Intermolecular alkyl radical addition to chiral N-acylhydrazones mediated by manganese carbonyl [14]

Full text of DOI:10.1021/ja011312k

9922
J. Am. Chem. Soc. 2001, 123, 9922-9923
Scheme 1
Intermolecular Alkyl Radical Addition to Chiral
N-Acylhydrazones Mediated by Manganese Carbonyl
Gregory K. Friestad* and Jun Qin
Department of Chemistry
UniVersity of Vermont
Burlington, Vermont, 05405
Table 1. Results of Metal-Mediated Radical Addition to
Propionaldehyde Hydrazone 2ag
ReceiVed May 30, 2001
Chiral R-branched amines are common substructures of bio-
active synthetic targets. Direct asymmetric amine synthesis by
radical addition to the CdN bond of carbonyl imino derivatives1
holds promise for improved efficiency by introducing the ste-
reogenic center and carbon-carbon bond in one step under mild,
nonbasic conditions. Because related additions of basic organo-
metallic reagents2 often suffer from competing aza-enolization3
or lack of generality and functional group tolerance, an ongoing
search for new stereocontrolled carbon-carbon bond-construction
methods has led to several promising developments,4 including
stereocontrolled intermolecular radical addition.5
We have designed and implemented chiral N-acylhydrazones
from N-amino-4-benzyl-2-oxazolidinone (1) for stereoselective
radical addition incorporating Lewis acid activation6 and restric-
tion of rotamer populations as key design elements.7 In this
approach (Scheme 1), as well as in radical additions by Naito8
and Bertrand,9 secondary and tertiary alkyl iodides were effective,
but additions of primary alkyl radicals have been undermined by
competing ethyl radical addition. We envisioned that new
conditions enabling the use of primary iodides would dramatically
(1) (a) Reviews of radical addition to CdN bonds: Friestad, G. K.
Tetrahedron 2001, 57, 5461. Fallis, A. G.; Brinza, I. M. Tetrahedron 1997,
53, 17543. (b) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: New York, 1986. (c) Jasperse, C.
P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237. (d) Giese, B.;
Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F.
Org. React. 1996, 48, 301.
(2) Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(b) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c)
Bloch, R. Chem. ReV. 1998, 98, 1407. (d) Enders, D.; Reinhold: U.
Tetrahedron Asymmetry 1997, 8, 1895. (e) Denmark, S. E.; Nicaise, O. J.-C.
J. Chem. Soc., Chem. Commun. 1996, 999.
(3) (a) Aza-enolization of imines with Grignard reagents: Stork, G.; Dowd,
S. R. J. Am. Chem. Soc. 1963, 85, 2178. Wittig, G.; Frommeld, H. D.;
Suchanek, P. Angew. Chem., Int. Ed. Engl. 1963, 2, 683. (b) Deprotonation
of iminium ions can be competitive with addition: Guerrier, L.; Royer, J.;
Grierson, D. S.; Husson, H.-P. J. Am. Chem. Soc. 1983, 105, 7754. (c) Less
basic organocerium reagents also exhibit aza-enolization: Enders, D.; Diez,
E.; Fernandez, R.; Martin-Zamora, E.; Munoz, J. M.; Pappalardo, R. R.;
Lassaleta, J. M. J. Org. Chem. 1999, 64, 6329.
(4) For selected recent examples, see: (a) Review of Strecker reactions:
Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (b) Mannich reactions: Notz,
W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett.
2001, 42, 199. (c) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (d) Saito, S.;
Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2, 1891. (e) Miura, K.; Tamaki,
K.; Nakagawa, T.; Hosomi, A. Angew. Chem., Int. Ed. 2000, 39, 1958.
(5) For reviews of acyclic stereocontrol in radical addition to CdC bonds,
see: (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163 and references
therein. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; Concepts, Guidelines, and Synthetic Applications; VCH: New
York; 1995.
a Irradiation was omitted. b Isolated yields of purified diastereomer
mixtures. R or S denotes the configuration of the new stereogenic center.
Addition of methyl iodide gives S configuration due to the lower priority
of the methyl ligand. c 20 equiv of R2X was used. d 1,8-Diazabicy-
clo[5.4.0]undec-7-ene (DBU) was used in removal of Mn byproducts.
e Ratio by HPLC (Chiralcel OD, 2-PrOH/hexane). f Ratio by 1H NMR.
g Reaction conditions: To a deoxygenated solution of InCl3 (2.2 equiv)
and hydrazone 2a in CH2Cl2 (0.1 M) was added the mediator and R2X
(10 equiv) followed by irradiation (300 nm, Pyrex) for 1-2 d at ca. 35
°C under N2.
expand the range of potential synthetic applications. We now
disclose such conditions: photolysis of manganese carbonyl
mediates highly stereoselective intermolecular radical addition of
primary alkyl halides to N-acylhydrazones.
We recognized two significant problems interfering with
primary radical addition using existing methods: Less stable 1°
radicals (versus 2° or 3°) might not be sufficiently long-lived to
avoid premature reduction by Bu3SnH, and generation of the
desired radical from a 1° alkyl iodide requires an unfavorable
iodine atom transfer to Et• when using Et3B or Et2Zn as the
initiator without Bu3SnH. Thus, we typically recovered hydrazones
unchanged when attempting the use of primary iodides in the
presence of Bu3SnH, while Et• addition was the major product
in the absence of Bu3SnH. These observations led us to consider
photolytic initiation in the presence of hexamethylditin.10 Unfor-
tunately, these conditions never reached desirable efficiencies for
Et• additions to hydrazone 2a (Table 1) in part due to complica-
tions from the use of acetone as a sensitizer.
(6) Protonation of imines leads to improved yields in radical addition.
Russell, G. A.; Yao, C.-F.; Rajaratnam, R.; Kim, B. H. J. Am. Chem. Soc.
1991, 113, 373. For a review of Lewis acid effects in radical reactions, see:
Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562.
(7) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329.
(8) Radical additions to camphorsultam-modified glyoxylate and malonate
oxime ether derivatives: (a) Miyabe, H.; Ushiro, C.; Naito, T. J. Chem. Soc.,
Chem. Commun. 1997, 1789. (b) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett.
1999, 1, 569. (c) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T.
J. Org. Chem. 2000, 65, 176. (d) Miyabe, H.; Konishi, C.; Naito, T. Org.
Lett. 2000, 2, 1443.
(9) Radical additions to chiral glyoxylate imines: Bertrand, M. P.; Feray,
L.; Nouguier, R.; Stella, L. Synlett 1998, 780. Bertrand, M. P.; Feray, L.;
Nouguier, R.; Perfetti, P. Synlett 1999, 1148. Bertrand, M. P.; Coantic, S.;
Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56, 3951.
(10) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc. 1996,
118, 5138. Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119, 5982. Ryu, I.;
Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-Y.; Kim, S. J. Am. Chem.
Soc. 1999, 121, 12190-12191.
10.1021/ja011312k CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/15/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 40, 2001 9923
Table 2. Preparation and Mn2(CO)10-Mediated Ethyl Radical
We were intrigued by the notion that the photolytic Mn-Mn
homolysis of manganese carbonyl [Mn2(CO)10],11 which requires
no sensitizer (λmax 340 nm, σMn-Mn f σ*Mn-Mn), could be
exploited for intermolecular addition of primary alkyl radicals to
CdN bonds. Interestingly, Parsons noted that reaction of •Mn-
(CO)5 with 1° halides was much more facile than with 2° or 3°
halides.12 Furthermore, avoiding the difficult removal of toxic tin
byproducts was attractive.
Addition to Aldehyde Hydrazones According to Scheme 1f
In a test case of ethyl iodide addition to 2a7 (Table 1),
irradiation (300 nm) of 2a, EtI (10 equiv), and Mn2(CO)10 (1
equiv) with InCl3 (2.3 equiv) as a Lewis acid13 in CH2Cl2 afforded
37 in 85% yield,14 a dramatic improvement over use of trieth-
ylborane or hexamethylditin. Several other halides, including
methyl iodide and difunctional halides,15 were also effective,
furnishing radical addition products 4S, 5R-13R16 with high
diastereomer ratios (Table 1). Products 10R, 12R, and 13R bear
undisturbed chloride substituents, offering opportunities for further
elaboration. Interestingly, 3-chloro-1-iodopropane led exclusively
to pyrrolidine 11R (eq 1), presumably via radical addition and in
situ nonradical cyclization; this constitutes a potentially useful
hybrid radical-ionic annulation.
a Isolated yield. b Isolated yield of diastereomer mixture. c 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) was used in removal of Mn
f
byproducts. d Ratio by HPLC. e Ratio by 1H NMR. Reaction conditions
for hydrazone formation: Aldehyde (5-10 equiv), 1, p-toluenesulfonic
acid, CH2Cl2, rt. For radical addition conditions see Table 1.
Scheme 2
Ethyl radical addition to nine additional hydrazones 2b-2j
(Table 2) occurred in good yields (with the exception of 2j). These
adducts 4R, 5S-13S are epimeric to 4S, 5R-13R (Table 1) with
respect to the new stereogenic center, demonstrating a useful
feature inherent in this carbon-carbon bond-construction ap-
proach to amine synthesis. The epimeric configuration can be
selected by either (A) employing the enantiomeric auxiliary or
(B) interchanging the roles of R1 and R2 in the alkyl halide and
aldehyde precursors of Scheme 1.17 By combining these two
tactics, the optimal roles of R1 and R2 with respect to yield and
selectivity can be chosen. Such strategic flexibility is not readily
achieved through Strecker, Mannich, or organometallic addition
strategies.
groups in the coupling partners (i.e., R1 and R2 of Scheme 1)
gave superior results. Accordingly, Mn-mediated radical addition
of 4-chlorobutyl iodide to 2c furnished 14 with high diastereo-
selectivity.19 Cyclization and reductive N-N cleavage20 afforded
R-coniine (four steps from butyraldehyde).21
In summary, manganese carbonyl mediates stereoselective
photolytic radical addition of alkyl iodides to chiral N-acylhy-
drazones with tolerance of additional functionality in both
coupling partners and excellent flexibility for synthetic planning.
To illustrate its potential in asymmetric amine synthesis, we
applied Mn-mediated radical addition to prepare the piperidine
alkaloid coniine (Scheme 2).18 Although propyl radical addition
to a difunctional hydrazone could be used, interchanging the alkyl
Acknowledgment. We thank the NSF (CHE-0096803), Research
Corporation, Petroleum Research Fund, Vermont EPSCoR, and the
University of Vermont for generous support.
Supporting Information Available: Characterization data for 2-14
with selected experimental procedures (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) (a) Reviews: Pauson, P. L. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, Vol. 2, pp 1471-
1474. Meyer, T. J.; Caspar, J. V. Chem. ReV. 1985, 85, 187. (b) Halogen
atom transfer to •Mn(CO)5: Herrick, R. S.; Herrinton, T. R.; Walker, H. W.;
Brown, T. L. Organometallics 1985, 4, 42.
JA011312K
(12) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A.
F.; Whittaker, D. T. E. Tetrahedron Lett. 1999, 40, 6095. Gilbert, B. C.; Kalz,
W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A. F.; Whittaker, D. T. E. J.
Chem. Soc., Perkin 1 2000, 1187.
(13) Use of ZnCl2 as the Lewis acid was precluded due to limited solubility.
(14) Control experiments revealed a requirement for both irradiation and
Mn2(CO)10. Without InCl3, the reaction was slow (21% yield after 2 d).
(15) Addition of 1,2-dihaloethanes occurred in rather low yield (0-14%),
probably due to radical fragmentation.
(18) Coniine is a common target for testing asymmetric amine synthesis
methodology. For selected asymmetric syntheses, see: (a) Guerrier, L. Royer,
J.; Grierson, D. S.; Husson, H.-P. J. Am. Chem. Soc. 1983, 105, 7754. (b)
Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173. (c) Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 1997, 38, 4623. (d) Reding, M. T.; Buchwald,
S. R. J. Org. Chem. 1998, 63, 6344. (e) Wilkinson, T. J.; Stehle, N. W.; Beak,
P. Org. Lett. 2000, 2, 155. (f) For reviews of asymmetric syntheses of
piperidine alkaloids, see: Laschat, S.; Dickner, T. Synthesis 2000, 1781.
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(16) Configurations are assigned by analogy with 9R and 14, which were
unambiguously determined through chemical correlation with valine and
coniine, respectively. See ref 7.
(17) For related examples of this tactic, see: (a) Enders, D. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; pp 275-
339. (b) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383.
(19) Identical results were observed on ca. 200-mg or 1-g scale.
(20) N-N cleavage with BH3‚THF: Feuer, H.; Brown, F., Jr. J. Org. Chem.
1970, 35, 1468. For recent examples, see: Enders, D.; Lochtman, R.; Meiers,
M.; Muller, S.; Lazny, R. Synlett 1998, 1182.
(21) Conversion of volatile R-coniine to its N-tert-butoxycarbonyl derivative
facilitated isolation and characterization.