Asymmetric copper-catalysed intramolecular C-H insertion reactions of α-diazo-β-keto sulfones

Article abstract of DOI:10.1039/c0ob00914h

Asymmetric copper-catalysed intramolecular C-H insertion reactions of a series of α-diazo-β-keto sulfones are reported. Enantioselectivities of up to 82% ee were achieved in moderate to good yield. These results represent the highest level of enantiocontr

Full text of DOI:10.1039/c0ob00914h

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Asymmetric copper-catalysed intramolecular C–H insertion reactions of
a-diazo-b-keto sulfones†
Catherine N. Slatterya and Anita R. Maguire*b
Received 21st October 2010, Accepted 15th November 2010
DOI: 10.1039/c0ob00914h
Asymmetric copper-catalysed intramolecular C–H insertion
reactions of a series of a-diazo-b-keto sulfones are reported.
Enantioselectivities of up to 82% ee were achieved in moderate
to good yield. These results represent the highest level
of enantiocontrol achieved to date for a copper-catalysed
cyclopentanone synthesis via C–H insertion.
diazo compounds were synthesized from the corresponding esters
following standard procedures.8–11
C–H insertion reactions of the a-diazo-b-keto sulfones were
conducted in refluxing CH2Cl2 with a copper catalyst generated
in situ from 5 mol% CuCl and 6 mol% ligand. Four chiral
bis(oxazoline) ligands 1–4 (Fig. 1) were examined for their ability
to induce enantioselectivity in the insertion reactions. Exclusive
trans-cyclopentanone formation was recorded in each of the
reactions conducted, however, in some cases, minor amounts of
byproducts were also observed.
C–H insertion reactions of a-diazocarbonyl compounds have
long attracted attention in organic synthesis owing to their
potential in synthesizing chemically complex structures via C–C
bond formation.1–3 While initial studies exploring C–H insertion
processes employed copper catalysts, rhodium(II) complexes have
dominated this field since their introduction in the early 1980s.4
Highly enantioselective diazo decompositions are possible in the
presence of chiral rhodium(II) catalysts, of which rhodium(II)
carboxylates and carboxamidates have found particular success.
In contrast, the application of asymmetric copper catalysts in
C–H insertion reactions has not been widely exploited in recent
times. Limited reports exist, however, the level of enantiocontrol
achieved has been generally moderate, up to a maximum of
60% ee5 for intramolecular C–H insertion and 88% ee6 for the
intermolecular reaction.
Recently, we demonstrated that the copper complex of chiral
bis(oxazoline) ligand 1 is a highly efficient catalyst for asym-
metric intramolecular C–H insertions of a-diazosulfones.7 In
this previous study, cyclic sulfones were prepared in up to 98%
ee, representing the highest enantioselectivity recorded to date
for a copper-catalysed C–H insertion reaction. As part of our
continuing investigations into the employment of chiral copper
complexes in diazocarbonyl chemistry, we report herein our
investigations on the enantioselective C–H insertion reactions of
a-diazo-b-keto sulfones to yield a-sulfonyl cyclopentanones.
Five a-diazo-b-keto sulfones 5–9 were chosen as substrates for
this study permitting examination of the steric and electronic
effects of the group adjacent to the C–H insertion site. The
Fig. 1 Bis(oxazoline) ligands.
Each of the copper complexes of ligands 1–4 catalysed the
desired reaction, generating the cyclopentanone products 10–
14 in moderate yield, with long reaction times typically re-
quired (Table 1, conditions A). The level of enantiocontrol
achieved for these initial reactions was poor, ranging from
0 to 33% ee. The use of NaBARF, {BARF = tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate} which functions as a non-
coordinating counterion, has previously been demonstrated by
us and other research groups to enhance the enantioselectivity of
diazo decomposition reactions.12–15 With these reports in mind,
6 mol% NaBARF was added to the catalytic mixture consisting
of CuCl and bis(oxazoline) ligand, with the objective that the
addition of this borate counterion would provide a similar
beneficial effect on enantiocontrol.
aDepartment of Chemistry and Analytical and Biological Chemistry
Research Facility, University College Cork, Ireland
bDepartment of Chemistry, School of Pharmacy and Analytical and Bi-
ological Chemistry Research Facility, University College Cork, Ireland.
E-mail: a.maguire@ucc.ie; Fax: +353-(0)21-4274097; Tel: +353-21-
4902125
† Electronic supplementary information (ESI) available: General Proce-
dures, characterisation data of the cyclopentanone products 10–14 and
chiral HPLC analysis See DOI: 10.1039/c0ob00914h
This was indeed found to be true; for each of the diazo substrates
examined a significant increase in asymmetric induction was
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Table 1 Copper-catalysed C–H insertion reactions
Time/h
A
Yielda (%)
A
% eeb,c (%)
Entry
a-Diazo-b-keto sulfone
R
Cyclopentanone
L*
B
B
A
B
1
2
3
4
5
6
7
8
5
5
5
5
6
6
6
6
7
7
7
7
8
8
8
8
9
9
9
9
Me
Me
Me
Me
Et
Et
Et
10
10
10
10
11
11
11
11
12
12
12
12
13
13
13
13
14
14
14
14
(R)-1
(R)-2
(R,S)-3
(S)-4
(R)-1
(R)-2
(R,S)-3
(S)-4
(R)-1
(R)-2
(R,S)-3
(S)-4
(R)-1
(R)-2
(R,S)-3
(S)-4
22
40
—
—
24
—
—
—
21
—
21
—
26
24
42
—
24
—
—
—
27
3
21
22
6
15
21
15
4
16
21
24
4
19
22
19
21
6
21
8
72
71
—
—
42
—
—
—
68
—
54
—
42
40
47
—
42
—
—
—
94
62
75
73
97
70
76
73
54
95
43
55
68
62
82
55
57
54
46
62
0
0
—
—
0
—
—
—
0
—
0
—
30 (2S,3R)
58 (2S,3R)
0
14 (2R,3S)
29 (2S,3R)
62 (2S,3R)
11 (2S,3R)
28 (2R,3S)
37 (2S,3S)
60 (2S,3S)
14 (2S,3S)
42(2R,3R)
49 (2S,3S)
82 (2S,3S)
58 (2S,3S)
64 (2R,3R)
28 (2S,3S)
57 (2S,3S)
0
Et
9
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
0
8 (2S,3S)
33 (2S,3S)
Ph
—
Bn
Bn
Bn
Bn
(R)-1
(R)-2
(R,S)-3
(S)-4
5 (2S,3S)
—
—
—
33 (2R,3R)
a Isolated after flash chromatography. b Determined by chiral HPLC (see ESI† for details). c Stereochemical assignments are in agreement with previously
reported data.16
observed for C–H insertion in the presence of NaBARF (Table 1,
conditions B). Ligand 2 was found to be the most enantioselective,
providing cyclopentanone 13 in 62% yield and 82% ee (Table 1,
entry 14).
To the best of our knowledge, this result represents the highest
level of asymmetric induction reported to date for cyclopentanone
synthesis via copper-catalysed C–H insertion, and parallels results
obtained with chiral rhodium(II) carboxylates for the decompo-
sition of a-diazo-b-keto esters, although in this earlier work very
sterically demanding ester substituents were required to achieve
high levels of enantioselection.17,18
As summarized in Fig. 2, a number of interesting trends
can be seen in terms of the enantioselectivity of the copper
complexes derived from each of the bis(oxazoline) ligands. With
Fig. 2 Trends in enantioselectivity for ligands 1–4.
the Ph-substituted ligand 1, relatively consistent enantiocontrol is
observed across the series of a-diazo-b-keto sulfones, typically
around 30% ee, with enhanced enantioselectivity (49% ee) for
insertion into the benzylic C–H bond. The Bn-substituted ligand
2 gives consistently good asymmetric induction in the region
of 60% ee, independent of the nature of the R group at the
insertion site. As was observed for ligand 1, the enantioselectivity
achieved with ligand 2 is increased (82% ee) in the formation
of 13.
In contrast, ligand 3, which features a diphenyl substitution
pattern, was found to proceed with modest enantiocontrol
(58% ee) for only one substrate (13); for each of the other diazo
sulfones, very little enantioselection was observed. With the t-
Bu-substituted ligand 4, a steady increase in enantiocontrol is
noted on increasing the size of the R group adjacent to the C–H
insertion site, indicating an important steric effect with this ligand.
As before, the best results for bis(oxazoline) 4 were achieved in the
synthesis of cyclopentanone 13.
Comparison of the results obtained with ligands 1 and 3
is particularly interesting. With substrates 5, 6, 7 and 9, the
enantiocontrol using ligand 3 is much less than that achieved
using ligand 1. Thus, the conformational impact of the additional
668 | Org. Biomol. Chem., 2011, 9, 667–669
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Ph substituent and the alteration to an unsubstituted methylene
bridge in ligand 3 appears to orient the ligand in a less favorable
position in terms of asymmetric induction than can be achieved
with the more conformationally mobile ligand 1. The only
exception to this pattern is with substrate 8, where 58% ee was
achieved using ligand 3.
In an attempt to improve the enantioselectivity of the decom-
position of 8, the reaction conditions were carefully optimized
using ligands 2 and 3 and NaBARF. A range of copper salts
were examined, including CuCl2, Cu(MeCN)4PF6 and Cu(OTf)2,
however no additional positive effect was detected. A change of
reaction solvent to toluene was found to result in a decrease in
overall enantiocontrol.
The experiments summarized in Table 1 involve pre-generation
of the catalytic species for 1.5 h prior to addition of the diazo
sulfone. A number of experiments were conducted where the
diazo compound and catalytic mixture were added directly to the
reaction flask prior to heating to reflux with significant detrimental
effect on the enantioselectivity, but without a noticeable effect on
reaction efficiency. Interestingly, this is in direct contrast to our
earlier reports on C–H insertion to form cyclic sulfones,7 where
preformed catalysts were not necessary to achieve the excellent
enantiopurities observed.
In conclusion, we have demonstrated that the use of copper
bis(oxazoline) catalysts, in the presence of the non-coordinating
counterion NaBARF, for C–H insertion reactions with a-diazo-
b-keto sulfones leads to enantioenriched cyclopentanones with
up to 82% ee. The results achieved in this study represent, to
the best of our knowledge, the highest enantioselectivity realised
to date in a copper-mediated C–H insertion cyclopentanone
synthesis. Further investigation is underway to explore substrate,
catalyst, ligand and counterion effects, with a view to deter-
mining the mechanism for asymmetric induction and expand-
ing the scope of this powerful enantioselective C–H insertion
process.
Acknowledgements
Financial support from the Irish Research Council for Science,
Engineering and Technology, and Eli Lilly is gratefully acknowl-
edged.
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