Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent

Article abstract of DOI:10.1039/c7ob00214a

Enantioselectivities in C-H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C-H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

Full text of DOI:10.1039/c7ob00214a

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Enantioselective copper catalysed intramolecular C–H insertion reactions of α‐diazo‐β‐keto
sulfones, α‐diazo‐β‐keto phosphine oxides and 2‐diazo‐1,3‐diketones; the influence of the carbene
substituent.
a
a
a
a
a
Amy E. Shiely, Catherine N. Slattery, Alan Ford, Kevin S. Eccles, Simon E. Lawrence and Anita R.
Maguire b,*
aDepartment of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
bDepartment of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and
Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland.
Abstract:
Enantioselectivities in C–H insertion reactions, employing the copper‐bis(oxazoline)‐NaBARF
catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the
carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the
sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C–H insertion reactions
of α‐diazo‐β‐keto phosphine oxides and 2‐diazo‐1,3‐diketones are reported for the first time.
Introduction:
Intramolecular carbenoid insertion into a previously unactivated C–H bond is a powerful
method for new C–C bond formation. The generation and subsequent reactions of carbenoids
from an α‐diazocarbonyl precursor via transition‐metal catalysis have been extensively
explored due to the diverse range of synthetically powerful reaction pathways observed,
including Wolff rearrangement, aromatic addition, cyclopropanation, ylide formation and X–
H insertion.1‐5
Rhodium and copper, are among the most utilised transition metals for catalysing
intramolecular C–H insertion reactions. Initial research in the area began with copper,
6
although poor reaction efficiencies were observed. The turning point in C–H insertion
chemistry came with the introduction of the rhodium carboxylate catalysts e.g. Rh
2
(OAc)
4
7
which made the reaction more generally applicable. The tendency for Rh
2
(OAc)
4
catalysed
8
C–H insertion to form five membered rings initially reported by Wenkert has been
extensively explored by Taber and developed to a useful methodology for the synthesis of
cyclopentanones.9‐11
1

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In most instances of the reports of C–H insertion, the “carbenoids” are acceptor‐acceptor
type, and usually both of the electron withdrawing groups are carbonyls with a couple of
exceptions including nitro, cyano, phosphoryl and sulfonyl groups.4, 12‐14
Focusing specifically on the effect of substitution on the carbene substituent, early work by
Hashimoto on α‐diazo‐β‐keto esters found that increasing the size of the alkoxy group of the
ester moiety led to an increased level of asymmetric induction, going from a methyl to a Ch(i‐
1
5
Pr) group resulted in an increase in enantiocontrol of 46 %ee to 76 %ee. Interestingly Taber
2
observed the opposite effect in the cyclisation of β‐ketoesters, when increasing the steric bulk
of the ester from a methyl group to a dimethylpentyl group, resulted in a decrease in
16
diastereomeric excess, 58 %de to 34 %de. Other electron withdrawing substituents on the
carbene carbon have been explored, albeit to a lesser extent than the esters. Corbel and co‐
workers conducted investigations into the intramolecular C–H insertion of α‐phosphorylated
cyclopentanones. They observed low yields of cyclopentanones due to the occurrence of the
Wolff rearrangement which competed with the C–H insertion reaction.13 Monteiro
synthesised 2‐phenylsulfonyl cyclopentanones from α‐diazo‐β‐keto sulfones via C–H insertion
in good yields of up to 75% which was comparable to their ester equivalents.12
For the first twenty years of research in this area the vast majority of carbocyclic rings formed
were five membered, with some exceptions,17‐19 when the insertion occurs into the sulfonyl
group rather than the carbonyl containing chain the presence of the sulfone alters the
geometry of the C–H insertion transition state enabling access to six membered thiopyrans,
and, where the six membered ring is not accessible, five membered sulfolanes (Scheme 1).17,
20‐22
Scheme 1 Copper catalysed C–H insertion reactions of α‐diazo‐β‐oxo‐sulfones.22
The first catalytic asymmetric C–H insertion reaction was carried out in 1990 in which a
cyclopentanone was generated in up to 12 %ee using a rhodium catalyst.23 Since this
pioneering work, insertion reactions have been further developed to achieve high levels of
enantiocontrol with a diverse range of chiral rhodium catalysts.1, 2
2

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Previous studies from our laboratory have shown that the use of a copper catalyst system
comprised of copper‐bis(oxazoline)‐NaBARF is very effective in inducing high levels of
enantiocontrol in C–H insertions of α‐diazocarbonyl compounds bearing arylsulfonyl
substituents. Thiopyrans 1, cyclopentanones 2 and γ‐lactams 3 have been synthesised in
22
24
25
excellent enantioselectivities of up to 98 %ee, 89 %ee and 78 %ee respectively (Scheme
2). The presence of the additive NaBARF was found to be essential for achieving high levels of
asymmetric induction,24, 26 through abstraction of chloride by the sodium cation of NaBARF,
thereby altering the catalyst geometry as Fraile has previously discussed.27, 28
Scheme 2 Copper catalysed C–H insertion reactions of α‐diazo‐β‐keto sulfones, α‐diazo‐β‐oxo sulfones and α‐
diazoacetamides.22, 25
The enantioselectivities described above are the highest reported for copper catalysed C–H
29
insertion reactions and, indeed, are comparable with the enantioselectivities reported for
the rhodium mediated C–H insertions.2
Our studies into enantioselective intramolecular C–H insertion reactions of α‐diazo‐β‐keto
sulfones have predominately focused on the steric and electronic effects of the substituent
adjacent to the C–H insertion site using phenyl sulfones. Specifically, we have observed that
more sterically demanding groups at the site of insertion lead to higher levels of
enantiocontrol.26 The presence of both electron withdrawing and electron donating
3

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substituents on the phenyl moiety, lead to a slight decrease in enantioselectivity relative to
3
0
the unsubstituted compound, in line with observations by Hashimoto. Interestingly, the
presence of an electron donating substituent leads to a less efficient C–H insertion reaction.31
Focusing on the substituent on the carbene, our work to date has been predominantly
conducted with phenyl sulfone derivatives. We briefly explored C–H insertion with α‐diazo‐β‐
ketophosphonates and α‐diazo‐β‐ketoester substrates; however, these proceeded with lower
enantioselectivities when compared to the sulfone containing compounds.32
Scheme 3 Enantioselective copper catalysed C–H insertion of various α‐diazocarbonyl compounds.
We report herein our recent investigations into the effect of a wider range of electron
withdrawing groups present on the carbene carbon (Scheme 3), firstly, by exploring the
importance of the substituent on the sulfone moiety and secondly, by expanding the
substrate scope to include phosphine oxides and diketones, both of which are the first reports
of asymmetric intramolecular C–H insertion for these types of compounds.
Results and Discussion:
Thirteen α‐diazocarbonyl substrates were selected for investigation including eleven α‐diazo‐
β‐keto sulfones (4a‐4k), an α‐diazo‐β‐keto phosphine oxide (5) and a 2‐diazo‐1,3‐diketone (6)
26
all of which were novel other than 4a. These compounds were chosen to enable exploration
of the impact of alteration of the substituent, including variation of the electronic and steric
properties of the sulfonyl substituents, in addition to the replacement of the sulfone by
phosphine oxides and ketones. To permit comparability across the series this investigation
was conducted with a phenyl substituent at the site of insertion, which, in our earlier studies,
had led to the optimum outcome.26
The substrates were synthesised following standard diazo transfer to the requisite sulfone,
phosphine oxide and diketone precursors (Scheme 4), (Scheme 6) and (Scheme 7)
4

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respectively. The precursor sulfones 4b–h were synthesised from the corresponding thiols by
methylation using iodomethane, followed by oxidation of the crude sulfide using hydrogen
peroxide to form methyl sulfones 7b to 7h, which were then treated with butyllithium in the
presence of ethyl 4‐phenylbutanoate 8 to form β‐ketosulfones 9a–g and 9i–k (Scheme 5). A
slightly modified sequence was required for the synthesis of the cyclohexyl sulfone 9h; as
condensation of methyl cyclohexylsulfone 7h with ethyl‐4‐phenylbutanoate 8 proved
unsuccessful, reaction with the aldehyde 10 followed by oxidation was employed to provide
the β‐ketosulfone 9h (Scheme 5). A similar approach was used for the synthesis of the
phosphine oxide, methyldiphenylphosphine oxide was lithiated and condensed with ethyl‐4‐
phenylbutanoate 8 to lead to the β‐keto phosphine oxide 11 (Scheme 6). To generate the
diketone precursor acetophenone was condensed with the acylbenzotriazole 12 (Scheme 7).
Scheme 4 General procedure for α‐diazo‐β‐keto sulfone synthesis 4a‐k.
a = phenyl, b = 4‐fluorophenyl, c = 2‐naphthalene, d = 1‐naphthalene, e = mesityl, f 2‐ethylphenyl, g = 4‐methoxyphenyl, h
=
cyclohexyl, i = 4‐methylphenyl, j = 4‐bromophenyl, k = methyl
5

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Scheme 5 Synthetic route to α‐diazo‐β‐keto cyclohexyl sulfone 4h.
Scheme 6 Synthetic route to α‐diazo‐β‐keto phosphine oxide 5.
6

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Scheme 7 Synthetic route to α‐diazo diketone 6.
Focusing initially on the sulfones, cyclisations were conducted with Rh
2
(OAc) to afford
4
racemic samples of cyclopentanones 13a–k; the reactions proceeded efficiently with reaction
times of ∼30 min which were comparable to similar substrates.26 For enantioselective
intramolecular C–H insertion reactions, in all cases the catalyst was prepared by pre‐mixing
the constituents, which we have previously reported. This involved refluxing the constituents:
copper(II) chloride (5 mol%), bis(oxazoline) ligand 14–18 (6 mol%) and NaBARF [sodium
tetrakis[(3,5‐trifluoromethyl)phenyl]borate] (6 mol%) for 1.5 h in dry dichloromethane under
an atmosphere of nitrogen, upon which a homogenous mixture was obtained. A solution of
α‐diazocarbonyl substrate in dry dichloromethane was added dropwise to this mixture.
Within the α‐diazo‐β‐ketosulfone substrate screen (Table 1 4a–4k and Figure 2) we found that
the bis(oxazoline) ligands 15 and 18 led to the highest levels of enantioselectivity in
cyclopentanone formation across a wide range of compounds. The indane ligand 18, was the
most effective ligand yielding the highest levels of asymmetric induction of up to 91 %ee (13i).
Interestingly, use of the benzyl ligand 15, was the most consistent with enantioselectivities of
approximately 70 %ee across the substrate range. Use of ligands 14, 16 and 17 led to lower
levels of enantiocontrol. This is consistent with results previously obtained with α‐diazo‐β‐
keto sulfones.26
Focusing first on the steric effect, it is clear that the steric demand of the sulfone substituent
has a significant impact on the enantioselectivity achieved. In general, replacing the phenyl
sulfone with the methyl sulfone resulted in significantly decreased enantioselectivities (other
than the benzyl ligand 15) while the increased steric demand in the 1‐naphthyl sulfone leads
to enhanced enantioselectivity across the ligand series although still not matching the
optimum achieved for 13i with ligand 18.
In contrast, electronic effects on the aryl substituent on the sulfone are less evident. While
there is some evidence of a slight increase in enantioselectivity with the p‐tolyl substituent
13i and a slight decrease with the p‐halo substituents 13b and 13j, the extent of this is minor.
Interestingly the cyclohexyl sulfone 13h revealed similar ligand trends but with overall
decrease in enantioselectivity relative to the aryl substituent.
7

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Figure 1. Bis(oxazoline) ligands 14‐18.
8

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Table 1 Enantioselective transition metal catalysed C–H insertion reactions of α‐diazo‐β‐keto sulfones, 4
4a‐k
13a‐k
Rh
2
(OAc)
4
CuCl
2
+ NaBARF + ligand 14–18
Diazo
R
(4R)‐Ph
(4R)‐Bn
(4R, 5S)‐
diPh
(4S)‐t‐Bu (3S, 8R)‐
Ind
Ligand 14 Ligand 15 Ligand 16 Ligand 17 Ligand 18
a
a
a
a
a
a
%
Yield
% Yield
% Yield
% Yield
% Yield
% Yield
b
b
b
b
b
b
(
%ee)
(%ee)
(%ee)
(%ee)
(%ee)
(%ee)
(2S, 3S)‐14
(2R, 3R)‐14
4
4
4
4
ac26
89(0)
69(0)
29(0)
74(0)
69(50)
56(52)
44(45)
61(37)
58(81)
66(78)
73(77)
66(78)
54(52)
23(56)
43(52)
55(47)
55(64)
53(89)
64(91)
62(87)
70(86)
i
64(55)
26(61)
64(58)
g
b
4
4
4
j
75(0)
82(0)
14(0)
59(37)
49(8)f
59(50)
60(72)
74(72)
60(76)
54(41)
23(2)
57(57)
73(34)
57(46)
52(89)
70(52)
52(78)
k
c
54(47)
4
d
60(0)
88(0)
54(81)
72(71)
51(76)
62(66)
67(81)
4h
10(33)
(‐)g
92(68)
47(66)
25(45)
(‐)g
51(47)
4(72)
62(78)
31(82)
ed
30 (0)
e
4
fd
27 (0)
e
(‐)g
34(78)
(‐)g
4(67)
53(87)
4
a
b
Total yield of cyclised products after chromatography. The enantiomeric excess measured by chiral HPLC analysis (for full
c
26 d
details see ESI). Data for 13a included for comparison. Calculated yields of cyclopentanone 13 from ratios of 13:19 (for
9

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e
2
full details see Table 2). Cyclisation’s were carried out with Cu(OTf) in order to obtain racemic samples of cyclopentanones
f
g
1
3e and 13f (for full details see Table 2). Opposite stereochemistry observed (2R, 3R). Not formed.
100
5
0
0
Cyclopentanones
Ligand 14
Ligand 16
Ligand 17
Ligand 15
Ligand 18
Figure 2. Impact of variation of the sulfone on enantioselectivity with the ligands 14–18.
In most cases the sulfonyl cyclopentanones 13 were formed very efficiently with only minor
1
byproducts evident in the H NMR spectra of the crude products (Table 1). However, for
compounds 4e and 4f a competing C–H insertion pathway leading to the sulfolane through
insertion into the aryl methyl (19e) and methylene (19f) group was observed. By X‐Ray
crystallography the absolute stereochemistry of 13a has been previously determined33
indicating that when the (4R)‐14, (4R)‐15 and (4R, 5S)‐16 ligands are used the (2S, 3S)
cyclopentanone is selectively formed, while using the (4S)‐17 and (3S, 8R)‐18 ligands
selectively leads to the (2R, 3R) cyclopentanone. The absolute stereochemistry of samples 13j
and 13k ‐derived from reactions using ligands (4R)‐15, (3S, 8R)‐18 and (4R)‐15 respectively,
were also determined (for full details see ESI) and it was found that the sense of
enantioselectivity agrees with our earlier report of phenylsulfonyl cyclopentanones.26, 33
By analogy (using HPLC data and specific rotations) the absolute stereochemistry of the
remaining cyclopentanone derivatives 13b–i is similarly assigned. Thus when using (4S)‐17
and (3S, 8R)‐18 the (2R, 3R) cylopentanone is formed while using (4R)‐14, (4R)‐15 and (4R,
5S)‐16, in general, the (2S, 3S) enantiomer of the cyclopentanone is formed. Interestingly
there is just one exception with (2R, 3R) 13k, formed with the opposite sense selectively with
10

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ligand (4R)‐14 albeit with a low %ee. This can be rationalised as replacement of the phenyl
sulfone with the methyl sulfone alters the ligand substrate interactions substantially.
Table 2 Enantioselective transition metal catalysed C–H insertion reactions of α‐diazo‐β‐keto sulfones 4e and 4f.
Ligand
Diazo Time Yielda
Crude Ratiob
(Purified Ratio)b
13
%eec
19
(h)
%
%eec
13:19
0
:100
Rh
2
(OAc)
4
4e
4e
4e
4e
4e
4e
4e
4f
24
8
78
70
74
71
60
43
62
74
68
13e
13e
13e
13e
13e
13e
13e
13f
‐
0
19e
19e
19e
19e
19e
19e
19e
19f
0
0
0
0
0
0
0
0
0
(
(
(
(
(
(
(
(
(
(
0:100)
7:73
38:62)
:100
0:100)
0:30
66:34)
:100
0:100)
6:84
10:90)
6:54
50:50)
:100
0:100)
7:63
37:63)
:100
2
Cu(OTf)
2
0
14
15
16
17
18
2.5
4
‐
7
66
‐
0
2.5
24
4.5
1.5
22
1
72
82
‐
4
0
Rh
2
(OAc)
4
3
Cu(OTf)
2
4f
13f
0
19f
0
1
4
5
4f
4f
6.5
22
75
47
13f
13f
‐
19f
19f
60
0
0:100)
72:28
1
78
1
1

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(
(
72:28)
:100
0:100)
0
16
17
18
4f
4f
4f
1.5
22
21
73
56
83
13f
13f
13f
‐
19f
19f
19f
74
5
1
7:83
67
87
(
7:93)
6
1:39
0
(
64:36)
a
b
1
Combined yield of cyclopentanone and sulfolane. Ratios of isomers were calculated from signals in the crude/purified H
NMR spectra: δ
9e and δ 1.13 (3H, t, J 7.4, CH
excess measured by chiral HPLC analysis (for full details see ESI).
H
3.92 [1H, d, J 7.6, C(2)H] for cyclopentanone 13e; δ
H
4.45 (1H, dd, X of ABX, JBX 8.5, JAX 5.7, CH) for sulfolane
c
1
H
2
CH ) for cyclopentanone 13f; δ
3
H
1.44 (3H, d, J 6.9, CH
3
) for sulfolane 19f. The enantiomeric
Previous studies had demonstrated that the preference for C–H insertion is
9
methine>methylene>methyl, however, in investigating the copper mediated reactions of 4e
and 4f, competition between C–H insertion into methylene and methyl C–H bonds was
observed leading to the formation of cyclopentanone (13e and f) and fused sulfolane (19e
and f) (Scheme 8). As summarised in Table 2, the regioselectivity of the C–H insertion
displayed sensitivity to the variation of the metal from rhodium to copper and, even more
remarkably, to the variation of the bis(oxazoline) ligand. When Rh
catalyst with 4e and 4f, the fused sulfolanes 19e and f were the sole product obtained while
use of Cu(OTf) led to racemic samples of 13e and f. Sulfolane 19f was predominantly
2
(OAc) was used as the
4
2
obtained as a single diastereomer, presumably trans, although, with Rh
2
(OAc) , minor signals
4
1
in the crude H NMR spectrum were ascribed to the cis isomer. Interestingly with the copper
catalysts significant formation of the cyclopentanone was only seen with the complexes from
the ligands 15 and 18. As these are the ligands which provide the highest enantioselectivities
in the cyclopentanones (Table 1), it is highly likely that specific substrate interactions
favouring C–H insertion to form the cyclopentanones are enabled with ligands 15 and 18. 26
All samples of sulfolane 19e recovered were racemic; this was as expected due to the single,
easily racemised, stereocentre. The samples of 19f obtained using ligands (4R)‐14, and (4R,
5S)‐16 displayed moderate enantioselectivity (60 and 74 %ee respectively) with a very low
enantiomeric excess obtained using ligand (4S)‐17 (5 %ee) with the opposite sense of
enantioselection, as anticipated.
1
2

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H
H
O
H
H
H
S
O
O
5e
O
S
S
O
O
O
O
O
20e
Ph
4e
1
Scheme 8 Possible C–H insertion pathways for mesityl substrate 4e.
Interesting patterns in terms of chemoselectivity and efficiency of the C–H insertions across
1
the substrate and ligand series were evident from comparison of the H NMR spectra of the
crude mixtures. In general use of Rh
2
(OAc) led to the cleanest insertions to provide the
4
cyclopentanone with little or no byproducts. In contrast, use of copper catalysts can lead to
minor competing reaction pathways including chlorine abstraction from the solvent and
hydride abstraction at the site of insertion leading to a tetrahydrofuran derivative (Scheme
3
1
9
). Notably C–H insertion to form cyclopentanone was most efficient with the benzyl or
indane ligand 15 and 18; use of phenyl or t‐butyl ligands 14 and 17 in general led to more of
the tetrahydrofuran product, while use of the diphenyl ligand 16 tended to lead to a more
complex mix of unidentified products.
Cl
RO S
2
O
SO R
2
O
Chlorine abstraction
Tetrahydrofuran derivative
Scheme 9 Possible byproducts formed in the copper catalysed C–H insertion reactions of 4a–k
As optimum enantioselectivities in the copper mediated C–H insertion were achieved with
the aryl sulfones, exploration of the substituent on the carbene was undertaken to explore
the effect of other electron withdrawing groups on the outcome of the insertion process.
32
Accordingly, extending our work with the phosphonates and esters, C–H insertions with α‐
1
3

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diazo‐β‐keto phosphine oxide (5) and 2‐diazo‐1,3‐diketone (6) were investigated.
Interestingly, these are the first reports of asymmetric intramolecular C–H insertion in these
types of compounds. Intramolecular C–H insertion reactions of 5 with the copper catalyst
system led to α‐phosphine oxide‐substituted cyclopentanone 20 in poor to moderate
enantioselectivities (Table 3); reaction times, were also significantly longer and yields poorer
than their sulfone counterparts. The longer reaction times may be due to the inferior
34
electron‐withdrawing abilities of the diphenyl phosphine oxide group (σᵨ0.53), compared to
the phenylsulfonyl moiety (σᵨ0.68),34 which results in a less electrophilic carbene in the
phosphine oxide series. In an effort to reduce reaction times two higher boiling point solvents,
chloroform and 1,2‐dichloroethane, were used. With chloroform, comparable times and
enantioselectivities were obtained to those seen in the reactions conducted in
dichloromethane. When 1,2‐dichloroethane was used the reaction time was reduced from
162 h to 22 h and the yield was increased by ∼50%; predictably however, the higher
temperature led to a dramatic decrease in asymmetric induction.
While the absolute stereochemistry of 20 has not been determined, as anticipated ligands
(
4R)‐14, (4R)‐15 and (4R, 5S)‐16 lead to the same major enantiomer of 20, while (4S)‐17 and
3S, 8R)‐18 lead to the opposite. It is reasonable to assume that this has the same
(
stereochemical preference as seen with the sulfonyl cyclopentanones 13 i.e. (4R)‐14, (4R)‐15
and (4R, 5S)‐16 lead to the (2S, 3S) cyclopentanone and (4S)‐17 and (3S, 8R)‐18 lead to the
(2R, 3R) cyclopentanone.
Table 3 Enantioselective transition metal catalysed C–H insertion reactions of α‐diazo‐β‐keto phosphine oxide, 5
5
20
Ligand
Rh (OAc)
Solvent
Time (h)
67
Yield (%)a
Rotation %eeb,
0
2
4
CH
CH
CH
2
2
2
Cl
2
Cl
2
Cl
2
64
26
5
1
4
5
19
(+)
(+)
29
30
1
124
1
4

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1
1
1
1
1
6
7
8
8
8
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
19
24
44
8
(+)
(−)
(−)
(−)
(−)
31
2
49
124
22
53
9
C
2
H
4
Cl
2
60
6
CHCl
3
124
11
a
b
Total yield of cyclised products after chromatography. The enantiomeric excess measured by chiral HPLC analysis (for full
details see ESI).
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
Ligand 15
Ligand 16
Ligand 18
COPh
σᵨ0.43)
Reaction times: 100‐152 h
PO(OMe)
2
PO(Ph)
2
CO
2
CH(i‐Pr)
2
2
SO Ph
(
(σᵨ0.50)
(σᵨ0.53)
(σᵨ0.56)
(σᵨ0.68)
48‐110 h
19‐124 h
2‐48 h
0.5 h
Figure 3 Impact of variation of the electron withdrawing group on the enantioselectivity with ligands 15, 16 and 18.
With diazodiketone 6, reaction times were significantly longer than for the sulfonyl
counterparts and yields of the cyclopentanone 21 were poor (Table 4). Across the series
altering the substituent on the carbene from the phenyl sulfone (
σ
ᵨ0.68),34 to the ester
ᵨ0.43),34
(
σ
ᵨ0.56),34 phosphine oxide ( ᵨ0.53),34 phosphonate ( ᵨ0.50),34 and ketone (
σ
σ
σ
resulted in a decrease in the electrophilicity of the carbene and a substantial increase in the
reaction times for the C–H insertion reactions (Figure 3). The products of reduction and Wolff
15

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rearrangement were evident as significant competing reaction pathways as the efficiency for
C–H insertion decreased. Interestingly, moderate enantioselectivities were achieved across
the ligand screen indicating that the ligand sensitivity in terms of enantioselectivity in this
insertion is much less than in the other systems studied to date. Furthermore, the low
enantioselectivity obtained with the benzyl ligand 15 contrasts with other results. Once again
ligands (4R)‐14, (4R)‐15 and (4R, 5S)‐16 lead selectively to one enantiomer of 21 while (4S)‐
17 and (3S, 8R)‐18 lead selectively to the opposite enantiomer and while it is reasonable to
assume that the sense of enantioselection follows that seen in the sulfonyl derivatives the
absolute stereochemistry has not been determined. The cyclopentanone 21 was initially
recovered as a mixture of keto and enol tautomers, however, over time the keto tautomer
was observed to predominate.
Table 4 Enantioselective transition metal catalysed C–H insertion reactions of α‐diazo‐diketone, 6
5
6
mol% CuCl2
mol% 15-19
O
OH
N2
O
O
6 mol% NaBARF
CH Cl ,
2
2
Ph
Ph
or
O
O
1 mol% Rh (OAc)4
2
Ph
Ph
CH Cl ,
2
2
6
21
Ligand
Rh (OAc)
Solvent
Time (hr)
1.5
Yield (%)a
%eeb,
‐
2
4
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
38
27
10
33
27
19
14
15
16
17
18
126
68
22
56
54
62
142
100
142
152
a
b
Total yield of cyclised products after chromatography. The enantiomeric excess measured by chiral HPLC analysis (for full
details see ESI).
Conclusions:
We have found that the copper‐bis(oxazoline)‐NaBARF catalytic system is efficient in
achieving high levels of enantiocontrol across a broad range of substrates. From our studies
to date, it is clear that the sulfonyl moiety leads to the highest levels of enantioselectivity in
intramolecular C–H insertion reactions of α‐diazocarbonyl compounds resulting in
1
6

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cyclopentanone formation. The indane bis(oxazoline) ligand 18 has consistently led to the
highest levels of enantiocontol across a wide variety of substrates. Within the α‐diazo‐β‐keto
sulfone series increasing the steric demand of the substituents attached to the sulfone moiety
leads to higher levels of asymmetric induction across the bis(oxazoline) ligand screen, while
electronic effects have little impact. In addition to impacting on the enantioselectivity,
changing from the sulfonyl group to a phosphine oxide or ketone with decreased electron
withdrawing character, decreased the efficiency of the C–H insertion.
Experimental:
All solvents were distilled prior to use by the following methods: dichloromethane (DCM) was
distilled from phosphorus pentoxide and when used for α‐diazocarbonyl cyclisations, was
further distilled from calcium hydride; ethyl acetate was distilled from potassium carbonate;
hexane was distilled prior to use. Organic phases were dried using anhydrous magnesium
sulfate. All reactions were carried out under a nitrogen atmosphere unless otherwise stated.
Infrared (IR) spectra were recorded as thin films on sodium chloride plates for oils or as
potassium bromide (KBr) discs for solids on a Perkin Elmer Paragon 1000 FT‐IR spectrometer.
NMR spectra were run on Bruker Avance 300 MHz, 400 MHz, 500 MHz and 600 MHz NMR
1
13
machines. H spectra were run at 300 MHz, 400 MHz, 500 MHz and 600 MHz and C spectra
were run at 75 MHz, 100 MHz, 125 MHz and 150 MHz. All spectra were recorded at room
temperature (∼20 °C) in deuterated chloroform (CDCl
tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ
parts per million (ppm) relative to TMS and coupling constants (J) are expressed in Hertz
3
), unless otherwise stated, using
H
and δ ) are reported in
C
13
(
Hz). C NMR spectra were calibrated using the solvent signals, i.e. CDCl
3
: δ 77.0 ppm and
C
were assigned with the aid of DEPT experiments.
Flash column chromatography was carried out using Kieselgel silica gel 60, 0.040–0.063
mm (Merck). Thin layer chromatography (TLC) was carried out on precoated silica gel plates
(Merck 60 PF254). Visualisation was achieved by UV (254 nm) detection, vanillin staining and
potassium permanganate staining.
Enantiopurity of the chiral compounds was determined by chiral stationary phase high
performance liquid chromatography (HPLC) performed on a Phenomenex® LUX Cellulose‐4,
Phenomenex® LUX Cellulose‐2, Phenomenex® LUX Amylose‐1, Chiralpak OJ‐H or Chiralcel OD‐
H column. HPLC analysis was performed on a Waters alliance 2690 separations module.
1
7

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Optical rotations were measured on a Perkin‐Elmer 141 polarimeter at 589 nm in a 10 cm cell;
ꢀ
ꢁ
concentrations (c) are expressed in g/100 mL. [α] 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 analysers. Low resolution mass spectra (LRMS) were 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; samples were made up in
acetonitrile. High resolution mass spectra (HRMS) were 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; samples were prepared in acetonitrile. Single crystal X‐
ray analysis was conducted using a Bruker APEX II DUO diffractometer at temperature 100 K
using graphite monochromatic Mo Kα (λ = 0.7107 Å) radiation fitted with an Oxford
Cryosystems Cobra low‐temperature device or a Bruker SMART X2S diffractometer. All
calculations and refinement were made using the APEX software. The structures were solved
using direct methods and refined on F2 using SHELXL‐97.17 Analysis was undertaken with the
SHELX suite of programs and diagrams prepared with Mercury 3.0.18 All non‐hydrogen atoms
were located and refined with anisotropic thermal parameters. Hydrogen atoms were
included in calculated positions or they were located and refined with isotropic thermal
1
parameters. H NMR spectra, IR spectra and melting point (mp) analysis were recorded for all
13
previously prepared compounds. For novel compounds, C NMR, LRMS and microanalysis
and/or HRMS were also obtained. HETCOR/HSQC, HMBC and COSY experiments were carried
out to aid the NMR assignment of novel chemical structures.
1
‐(1H‐Benzo[d][1,2,3]triazol‐1‐yl)‐4‐phenylbutan‐1‐one 12. Thionyl chloride (0.88 mL,
0.0122 mol) was added in one portion to a solution of benzotriazole (5.80 g, 0.0487 mol) in
dichloromethane (50 mL), the reaction mixture was stirred at room temperature for 30 min.
‐Phenylbutyric acid (2.00 g, 0.0122 mol) was added in one portion and a colour change from
4
yellow to cloudy white was observed. The reaction mixture was stirred for 2 h at room
temperature. The white precipitate was removed by filtration and extracted with
dichloromethane (2 x 50 mL). The combined organic extracts were washed with aqueous
sodium hydroxide (1.0 M, 3 x 60 mL), dried with magnesium sulfate and concentrated under
−
1
reduced pressure to yield the acylbenzotriazole 12 as a white sticky oil; νmax(neat)/cm 1704
18

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(
C=O), 1210, 743, 698; δ
C(4)H
1H, m, aromatic H of benzotriazole group), 7.61–7.68 (1H, m, aromatic H of benzotriazole
group), 8.11 (1H, d, J 8.3, aromatic H of benzotriazole group), 8.28 (1H, d, J 8.3, aromatic H of
benzotriazole group); δ (106.6 MHz) 26.3 [CH , C(3)H ], 33.4 [CH , C(4)H ], 35.0 [CH , C(2)H ],
15.5 (CH, aromatic CH), 126.1 (CH, aromatic CH), 126.3 (CH, aromatic CH), 128.45 (CH,
H
(400 MHz) 2.26 [2H, apparent qu, J 7.5, C(3)H ], 2.82 [2H, t, J 7.6,
2
2
], 3.45 (2H, t, J 7.4, C(2)H ), 7.15–7.32 (5H, m, aromatic H of phenyl group), 7.47–7.53
2
(
C
2
2
2
2
2
2
1
aromatic CH), 128.51 (CH, aromatic CH), 138.8 (C, C), 141.3 (C, C), 179.2 (C, CO); HRMS (ESI+):
+
Exact mass calculated for C16
H
16
N
3
O [M+H] , 266.1293 Found 266.1286. m/z (ESI+): 266.1
[
M+H]+.
Note: The crude products were sufficiently pure to use for diazo transfer but contained some
unreacted methyl sulfone 7b‐7h. Purification by careful column chromatography was
necessary to separate the closely eluting products in order to obtain an analytically clean
sample.
1‐Phenylsulfonyl‐5‐phenylpentan‐2‐one 9a. n‐Butyllithium (1.6 M solution in hexanes;
46.0mL, 0.0740 mol), was added dropwise to a solution of methyl phenyl sulfone (5.62 g,
0.0360 mol) in THF (230 ml) while stirring at 0 °C. The resulting cloudy yellow solution was
stirred for 1.5 h at 0 °C then a solution of ethyl 4‐phenylbutanoate 8 (7.00 g, 0.0360 mol) in
THF (20 mL) was added dropwise over 15 min producing a light orange solution. The reaction
mixture was stirred overnight and then was quenched with saturated ammonium chloride
solution (75 mL). The organic layer was isolated and the aqueous layer washed with diethyl
ether (3  50 mL). The organic layers were combined and washed with brine (50 mL), dried
with magnesium sulfate, filtered and concentrated under reduced pressure to give the crude
β‐keto sulfone 9a as a sticky yellow solid. Purification by careful column chromatography,
employing 20% ethyl acetate in hexane as eluent, gave the pure β‐keto sulfone 9a (4.46 g,
35
4
1%) as a white solid, Rf = 0.39 (40:60 ethyl acetate/hexane); mp 80–81 °C (lit., 79–80 °C);
ν
max(KBr)/cm−1 1718 (C=O), 1319, 1150 (SO
2
); δ (300 MHz) 1.90 [2H, apparent qu, J 7.4,
H
1
9

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2 2
C(4)H ], 2.61 [2H, t, J 7.5, C(5)H ], 2.71 [2H, t, J 7.2, C(3)H
2 2
], 4.11 [1H, s, C(1)H ], 7.13–7.32
(5H, m, aromatic H of phenyl group), 7.54–7.60 (2H, m, aromatic H of phenylsulfonyl group),
7
.65–7.71 (1H, m, aromatic H of phenylsulfonyl group), 7.85–7.88 (2H, m, aromatic H of
(75.5 MHz) 24.6 (CH , C(4)H ), 34.6 (CH , C(5)H ), 43.5 (CH , C(3)H ),
), 126.0 (CH, aromatic C), 127.2 (CH, aromatic CH), 128.2 (CH, aromatic CH),
28.4 (CH, aromatic CH), 129.3 (CH, aromatic CH), 134.2 (CH, aromatic CH), 138.9 (C, aromatic
phenylsulfonyl group); δ
C
2
2
2
2
2
2
66.0 (CH
2
, C(1)H
2
1
C), 141.2 (C, aromatic C), 197.9 (C, CO). Spectral characteristics were consistent with
previously reported data.35
1
‐[(4‐Fluorophenyl)sulfonyl]‐5‐phenylpentan‐2‐one 9b. 1‐Fluoro‐4‐(methylsulfonyl)benzene
b (2.28 g, 0.0131 mol), n‐butyllithium (2.5 M solution in hexanes; 10.47mL, 0.0262 mol),
7
ethyl 4‐phenylbutanoate 8 (2.52 g, 0.0131 mol) and THF (185 mL) were used following the
procedure described for 9a to give the crude β‐ keto sulfone 9b as a red oil. Purification by
careful column chromatography, employing 20% ethyl acetate in hexane as eluent, gave the
pure β‐keto sulfone 9b (1.83 g, 44%) as a white solid, Rf = 0.20 (20:80 ethyl acetate/hexane);
−
1
mp 98–100 °C; νmax(neat)/cm 1716 (C=O), 1321, 1145 (SO
qu, J 7.4, C(4)H ], 2.62 [2H, t, J 7.5, C(5)H ], 2.70 [2H, t, J 7.2, C(3)H
.33 (7H, m, aromatic H 5 x phenyl and 2 x 4‐fluorophenyl group), 7.86–7.92 (2H, m, aromatic
H of 4‐fluorophenyl group); δ (376.5 MHz) ‐102.2 (1F, s, p‐F); δ (100.6 MHz) 24.6 [CH
C(4)H ], 34.7 [CH , C(5)H ], 43.6 [CH , C(3)H ], 66.8 [CH , C(1)H
], 116.7 (CH, d, 2JCF, 22.8,
aromatic CH), 126.2 (CH, aromatic CH), 128.46 (CH, aromatic CH), 128.49 (CH, aromatic CH),
2
); δ
H
(400 MHz) 1.91 [2H, apparent
2
2
2
], 4.10 [1H, s, C(1)H ], 7.11–
2
7
F
C
2
,
2
2
2
2
2
2
2
1
1
C
31.4 (CH, d, 3JCF 9.7, aromatic CH), 134.7 (C, d, 4JCF, 3.1, aromatic C), 141.1 (C, aromatic C),
66.2 (C, 1JCF 257.5, aromatic CF), 197.9 (C, CO); HRMS (ESI): Exact mass calculated for
‐
‐
17
H
16FO S [M‐H] , 319.0804. Found 319.0803. m/z (ESI‐): 319.1 [M‐H] .
3
2
0

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1
‐(Naphthalen‐2‐ylsulfonyl)‐5‐phenylpentan‐2‐one 9c. n‐Butyllithium (2.5 M solution in
hexanes; 11.64 mL, 0.0291 mol) was added dropwise to a stirring solution of freshly distilled
diisopropylamine (4.28 mL, 0.0305 mol) in THF (25 mL) at 0 °C. 2‐(Methylsulfonyl)naphthalene
7c (3.00 g, 0.0146 mol) in THF (85 mL) was added dropwise to this solution over 5 min and the
resulting cloudy orange solution was stirred for 1.5 h at 0 °C. To this solution ethyl 4‐
phenylbutanoate 8 (2.80 g, 0.0146mol) in THF (15 mL) was added dropwise over 15 min
producing a light orange solution. The reaction mixture was stirred overnight and then was
quenched with saturated ammonium chloride solution (75 mL). The organic layer was isolated
and the aqueous layer washed with diethyl ether (3 x 50 mL). The organic layers were
combined and washed with brine (50 mL), dried with magnesium sulfate, filtered and
concentrated under reduced pressure to give the crude β‐keto sulfone 9c as an orange solid.
Purification by careful column chromatography, employing 20% ethyl acetate in hexane as
eluent, gave the pure β‐keto sulfone 9c (2.72 g, 53%) as a white solid, Rf = 0.14 (20:80 ethyl
acetate/hexane); mp 121–123 °C; (Found C, 71.54; H, 5.73. C21
H
20
O
3
S requires C, 71.57; H,
(300 MHz) 1.89 [2H, apparent qu, J
], 2.72 [2H, t, J 7.2, C(3)H ], 4.18 [2H, s, C(1)H ], 7.08–7.31
5
.72%); νmax(neat)/cm−1 1720 (C=O), 1301, 1149 (SO
.4, C(4)H ], 2.59 [2H, t, J 7.6, C(5)H
2
); δ
H
7
2
2
2
2
(
5H, m, 5 x aromatic H of phenyl group), 7.57–7.75 (2H, m, 2 x aromatic H of 2‐naphthyl
group), 7.82 (1H, dd, J 8.7, 1.9, aromatic H of 2‐naphthyl group), 7.89–8.04 (3H, m, 3 x
aromatic H of 2‐naphthyl group), 8.45 (1H, d, J 1.5, aromatic H of 2‐naphthyl group); δ (100.6
MHz) 24.7 [CH , C(4)H ], 34.7 [CH , C(5)H ], 43.7 [CH , C(3)H ], 67.0 [CH , C(1)H ], 122.6 (CH,
aromatic CH), 126.1 (CH, aromatic CH), 127.9 (CH, aromatic CH), 128.1 (CH, aromatic CH),
28.4 (CH, aromatic CH), 129.59 (CH, aromatic CH), 129.62 (CH, aromatic CH), 129.7 (CH,
aromatic CH), 130.3 (CH, aromatic CH), 132.1 (C, aromatic C), 135.6 (C, aromatic C), 135.7 (C,
C
2
2
2
2
2
2
2
2
1
2
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aromatic C), 141.2 (C, aromatic C), 197.9 (C, CO); HRMS (ESI+): Exact mass calculated for
+
+
C
21
H
21
O S [M+H] , 353.1211. Found 353.1227. m/z (ESI+): 353.1 [M+H] .
3
1
‐(Naphthalen‐1‐ylsulfonyl)‐5‐phenylpentan‐2‐one 9d. 1‐(Methylsulfonyl)naphthalene 7d
(2.25 g, 0.0109 mol), n‐butyllithium (2.5 M solution in hexanes; 8.75 mL, 0.0219mol), ethyl 4‐
phenylbutanoate 8 (2.10 g, 0.0109 mol) and THF (185 mL) were used following the procedure
described for 9a to give the crude β‐keto sulfone 9d as a brown oil. Purification by careful
column chromatography, employing 20% ethyl acetate in hexane as eluent, gave the pure β‐
keto sulfone 9d (2.15 g, 56%) as a white solid, Rf = 0.21 (20:80 ethyl acetate/hexane); mp 93–
9
5 °C; (Found C, 71.41; H, 5.65. C21
C=O), 1309, 1124 (SO ); δ (400 MHz) 1.87 [2H, apparent qu, J 7.4, C(4)H
], 2.70 [2H, t, J 7.1, C(3)H ], 4.28 [2H, s, C(1)H ], 7.04–7.31 (5H, m, 5 x aromatic H of
H
20
O
3
S requires C, 71.57; H, 5.72%); νmax(neat)/cm−1 1718
(
2
H
2
], 2.57 [2H, t, J 7.6,
C(5)H
2
2
2
phenyl group), 7.54–7.77 (3H, m, 3 x aromatic H of 1‐naphthyl group), 7.99 (1H, d, J 8.0,
aromatic H of 1‐naphthyl group), 8.16 (1H, d, J 8.1, aromatic H of 1‐naphthyl group), 8.25 (1H,
d, J 7.3, aromatic H of 1‐naphthyl group), 8.68 (1H, d, J 8.6, aromatic H of 1‐naphthyl group);
δ
C
(100.6 MHz) 24.6[CH
2 2
, C(4)H ], 34.7 [CH
2
, C(5)H
2
], 43.9 [CH
2 2 2 2
, C(3)H ], 66.4 [CH , C(1)H ],
123.6 (CH, aromatic CH), 124.4 (CH, aromatic CH) 126.1(CH, aromatic CH), 127.2 (CH, aromatic
CH), 128.4 (CH, aromatic CH), 128.6 (C, aromatic C), 129.2 (CH, aromatic CH), 129.6 (CH,
aromatic CH), 131.1 (CH, aromatic CH), 133.7 (C, aromatic C), 134.2 (C, aromatic C), 135.9 (CH,
aromatic CH), 141.2 (C, aromatic C), 197.6 (C, CO); HRMS (ESI+): Exact mass calculated for
+
+
C
21
H
21
O S [M+H] , 353.1211. Found 353.1202. m/z (ESI+): 353.1 [M+H] .
3
1
‐(Mesitylsulfonyl)‐5‐phenylpentan‐2‐one 9e. n‐Butyllithium (2.5 M solution in hexanes;
.05 mL, 0.0201 mol), freshly distilled diisopropylamine (2.96 mL, 0.0211 mol), mesityl methyl
sulfone 7e (2.00 g, 0.0101 mol), ethyl 4‐phenylbutanoate 8 (1.93 g, 0.0101mol) and THF (135
8
2
2

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mL) were added following the procedure described for 9c to give the crude β‐keto sulfone 9e
as an orange solid. Purification by careful column chromatography, employing 20% ethyl
acetate in hexane as eluent, gave the pure β‐keto sulfone 9e (1.65 g, 48%) as a white solid, Rf
=
0.40 (20:80 ethyl acetate/hexane); mp 78–80 °C; (Found C, 70.06; H, 7.07. C20
C, 69.74; H, 7.02%); νmax(neat)/cm−1 1717 (C=O), 1311, 1133 (SO
); δ (300 MHz) 1.90 [2H,
), 2.57–2.65 [8H, m, C(5)H contains s at δ2.16 for
], 6.97 (2H, s, aromatic H of mesityl
H
24
O
3
S requires
2
H
apparent qu, J 7.4, C(4)H
2
], 2.31 (3H, s, CH
3
2
2
3
2
x CH ], 2.73 [2H, t, J 7.2, C(3)H ], 4.09 [2H, s, C(1)H
2
group), 7.11–7.23 (3H, m, aromatic H of phenyl group), 7.23–7.32 (2H, m, aromatic H of
phenyl group); δ (100.6 MHz) 21.1 (CH , p‐CH ), 22.8 (CH , 2 x o‐CH ), 24.7 [CH , C(4)H ], 34.7
], 44.0 [CH , C(3)H ], 66.9 [CH , C(1)H ], 126.1 (CH, aromatic CH of phenyl group),
28.5 (CH, aromatic CH of phenyl group), 132.4 (CH, aromatic CH of mesityl group), 140.1 (C,
C
3
3
3
3
2
2
[
CH
2
, C(5)H
2
2
2
2
2
1
aromatic C), 141.3 (C, aromatic C), 144.0 (C, aromatic C), 198.2 (C, CO); HRMS (ESI+): Exact
+
+
mass calculated for C20
H
25
O S [M+H] , 345.1520. Found 345.1524. m/z (ESI+): 345.2 [M+H] .
3
1
‐[(2‐Ethylphenyl)sulfonyl]‐5‐phenylpentan‐2‐one 9f. 1‐Ethyl‐2‐(methylsulfonyl)benzene 7f
(2.16 g, 0.0117 mol), n‐butyllithium (2.5 M solution in hexanes; 4.68 mL, 0.0234 mol), ethyl 4‐
phenylbutanoate 8 (2.25 g, 0.0117 mol) and THF (115 mL) were used following the procedure
described for 9a to give the crude β‐keto sulfone 9f as a brown oil. Purification by careful
column chromatography, employing 20% ethyl acetate in hexane as eluent, gave the pure β‐
keto sulfone 9f (1.48 g, 38%) as a white solid, Rf = 0.14 (20:80 ethyl acetate/hexane); mp 59–
−
1
6
2 °C; (Found C, 69.17; H, 6.71. C19
C=O), 1303, 1148 (SO ); δ (300 MHz) 1.33 (3H, t, J 7.5, CH
.60 [2H, t, J 7.6, C(5)H ], 2.72 [2H, t, J 7.2, C(3)H ], 3.04 (2H, q, J 7.5, CH
], 7.11–7.23 (3H, m, aromatic H of phenyl group), 7.24–7.46 (4H, m, aromatic H of 2 x
phenyl group and 2 x 2‐ethylphenyl group), 7.59 (1H, dt, J 7.6, 1.4, aromatic H of 2‐ethylphenyl
22
H O
3
S requires C, 69.06; H, 6.71%); νmax(neat)/cm 1716
CH ), 1.88 [2H, qu, J 7.5, C(4)H ],
CH ), 4.13 [2H, s,
(
2
H
2
3
2
2
2
2
2
3
C(1)H
2
2
3

Organic & Biomolecular Chemistry
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group), 7.91 (1H, dd, J 8.0, 1.3, aromatic H of 2‐ethylphenyl group); δ
C
(75.5 MHz) 15.9 (CH
, C(3)H ], 67.1 [CH
], 126.1 (CH, aromatic CH), 126.6 (CH, aromatic CH), 128.5 (CH, aromatic CH), 130.3 (CH,
3
),
24.7 [CH
2 2
, C(4)H ], 26.1 (CH
2
, CH
2
CH
3
), 34.7 [CH
2 2
, C(5)H ], 43.7 [CH
2
2
2
,
C(1)H
2
aromatic CH), 131.2 (CH, aromatic CH), 134.4 (CH, aromatic CH), 136.6 (C, aromatic C), 141.2
(C, aromatic C), 144.5 (C, aromatic C), 197.8 (C, CO); HRMS (ESI+): Exact mass calculated for
+
+
C
19
H
23
O S [M+H] , 331.1368. Found 331.1366. m/z (ESI+): 331.1 [M+H] .
3
1
‐[(4‐Methoxyphenyl)sulfonyl]‐5‐phenylpentan‐2‐one
9g.
1‐Methoxy‐4‐
(
methylsulfonyl)benzene 9g (4.00 g, 0.0215 mol), n‐butyllithium (1.75 M solution in hexanes;
4.55 mL, 0.0430 mol), ethyl 4‐phenylbutanoate 8 (4.13 g, 0.0215 mol) and THF (115 mL) were
2
used following the procedure described for 9a to give the crude β‐keto sulfone 9g as an
orange oil. Purification by careful column chromatography, employing 20% ethyl acetate in
hexane as eluent, gave the pure β‐keto sulfone 9g (2.10 g, 29%) as a white solid, Rf = 0.09
−
1
(
20:80 ethyl acetate/hexane); mp 65–67 °C; νmax(neat)/cm 1714 (C=O), 1299, 1148 (SO
300 MHz) 1.90 [2H, apparent qu, J 7.4, C(4)H ], 2.61 [2H, t, J 7.6, C(5)H ], 2.71 [2H, t, J 7.2,
], 3.88 (3H, s, OCH ), 4.08 [2H, s, C(1)H ], 6.97–7.04 (2H, m, aromatic H of 4‐
methoxyphenyl group), 7.12–7.33 (5H, m, aromatic H of phenyl group), 7.73–7.81 (2H, m,
aromatic H of 4‐methoxyphenyl group); δ (75.5 MHz) 24.7 [CH , C(4)H ], 34.7 [CH , C(5)H ],
3.6 [CH , C(3)H ], 55.7 (CH , OCH ), 67.2 [CH , C(1)H ], 114.5 (CH, aromatic CH), 126.1 (CH,
aromatic CH), 128.5 (CH, aromatic CH), 130.2 (C, aromatic C), 130.6 (CH, aromatic CH), 141.2
2
); δ
H
(
2
2
C(3)H
2
3
2
C
2
2
2
2
4
2
2
3
3
2
2
(
3
C, aromatic C), 164.2 (C, aromatic COCH ), 198.3 (C, CO); HRMS (ESI+): Exact mass calculated
+
+
for C18
21
H O
4
S [M+H] , 333.1161. Found 333.1157. m/z (ESI+): 333.1 [M+H] .
2
4

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DOI: 10.1039/C7OB00214A
1
‐(Cyclohexylsulfonyl)‐5‐phenylpentan‐2‐ol 24. n‐Butyllithium (2.5 M solution in hexanes;
0.25 mL, 0.63 mmol) was added to a solution of (methylsulfonyl)cyclohexane 7h (0.10 g, 0.62
mmol) in dry tetrahydrofuran (10 mL) while stirring at −78 °C. The resultant mixture was
stirred for 20 min at −78 °C followed by the addiꢀon of 4‐phenylbutanal 8 (0.14 g, 0.93 mmol)
in dry tetrahydrofuran (2 mL) dropwise over 1 h while stirring at −78 °C. Sꢀrring was conꢀnued
for 4 h while the solution was warmed to room temperature, then the reaction mixture was
diluted with ether (10 mL) and quenched with saturated ammonium chloride solution (15
mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate, filtered
and concentrated to give the crude β‐hydroxysulfone 24 as an oil. Purification by column
chromatography, employing 20% ethyl acetate in hexane as eluent, gave the pure β‐
hydroxysulfone 24 (0.03 g, 27%) as a white solid, Rf = 0.16 (20:80 ethyl acetate/hexane); mp
−
1
7
4–76 °C; (Found C, 65.80; H, 8.20 C17
H
26
O
3
S requires C, 65.77; H, 8.44%); νmax(neat)/cm 3493
); δ (400 MHz) 1.10–2.25 [14H, m, C(3)H , C(4)H and
], 2.65 [2H, t, J 7.4, C(5)H ], 2.86–2.98 [2H, m, cyclohexyl CH and 1 x C(1)H ],
.00–3.10 [1H, m, 1 x C(1)H ], 3.27 (1H, bs, OH), 4.25–4.42 [1H, m, C(2)H], 7.12–7.22 (3H, m,
x aromatic H), 7.24–7.32 (2H, m, 2 x aromatic H); δ (100.6 MHz) 24.6 (CH , CH ), 25.00 (CH
), 25.04 (CH , CH ), 25.2 (CH , CH ), 26.9 (CH , CH ), 35.5 [CH , C(5)H ], 36.2 (CH , CH
5.4 [CH , C(1)H ], 62.3 (CH, cylcohexyl CH), 65.6 [CH, C(2)H], 125.9 (CH, aromatic CH), 128.41
CH, aromatic CH), 128.43 (CH, aromatic CH), 141.8 (C, CO); HRMS (ESI+): Exact mass
(OH), 2930, 2850 (CH), 1299, 1124 (SO
2
H
2
2
5
3
3
x cyclohexyl CH
2
2
2
2
C
2
2
2
,
CH
2
2
2
2
2
2
2
2
2
2
2
),
5
2
2
(
+
+
calculated for C17
H
27
O S [M+H] , 311.1681. Found 311.1671. m/z (ESI+): 311.2 [M+H] .
3
1
‐(Cyclohexylsulfonyl)‐5‐phenylpentan‐2‐one 9h. 1‐(Cyclohexylsulfonyl)‐5‐phenylpentan‐2‐
ol 24 (0.47 g, 0.0015 mol), pyridinium chlorochromate (PCC) (0.59 g, 0.0027 mol) and 4Å
molecular sieves (2.00 g) in dichloromethane (20 mL) were stirred at room temperature for
24 h. The reaction mixture was diluted with ether (60 mL) and filtered through a short plug of
2
5

Organic & Biomolecular Chemistry
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silica gel and the filtrate was concentrated under reduced pressure to give the crude β‐keto
sulfone 9h as a light brown solid. Purification by column chromatography, employing 10%
ethyl acetate in hexane as eluent, gave the pure β‐keto sulfone 9h (0.39 g, 85%) as a white
solid, Rf = 0.20 (20:80 ethyl acetate/hexane); mp 55–57 °C; (Found C, 66.44; H, 7.74. C17
requires C, 66.20; H, 7.84%); νmax(neat)/cm−1 1714 (C=O), 1305, 1121 (SO
); δ (400 MHz)
.13–1.40 (3H, m, 3 x cyclohexyl CH), 1.46–1.61 (2H, m, 2 x cyclohexyl CH), 1.67–1.78 (1H, m,
x cyclohexyl CH), 1.87–2.00 [4H, m, 2 x C(4)H and 2 x cyclohexyl CH], 2.15 (2H, bd, J 12.6, 2
], 2.74 [2H, t, J 7.6, C(3)H ], 3.03–3.15 (1H, m,
], 7.13–7.22 (3H, m, 3 x aromatic H of phenyl group), 7.23–
.32 (2H, m, 2 x aromatic H of phenyl group); δ (100.6 MHz) 24.6 (CH , cyclohexyl CH ), 24.8
), 25.0 (CH , cyclohexyl CH ), 34.7 [CH , C(5)H ],
], 61.4 (CH, cyclohexyl CH), 126.1 (CH, aromatic CH), 128.5
24
H O
3
S
2
H
1
1
2
x cyclohexyl CH), 2.64 [2H, t, J 7.6, C(5)H
2
2
cyclohexyl CH), 3.93 [2H, s, C(1)H
2
7
C
2
2
(CH
2
, cyclohexyl CH
2
), 24.9 (CH
2
, cyclohexyl CH
2
2
2
2
2
4
4.1 [CH , C(3)H ], 60.3 [CH
2
2
2
, C(1)H
2
(CH, aromatic CH), 141.2 (C, aromatic C), 199.5 (C, CO); HRMS (ESI+): Exact mass calculated
+
+
for C17
H
25
O S [M+H] , 309.1524. Found 309.1518. m/z (ESI+): 309.2 [M+H] .
3
1
‐[(4‐Methylphenyl)sulfonyl]‐5‐phenylpentan‐2‐one 9i. n‐Butyllithium (2.5 M solution in
hexanes; 14.08 mL, 0.0352 mol), freshly distilled diisopropylamine (5.22 mL, 0.0369 mol), 4‐
methylsulfonyl)toluene (3.00 g, 0.0176 mol), ethyl 4‐phenylbutanoate 8 (3.38 g, 0.0176mol)
(
and THF (135 mL) were added following the procedure described for 9c to give the crude β‐
keto sulfone 9i as an orange solid. Purification by careful column chromatography, employing
2
0% ethyl acetate in hexane as eluent, gave the pure β‐keto sulfone 9i (3.21 g, 58%) as a white
solid, Rf = 0.62 (40:60 ethyl acetate/hexane); mp 96–98 °C; (Found C, 68.17; H, 6.32. C18
H
20
O S
3
−1
requires C, 68.33; H, 6.37%); νmax(neat)/cm 1715 (C=O), 1319, 1146 (SO
2H, qu, J 7.3, C(4)H ], 2.44 (3H, s, CH ), 2.61 [2H, t, J 7.3, C(5)H ], 2.71 [2H, t, J 7.2, C(3)H
.08 [2H, s, C(1)H ], 7.10–7.22 (3H, m, 3 x aromatic H of phenyl group), 7.23–7.31 (2H, m, 2 x
2
); δ
H
(300 MHz) 1.89
[
2
3
2
2
],
4
2
2
6

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DOI: 10.1039/C7OB00214A
aromatic H of phenyl group), 7.35 (2H, d, J 7.4, aromatic H of 4‐methylphenyl group), 7.73
2H, d, J 8.2, aromatic H of 4‐methylphenyl group); δ (100.6 MHz) 21.7 (CH ), 24.7 [CH
C(4)H ], 34.7 [CH , C(5)H ], 43.6 [CH , C(3)H ], 67.1 [CH , C(1)H ], 126.1 (CH, aromatic CH),
28.3 (CH, aromatic CH) 128.5 (CH, aromatic CH), 130.0 (CH, aromatic CH), 135.8 (C, aromatic
C), 141.2 (C, aromatic C), 145.4 (C, aromatic C), 198.1 (C, CO); HRMS (ESI+): Exact mass
(
C
3
2
,
2
2
2
2
2
2
2
1
+
+
calculated for C18
H
21
O S [M+H] , 317.1211. Found 317.1227. m/z (ESI+): 317.1 [M+H] .
3
1
‐[(4‐Bromophenyl)sulfonyl]‐5‐phenylpentan‐2‐one 9j. n‐Butyllithium (1.6 M solution in
hexanes; 14.8 mL, 0.023 mol), freshly distilled diisopropylamine (3.5 mL, 0.025 mol), 1‐Bromo‐
‐(methylsulfonyl) benzene (2.78 g, 0.0118 mol), ethyl 4‐phenylbutanoate 8 (2.27 g, 0.0360
4
mol) in THF (95 mL) were then added following the procedure described for 9a to give the
crude β‐keto sulfone 9j as an orange sticky solid. Purification by careful column
chromatography, employing 20% ethyl acetate in hexane as eluent, gave the pure β‐keto
sulfone 9j (1.37 g, 30%) as a light yellow solid, Rf = 0.32 (20:80 ethyl acetate : hexane); mp
9
5–99 °C, (Found C, 53.89; H, 4.55. C17
715 (C=O), 1323, 1149 (SO ); δ (300 MHz) 1.91 [2H, apparent qu, J 7.4, C(4)H
], 2.70 [2H, t, J 7.2, C(3)H ], 4.10 [2H, s, C(1)H ], 7.14–7.33 (5H, m, aromatic H of
phenyl group), 7.72 (4H, s, aromatic H of p‐bromophenylsulfonyl group); δ (75.5 MHz) 24.6
CH , C(4)H ], 34.6 [CH , C(5)H ], 43.7 [CH , C(3)H ], 66.6 [CH , C(1)H ], 126.2 (CH, aromatic
H
17BrO
3
S requires C, 53.55; H, 4.49%); νmax(KBr)/cm−1
1
2
H
2
], 2.62 [2H, t,
J 7.6, C(5)H
2
2
2
C
[
2
2
2
2
2
2
2
2
CH), 128.47 (CH, aromatic CH), 128.50 (CH, aromatic CH), 129.8 (C, aromatic CBr), 129.9 (CH,
aromatic CH), 132.7 (CH, aromatic CH), 137.5 (C, aromatic C), 141.9 (C, aromatic C), 197.9 (C,
–
79
81
CO); m/z (ES–) 379.1/381.1 [(M–H) , ( Br : Br, 1 : 1)].
‐(Methylsulfonyl)‐5‐phenylpentan‐2‐one 9k. Dimethyl sulfone (1.94 g, 0.0206 mol), n‐
butyllithium (2.0 M solution in hexanes; 20.6 mL, 0.041 mol), ethyl 4‐phenylbutanoate 8 (3.96
1
2
7

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g, 0.0206 mol) in THF (200 mL) were used following the procedure described for 9a to give,
following purification by column chromatography employing 10% ethyl acetate in hexane as
eluent, the sulfone 9k (2.09 g, 42%) as a white solid, Rf = 0.54 (20:80 ethyl acetate/hexane);
mp 72–75 °C; (Found C, 60.37; H, 6.77. C12
709 (C=O), 1312, 1144 (SO ); δ (400 MHz) 1.96 [2H, apparent qu, J 7.4, C(4)H
J 7.6, C(5)H2], 2.71 [2H, t, J 7.2, C(3)H ], 3.03 (3H, s, CH SO ), 3.97 [2H, s, C(1)H
3H, m, aromatic H), 7.25–7.32 (2H, m, aromatic H); δ (75.5 MHz) 24.5 [CH , C(4)H
CH , C(5)H ], 41.5 (CH , CH SO ), 44.1 [CH , C(3)H ], 64.58 [CH , C(1)H ], 126.2 (CH, aromatic
H
16
O
3
S requires C, 59.97; H, 6.71%); νmax(KBr)/cm−1
], 2.65 [2H, t,
], 7.14– 7.23
], 34.6
1
2
H
2
2
3
2
2
(
[
C
2
2
2
2
3
3
2
2
2
2
2
CH), 128.5 (CH, aromatic CH), 141.0 (C, aromatic C), 199.4 (C, CO); m/z (ES+) 281.0
+
+
[
(M+MeCN) , 10%], 354.4 [(M+H+TFA) , 36%].
1
‐Hydroxy‐1,6‐diphenylhex‐1‐en‐3‐one 9l. Lithium bis(trimethylsilyl)amide [(LiHMDS), 1.0 M
in THF, 2.0 mL, 2.00 mmol] was diluted in freshly distilled tetrahydrofuran (6 mL) and cooled
to −78 °C. A solution of acetophenone (0.22 mL, 1.88 mmol) in tetrahydrofuran (2 mL) was
added dropwise over 4 min. The reaction mixture was stirred at −78 °C for 1 h, then a solution
containing 1‐(1H‐benzo[d][1,2,3]triazol‐1‐yl)‐4‐phenylbutan‐1‐one 12 (0.5 g, 1.88 mmol) in
tetrahydrofuran (2mL) was added in one portion. The reaction mixture was allowed to slowly
warm to room temperature and stirred overnight. The reaction mixture was diluted with
aqueous hydrochloric acid (2.0 M, 20 mL) and stirred for 10 min. The layers were separated
and the aqueous layer was extracted with ether (2 x 50 mL). The combined organic extracts
were washed with brine (20 mL), dried with magnesium sulfate and concentrated to yield a
yellow oil. The resulting oil was redissolved in ether (100 mL), washed with aqueous
hydrochloric acid (2.0 M, 3 x 20 mL), brine (20 mL) and concentrated under reduced pressure
to yield the crude diketone 9l as light yellow oil. Purification by column chromatography
employing 20% ethyl acetate in hexane as the eluent gave the purified diketone 9l (1.61 g,
2
8

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DOI: 10.1039/C7OB00214A
1
3
2%) as a cloudy oil that solidifies upon storage to a white solid. H NMR indicates this exists
predominately as the enol form in CDCl ~4% keto at 4.05ppm [s, C(2)H ]. Rf = 0.54 (20:80
ethyl acetate/hexane); mp 25–27 °C; νmax(neat)/cm 2946 (OH), 1598, 1571 (C=O), 737, 752,
88; δ (400 MHz) 2.02 [2H, apparent qu, J 7.6, C(5)H ], 2.45 [2H, t, J 7.6, C(6)H ], 2.70 [2H, t,
J 7.6, C(4)H ], 6.15 [1H, s, C(2)H], 7.12–7.34 (5H, m, aromatic H), 7.38–7.58 (3H, m, aromatic
H), 7.84–7.90 (2H, m, aromatic H), 16.19 (1H, s, OH); δ (106.6 MHz) 27.3 [CH , C(5)H ], 35.3
CH , C(6)H ], 38.6 [CH , C(3)H ], 96.2 [CH, C(2)H ], 126.1 (CH, aromatic CH), 127.0 (CH,
aromatic CH), 128.45 (CH, aromatic CH), 128.54 (CH, aromatic CH), 128.6 (CH, aromatic CH),
3
2
−1
6
H
2
2
2
C
2
2
[
2
2
2
2
2
132.3 (CH, aromatic CH), 135.0 (C, aromatic C), 141.5 (C, aromatic C), 183.4 (C, COH), 196.9
+
(
C, CO); HRMS (ESI+): Exact mass calculated for C18
H
19
O
2
[M+H] , 267.1373. Found 267.1385.
+
m/z (ESI+): 267.1 [M+H] . Keto peaks seen at δ
H
(400 MHz) 4.05 [2H, s, C(2)H
), 128.4(CH, aromatic CH), 128.5(CH, aromatic CH),
28.6(CH, aromatic CH), 128.7(CH, aromatic CH), 128.8(CH, aromatic CH), 133.2(CH, aromatic
2
]; δ
C
(106.6 MHz)
2
5.0 (CH
2
), 34.9 (CH
2
), 42.6 (CH
2
), 54.0 (CH
2
1
CH), 133.8 (CH, aromatic CH), 136.3 (C, aromatic C), 137.2 (C, aromatic C), 194.0 (C, CO), 204.2
C, CO).
‐(Diphenylphosphoryl)‐5‐phenylpentan‐2‐one 11. n‐Butyllithium (2.5 M solution in
hexanes; 8.07 mL, 0.0210 mol) was added dropwise to solution of
(
1
a
methyl(diphenyl)phosphine oxide (4.50 g, 0.0210 mol) in THF (90 mL) while stirring at −78 °C.
The resulting translucent yellow solution was stirred for 1 h at −78 °C. A solution of ethyl‐4‐
phenylbutanoate 8 (3.00 g, 0.0155 mol) in THF (10 mL) was added dropwise over 15 min
producing a light yellow solution. The reaction mixture was stirred for an hour at −78 °C
followed by a quench with saturated ammonium chloride solution (75 mL). The organic layer
was isolated and the aqueous layer washed with diethyl ether (3  50 mL). The organic layers
were combined and washed with brine (50 mL), dried with magnesium sulfate, filtered and
2
9