Chemoselective aromatic C-H insertion of α-diazo-β-ketoesters catalyzed by dirhodium(II) carboxylates

Article abstract of DOI:10.1021/ol202968z

The ability of α-diazo-β-ketoesters bearing a substituent on the benzylic position to undergo aromatic C-H insertion is described. Good to excellent yields of the aromatic C-H insertion products were observed with Rh₂(tpa)₄ or Rh

Full text of DOI:10.1021/ol202968z

ORGANIC
LETTERS
2012
Vol. 14, No. 1
238–240
Chemoselective Aromatic CꢀH Insertion
of r-Diazo-β-ketoesters Catalyzed by
Dirhodium(II) Carboxylates
†
‡
†
‡
ꢀ
ꢀ
´
Esdrey Rodriguez-Cardenas, Rocıo Sabala, Moises Romero-Ortega, Aurelio Ortiz,
and Horacio F. Olivo*,†
Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa
52242, United States, and Facultad de Ciencias Quimicas, Benemerita Universidad
Autonoma de Puebla, Puebla 72570, Mexico
horacio-olivo@uiowa.edu
Received November 3, 2011
ABSTRACT
The ability of R-diazo-β-ketoesters bearing a substituent on the benzylic position to undergo aromatic CꢀH insertion is described. Good to
excellent yields of the aromatic CꢀH insertion products were observed with Rh2(tpa)4 or Rh2(esp)2 catalysts. This is an attractive strategy to
prepare tetralins carrying a methyl group on the benzylic position, a structural motif found in several types of natural products.
Several families of natural products possess a tetralin
substructure bearing a methyl group on a chiral benzylic
carbon. The aromatic sesquiterpenes (heritol,1 laevigatin,2
calamenenes),3 diterpenes with a serrulatane (seco-pseudo-
terosins,4 erogorgiaenes),5 and those with an amphilectane
skeleton (pseudopterosins,6 helioporins,7 pseudoteroxazoles)8
contain this structural motif. We envisioned a very attractive
strategy to build this tetralin framework by employing our
conjugate addition products (Xc = oxazolidinethione chiral
auxiliary)9 and a Rh(II)-catalyzed aromatic CꢀH insertion of
an acceptor/acceptor carbenoid species.10 This strategy should
be superior to an Ullman reaction because it avoids starting
from an arylhalide.11
Rh(II)-carboxylate and carboxamide catalyzed intra-
molecular C;H insertion reactions of R-diazo carbonyl
compounds have developed into powerful methods for the
construction of carbocycles and heterocycles.12 Remark-
ablyhigh chemoselectivity can be achieved ina broadarray
of carbenoid transformations, such as X;H insertion,
CdC addition, or ylide formation, by simply selecting the
† The University of Iowa.
‡
ꢀ
ꢀ
Benemerita Universidad Autonoma de Puebla.
(1) Miles, D. H.; Lho, D.-S.; de la Cruz, A. A.; Gomez, E. D.; Weeks,
J. A.; Atwood, J. L. J. Org. Chem. 1987, 52, 2930–2932.
(2) Braga de Oliveira, A.; Oliveira, G. G.; Crazza, F.; Braz Filho, R.;
Moreira-Bacha, C. T.; Bauer, L.; Silva, G. A.; de, A. B.; Siqueira,
N. C. S. Tetrahedron Lett. 1978, 30, 2653–2654.
(3) Bordoloi, M.; Shukla, V. S.; Nath, S. C.; Sharma, R. P. Phyto-
chemistry 1989, 28, 2007–2037.
(4) Look, S. A.; Fenical, W. Tetrahedron 1987, 43, 3363–3370.
´ ´
(5) Rodrıguez, A. D.; Ramırez, C. J. Nat. Prod. 2001, 64, 100–102.
(6) Look, S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl.
Acad. Sci. U.S.A. 1986, 83, 6238–6240.
(10) Reviews on Rh(II) chemistry: (a) Doyle, M. P. Chem. Rev. 1986,
86, 919–939. (b) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348–356. (c)
Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263–309. (d) Padwa,
A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1797–1815. (e)
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903.
(f) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (g)
Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061–3071. (h)
Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110,
704–724.
(7) Tanaka, J.-I.; Noboru, O.; Liang, J.; Higa, T. Tetrahedron 1993,
49, 811–822.
ꢀ
´
rez, C.; Rodrıguez, I. I.; Gonzalez, E.
(8) Rodrı
´
guez, A. D.; Ramı
´
Org. Lett. 1999, 1, 527–530.
(11) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427–6431.
(12) Taber, D. F.; Raman, K. J. Am. Chem. Soc. 1983, 105, 5935–
5937.
ꢀ
(9) Sabala, R.; Hernandez-Garcı
´
a, L.; Ortiz, A.; Romero, M.; Olivo,
H. F. Org. Lett. 2010, 12, 4268–4270.
r
10.1021/ol202968z
Published on Web 11/30/2011
2011 American Chemical Society

appropriate dirhodium(II) ligand.13 Cyclization of alipha-
tic R-diazo-β-ketoesters provides highly functionalized
cyclopentane derivatives.14 The efficient intramolecular aro-
matic C;H insertion of R-diazo-β-ketoesters to form an
indene skeleton was originally reported by Taber and Ruckle
using Rh2(OAc)4 as the catalyst.15 The selectivity between
aliphatic and aromatic C;H insertion can also be tuned by
the Rh(II) ligand. The Rh(II) catalyst exhibited an excep-
tionally high order of selectivity for aromatic C;H insertion
over both aliphatic C;H insertion and cyclopropanation
reactions when the bulky triphenylacetate ligand was used.16
In the same manner, a perfluorocarboxamide ligand also
favored aromatic over aliphatic C;H insertion.17 Although
five-membered ring cyclization of Rh(II) carbenoids has been
widely explored, only a few isolated cases have been reported
for the six-membered ring cyclization.18
We decided to investigate the Rh(II) carbenoid aromatic
CꢀH insertion of R-diazo-β-ketoesters 5aꢀf, Scheme 1,
Tables 1 and 2. Ethyl 3-oxo-5-phenylpentanoate (4a) was
obtained from commercial sources. R-Diazo-β-ketoesters
substituted at the benzylic position 5bꢀe were prepared in
two steps starting from the corresponding Michael addition
products of chiral N-enoyl oxazolidinethiones (Scheme 1).9
Displacement of the chiral auxiliary (Xc = oxazolidine-
thione) to yield the corresponding β-ketoesters 4bꢀe was
easily carried out employing known conditions.19 The
β-ketoester 4f was prepared from 3,3-diphenylpropionyl chlo-
ride in two steps according to literature procedures.20 Regitz
diazotransfer reaction of β-ketoester 4aꢀ4f, with DBU and
Table 1. Screening CꢀH Aromatic Insertion of R-Diazo-β-
Ketoester 5a with Rh2(OAc)4
CH2Cl2
(mL)
yield
yield
entrya
temp
timeb
(%) 6a
(%) 7
1
2
3
4
5
6
4
4
0 °C
rt
5 min
12 h
5 min
1 h
traces
traces
traces
20
ꢀ
ꢀ
6
reflux
rt
ꢀ
6
24
32
42
12
20
rt
1 h
6
rt
1 h
20
a Reactions were carried out with 0.5 mmol of compound 5a and
catalytic amount of Rh2(OAc)4. b Time of addition of the R-diazo-β-
ketoester 5a utilizing a mechanical syringe.
p-acetamidobenzensulfonyl azide (p-ABSA),21 afforded the
R-diazo-β-ketoesters 5aꢀ5f in very good to excellent yields.
Initially, the Rh(II)-catalyzed cyclization of simple
R-diazo-β-ketoester 5a was investigated (Table 1). When
diazoketoester 5a was added either rapidly or very slowly
to the catalyst suspended in CH2Cl2, only trace amounts of
thedesired product wereisolatedfromthereactionmixture
(entries 1 and 2). The poor yield did not improve when the
reaction was subjected to higher temperatures (entry 3) or
when toluene was used as solvent. A small amount of
desired product 6a together with dimer 7 was obtained
when the substrate was added over 0.5 to 1 h (entries 4ꢀ6).
Dimer 7 was isolated as an inseparable mixture of threo
and erythro isomers. Increased dilution of the reaction
resulted in larger yields of dimer 7 (entries 5 and 6). Other
catalysts were then screened utilizing the best conditions
found in these experiments (Table 2).22
Scheme 1
Use of the bulky catalyst dirhodium(II) tetra(triphenyl-
acetate), Rh2(tpa)4, gave a similar yield for the aromatic
(22) General procedure for the aromatic C-H insertion. A suspension
of R-diazo-β-ketoester (0.5 mmol) in CH2Cl2 (5 mL) is added via syringe
pump at a rate of 5ꢀ10 mL/h to a stirred suspension of rhodium(II)
catalyst (5 mg) in anhydrous CH2Cl2 (5 mL) at room temperature under
a nitrogen atmosphere. After the addition is complete, the reaction
mixture is stirred for 3 h. The solution is concentrated under reduced
pressure. A sample is analyzed by NMR. Products are purified by silica
gel chromatography eluting with petroleum etherꢀethyl acetate, 98:2.
(23) Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett.
1992, 33, 2709–2712.
(13) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1984, 114, 1874–1876.
(14) (a) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808–4809.
(b) Taber, D. F.; Petty, E. H.; Raman, K. J. Am. Chem. Soc. 1985, 107,
196–199.
(15) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108,
7686–7693.
(16) Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. J. Chem. Soc.,
Chem. Commun. 1992, 1508–1510.
(17) (a) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A. Tetra-
hedron 1993, 49, 5109–5126. (b) Moody, C. J.; Doyle, K. J.; Elliot, M. C.;
Mowlem, T. J. Pure Appl. Chem. 1994, 66, 2107–2110.
(18) Appelbe, R.; Casey, M.; Dunne, A.; Pascarella, E. Tetrahedron
Lett. 2003, 44, 7641–7644.
(24) Espino, C. G.; Williams-Fiori, K.; Kim, M.; Du Bois, J. J. Am.
Chem. Soc. 2004, 126, 15378–15379.
(25) See Supporting Information for spectroscopic data.
(19) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.;
Carroll, K. A.; van Alpen, S. Org. Lett. 2004, 6, 2317–2320.
(20) Schweizer, E. E.; Lee, K.-J. J. Org. Chem. 1982, 47, 2768–2773.
(21) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709–1716.
(26) Taber, D. F.; Ruckle, R. E., Jr. Tetrahedron Lett. 1985, 26, 3059–
3062.
Org. Lett., Vol. 14, No. 1, 2012
239

catalyst. When the 4-methyl aromatic diazo derivative
5c was subjected to Rh(II) catalyzed cyclization (entries
7 and 8), we achieved the same yield as was observed
with the Rh2(tpa)4 catalyst, but a higher yield was
achieved with the Du Bois catalyst. The aliphatic
CꢀH insertion product cyclopentanone 8 was also
observed in slightly smaller amounts when the ethyl
substituted substrate 5d was reacted with the Rh(II)
catalysts (entries 9 and 10).25 A similar cyclopentanone
(methyl ester) was reported by Taber as the only
product when Rh2(OAc)4 was used as the catalyst.26
Interestingly, we only observed and isolated the cy-
clized products 6c and 6e when the corresponding
substrates carrying a methyl and an isopropyl group
on the benzylic position were subjected to these two
catalysts, and no aliphatic insertion product was iso-
lated (entries 7, 8, 11, and 12). These results suggest that
aromatic insertion is preferred over insertion to methyl
or methine hydrogens when employing either Rh2(tpa)4
or Rh2(esp)2 catalysts. An excellent yield of tetralin
6f was obtained when the diphenyl derivative 5f was
subjected to the Rh2(tpa)4 catalyst (entry 13).
In summary, we have shown a valuable chemoselective
Rh(II)-catalyzed CꢀH aromatic insertion reaction. The
reaction involves the insertion of a carbenoid moiety into a
CꢀH aromatic bond, delivering a tetralin possessing a
benzylic stereogenic center. Both Rh2(tpa)4 and Rh2(esp)2
were shown to be superior to a Rh2(OAc)4 catalyst for this
chemoselective reaction. Further studies of this CꢀH
insertion reaction and its applications to the syntheses of
natural products containing this structural motif are cur-
rently underway in our laboratory.
Table 2. Catalyzed Rh(II) Aromatic CꢀH Insertion
R-diazo-
yield
(%)a
entry
β-ketoester
Rh(II)
6
1
2
3
4
5a R1 = H, R2 = H
5a R1 = H, R2 = H
5a R1 = H, R2 = H
5b R1 = CH3,
R2 = H
Rh2(OAc)4
Rh2(tpa)4
Rh2(esp)2
Rh2(OAc)4
6a
6a
6a
6b
20
20
45
10
5
5b R1 = CH3,
R2 = H
Rh2(tpa)4
Rh2(esp)2
Rh2(tpa)4
Rh2(esp)2
Rh2(tpa)4
Rh2(esp)2
Rh2(tpa)4
Rh2(esp)2
6b
6b
6c
6c
58
20
57
80
6
5b R1 = CH3,
R2 = H
7
5c R1 = CH3,
R2 = CH3
5c R1 = CH3,
R2 = CH3
5d R1 = CH2CH3,
R2 = H
5d R1 = CH2CH3,
R2 = H
5e R1 = i-Pr,
R2 = H
5e R1 = i-Pr,
R2 = H
5f R1 = Ph, R2 = H
5f R1 = Ph, R2 = H
8
9
6d,
8
54,
39
10
11
12
6d,
8
60,
40
6e
70
6e
47
13
14
Rh2(tpa)4
Rh2(esp)2
6f
6f
98
56
a Yield of purified product.
insertion product 6a, Table 2 (entry 2).23 An improved
yield of cyclized product 6a was achieved employing Du
Bois’ catalyst bis[rhodium (R,R,R0,R0-tetramethyl-1,3-ben-
zenedipropionic acid)], Rh2(esp)2 (entry 3). This tetra-
carboxylate Rh dimer has proven exceptionally effec-
tive for nitrene insertion of tertiary CꢀH bonds.24
Various substrates possessing a benzylic substit-
uent were submitted to the catalyzed Rh(II) reaction
(entries 4ꢀ14). These three catalysts were also screened
to catalyze the reaction of the methyl substituted diazo
compound 5b (entries 4ꢀ6). The highest yield of the
cyclized product 6b was obtained with the Rh2(tpa)4
Acknowledgment. We thank CONACyT for a predoc-
toral fellowship to E.R.C. (Grant 83731) and Grant
Project 80915 (A.O.).
Supporting Information Available. General procedures
and spectroscopy data for compounds 4aꢀf, 6aꢀf, 7, and
8, and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.
acs.org.
240
Org. Lett., Vol. 14, No. 1, 2012