Radical addition approach to asymmetric amine synthesis: Design, implementation, and comparison of chiral N-acylhydrazones

Article abstract of DOI:10.1021/jo050756m

Intermolecular radical addition to C=N bonds with acyclic stereocontrol offers excellent potential as a mild, nonbasic carbon-carbon bond construction approach to chiral amines. Here, complete details of the first radical additions to chiral N-acylhydrazones as an approach to asymmetric amine synthesis are disclosed. Novel N-acylhydrazones were designed as chiral C=N radical acceptors with Lewis acid activation, restriction of conformational mobility, and commercial availability of precursors. Amination of 4-alkyl-2-oxazolidinones with O-(mesitylenesulfonyl)hydroxylamine or O-(p-nitrobenzoyl)hydroxylamine afforded N-aminooxazolidinones which were condensed with aldehydes to afford N-acylhydrazones 3-8. Three synthetic methods were developed, implementing these N-acylhydrazones in Lewis acid-promoted intermolecular radical additions to C=N bonds. First, additions of various secondary and tertiary alkyl iodides to propionaldehyde and benzaldehyde hydrazones (3 and 7) under tin hydride radical chain conditions in the presence of ZnCl₂ gave N-acylhydrazine adducts with diastereomeric ratios ranging from 93:7 to 99:1. Radical additions to a series of N-acylhydrazones with different substituents on the oxazolidinone revealed that benzyl and diphenylmethyl were more effective stereocontrol elements than those with the aromatic ring directly attached to the oxazolidinone. Second, a tin-free method, exploiting dual functions of triethylborane for both initiation and chain propagation, enabled improved yields in addition of secondary alkyl iodides. Third, under photolytic conditions with hexamethylditin, primary radical addition could be achieved with ethyl iodide in the presence of diethyl ether as cosolvent; the 1-ethoxyethyl adduct was observed as a minor product. Chloromethyl addition was achieved under both the tin-free and photolytic conditions; in this case, the adduct bears alkyl chloride functionality with potential for further elaboration.

Full text of DOI:10.1021/jo050756m

Radical Addition Approach to Asymmetric Amine Synthesis:
Design, Implementation, and Comparison of Chiral
N-Acylhydrazones
Gregory K. Friestad,*,† Cristian Draghici,‡ Mustapha Soukri,‡ and Jun Qin‡
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, and Department of Chemistry,
University of Vermont, Burlington, Vermont 05405
gregory-friestad@uiowa.edu
Received April 14, 2005
Intermolecular radical addition to CdN bonds with acyclic stereocontrol offers excellent potential
as a mild, nonbasic carbon-carbon bond construction approach to chiral amines. Here, complete
details of the first radical additions to chiral N-acylhydrazones as an approach to asymmetric amine
synthesis are disclosed. Novel N-acylhydrazones were designed as chiral CdN radical acceptors
with Lewis acid activation, restriction of conformational mobility, and commercial availability of
precursors. Amination of 4-alkyl-2-oxazolidinones with O-(mesitylenesulfonyl)hydroxylamine or O-(p-
nitrobenzoyl)hydroxylamine afforded N-aminooxazolidinones which were condensed with aldehydes
to afford N-acylhydrazones 3-8. Three synthetic methods were developed, implementing these
N-acylhydrazones in Lewis acid-promoted intermolecular radical additions to CdN bonds. First,
additions of various secondary and tertiary alkyl iodides to propionaldehyde and benzaldehyde
hydrazones (3 and 7) under tin hydride radical chain conditions in the presence of ZnCl2 gave
N-acylhydrazine adducts with diastereomeric ratios ranging from 93:7 to 99:1. Radical additions
to a series of N-acylhydrazones with different substituents on the oxazolidinone revealed that benzyl
and diphenylmethyl were more effective stereocontrol elements than those with the aromatic ring
directly attached to the oxazolidinone. Second, a tin-free method, exploiting dual functions of
triethylborane for both initiation and chain propagation, enabled improved yields in addition of
secondary alkyl iodides. Third, under photolytic conditions with hexamethylditin, primary radical
addition could be achieved with ethyl iodide in the presence of diethyl ether as cosolvent; the
1-ethoxyethyl adduct was observed as a minor product. Chloromethyl addition was achieved under
both the tin-free and photolytic conditions; in this case, the adduct bears alkyl chloride functionality
with potential for further elaboration.
Background and Introduction
stereocontrolled carbon-carbon bond construction meth-
ods would broaden the scope of the direct asymmetric
amine synthesis strategy for access to chiral amines. An
ongoing search for more versatile methods for addition
to CdN bonds under mild conditions has led to several
promising developments, including intermolecular radical
addition to imino compounds.2-5
Chiral R-branched amines are common substructures
of bioactive synthetic targets. Direct asymmetric amine
synthesis by addition to the CdN bond of carbonyl imino
derivatives1 holds promise for improved efficiency by
introducing the stereogenic center and carbon-carbon
bond in one step under mild, nonbasic conditions. New
The radical addition approach to chiral amines (Figure
1) offers the potential for practical advantages in chemose-
lectivity and versatility typical of radical reactions.6,7 One
illustration is seen by comparison with related additions
of basic organometallic reagents.1 These often suffer from
competing aza-enolization8 or lack of generality and
functional group tolerance. For example, a complication
† University of Iowa.
‡
University of Vermont.
(1) Reviews: Alvaro, G.; Savoia, D. Synlett 2002, 651-673. Koba-
yashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094. Bloch, R. Chem.
Rev. 1998, 98, 1407-1438. Davis, F. A.; Zhou, P.; Chen, B.-C. Chem.
Soc. Rev. 1998, 27, 13. Enders, D.; Reinhold: U. Tetrahedron: Asym-
metry 1997, 8, 1895-1946. Denmark, S. E.; Nicaise, O. J.-C. J. Chem.
Soc., Chem. Commun. 1996, 999-1004.
10.1021/jo050756m CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/07/2005
6330
J. Org. Chem. 2005, 70, 6330-6338

Radical Addition Approach to Asymmetric Amine Synthesis
of constructing hindered C-C bonds. The high basicity
associated with these organometallic nucleophiles is
complemented by the milder conditions inherent to
Strecker,11 Mannich,12 and allylsilane additions,13 along
with other recently developed addition reactions.14 Still,
these place significant restrictions on the identity of the
incoming nucleophile destined to become R2 of the chiral
amine (Figure 1). On the other hand, radical reactions
can accommodate a broad range of functionality within
the radical itelf. This suggests great potential scope in
their future application in asymmetric amine synthesis,
pending development of versatile imino acceptors capable
of effective stereocontrol.
Previous intermolecular radical additions by Naito3
and Bertrand4 showed that imino acceptors could be
effectively employed in additions of secondary and ter-
tiary alkyl iodides. These reactions exploited triethylbo-
rane or diethylzinc as initiators, with or without tribu-
tyltin hydride. In some cases, the additions have been
rendered stereoselective by employing a chiral auxiliary
attached either to the carbon or nitrogen of the CdN
bond.3a,f,i,p,4b,d These seminal precedents established that
stereochemical information can be transferred through
the carbon branch or nitrogen substituent of the imine
(Figure 2a). However, in each case, a second independent
activating substituent was employed, and thus, the imino
acceptors required modifications to both nitrogen and
carbon substituents of the imine.
FIGURE 1. Radical carbon-carbon bond disconnection of
chiral amines.
can be observed with branched organometallic reagents
such as i-PrMgBr, which can competitively reduce the
CdN bond via hydride transfer.9 Hindered reagents such
as t-BuMgBr or t-BuLi often fail to give addition prod-
ucts,10 whereas tert-butyl radical addition is quite capable
(2) Reviews of radical additions to imines and related acceptors: (a)
Friestad, G. K. Tetrahedron 2001, 57, 5461-5496. (b) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543-17594. (c) For selected
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Yoshioka, N.; Ueda, M.; Naito, T. J. Chem. Soc., Perkin Trans. 1 1998,
3659-3660. (d) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.;
Naito, T. Tetrahedron 1998, 54, 11431-11444. (e) Miyabe, H.; Ueda,
M.; Yoshioka, N.; Naito, T. Synlett 1999, 465-467. (f) Miyabe, H.; Fujii,
K.; Naito, T. Org. Lett. 1999, 1, 569-572. (g) Miyabe, H.; Fujishima,
Y.; Naito, T. J. Org. Chem. 1999, 64, 2174-2175. (h) Miyabe, H.;
Yamakawa, K.; Yoshioka, N.; Naito, T. Tetrahedron 1999, 11209-
11218. (i) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T.
J. Org. Chem. 2000, 65, 176-185. (j) Miyabe, H.; Ueda, M.; Yoshioka,
N.; Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413-2420. (k)
Miyabe, H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443-1445. (l)
Miyabe, H.; Ueda, M.; Naito, T. J. Chem. Soc., Chem. Commun. 2000,
2059-2060. (m) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000,
5043-5047. (n) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. J.
Chem. Soc., Chem. Commun. 2002, 1454-1455. (o) Ueda, M.; Miyabe,
H.; Nishimura, A.; Sugino, H.; Naito, T. Tetrahedron: Asymmetry 2003,
14, 2857-2859. (p) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.;
Naito, T. J. Chem. Soc., Chem. Commun. 2003, 426-427. (q) Miyabe,
H.; Konishi, C.; Naito, T. Chem. Pharm. Bull. 2003, 51, 540-544. (r)
Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 2003, 1, 381-390.
(s) Ueda, M.; Miyabe, H.; Nishimura, A.; Miyata, O.; Takemoto, Y.;
Naito, T. Org. Lett. 2003, 5, 3835-3838. (t) Miyabe, H.; Ueda, M.;
Nishimura, A.; Naito, T. Tetrahedron 2004, 60, 4227-4235. (u)
McNabb, S. B.; Ueda, M.; Naito, T. Org. Lett. 2004, 6, 1911-1914. (v)
For a review of the Naito group’s work in this area, see: Miyabe, H.;
Ueda, M.; Naito, T. Synlett 2004, 1140-1157.
(4) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett
1998, 780-782. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti,
P. Synlett 1999, 1148-1150. (c) Bertrand, M. P.; Feray, L.; Nouguier,
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56, 3951-3961. (e) Bertrand, M.; Feray, L.; Gastaldi, S. C. R. Acad.
Sci. Paris, Chim. 2002, 5, 623-638.
(5) For recent examples not cited in ref 2, see: (a) Yamada, K.;
Yamamoto, Y.; Maekawa, M.; Tomioka, K. J. Org. Chem. 2004, 69,
1531-1534. (b) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org. Lett.
2003, 5, 1797-1799. (c) Yamada, K.; Fujihara, H.; Yamamoto, Y.;
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Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985-1987. (e) Ferna´ndez,
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J.; Fortes, G.; Guimara˜es, E.; Lemos, A. Synlett 2003, 1403-1406. (h)
Liu, X.; Zhu, S.; Wang, S. Synthesis 2004, 683-691. (i) Singh, N.;
Anand, R. D.; Trehan, S. Tetrahedron Lett. 2004, 45, 2911-2913. (j)
Halland, N.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 2001,
1290-1295.
A potentially more versatile approach to stereocon-
trolled radical addition to imines would achieve both
activation and stereocontrol from a single modification
to the nitrogen substituent of the imino acceptor (Figure
(7) 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.
(8) (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.; Lassaletta, J. M. J. Org. Chem.
1999, 64, 6329-6336.
(9) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913-9914.
(10) Moody, C. J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M.
Z. J. Org. Chem. 1999, 64, 4419-4425.
(11) Selected asymmetric Strecker reactions: Keith, J. M.; Jacobsen,
E. N. Org. Lett. 2004, 6, 153-155. Masumoto, S.; Usuda, H.; Suzuki,
M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634-
5635. Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875-877.
(12) Selected asymmetric Mannich reactions: Hamada, T.; Manabe,
K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7768-7769. Akiyama,
T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
1566-1568. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 12964-12965. Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas,
C. F., III. Tetrahedron Lett. 2001, 42, 199-201. List, B. J. Am. Chem.
Soc. 2000, 122, 9336-9337. Saito, S.; Hatanaka, K.; Yamamoto, H.
Org. Lett. 2000, 2, 1891-1894. Miura, K.; Tamaki, K.; Nakagawa, T.;
Hosomi, A. Angew. Chem., Int. Ed. 2000, 39, 1958-1960.
(13) Selected asymmetric allylsilane additions to CdN bonds: Berg-
er, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686-
5687. Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am Chem.
Soc. 2003, 125, 6610-6611. Fernandes, R. A.; Yamamoto, Y. J. Org.
Chem. 2004, 69, 735-738.
(6) General reviews of radical reactions and their stereocontrol: (a)
Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-
VCH: New York; 2001. (b) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions: Concepts, Guidelines, and
Synthetic Applications; VCH: New York, 1995. (c) Sibi, M. P.; Porter,
N. A. Acc. Chem. Res. 1999, 32, 163-171. (d) Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2563-2579. (e) Giese, B.; Kopping,
B.; Gobel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org.
React. 1996, 48, 301-856. (f) Jasperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237-1286. (g) Giese, B. Radicals in Organic
Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press:
New York, 1986. (h) Hart, D. J. Science 1984, 223, 883-887.
(14) (a) For examples, see ref 1. Also see: (b) Aziridine formation:
Williams, A. L., Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612-
1613. Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518-4521. (c) Nitroalkane addition: Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933-971.
J. Org. Chem, Vol. 70, No. 16, 2005 6331

Friestad et al.
FIGURE 2. Approaches to stereocontrol for radical addition
to CdN bonds. (a) Previous approaches showing the require-
ment for both C- and N-substituents of the CdN bond to play
separate roles for activation and stereocontrol. (b) In the
approach developed here, the C-substituent serves no role in
the reaction, enabling improved versatility.
FIGURE 3. (a) Design of a hypothetical N-linked auxiliary
approach for stereocontrolled radical addition to CdN bonds,
with Lewis acid (LA) chelation inducing a rigid, electronically
activated radical acceptor. (b) Implementation with N-acyl-
hydrazones derived from 4-benzyl-2-oxazolidinone.
The exothermicity of 6-aza-5-hexenyl cyclization of a
dimethylhydrazone (eq 1, X ) NMe2; ∆H ) -11.6 kcal/
mol) suggests an early transition state for the addition
step.2a This assumption simplifies the design of a stereo-
control model because it enables the ground-state struc-
ture to serve as a reasonable approximation of the
transition-state geometry for radical addition to the
hydrazones. Together, these factors prompted our choice
of hydrazones as a platform for auxiliary design. We
hypothesized that steric blocking of one of the enan-
tiotopic approach trajectories by a substituent above or
below the plane of the hydrazone should lead to an
enantioselective process.
2b). Successful addition would then be independent of
the identity of the aldehyde precursor to the imine, which
would potentially broaden the scope of the reaction.
Toward this end, we conceived a nitrogen-linked chiral
auxiliary approach incorporating Lewis acid activation15
and restriction of rotamer populations as key design
elements. We now disclose complete details of the design
and preparation of novel chiral N-acylhydrazones from
2-oxazolidinones and their implementation for highly
stereoselective intermolecular radical addition reac-
tions.16
Results and Discussion
The design process next focused on incorporating
specific features desirable for stereocontrol, namely
restricted rotamer populations and Lewis acid activation,
beginning with a hydrazone bearing a proximal stereo-
genic center (A, Figure 3). Constraining the C-N bond
within a ring and including a carbonyl group would
enable two-point binding of a Lewis acid to afford a rigid
chelate structure (B) with the stereocontrol element
localized over one face of the hydrazone. The Lewis acid
would also increase reactivity toward nucleophilic radi-
cals by lowering the LUMO energy of the CdN bond.6,15
Finally, we noted the facility of reductive cleavage of
N-N bonds,18 whereby an N-linked auxiliary could be
released for reuse after stereoisomer purification. Ox-
azolidinones19,20 emerged as obvious initial candidates to
test our hypothesis.
Experimental evaluation of our design hypothesis
began with preparation of the requisite hydrazones. Prior
to our work, N-amino derivatives of oxazolidinones had
appeared in the literature only rarely21 and to our
knowledge had never been used for asymmetric synthe-
sis. Initially, we employed commercially available (S)-4-
benzyl-2-oxazolidinone (1a, Scheme 1), using White’s
amination procedure for related oxazolidinones.21a This
entailed sequential treatment of 1a with n-butyllithium
Design and Synthesis of Chiral N-Acylhydra-
zones. Early in the design phase, the hydrazone func-
tional group emerged as a desirable starting point for a
new chiral radical acceptor; some basic aspects of hydra-
zone structure and reactivity supported this notion.
Although formation of E/Z mixtures frequently compli-
cates the use of oxime ethers, aldehyde hydrazones
generally adopt CdN E-geometry. In hydrazones, the
nitrogen external to the CdN offers two valences from
which to build a stereocontrol element, a further advan-
tage over oxime ethers. Spectroscopic methods have
shown N,N-dialkylhydrazones to have a predominant
conformer with the N-alkyl bond nearly coplanar with
CdN bond.17 Hydrazones are more effective than imines
as radical acceptors for nucleophilic alkyl radicals. Rate
constants for 6-aza-5-hexenyl radical cyclizations (eq 1)
of N-benzylimine, O-benzyloxime, and N,N-diphenylhy-
drazone are 6.0 × 106 s-1, 2.4 × 107 s-1, and 1.6 × 108
s-1 (80 °C), respectively.2a This trend may be attributed
to beneficial effects of the heteroatom substituent X of
the CdN-X system, combining inductive activation of the
acceptor toward nucleophilic radicals and stabilization
of the adduct aminyl radical by the adjacent nonbonding
electrons.
(18) (a) For discussion and leading references, see: Ding, H.;
Friestad, G. K. Org. Lett. 2004, 6, 637-640. (b) Burk, M. J.; Feaster,
J. E. J. Am. Chem. Soc. 1992, 114, 6266-6267. (c) Sturino, C. F.; Fallis,
A. G. J. Am. Chem. Soc. 1994, 116, 7447-7448.
(19) Evans, D. A.; Kim, A. S. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 1, pp 345-
356.
(15) Protonation of imines leads to improved yields in radical
addition. For reviews of Lewis acid effects in radical reactions, see (a)
ref 6d. (b) Guerin, B.; Ogilvie, W. W.; Guindon Y. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: New York,
2001; pp 441-460.
(20) Oxazolidinones have been used previously for stereocontrolled
radical addition to alkenes. (a) Sibi, M. P.; Jasperse, C. P.; Ji, J. J.
Am. Chem. Soc. 1995, 117, 10779-10780. (b) Sibi, M. P.; Ji, J.; Sausker,
J. B.; Jasperse, C. P. J. Am. Chem. Soc. 1999, 121, 7517-7526.
(21) (a) Kim, M.; White, J. D. J. Am. Chem. Soc. 1977, 99, 1172-
1180. (b) Ciufolini, M. A.; Shimizu, T.; Swaminathan, S.; Xi, N.
Tetrahedron Lett. 1997, 38, 4947-4950. (c) Evans, D. A.; Johnson, D.
S. Org. Lett. 1999, 1, 595-598.
(16) Some of this work has appeared in a preliminary communica-
tion: Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329-
8330.
(17) Rademacher, P.; Pfeffer, H.-U.; Enders, D.; Eichenaur, H.;
Weuster, P. J. Chem. Res., Synop. 1979, 222-223.
6332 J. Org. Chem., Vol. 70, No. 16, 2005

Radical Addition Approach to Asymmetric Amine Synthesis
SCHEME 1
Additional practical notes are worth mentioning. The
method described above affords good yields of chiral
N-acylhydrazones from small to multigram scale. For
example, benzaldehyde hydrazone 7 (9.4 g) was obtained
in 74% yield from 1a employing crystallization (ethanol)
to recover most of the pure hydrazone before chromatog-
raphy of the mother liquors.22 Small amounts of 1a which
may remain after amination do not interfere with the
condensation of 2a with aldehydes. Therefore, it is
generally convenient to use unpurified 2a directly in the
condensation step. If desired, the N-aminooxazolidinone
2a may be purified via its hydrochloride salt; addition of
dry HCl to a diethyl ether solution of 2a causes precipita-
tion of the hygroscopic salt, which can be separated by
filtration and converted back to the free base.
TABLE 1. Amination of Oxazolidinones and
Condensation with Aldehydes (Scheme 1)
The N-acylhydrazones 3-8 represent a novel and
potentially versatile chiral hydrazone moiety. Following
the preliminary communication of this work, several
related applications of these chiral N-acylhydrazones
have been reported,24,25 suggesting the general utility of
this novel chiral auxiliary system for asymmetric amine
synthesis. It is worthwhile to compare the preparations
of the N-amino-oxazolidinones 2 with those of the well-
known Enders chiral hydrazines SAMP and RAMP. The
latter are prepared in six steps from proline or can be
purchased for about $100/g. Our N-amino-oxazolidinone
2a can be prepared in one step from commercial 1a (or
three steps from phenylalanine). With the exception of
1c,26 the oxazolidinones we have examined are efficiently
and reliably transformed into good-to-excellent yields of
the N-acylhydrazones. Both enantiomers of 1a-e and
various other chiral 2-oxazolidinones bearing numerous
substitution patterns are commercially available.27 Fur-
thermore, a wide range of related oxazolidinones may be
easily accessed from well-established methods.28 Numer-
ous applications of these chiral N-acylhydrazones may
be envisioned.
Tin-Mediated Addition of Secondary and Ter-
tiary Radicals. To examine the potential of oxazolidi-
none-derived chiral N-acylhydrazones in radical addition
reactions, the addition of isopropyl iodide to propional-
dehyde hydrazone 3a was chosen for initial screening.
Using the tin hydride method with triethylborane initia-
tion29 (Bu3SnH, Et3B/O2), the effects of Lewis acids were
assessed (Scheme 2, Table 2). A blank control revealed
that inefficient reaction occurred in the absence of Lewis
acid (entry 1). Next, a survey of a variety of simple Lewis
entry oxazolidinone
R1
methoda product, yieldb (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
Et
A
3a, 81
4, 70
i-Pr
t-Bu
c-C6H11
Ph
Ph
CO2Me
Et
A
3
A
5, 72
4
A
6, 65
5
A
7, 67
6c
7
Bd
A
7, 80 (74)e
8, 71
8
9
10
11
B
B
3b, 99
3c, 84
3d, 76
3e, 83
Et
Et
Bd
B
Et
a Method A: (i) n-BuLi, THF, -78 °C, 40 min; (ii) MtsONH2,
-78 °C f rt; (iii) R1CHO, rt. Method B: (1) (i) KH, dioxane, 60
°C, 1 h; (ii) NBzONH2, rt; (2) R1CHO, cat. p-TsOH, toluene, rt.
b Isolated yield from 1. c Reference 22. d NaH was used place of
KH. e Yield on 10 g scale, employing crystallization.
and O-(mesitylenesulfonyl)hydroxylamine (MtsONH2)
and furnished novel N-aminooxazolidinone 2a in 75%
yield. Condensation with various aldehydes (toluene, cat.
p-toluenesulfonic acid) afforded chiral N-acylhydrazones
3a-8 as single isomers in very good overall yields from
2a (Table 1). Alternatively, introduction of aldehydes
directly to the amination reaction mixture gave hydra-
zones via a convenient one-pot protocol.
After the preliminary communication of this work,
O-(p-nitrobenzoyl)hydroxylamine (NbzONH2) was adopted
as the reagent of choice for the amination reaction.22,23
This electrophilic ammonia equivalent is more easily
prepared, handled, and stored than MtsONH2; the latter
has a tendency toward exothermic decomposition. Our
optimized procedure for N-amination using NbzONH2
involved heating the oxazolidinones with NaH (or KH)
in dioxane, followed by introduction of NbzONH2 as a
solid at ambient temperature. The condensation with
aldehydes may be conducted without added acid, al-
though trace amounts of p-TsOH can be beneficial.
Employing this optimized procedure, a series of other
chiral N-acylhydrazones bearing different substituents
on the oxazolidinone were prepared starting from com-
mercially available chiral oxazolidinones 1b-e (Scheme
1). Amination and condensation with propionaldehyde
provided hydrazones 3b-e.
(24) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40,
4491-4493. Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123,
9922-9923.
(25) (a) Radical addition: Ferna´ndez, M.; Alonso, R. Org. Lett. 2003,
5, 2461-2464. (b) Allylindium addition: Cook, G. R.; Maity, B. C.;
Kargbo, R. Org. Lett. 2004, 6, 1741-1743. (c) Mannich-type reaction:
Jacobsen, M. F.; Ionita, L.; Skrydstrup, T. J. Org. Chem. 2004, 69,
4792-4796.
(26) Lower yields with 1c sometimes occur as a result of poor
conversion in the amination step.
(27) For example, 4-(benzoyloxy)methyl-, 4-benzyl-5,5-dimethyl-,
4-tert-butyl-, 5,5-dimethyl-4-phenyl-, cis-4,5-diphenyl-, 5,5-diphenyl-
4-benzyl-, 4-isopropyl-5,5-dimethyl, 4-isopropyl-5,5-diphenyl-, cis-4-
methyl-5-phenyl-, and 4,5,5-triphenyl-2-oxazolidinone are also com-
mercially available.
(28) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835-875.
(29) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403-409. Brown, H. C.; Midland, M. M. Angew. Chem., Int. Ed.
Engl. 1972, 11, 692-700.
(22) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236-6239.
(23) Hynes et al. have recently reported a simple, scalable method
for N-amination of heterocyclic amines with monochloramine: Hynes,
J., Jr.; Doubleday: W. W.; Dyckman, A. J.; Godfrey, J. D., Jr.; Grosso,
J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368-1371.
J. Org. Chem, Vol. 70, No. 16, 2005 6333

Friestad et al.
TABLE 3. Scope of Tin-Mediated Radical Addition to
SCHEME 2
N-Acylhydrazones (R3 ) Bn) in the Presence of ZnCl2
a
R1 of
hydrazone
R2 of
halide
recovered
product,
entry
hydrazoneb (%)
yieldb (%)
1
2
Et (3a)
Et (3a)
Et (3a)
Et (3a)
Et (3a)
Et (3a)
i-Pr (4)
i-Pr (4)
c-C6H11 (6)
c-C6H11 (6)
Ph (7)
i-Pr
29
c
9aC, 60
9aD, 59
9aE, 28
9aF, 54
9aG, 6
c-C5H9
c-C6H11
t-Bu
3
60
14
50
73
88
77
61
79
33
23
64
c
4
5
i-Bu
6
allyl
9aH, 7
TABLE 2. Survey of Lewis Acids for Promotion of
Radical Addition to Propionaldehyde Hydrazone 3a
(Scheme 2)a
7
Et
10aB, 6
10aE, 9
11aB, 15
11aC, 9
12aC, 42
12aD, 59
12aE, 30
12aF, 83
1a, 57
8
c-C6H11
Et
9c
10
11
12
13
14
15
i-Pr
i-Pr
yield of
recovery
product ratio
entry Lewis acid 9aCb (%) of 3ab (%) (9aC/9aB/9aA)c
Ph (7)
c-C5H9
c-C6H11
t-Bu
1
2
3
4
5
6
7
8
9
none
BF3‚Et2O
MgBr2
InCl3
ZnCl2
Zn(OTf)2
Sc(OTf)3
La(OTf)3
Yb(OTf)3
13
0
70
Ph (7)
0:0:100
Ph (7)
NR
55
60
53
CO2Me (8)
i-Pr
0
92:8:0
91:9:0
93:7:0
a Reaction conditions: see Table 2. b Isolated yield (or recovery).
c Not determined.
29
24
15d
20d
32
80d
abstraction from solvent, although that fate was not
confirmed by experiment. On the other hand, allylic
radical intermediates may not be sufficiently reactive for
the addition step: allyl iodide gave a 7% yield with 73%
recovery of the reactant hydrazone (entry 6). As may be
expected for an electrophilic radical, electronically mis-
matched with an electrophilic acceptor, ethyl iodoacetate
gave none of the desired adduct. This negative result is
consistent with the description of Lewis acid-chelated
N-acylhydrazones as electrophilic radical acceptors.
96:4:0
a NR ) no reaction. Reaction conditions: Bu3SnH (5 equiv) and
O2 (7 mL/mmol 3a) by syringe pump, i-PrI (10 equiv), Et3B (10
equiv), and Lewis acid (2 equiv), 2:1 CH2Cl2/ether, -78 °C f rt.
b Isolated yield except where noted. c Ratios by 1H NMR spectra
after removal of tin residues. d Yield estimated from 1H NMR
spectrum.
SCHEME 3
A variety of aldehyde hydrazones were screened (Table
3, entries 7-15). Branching at a saturated R-carbon was
detrimental (entries 7-10); in the extreme case of the
pivalaldehyde hydrazone 5 (R1 ) t-Bu), no ethyl adduct
could be detected (not shown). On the other hand, the
aromatic benzaldehyde hydrazone 7 offered successful
additions, with yields ranging from 30 to 83% (entries
11-14). In one experiment with highly electrophilic
glyoxylate derivative 8 as the radical acceptor, 1a was
obtained as the major product (57% yield, entry 15). The
formation of 1a from 8 involves cleavage of the N-N
bond, which may be explained by Skrydstrup’s mecha-
nistic rationale in a related process.30 With the exception
of 8, however, the reactions were quite clean. Even in
the examples with lower yields, the mass balance after
recovery of the hydrazone precursor was generally 80-
90%, demonstrating the excellent chemoselectivity of the
reactions of radicals with N-acylhydrazones.
Diastereoselectivity. For analysis of the diastereo-
selectivity in these radical additions, the synthetically
useful secondary and tertiary radical additions to hydra-
zones 3 and 7 were selected (Table 4). We were delighted
to find that the radical additions had occurred with
excellent stereocontrol in all cases, with diastereomer
ratios ranging from 93:7 to 99:1. Authentic diastereo-
meric mixtures, prepared by reduction of ketone hydra-
zones,31 were used as standards for spectroscopic and
chromatographic analysis by HPLC and GCMS.
acids was conducted. With BF3‚OEt2, undesired CdN
reduction occurred to afford 9aA in quantitative yield
within 5 min (entry 2), indicating that 3a was remark-
ably prone to Lewis acid activation. Magnesium bromide
did not promote radical addition (entry 3). On the other
hand, InCl3 and Zn(II) salts afforded clean (albeit incom-
plete) conversion to desired adduct 9aC (entries 4-6).
Scandium triflate and lanthanide triflates (entries 7-9)
gave modest yields. Gratifyingly, initial examination by
1H NMR spectroscopy showed a single diastereomer (dr
>98:2). In contrast, 9aC was produced with poor selectiv-
ity (dr 2:1) in the absence of Lewis acid.
The scope of the reaction was evaluated by variations
to both the radical and the radical acceptor. In the
presence of ZnCl2, the propionaldehyde N-acylhydrazone
3a was subjected to radical additions of various organic
iodides (Scheme 3, Table 3, entries 1-6). Ethyl radical
(from the triethylborane) can compete for the radical
acceptor, and as a result, the separable ethyl radical
adduct 9aB was observed (<10% yield) in all cases.
Radical reactivity is important in predicting the success
of the addition reactions. With simple secondary and
tertiary alkyl iodides as radical precursors (entries 1-4),
additions to 3a occurred with moderate yields to afford
N-acylhydrazines 9aC-9aF. A primary radical precur-
sor, 1-iodo-2-methylpropane, gave a low yield of isobutyl
adduct 9aG (entry 5). Not unexpectedly, iodobenzene
gave no phenyl adduct (not shown). The more reactive
radicals formed in these cases likely suffer hydrogen atom
(30) Reduction or radical addition of 8 could be followed by proton
transfer from the R-carbon of the amine and â-elimination of 1a. The
adjacent carbomethoxy substituent would be expected to facilitate the
proton transfer. See ref 25c.
6334 J. Org. Chem., Vol. 70, No. 16, 2005

Radical Addition Approach to Asymmetric Amine Synthesis
TABLE 4. Diastereoselectivity in Tin-Mediated Radical
Additions of Various Alkyl Iodides with Hydrazones
SCHEME 4
entry
hydrazone
R2
product, diastereomer ratioc
1
2
3a
3a
3a
3a
7
i-Pr
9aC, 99:1
c-C5H9
c-C6H11
t-Bu
9aD, 96:4
3
9aE, 97:3
4
9aF, 95:5
5
i-Pr
12aC, 99:1
6
7
c-C5H9
c-C6H11
t-Bu
12aD, 96:4
7
7
7
3b
3c
3d
3e
12aE, 99:1
8
12aF, 93:7
9
i-Pr
9bC (15%),b >98:2
9cC (16%),b -d
9dC (35%),b 94:6
9eC (50%),b 95:5
10
11
12
i-Pr
i-Pr
i-Pr
a Reaction conditions: Table 2. b Isolated yield. c Ratios by
HPLC (9aC-9aF, 9eC), GCMS (12aC-12aF), or 1H NMR inte-
gration (9bC, 9dC) versus authentic mixtures. In separate reac-
tions, diastereomer ratios of 9aE and 9aF were reproduced within
0.5%. Yields for entries 1-8 are found in Table 3. d Ratio not
available; no method was found to resolve the diastereomers 9cC.
The two lowest selectivities are those involving tert-
butyl addition, which is surprising considering the later
transition state expected for addition of this more stable
radical. Later diastereomeric transition states might be
expected to be more effectively differentiated by the steric
control. However, the design of the chiral N-acylhydra-
zone motif was built around the assumption of reactant-
like planar geometry at the CdN bond. The decreased
stereoselectivity with tert-butyl addition may be rational-
ized by considering the limitations of this assumption;
later transition states may be deformed from the simple
ground-state geometry of Figure 3 by further rehybrid-
ization (i.e., from sp2 to sp3 at the imine carbon). Thus,
the addition of more stable radicals such as tert-butyl
may require refining of the model.
additions the simple benzyl control element affords the
highest selectivity. This distinction can be attributed to
the closer proximity of the control element and acceptor
carbon in hydrazones 3a and 7 relative to N-enoyloxazo-
lidinones, resulting in more effective steric blocking while
limiting rotational freedom.
Reductive N-N Bond Cleavage. For synthetic ac-
cess to chiral R-branched amines, cleavage of the N-N
bond of the adduct hydrazines is required (Scheme 4).
Because reported conditions for such N-N bond cleavage
reactions appeared to be highly substrate dependent, we
screened a variety of conditions. The results were initially
discouraging. Treatment of 9aC with SmI2 in THF/
HMPA gave no reaction at all, and other one-electron
reductants (Na/NH3 or sodium naphthalenide) resulted
in complex reaction mixtures. Neither Zn/HOAc33 nor
Raney nickel34 was effective; the starting material was
Next, the effects of varying the stereocontrol element
substituents on the oxazolidinone moiety were assessed,
with the main goal to examine the change in diastereo-
selectivity. Isopropyl radical additions to several N-
acylhydrazones 3a-e are compared in Table 4. Although
the yields given for reactions of 3b-e (entries 9-12) were
inferior to the previous addition to 3a (entry 1, see Table
3), they were not optimized for yield and there was no
attempt to achieve complete conversion. All of the
auxiliaries gave very high diastereoselectivity in the
addition reactions, using the specific case of addition of
isopropyl radical to propionaldehyde hydrazone. Compar-
ing entry 1 with entries 9-12, the benzyl (dr 99:1 by
HPLC) and diphenylmethyl (dr >98:2 by 1H NMR)
blocking groups gave the most effective stereocontrol.
With diphenylmethyl, none of the minor diastereomer
35
recovered. Likewise, hydrogenation with Pd(OH)2
(HCOONH4 or 1 atm H2) in neutral or acidic conditions
produced no cleavage of the auxiliary. Considering the
strong precedent for cleavage of benzoic hydrazides with
SmI2, we finally resorted to benzoylation of the basic
nitrogen of hydrazide 9aC. This was readily achieved by
sequential treatment with n-BuLi and benzoyl chloride,
affording benzamide derivative 13 in 83% yield (Scheme
4). Exposure of 13 to SmI2 cleanly afforded 14 (99% yield)
and 1a (97% yield) within 5 min.36
1
Stereochemical Assignment. Chemical correlation
and X-ray crystallographic analysis were employed for
could be detected by H NMR. The reason for decreased
stereoselectivity in additions to 3d and 3e is unclear, but
it might be speculated that increased rigidity of the
blocking group on the oxazolidinone prevents the aro-
matic π-system from effectively blocking the face of the
CdN bond.
(32) Sibi et al. found that 4-(diphenylmethyl)-2-oxazolidinone was
needed for good stereocontrol (dr ) 45: 1) in isopropyl radical addition
to N-cinnamoyl derivatives (4-benzyl-2-oxazolidinone gave dr ) 2:1).
See ref 20b.
(33) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595-598.
(34) (a) Enders, D.; Schubert, H.; Nubling, C. Angew. Chem., Int.
Ed. Engl. 1986, 25, 1109-1110. (b) Evans, D. A.; Britton, T. C.; Dorow,
R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986, 108, 6395-6396. (c)
Alexakis, A.; Lensen, N.; Mangeney, P. Synlett 1991, 625-626.
(35) Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543-5546.
(36) When hydrazide 9aC was acylated by n-BuLi/MeOCOCl (81%
yield) or n-BuLi/CbzCl (89% yield), the products did not react with
SmI2.
In contrast to related additions to R,â-unsaturated
amides which require a larger blocking group,20,32 in these
(31) Reduction (Bu3SnH, BF3‚OEt2) of N-acylhydrazones proved to
be generally efficient. For details regarding this stereospecific reduction
reaction, see: Qin, J.; Friestad, G. K. Tetrahedron 2003, 59, 6393-
6402.
J. Org. Chem, Vol. 70, No. 16, 2005 6335

Friestad et al.
TABLE 5. Scope of Radical Precursor in Tin-Free
TABLE 6. PhotolyticTin-Mediated Radical Addition to
a
a
Radical Addition to 3a in the Presence of InCl3
N-Acylhydrazone 3a in the Presence of InCl3
entry
R2 of halide
product, yieldb (%)
entry
R2 of halide
recovered 3ab (%)
product, yieldb (%)
1
2
3
4
5
Et
9aB, 33
9aC, 75c
9aD, 47
9aE, 56
9aI, 33
1c
2
3
4
5
6
Et
8
9aB, 56
9aC, 50d
e
9aH, 25
9aI, 32
9aJ, 9
i-Pr
i-Pr
t-Bu
allyl
CH2Cl
Me
(33)
(63)
e
c-C5H9
c-C6H11
CH2Cl
30
25
a Reaction conditions: as in entry 4 of Table 2, minus Bu3SnH.
b Isolated yield. c dr > 95:5 (1H NMR).
a Reaction conditions: R2-I (10 equiv), Me3SnSnMe3 (1.2 equiv),
InCl3 (2.3 equiv), acetone (5 equiv), CH2Cl2, hν (300 nm, Rayonet),
ca. 30-35 °C. a Isolated yield (or recovery). Numbers in paren-
theses are for acetone hydrazone 16. b EtI: 2 equiv. c dr > 95:5
(1H NMR). d Not detected.
assignment of the absolute configurations of 9aC and
12aF. Starting from (S)-valinol (Scheme 4), Boc-protec-
tion, O-tosylation, homologation with Me2CuLi, and
exchange of the carbamate for benzamide afforded 14,
[R] ) +10.0 (c 1.0, CHCl3). The same compound, when
obtained by N-N bond cleavage of 13 as described above,
had virtually identical specific rotation: [R] ) +10.2 (c
0.24, CHCl3). The (R) configuration can thus be assigned
to benzamide 14 and isopropyl radical addition product
9aC. Configurations of the other adducts 9-11 were
assigned by analogy with 9aC. Extension of this assign-
ment to benzaldehyde-derived adducts 12 was bolstered
by X-ray crystallographic analysis of 15, obtained by
benzoylation of 12aF. Here the (S) configuration was
observed (see the Supporting Information), enabling
unambiguous assignment of the same configuration to
12aC-12aE. It should be noted that the configurational
designations in this case imply the same transition state
topology for formation of 9aC and 12aF; they differ only
due to different substituent priorities in the products. All
the available stereochemical evidence is consistent with
radical addition to the si face of the chelated model B
(Figure 3).
Tin-Free Radical Addition. An attractive attribute
of the use of triethylborane or diethylzinc as initiators
in radical additions to CdN bonds is the potential for a
radical chain process without tin hydride. In the absence
of tin hydride, the Et3B and Et2Zn were proposed to have
multiple roles, including both initiation and chain
transfer.3e,4b Chain propagation in this scenario has been
proposed to involve a homolytic substitution at the boron
center by the adduct aminyl radical, releasing another
ethyl radical. Thus, because the triethylborane serves as
both initiator and chain transfer agent, stoichiometric
quantities are consumed.
In search of improvement of the radical additions to
N-acylhydrazones, triethylborane-mediated tin-free ad-
ditions of various halides were attempted, using InCl3
as the Lewis acid (Table 5). As in the case of tin-mediated
additions, the secondary iodides worked quite well in
additions to the propionaldehyde hydrazone (entries
2-4). Toward more synthetic versatility, additions of a
series of functionalized radicals of general formula •CH2X
were attempted using N-acylhydrazone 3a. These were
chosen on the basis of the expectation of favorable
reactivity in the crucial iodine atom-transfer step. Using
triethylborane initiation, ethyl radical from triethylbo-
rane must abstract iodine atom from the alkyl iodide, a
process which is favored by formation of a more stable
radical. Unfortunately, despite numerous attempts, the
functionalized radical additions were mostly unsuccess-
ful.37 However, chloroiodomethane did lead to successful
modest 33% yield (entry 5). The adduct, which retains
the chloride, offers the potential for subsequent functional
group manipulations of the radical-derived alkyl group.
Tin-Mediated Addition of Primary Radicals. De-
spite the success in addition of chloromethyl and simple
alkyl radicals in both tin-mediated and tin-free methods,
the synthetic potential of these intermolecular radical
additions could be dramatically enhanced by development
of conditions compatible with primary radicals. We
recognized two significant problems interfering with
primary radical addition using existing methods: Less
stable primary radicals (versus secondary or tertiary)
might not be sufficiently long-lived to avoid premature
reduction by hydrogen atom abstraction processes, and
generation of the desired radical from a primary alkyl
iodide under tin-free conditions requires an unfavorable
iodine atom transfer to the Et• produced from the Et3B/
O2 initiator. 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 observa-
tions led us to consider alternatives to Et3B/O2 initiation.
Kim has extensively developed the use of nonreductive
radical addition-elimination reactions to C-sulfonyl oxime
ethers.38,39 In these reactions, photochemical initiation
with acetone as a sensitizer enables hexamethylditin to
mediate addition of various simple and functionalized
primary alkyl halides. We wondered if these conditions
might also offer a solution to the problem of reductive
radical addition of primary alkyl iodides to our N-
acylhydrazones.
Applying the Kim conditions in the presence of InCl3,
iodoethane underwent addition to hydrazone 3a in 56%
yield (entry 1, Table 6). Use of related In(III) salts offered
(37) (a) Other functionalized halide precursors attempted without
success (<5% yield) include ethyl iodoacetate, iodomethyl methyl ether,
bromomethyl acetate, iodomethyltrimethylsilane, and allyl iodide. (b)
The tin-free conditions did not solve the problem of branched hydra-
zones: only 6% yield was obtained in ethyl iodide addition to cyclo-
hexanecarboxaldehyde hydrazone 6 (48% recovery of 6).
(38) (a) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc.
1996, 118, 5138-5139. Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997,
119, 5982-5983. Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.;
Yoon, J.-Y.; Kim, S. J. Am. Chem. Soc. 1999, 121, 12190-12191. Jeon,
G.-H.; Yoon, J.-Y.; Kim, S.; Kim, S. S. Synlett 2000, 128-130. Kim, S.;
Kim, N.; Yoon, J.-Y.; Oh, D. H. Synlett 2000, 1148-1150. Kim, S.;
Kavali, R. Tetrahedron Lett. 2002, 43, 7189-7191. (b) For a related
method using primary alkyl tellurides, see: Kim, S.; Song, H.-J.; Choi,
T.-L.; Yoon, J.-Y. Angew. Chem., Int. Ed. 2001, 40, 2524-2526.
(39) Nonreductive additions of 1,3-cyclohexanediones to imines using
Mn(OAc)3 as an oxidant have recently been reported. Zhang, Z.; Wang,
G.-W.; Miao, C.-B.; Dang, Y.-W.; Shen, Y.-B. Chem. Commun. 2004,
1832-1833.
•
addition of the CH2Cl group to afford 9aI, albeit in
6336 J. Org. Chem., Vol. 70, No. 16, 2005

Radical Addition Approach to Asymmetric Amine Synthesis
SCHEME 5
useful for addition of secondary and tertiary radicals,
although chloromethyl and allyl have been added using
two complementary methods. New insights and elements
of expanded scope are highlighted in this full paper: (1)
Comparison of several other control elements on the
oxazolidinone showed that all were effective. Although
the benzyl substituent gives slightly higher diastereomer
ratios, only slight differences were noted which are
insignificant from a synthetic standpoint. (2) Tin-free
reactions were developed exploiting dual functions of
triethylborane for both initiation and chain propagation.
(3) Photolytic reactions with hexamethylditin enabled
addition of primary radicals in modest yields.
no improvement.40 Isopropyl iodide addition proceeded
in 50% yield (entry 2), although tert-butyl addition (entry
3) failed. Chloromethyl and allyl additions under these
conditions gave low yields (entries 4 and 5), and other
attempts to use functionalized primary radicals (•CH2-
Experimental Section43
•
•
•
OMe, CH2SiMe3, CH2CO2Me, CH2CH2OH) resulted in
no observed adduct. Methyl addition afforded only a very
low yield of 9aJ (entry 6). A further increase in efficiency
was never achieved, in part due to complications from
the use of acetone as a sensitizer. Acetone replaced the
aldehyde component of the hydrazone through a carbonyl
exchange side reaction41 to provide variable amounts of
hydrazone 16. For example, the isopropyl adduct was
accompanied by 33% yield of 16 (entry 2), while a 63%
yield of this byproduct was the only material recovered
in an attempted tert-butyl addition (Entry 3).
(S)-3-Amino-4-phenylmethyl-2-oxazolidinone (2a). To
a solution of (S)-(-)-4-benzyl-2-oxazolidinone (1a) (3.50 g, 19.77
mmol) in THF (350 mL) was added n-BuLi (12.35 mL, 2.0 M
in hexane, 24.7 mmol) at -78 °C. After 1 h, O-(mesitylene-
sulfonyl)hydroxylamine [MtsONH2, CAUTION44] (5.53 g, 25.7
mmol) was added, and the reaction mixture was allowed to
warm to room temperature. Concentration and gradient flash
chromatography (hexane f 1:5 hexane/EtOAc) afforded 2a as
a pale yellow oil (2.85 g, 75% yield): [R]22D +72.8 (c 3.7, CHCl3);
IR (film) 3339, 3215, 3061, 2921, 1762, 1625, 1454, 1230, 1091,
1
1025, 921 cm-1; H NMR (500 MHz, CDCl3) δ 7.30 (dd, J )
7.3, 7.3 Hz, 2H), 7.23 (dd, J ) 7.3, 7.3 Hz, 1H), 7.14 (d, J )
7.3 Hz, 2H), 4.14 (dd, J ) 7.5, 7.5 Hz, 1H), 3.98-3.90 (m, 4H),
3.27 (dd, J ) 13.8, 3.6 Hz, 1H), 2.70 (dd, J ) 13.6, 8.7 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 159.1, 135.5, 129.0, 128.7,
126.9, 66.0, 59.5, 37.3; MS (CI) m/z (relative intensity) 193 ([M
+ H]+, 100), 178 (100). Anal. Calcd for C10H12N2O2: C, 62.49;
H, 6.29; N, 14.57. Found: C, 62.05; H, 6.34; N, 14.27.
Preparation of Hydrazones (Table 1): General Pro-
cedures. Compounds 3-8 were prepared by general proce-
dures A and B as indicated in Table 1, with details provided
in the Supporting Information. Although this general proce-
dure A was used to obtain 4-8 for our initial studies, we now
recommend the alternative general procedure B. Representa-
tive preparations of 3a and 3b are described below.
Further insight was gleaned from the exploratory
studies of the photolytic conditions. Interestingly, when
trials of ethyl radical addition were carried out in the
presence of diethyl ether as a cosolvent, adduct 9aK was
obtained as a minor product (14% yield) along with the
expected 9aB (25% yield). This product can be attributed
to a hydrogen atom abstraction process by ethyl radicals
or aminyl radicals (i.e., hydrazone adduct radicals) in
which diethyl ether serves as the H-atom donor (Scheme
5).42 This provides a 1-ethoxyethyl radical which can
compete for the N-acylhydrazone acceptor. Importantly,
evidence of slight stereocontrol was seen at the ethoxy-
ethyl stereocenter (dr 2:1), suggesting that it may be
possible to design an approach to stereocontrol in addition
of related prochiral radicals.
General Procedure A. To a solution of 1 in THF (0.06 M)
was added n-BuLi (2.5 M in hexane, 1.1 equiv) at -78 °C. After
40 min, MtsONH21 (1.2 equiv) was added, the reaction mixture
was allowed to warm to room temperature, and the appropri-
ate aldehyde (5 equiv) was introduced. When the reaction was
complete (TLC), the mixture was diluted with twice its volume
of ether and partitioned between ether and water. The organic
phase was dried over Na2SO4 and concentrated. Gradient flash
chromatography (hexane f 3:1 hexane/EtOAc) furnished pure
1
hydrazones as single CdN isomers (>98:2, H NMR).
(S)-3-(Propylidene)amino-4-phenylmethyl-2-oxazolidi-
none (3a). From 1a (400 mg, 2.26 mmol) and propionaldehyde
by general procedure A was obtained 3a (425 mg, 81% yield)
as a pale yellow oil: [R]25D +7.5 (c 3.8, CHCl3); IR (film) 3062,
2935, 2877, 1762, 1632, 1478, 1405, 1208, 1093, 930 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.98 (t, J ) 5.2 Hz, 1H), 7.27-7.11
(m, 5H), 4.31 (dddd, J ) 8.2, 8.2, 4.0, 4.0 Hz, 1H), 4.17 (dd, J
) 8.8, 8.8 Hz, 1H), 4.02 (dd, J ) 8.8, 5.6 Hz, 1H), 3.16 (dd, J
) 13.9, 3,7 Hz, 1H), 2.76 (dd, J ) 13.9, 8.6 Hz, 1H), 2.37-2.34
(m, 2H), 1.10 (t, J ) 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
Conclusion
In conclusion, a novel N-acylhydrazone auxiliary ap-
proach gives excellent stereocontrol in radical addition
to CdN bonds. Notably, this is the first intermolecular
radical addition to CdN bonds which does not require
adjacent carbonyl functionality for auxiliary linkage or
acceptor activation. The tin-mediated reaction is mainly
(43) A statement of general experimental procedures is provided in
the Supporting Information.
(40) Use of other In(III) Lewis acids led to the following yields of
9aB: InF3 (16%), InI3 (54%), In(OAc)3 (12%), and In(OTf)3 (30%).
(41) We have previously described preparative exchange reactions
between certain N-acylhydrazones and carbonyl compounds. See ref
22.
(42) The presence of several other potential H-atom donors, includ-
ing EtOH, Et3SiH, Ph3SiH, (Me3Si)3SiH, resulted in a decreased yield
of 9aB.
(44) CAUTION: O-(Mesitylenesulfonyl)hydroxylamine (MtsONH2)
shows a tendency toward exothermic spontaneous decomposition
during its preparation and storage. Although most of the work
described here was conducted using MtsONH2, we have discontinued
use of this compound in favor of the alternative amination reagent
O-(p-nitrobenzoyl)hydroxylamine (NbzONH2), which gives similar
results in the amination of oxazolidinones. Another viable alternative
is O-(diphenylphosphinoyl)hydroxylamine (DppONH2).
J. Org. Chem, Vol. 70, No. 16, 2005 6337

Friestad et al.
δ 157.3, 154.3, 135.2, 129.1, 128.7, 127.0, 65.6, 57.6, 37.1, 26.5,
10.5; MS (CI) m/z (relative intensity) 233 ([M + H]+, 100), 232
(M, 7). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06.
Found: C, 66.98; H, 6.83; N, 12.06.
Tin-Free Radical Addition Using InCl3 with Trieth-
ylborane Initiation (Table 5): General Procedure D. The
standard method for tin-mediated radical addition (general
procedure C) was employed, with the following modifications:
InCl3 was substituted for ZnCl2, and Bu3SnH was omitted.
(4S,2′R)-3-(1′-Chloro-2′-butanamino)-4-phenylmethyl-
2-oxazolidinone (9aI). From 3a (48 mg, 0.21 mmol) and
chloroiodomethane (0.15 ml, 2.07 mmol) by general procedure
General Procedure B. As described in detail elsewhere,22
hydrazones 3b-e were prepared by the following sequence:
(i) NaH (or KH; 1.05 equiv), dioxane, reflux; (ii) O-(p-nitroben-
zoyl)hydroxylamine (NbzONH2; 1.05 equiv); (iii) aldehyde,
p-TsOH, toluene.)
D was obtained 9aI (19 mg, 33% yield) as a colorless oil: [R]27
D
(S)-3-(Propylidene)amino-4-diphenylmethyl-2-oxazo-
lidinone (3b). From 1b (160 mg, 1.03 mmol) and propional-
dehyde by general procedure B was obtained 3b (192 mg, 99%
+44.9 (c 3.4, CHCl3); IR (film) 3286, 3028, 2966, 2878, 1758,
1
1497, 1400, 1240, 1217, 1091, 1207, 745, 702 cm-1; H NMR
(500 MHz, CDCl3) δ 7.31 (dd, J ) 8.0, 8.0 Hz, 2H), 7.25 (dd, J
) 7.9, 7.9 Hz, 1H), 7.16 (d, J ) 7.6 Hz, 2H), 4.13 (dd, J ) 8.6,
8.6 Hz, 1H), 4.03 (dd, J ) 8.9, 5.8 Hz, 1H), 3.93-3.88 (m, 1H),
4.25-3.85 (br s, 1H), 3.62 (ABX, ∆νAB ) 28 Hz, JAB ) 11.4 Hz,
JAX ) 4.6 Hz, JBX ) 4.9 Hz, 2H), 3.41 (dd, J ) 13.4, 3.6 Hz,
1H), 3.24 (dddd, J ) 5.5, 5.5, 5.5, 5.5 Hz, 1H), 2.63 (dd, J )
13.3, 10.1 Hz, 1H), 1.70-1.56 (m, 2H), 1.01 (t, J ) 7.4 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 159.0, 135.8, 129.0, 128.9,
127.1, 66.2, 61.3, 59.7, 45.5, 37.1, 23.4, 9.8; MS (CI) m/z
(relative intensity) 283 ([M + H]+, 100). Anal. Calcd for
C14H19N2O2Cl: C, 59.47; H, 6.77; N, 9.91. Found: C, 59.69; H,
6.82; N, 9.80.
yield) as a pale yellow oil: [R]28 +32.3 (c 0.65, CHCl3); IR
D
(film) 3493, 2982, 2913, 1753, 1495, 1410, 1222, 1091, 1030
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.82 (t, J ) 4.35 Hz, 1H),
7.21-7.04 (m, 10H), 4.81 (ddd, J ) 8.5, 6.1, 6.1 Hz, 1H), 4.38
(d, J ) 6.4 Hz, 1H), 4.33 (dd, J ) 8.7, 8.7 Hz, 1H), 4.06 (dd, J
) 9.0, 5.6 Hz, 1H), 2.14-2.08 (m, 2H), 0.86 (t, J ) 7.5 Hz,
3H); 13C NMR (500 MHz, CDCl3) δ 159.2, 154.7, 140.2, 139.1,
128.8 (2C), 128.7, 128.6, 127.4, 126.9, 64.9, 59.9, 53.1, 26.5,
10.2; MS (CI) m/z (relative intensity) 309.5 ([M + H]+, 100%).
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08.
Found: C, 73.82; H, 6.60; N, 8.85.
Tin-Mediated Radical Addition to Hydrazones (Tables
2-4): General Procedure C. To a solution of the hydrazone
in CH2Cl2 (ca. 0.25 M) was added ZnCl2 (1 M in Et2O, 2 equiv).
After 1 h at room temperature, the mixture was cooled to -78
°C, followed by addition of Et3B (10 equiv) and the appropriate
alkyl iodide (10 equiv). Bu3SnH (0.25 M in CH2Cl2, 5 equiv)
and O2 (ca. 7 mL/mmol hydrazone) were introduced by syringe
pump over ca. 5 h. The reaction mixture was allowed to warm
slowly to room temperature. After 2 d, stannanes were
removed by dilution with EtOAc, stirring overnight with excess
KF, and filtration through a short pad of silica gel. Concentra-
tion and radial chromatography (hexane/EtOAc) afforded
N-acylhydrazines 9-12. Side products 9aA and 9aB were
obtained in varying amounts in some experiments. For those
N-acylhydrazines for which diastereomer ratios are reported,
control experiments established that no change in the dias-
tereomer ratios occurred prior to analysis. Diastereomer ratios
were determined by comparison with authentic diastereomer
mixtures prepared by an alternative route.5 Diastereomer
ratios of 9aC-9aF and 9eC were determined by HPLC.
Diastereomer ratios of N-acylhydrazines 12aC-12aF were
determined by GCMS. Diastereomer ratios of 9bC and 9cC
Photolytic Tin-Mediated Radical Addition (Table 6):
Hydrazines 9aB and 9aK (General Procedure E). To a
solution of hydrazone 3a (60 mg, 0.26 mmol) and InCl3 (132
mg, 0.60 mmol) in CH2Cl2/Et2O (2 mL/2 mL) were added EtI
(41 µL, 0.52 mmol), (CH3)3SnSn(CH3)3 (102 mg, 0.31 mmol),
and acetone (95 µL, 1.30 mmol), and the mixture was irradi-
ated for 18 h under N2. Stannanes were removed by dilution
with EtOAc, stirring overnight with excess KF, and filtration
through a short pad of silica gel. Concentration and gradient
flash chromatography (hexane to hexane/EtOAc 3:1) afforded
9aK45 (7 mg of major isomer, 4 mg of minor isomer, 14% yield)
and 9aB (17 mg, 25% yield) as a colorless oil: [R]23 +33.5 (c
D
0.21, CHCl3); IR (film) 3291, 3028, 2963, 1758, 1604, 1454,
1
1239, 1088 cm-1; H NMR (500 MHz, CDCl3) δ 7.32 (dddd, J
) 7.0, 7.0, 1.6, 1.6 Hz, 2H), 7.25 (dddd, J ) 7.3, 7.3, 1.3, 1.3
Hz, 1H), 7.16 (ddd, J ) 7.1, 1.5, 1.5 Hz, 2H), 4.14 (dd, J ) 8.8,
7.6 Hz, 1H), 4.03 (dd, J ) 8.9, 4.8 Hz, 1H), 3.95 (d, J ) 3.8 Hz,
1H), 3.92-3.87 (m, 1H), 3.34 (dd, J ) 13.5, 3,6 Hz, 1H), 2.98-
2.92 (m, 1H), 2.62 (dd, J ) 13.5, 10.0 Hz, 1H), 1.53-1.45 (m,
4H), 1.00-0.94 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 158.6,
136.1, 129.1, 128.9, 127.0, 65.7, 61.5, 59.8, 37.0, 24.2, 24.1, 9.7,
9.1; MS (CI) m/z (relative intensity) 263 ([M + H]+, 100). Anal.
Calcd for C15H22N2O2: C, 68.67; H, 8.45; N, 10.68. Found: C,
68.44; H, 8.42; N, 10.54.
1
were determined by integration of H NMR data obtained in
the presence of the NMR shift reagent tris(6,6,7,7,8,8,8-
heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III) (Siev-
er’s reagent).
A similar experiment in the absence of Et2O afforded 9aB
in 56% yield; 9aK was not observed. The rest of the results in
Table 6 were also obtained in the absence of Et2O.
(4S,3′R)-3-(2′-Methyl-3′-pentylamino)-4-phenylmethyl-
2-oxazolidinone (9aC). From 3a (32 mg, 0.138 mmol) and
2-iodopropane by general procedure C was obtained 9aC (23
mg, 60% yield, S,R/S,S ) 99:1) as a colorless solid: HPLC
Acknowledgment. We thank the NSF (CHE-
0096803), Research Corporation, Petroleum Research
Fund, and Vermont EPSCoR (fellowship to J.Q.) for
generous support. We thank Dr. Patrick J. Carroll
(University of Pennsylvania) for X-ray crystallography
and Dr. Jean-Charles Marie´ for valuable assistance in
preparation of this manuscript.
retention time 11.3 min; mp 75-76 °C; [R]26 + 38.3 (c 0.65,
D
CHCl3); IR (film) 3296, 3089, 3026, 2960, 2927, 1779, 1604,
1491, 1392, 1368, 1252, 1082, 953, 833 cm-1 1H NMR (500
;
MHz, CDCl3) δ 7.29 (dd, J ) 7.2, 7.2 Hz, 2H), 7.23 (dd, J )
7.4, 7.4 Hz, 1H), 7.13 (d, J ) 7.2 Hz, 2H), 4.09 (dd, J ) 8.6,
8.6 Hz, 1H), 4.00 (dd, J ) 8.8, 4.9 Hz, 2H), 3.89-3.84 (m, 1H),
3.32 (dd, J ) 13.4, 3.5 Hz, 1H), 2.75 (m, apparent quartet, J
) 6.1 Hz, 1H), 2.59 (dd, J ) 13.4, 10.0 Hz, 1H), 1.83 (m,
apparent octet, J ) 4.8 Hz, 1H), 1.52-1.44 (m, 1H), 1.43-
1.35 (m, 1H), 0.98-0.92 (m, 9H); 13C NMR (125 MHz, CDCl3)
δ 158.6, 136.1, 129.1, 128.9, 127.0, 65.8, 59.7, 37.0, 28.2, 21.5,
18.4, 17.9, 10.2; MS (CI) m/z (relative intensity) 277 ([M +
H]+, 100), 276 (M, 8); HRMS (FAB+) calcd for C16H24N2O2Li
283.1998, found 283.1993.
Supporting Information Available: Characterization
data for 2-16 with selected experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050756M
(45) For characterization data, see the Supporting Information.
6338 J. Org. Chem., Vol. 70, No. 16, 2005