Regio- and stereocontrol elements in Rh(II)-catalyzed intramolecular C-H insertion of α-diazo-α-(phenylsulfonyl)-acetamides

Article abstract of DOI:10.1021/ol016647l

(matrix presnted) Intramolecular C-H insertion reaction of α-diazo-α-(phenylsulfonyl)acetamides proceeded with high regio- and stereoselectivities to afford highly functionalized y-lactams predominantly or exclusively. The high regioselectivity was attrib

Full text of DOI:10.1021/ol016647l

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3539-3542
Regio- and Stereocontrol Elements in
Rh(II)-Catalyzed Intramolecular C−H
Insertion of r-Diazo-r-(phenylsulfonyl)-
acetamides
Cheol Hwan Yoon, Michael J. Zaworotko, Brian Moulton, and Kyung Woon Jung*
Department of Chemistry, UniVersity of South Florida, 4202 E. Fowler AVenue,
Tampa, Florida 33620-5250
kjung@chuma.cas.usf.edu
Received August 24, 2001
ABSTRACT
Intramolecular C−H insertion reaction of r-diazo-r-(phenylsulfonyl)acetamides proceeded with high regio- and stereoselectivities to afford
highly functionalized γ-lactams predominantly or exclusively. The high regioselectivity was attributed to the use of the phenylsulfonyl moiety,
which altered electron density at the carbenoid center and exerted a steric effect during the insertion reaction. Also described herein are three
control elements to determine regioselectivity, which are amide conformational, stereoelectronic, and substituent effects.
The pyrrolidinone functionality is a prevalent scaffold in
various syntheses and serves as a crucial synthetic intermedi-
ate for numerous natural products. A vast number of synthetic
methods have been developed for the construction of
γ-lactam rings,1 and intramolecular C-H insertion reaction
of R-diazoamides appeared to be an attractive procedure.2
However, insertion reactions of various R-diazoamides
resulted in the formation of regioisomers including â- and
γ-lactams as well as stereoisomers. The ratio of each product
depended on the nature of the substrates examined and
rhodium catalyst ligands utilized.3
regioselectivity during the course of the C-H insertion
reaction.2d,e In our related studies to vary R-substituents, we
discovered the phenylsulfonyl moiety4 altered electron
density of the metallocarbenoid and exerted a steric effect
(2) For the synthesis of the γ-lactams by the intramolecular C-H
insertion reaction, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds;
Wiley-Interscience: New York, 1998. See also references therein. (b) Doyle,
M. P.; Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397. (c) Doyle,
M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q. J. Org. Chem. 1991, 56, 820.
(d) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404. (e)
Padwa, A. P.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669. (f) Wee, A. G. H.; Slobodian, J. J. Org. Chem. 1996, 61, 2897.
(g) Doyle, M. P.; Kalinin, A. V. Tetrahedron Lett. 1996, 37, 1371. (h)
Hashimoto, S.-I.; Anada, M. Tetrahedron Lett. 1998, 39, 79. (i) Wee, A.
G. H.; Liu, B.; McLeod, D. D. J. Org. Chem. 1998, 63, 4218. (j) Moody,
C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C.
Tetrahedron 1998, 54, 9689.
Padwa and Wee demonstrated that the R-substituent of
carbenoid carbon could affect the chemoselectivity and
(1) (a) Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1992, 57, 1656. (b)
Knaus, E. E.; Wei, Z.-Y. Tetrahedron Lett. 1993, 34, 4439. (c) Gennari,
C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60, 6248. (d) DiCosimo, R.;
Gavagan, J. E.; Fager, S. K.; Fallon, R. D.; Folsom, P. W.; Herkes, F. E.;
Eisenberg, A.; Hann, E. C. J. Org. Chem. 1998, 63, 4792. (e) Komatsu,
M.; Ryu, I.; Matsu, K.; Minakata, S. J. Am. Chem. Soc. 1998, 120, 5838.
(f) Poli, G.; Giambastiani, G.; Pacini, B.; Porcelloni, M. J. Org. Chem.
1998, 63, 804. (g) Buono, G.; Fotiadu, F.; Pardigon, O. Tetrahedron Lett.
1999, 40, 867. (h) Woerpel, K. A.; Roberson, C. W. J. Org. Chem. 1999,
64, 1434. (i) Dieter, R. K.; Lu, K. Tetrahedron Lett. 1999, 40, 4011 and
references therein.
(3) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1797.
(4) For leading references to other studies with R-diazo-R-phenylsulfonyl
compounds, see: (a) References 2d and 2f. (b) Monteiro, H. J. Tetrahedron
Lett. 1987, 28, 3459. (c) Durst, T.; Babu, S. D.; Hrytsak, M. D. Can. J.
Chem. 1989, 67, 1071. (d) Kennedy, M.; McKervey, M. A.; Maguire, A.
R.; Roos, G. H. J. Chem. Soc., Chem. Commun. 1990, 361. (e) Moody, C.
J.; Davies, M. J. J. Chem. Soc., Perkin Trans. 1 1991, 9. (f) Padwa, A.;
Straub, C. S. Org. Lett. 1999, 1, 83.
10.1021/ol016647l CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/05/2001

to enhance regio- and stereoselectivities. We herein describe
a detailed study of the intramolecular C-H insertion reaction
using various R-diazo-R-(phenylsulfonyl)acetamides as pre-
cursors.
Padwa and Doyle reported that C-H insertion of the
R-diazo-R-acetoacetamide analogue to 1 afforded a mixture
of the â- and γ-lactam, which was obtained through both
transition states.7 The selectivity was improved in favor of
the γ-lactam when a Rh catalyst with an electron-donating
ligand was used. Presumably, the electron-donating ligand
would stabilize the electrophilic carbenoid carbon, thereby
causing the insertion reaction to proceed through a relatively
late transition state with a resulting increase in selectivity.3,8
Likewise, the excellent result of our phenylsulfonyl carbenoid
insertion implied that the insertion reaction of R-diazo-R-
(phenylsulfonyl)acetamide would proceed via a later transi-
tion state as a result of the extra stabilization by a
phenylsulfonyl group. Hence, the cyclization would occur
through the stereoelectronically favorable transition state 5
(stereoelectronic effect). The formation of trans-stereo-
chemistry at C-3/C-4 was also explained by the adopted
chairlike transition state 5, wherein the C-Rh bond would
be aligned with the target C-H bond and the phenyl group
would occupy a pseudoequatorial position.9
As representatively shown in Scheme 1, C-H insertion
reaction of the diazo substrate 15 was performed using
Scheme 1
Rh2(OAc)4, which surprisingly afforded trans γ-lactam 26
exclusively in 95% yield without the formation of â-lactam
or aromatic cycloaddition product.
The outstanding regio- and stereoselectivities are rational-
ized in Scheme 2. During the insertion reaction, the confor-
In addition to the aforementioned effects, a substituent
effect was also envisioned to be in play, and electron density
at the insertion center was varied (Scheme 3). Intramolecular
Scheme 2
Scheme 3
mationally restricted metallocarbenoid 3 would adopt a s-cis
conformer as a result of the severe nonbonded interaction
between the tert-butyl group and the carbonyl substituents
present in the s-trans conformer (conformational effect). Only
the s-cis conformer is suitable for cyclization, and the two
regioisomers â- and γ-lactam can be obtained through
transition states 4 and 5, respectively.
C-H insertion of 7 afforded only â-lactam 8 in nearly
quantitative yield,10 which resulted from the deactivating
influence of the carboethoxy group on C-H insertion into
the adjacent methylene group.11 However, insertion reaction
of substrate 9, which possessed an electron-donating TBS
ether,12 yielded trans γ-lactam 10 exclusively in high yield.
With different alkyl groups introduced, only methine C-H
bonds were reacted, giving rise to the formation of â- and
(5) R-Diazo-R-(phenylsulfonyl)acetamides iii were easily prepared from
secondary amines i via the corresponding R-(phenylsulfonyl)acetamides ii.
Acylation of secondary amines i with R-bromoacetyl bromide in TEA and
dichloromethane at 0 °C followed by treatment with sodium benzenesulfinate
in DMF at room temperature afforded R-(phenylsulfonyl)acetamides ii.
Subsequent diazo transfer of ii with p-acetamidobenzenesulfonyl azide (p-
ABSA) and DBU yielded the corresponding R-diazo-R-(phenylsulfonyl)-
acetamides iii.
(7) Reference 2e. A typical example is shown below.
(6) The stereochemistry of 4-substituted-3-phenylsulfonyl-2-pyrrolidinone
derivatives was assigned by the coupling constant between C3 and C4
protons, which of the trans γ-lactam fell in the range of 1.0-3.0 Hz.
(8) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(9) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
118, 547.
3540
Org. Lett., Vol. 3, No. 22, 2001

conformers. For this reason, the diazo precursor 17 led to
an equimolar amount of γ-lactams 18 and 19. The stereo-
chemical assignment for 18 was confirmed by X-ray crystal-
lographic analysis as shown in Figure 1. Similarly, 20 and
Scheme 4
γ-lactams (12 and 14), respectively (Scheme 4).13 Apparently,
biased reactivities depending on substituents of the insertion
center influenced the reaction pathways, and electron-
enriched groups activated the C-H bond for insertion.
Although the stereoelectronic effect offers γ-lactams, the
other two factors often play contradictory roles to give
â-lactams or regioisomeric mixtures. For instance, the
conformational preference in 15 favored the s-cis rotamer,
and the substituent effect of the ester group forced the
cyclization to provide the â-lactam 16 solely (Scheme 5).10
Scheme 5
Figure 1. Ortep view of 18.
23 furnished γ- and â-lactams in a ratio of 4:1. Despite the
small difference in the relative stabilities of the two amide
conformers, the stereoelectronic effect was significant to form
γ-lactams, which was noteworthy in the insertion into the
electronically unfavorable methyl C-H bond of the substrate
20.
With unbiased conformational effect, we sought electroni-
cally and sterically different substituents to force the cy-
clization to occur, resulting in the formation of γ-lactams
(Scheme 7). Fortunately, acrylate incorporated R-diazo-R-
When the substituent effect was negligible as shown in
Scheme 6, the distribution of products was considered to
depend on the relative stabilities of the two possible amide
Scheme 7
Scheme 6
(phenylsulfonyl)acetamides 26 and 28 underwent the intra-
molecular C-H insertion smoothly to afford only γ-lactams
(10) The ratio of cis and trans isomers was based on the integration of
the R-methylene proton to carboethoxy group by 1H NMR analysis of
â-lactam 8. The cis and trans isomers were assigned by the comparison of
the coupling constant C3-C4. See: (a) Barrow, K. D.; Spotswood, T. M.
Tetrahedron Lett. 1988, 29, 2283. (b) Kagan, H. B.; Basselier, J. J.; Luche,
J. L. Tetrahedron Lett. 1964, 941. Jtrans is in the range of 2.2-2.8 Hz and
Jcis is 4.9-5.9 Hz.
(11) Stork, G.; Nakatani, K. Tetrahedron Lett. 1988, 29, 2283.
Org. Lett., Vol. 3, No. 22, 2001
3541

27 and 29, respectively, without formation of â-lactams and
carbonyl ylide byproducts, which were observed in the case
of R-diazo-R-acetoacetamide.14 In these cases, two substit-
uents were comparable in size, but the difference in sub-
stituent effects caused the insertion into the â-propionate
substituent to be retarded. To our knowledge, this showcase
is the first example to give one regioisomer in the presence
of two possible amide conformers.
In conclusion, we have developed a highly regio- and
stereoselective C-H insertion reaction with R-diazo-R-
(phenylsulfonyl)acetamides for the synthesis of γ-lactams.
Common side reactions such as aromatic cycloaddition2e and
carbonyl ylide formation2b,c were not observed at all. Three
control elements including conformational, stereoelectronic,
and substituent effects were studied, and these were ma-
nipulated with great ease to govern regio- and stereo-
selectivities. Further evidence and pragmatic utility will be
reported in due course.
(12) (a) Spero, D. M.; Adams, J. Tetrahedron Lett. 1987, 28, 4773.
(b) Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995,
321.
(13) (a) Taber, D.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108,
7686. (b) Lee, E.; Jung, K. W.; Kim, Y. S. Tetrahedron Lett. 1990, 31,
1023.
(14) References 2b and 2e. A typical example is shown below.
Acknowledgment. We acknowledge generous financial
support from the National Institutes of Health (R01 GM
62767).
Supporting Information Available: Representative ex-
perimental procedures with spectral data and X-ray crystal-
lography data for compound 18. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016647L
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Org. Lett., Vol. 3, No. 22, 2001