Investigation of additive effects in enantioselective copper-catalysed C-H insertion and aromatic addition reactions of α-diazocarbonyl compounds

Article abstract of DOI:10.1055/s-0031-1290598

Significant enhancements in enantioselectivities and reaction efficiencies in asymmetric copper-catalysed C-H insertion and aromatic addition reactions of -diazocarbonyl compounds in the presence of various group I salts are reported. For the first time i

Full text of DOI:10.1055/s-0031-1290598

LETTER
765
Investigation of Additive Effects in Enantioselective Copper-Catalysed C–H
Insertion and Aromatic Addition Reactions of a-Diazocarbonyl Compounds
A
a
dditive Effects
i
n Enantios
t
elective
h
Copper-Ca
t
alysed C–H
r
I
nsertio
i
n of
a
-
n
Diazocarbon
e
yl Compounds N. Slattery,a Leslie-Ann Clarke,a Shane O’Neill,a Aoife Ring,a Alan Ford,a Anita R. Maguire*b
b
Cork, Ireland
Fax +353(21)4274097; E-mail: a.maguire@ucc.ie
Received 4 November 2011
O
O
Abstract: Significant enhancements in enantioselectivities and re-
action efficiencies in asymmetric copper-catalysed C–H insertion
and aromatic addition reactions of a-diazocarbonyl compounds in
the presence of various group I salts are reported. For the first time
in carbenoid chemistry, evidence for the critical role of the metal
cation is described.
O
O
N
N
N
N
Ph
Ph
1
2
Figure 1 Bis(oxazoline) ligands
Key words: diazocarbonyl, copper catalysis, C–H insertion,
Buchner reaction, bis(oxazoline) ligands
(Table 1, entry 1). Addition of NaBARF to the catalytic
mixture was found to result in a dramatic increase in enan-
tiocontrol (Table 1, entry 2), and this high level of asym-
metric induction was largely maintained for reactions
employing NaPF6 as additive (Table 1, entry 3). In con-
trast, no significant enhancement in enantioselectivity
was recorded for reactions in the presence of either
NaBPh4 or NaBF4 (Table 1, entries 4 and 5).
Carbenoid C–H insertion and aromatic addition reactions
of a-diazocarbonyl compounds are very important reac-
tions in organic synthesis for the formation of C–C
bonds.1–4 While traditionally conducted in the presence of
rhodium catalysts, chiral copper systems have also been
shown to be highly effective catalysts for enantioselective
C–H insertion5–7 and Buchner reactions.8,9 We7,8 and
Zhou10,11 have recently demonstrated that the addition of
NaBARF {BARF = tetrakis[3,5-bis(trifluoromethyl)phe-
nyl]borate} to the catalytic complex comprising a copper
source and a bis(oxazoline) ligand results in enhanced re-
action efficiencies and enantioselectivities in X–H inser-
tion reactions. However, to date the mechanistic role of
NaBARF in carbenoid insertion reactions has not been
discussed. Herein we report our findings on the key role
of the additive in enantioselective C–H insertion and aro-
matic addition reactions.
A slight increase in enantioinduction (91% ee) was ob-
served for insertion of 3 with KBARF (Table 1, entry 6)
Table 1 C–H Insertion Reactions of 1-Diazo-1-phenylsulfonyl-5-
phenylpentan-2-one (3)
CuCl2 (5 mol%),
O
1 (6 mol%),
O
additive (6 mol%)
SO2Ph
Ph
SO2Ph
CH2Cl2, reflux
N2
Ph
3
4
Entry
Additive
–
Yield (%)a ee (%)b,c
Two a-diazo sulfones [1-diazo-1-phenylsulfonyl-5-phe-
nylpentan-2-one (3) and methyl 2-diazo-2-(4-phenylbu-
tylsulfonyl)acetate (5)] were chosen for this initial study.
C–H insertion reactions of 3 and 5 were conducted in re-
fluxing dichloromethane in the presence of a copper cata-
lyst generated in situ from 5 mol% CuCl2, 6 mol%
bis(oxazoline) ligand (Figure 1), and 6 mol% additive. In
general, trans-cyclopentanone 4 and cis-thiopyran 6 were
the major products for the insertion reactions of 3 and 5,
respectively.
1
2
3
4
5
6
7
8
9
62
87
66
77
63
59
43
78
63
14
89
83
25
11
91
35
71
25
NaBARF
NaPF6
NaB(C6H5)4
NaBF4
KBARF
KPF6
As was observed in our previous study examining CuCl-
catalysed reactions,7 C–H insertion of a-diazo-b-keto sul-
fone 3 in the presence of CuCl2 and bis(oxazoline) ligand
was seen to result in very low levels of enantioselectivity
LiPF6
NaBARF + 15-crown-5d
a Isolated after flash chromatography.
b Determined by chiral HPLC (see Supporting Information for de-
tails).
SYNLETT 2012, 23, 765–767
Advanced online publication: 28.02.2012
DOI: 10.1055/s-0031-1290598; Art ID: D62911ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
2
c Absolute configuration is 2R,3R.
d 8 mol% 15-crown-5 added to catalytic mixture.

766
C. N. Slattery et al.
LETTER
relative to cyclisation with NaBARF. Notably, this result Insertion reactions with methyl 2-diazo-2-(4-phenylbutyl-
represents the highest level of asymmetric induction re- sulfonyl)acetate (5) were also conducted (Table 2). Al-
corded to date for cyclopentanone synthesis via C–H in- though in this case the enantioselectivity achieved for
sertion. Reactions with the potassium and lithium salts cyclisation in the absence of additives (Table 2, entry 1) is
KPF6 and LiPF6 resulted in decreased levels of enantiose- much higher than the corresponding insertion with a-di-
lectivity relative to reactions employing NaPF6 (Table 1, azo sulfone 3 (Table 1, entry 1), enhancement of asym-
entries 7 and 8 vs. 3).
metric induction is still possible for reactions employing
NaBARF, KBARF, and NaPF6 (Table 2, entries 2, 3, and
6). In this instance, high levels of enantiocontrol were ob-
served for insertions in the presence of KPF6 and NaBF4
(Table 2, entries 5 and 7). This observation is in contrast
with results recorded for insertion with a-diazo-b-keto
sulfone 3 in which a decrease in enantiomeric excess was
noted for insertion in the presence of KPF6 and NaBF4
(Table 1, entry 5 and 7). As was previously noted for cy-
clisation of 3, reduced enantioselectivity was observed for
insertion employing LiPF6 (Table 2, entry 8). Surprising-
ly, use of NaBPh4 as additive resulted in the formation of
very little C–H insertion product, with several competing
side reactions instead observed (Table 2, entry 4).
From the results presented in Table 1, it is evident that the
choice of additive has a significant effect on the level of
enantioselectivity that can be achieved in the C–H inser-
tion reactions of a-diazo sulfone 3. Highest enantiocontrol
was achieved for reactions in the presence of BARF–,
which behaves as a very weakly coordinating anion.12 Re-
–
actions employing less weakly coordinating anions [PF6 ,
–
–
BPh4 , BF4 ] resulted in decreased levels of asymmetric
induction. Thus, as decreased anion coordination appears
to correlate to an increase in enantioselectivity, it is prob-
able that the main role of these additives is to provide a
‘naked’ alkali metal cation in solution which may play a
key role in permitting formation of a highly efficient cat-
alytic complex. It is envisioned that the role of the metal
cation is to effect complete or partial chloride
abstraction13–15 from the copper complex, thereby altering
the active catalyst species. Evidence for this includes iso-
lation of small amounts of sodium chloride which precip-
itate from the reaction mixture.16 More significantly,
when reactions were conducted in the presence of
NaBARF and the crown ether 15-crown-5, which is
known to effectively complex sodium cations, the enanti-
oselectivity decreases substantially, reversing the en-
hancement previously seen for addition of the additive
species (Table 1, entry 9 vs. 2).
Table 3 Buchner Reaction of Diazo Ketones 7a and 7b
O
CuCl (5 mol%),
O
2 (6 mol%),
X
additive (6 mol%),
CH2Cl2, reflux
N2
X
7
a: X = H
b: X = Cl
O
X
8
Table 2 C–H Insertion Reactions of Methyl 2-Diazo-2-(4-phenyl-
butylsulfonyl)acetate (5)
Entry
1
X
Additive
Yield (%)a ee (%)b
CuCl2 (5 mol%),
2 (6 mol%),
O
O
O
O
H
–
31
57
65
55
50
47
49
54
56
47
66
67
37
78
78
80
49
56
0
CO2Me
Ph
S
additive (6 mol%)
S
CO2Me
2
H
NaBARFc
Ph
CH2Cl2, reflux
N2
5
6
3
H
NaPF6
Yielda (%)
ee (%)b,c
79
4
H
KBARF
Entry
Additive
–
5
H
LiPF6
1
2
3
4
5
6
7
8
48
61
68
4
6
H
NaBARF + 15-crown-5d
NaBARF
NaPF6
95
7
Cl
Cl
Cl
Cl
Cl
Cl
–
97
8
NaBARFc
NaPF6
78
73
71
54
45
d
NaB(C6H5)4
NaBF4
KBARF
KPF6
–
9
43
46
45
47
93
98
92
83
10
11
12
KBARF
LiPF6
NaBARF + 15-crown-5d
LiPF6
a Isolated after flash chromatography.
a Isolated after flash chromatography.
b Determined by chiral shift 1H NMR experiments using
(+)-Eu(Hfc)3.
b Determined by chiral HPLC (see Supporting Information for de-
tails).
c Previously published results.8,
c Absolute configuration is 2S,3S.
d Not determined.
d 8 mol% 15-crown-5 added to catalytic mixture.
Synlett 2012, 23, 765–767
© Thieme Stuttgart · New York

LETTER
Additive Effects in Enantioselective Copper-Catalysed C–H Insertion of a-Diazocarbonyl Compounds
767
Enhancement of enantioselectivity in the presence of
NaBARF has also been observed in copper-catalysed
Buchner reactions of a-diazo ketones.8 As summarised in
Table 3, alteration of the counterion has a significant ef-
fect on asymmetric induction in the intramolecular aro-
matic addition reactions of diazo ketones 7a and 7b. In the
absence of the sodium cation, little or no enantioselectiv-
ity is achieved using CuCl and bis(oxazoline) ligand 1
(Table 3, entries 1 and 7), while addition of NaBARF,
KBARF, or NaPF6 to the catalytic mixture results in good
enantioselectivity in each case (Table 3, entries 2–4 and
8–10). As was previously observed for the C–H insertion
reactions of 3, use of LiPF6 as an additive is less effective
than NaPF6 in facilitating highly enantioselective reac-
tions (Table 3, entries 5 and 11). Once again, addition of
15-crown-5, together with NaBARF (Table 3, entries 6
and 12) resulted in a substantial decrease in asymmetric
induction in line with results reported for C–H insertion of
a-diazo sulfone 3.
References and Notes
(1) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010,
66, 6681.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
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Wiley-Interscience: New York, 1998.
(3) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev.
2010, 110, 704.
(4) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
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(5) Flynn, C. J.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R.
J. Am. Chem. Soc. 2010, 132, 1184.
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Lett. 2007, 9, 731.
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667.
(8) O’Neill, S.; O’Keeffe, S.; Harrington, F.; Maguire, A. R.
Synlett 2009, 2312.
(9) O’Keeffe, S.; Harrington, F.; Maguire, A. R. Synlett 2007,
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(10) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am.
Chem. Soc. 2007, 129, 5834.
(11) Chen, C.; Zhu, S.-F.; Liu, B.; Wang, L.-X.; Zhou, Q.-L.
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(13) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L.
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In conclusion, we have demonstrated for the first time the
key role of the alkali metal cation in producing highly
enantioenriched products via C–H insertion and aromatic
addition of a-diazocarbonyl compounds. Work is current-
ly under way to further investigate the influence of addi-
tives in copper-catalysed carbenoid transformations.
(15) Krumper, J. R.; Gerisch, M.; Suh, J. M.; Bergman, R. G.;
Tilley, T. D. J. Org. Chem. 2003, 68, 9705.
(16) Presence of NaCl confirmed by PXRD analysis (see
Supporting Information for details).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support from the Irish Research Council for Science, En-
gineering and Technology, Programme for Research in Third Level
Institutions Cycle 4 and Eli Lilly is gratefully acknowledged.
© Thieme Stuttgart · New York
Synlett 2012, 23, 765–767

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