Copper-catalysed enantioselective intramolecular C-H insertion reactions of α-diazo-β-keto esters and α-diazo-β-keto phosphonates

Article abstract of DOI:10.1016/j.tetlet.2013.03.078

Copper-catalysed intramolecular C-H insertion reactions of α-diazo-β-keto esters and α-diazo-β-keto phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions employing the borate additive sodium tetrakis[3,5-bis

Full text of DOI:10.1016/j.tetlet.2013.03.078

Tetrahedron Letters 54 (2013) 2799–2801
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Tetrahedron Letters
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Copper-catalysed enantioselective intramolecular C–H insertion reactions
of
a
-diazo-b-keto esters and
a
-diazo-b-keto phosphonates
Catherine N. Slattery a, Anita R. Maguire b,
⇑
a Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry, School of Pharmacy and Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper-catalysed intramolecular C–H insertion reactions of
a-diazo-b-keto esters and a-diazo-b-keto
Received 21 January 2013
Revised 7 March 2013
Accepted 13 March 2013
Available online 22 March 2013
phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions
employing the borate additive sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF). Notably,
the first example of asymmetric induction reported to date for intramolecular C–H insertion of an
a-diazo-b-keto phosphonate is also described.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Diazocarbonyl
C–H insertion
Copper catalysis
Bis(oxazoline)
NaBARF
Carbenoid insertion into C–H bonds remains a key synthetic
strategy in organic chemistry for the formation of C–C bonds. The
use of copper catalysts dominated early investigations of C–H
insertions, however, low levels of selectivity were a common fea-
ture of these studies.1 Since the first successful example of carbe-
noid insertion into a C–H bond in the presence of a rhodium
catalyst in 1981,2 rhodium complexes have remained the catalysts
of choice for the vast majority of C–H insertion processes. Great
success has since been achieved for C–H insertion reactions
employing a variety of rhodium(II) carboxylate and carboxamidate
catalysts, providing access to a diverse range of insertion products
with high chemo-, regio- and enantioselectivities commonly
observed.3,4
borate species appears to be the generation of a naked sodium cat-
ion in the reaction medium. This alkali metal cation is believed to
effect complete or partial chloride abstraction from the catalytic
copper complex resulting in alteration of catalyst geometry leading
to higher levels of enantiocontrol.
In order to extend the scope of copper-bis(oxazoline) catalysed
C–H insertions in the presence of NaBARF beyond the use of
a
-diazosulfones, we report herein the enantioselective
copper-catalysed C–H insertions of -diazo-b-keto ester 1 and
diazo-b-keto phosphonate 2 providing -carboalkoxy cyclopenta-
none 3 and -phosphoryl cyclopentanone 4, respectively, (Table 1).
a
a-
a
a
Asymmetric C–H insertion reactions employing a-diazo-b-keto
esters have previously been conducted by both Hashimoto9–11 and
Müller.and Boléa.12 Hashimoto and co-workers examined a range
We have demonstrated that copper-bis(oxazoline) complexes
are highly effective catalysts for C–H insertion reactions of
of a-diazo-b-keto ester substrates in the early 1990s, investigating
a
-diazosulfones.5–8 In this previous work, thiopyran and cyclo-
a large variety of ester alkoxy groups and substituents adjacent to
the C–H insertion site.9–11 Large variations in enantioselectivity
were reported for these rhodium-catalysed cyclisations, ranging
from 24% to 80% ee. Notably, high levels of asymmetric induction
were achieved only for substrates possessing bulky substituents
at the C–H insertion site and the alkoxy ester position. Copper-cat-
alysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-dia-
zo-3-oxo-6-phenylhexanoate (1) were reported by Müller and
Boléa in 2001.12 Reactions in this previous study were carried
out in the presence of various chiral bis(oxazoline) ligands, with
moderate enantioselectivity (51–60% ee) obtained only for inser-
tions employing sterically bulky binaphthyl-derived ligand
structures.
pentanone products were prepared in up to 98% and 91% ee,
respectively, representing the highest levels of enantioselectivity
reported to date for copper-catalysed C–H insertion, and thereby
contributing to the re-emergence of copper compounds as a viable
catalytic option for asymmetric C–H insertion reactions.
In our previous work, the presence of NaBARF {BARF = tetrakis
[3,5-bis(trifluoromethyl)phenyl]borate} in the reaction mixture
was shown to be crucial for achieving insertions with high levels
of enantioselectivity.6–8 The key role of this weakly-coordinating
⇑
Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4901770.
E-mail address: a.maguire@ucc.ie (A.R. Maguire).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.078

2800
C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
Table 1
Copper-catalysed C–H insertion reactions of 2,4-dimethylpentan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl (1-diazo-2-oxo-5-phenylpentyl)phosphonate (2)
O
O
CuCl2, L*, NaBARF
EWG
Ph
EWG
reflux
N2
Ph
1/2
3/4
Entry
Diazocarbonyl
EWG
Solvent
L⁄
Time (h)
Cyclopentanone
Yielda (%)
eeb,c (%)
1
2
3
4
1
1
1
1
1
1
1
2
2
2
2
2
2
2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
CO2CH(i-Pr)2
PO(OMe)2
PO(OMe)2
PO(OMe)2
PO(OMe)2
PO(OMe)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C2H4Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C2H4Cl2
C2H4Cl2
5
6
7
8
9
8
8
5
6
7
8
9
6
6
48
2
2
3
3
3
3
3
3
3
4
4
4
4
4
4
4
89d
93d
48d
53d
82d
––f
––g
77
71
42
64
64
65 (À)
51 (+)
37 (+)
61 (+)
46 (À)
––
2
5
48
72
24
48
72
48
45
110
2
6e
7e
8
––
32 (À)
52 (+)
30 (+)
45 (+)
0
9
10
11
12
13
14e
PO(OMe)2
PO(OMe)2
84
62
46 (+)
28 (+)
4
a
b
c
Isolated yield after flash chromatography.
Enantioselectivity values were determined by chiral HPLC (see Supplementary data for details).
Stereochemical assignments for 3 are in agreement with previously reported data [(+) = (1S,5R), (À) = (1R,5S)];19 stereochemical assignments for 4 were assigned by
analogy to 3 and 2-phenylsulfonyl-3-phenylcyclopentanone,6 [(+) = (2S,3S), (À) = (2R,3R)].
d
Isolated product contained a mixture of keto (major) and enol (minor) tautomers; only the keto form was observed following prolonged product storage. No evidence for
the presence of the product arising from insertion into the alkyl ester moiety of 1 was observed by 1H NMR analysis.
e
No NaBARF present in the reaction mixture.
f
Only starting material (1) was observed in the 1H NMR spectrum of the reaction mixture after reflux for 72 h.
g
A complex mixture of unknown decomposition products was observed in the 1H NMR spectrum of the reaction mixture after reflux for 24 h.
Limited examples exist of asymmetric
pentanone synthesis via C–H insertion. Afonso and co-workers
examined the intramolecular cyclisation of -diazo-(dialkoxyphos-
a-phosphoryl cyclo-
O
O
O
O
N
N
a
N
N
phoryl)acetamides in the presence of various chiral rhodium(II)
catalysts, however poor levels of enantioselectivity were achieved
(640% ee).13 In 2006, Davies and co-workers reported the intermo-
lecular rhodium-catalysed C–H insertions of dimethyl
[diazo(phenyl)methyl]phosphonate and cyclohexa-1,4-diene.14
Good asymmetric induction (92% ee) was possible for this intermo-
lecular reaction in the presence of Rh2(S-PTAD)4, however, inser-
tions with other chiral rhodium catalysts were found to result in
decreased levels of enantiocontrol.
The intramolecular C–H insertion reactions of 2,4-dimethylpen-
tan-3-yl 2-diazo-3-oxo-6-phenylhexanoate (1) and dimethyl
(1-diazo-2-oxo-5-phenylpentyl)phosphonate (2) were carried out
in refluxing dichloromethane in the presence of a copper catalyst
generated in situ from CuCl2 (5 mol %), a bis(oxazoline) ligand
(6 mol %) and NaBARF (6 mol %). Five different chiral bis(oxazoline)
ligands 5–9 (Figure 1) were employed in this study. trans-Cyclo-
pentanones 3 and 4 were the major products of the insertion reac-
tions of 1 and 2, respectively, with minor amounts of by-product
formation also observed in certain cases.
R
R
5
6
: R = (R)-Bn
7: R= (R)-Ph
O
O
O
O
Ph
Ph
N
N
N
N
t-Bu
Ph
t-Bu
Ph
8
9
(S)-
(R,S)-
Figure 1. Bis(oxazoline) ligands.
beginning of this study to confirm the validity of our analytical
method. The enantioselectivity for this reaction (72% ee) was found
to be in the same range as that recorded by Hashimoto et al. (76%
ee).10 Variations in enantioselectivities were recorded for our cop-
per bis(oxazoline) catalysed cyclisations of 1 (37–65% ee). As was
Investigation of the a-diazo-b-keto ester C–H insertion was first
conducted employing, for comparison purposes, the ester substrate
1, used in both Hashimoto’s and Müller’s previous studies.10–12 The
time taken for complete insertion of 2,4-dimethylpentan-3-yl
2-diazo-3-oxo-6-phenylhexanoate (1) was seen to vary (Table 1,
entries 1–5). Cyclisations in the presence of bis(oxazolines) 6–8
were complete after 2 h of reflux, however, reactions employing
ligands 5 and 9 required a reaction time of 48 h. This increased
reaction time did not appear to affect the recorded yields or
enantioselectivity. An attempted insertion reaction of
observed for our previous a
-diazo-b-keto sulfone reactions,7 the
indane-derived bis(oxazoline) 5 was found to provide the highest
level of enantiocontrol (65% ee) (Table 1, entry 1), with the
bis(oxazoline) 8 also providing good asymmetric induction (61%
ee) (Table 1, entry 4). Although only moderate ee was recorded
for the remaining ligands 6, 7 and 9 (Table 1, entries 2, 3 and 5),
these results represent an improvement upon those previously
recorded by Müller for Cu(OTf)2-catalysed C–H insertion of 1, in
which poor levels of enantioselectivity (15–31% ee) were observed
for reactions in the presence of similar bis(oxazoline) catalysts.12 In
particular, a dramatic increase to 65% ee was observed for the cyc-
a-diazo-b-keto ester 1 at room temperature employing ligand 8
provided no product after seven days.
Hashimoto’s rhodium-catalysed insertion of
a-diazo-b-keto
lisation of
a-diazo-b-keto ester 1 with ligand 5 (Table 1, entry 1)
ester 1 in the presence of Rh2(S-PTPA)4 was repeated at the
under our copper catalysis conditions (CuCl2, NaBARF) versus

C. N. Slattery, A. R. Maguire / Tetrahedron Letters 54 (2013) 2799–2801
2801
Müller’s Cu(OTf)2-catalysed reaction employing the same ligand
(31% ee). The enantioselectivities presented in this study for the
C–H insertions of 1 are also comparable to those previously re-
ported by Hashimoto and co-workers for the rhodium-catalysed
reactions of the same substrate,10 in which ees in the range of
53–76% were recorded for cyclisations in the presence of a variety
of chiral rhodium(II) carboxylate catalysts.
Removal of these unwanted products was possible by column
chromatography on silica gel, providing analytically pure
2-dimethoxyphosphoryl cyclopentanone 4 for chiral HPLC analysis.
In conclusion, we have demonstrated that copper bis(oxazoline)
catalysts, in the presence of the borate additive NaBARF, may be
successfully employed in the intramolecular C–H insertion reac-
tions of
a-diazo-b-keto ester 1 and a-diazo-b-keto phosphonate
Reaction of
a
-diazo-b-keto ester 1 with CuCl2 and bis(oxazo-
2. Although moderate enantioselectivities were obtained, these
values represent an improvement upon Müller’s previous results
in the ester series for Cu(OTf)2-catalysed insertion of 1 using sim-
ilar ligand structures.11 In addition, the first example of enantiose-
lectivity (up to 52% ee) reported to date for intramolecular C–H
line) 8 in the absence of NaBARF (Table 1, entry 6) failed to produce
any cyclopentanone product 3 after reflux for 72 h in dichloro-
methane. Attempted C–H insertion of 1 in refluxing dichloroethane
with no NaBARF present (Table 1, entry 7) also resulted in no prod-
uct formation after 24 h, with a complex mixture of unknown
decomposition products instead observed.
insertion of
a-diazo-b-keto phosphonates has been achieved. The
importance of NaBARF in the catalytic complex was once
again6–8 observed, with reactions in the absence of this additive
resulting in no product formation for the reaction of 1 and reduced
asymmetric induction for the insertion of 2.
C–H insertion reactions of
next conducted. As was observed for the reactions of
a-diazo-b-keto phosphonate 2 were
a-diazo-
b-keto ester 1, large variations in reaction times were recorded
for insertion in refluxing dichloromethane, ranging from 45–
110 h (Table 1, entries 8–12). Thus, reactions were slower than
Acknowledgments
those with the comparable a
-diazo-b-keto sulfones,6,7 which were
typically complete after 2 h of reflux. The longer reaction times
observed for the phosphonates may be rationalised by the inferior
electron-withdrawing abilities of the dimethyl phosphonate group
Financial support from the Irish Research Council for Science,
EngineeringandTechnology,andEliLillyisgratefullyacknowledged.
(r r
p = 0.50)15 compared to the phenylsulfonyl moiety ( p = 0.68),15
Supplementary data
which results in a less electrophilic carbene in the phosphonate
series.16,17 Reduction of the reaction time was possible by changing
to a higher boiling point solvent (1,2-dichloroethane) (Table 1,
entry 13), however, interestingly, increasing the reaction tempera-
ture was found to lead to only a modest decrease in enantiocontrol
(Table 1, entry 13 vs entry 9).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013
.03.078.
References and notes
The level of enantioselectivity obtained for the cyclisations of 2
was found to be poor to moderate (0–52% ee). The highest enantio-
control (52% ee) was observed for insertion in the presence of
bis(oxazoline) 6 (Table 1, entry 9). Notably, this result represents,
to the best of our knowledge, the highest level of enantioselectivity
1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
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Commun. 1981, 688.
3. Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681.
4. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704.
5. Flynn, C. J.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R. J. Am. Chem. Soc. 2010,
132, 1184.
6. Slattery, C. N.; Maguire, A. R. Org. Biomol. Chem. 2011, 9, 667.
7. Slattery, C. N.; Clarke, L.-A.; O’Neill, S.; Ring, A.; Ford, A.; Maguire, A. R. Synlett
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8. Slattery, C. N.; Clarke, L.-A.; Ford, A.; Maguire, A. Tetrahedron 2013, 69, 1297–
1301.
reported to date for intramolecular C–H insertion of
phosphonates, and the only example of asymmetric catalysis with
-diazo-b-keto phosphonates in the literature. Low levels of
a-diazo
a
enantioselectivity (30–45% ee) were recorded for reactions with
ligands 5, 7 and 8 (Table 1, entries 8, 10 and 11), while no
asymmetric induction was observed for insertion employing the
tert-butyl-derived ligand 9 (Table 1, entry 12) indicating that this
is an unfavourable catalyst-substrate pairing. Once again, the ab-
sence of NaBARF from the catalytic mixture was found to result
in reduced asymmetric induction (Table 1, entry 14 vs entry 13).
9. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990, 31, 5173.
10. Hashimoto, S.-i.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S. Tetrahedron Lett.
1993, 34, 5109.
11. Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Synlett 1994, 353.
12. Müller, P.; Bolea, C. Molecules 2001, 6, 258.
13. Gois, P. M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal. A: Chem. 2005, 227,
17.
Yields recorded for the C–H insertion reactions of
a-diazo-
b-keto phosphonate 2 were moderate to good, ranging from 42%
to 77%. For all reactions conducted, a minor amount of by-product
formation was observed in the 1H NMR spectra of the crude reac-
tion mixtures. These by-products likely arise in part via Wolff rear-
rangement of the starting material which is a well documented
14. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437.
15. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
16. Corbel, B.; Hernot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron Lett. 1987, 28, 6605.
17. Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798.
18. Dayoub, W.; Diab, Y.; Doutheau, A. Tetrahedron Lett. 2001, 42, 845.
19. Müller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947.
competing reaction for insertions with a
-diazo phosphonates.16,18