Rhodium-catalyzed intramolecular C-H insertion of α-aryl-α- diazo ketones

Article abstract of DOI:10.1021/jo0624694

(Chemical Equation Presented) Direct diazo transfer proceeds smoothly with α-aryl ketones. The derived α-aryl-α-diazo ketones cyclize efficiently with Rh catalysis to give the corresponding α-aryl cyclopentanones.

Full text of DOI:10.1021/jo0624694

Rhodium-Catalyzed Intramolecular C-H Insertion of
r-Aryl-r-diazo Ketones
Douglass F. Taber* and Weiwei Tian
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed December 2, 2006
Direct diazo transfer proceeds smoothly with R-aryl ketones. The derived R-aryl-R-diazo ketones cyclize
efficiently with Rh catalysis to give the corresponding R-aryl cyclopentanones.
SCHEME 1
Introduction
R-Aryl cyclopentanones are a class of useful intermediates
for the synthesis of natural products and for pharmaceutical
applications.1 A number of effective methods have been
developed for the synthesis of R-aryl cyclopentanones, including
the Pd-catalyzed arylation of cyclopentanones,2a the Heck
arylation of enol ethers,2b and epoxide rearrangement.2c,d
It occurred to us that acyclic R-aryl ketones such as 1a
(Scheme 1) could be prepared by convergent coupling. If diazo
transfer and Rh-mediated intramolecular C-H insertion were
efficient, we would have established a new route to R-aryl
cyclopentanones.
SCHEME 2
Results and Discussion
The diazo center has two substituents. They can be both
electron-withdrawing, one electron-withdrawing and one neutral,
or one electron-withdrawing and one electron-donating. With
two electron-withdrawing substituents, the intermediate car-
benoid formed is highly electrophilic and so potentially not
highly selective. With one electron-withdrawing and one
electron-donating substituent, the intermediate carbenoid is
stabilized and so is more likely to be selective. The first
examples of intermolecular C-H insertion with this class of
carbenoids were reported by Davies in 1997.7,8
R-Diazo carbonyl compounds are ideal substrates for generat-
ing carbenes,3 by reaction of the diazo precursors with transition-
metal catalysts.4 Dirhodium catalysts, in particular, can direct
highly chemo-, regio-, and stereoselective reactions.5 Selectivity
is determined not only by the nature of the catalyst but also by
the steric demand and electronic characteristics of the diazo
precursors.6
(1) For leading references to R-aryl cyclopentanones in target-directed
synthesis, see: (a) Takano, S.; Inomata, K.; Sato, T.; Takahashi, M.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1990, 290. (b) Srikrishna,
A.; Reddy, T. Tetrahedron 1998, 54, 8133. (c) Kita, Y.; Furukawa, A.;
Futamura, J.; Higuchi, K.; Ueda, K.; Fujioka, H. Tetrahedron Lett. 2000,
41, 2133. (d) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.;
Fujioka, H. J. Org. Chem. 2003, 68, 5917. (e) Thede, K.; Diedrichs, N.;
Ragot, J. P. Org. Lett. 2004, 6, 4595. (f) Kuethe, J. T.; Marcoux, J.-F.;
Wong, A.; Wu, J.; Hillier, M. C.; Dormer, P. G.; Davies, I. W.; Hughes,
D. L. J. Org. Chem. 2006, 71, 7378. (g) Finke, P. E.; Meurer, L. C.; Levorse,
D. A.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao,
K.-L.; Chicchi, G. G.; Metzger, J. M.; MacIntyre, D. E. Biorg. Med. Chem.
Lett. 2006, 16, 4497.
The extension to intramolecular C-H insertion, using an all
sp3-hybridized tether, seemed to be straightforward and, in fact,
had been attempted (Scheme 2),9 but it had been reported not
(2) (a) Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1261. (b) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem.
Soc. 2003, 125, 3430. (c) Shen, Y.; Wang, B.; Shi, Y. Angew. Chem., Int.
Ed. 2006, 45, 1429. (d) Gora, M.; Luczynski, M. K.; Sepiol, J. J. Synthesis
2005, 10, 1625.
(3) (a) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765. (b) Miller,
D. J.; Moody, C. J. Tetrahedron 1995, 51, 10881.
10.1021/jo0624694 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/27/2007
J. Org. Chem. 2007, 72, 3207-3210
3207

Taber and Tian
TABLE 1. Preparation of the r-Aryl Ketones
a Previously reported (ref 12).
to proceed. In contrast to this conclusion, we now report that
intramolecular C-H insertion of R-aryl-R-diazo ketones is a
useful and efficient process.
approaches, different substitution patterns on the arene and
different C-H insertion sites were easily accessible.
Diazo-Transfer Reaction. There were several procedures
available for the diazo-transfer reaction.9,13 Although mesyl
azide13b with DBU worked well for ketone 1c (entry 1,
Table 2), these conditions gave poor yields with ketone 1e
(entry 2). 4-Nitrobenzenesulfonyl azide (PNBSA)14 gave a
similar yield (entry 3). Since the only difference between 1c
and 1e was the different substituent on the benzene ring, it was
apparent that the electron-donating group on the para position
of the aromatic ring made the R-position of the ketone less
reactive. This was in contrast to diazo transfer on a range of
arylacetic esters.15 To solve this problem, we screened several
diazo-transfer reagents along with different solvents (Table 2).
We found that exactly 1.0 equiv of 2,4,6-triisopropylbenzene-
sulfonyl azide (TIBSA)13c in toluene gave the best yield.
Preparation of the R-Aryl Ketones. This approach to R-aryl
cyclopentanones was particularly attractive because the requisite
R-aryl ketones10 could be prepared by convergent coupling of
Grignard reagents with epoxides (Table 1). PCC-catalyzed
oxidation11 efficiently converted the alcohols so formed to the
desired ketones. Epoxide 4c was prepared by coupling of allyl
bromide with (4-bromophenyl)magnesium bromide followed by
bromohydrin formation and exposure to base. Alternatively, aryl
Grignard reagents could be used to open the commercially
available epoxides 4a, 4b, and 4d. By these two complementary
(4) (a) Doyle, M. P. Chem. ReV. 1986, 86, 919. (b) Doyle, M. P.; Forbes,
D. C. Chem. ReV. 1998, 98, 911. (c) Boche, G.; Lohrenz, J. C. W. Chem.
ReV. 2001, 101, 697.
(5) (a) Davies, H. M. L. In ComprehensiVe Organic Synthesis: SelectiVity
Strategy and Efficiency in Modern Organic Chemistry; Pergamon: Oxford,
1991; Vol. 4, p 1031. (b) Taber, D. F. In ComprehensiVe Organic
Synthesis: SelectiVity Strategy and Efficiency in Modern Organic Chemistry;
Pergamon: Oxford, 1991; Vol. 3, p 1045. (c) Padwa, A.; Krumpe, K. E.
Tetrahedron 1992, 48, 5385. (d) Ye, T.; McKervey, M. A. Chem. ReV.
1994, 94, 1091. (e) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: from
Cyclopropanes to Ylides; Wiley: New York, 1998.
(6) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 8, 1137.
(7) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(8) For recent reviews, see: (a) Davies, H. M. L.; Beckwith, R. E. J.
Chem. ReV. 2003, 103, 2861. (b) Davies, H. M. L.; Nikolai, J. Org. Biomol.
Chem. 2005, 3, 4176.
(9) For the cyclization of R-diazo-R-aryl ketones with an alkene tether
between the ketone and the target C-H, see: (a) Ferna´ndez-Mateos, T.
A.; Pascual, Coca, G.; Pe´rez Alonso, J. J.; Rubio Gonza´lez, R.; Simmonds,
M. S. J.; Blaney, W. M. Tetrahedron 1988, 54, 14989. (b) Ferna´ndez-
Mateos, A.; Pascual, Coca, G.; Pe´rez Alonso, J. J.; Rubio Gonza´lez, R.;
Herna´ndez, C. T. Synlett 1996, 1134.
(10) Several general methods have been developed for the preparation
of R-aryl ketones. For example: (a) Abramovitch, R. A.; Barton, D. H. R.;
Finet, J. P. Tetrahedron 1988, 44, 3039. (b) Palucki, M.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 11108. (c) Angle, S. R.; Neitzel, M. L. J.
Org. Chem. 2000, 65, 6458. (d) Justik, M. W.; Koser, G. F. Tetrahedron
Lett. 2004, 45, 6159. (e) Whitesell, J. K.; Lawrence, R. M.; Chen, H. H. J.
Org. Chem. 1986, 51, 4779.
(11) Hunsen, M. Tetrahedron Lett. 2005, 46, 1651.
(12) Several of the substances reported here were previously described.
(a) 1a: Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058. (b) 1b:
Utimoto, K.; Takai, K. NATO ASI Series, Series, C 1989, 269, 379. (c) 2b:
ref. 9b. (d) 4c: Quelet, R. Bull. Soc. Chim. Fr. 1929, 75.
(13) (a) Hodgson, D. M.; Glena, R.; Redgrave, A. J. Tetrahedron Lett.
2002, 43, 3927. (b) Taber, D. F.; Ruckle, R. E.; Hennessy, M. J. J. Org.
Chem. 1986, 51, 4077. (c) Lombardo, L.; Mander, L. N. Synthesis 1980,
368.
(14) Taber, D. F.; You, K.; Song, Y. J. Org. Chem. 1995, 60, 1093.
(15) Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. J. Org. Chem. 2005,
70, 10737.
3208 J. Org. Chem., Vol. 72, No. 9, 2007

Rh-Catalyzed C-H Insertion of R-Aryl-R-diazo Ketones
TABLE 4. Preparation and Cyclization of r-Aryl-r-diazo Ketones
TABLE 2. Optimization of the Diazo-Transfer Reaction
time yield
equiv base equiv solvent (h) (%)
entry ketone
reagent
mesyl azide 1.5 DBU 1.5 CH2Cl2
mesyl azide
PNBSA
BSA
AABSA
TIBSA
TIBSA
TIBSA
1
2
3
4
5
6
7
8
1c
1e
1e
1e
1e
1e
1e
1e
2
3
8
79
13
15
26
38
53
68
80
3
3
DBU
DBU
3
3
CH2Cl2
CH3CN
1.2 DBU 1.5 CH3CN 0.5
2
DBU 1.5 CH3CN
1
2
3
3
1.0 DBU 1.2 CH3CN
1.1 DBU 1.4 toluene
1.0 DBU
3
toluene
a Benzenesulfonyl azide (ref 16). b 4-Acetybenzenesulfonyl azide (ref 17).
TABLE 3. Optimization of the C-H Insertion Reaction
diazo
order of
T
yield
entry ketone Rh catalyst mol % solvent addition (°C) (%)
a
1
2
3
4
5
6
7
8
9
10
11
12
13
2f
2f
Rh2(tbsp)4
Rh2(ptpa)4
Rh2(oct)4d
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(ptpa)4
Rh2(ptpa)4
1
1
2
2
2
2
2
1
1
1
1
1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
Ab
A
A
A
Be
A
A
A
A
A
A
A
A
0
0
40
rt
rt
rt
-78
rt
rt
rt
45
rt
43
38
50
57
30
69
0
53
74
72
77
79
81
c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2f
a Yield of the diazo ketone. b Yield after equilibration of the epimeric
products with DBU. c Previously reported (ref 12). d The product is a
mixture of ring fusion diastereomers.
f
Rh2(pttl)4
Rh2(pttl)4
Rh2(pttl)4
Rh2(pttl)4
rt
a Tetrakis[1-[(4-tert-butylphenyl)sulfonyl]-(2S)-pyrrolidinecarboxylate]-
dirhodium(II). b Diazo ketone was added into rhodium catalyst. c Tetrakis[N-
phthaloyl-(S)-phenylalaninato]dirhodium ethyl acetate adduct. d Rhodium(II)
octanoate, dimer. e Rhodium catalyst was added into diazo ketone. f Tet-
rakis[N-phthaloyl-(S)-tert-leucinato]dirhodium bis(ethyl acetate) adduct.
The results of the diazo-transfer reaction and the C-H insertion
reaction under these optimized conditions are summarized in
Table 4. Entry 2 is particularly noteworthy, as the cyclization
had previously been reported not to proceed.9
Limitations. The diazo-transfer reaction conditions (TIBSA/
DBU/toluene) worked extremely well for each of the ketones.
Our attempted preparation of a 4-methoxyphenyl diazo ketone
failed, however. Diazo transfer at low temperature followed by
low-temperature flash chromatography had been reported to
deliver such a diazo ketone.19 We did not pursue this, as a
variety of derivatives, including methoxy, can be prepared from
the 4-bromo substituent.20
For C-H insertion reactions, in the cases of 3a, 3d, 3e, and
3f, both cis and trans products were formed after the reaction.
In order to simplify analysis, we epimerized the cis cyclopen-
tanones to trans by the addition of a catalytic amount of DBU
before workup. In the case of 3b, the product is a mixture of
ring fusion diasteromers.21 The two ketones were not separable
by column chromatography, so they are reported here as a
mixture.
Additional TIBSA was not necessary and should be avoided
since separation of the excess TIBSA was difficult. A simplified
workup procedure was also developed, which ensured a high
yield of the pure diazo ketones.
Optimization of the C-H Insertion. We screened conditions
for the C-H insertion reaction using diazo ketones 2c and 2f.
The results are summarized in Table 3. We found out that as
the solvent, toluene gave better yields than dichloromethane
(entries 4 and 6). The addition sequence is critical to this reaction
(entries 4 and 5). Addition of the rhodium catalyst into the
solution of diazo ketone led to more dimer and thus less of the
cyclized product than the reversed addition. The reaction was
fast at room temperature, going to completion usually within
seconds. A reaction run at -78 °C gave no cyclized product
(entry 7). We decided to use the Hashimoto (Rh2(pttl)4)18 catalyst
in our further studies since it consistently gave the highest yields.
The efficiencies for Rh2(pttl)4-catalyzed intramolecular C-H
insertion on R-aryl-R-diazo ketones were allylic C-H insertion
(16) Yamazaki, S.; Kohgami, K.; Okazaki, M.; Yamabe, S.; Arai, T. J.
Org. Chem. 1989, 54, 240.
(17) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(19) Zeller, K. P. Chem. Ber. 1979, 112, 678.
(20) Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci,
M. Tetrahedron 1983, 39, 193.
(18) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79.
(21) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108, 7686.
J. Org. Chem, Vol. 72, No. 9, 2007 3209

Taber and Tian
SCHEME 3
mixture was kept at reflux by heating until the Mg disappeared
(about 30 min). After the mixture was cooled to -30 °C, copper-
(I) bromide-dimethyl sulfide complex (0.62 g, 3.0 mmol) was
added. After 5 min, 1,2-epoxyoctane (3.46 g, 27.0 mmol) in THF
(10 mL) was added dropwise in 1 min. The cooling bath was
removed, and the mixture was stirred for an additional 0.5 h. Then
the reaction mixture was diluted with 500 mL of MTBE and passed
through a pad of silica gel. The collected liquid was concentrated,
and the residue was chromatographed (TLC Rf ) 0.38, 20% MTBE/
pet ether) to afford the alcohol (4.12 g) as a colorless oil.
To 100 mL of acetonitrile was added 4.48 g (197 mmol) of H5-
IO6, and the mixture was stirred vigorously at rt for 15 min. After
the mixture was cooled to 0 °C, the alcohol (4.12 g, 18.7 mmol)
was added followed by the addition of 81 mg (2 mol %) of PCC
in 2 mL of acetonitrile. The reaction mixture was stirred for 2 h at
0 °C. Then the reaction mixture was diluted with 500 mL of MTBE
and passed through a pad of silica gel. The collected liquid was
concentrated, and the residue was chromatographed to afford the
ketone 1e as a colorless oil (3.63 g, 16.7 mmol, 62% yield from
the epoxide): TLC Rf (PE/MTBE ) 8/2) ) 0.64; 1H NMR δ 0.85
(3H, t, J ) 7.0 Hz), 1.18-1.28 (6H, m), 1.49-1.57 (2H, m), 2.32
(3H, s), 2.41 (2H, t, J ) 7.0 Hz), 3.62 (2H, s), 7.06-7.13 (4H, m);
13C NMR22 δ u 22.7, 23.9, 29.0, 31.8, 42.1, 50.0, 131.6, 136.7,
209.0; d 14.2, 21.2, 129.4, 129.6; IR (film, cm-1) 2928, 2858, 1714,
1514, 805; HRMS calcd for C15H23O (M + H) 219.1749, obsd
219.1749.
Optimized procedure for the diazo-transfer reaction:
1-Diazo-1-(4-methylphenyl)-2-octanone (2e). To 3.5 mL of
toluene were added ketone 3e (76 mg, 0.35 mmol), DBU (222 mg,
1.46 mmol), and 2,4,6-triisopropylbenzenesulfonyl azide (108 mg,
0.35 mmol) sequentially at rt. The reaction mixture was maintained
in darkness and stirred at rt for 3 h. Then the reaction mixture was
directly chromatographed to afford 2e as a yellow oil (68 mg, 0.28
≈ tertiary aliphatic C-H insertion > secondary aliphatic C-H
insertion (entries 6, 3, and 1), which is consistent with previously
reported4,5,21 electronic effects. Electronic effects induced by
the substitution on the benzene ring also influenced the C-H
insertion reaction. Substituents on the para position affected the
yields more than did meta substituents. A 4-methyl substituent,
moderately electron donating, reduced the yield almost one-
third compared to bromo (entries 1 and 5). In contrast, a
3-methoxy group did not show any influence on either the diazo-
transfer reaction or the C-H insertion reaction (entry 4).
Since Rh2(pttl)4 is enantiomerically pure, and was developed18
to effect enantioselective C-H insertion, we assessed the
enantiomeric purities of ketone 3d and of ketone 3f. To this
end, we converted 3d (Scheme 3) into the diastereomeric
mixture of ketals 6d/7d. These were not separated, and the
relative configurations were not assigned. The ratio of the two,
easily determined by integrating the methines at δ 2.92 (minor)
and δ 3.04 (major) in the 1H NMR spectrum, was 2.9, indicating
an enantiomeric excess of 49%. Similarly, the ratio of 6f/7f
(methines at δ 3.04 (minor) and δ 3.16 (major) in the 1H NMR
spectrum) was 2.6, indicating an enantiomeric excess of 44%.
1
mmol, 80% yield): TLC Rf (PE/MTBE ) 8/2) ) 0.64; H NMR
δ 0.88 (3H, t, J ) 7.0 Hz), 1.26-1.36 (6H, m), 1.64-1.71 (2H,
m), 2.35 (3H, s), 2.56 (2H, t, J ) 7.6 Hz), 7.20-7.23 (2H, m),
7.37 (2H, d, J ) 8.0 Hz); 13C NMR δ u 22.6, 24.9, 29.0, 31.7,
39.2, 122.5, 137.1, 151.0; d 14.1, 21.2, 124.2, 129.8; IR (film, cm-1
)
2927, 2066, 1652, 1513, 811; HRMS calcd for C15H20O (M - N2)
216.1514, obsd 216.1517.
Optimized procedure for the C-H insertion reaction:
2-(4-Bromophenyl)-3-pentylcyclopentanone (3a). Rh2(pttl)4
(4.2 mg, 0.003 mmol) was dissolved in 2.0 mL of toluene at rt. A
solution of 2a (100 mg, 0.30 mmol) in 0.8 mL of toluene was added
dropwise over 2 min. The reaction was continued for an additional
10 min at rt. Then DBU (1 drop) was added before the reaction
mixture was chromatographed to afford 3a as a colorless oil
(56 mg, 0.18 mmol, 61% yield): TLC Rf (PE/MTBE ) 8/2) )
1
0.21; H NMR δ 0.85 (3H, t, J ) 7.2 Hz), 1.15-1.45 (7H, m),
1.50-1.60 (2H, m), 2.15-2.35 (3H, m), 2.49-2.56 (1H, m), 2.86
(1H, d, J ) 12.0 Hz), 6.96 (2H, d, J ) 8.4 Hz), 7.45 (2H, d, J )
8.4 Hz); 13C NMR δ u 22.7, 26.8, 27.3, 32.0, 34.4, 38.5, 121.1,
137.1, 217.5; d 14.1, 45.2, 62.7, 130.6, 131.9; IR (film, cm-1) 2926,
1744, 1488, 1011, 808; HRMS calcd for C16H2179BrO (M+)
308.0776, obsd 308.0774.
Conclusion
R-Aryl-R-diazo ketones are easily assembled. Rh-catalyzed
cyclization works well, even with a substrate previously reported
to be unsuccessful (2b). This approach allows readily access to
R-aryl-â-alkyl cyclopentanones.
Acknowledgment. This work was supported by the National
Institutes of Health (GM 60287).
Supporting Information Available: Experimental details and
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental Section
General procedure for the preparation of the ketones:
JO0624694
1-(4-Methylphenyl)-2-octanone (1e). In a round-bottom flask,
4-bromotoluene (5.00 g, 29.3 mmol), Mg (0.71 g, 29.3 mmol),
iodine (trace), and 50 mL of THF were combined. The reaction
was exothermic, reaching reflux after 10 min. Then the reaction
(22) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”
and for methylene and quaternary carbons as “u”.
3210 J. Org. Chem., Vol. 72, No. 9, 2007