(-)
0
(37)
23
(40) g
22
1
6
L4
18
62
(54) h
10
(33)
7
(-)
0
(19)
27
(31)
21
L5
(
80) h
(37)
(-)
(~0)
(32)
a
1
b
c
Ratios of products were calculated from signals in the crude H NMR spectra. Isolated yield after chromatography. The
d
enantiomeric excess was measured by chiral phase HPLC analysis (for full details see the Supporting Information). Difficult
e
to isolate 36d pure due to co-elution with 37, and reduction product. Difficult to isolate 37 pure due to co-elution with 36d,
f
g
and reduction product. The major enantiomer is 2S,3R,4S. The sample of 37 was measured as 8% ee after storage in 2-
h
propanol for six months at room temperature. The major enantiomer is 2R,3S,4R.
Interestingly, enantiocontrol remained high in the insertion to form 36a, especially with the
(4R)-Ph L1 and (4R,5S)-diPh L3 ligands (Table 5, entry 3 and 5, respectively), in line with
the enantiocontrol observed in the formation of 29a, 31a, and 33a, albeit with slightly
decreased levels of enantioselectivity (up to 90% ee for 36a cf 98% ee for 29a). In contrast,
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2
2
2
2
2
2
2
3
3
3
3
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4
4
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5
5
5
5
5
5
5
5
5
6
3
6b and 36d were isolated with modest enantiomeric excess. The thiopyran diastereomer,
36b, was isolated in yields of 7–11%, with enantiomeric excess ranging from 33–59% ee
across the bis(oxazoline) series (Table 5, entry 3–7). The 5-membered sulfolane 37, was
isolated in 21–30% yield with up to 40% ee using the (4R,5S)-diPh L3 ligand (Table 5, entry
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
), reminiscent of our earlier result describing the formation of a 5-membered sulfolane
bearing a methyl ketone also in 40% ee.40
In the proton NMR of the crude product mixtures from 17, there was evidence for the
presence of the diastereoisomer 36c [a doublet of doublets at δ 4.89 ppm (J 4.7, 2.0 Hz) in
H
various ratios, which markedly resembles the distinctive signal observed in 33c (δ 4.89 ppm,
H
dd, J 5.5, 1.6 Hz)] but this component was never isolated following chromatography and is
possible that this diastereomer epimerizes on silica gel to form 36d, and this may contribute
to decreased levels of enantiopurities. Similarly, epimerization can lead to interconversion of
3
6a and 36b, and in fact evidence of this epimerization was observed during TLC. In
contrast, there was no evidence of interconversion of the fused diastereomers via
epimerization, presumably due to conformational effects. It is important to note, self-
disproportionation of enantiomers (SDE)45-49 was observed during the chromatographic
separation of 36a [Table 5, entry 3 (91–83% ee), entry 5 (89–83% ee), entry 6 (56–52% ee),
entry 7 (84–73% ee)], while it was not observed with the other isolated thiopyrans or
sulfolanes. In order to obtain an accurate measure of enantioselectivity, the values in Table 5
of 36a are a weighted average (for full details see the Supporting Information). While the
relative and absolute stereochemistry of thiopyrans 29a, 31a and 33a were confirmed
crystallographically, the absolute stereochemistry of 36a is assigned by analogy on the basis
of HPLC data and specific rotations.
Overall, a consistently high level of enantioselectivity was observed for the isolated cis
substituted thiopyrans (29a, 31a, 33a, 36a) (Figure 6), and excellent levels of copper
catalyzed desymmetrization was observed when inserting into a 2° C–H bond of a
cyclohexane ring in the formation of a 6-membered heterocycle, with 98% ee and a 98:2 dr
for 29a (Table 2, entry 5), and 94% ee and a 97:3 dr for 31a (Table 4, entry 3). Interestingly,
in the conformationally more flexible substrate, 17, while the enantioselectivities were
slightly lower, the ligand trends remained the same and up to 90% ee was obtained using the
preferred (4R)-Ph ligand L1 which has consistently led to the highest enantioselectivities in
C–H insertion to form thiopyrans.
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Figure 6: Consistently high levels of enantioselectivity observed across the bis(oxazoline)
series for the isolated cis substituted thiopyrans (29a, 31a, 33a, 36a)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cyclopentanone Formation
As discussed previously, desymmetrization by C–H insertion using rhodium catalysts has
been explored with α-diazocarbonyl compounds containing cyclic substituents, resulting in
high yields and high enantioselectivities of 5-membered rings (Figure 1 (a) and (b)).
Building on our earlier work which has shown that the copper–bis(oxazoline)–NaBARF
catalyst system provides high levels of enantioselectivity in the formation of cyclopentanones
in freely rotating systems,41, 50 the -diazo--oxosulfone 18 was designed to enable
exploration of desymmetrization in C–H insertion to form cyclopentanones (Table 6).
The rhodium acetate catalyzed C–H insertion of -diazo--oxosulfone 18 was complete after
1
5
hours, leading to the cyclopentanone 38. The H NMR spectrum of the crude product
mixture showed a 1 : 0.15 : 0.17 ratio of three cyclopentanone diastereoisomers
38a/38b/38c). The trans fused, 1,7a trans substituted cyclopentanone 38a together with a
(
minor amount of 38c (1 : 0.04, 38a/38c ratio) was isolated in 53% yield (Table 6, entry 1)
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1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
after chromatography, as evidenced by a characteristic doublet at δ 3.7 ppm ( J 7.7 Hz ) for
H
the α-proton of 38c. While pure 38a was isolated by recrystallisation, it was not possible to
isolate 38c as a pure compound and accordingly its relative stereochemistry has not been
confirmed.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 6: Transition metal catalyzed C–H insertion of α-diazo-β-oxosulfone 18
Rh (OAc) /
2
4
Cu(CH CN) PF
6
3
4
or
O
O
O
O O
S
O O
S
O O
S
CuCl , Ligand,
2
O
O O
S
NaBARF
Ph
Ph
Ph
Ph
CH Cl , Reflux,
H
H
H
H
H
H
2
2
N2
N2
1
8
38a
38b
Yieldb,c
8a (%) 38b (%)
38c
Yieldb
38b eed
(%)
Time
38a eed
(%)
Entry
Catalyst
Ligand Additive
38a : 38b : 38ca
(h)
3
1
2
3
4
5
6
Rh
2
(OAc)
CN)
4
-
-
5
1 : 0.15 : 0.17
1 : 0.21 : 0.04
1 : 0.34 : 0.03
1 : 0.17 : 0.02
1 : 0.20 : 0.04
1 : 0.21 : 0.02
53
43
44
53
59
51
54
2
6
0
0
Cu(CH
3
4
PF
6
-
-
27
6
0
0
38 e
7 f
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
L1
L2
L3
L4
L5
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
14
2
5
64 e
20 e
50 f
22 f
6
11
2
28
7
59 g
32 h
54 g
7 h
7
1 : 0.21 : 0.04
9
a
1
b
c
Ratios of products were calculated from signals in the crude H NMR spectra. Isolated yield after chromatography. 38c
d
(
<5%, in all cases) co-eluted with 38a. The enantiomeric excess was measured by chiral phase HPLC analysis (for full
details see the Supporting Information). eThe major enantiomer is 1S,3aS,7aR. Major enantiomer with unassigned
configuration. Specific rotation of 38b was positive. gThe major enantiomer is 1R,3aR,7aS. hMajor enantiomer with
unassigned configuration. Specific rotation of 38b was negative.
f
Interestingly, Taber’s report of rhodium acetate catalyzed C–H insertion using a similar α-
diazo-β-keto ester led to a diastereomeric ratio of 1:3.11 The increased diastereoselectivity
with the sulfone derivative 18 may be due to the impact of the sulfone moiety relative to the
ester.
Achiral Cu(CH CN) PF required a longer reaction time to catalyze C–H insertion of 18 and
3
4
6
yielded 43% of the major cyclopentanone 38a (containing 4% of 38c) and 6% of the cis
fused, 1,7a trans substituted cyclopentanone 38b (Table 6, entry 2). The employment of the
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copper–bis(oxazoline)–NaBARF catalyst system led to relatively efficient formation for the
5-membered cyclopentanone 38 and showed very consistent diastereoselectivity across the
ligand series (Table 6, entry 3–7). The cyclopentanone, 38a, was observed as the major
1
product in the H NMR spectra of the crude product mixtures and was isolated in yields of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
4–59% (containing minor amounts of 38c, <5% in all cases).
In line with our previous reported results for enantioselective C–H insertion leading to
cyclopentanones,50 the highest enantioselectivities for 38a were obtained using the ligands
(4R)-Bn L2 and (3S,8R)-Ind L4 (64% ee and 59% ee respectively, Table 6, entries 4 and 7)
and the extent of enantioselectivity was very similar to the outcome in freely rotating
systems. Interestingly, the enantioselectivities recorded with the other ligands were somewhat
higher than those obtained in the earlier study, most notably with the (4S)-t-Bu ligand L5
(54% ee for 38a cf 14–28% ee previously). The α-diazoketone 18 underwent C–H insertion
with enantioselectivity values ranging from 20–64% ee for 38a, revealing some sensitivity
towards the bis(oxazoline) ligands (Table 6, entry 3–7). The X-ray structure of a single
crystal of 38a, recrystallized from the reaction using the (4R)-Bn ligand L2 (Table 6, entry 4),
confirmed the 1S,3aS,7aR absolute configuration. The enantiomeric series was verified by
chiral HPLC analysis of the single crystal used for crystallographic determination.
The cis fused, 1,7a trans substituted cyclopentanone 38b was isolated as the minor product
across the catalyst study (up to 14% yield) with lower enantioselectivity compared to the
major cyclopentanone 38a, but interestingly with similar ligand patterns with the highest
enantioselectivity obtained with L2 and L4 (50% ee and 32% ee, respectively, Table 6).
Overall, a modest degree of desymmetrization was achieved for substrate 18 with the (4R)-Bn
ligand L2 in the formation of 38a (Table 6, entry 4), with decreased selectivity relative to that
achieved in the formation of the thiopyrans 29a, 31a, and 33a. This mirrors the earlier results
in the C–H insertions in freely rotating systems where higher enantioselectivities are seen for
the thiopyrans relative to the cyclopentanones with the copper–bis(oxazoline)–NaBARF
system.40-41, 44, 50
Similar to the investigation into thiopyran formation, for the cyclopentanone study the C–H
insertion into the acyclic substrate 19 was compared to insertion into the cyclic structure
substrate 18. Rhodium acetate catalysed C–H insertion of α-diazo-β-oxosulfone 19 in
1
refluxing dichloromethane provided access to cyclopentanone 39. In the H NMR spectrum
for the crude reaction mixture, four sets of doublets were observed at δ 3.33, 3.40, 3.71, and
H
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
.84, in a 1.00 : 0.61 : 1.52 : 0.31 ratio. The doublet signals at δ 3.33 and 3.40 were assigned
H
to 39a and 39b, respectively. The doublet signals at δ 3.71 and 3.84 were not observed in
H
1
the H NMR spectrum of the purified material after column chromatography. These signals
were ascribed to the cis diastereomer at C2 and C3, in line with the earlier reported
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
observation of exclusive isolation of trans cyclopentanones after chromatography.12
Table 7: Transition metal catalyzed C–H insertion of α-diazo-β-oxosulfone 19
Cu(OTf)2
or
O
O O
S
O
O
CuCl , Ligand,
O O
S
O O
S
2
NaBARF
Ph
Ph
Ph
N2
CH Cl , Reflux,
2
2
N2
Me
Me
19
39a
39b
Yieldb,c
39a eed
39b eed
Entry
Catalyst
Cu(OTf)
Ligand
Additive Time (h) 39a: 39b
(
%)
89
93
95
89
99
99
(%)
(%)
1
2
3
4
5
6
2
-
-
4
12
4
1 : 0.38
1 : 0.71
1 : 0.48
1 : 0.63
1 : 0.59
1 : 0.34
0
0
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
L1
L2
L3
L4
L5
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
14 e
63 e
~0
64
~0
75
35
2
13 e
59 f
3
10
19 e
a
1
b
c
Ratios of products were calculated from signals in the crude H NMR spectra. Isolated yield after chromatography. A
d
combined yield of 39a and 39b. The enantiomeric excess was measured by chiral phase HPLC analysis (for full details see
e
f
the Supporting Information). The major enantiomer is 2S,3R,5S. The major enantiomer is 2R,3S,5R.
The Cu(OTf) catalyzed C–H insertion of α-diazo-β-keto sulfone 19 exclusively led to trans
2
stereochemistry across the C2–C3 bond (Table 7, entry 1). A 1 : 0.38 mixture of isomers
(39a/39b) was observed in a combined isolated yield of 87%. The results of the
enantioselective copper–bis(oxazoline)–NaBARF catalyzed C–H insertion of 19 are shown in
Table 7 (entries 2–6). For all reactions, preferential formation of 39a over 39b was recorded,
1
with efficient C–H insertion observed from the H NMR spectra of the crude product
mixture, and the combined isolated yields ranged from 89–99% (Table 7, entry 2–6).
1
Moderate levels of diastereocontrol were observed in the H NMR spectra of the crude
product mixtures across the bis(oxazoline) series with ratios ranging from 58:42 to 75:25
(39a/39b), in contrast to the dr of 73:25:2 to 84:14:2 (38a/38b/38c) observed with 18.
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The (4R)-Bn L2 and (3S,8R)-Ind L4 ligands were found to afford the best enantiocontrol for
39a, with up to 63% ee in the presence of L2 (Table 7, entry 3). Interestingly, the
enantioselectivity induced using the (4R)-Bn L2 and (3S,8R)-Ind L4 ligands for 19 are
comparable to the values recorded for substrate 18 (64% ee for 38a cf 63% ee for 39a (L2)
and 59% ee for 38a cf 59% ee for 39a (L4)). On the other hand, very poor enantioselectivity
was observed with substrate 19 in the presence of (4R)-Ph L1, (4R,5S)-diPh L3, and (4S)-t-
Bu L5 ligands (Table 7, entry 2, 4, 6). While 39b was not isolated in a pure state,
enantioselectivities of 64% ee and 75% ee were recorded for the reactions using the (4R)-Bn
L2 and (3S,8R)-Ind L4 ligands (Table 7, entry 3, 5) showing higher ee values relative to 38b.
Curiously, use of the (4S)-t-Bu ligand L5 led to the formation of cyclopentanone 39a with the
opposite stereochemistry to that observed when using (3S,8R)-Ind L4, albeit at modest
absolute values. Single crystal analysis of 39a, obtained from the reaction in the presence of
L4 (Table 7, entry 5) confirmed the absolute stereochemistry of 2R,3S,5R as the major
enantiomer isolated.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Overall, the enantioselectivities obtained for C–H insertion reactions of 19 are remarkably
similar to those obtained for the analogous copper–bis(oxazoline)–NaBARF catalyzed
cyclisations of 18, although the diastereoselectivity in 39 is notably lower, presumably
reflecting the formation of non-fused versus fused products, and appears to be more sensitive
to alteration of the bis(oxazoline) ligands; with the (4R)-Ph ligand L1 showing a 1 : 0.71
(
39a/39b) ratio, while the (4S)-t-Bu L5 ligand produced a more noteworthy 1 : 0.34
39a/39b) ratio.
(
In general, asymmetric copper catalyzed C–H insertion reactions of 18 and 19 led to
moderate levels of desymmetrization in the formation of cyclopentanones.
Stereochemistry
Flynn
This work
O
H
n
O O
S
O
O O
S
R
OMe
Ph
H
cis substituted
thiopyran
trans fused cis substituted
29a R = OMe, n = 2
31a R = Ph, n = 2
11
33a R = Ph, n = 1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 7: The relative stereochemistry and the sense of enantioselectivity in C–H insertion to
form thiopyrans using the (4R)-Ph bis(oxazoline) ligand L1.
Across the desymmetrization study using the diazo substrates 14, 15, 16, and 18, the trans
fused, cis substituted diastereoisomers 29a, 31a, 33a were consistently isolated as the major
thiopyran products, and the trans fused, trans substituted diastereoisomer 38a was isolated as
the major cyclopentanone product, irrespective of the bis(oxazoline) ligand employed.
Significantly, the sense of enantioselectivity (1S,4aS,8aR, for 29a and 31a with L1, L2 and
L3, and 1R,4aR,8aS, for 29a and 31a with L4 and L5; 1S,4aS,7aR, for 33a with L1, L2 and
L3, and 1R,4aR,7aS, for 33a with L4 and L5) and the cis relative stereochemistry on the
thiopyran ring matches exactly that seen in our original study of C–H insertion to form
thiopyrans (Figure 7).40 The selective formation of the major isolated stereoisomer,
1S,4aS,8aR, for 29a and 31a, 1S,4aS,7aR, for 33a can be rationalized in terms of ligand-
substrate interactions in a similar fashion to that described by our earlier work in the
formation of cis thiopyrans using the (4R)-Ph bis(oxazoline) ligand L1.44
0
1
2
3
4
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8
9
0
In theoretical studies of diastereoselective rhodium mediated C–H insertions, 51 Yoshikai and
Nakamura calculated that the most favorable transition state for forming fused bicyclic
products involves insertion into the equatorial C–H bond of an equatorial ring substituent to
give the trans fused product. In line with this analysis it is clear from our results that for
thiopyran formation this is also the preferred pathway (Figure 8).
E
E
H
[
M]
S
H
S
O
O
O
O
Figure 8: The favored approach of the copper–carbenoid to the equatorial C–H bond of an
equatorial ring substituent.
The observed enantio- and diastereoselectivity to preferentially lead to the trans fused cis
substituted 29a through C–H insertion can be rationalized on the basis of the transition state
illustrated in Figure 9A. When inserting into the equatorial methylene C–H bond of the
equatorial cyclohexane ring, the Cu-carbenoid orientates into the least sterically hindered
pseudo-equatorial position with the methyl ester substituent occupying a pseudo-axial
position. Effective desymmetrization results from the difference between TS A and B (Figure
9
), with unfavorable substrate-ligand interactions due to approach from the opposite face of
the copper carbenoid leading to steric interaction between the cyclohexyl ring and the phenyl
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substituent on the ligand in the upper quadrant in TS B. High diastereoselectivity arises from
the difference between transition states A and C, where rotation of the cyclohexyl ring leads
to unfavorable ligand interactions with the axial hydrogen at the ring junction. The least
favorable transition state D suffers from the combined disadvantages of TS B and C. This
results in the overall diastereoselectivity observed in the copper mediated insertions which
proceed predominantly via TS A.
1
1
1
1
1
1
1
1
1
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0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 9: Proposed transition states leading to thiopyran formation using the (4R)-Ph
bis(oxazoline) ligand L1.
The outcome of the copper mediated insertions with α-diazo-β-oxosulfones 15 and 16 are
similarly rationalized leading selectively to the analogous trans fused cis substituted
stereochemistry in 31a and 33a. The selective formation of cyclopentanone 38a can be
similarly rationalized; notably the diastereoselectivity is in agreement with Nakamura’s
analysis.51
Conclusion
In conclusion, we have shown that the copper–bis(oxazoline)–NaBARF catalyst system is
effective in achieving high levels of desymmetrization in the C–H insertion reactions of
cyclic α-diazo-β-oxosulfones 14, 15, 16, 18 to form fused thiopyrans 29a, 31a, 33a or a fused
cyclopentanone 38a.
For each of the thiopyrans 29a, 31a, 33a, the trans fused, cis substituted thiopyran
diastereoisomers are the major products with up to 98:2 dr and up to 98% ee mirroring both
the sense and extent of enantioselection seen in our earlier work on formation of thiopyrans
by insertion into an unconstrained alkyl chain. Significantly, the optimum ligand for the
enantioselective C–H insertion, (4R)-Ph bis(oxazoline) ligand L1, also leads to the best
outcome in the desymmetrization C–H insertions. Furthermore, the outcome of the
desymmetrization displayed little alterations between α-diazoester 14 and α-diazoketone 15
precursors. The C–H insertion at the 3° bond to form the spiro sulfolane 34 competed more
effectively with the thiopyran formation for the precursor containing the more
conformationally constrained cyclopentane ring in certain cases, however the
enantioselectivity of the major trans fused cis substituted thiopyran diastereoisomer isolated
was comparable across the bis(oxazoline) ligand series. While not providing the highest
enantioselectivies across the series, the use of the (4S)-t-butyl bis(oxazoline) ligand L5
provided the most consistent C–H insertion results, with regards to the isolated yields,
diastereo- and enantioselectivity in the reactions of 14, 15 and 16. The outcome of the
desymmetrization with the α-diazoester 14 was somewhat insensitive to variation of the
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copper source or solvent. Interestingly, in the more conformationally mobile precursor 17
while the enantiopurity of the resulting thiopyran 36a was consistent with enantiopurities of
the fused thiopyrans, there was a significant change in the diastereoselectivity of the C–H
insertion process.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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7
8
9
0
Desymmetrization in the formation of the fused cyclopentanone 38a resulted in similar
efficiencies and enantioselectivies to those seen in cyclopentanone formation using
conformationally unconstrained precursors, with lower levels of enantiopurity seen in
comparison to the thiopyrans with the copper–bis(oxazoline)–NaBARF catalyst system. The
isolated trans fused trans substituted cyclopentanone 38a is synthesized with consistent
diastereoselectivity across the bis(oxazoline) series and with moderate levels of
enantioselectivity in comparison to the freely rotating alkyl chain system 19 where the
diastereoselectivity observed is ligand sensitive. However across the cyclopentanone series,
the sense of enantioselectivity remains the same.
Overall, the copper–bis(oxazoline)–NaBARF catalyst system which has led successfully to
thiopyran and cyclopentanone formation via C–H insertions, is equally effective as a
desymmetrization catalyst system leading to fused derivatives extending the synthetic utility
of this methodology. Clearly, the catalyst-ligand-substrate interactions which result in
enantiocontrol persist in the desymmetrization process.
Experimental Section
General Procedures:
Solvents were distilled prior to use as follows: tetrahydrofuran (THF) was distilled from
sodium benzephenone ketyl; dichloromethane (DCM) was distilled from phosphorus
pentoxide and, when used for C–H insertion reactions, was further distilled from calcium
hydride; ethyl acetate was distilled from potassium carbonate; and hexane was distilled prior
to use. All commercial reagents were used without further purification unless otherwise
stated.
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded on a 300 MHz NMR
1
spectrometer. H (400 MHz) NMR spectra were recorded on a 400 MHz NMR spectrometer.
All spectra were recorded at 300 K in deuterated chloroform (CDCl ) unless otherwise stated,
3
using tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ and δ ) are
H
C
reported in parts per million (ppm) relative to TMS, and coupling constants are expressed in
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1
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1
1
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2
2
2
2
2
2
2
3
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3
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4
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1
Hertz (Hz). Splitting patterns in H NMR spectra are designated as s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets),
dq (doublet of quartets), ddd (doublet of doublet of doublets), dddd (doublet of doublet of
doublet of doublets), dt (doublet of triplets), ddt (doublet of doublet of triplets), td (triplet of
0
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9
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1
2
3
4
5
6
7
8
9
0
13
doublets), tt (triplet of triplets), qd (quartet of doublets), and m (multiplet). C NMR spectra
were calibrated using the solvent signal, i.e. CDCl : δ 77.0 ppm, and multiplicities were
3
C
assigned with the aid of DEPT experiments.
Infrared spectra were measured using a FTIR UATR2 spectrometer or were recorded as
potassium bromide discs (for solids) and as this films on sodium chloride plates (for liquids)
on a PerkinElmer Paragon 1000 FT-IR spectrometer.
Flash column chromatography was carried out using Kieselgel silica gel 60, 0.035–0.075 mm
(
Merck). Thin layer chromatography (TLC) was carried out on pre-coated silica gel plates
Merck 60 PF254). Visualization was achieved by UV (254 nm) light absorption, and
(
potassium permanganate staining.
The enantiopurity of chiral compounds was measured using chiral stationary phase high
performance liquid chromatography (HPLC), carried out on a Lux® 3μm Amylose-1
®
purchased from Phenomenexon, or a Chiralpak OJ-H purchased from Daciel Chemical
Industries Limited. Details of the column conditions and mobile phase employed are included
in the supporting information. HPLC analysis was performed on a Waters alliance 2695
separations module with a Waters alliance 2996 Photodiode Array detector. Optical rotations
were measured on an Autopol V Plus Automatic Polarimeter at 589 nm in a 10 cm cell;
concentrations (c) are expressed in g/100 mL. [α]DT is the specific rotation of a compound and
−1
2
−1
is expressed in units of 10 deg cm g .
The Microanalysis Laboratory, National University of Ireland, Cork, performed elemental
analysis using a Perkin-Elmer 240 and Exeter Analytical CE440 elemental analyzer. Low
resolution mass spectra (LRMS) was recorded on a Waters Quattro Micro triple quadrupole
instrument in electrospray ionization (ESI) mode using 50% acetonitrile–water containing
0
.1% formic acid as eluent. High resolution (precise) mass spectra (HRMS) was recorded on
a Waters LCT Premier Tof LC-MS instrument in electrospray ionization (ESI) mode using
50% acetonitrile–water containing 0.1% formic acid as eluent. High resolution (precise) mass
spectra (HRMS) were also recorded on an Agilent 6530B Accurate Mass Q-TOF LC/MS
instrument in electrosprayionization mode using 50% acetonitrile–water containing 0.1%
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formic acid as eluent. Samples prepared for either LRMS or HRMS by employing acetonitrile
as solvent.
Melting points were obtained using a unimelt Thomas–Hoover capillary melting point
apparatus and are uncorrected.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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2
3
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8
9
0
1
2
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4
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8
9
0
Single crystal X-ray analysis was performed on a Bruker APEX II DUO diffractometer at
room temperature using either graphite monochromatic Mo Kα (λ = 0.7107 Å) or Cu Kα (λ =
1.5418 Å) radiation from a microfocus source fitted with an Incoatec Montel Multilayer
5
2
Mirror. All calculations and refinement were made using the APEX software, except for the
5
3
use of PLATON for a disordered solvent in 33a. Analysis was undertaken with the SHELX
suite of programs and diagrams prepared with Mercury 3.8.54-55 All non-hydrogen atoms were
located and refined with anisotropic thermal parameters, except for the minor disordered
component in 39a. Hydrogen atoms were included in calculated positions or were located and
refined with isotropic thermal parameters.
Synthesis of alkyl iodides
(Iodomethyl)cyclohexane (24)
I
Bromomethylcyclohexane (5.00 g, 3.94 mL, 28.2 mmol) was added neat to a mixture of
sodium iodide (12.69 g, 84.7 mmol) in acetone (100 mL). The reaction mixture was stirred
while heating under reflux for 40 h. The reaction mixture was cooled before being diluted
with aqueous sodium thiosulfate (15%, 100 mL) and extracted with diethyl ether (2 × 75
mL). The combined organic layers were washed with brine (100 mL), dried (MgSO ) and
4
concentrated under reduced pressure to give the crude product as a pale pink/red oil. The
crude oil was redissolved in diethyl ether (25 mL) and washed with aqueous sodium
thiosulfate (15%, 3 × 25 mL) for a second time, dried (MgSO ) and concentrated under
4
reduced pressure to give (iodomethyl)cyclohexane 24 as a colorless oil (5.44 g, 86%); νmax
−
1
(
ATR)/cm (neat) 2920, 2850, 1447, 1170, 597; δ (CDCl , 300 MHz) 0.86–1.04 (2H, m),
H 3
1
.04–1.35 (3H, m), 1.35–1.51 (1H, m), 1.56–1.66 (1H, m), 1.66–1.79 (2H, m), 1.79–1.93
1
(
2H, m), 3.09 (2H, d, J 6.4 Hz); δ { H} (CDCl , 75.5 MHz) 16.2 (CH ), 25.9 (CH ), 26.1
c
3
2
2
(
CH ), 33.5 (CH ), 40.0 (CH). Spectroscopic characteristics were consistent with previously
2
2
reported data.56
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(
Iodomethyl)cyclopentane (25)
I
The title compound was prepared using the procedure described for (iodomethyl)cyclohexane
24 using bromomethylcyclopentane (2.54 g, 15.6 mmol) and sodium iodide (7.01 g, 46.8
mmol) in acetone (100 mL) which was stirred under reflux for 40 h. Following the work up
described previously, (iodomethyl)cyclopentane 25 was obtained as a transparent yellow oil
0
1
2
3
4
5
6
7
8
9
0
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2
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7
8
9
0
−
1
(2.71 g, 83%); νmax (ATR)/cm (neat) 2948, 2863, 1178, 583; δ (CDCl , 300 MHz) 1.14–
H
3
1
.33 (2H, m), 1.51–1.76 (4H, m), 1.76–1.93 (2H, m), 2.08–2.27 (1H, apparent septet, J 7.5
1
Hz), 3.20 (2H, d, J 6.9 Hz); δ { H} (CDCl , 75.5 MHz) 14.3 (CH ), 25.6 (CH ), 33.5 (CH ),
c
3
2
2
2
2.8 (CH). Spectroscopic characteristics were consistent with previously reported data.57
4
4
-(Iodomethyl)heptane (26)
I
A mixture of triphenylphosphine (15.11 g, 57.6 mmol) and iodine (14.62 g, 57.6 mmol) in
dry dichloromethane (300 mL) was stirred at room temperature for 10 min, followed by the
addition of imidazole (6.54 g, 96.0 mmol). The mixture was stirred for an additional 10 min
before 2-propyl-1-pentanol (5.0 g, 38.4 mmol, 6.02 mL) was added neat, and the resulting
mixture was stirred at room temperature for 4 h before being heated to 40 °C overnight. The
reaction mixture was cooled to room temperature and quenched using saturated sodium
metabisulfite (100 mL). The separated organic layer was washed further with saturated
sodium metabisulfite (2 × 40 mL) and the combined aqueous layers were extracted with
diethyl ether (2 × 30 mL). The combined organic layers were washed with brine (80 mL),
dried (MgSO ) and concentrated under reduced pressure to give a crude colorless oil.
4
Following purification by column chromatography on silica gel, using hexane (100%) as
eluent, 4-(iodomethyl)heptane 26 was isolated as a colorless oil (7.84 g, 85%); Anal. Calcd
−
1
for C H I: C, 40.02; H, 7.14. Found: C, 40.23; H, 6.99; ν (ATR)/cm (neat) 2956, 2926,
8
17
max
1
464, 1186, 585; δ (CDCl , 300 MHz) 0.82–1.01 (6H, m), 1.08–1.43 (9H, m), 3.26 (2H, d,
H 3
1
J 4.39 Hz); δ { H} (CDCl , 75.5 MHz) 14.2 (CH ), 16.6 (CH ), 19.7 (CH ), 36.7 (CH ), 38.2
c
3
3
2
2
2
(CH).
Synthesis of β-oxosulfones
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Methyl 2-((2-cyclohexylethyl)sulfonyl)acetate (20)
O
O O
S
OMe
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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9
0
Potassium carbonate (1.94 g, 14.0 mmol) was added as a solid to a solution of methyl
thioglycolate (1.36 g, 1.14 mL, 12.8 mmol) in acetone (50 mL). The reaction mixture was
stirred at room temperature for 15 minutes. 1-Bromo-2-cyclohexylethane (2.44 g, 2.0 mL,
1
2.8 mmol) was added dropwise over 2 minutes, neat, to the reaction mixture. The reaction
mixture was stirred while heating under reflux for 22 h. The mixture was cooled, filtered to
remove insoluble salts, and concentrated under reduced pressure to give the crude sulfide,
methyl 2-((2-cyclohexylethyl)thio)acetate as a colorless oil (3.10 g, >100% yield), which was
used without further purification (due to its malodourous nature). A suspension of m-CPBA
(~77% w/w, 7.71 g, 44.6 mmol) in dichloromethane (50 mL) was added dropwise to a
solution of methyl 2-((2-cyclohexylethyl)thio)acetate (3.10 g, 14.3 mmol) in dichloromethane
(100 mL) over approximately 30 min while stirring at 0 °C. The resulting mixture was stirred
for 23 h, while warming to room temperature. The crude mixture was washed with saturated
aqueous sodium metabisulfite solution (2 × 50 mL), saturated aqueous sodium bicarbonate (3
×
150 mL), and the separated organic layers were washed with brine (200 mL), dried
(
MgSO ) and concentrated under reduced pressure to give the crude sulfone. Following
4
purification by column chromatography on silica gel, using ethyl acetate/hexane (50:50) as
eluent, methyl 2-((2-cyclohexylethyl)sulfonyl)acetate 20 was isolated as a colorless oil (3.17
g, 89%); Anal. Calcd for C H O S: C, 53.20; H, 8.12. Found: C, 52.95; H, 8.06; ν
max
1
1
20
4
−1
(
ATR)/cm (neat) 1740 (CO), 1312, 1104 (SO ); δ (CDCl , 300 MHz) 0.86–1.06 (2H, m),
2 H 3
1.06–1.47 (4H, m), 1.59–1.82 (7H, m), 3.20–3.31 (2H, symmetrical m), 3.82 (3H, s), 3.97
1
(
2H, s); δ { H} (CDCl , 75.5 MHz) 25.9 (CH ), 26.1 (CH ), 28.8 (CH ), 32.6 (CH ), 36.5
c
3
2
2
2
2
+
(
CH), 51.5 (CH ), 53.2 (CH ), 56.9 (CH ), 163.5 (C); HRMS (ESI−TOF) (m/z): [M+H]
2
3
2
calcd for C H O S, 249.1161; found 249.1161.
1
1
21
4
2
-((2-Cyclohexylethyl)sulfonyl)-1-acetophenone (21)
O
O O
S
Ph
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