Mn-mediated coupling of alkyl iodides and chiral N-acylhydrazones: Optimization, scope, and evidence for a radical mechanism

Article abstract of DOI:10.1021/jo061158q

Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to C=N bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals, a serious limitation from the perspective of synthetic applications. Here, we provide full details of the use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn ₂(CO)₁₀ and InCl₃ as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2 at ca. 35 °C. The reaction tolerates additional functionality in either reactant, enabling subsequent transformations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further mechanistic control experiments confirmed the intermediacy of radicals and showed that independently prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid toxic tin reagents and enable stereoselective intermolecular radical additions to C=N bonds with the broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.

Full text of DOI:10.1021/jo061158q

Mn-Mediated Coupling of Alkyl Iodides and
Chiral N-Acylhydrazones: Optimization, Scope, and
Evidence for a Radical Mechanism
Gregory K. Friestad,*,† Jean-Charles Marie´,† YoungSung Suh,‡ 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 June 6, 2006
Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond
constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to CdN
bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals,
a serious limitation from the perspective of synthetic applications. Here, we provide full details of the
use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to
N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn2(CO)10
and InCl3 as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2
at ca. 35 °C. The reaction tolerates additional functionality in either reactant, enabling subsequent trans-
formations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing
different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol
revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further
mechanistic control experiments confirmed the intermediacy of radicals and showed that independently
prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the
N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid
toxic tin reagents and enable stereoselective intermolecular radical additions to CdN bonds with the
broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.
Introduction
ence of complicating structural features. In this context, devel-
opment of general methods for acyclic stereocontrol remains a
significant challenge, especially within the constraints of mild
reaction conditions compatible with complex multifunctional
precursors.
Chiral R-branched amines are common substructures of
bioactive synthetic targets such as alkaloids and amino acids.
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. Furthermore, the most versatile
methods to achieve this objective would enable disconnection
of either C-C bond at the amine stereogenic center (Scheme 1);
the choice could be made depending on issues of synthetic
expediency, such as the availability of precursors and the pres-
Stereocontrolled intermolecular radical addition2 to imino
compounds is an attractive approach to asymmetric amine
(1) Reviews: Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr.
Org. Chem. 2005, 9, 1315-1392. Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984-995. Alvaro, G.; Savoia, D. Synlett 2002,
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† University of Iowa.
‡ University of Vermont.
10.1021/jo061158q CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/11/2006
7016
J. Org. Chem. 2006, 71, 7016-7027

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
SCHEME 1
SCHEME 2
synthesis.3 Additions of basic organometallic reagents often
suffer from competing aza-enolization4 or lack of generality and
functional group tolerance. In contrast, carbon-centered radicals
are nonbasic, avoiding aza-enolization, and can be generated
under mild conditions. Their intermolecular addition reactions
to π systems can accommodate the presence of additional func-
tionality in both precursors because they exhibit good chemo-
selectivity for addition to CdC and CdN bonds. The reaction
conditions are quite flexible; although neutral conditions are
typical, nonpolar radical intermediates are usually compatible
with Lewis acids or bases. Many of these attributes offer signif-
icant advantages relative to reactions of traditional organo-
metallic nucleophiles. Seminal work by Naito5 and Bertrand6
to develop intermolecular radical additions to imino compounds
has inspired increasing effort toward this goal.7,8
of primary alkyl halides to N-acylhydrazones.9 Here, we disclose
optimization and expansion of the scope of these novel Mn-
mediated reactions, along with studies of stereoselectivity and
new experimental evidence regarding the mechanism; a com-
plete discussion of the development of the methodology is also
provided.
Background
We have designed novel chiral N-acylhydrazones as chiral
imino acceptors incorporating Lewis acid activation10 and
restriction of rotamer populations (Scheme 2). Versatile and
reliable methods for their efficient preparation from N-amino-
2-oxazolidinones (e.g., 1) have been developed,11 such that the
hydrazones exemplified by 2 have been prepared successfully
from every aldehyde attempted (greater than 60 to date). Our
initial studies of radical12 and allylsilane13 additions uncovered
the excellent synthetic potential of these novel chiral hydrazones,
and several other related addition reactions have since been
reported.14 Despite the effectiveness of this stereocontrol design
for radical additions to N-acylhydrazones, the earlier reactions
We envisioned that new radical addition conditions enabling
the use of primary iodides would dramatically expand the range
of potential synthetic applications of radical additions to CdN
bonds. We were indeed successful in developing suitable con-
ditions to achieve this goal: photolysis of manganese carbonyl
mediates highly stereoselective intermolecular radical addition
(2) General reviews of radical reactions and their stereocontrol: (a)
Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH:
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1999, 32, 163-171. (d) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed.
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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-
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Carbon Bonds; Pergamon Press: New York, 1986. (h) Hart, D. J. Science
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Chem. 2004, 69, 1531-1534. (d) Yamada, K.; Yamamoto, Y.; Tomioka,
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R.; Panzeri, W.; Pastori, N.; Regolini, E.; Porta, O. Tetrahedron Lett. 2005,
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(9) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922-9923.
(10) 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.
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(11) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236-6239.
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(3) Reviews of radical additions to imines and related acceptors: (a)
Friestad, G. K. Tetrahedron 2001, 57, 5461-5496. (b) Fallis, A. G.; Brinza,
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(4) (a) Aza-enolization of imines with Grignard reagents: Stork, G.;
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H. D.; Suchanek, P. Angew. Chem., Int. Ed. Engl. 1963, 2, 683-684. Wittig,
G.; Reiff, H. Angew. Chem., Int. Ed. Engl. 1968, 7, 7-14. (b) Even
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group’s work in this area, see: Miyabe, H.; Ueda, M.; Naito, T. Synlett
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Ueda, M.; Miyabe, H.; Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3,
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H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed. 2005, 44, 6190-6193.
(6) Radical additions to chiral glyoxylate imines: Bertrand, M. P.; Feray,
L.; Nouguier, R.; Stella, L. Synlett 1998, 780-782. Bertrand, M. P.; Feray,
L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148-1150. Bertrand, M. P.;
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3951-3961. Bertrand, M.; Feray, L.; Gastaldi, S. Comptes Rend. Acad.
Sci. Paris, Chimie 2002, 5, 623-638.
(14) (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, 1749-1752. (c) Mannich-type reaction: Jacobsen,
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J. Org. Chem, Vol. 71, No. 18, 2006 7017

Friestad et al.
were limited to secondary and tertiary radicals.12 In fact, this is
a routine limitation to intermolecular radical addition reactions.
In the previous studies, we typically recovered unchanged
hydrazones when attempting the addition of primary iodides in
the presence of Bu3SnH, whereas Et• addition (from Et3B/O2
initiation15) was the major product in the absence of Bu3SnH.
The latter is a common problem associated with the use of
triethylborane or diethylzinc as radical initiators. These observa-
tions can be attributed to some significant problems which have
plagued most efforts to apply intermolecular additions of
primary alkyl radicals using existing methods: First, less-stable
1° radicals (vs 2° or 3°) might not be sufficiently long lived to
avoid premature reduction by hydrogen-atom abstraction from
solvent (H-S, eq 1). Second, in most cases, the iodine atom
transfer between the primary Et• and a primary alkyl iodide
(eq 2) is thermoneutral and disfavored relative to side reactions
of Et• (e.g., undesired addition reactions of Et• or quenching by
H-atom transfer from solvent according to eq 1).
mercially available yellow solid has a molecular structure
consisting of two Mn(CO)5 units, each with octahedral coordi-
nation, linked by a weak manganese-manganese single bond
(38 kcal mol-1).17 Mn2(CO)10 is UV active; its λmax is 324 nm
(cyclohexane), associated with the σ f σ* transition of the
Mn-Mn bond, which may be homolyzed by thermal or photo-
chemical conditions (eq 3).18,19 The resulting •Mn(CO)5 has been
detected using EPR spectroscopy and spin-trapping techniques.20
(CO)5Mn-Mn(CO)5
9
hν8 2(CO)5Mn•
(3)
(4)
(CO)5Mn• + I-R f (CO)5Mn-I + •R
•
The reactivity profile of Mn(CO)5 includes hydrogen-21 or
halogen-atom22 abstraction reactions (eq 4); the latter behavior
is quite similar to that of •SnR3. Halogen-atom abstraction from
•
alkyl halides by Mn(CO)5 generates alkyl radicals along with
products of the type X-Mn(CO)517b at rates (C-I > C-Br >
C-Cl) which are inversely proportional to the strength of the
C-X bond. Brown has shown that the rates are also decreased
by steric hindrance: when bulky phosphines replace carbonyl
ligands on the Mn, the halogen-atom abstraction is inhibited.22b
R• + H-S f R-H + •S
Et• + I-R f Et-I + •R
(1)
(2)
These considerations led us to examine photolytic initiation.
Kim has employed nonreductive radical conditions using photo-
chemical initiation and hexamethylditin to mediate addition-
elimination reactions of C-sulfonyl oxime ethers, a rare exam-
ple of the successful intermolecular addition of various func-
tionalized primary alkyl halides.16 Though Kim’s addition-
elimination reactions were mechanistically distinct from our
desired process, and did not result in a new stereogenic center,
the precedent was encouraging, and we in fact attempted the
use of Kim’s conditions in our earlier study of tin- and boron-
mediated radical additions.12 Although ethyl iodide addition to
acylhydrazone 2 provided a promising 56% yield, unfortunately,
the reaction was not general and was complicated by exchange
of the carbonyl component with the acetone sensitizer. This
previous study suggested a possible improvement of these photo-
chemical nonreductive conditions through the use of a reagent
which could react in a fashion similar to Me3SnSnMe3 but which
would not require a sensitizer.
Unlike the more well-established oxidative radical reactions
using Mn(OAc)3,23 applications of Mn2(CO)10 in organic syn-
thesis are just beginning to emerge. Recent explorations by
Parsons and others with Wurtz-type homocoupling,24 radical
cyclizations,25 TEMPO trapping,25b and polymerization26 have
shown some interesting attributes of this reagent. In the case of
the homocoupling, success was ascribed in part to high concen-
trations of the carbon-centered radicals produced in the photol-
ysis with Mn2(CO)10. Interestingly, Parsons noted that reaction
•
of Mn(CO)5 with 1° halides was much more facile than with
2° or 3° halides. This is contrary to the usual order of reactivity
for generation of alkyl radicals, yet in agreement with Brown’s
(18) Geoffroy, G. L.; Wrighton, M. S. Organometallic Photochemistry;
Academic Press: New York, 1979.
(19) Reviews: (a) Pauson, P. L. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 2, pp 1471-
1474. (b) Meyer, T. J.; Caspar, J. V. Chem. ReV. 1985, 85, 187. Gilbert, B.
C.; Parsons, A. F. J. Chem. Soc., Perkin Trans. 2 2002, 367-387.
(20) (a) Hudson, A.; Lappert, M. F.; Lednor, P. W.; Nicholson, B. K. J.
Chem. Soc., Chem. Commun. 1974, 966-967. (b) Hudson, A.; Lappert,
M. F.; Nicholson, B. K. J. Chem. Soc., Dalton Trans. 1977, 551-554.
(21) (a) McCullen, S. B.; Brown, T. L. J. Am. Chem. Soc. 1982, 104,
7496-7500. (b) Freidlina, R. K.; Terent’ev, A. B.; Petrova, R. G.; Churkina,
T. D.; Moskalenko, M. A. Dokl. Akad. Nauk SSSR 1986, 288, 1436-1439.
(c) Chukovskaya, E. T.; Kuz’mina, N. A.; Blinova, N. V.; Friedlina, R. K.
IzV. Akad. Nauk SSR, Ser. Khim. 1984, 2061-2064.
(22) (a) Connor, J. A.; Zafarani-Moattar, M. T.; Bickerton, J.; Saied, N.
I. E.; Suradi, S.; Carson, R.; Takhin, G. A.; Skinner, H. A. Organometallics
1982, 1, 1166-1174. (b) Herrick, R. S.; Herrinton, T. R.; Walker, H. W.;
Brown, T. L. Organometallics 1985, 4, 42-45. (c) Biddulph, M. A.; Davis,
R.; Wilson, F. I. C. J. Organomet. Chem. 1990, 387, 277-293. For selected
studies by Friedlina et al. of the reactions of polychlorinated compounds
with Mn2(CO)10, see: (d) Chukovskaya, E. T.; Rozhkova, M. A.; Kuz’mina,
N. A.; Freidlina, R. K. IzV. Akad. Nauk SSR, Ser. Khim. 1982, 354-359.
(e) Gasanov, R. G.; Friedlina, R. K. Dokl. Akad. Nauk SSSR 1979, 246,
111-114.
It became interesting to consider whether dimanganese deca-
carbonyl [Mn2(CO)10] might offer a solution to the problem of
primary alkyl radical addition to N-acylhydrazones. This com-
(15) Under Et3B or Et2Zn conditions, the action of O2 on these initiators
results in formation of Et•; iodine atom transfer to Et• from an alkyl iodide
(R-I) generates the desired radical R•. Nozaki, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. Jpn. 1991, 64, 403-409.
(16) (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.
(17) (a) The experimental measurements of D(Mn-Mn) by a variety of
methods range from 19 to 42 kcal mol-1 and have been reviewed
critically: Martinho Simo˜es, J. A.; Beauchamp, J. A. Chem. ReV. 1990,
(23) (a) For a review, see: Snider, B. B. Chem. ReV. 1996, 96, 339-
363. (b) 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.
(24) (a) Gilbert, B. C.; Lindsay, C. I.; McGrail, P. T.; Parsons, A. F.;
Whittaker, D. T. E. Synth. Commun. 1999, 29, 2711-2718. (b) Masters,
A. P.; Sorensen, T. S. Can. J. Chem. 1990, 68, 492-501.
90, 629-688. In that review, the value of choice was 38 ( 5 kcal mol-1
,
determined by photoacoustic calorimetry: Goodman, J. L.; Peters, K. S.;
Vaida, V. Organometallics 1986, 5, 815-816. (b) Bond strengths D(Mn-
X) for I-Mn(CO)5, Br-Mn(CO)5, and Cl-Mn(CO)5 are 54, 66, and 78
kcal mol-1, respectively. Collman, J. P.; Hegedus, L. S.; Norton, J. R.;
Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, California, 1987; p 368.
7018 J. Org. Chem., Vol. 71, No. 18, 2006

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
TABLE 1. Results of Metal-Mediated Radical Addition to
Propionaldehyde Hydrazone 2a*
assessment of the importance of steric hindrance in the halogen-
atom transfer reactions of Mn(0)-centered radicals.22b
Some practical considerations also warrant mention. Unlike
the organotin reagents, Mn2(CO)10 is a solid; it may be easily
handled for short periods in an ambient laboratory atmosphere
(e.g., for measurement and transfer) and stored for long periods
under an inert atmosphere in the freezer without decomposition.
In contrast to tin halides such as Bu3SnBr, the manganese(I)
halide byproducts obtained from atom abstraction reactions with
alkyl halides are relatively easy to remove.
On the basis of the above considerations, dimanganese deca-
carbonyl emerged as a promising candidate for improving the
synthetic potential of radical additions to imino compounds.
Despite the interesting features of Mn-mediated radical reactions,
their applications in synthesis have been sporadic to date, and
their use in addition to CdN bonds had not been reported prior
to this study. In particular, we were intrigued by the notion that
the photolytic Mn-Mn homolysis of manganese carbonyl [Mn2-
(CO)10], which requires no sensitizer, could be exploited for
intermolecular addition to CdN bonds. This hypothesis was
addressed experimentally, resulting in dramatically broadened
scope of this important class of reactions to include primary
alkyl iodides and R,ω-dihaloalkanes as radical precursors with
enhanced synthetic potential.
* 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 days at ca. 35 °C
under N2. 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-Diazabicyclo[5.4.0]un-
dec-7-ene (DBU) was used in the removal of Mn byproducts. e Ratio by
HPLC (Chiralcel OD, 2-PrOH/hexane). f Ratio by 1H NMR. g InCl3 and
hydrazone were stored under vacuum (ca. 1 mmHg) overnight prior to use,
and a smaller amount of i-PrI (3 equiv) was used.
Results and Discussion
Manganese-Mediated Addition of Primary and Secondary
Radicals. As an initial test case for the Mn-mediated addition,
ethyl iodide addition to 2a12 (Table 1) was chosen. This would
generate no new stereogenic centers but would offer an impor-
tant challenge to the hypothesis that this reagent could allow
primary radical addition. Irradiation (300 nm, Rayonet) of 2a,
EtI (10 equiv), and Mn2(CO)10 (1 equiv) with InCl3 (2.3 equiv)
as a Lewis acid27 in CH2Cl2 afforded 312 in 85% yield, a
dramatic improvement over the use of triethylborane or hexa-
methylditin.
obtained from a range of n-alkyl iodides. On the other hand,
allyl bromide gave low yield, whereas benzyl and tert-butyl
bromides gave no addition products.29 However, the versatility
of the method extends to functionalized radical precursors,
specifically R,ω-dihaloalkanes bearing iodine along with less-
reactive chlorine. These transferred synthetically attractive
ω-chloroalkyl groups. Products 10R-13R retain functionality
originating in the difunctional radical precursor, offering oppor-
tunities for further elaboration.
Several other halides were also effective, furnishing radical
addition products 4S and 5R-13R28 with high diastereomer
ratios (Table 1). Methyl iodide underwent the reaction in 48%
yield despite its volatility. Consistent positive results were
(25) (a) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons,
A. F.; Whittaker, D. T. E. Tetrahedron Lett. 1999, 40, 6095-6098. (b)
Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A. F.;
Whittaker, D. T. E. J. Chem. Soc., Perkin Trans. 1 2000, 1187-1194. (c)
Huther, N.; McGrail, P. T.; Parsons, A. F. Tetrahedron Lett. 2002, 43,
2535-2538. (d) Huther, N.; McGrail, P. T.; Parsons, A. F. Eur. J. Org.
Chem. 2004, 1740-1749.
(26) (a) Jenkins, D. W.; Hudson, S. M. Macromolecules 2002, 35, 3413-
3419. (b) Gilbert, B. C.; Harrison, R. J.; Lindsay, C. I.; McGrail, P. T.;
Parsons, A. F.; Southward, R.; Irvine, D. J. Macromolecules 2003, 36,
9020-9023. For selected earlier studies of related telomerization reactions,
see: (c) Terent’ev, A. B.; Moskalenko, M. A.; Friedlina, R. K. IzV. Akad.
Nauk SSR, Ser. Khim. 1981, 374-379. (d) Grigor’ev, N. A.; Tumanskaya,
A. L.; Friedlina, R. K. IzV. Akad. Nauk SSR, Ser. Khim. 1983, 1122-1125.
(e) Terent’ev, A. B.; Moskalenko, M. A.; Friedlina, R. K. IzV. Akad. Nauk
SSR, Ser. Khim. 1984, 2825-2827.
(27) Use of ZnCl2 as the Lewis acid was precluded due to limited solu-
bility. A brief screen of In(III) Lewis acids (InCl3, InF3, InI3, In(OAc)3) in
hexamethylditin-mediated photolysis indicated InCl3 to be superior (see ref
12b). InCl3 is also only slightly soluble in CH2Cl2. Significant dissolution
of the InCl3 occurs when all reaction components are present, although the
reaction mixture is still not homogeneous. Lower stoichiometries of InCl3
result in lower conversion.
(28) Configurations are assigned by analogy with 9R and 15, which were
unambiguously determined through chemical correlation with valine and
coniine, respectively.
The addition of ω-haloalkyl radicals deserves further com-
ment. Although the 1,1-, 1,3-, and 1,4-dihaloalkanes all gave
reasonable yields of adducts (Table 1), the additions of 1,2-
dihaloethanes were unsuccessful. These anomalies may be attrib-
utable to â-elimination of the halogen atom from intermediate
radicals, which bear an exceptionally weak C-X bond. For
example, 1,2-diiodoethane gave none of the 2-iodoethyl adduct,
and the yield of 2-chloroethyl adduct 14 from 1-chloro-2-
iodoethane was only 14% (eq 5). The difference between the
efficiencies of the latter two reactions may reflect C-X bond
dissociation energies (BDE) in the corresponding radical inter-
mediates, which have been examined theoretically by Zewail
et al.30 For ICH2CH2 , the BDE(C-I) was calculated (B3LYP)
•
(29) Allyl bromide gave 12% of the allyl adduct. Benzyl bromide led to
recovery of the starting hydrazone, and tert-butyl bromide resulted in
decomposition.
(30) Ihee, H.; Zewail, A. H.; Goddard, W. A., III. J. Phys. Chem. A
1999, 103, 6638-6649.
J. Org. Chem, Vol. 71, No. 18, 2006 7019

Friestad et al.
TABLE 2. Preparation and Mn2(CO)10-Mediated Iodoethane
Addition to Aldehyde Hydrazones According to Scheme 1*
SCHEME 3
Numerous synthetic applications of this new Mn-mediated
addition methodology may be envisioned; its appealing features
include accommodation of primary alkyl radicals and tolerance
of multifunctional precursors.32 Furthermore, the epimeric con-
figuration in the adducts can be selected by either (A) employing
the enantiomeric auxiliary or (B) interchanging the roles of R1
and R2 in Scheme 1 (i.e., the alkyl halide and aldehyde pre-
cursors of Scheme 2).33 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.
Hybrid Radical-Ionic Annulation. Interestingly, addition
of 3-chloro-1-iodopropane to propionaldehyde hydrazone 2a led
exclusively to pyrrolidine 11R (Scheme 3), presumably via
3-chloropropyl radical addition and in situ nonradical cycliza-
tion. When the 3-chloropropyl group was linked to the CdN
moiety in hydrazone 2h, the epimeric pyrrolidine 11S was
obtained upon ethyl addition. These are two examples of a
potentially useful hybrid radical-ionic annulation, a novel entry
to a class of reactions known as radical-polar crossover
reactions.34
* Reaction conditions for hydrazone formation: Aldehyde (5-10 equiv),
1, p-toluenesulfonic acid, CH2Cl2, rt. For radical addition conditions, see
Table 1. a Isolated yield. b Isolated yield of the diastereomer mixture. c 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) was used in the removal of Mn
1
byproducts. d Ratio by HPLC. e Ratio by H NMR. f InCl3 and hydrazone
were stored under vacuum (ca. 1 mmHg) overnight prior to use, and a
smaller amount of EtI (3 equiv) was used.
•
at 5 kcal/mol, whereas for ClCH2CH2 , the same calculation
yields BDE(C-X) of 12 kcal/mol. Experimental data indicate
an even greater difference.31
To illustrate its potential in asymmetric amine synthesis, we
applied Mn-mediated radical addition to prepare the simple
piperidine alkaloid coniine (Scheme 4).35 We envisioned a
radical addition followed by cyclization, as suggested by the
previous experiments of Scheme 3. Two alternative disconnec-
tions can be considered. The exocyclic propyl group may be
introduced as part of the radical acceptor (path A) or may
originate in the radical precursor (path B).
To examine the generality of the reaction with respect to the
radical acceptor, additional hydrazones 2b-2j were prepared
in excellent yield by condensation of N-aminooxazolidinone 1a
with the corresponding aldehyde or acetal (Table 2). Iodoethane
addition to these hydrazones occurred in good yields (57-77%)
with the exception of 2j (34%). The adducts 4R and 5S-13S
(Table 2) are epimeric to 4S and 5R-13R (Table 1) with respect
to the new stereogenic center, demonstrating the flexibility
inherent in this carbon-carbon bond construction approach to
amine synthesis.
Propyl radical addition to a difunctional hydrazone was
attempted first (path B). However, it was noted previously that
(32) During preparation of this manuscript, Tomioka et al. have very
recently reported some impressive intermolecular radical additions to
N-tosylimines using alkyl iodide stoichiometries from 1.5 to 5 equiv. See
ref 7a.
Remarkably, these intermolecular additions appear to be
amenable to the use of only small excesses of alkyl iodide, a
very unusual finding among intermolecular radical addition
reactions. Our current practice, based on an empirically dis-
covered improvement in yields, is to (a) reduce the stoichiometry
of the alkyl iodide to 3 equiv and (b) store the InCl3 and hydra-
zone separately under an oil-pump vacuum overnight prior to
use. The effectiveness of this modified method can be seen from
the data in Table 1, entry 9, and Table 2, entry 5, where the
yield is increased by about 20% relative to the control experi-
ments. Although reaction times of 1-2 days were used in most
of these experiments, we have since discovered that the reaction
is complete after ca. 8 h (or after overnight irradiation). In cases
when the reaction is incomplete, addition of another portion of
Mn2(CO)10 does not lead to further conversion, a point which
is not yet understood.
(33) 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, 383-394.
(34) (a) Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. J.
Chem. Soc., Perkin Trans. 1 1999, 995-1001. (b) Jahn, U.; Muller, M.;
Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212-5213. (c) Rivkin, A.;
Nagashima, T.; Curran, D. P. Org. Lett. 2003, 5, 419-422. (d) Denes, F.;
Chemla, F.; Normant, J. F. Angew. Chem., Int. Ed. 2003, 42, 4043-4046.
(e) Bazin, S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. Tetrahedron 2005,
61, 4261-4274. (f) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito,
T. Angew. Chem., Int. Ed. 2005, 44, 6190-6193.
(35) Coniine is a common target for testing the 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,
7754-7755. (b) Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173-
177. (c) Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1997, 38, 4623-
4636. (d) Reding, M. T.; Buchwald, S. R. J. Org. Chem. 1998, 63, 6344-
6347. (e) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-
158. (f) For reviews of asymmetric syntheses of piperidine alkaloids, see:
Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813. O’Hagan, D. Nat.
Prod. Rep. 2000, 17, 435-446.
(31) Comparison of the estimated experimental values reported by Zewail
•
et al. (ref 30) shows that C-X bond dissociation of Cl-CH2CH2 is 28
•
kcal/mol higher than that of I-CH2CH2 .
7020 J. Org. Chem., Vol. 71, No. 18, 2006

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
SCHEME 4
SCHEME 6
SCHEME 5
SCHEME 7
by easily detected amounts of the unchanged hydrazone. In
contrast, no reactant hydrazone was found after reaction of
tosylate 16, suggesting decomposition which would be consistent
with the intermediacy of iminium ion D.
Interchanging the alkyl groups in the coupling partners (i.e.,
R1 and R2 of Scheme 2) gave superior results. Accordingly,
Mn-mediated radical addition of 4-chlorobutyl iodide to 2c
furnished 18 with high diastereoselectivity (Scheme 6).37 Cycli-
zation occurred under Finkelstein conditions, affording piperi-
dine derivative (R,S)-17, identical to the minor diastereomer
obtained by the previous route. Reduction with BH3‚THF38
afforded (R)-coniine (19). After conversion to the tert-butyl
carbamate (N-Boc) derivative 20 for ease of isolation (coniine
is volatile), the yield was 66%. The absolute configuration of
addition of an ethyl radical to difunctional 5-chloropentanal
hydrazone 2i (Table 2) did not result in cyclization in situ. It
was expected that replacing the chloride substituent with a
tosylate nucleofuge would facilitate the polar cyclization after
radical addition. The requisite N-acylhydrazone 16 (Scheme 5)
was obtained in 85% yield by condensing N-aminooxazolidinone
1a with 5-(p-toluenesulfonyl)oxypentanal36 (15) in the presence
of p-toluenesulfonic acid in CH2Cl2. The Mn-mediated addition
of iodopropane to N-acylhydrazone 16 indeed provided the
expected annulation product 17 in 59% yield. Unfortunately,
anomalously poor stereocontrol was observed (dr 3:1). The
major diastereomer was assigned the indicated configuration
by analogy to previous additions to N-acylhydrazones and was
confirmed later upon preparation of the minor diastereomer by
a different route (vide infra).
The lack of high selectivity in the addition to 5-tosyloxy-
pentanal hydrazone 16 is unique among all the examples of Mn-
mediated addition to CdN seen to this point. Of most relevance
is the contrasting highly diastereoselective ethyl addition to the
related chloropentanal hydrazone 2i (dr 97:3, 63% yield, Table
2). Upon ethyl addition, 2i does not undergo the polar cycliza-
tion; the product retains the chloride. Together, these compari-
sons of 2i and 16 suggest a mechanistic difference. For 16, the
cyclization could occur either before or after radical addition.
The lower stereoselectivity provides evidence for a polar
cyclization to form iminium ion D (Scheme 5) prior to radical
addition; such a cyclization would be detrimental to stereo-
selectivity due to the loss of two-point binding of the Lewis
acid. The mass balance in the Mn-mediated additions is routinely
80-100%, so yields in the range of 60% are often accompanied
26
20 was determined by comparison of its optical rotation, [R]D
) -28.1 (c ) 1.0, CHCl3), with the literature value.39 The cor-
relation of (R,S)-17 to (R)-coniine also establishes the configura-
tions of the minor (R,S) and major (S,S) diastereomers obtained
by propyl addition to tosyloxypentanal hydrazone 16.
Additional information establishing the configuration of 17
was obtained by an alternative route leading to N-benzoyl (R)-
coniine (Scheme 7). Benzoylation of hydrazine 18 (94% yield)
and N-N bond cleavage by SmI2 (97% yield) afforded 21, along
with 94% recovery of (S)-4-benzyl-2-oxazolidinone. Finkelstein
reaction and base treatment of the resulting iodide provided
N-benzoyl (R)-coniine (22) in 77% yield for two steps. The abso-
lute configuration was confirmed by comparison of the optical
rotation, [R]D27 ) -37.5 (c ) 0.80, CHCl3), with the literature
data.40
(37) Identical results were observed on ca. a 200 mg or 1 g scale.
(38) N-N cleavage with BH3‚THF: Feuer, H.; Brown, F., Jr. J. Org.
Chem. 1970, 35, 1468-1471. For recent examples, see: Enders, D.;
Lochtman, R.; Meiers, M.; Muller, S.; Lazny, R. Synlett 1998, 1182-1184.
(39) For (R)-N-Boc-coniine, [R]23 ) -31.6 (c ) 0.86, CHCl3). Ref
D
35b.
(40) For N-benzoyl-D-coniine, [R]26 ) +37.7. Ladenburg, A. Chem.
D
(36) Bo¨rjeson, L.; Welch, C. J. Tetrahedron 1992, 48, 6325-6334.
Ber. 1893, 26, 854-865.
J. Org. Chem, Vol. 71, No. 18, 2006 7021

Friestad et al.
TABLE 3. Comparison of Chiral Auxiliaries*
TABLE 4. Mechanistic Control Experiments with Hydrazone 2a*
hydrazone R• adduct,
entry
RI
reaction conditions
recoverya
yieldb
1
2
3
4
5
EtI
EtI
EtI
EtI
EtI
Mn2(CO)10, hν,b InCl3
hν,b InCl3
-
3, 85%
-
nrd
Mn2(CO)10, dark,c InCl3
Mn2(CO)10, hνb
nrd
18%
45%
-
3, 21%
3, 24%
Mn2(CO)10, indoor
ambient light, InCl3
6
7
n-C5H11I Mn2(CO)10, hν,b InCl3,
galvinoxyl (0.5 equiv)
75%
80%
7R, 12%
7R, 0%
n-C5H11I Mn2(CO)10, hν,b InCl3,
galvinoxyl (2.5 equiv)
entry
hydrazone
product (yielda,b), drc
1
2
3
4
5
2a
9R (94%), 95:5 (Table 1)
9B (90%), 98:2
* Reaction conditions: see Table 1; reaction time 18-24 h. a Isolated
yield. b Rayonet, 300 nm. c Al foil was wrapped around the reaction flask.
d nr ) no reaction; amount of 2a was not quantified, but 2a was unchanged
(as judged by TLC).
2aB
2aC
2aD
2aE
9C (88%), 98:2d
9D (95%), 95:5
9E (81%), 95:5e
* Reaction conditions: Table 1. a Isolated yield. b InCl3 and hydrazone
were stored under vacuum (ca. 1 mmHg) overnight prior to use. c dr )
diastereomer ratio, measured by 1H NMR spectrometry vs authentic
mixtures. d Estimated ratio. The minor diastereomer was not detected in
13C NMR or 1H NMR spectra, although 1H resonances were poorly resolved.
e By HPLC (Chirex 3014, 9:1 hexane-CHCl3), the dr measurement was
96.7:3.3.
zones 23 and 23B (eq 6) afforded 9S and 24B in very high
diastereoselectivity (as judged by 1H NMR and 13C NMR
spectra).45 These products established the viability of additions
Attempts to cleave the N-N bond of 17 by other methods
were disappointing. Hydrogenation with pressures up to 160
psi, using a variety of catalysts (Raney Ni,41 Pd/C, PtO2,42 Pt/C,
or Pd(OH)243), resulted in the saturation of the benzyl group of
the auxiliary but did not cleave the N-N bond. Raney nickel
reduction with ultrasonic irradiation41c gave no reaction. Oxida-
tive cleavage of the N-N bond with magnesium monoperoxy-
phthalate hexahydrate (MMPP)44 was achieved, as judged by
recovery of (S)-4-benzyl-2-oxazolidinone in 92% yield, but the
basic amine component (coniine) was not isolated under these
conditions, presumably due to oxidative decomposition.
Stereocontrol. The conversion of 18 to (R)-coniine by two
alternative routes (Schemes 5 and 6), as well as the configuration
established in sequence 18 f 22 (Scheme 7), provided further
support for the general stereocontrol model previously proposed
for reactions of these N-acylhydrazones in the presence of
chelate-forming Lewis acids. All available evidence along these
lines suggests the hydrazone acceptor adopts the chelate structure
illustrated in Scheme 2; the benzyl substituent blocks the re
face such that bond formation occurs on the opposite face.
A series of related N-acylhydrazones were prepared, as
described previously,12b to assess the importance of variations
to the stereocontrol element in the chiral auxiliary. Hydrazones
2aB-2aE were submitted to isopropyl addition via the Mn-
mediated photolysis conditions (Table 3), and without exception,
all diastereomer ratios of the products 9B-9E12b were quite
high. This observation is consistent with earlier findings regard-
ing the stereocontrol of tin- and boron-mediated radical additions
to the N-acylhydrazone radical acceptors.12b A second series of
reactions involving ethyl addition to isobutyraldehyde hydra-
to R-branched imino compounds for the first time and also
served as standards to prepare authentic mixtures for the HPLC
analysis reported in Table 3. The additions with all different
oxazolidinone auxiliaries proceeded with high diastereoselection,
indicating that there is little practical importance of the identity
of the stereocontrol element among those examined here.
Qualitative Mechanistic Data. With some documented
utility of this Mn-mediated addition process, we began to look
more carefully at mechanistic questions. Control experiments
revealed some basic information about the roles of the reaction
components (Table 4). In the absence of Mn2(CO)10, there was
no reaction after irradiation for 24 h (entry 2). Similarly, without
irradiation, no reaction occurred (entry 3). In contrast, some 3
was obtained (21% yield) in the absence of InCl3 (entry 4),
although the reaction was slow. This shows that the indium
chloride is not a mechanistic requirement; rather, it appears to
only facilitate the reaction as a Lewis acid activator. In ambient
light, the addition proceeded but was much less efficient than
the reaction employing UV irradiation (compare entries 1 and
5). The presence of galvinoxyl inhibited the reaction, but large
quantities of this radical scavenger were required to completely
shut down the reaction (entries 6 and 7). This suggests a non-
chain radical process46 or a very short chain length.
The mass balance of an addition involving 4-(tert-butyldi-
methylsilyloxy)butyl iodide (Scheme 8) gave further insights
about the nature of the addition reaction. In addition to expected
adduct 25, an interesting side product, dichloromethyl adduct
13R, was detected in 19% yield; the dichloromethyl group
clearly originated from the solvent. This product has also been
detected in small amounts in other additions. Considering the
(41) (a) Enders, D.; Schubert, H.; Nu¨bling, 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, 6395-6397. (c) Alexakis,
A.; Lensen, N.; Mangeney, P. Synlett 1991, 625-626.
(42) Claremon, D. A.; Lumma, P. K.; Phillips, B. T. J. Am. Chem. Soc.
1986, 108, 8265-8266.
(43) Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543-5546.
(44) Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge,
A. Angew. Chem., Int. Ed. 2000, 39, 2893-2897. Ferna´ndez, R.; Ferrete,
A.; Llera, J. M.; Magriz, A.; Mart´ın-Zamora, E.; D´ıez, E.; Lassaletta, J. M.
Chem.-Eur. J. 2004, 10, 737-745.
(45) The compound 24B was shown by GC to have dr ) 94:6.
(46) A nonchain radical character was also identified in studies of photo-
and electrochemical carbonylation of alkyl iodides in the presence of CO,
MeOH, and Mn2CO10. Kondo, T.; Sone, Y.; Tsuji, Y.; Watanabe, Y. J.
Organomet. Chem. 1994, 473, 163-173.
7022 J. Org. Chem., Vol. 71, No. 18, 2006

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
SCHEME 8
SCHEME 9
nonbasic conditions of the reaction, the most reasonable expla-
nation for this result is H-atom transfer from CH2Cl2, followed
by competitive additions of the resulting •CHCl2 and •CH2(CH2)3-
OTBS (26). Either this latter alkyl radical or the N-centered
radical 27 may be responsible for the H-atom abstraction; in
the presence of a Lewis acid, the aminyl radical should be quite
reactive.47
The scenario above predicts that switching to a solvent less
prone to H-atom abstraction might lead to minimized consump-
tion of alkyl iodide. In fact, when the reaction of Scheme 8
was conducted in a mixture of 10:1 benzene/acetonitrile, using
only 1.5 equiV of the iodide, compound 25 was isolated in 63%
yield. The generality of reactions with low iodide stoichiometry
is under further investigation.
The photolysis of dimanganese decacarbonyl in the presence
of alkyl iodides is well-known to generate alkyl radicals which
can be used for various reactions,17-26 so the more interesting
mechanistic questions are found in subsequent steps proposed
in Scheme 9. One alternative is of course a one-electron free-
radical process, consisting of alkyl radical addition followed
by recombination of the resulting aminyl radical with a penta-
carbonylmanganese radical (the manganese amide has been
neither observed nor ruled out) or H-atom abstraction from
solvent (path A). This photolysis chemistry also produces alkyl-
manganese species from iodides by radical-radical coupling.
So, one must consider the alternative possibility that such a
species could undergo a two-electron carbometalation-type
reaction leading to the same adduct (path B). Further, photolysis
of R-Mn(CO)5 is known to generate R• species.20,48 If the
photolysis conditions employed in our additions to N-acyl-
hydrazones could permit a reversible homolysis and recombi-
nation of R-Mn(CO)5, these alkylmanganese species could
modulate the reactivity of radicals via the persistent radical effect
(PRE).49 Specifically, the buildup of a small excess of persistent
metal-centered radicals could suppress the destructive homo-
coupling of transient alkyl radicals. This could serve to focus
the conversion of alkyl radicals along the desired reaction
pathway, addition to the N-acylhydrazone acceptor. On the other
hand, it is also known that photolysis of R-Mn(CO)5 does result
in formation of Mn2(CO)10, a point which clearly differentiates
this system from ideal examples of PRE wherein the homo-
coupling of the persistent radical is not observed to any signif-
icant extent.50 To clarify these issues, it was clearly desirable
to probe for the presence of alkylmanganese species.
The first approach to evaluate the importance of alkyl-
manganese intermediates was to prepare the R-Mn(CO)5 com-
pounds by an alternative method and examine their reactivity
with N-acylhydrazones. Acyl- and alkylmanganese penta-
carbonyls are well-known compounds, easily prepared by simple
methods.51 For example, (C5H11)Mn(CO)5 (26a) and its corre-
sponding migratory insertion product, (C5H11CO)Mn(CO)5
(26b), were prepared from NaMn(CO)5 by alkylation with
1-iodopentane or acylation with hexanoyl chloride, respectively.
Tridecyl analogues (C13H27)Mn(CO)5 (28a) and (C13H27CO)-
Mn(CO)5 (28b) were prepared in the same fashion. The expected
types of reactivity were observed; these pairs of compounds
interconverted thermally and photochemically, with the latter
conditions leading to decomposition to alkane. Photolysis in
CH2Cl2 in the absence of N-acylhydrazone gave tridecane in
46% yield from 28a and in 25% yield from 28b, and the alkyl
dimer (C26H54) was not detected. Apparently, H-atom abstraction
from CH2Cl2 predominates under these conditions.
Next, we systematically examined the reactivity of 26a and
26b in combination with the propionaldehyde-derived N-
acylhydrazone 2a (Scheme 10). No reaction took place in the
(49) (a) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925-3927. (b) Daikh,
B. E.; Finke, R. G. J. Am. Chem. Soc. 1992, 114, 2938-2943. (c) For
reviews of the persistent radical effect, see: Fischer, H. Chem. ReV. 2001,
101, 3581-3610. Studer, A. Chem.-Eur. J. 2001, 7, 1159-1164. Studer,
A. Chem. Soc. ReV. 2004, 33, 267-273. (d) For selected examples of
applications in synthesis, see: Hart, D. J.; Seely, F. L. J. Am. Chem. Soc.
1988, 110, 1631-1633. Branchaud, B. P.; Yu, G.-X. Organometallics 1993,
12, 4262-4264. Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108-1111.
Wetter, C.; Studer, A. J. Chem. Soc., Chem. Commun. 2004, 174-175.
(50) Although the homocoupling of the persistent radical •Mn(CO)5 does
occur, its reversibility under the photolysis conditions may maintain a slight
(47) (a) A deuterium incorporation experiment is complicated by the
potential for NH exchange on processing the reaction product. (b) Horner,
J. H.; Martinez, F. N.; Musa, O. M.; Newcomb, M.; Shahin, H. E. J. Am.
Chem. Soc. 1995, 117, 11124-11133. Ha, C.; Musa, O. M.; Martinez, F.
N.; Newcomb, M. J. Org. Chem. 1997, 62, 2704-2710. Newcomb, M.;
Musa, O. M.; Martinez, F. N.; Horner, J. H. J. Am. Chem. Soc. 1997, 119,
4569-4577. Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J.
Am. Chem. Soc. 1998, 120, 7738-7748.
•
excess of Mn(CO)5 (a necessary condition for the PRE).
(51) Coffield, T. H.; Kozikowski, J.; Closson, R. D. J. Org. Chem. 1957,
22, 598. Anderson, J. M.; Moss, J. R. Organometallics 1994, 13, 5013-
5020.
(48) Young, K. M.; Wrighton, M. S. J. Am. Chem. Soc. 1990, 112, 157-
166.
J. Org. Chem, Vol. 71, No. 18, 2006 7023

Friestad et al.
SCHEME 10
compounds can result in photolytic reduction to alkane (pre-
sumably a radical process) yet do not undergo addition to any
great extent. One possible explanation involves a solvent cage
effect. The alkyl- or acylmanganese homolysis produces a caged
radical pair, kinetically distinguishing its alkyl radical compo-
nent from the free alkyl radical produced by bimolecular
halogen-atom abstraction. In the latter case, intermolecular addi-
tion to the N-acylhydrazone is facilitated; in-cage recombination
is obviated because the Mn-containing component in the solvent
•
cage is I-Mn(CO)5, not Mn(CO)5.
dark or in ambient light, with or without Lewis acid; the results
of Tables 1 and 2 were not reproduced by these experiments. It
is clear from these negative results that the organomanganese
compounds do not react directly with the N-acylhydrazones (e.g.,
via a two-electron carbometalation or migratory insertion of the
CdN bond). Upon photolysis of 26a with 2a at 300 nm in the
presence of InCl3, the n-pentyl radical adduct 7R was found in
small amounts (<15% yield), along with small amounts of
dimanganese decacarbonyl. Upon employing 26b in the latter
experiment, no addition took place, although formation of 26a
by decarbonylation of 26b was observed.
We wondered if some interaction between the possible Mn-
containing components could be important to provide some
reactivity which would not be duplicated by the isolated alkyl-
manganese compound. For example, mixtures containing R-Mn-
(CO)5 and I-Mn(CO5 are generated in situ during photolysis,
and the reversible migratory insertion can also provide RC(O)-
Mn(CO)5. Mixtures of (a) R-Mn(CO)5 and I-Mn(CO5 or (b)
R-Mn(CO)5, RC(O)-Mn(CO)5, I-Mn(CO)5, and Mn2(CO)10
were prepared separately, then mixed with the N-acylhydrazone
2a and submitted to the standard photolysis conditions in the
presence of InCl3. Still, the results typical in Tables 1 and 2
were not duplicated; no significant amount of addition product
was found.
Finally, a crossover experiment was employed to examine
the role of the alkyl iodide. When C13H27COMn(CO)5 (28b)
was used in the photolysis, irradiation for several hours produced
no observable addition reaction (TLC). Consistent with the
observations noted above, a significant amount of Mn2(CO)10
formed during this period, detected qualitatively by TLC and
visual inspection (yellow solid on the upper walls of the reaction
vessel). At this point, iodopentane was added to the flask, and
upon further irradiation, the addition reaction appeared to take
its normal course (as observed in Tables 1 and 2). The only
addition product detected contained the pentyl group (7R, 44%
yield); the tridecyl group from 28b was not incorporated to any
detectable extent.52 This clearly identified the origin of the alkyl
group; it must have come from pentyl iodide without the
interVention of an alkylmanganese species.
To summarize the results of these experiments, we can
conclude that nonradical reactions of alkyl- or acylmanganese
species do not play a significant role under the conditions of
Tables 1 and 2. The free-radical addition appears to either be
nonchain or have a short chain length, and it requires generation
of radicals from the alkyl iodide. Together, all these results
suggest that the effectiveness of the Mn-mediated additions may
derive from relatively high radical concentrations, as Parsons
has noted previously in the context of Wurtz-type dimerization
of alkyl halides. It is curious that the alkyl- and acylmanganese
Conclusion
In summary, manganese carbonyl mediates stereoselective
photolytic radical addition of alkyl iodides to chiral N-acylhydra-
zones with tolerance of additional functionality in both coupling
partners and excellent flexibility for synthetic planning. The
stoichiometry of alkyl iodide can be limited to three equivalents
without any decrease in yield. Qualitative mechanistic studies
confirm the importance of free radicals, imply that this is a
nonchain (or short chain length) free-radical process, and reveal
that organomanganese compounds are not a viable source of
alkyl radicals for the addition reaction under the conditions
examined here.53
Experimental Section
Preparation of N-Acylhydrazones (General Procedure A). To
a solution of (S)-3-amino-4-phenylmethyl-2-oxazolidinone (1) in
CH2Cl2 (0.2 M) was added TsOH‚H2O (cat.) and aldehyde (5-10
equiv) at room temperature.54 When the reaction was complete
(TLC), the mixture was concentrated and purified by gradient flash
chromatography (hexane f 1:1 hexane/EtOAc) to afford the hydra-
zone as a single CdN isomer (>98:2). In some cases, small amounts
(<5%) of another component (tentatively identified as an enamine
derived from 4-phenylmethyl-2-oxazolidinone) were detected by
1H NMR and were not removed prior to subsequent radical addition
reactions. For specific data concerning preparation and characteriza-
tion data of N-acylhydrazones, see Supporting Information.
Radical Addition to N-Acylhydrazones (General Procedure
B). To a deoxygenated (N2) solution of the hydrazone (e.g., 2a) in
CH2Cl2 (ca. 0.1 M) was added InCl3 (2.2 equiv) at room temper-
ature. After 40 min, the appropriate alkyl iodide (3-20 equiv, see
Tables 1 and 2) and Mn2(CO)10 (1-2 equiv) were added and the
mixture was irradiated for 8-24 h before product isolation
according to workup A or workup B. Longer irradiation times have
been used in some cases (as reported in the preliminary com-
munication), but there is no evidence of any advantage. Workup
A: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv) was added,
and the mixture was stirred for 40 min and concentrated. Gradient
flash chromatography, with care to avoid enrichment of the dia-
stereomer ratio, afforded N-acylhydrazines 4S and 5R-13R as
diastereomer mixtures. Diastereomer ratios were determined by
comparison with authentic diastereomer mixtures prepared by an
admixture of 4R and 5S-13S prepared by a similar route (see
Supporting Information). Workup B: Same as workup A except
treatment with DBU was omitted.
(S)-3-(3′-Pentanamino)-4-phenylmethyl-2-oxazolidinone (3).
From (S)-3-(propylidene)amino-4-phenylmethyl-2-oxazolidinone
(54 mg, 0.233 mmol) and iodoethane (0.186 mL, 2.33 mmol) by
general procedure B and workup B was obtained 312 (52 mg, 85%)
as a colorless oil.
(52) Unreacted N-acylhydrazone 2a was recovered (48%), giving mass
balance of 92% for this experiment. Traces of side products among the
remaining 8% of mass were examined carefully by 1H NMR spectrometry,
but there was no evidence of a tridecyl adduct.
(53) Although this study is focused on intermolecular addition, precedent
suggests applicability to cyclizations (ref 25).
(54) A statement of general experimental procedures is provided in the
Supporting Information.
7024 J. Org. Chem., Vol. 71, No. 18, 2006

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
(4S,2′S)-3-(2′-Butanamino)-4-phenylmethyl-2-oxazolidinone
(4S). From (S)-3-(propylidene)amino-4-phenylmethyl-2-oxazolidi-
none (76 mg, 0.33 mmol) and iodomethane (0.41 mL, 6.54 mmol)
by general procedure B and workup A was obtained 4S (39 mg,
(4S,3′R)-3-(5′-Methyl-3′-hexanamino)-4-phenylmethyl-2-ox-
azolidinone (8R). From (S)-3-(propylidene)amino-4-phenylmethyl-
2-oxazolidinone (74 mg, 0.32 mmol) and isobutyl iodide (0.74 mL,
6.4 mmol) by general procedure B and workup B was obtained 8R
(50 mg, 54%; S,R/S,S ) 95:5, NMR analysis) as a colorless oil:
26
48%; S,S/S,R ) 95:5, HPLC analysis) as a colorless oil: [R]D
25
+49.2 (c 0.65, CHCl3); IR (film) 3288, 3028, 2966, 2877, 1758,
1498, 1454, 1399, 1218, 1088 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.32 (dd, J ) 7.1, 7.1 Hz, 2H), 7.25 (dd, J ) 7.2, 7.2 Hz, 1H),
7.16 (d, J ) 7.0 Hz, 2H), 4.15 (dd, J ) 8.3, 8.3 Hz, 1H), 4.03 (dd,
J ) 8.8, 5.3 Hz, 1H), 3.93-3.88 (m, 1H), 4.30-3.70 (brs, 1H),
3.33 (dd, J ) 13.5, 3.6 Hz, 1H), 3.19-3.10 (m, 1H), 2.62 (dd, J )
13.4, 9.9 Hz, 1H), 1.60-1.57 (m, 1H), 1.41-1.32 (m, 1H), 1.08
(d, J ) 6.4 Hz, 3H), 0.95 (dd, J ) 7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 158.8, 136.0, 129.1, 128.8, 127.0, 66.0, 59.7, 56.0,
37.3, 27.5, 18.0, 9.7; MS (CI) m/z (relative intensity) 249 ([M +
H]+, 100%). Anal. Calcd for C14H20N2O2: C, 67.71; H, 8.12; N,
11.28. Found: C, 67.79; H, 8.09; N, 11.22.
[R]D +19.5 (c 0.85, CHCl3); IR (film) 3299, 3028, 2958, 2872,
1
1758, 1497, 1454, 1399, 1238, 1091, 1030 cm-1; H NMR (500
MHz, CDCl3) δ 7.32 (dd, J ) 7.6, 7.6 Hz, 2H), 7.25 (dd, J ) 7.4,
7.4 Hz, 1H), 7.16 (d, J ) 7.0 Hz, 2H), 4.14 (dd, J ) 8.2, 8.2 Hz,
1H), 4.03 (dd, J ) 8.9, 4.4 Hz, 1H), 3.92-3.87 (m, 1H), 3.97 (br
s, 1H), 3.35 (dd, J ) 13.5, 3.4 Hz, 1H), 3.12-3.03 (m, 1H), 2.60
(dd, J ) 13.4, 10.1 Hz, 1H), 1.82-1.73 (m, 1H), 1.58-1.42 (m,
2H), 1.29 (dd, J ) 6.9, 6.9 Hz, 2H), 0.99-0.94 (m, 9H); 13C NMR
(125 MHz, CDCl3) δ 158.5, 136.1, 129.1, 128.9, 127.0, 65.6, 60.1,
58.4, 41.1, 36.8, 25.4, 24.9, 23.1, 22.7, 8.9; MS (CI) m/z (relative
intensity) 291 ([M + H]+, 100%). Anal. Calcd for C17H26N2O2:
C, 70.31; H, 9.02; N, 9.65. Found: C, 70.21; H, 8.97; N, 9.55.
(4S,3′R)-3-(2′-Methyl-3′-pentanamino)-4-phenylmethyl-2-ox-
azolidinone (9R). From (S)-3-(propylidene)amino-4-phenylmethyl-
2-oxazolidinone (54 mg, 0.23 mmol) and 2-iodopropane (0.24 mL,
2.3 mmol) by general procedure B and workup B was obtained
9R12 (48 mg, 75%; S,R/S,S ) 95:5, NMR analysis) as a colorless
solid.
(4S,3′R)-3-(3′-Hexanamino)-4-phenylmethyl-2-oxazolidi-
none (5R). From (S)-3-(propylidene)amino-4-phenylmethyl-2-ox-
azolidinone (50 mg, 0.22 mmol) and 1-iodopropane (0.21 mL, 2.16
mmol) by general procedure B and workup B was obtained 5R
(39 mg, 66%; S,R/S,S ) 94:6, HPLC analysis) as a colorless oil:
26
[R]D +31.6 (c 1.5, CHCl3); IR (film) 3292, 3063, 3028, 2960,
1
2873, 1758, 1454, 1399, 1238, 1090, 1029 cm-1; H NMR (500
(4S,2′R)-3-(1′-Chloro-2′-butanamino)-4-phenylmethyl-2-ox-
azolidinone (10R). From (S)-3-(propylidene)amino-4-phenyl-
methyl-2-oxazolidinone (50 mg, 0.22 mmol) and chloroiodomethane
(0.16 mL, 2.16 mmol) by general procedure B and workup B was
obtained 10R (38 mg, 63%; S,R/S,S ) 93:7, HPLC analysis) as a
MHz, CDCl3) δ 7.23 (dd, J ) 6.8, 6.8 Hz, 2H), 7.25 (dd, J ) 7.2,
7.2 Hz, 1H), 7.16 (d, J ) 7.5 Hz, 2H), 4.14 (dd, J ) 8.2, 8.2 Hz,
1H), 4.03 (dd, J ) 8.8, 4.6 Hz, 1H), 3.93-3.88 (m, 1H), 3.95 (br
s, 1H), 3.34 (dd, J ) 13.4, 3.5 Hz, 1H), 3.05-2.97 (m, 1H), 2.61
(dd, J ) 13.4, 10 Hz, 1H), 1.54-1.38 (m, 6H), 0.96 (dd, J ) 7.4,
7.4 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 158.6, 136.0, 129.1,
128.9, 127.0, 65.7, 60.1, 59.9, 36.9, 33.7, 24.8, 18.8, 14.3, 9.0;
MS (CI) m/z (relative intensity) 277 ([M + H]+, 100%), 193 (30%).
Anal. Calcd for C16H24N2O2: C, 69.53; H, 8.75; N, 10.14. Found:
C, 69.46; H, 8.85; N, 10.01.
27
colorless oil: [R]D +44.9 (c 3.4, CHCl3); IR (film) 3286, 3028,
1
2966, 2878, 1758, 1497, 1400, 1240, 1217, 1091, 1207 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), 3.65 (dd, J ) 11.4, 4.6 Hz, 1H), 3.59
(dd, J ) 11.4, 4.9 Hz, 1H), 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 (dd, J ) 7.4, 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.
(4S,3′R)-3-(3′-Heptanamino)-4-phenylmethyl-2-oxazolidi-
none (6R). From (S)-3-(propylidene)amino-4-phenylmethyl-2-ox-
azolidinone (100 mg, 0.43 mmol) and 1-iodobutane (0.49 mL, 4.31
mmol) by general procedure B and workup B was obtained 6R
(98 mg, 78%; S,R/S,S ) 95:5, HPLC analysis) as a colorless oil:
26
[R]D +28.3 (c 2.8, CHCl3); IR (film) 3292, 3028, 2960, 2873,
1
1758, 1498, 1455, 1399, 1217, 1198, 1091 cm-1; H NMR (500
MHz, CDCl3) δ 7.32 (dd, J ) 7.6, 7.6 Hz, 2H), 7.25 (dd, J ) 7.3,
7.3 Hz, 1H), 7.16 (d, J ) 7.0 Hz, 2H), 4.13 (dd, J ) 8.8, 7.7 Hz,
1H), 4.03 (dd, J ) 8.9, 4.6 Hz, 1H), 3.92-3.88 (m, 1H), 4.18-
3.85 (br s, 1H), 3.33 (dd, J ) 13.4, 3.5 Hz, 1H), 3.01 (dddd, J )
5.5, 5.5, 5.5, 5.5 Hz, 1H), 2.61 (dd, J ) 13.4, 10.0 Hz, 1H), 1.55-
1.31 (m, 8H), 0.97-0.91 (m, 6H); 13C NMR (125 MHz, CDCl3) δ
158.7, 136.1, 129.1, 128.9, 127.0, 65.7, 60.3, 59.9, 37.0, 31.2, 27.8,
24.7, 22.9, 14.0, 9.0; MS (EI) m/z (relative intensity) 91 (100%),
117 (80%), 233 (60%), 290 (M+, 8%). Anal. Calcd for C17H26-
N2O2: C, 70.31; H, 9.02; N, 9.65. Found: C, 70.29; H, 9.08; N,
9.72.
(4S,2′R)-3-(2′-Ethyl-pyrrolidin-1-yl)-4-phenylmethyl-2-ox-
azolidinone (11R). From (S)-3-(propylidene)amino-4-phenyl-
methyl-2-oxazolidinone (50 mg, 0.22 mmol) and 1-chloro-3-iodo-
propane (0.23 mL, 2.16 mmol) by general procedure B and workup
B was obtained 11R (31 mg, 52%; S,R/S,S ) 96:4, NMR analysis)
26
as a colorless oil: [R]D +34.6 (c 0.85, CHCl3); IR (film) 3054,
1
3004, 2968, 2875, 1731, 1494, 1415, 1237, 1118, 1016 cm-1; H
NMR (500 MHz, CDCl3) δ 7.32 (dd, J ) 7.1, 7.1 Hz, 2H), 7.25
(dd, J ) 7.3, 7.3 Hz, 1H), 7.17 (d, J ) 7.2 Hz, 2H), 4.14 (dd, J )
8.5, 8.5 Hz, 1H), 4.01-3.92 (m, 2H), 3.60-3.52 (m, 2H), 3.42
(dd, J ) 13.3, 3.6 Hz, 1H), 3.16-3.12 (m, 1H), 2.61 (dd, J )
13.3, 10.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.95-1.86 (m, 1H), 1.82-
1.74 (m, 1H), 1.70-1.62 (m, 1H), 1.47-1.31 (m, 2H), 0.93 (dd, J
) 7.4, 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.7, 136.1,
129.0, 128.8, 126.9, 66.3, 62.5, 60.2, 52.1, 38.8, 28.5, 27.1, 21.7,
10.1; MS (CI) m/z (relative intensity) 275 ([M + H]+, 100%). Anal.
Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C,
70.10; H, 8.11; N, 10.01.
(4S,3′R)-3-(3′-Octanamino)-4-phenylmethyl-2-oxazolidi-
none (7R). From (S)-3-(propylidene)amino-4-phenylmethyl-2-ox-
azolidinone (91 mg, 0.39 mmol) and 1-iodopentane (0.51 mL, 3.92
mmol) by general procedure B and workup B was obtained 7R
(94 mg, 79%; S,R/S,S ) 95:5, HPLC analysis) as a colorless oil:
25
[R]D +23.3 (c 2.2, CHCl3); IR (film) 3293, 3063, 2958, 2931,
1760, 1498, 1455 cm-1;1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J
) 7.6, 7.6 Hz, 2H), 7.25 (dd, J ) 7.4, 7.4 Hz, 1H), 7.16 (d, J )
7.0 Hz, 2H), 4.13 (dd, J ) 8.6, 8.6 Hz, 1H), 4.03 (dd, J ) 8.8, 4.3
Hz, 1H), 3.94-3.85 (m, 1H), 4.30-3.75 (br s, 1H), 3.33 (dd, J )
13.3, 2.5 Hz, 1H), 3.08-2.95 (m, 1H), 2.61 (dd, J ) 13.2, 9.9 Hz,
1H), 1.55-1.25 (m, 10H), 0.95 (dd, J ) 7.2, 7.2 Hz, 3H), 0.90
(dd, J ) 6.8, 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.7,
136.1, 129.1, 128.9, 127.0, 65.7, 60.3, 59.9, 37.0, 32.1, 31.5, 25.2,
24.7, 22.6, 14.0, 9.0; MS (EI) m/z (relative intensity) 91 (100%),
117 (77%), 304 (M+, 9%). Anal. Calcd for C18H28N2O2: C, 71.02;
H, 9.27; N, 9.20. Found: C, 71.12; H, 9.34; N, 9.04.
(4S,3′R)-3-(7′-Chloro-3′-heptanamino)-4-phenylmethyl-2-ox-
azolidinone (12R). From (S)-3-(propylidene)amino-4-phenyl-
methyl-2-oxazolidinone (75 mg, 0.32 mmol) and 1-chloro-4-iodo-
butane (0.40 mL, 3.23 mmol) by general procedure B and workup
B was obtained 12R (58 mg, 55%; S,R/S,S ) 96:4, HPLC analysis)
26
as a colorless oil: [R]D +34.0 (c 0.6, CHCl3); IR (film) 3291,
3063, 3028, 2960, 2873, 1757, 1454, 1400, 1238, 1090, 1029 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J ) 7.0, 7.0 Hz, 2H),
7.26 (dd, J ) 7.3, 7.3 Hz, 1H), 7.16 (d, J ) 6.9 Hz, 2H), 4.14 (dd,
J ) 8.8, 7.7 Hz, 1H), 4.03 (dd, J ) 8.9, 4.8 Hz, 1H), 3.94-3.87
J. Org. Chem, Vol. 71, No. 18, 2006 7025

Friestad et al.
(m, 2H), 3.56 (dd, J ) 6.6, 6.6 Hz, 2H), 3.32 (dd, J ) 13.5, 3.6
Hz, 1H), 3.07-2.95 (m, 1H), 2.62 (dd, J ) 13.4, 9.9 Hz, 1H),
1.85-1.77 (m, 2H), 1.60-1.44 (m, 6H), 0.96 (dd, J ) 7.5, 7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 158.6, 135.9, 129.0, 128.9,
127.0, 65.7, 60.1, 59.7, 44.8, 37.0, 32.7, 30.7, 24.7, 22.8, 9.1; MS
(CI) m/z (relative intensity) 325 ([M + H]+, 100%). Anal. Calcd
for C17H25N2O2Cl: C, 62.86; H, 7.76; N, 8.62. Found: C, 63.07;
H, 7.77; N, 8.45.
was irradiated for 2 days. DBU (2.49 mL, 16.4 mmol) was added,
and after 1 h, the mixture was concentrated and purified by gradient
flash chromatography (hexane f 1:1 hexane/EtOAc) to afford 18
as a pale yellow oil (910 mg, 66% yield). From a separate smaller-
scale reaction, 225 mg of 2c gave 18 in 65% yield (S,R/S,S ) 95:
5, HPLC analysis) as a colorless oil: [R]D26 +28.2 (c 2.0, CHCl3);
IR (film) 3292, 3028, 2956, 2933, 1757, 1497, 1455, 1399, 1238,
1
1089, 1029 cm-1; H NMR (500 MHz, CDCl3) δ 7.32 (dd, J )
7.2, 7.2 Hz, 2H), 7.26 (dd, J ) 7.2, 7.2 Hz, 1H), 7.16 (d, J ) 7.1
Hz, 2H), 4.15 (dd, J ) 8.7, 7.7 Hz, 1H), 4.03 (dd, J ) 8.9, 4.7 Hz,
1H), 3.92-3.86 (m, 1H), 4.20-3.80 (br s, 1H), 3.56 (dd, J ) 6.5,
6.5 Hz, 2H), 3.32 (dd, J ) 13.4, 3.6 Hz, 1H), 3.04 (dddd, J ) 5.3,
5.3, 5.3, 5.3 Hz, 1H), 2.62 (dd, J ) 13.4, 9.9 Hz, 1H), 1.87-1.74
(m, 2H), 1.63-1.34 (m, 8H), 0.95 (dd, J ) 6.8, 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 158.7, 135.9, 129.0, 128.9, 127.0, 65.8,
59.7, 58.8, 44.8, 37.0, 34.5, 32.7, 31.4, 22.8, 18.4, 14.3; MS (CI)
m/z (relative intensity) 339 ([M + H]+, 100%). Anal. Calcd for
C18H27N2O2Cl: C, 63.80; H, 8.03; N, 8.27. Found: C, 64.02; H,
7.99; N, 8.19.
(4S,2′R)-3-(1′,1′-Dichloro-2′-butanamino)-4-phenylmethyl-2-
oxazolidinone (13R). From (S)-3-(propylidene)amino-4-phenyl-
methyl-2-oxazolidinone (50 mg, 0.22 mmol) and bromodichloro-
methane (0.36 mL, 2.16 mmol) by general procedure B and workup
A was obtained 13R (26 mg, 38%; S,R/S,S ) 98:2, NMR analysis)
26
as a colorless oil: [R]D +59.2 (c 0.9, CHCl3); IR (film) 3293,
1
3028, 2971, 1759, 1497, 1455, 1402, 1220, 1091, 1027 cm-1; H
NMR (500 MHz, CDCl3) δ 7.33 (dd, J ) 7.1, 7.1 Hz, 2H), 7.27
(dd, J ) 7.2, 7.2 Hz, 1H), 7.16 (d, J ) 7.1 Hz, 2H), 6.06 (d, J )
2.6 Hz, 1H), 4.44-4.30 (br s, 1H), 4.16 (dd, J ) 8.9, 8.9 Hz, 1H),
4.07 (dd, J ) 8.9, 5.0 Hz, 1H), 3.93-3.88 (m, 1H), 3.43 (dd, J )
13.4, 3.4 Hz, 1H), 3.28-3.23 (m, 1H), 2.63 (dd, J ) 13.3, 10.2
Hz, 1H), 1.99-1.91 (m, 1H), 1.69-1.59 (m, 1H), 1.15 (dd, J )
7.4, 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.0, 135.6,
129.0 (2C), 127.2, 74.3, 68.9, 66.1, 59.4, 36.7, 20.7, 10.7; MS (CI)
m/z (relative intensity) 317 ([M + H]+, 100%). Anal. Calcd for
C14H18N2O2Cl2: C, 53.01; H, 5.72; N, 8.83. Found: C, 53.18; H,
5.82; N, 8.65.
(4S,3′S)-3-(2′-Methyl-3′-pentanamino)-4-phenylmethyl-2-ox-
azolidinone (9S). From 23 (60 mg, 0.24 mmol) and ethyl iodide
(0.12 mL, 1.46 mmol) by general procedure B and workup B was
obtained unreacted 23 (29 mg, 49%) and 9S (28 mg, 41% yield)
25
as a colorless oil: [R]D +17.4 (c 0.17, CHCl3); IR (film) 3304,
2960, 2929, 2873, 1759, 1498, 1453, 1397, 1365, 1259, 1238, 1216,
1
1090, 1029 cm-1; H NMR (500 MHz, CDCl3) δ 7.32 (dd, J )
7.2, 7.2 Hz, 2H), 7.25 (dd, J ) 7.4, 7.4 Hz, 1H), 7.15 (d, J ) 7.1
Hz, 2H), 4.13 (dd, J ) 7.7, 7.7 Hz, 1H), 4.04 (dd, J ) 8.9, 4.2 Hz,
1H), 4.02 (br s, 1H), 3.92-3.87 (m, 1H), 3.35 (dd, J ) 13.4, 2.7
Hz, 1H), 2.80 (m, 1H), 2.61 (dd, J ) 13.4, 10.1 Hz, 1H), 1.92-
1.85 (m, 1H), 1.53-1.47 (m, 1H), 1.39-1.29 (m, 1H), 1.04 (dd,
J ) 7.5, 7.5 Hz, 3H), 0.99 (d, J ) 6.9 Hz, 3H), 0.94 (d, J ) 6.9
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4, 136.1, 129.1, 128.9,
127.0, 66.2, 65.5, 59.6, 36.8, 28.6, 20.8, 18.4, 16.9, 10.9; MS (EI)
m/z (relative intensity) 276 (M+, 2%), 247 (3%), 233 (100%). Anal.
Calcd for C16H24N2O2: C, 69.53; H, 8.75; N, 10.14. Found: C,
69.76; H, 8.85; N, 10.14.
(4S,3′R)-3-(1′-Chloro-3′-pentanamino)-4-phenylmethyl-2-ox-
azolidinone (14). From 2a (53 mg, 0.23 mmol) and 1-chloro-2-
iodoethane (104 µL, 1.14 mmol) by general procedure B and
workup B was obtained 14 as an inseparable mixture with the
starting material (44 mg, 14% yield and 65% 2a by 1H NMR). For
characterization, a pure sample was obtained by an alternative
method55 as a colorless oil: [R]D25 +26.5 (c 0.8, CHCl3); IR (film)
3289, 2964, 2931, 2876, 1755, 1497, 1454, 1400, 1363, 1239, 1091,
1
1029 cm-1; H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 3H),
7.18 (dd, J ) 6.6, 1.6 Hz, 2H), 4.16 (dd, J ) 8.6, 7.6 Hz, 1H),
4.04 (dd, J ) 8.8, 5.7 Hz, 1H), 3.99-3.91 (m, 2H), 3.81-3.62 (m,
2H), 3.37 (dd, J ) 13.4, 3.6 Hz, 1H), 3.13 (m, 1H), 2.67 (dd, J )
13.4, 9.8 Hz, 1H), 1.97-1.90 (m, 2H), 1.64-1.45 (m, 2H), 0.99
(dd, J ) 7.5, 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0,
135.7, 128.9 (2C), 127.0, 66.0, 59.8, 58.4, 41.7, 37.2, 34.8, 25.0,
9.5; MS (EI) m/z (relative intensity) 296 (M+, 6%), 267 (19%),
233 (42%), 205 (57%). Anal. Calcd for C15H21ClN2O2: C, 60.70;
H, 7.13; N, 9.44. Found: C, 60.99; H, 7.17; N, 9.40.
(4S,3′S)-3-(2′-Methyl-3′-pentanamino)-4-diphenylmethyl-2-
oxazolidinone (24B). From 23B (80 mg, 0.25 mmol) and ethyl
iodide (0.20 mL, 2.48 mmol) by general procedure B and workup
B was obtained unreacted 23B (25 mg, 31%) and 24B (46 mg,
25
52% yield) as colorless needles: mp 132-134 °C; [R]D +66.0
(c 0.5, CHCl3); IR (film) 3301, 2961, 2929, 1755, 1494, 1451, 1406,
1221, 1090, 1031, 1009 cm-1; 1H NMR (500 MHz, CDCl3) 7.35-
7.29 (m, 4H), 7.27-7.24 (m, 2H), 7.19 (d, J ) 7.2 Hz, 2H), 7.15
(d, J ) 7.1 Hz, 2H), 4.66 (d, J ) 5.2 Hz, 1H), 4.56-4.52 (m, 1H),
4.37 (dd, J ) 8.8, 8.8 Hz, 1H), 4.27 (dd, J ) 9.1, 3.4 Hz, 1H),
2.71 (ddd, J ) 7.8, 4.3, 4.3 Hz, 1H), 1.78-1.72 (m, 1H), 1.46-
1.38 (m, 1H), 1.32-1.24 (m, 2H), 0.95 (dd, J ) 7.5, 7.5 Hz, 3H),
0.85 (d, J ) 6.9 Hz, 3H), 0.82 (d, J ) 6.9 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 157.5, 140.7, 139.0, 128.8 (2C), 128.7, 128.3,
127.4, 127.0, 65.1, 64.1, 59.5, 50.9, 28.6, 20.7, 18.4, 17.1, 10.7;
MS (EI) m/z (relative intensity) 352 (M+, 2%), 309 (52%), 185
(100%). Anal. Calcd for C22H28N2O2: C, 74.97; H, 8.01; N, 7.95.
Found: C, 74.70; H, 7.97; N, 7.91.
(4S,2′S)-3-(2′-Propyl-piperidin-1-yl)-4-phenylmethyl-2-ox-
azolidinone [(S,S)-17]. From 16 (50 mg, 0.12 mmol) and 1-iodo-
propane (0.23 mL, 2.3 mmol) by general procedure B was obtained
(S,S)-17 (16 mg, 45%, S,S/S,R ) 3.2:1, NMR analysis) as a colorless
oil: IR (film) 3028, 2936, 2860, 1758, 1495, 1454, 1398, 1365,
1
1231, 1186, 1084 cm-1; H NMR (500 MHz, CDCl3) δ 7.31 (dd,
J ) 7.6, 7.6 Hz, 2H), 7.24 (dd, J ) 7.5, 7.5 Hz, 1H), 7.16 (d, J )
7.1 Hz, 2H), 4.14 (dd, J ) 8.3, 8.3 Hz, 1H), 4.00 (dd, J ) 8.8, 8.8
Hz, 1H), 3.95-3.84 (m, 1H), 3.45-3.28 (m, 2H), 2.96 (br d, J )
10.9 Hz, 1H), 2.53 (dd, J ) 13.6, 10.7 Hz, 1H), 1.93-1.04 (m,
10H), 0.94 (dd, J ) 7.3, 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 156.2, 136.5, 128.8, 128.7, 126.9, 67.5, 59.6, 56.6, 49.9, 39.1,
35.5, 32.0, 26.4, 24.0, 18.9, 14.4; MS (CI) m/z (relative intensity)
303 ([M]+, 96%), 259 (100%). Anal. Calcd for C18H26N2O2: C,
71.49; H, 8.67; N, 9.26. Found: C, 71.41; H, 8.68; N, 9.21.
(4S,4′R)-3-(8′-Chloro-4′-octanamino)-4-phenylmethyl-2-ox-
azolidinone (18). To a deoxygenated (N2) solution of 2c (1.01 g,
4.10 mmol) in CH2Cl2 (40 mL) was added InCl3 (2.00 g, 9.03
mmol). After 40 min, Mn2(CO)10 (3.20 g, 8.20 mmol) and 1-chloro-
4-iodobutane (5.03 mL, 41.0 mmol) were added and the mixture
(4S,3′S)-3-(7′-(tert-Butyldimethylsilyloxy)-3′-heptanamino)-4-
phenylmethyl-2-oxazolidinone (25). A mixture of hydrazone 2a
(75 mg, 0.32 mmol) and InCl3 (143 mg, 0.64 mmol) in benzene/
CH3CN (10:1 v/v, 2.2 mL) was stirred at room temperature under
N2 for 30 min. Then Mn2(CO)10 (250 mg, 0.64 mmol) and TBSO-
(CH2)4I (151 mg, 0.48 mmol) were added, and the mixture was
irradiated for 16 h. Gradient flash chromatography (hexane/EtOAc
7:1 to 1:1) afforded hydrazine 25 (82 mg, 0.195 mmol, 63% yield,
1
29
>98:2 dr, H NMR analysis) as a colorless oil: [R]D +6.6° (c
2.4, CHCl3); IR (film) 3292, 3028, 2930, 2858, 1761, 1498, 1462,
1472, 1395, 1361, 1252, 1095, 1030, 1006 cm-1; H NMR (500
1
(55) Addition of iodoethanol to 2a according to general procedure B,
followed by conversion of the alcohol to chloride (PPh3, CCl4, DMF, 75%
yield) gave 14 which matched the NMR data of 14 as observed in the
mixture of 14 and 2a. Details will be reported elsewhere.
MHz, CDCl3) δ 7.31 (dd, J ) 7.9, 7.9 Hz, 2H), 7.25 (dd, J ) 6.8,
6.8 Hz, 1H), 7.15 (d, J ) 7.9 Hz, 2H), 4.13 (dd, J ) 7.9, 7.9 Hz,
1H), 4.03 (dd, J ) 9.1, 4.1 Hz, 1H), 3.93-3.85 (m, 1H), 4.22-
7026 J. Org. Chem., Vol. 71, No. 18, 2006

Coupling of Alkyl Iodides and Chiral N-Acylhydrazones
3.72 (br s, 1H), 3.63 (dd, J ) 6.4, 6.4 Hz, 2H), 3.33 (dd, J ) 13.6,
3.4 Hz, 1H), 3.06-2.94 (m, 1H), 2.61 (dd, J ) 13.9, 9.8 Hz, 1H),
1.64-1.37 (m, 8H), 0.95 (dd, J ) 7.5, 7.5 Hz, 3H), 0.89 (s, 9H),
0.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 158.6, 136.0, 129.0,
128.8, 127.0, 65.7, 62.9, 60.3, 59.9, 37.0, 33.0, 31.3, 25.9, 24.6,
21.8, 18.3, 9.0, -5.4; MS (CI) m/z (relative intensity) 421.1 ([M
+ H]+, 100%); HRMS (EI) calcd for C23H40N2O3Si: 420.2808.
Found: 420.2811.
Acknowledgment. We thank the NSF (CHE-0096803),
Research Corporation, Petroleum Research Fund, Vermont
EPSCoR, and the University of Iowa for generous support.
Supporting Information Available: Characterization data and
selected experimental procedures (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061158Q
J. Org. Chem, Vol. 71, No. 18, 2006 7027