Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

Article abstract of DOI:10.1021/ja060553v

In this work, mechanistic studies were performed to understand the SmI₂/H₂O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing γ-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the α,β-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI₂/H₂O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI₂/H₂O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the γ-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion. Copyright

Full text of DOI:10.1021/ja060553v

Published on Web 07/11/2006
Mechanistic Evidence for Intermolecular Radical Carbonyl Additions
Promoted by Samarium Diiodide
†
†
‡
†
Anna Mette Hansen, Karl B. Lindsay, P. K. Sudhadevi Antharjanam, Jakob Karaffa,
†
,‡
,†
Kim Daasbjerg, Robert A. Flowers II,* and Troels Skrydstrup*
Center of Insoluble Protein Structures (inSPIN), Department of Chemistry, Interdiscplinary Nanoscience Center,
UniVersity of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark, and Department of Chemistry, Lehigh
UniVersity, Bethlehem, PennsylVania 18015
Received February 5, 2006; E-mail: ts@chem.au.dk
Since the introduction of SmI
late 1970’s, this single-electron transferring agent has steadily
developed into a successful reagent for promoting a multitude of
2
by Kagan and co-workers in the
To shed light onto this mechanistic enigma, the coupling potential
of the cyclopropyl derivative 1 with the electron-deficient alkenes
was examined (Scheme 2). Participation of a ketyl radical anion
intermediate was predicted to lead to rapid ring opening of the
cyclopropane substituent.12 Conversely, normal coupling products
with an intact cyclopropane ring would support a mechanism
1
synthetic organic transformations. Intermolecular alkyl addition
reactions to carbonyl substrates represents a principal category of
such useful transformations (e.g., Barbier reaction). Kagan proposed
a number of possible mechanistic scenarios for this reaction,
including the addition of an alkyl radical to a carbonyl compound
as the crucial C-C bond-forming step resulting in an alkoxy radical
involving nucleophilic acyl substitution. Treatment of 1 with SmI
2
/
2
H O for 24 h at -78 °C led to the ring-opened product 2 along
with substantial amounts of unreacted 1. While this experiment
demonstrates the feasibility of electron transfer to the carbonyl of
1, the reaction is slow.10 Yet, when either n-octyl acrylate or tert-
butyl acrylamide was added to identical reaction conditions, only
the products 3 and 4 could be isolated in yields of 54 and 52%,
consistent with a mechanism invoking nucleophilic acyl substitution.
Additional experiments were performed to examine the validity
of this proposal (Scheme 3). Subjecting n-octyl acrylate and tert-
butyl acrylamide to the same reduction conditions without the
N-acyl oxazolidinone produced the dimer 5 in 70% yield (93% yield
2
intermediate. This mechanism was dispensed for several reasons
including the low rate constants for bimolecular additions of radicals
to ketones.3b Through elegant mechanistic studies by the Curran,
Molander, Kagan, and Flowers groups,3-6 it is now widely accepted
that such reactions proceed through an ionic pathway, where alkyl
radical intermediates, generated via the reduction of corresponding
halides, are reduced to an organosamarium species prior to carbonyl
addition. In this communication, we report experimental evidence
that for certain SmI -promoted C-C bond-forming reactions
2
intermolecular radical addition to carbonyl compounds can proceed
with high efficiency without the intervention of an organosamarium
intermediate.7
2
with 16 equiv of H O) and a quantitative yield of tert-butyl
propionamide 6, respectively. However, in the presence of the
8
N-acyl oxazolidinone 7, the γ-keto ester 8 and amide 9 were
obtained in good yields with only traces of 5 and 6, respectively.
Scheme 1
Scheme 3
We recently reported the aptitude of N-acyl oxazolidinones to
couple with acrylates/acrylamides in the presence of SmI
providing a general route to γ-carbonyl esters/amides (Scheme 1).
2 2
/H O,
8
,9
Although we originally proposed a mechanism proceeding via a
metalated ketyl radical anion intermediate, after continual probing
of the substitution pattern of both coupling partners, several
observations suggested that an alternative mechanism was operating
involving possibly initial reduction of the acrylate/acrylamide to a
dianion, followed by subsequent nucleophilic acyl substitution of
the N-acyl oxazolidinone.10,11
These experiments are inconsistent with a nucleophilic acyl
substitution mechanism. There is no literature precedence for
organosamarium species undergoing conjugate additions, indicat-
Scheme 2
13
ing that 5 arises from either the dimerization of 10 or the initial
radical addition of 10 to the acrylate. The formation of 8 suggests
that this C-C bond-forming reaction is faster than the radical
dimerization/addition step inVolVing the acrylate. We conclude,
therefore, that the coupling reactions with acrylates proceed through
a radical mechanism. The experiments with the tert-butyl acrylamide
are less-conclusive, as only the reduced product 6 was obtained.
Further evidence suggests that nucleophilic acyl substitution is not
†
University of Aarhus.
Lehigh University.
‡
9616
9
J. AM. CHEM. SOC. 2006, 128, 9616-9617
10.1021/ja060553v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Observed Rate Constants for the Reduction of the
Substrates by SmI2/H2O in THF
addition to this CdO bond becomes favorable. Second, the metal
center acts as a tether, thereby appropriately positioning the radical
for a pseudo-intramolecular addition. The alkoxy radical formed
a
2
is then reduced by a second SmI .
In conclusion, we have provided evidence lending support to a
mechanism involving intermolecular alkyl radical addition to
carbonyl compounds for the SmI -promoted coupling of R,â-
2
unsaturated esters/amides to N-acyl oxazolidinones. Further work
is underway to provide additional kinetic data for these reactions,
as well as to examine the generality of this mechanism for other
a
SmI2] ) 10 mM, [H2O] ) 40 mM, [substrate] ) 0.10 M. b Upper
[
SmI -promoted C-C bond-forming reactions.
2
limit value.
Acknowledgment. The Danish National Research Foundation,
The Lundbeck Foundation, and the University of Aarhus are
gratefully acknowledged for financial support to this project. RAF
is grateful to the National Science Foundation (CHE-0413845) for
support of the work at Lehigh University.
the mechanistic pathway for this reaction (Scheme 4). The Pfp-
ester 12 should provide a superior substrate for this coupling
reaction due to its significantly enhanced leaving group ability
compared to that of an oxazolidinone. Attempted coupling of 12
with tert-butyl acrylamide led to recovered 12 and tert-butyl
propionamide 6, according to the H NMR spectrum of the crude
reaction mixture. On the other hand, coupling of the phenylalanine
derivative 11 to the acrylamide leads to ketone 13 in 58% yield.
1
Supporting Information Available: General experimental methods
for the radical addition reactions and spectroscopic data for the coupling
1
13
products, including copies of H and C NMR spectra, and Note added
in Proof. This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 4
References
(
1) For some recent reviews, see: (a) Edmonds, D. J.; Johnston, D.; Procter,
D. J. Chem. ReV. 2004, 104, 3371. (b) Kagan, H. B. Tetrahedron 2003,
59, 10351. (c) Steel, P. G. J. Chem. Soc., Perkin Trans. I 2001, 2727. (d)
Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (e) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321. (f) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307.
(
2) Kagan, H. B.; Namy, J. L.; Girard, P. Tetrahedron 1981, 37 (Suppl. 1),
175.
(
3) (a) Curran, D. P.; Fevig, T. L.; Totleben, M. J. Synlett 1990, 773. (b)
Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992,
Finally, it was also expected that an anionic mechanism would
be sensitive to the number of equivalents of water in the reaction
mixture, where competing protonation of the dianion species would
reduce coupling yields. However, coupling reactions of 7 and the
same acrylamide proceeded in over 50% yields, even with up to
9
43. (c) Curran, D. P.; Gu, X.; Zhang, W.; Dowd, P. Tetrahedron 1997,
53, 9023.
(
4) (a) Molander, G. A.; Harring, L. S. J. Org. Chem. 1990, 55, 6171. (b)
Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132.
(
(
5) Namy, J. L.; Collin, J.; Bied, C.; Kagan, H. B. Synlett 1992, 733.
6) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6895.
4
0 equiv of water.
As a final point, rate measurements for the reduction of an
(7) Mechanistic studies by Curran and co-workers (ref 3c) could not exclude
the possibility of a radical carbonyl addition mechanism for intramolecular
Barbier reactions.
acrylate, acrylamide, and a N-acyl oxazolidinone were carried out,
the results of which support the favored reduction of the R,â-
unsaturated ester or amide by SmI /H O in the presence of the
2 2
derivatized oxazolidinone. Measurements were performed using
stopped-flow spectrophotometry under pseudo first-order conditions,
and the data are shown in Table 1. Although the rate constant for
the oxazolidinone is only half that of the acrylamide, the value is
an upper limit estimated from the rate data.14
(8) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa, J.; Hansen, A.
M.; Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544.
(
9) For similar reactions with thioesters, see: (a) Blakskjær, P.; Høj, B.; Riber,
D.; Skrydstrup, T. J. Am. Chem. Soc. 2003, 125, 4030. (b) Mikkelsen, L.
M.; Jensen, C. M.; Høj, B.; Blakskjær, P.; Skrydstrup, T. Tetrahedron
2
003, 59, 10541. (c) Jensen, C. M.; Lindsay, K. B.; Andreasen, P.;
Skrydstrup, T. J. Org. Chem. 2005, 70, 7512. (d) Lindsay, K. B.;
Skrydstrup, T. J. Org. Chem. 2006, 71, 4766.
(
10) For a discussion concerning these observations, see SI.
(11) For several examples of SmI -mediated nucleophilic acyl substitutions,
2
see: (a) Molander, G. A.; Brown, G. A.; Storch de Gracia, I. J. Org.
Chem. 2002, 67, 3459. (b) Molander, G. A.; Harris, C. R. J. Org. Chem.
1
6
1
998, 63, 4374. (c) Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998,
3, 4366. (d) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1996,
18, 4059.
Scheme 5
(
12) (a) Chahma, M.; Li, X.; Phillips, J. P.; Schwartz, P.; Brammer, L. E.;
Wang, Y.; Tanko, J. M. J. Phys. Chem. A 2005, 109, 3372. (b) Tanko, J.
M.; Gillmore, J. G.; Friedline, R.; Chahma, M. J. Org. Chem. 2005, 70,
4
170. (c) Stevenson, J. P.; Jackson, W. F.; Tanko, J. M. J. Am. Chem.
Soc. 2002, 124, 4271.
(
13) Transmetalation with copper(I) salts does allow conjugate addition
reactions: Totleben, M. J.; Curran, D. P.; Wipf, P. J. Org. Chem. 1992,
5
7, 1740.
(
14) Precipitation of the SmI
2
-coordinated oxazolidinone out of the THF
Scheme 5 depicts a possible mechanistic scenario consistent with
the results described in the preceding discussion. The oxazolidinone
solution under the conditions of the experiment provided an accelerated
rate due to apparent loss of the Sm(II) absorption monitored during the
course of the experiment. Visible inspection of the reactions shows that
likely has a high affinity for Sm(II) coordinating to SmI
2
and acting
2
the loss of color in the SmI /oxazolidinone system is significantly slower
as a ligand such as HMPA.1
5,16
than it is for the acrylate and the acrylamide, suggesting that the rate is
considerably slower than the upper limit shown in Table 1.
This complex then reduces the
acrylate/acrylamide to a radical anion, providing a chelated
intermediate I. The effect of the lanthanide center is 2-fold for
overcoming the otherwise slow rate constants for intermolecular
radical additions to carbonyl groups.3b First, its hard Lewis acid
(15) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6357 and
references therein.
(
16) CV studies show that the presence of a 2-fold excess of the bidentate
ligand 7 only has a negligible effect (20 mV) on the reducing power of
2
SmI compared to the 800 mV change with 4 equiv of HMPA (ref 15).
character lowers the π*CdO orbital to such an extent that radical
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