Dual activation in asymmetric allylsilane addition to chiral N-acylhydrazones: Method development, mechanistic studies, and elaboration of homoallylic amine adducts

Article abstract of DOI:10.1021/jo052037d

Chiral N-acylhydrazones derived from commercially available 4-benzyl-2-oxazolidinone provide a rigid, conformationally restricted template to impart facial selectivity in additions to C=N bonds. In the presence of indium(III) trifluoromethanesulfonate [In

Full text of DOI:10.1021/jo052037d

Dual Activation in Asymmetric Allylsilane Addition to Chiral
N-Acylhydrazones: Method Development, Mechanistic Studies, and
Elaboration of Homoallylic Amine Adducts
Gregory K. Friestad,*,† Chandra Sekhar Korapala,† and Hui Ding‡
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 September 28, 2005
Chiral N-acylhydrazones derived from commercially available 4-benzyl-2-oxazolidinone provide a rigid,
conformationally restricted template to impart facial selectivity in additions to CdN bonds. In the presence
of indium(III) trifluoromethanesulfonate [In(OTf)3], N-acylhydrazones undergo highly diastereoselective
fluoride-initiated additions of allylsilanes (aza-Sakurai reaction). Mechanistic studies including control
experiments and comparisons with allyltributylstannane, allylmagnesium bromide, and allylindium species
implicate a dual activation mechanism involving addition of an allylfluorosilicate species to a chelate
formed from In(OTf)3 and the chiral N-acylhydrazone. The N-N bonds of the adducts are readily cleaved
in a two-step protocol to provide synthetically useful homoallylic N-trifluoroacetamides. Further elaboration
of the latter compounds through Wacker oxidation and olefin metathesis provides diversely functionalized
building blocks and expands the potential applications of this C-C bond construction approach to
asymmetric amine synthesis.
Introduction
glycine derivatives. Homoallylic amines are not only valuable
building blocks, but are found in their native form within a
variety of compounds of biological relevance, including the
natural products cryptophycin 337,8 angustifoline,9 and epone-
mycin.10 Allylglycine residues in synthetic renin inhibitors11 and
aspartic proteinase inhibitors12 further exemplify the widespread
importance of homoallylic amines.
Asymmetric amine synthesis by addition of allylic nucleo-
philes to the CdN bond of carbonyl imino derivatives offers
direct access to these substructures by introducing a stereogenic
Chiral homoallylic amines enjoy a privileged position among
chiral amines because of their value as versatile building blocks
for natural product synthesis.1 For example, transformations
from the terminal alkene have provided key intermediates en
route to natural products such as indolizomycin,2 (+)-desoxo-
prosopinine,3 and various azacyclic targets including anabasine4
and the spirocyclic core of halichlorine.5 In addition, medicinally
important immunostimulating lipopeptides6 and dual metallo-
protease inhibitors7 have been synthesized with use of allyl-
† University of Iowa.
(7) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono,
D. E.; Bird, J. E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med.
Chem. 1996, 39, 494-502.
‡ University of Vermont.
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Lebreton, J. J. Org. Chem. 2001, 66, 6305-6312.
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10.1021/jo052037d CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
J. Org. Chem. 2006, 71, 281-289
281

Friestad et al.
center and carbon-carbon bond in one step. As a result,
extensive efforts have been directed toward stereoselective allyl
addition to chiral imines, iminium ions, and related CdN
electrophiles.13 The arsenal of more general procedures for alkyl
addition to the CdN bond14 has also been applied to allyl
additions; the latter often benefit from enhanced asymmetric
induction through chelation and formation of chair transition
states.1 Despite the value of organometallic nucleophiles for
various additions to imino acceptors, particularly those which
are nonenolizable, the strongly basic or harsh Lewis acidic
conditions often employed for these reactions may be problem-
atic.14 Complications of competitive metalloenamine formation
and functional group incompatibilities often interfere with
broader application, so development of milder conditions for
stereocontrolled allylmetal addition to the CdN bond is of
considerable importance. Nonbasic main group organometallics
such as allylsilanes offer an attractive solution to these problems,
but have been rarely applied in additions to neutral, isolable
imines. This inattention may be attributed to an historical
perception that allylsilanes are rather unreactive toward imines
without resort to iminium ions or the use of strong Lewis acids.15
Recent studies have explored activation of allylsilane reagents16
with ring strain,17 nucleophiles,18 or transition metal-catalyzed
processes,19 resulting in several elegant stereocontrolled addi-
tions to imino acceptors.
We envisioned a dual activation scenario wherein both
allylsilane donor and acceptor would be activated in comple-
mentary fashion to promote C-C bond construction under
relatively mild conditions.20-22 Nucleophilic activation may be
readily accomplished with allyltrichlorosilanes, but these re-
agents are highly moisture-sensitive and corrosive. To maintain
ease of handling and nonacidic conditions, we chose allylsilanes
bearing alkyl substituents, while recognizing that a less elec-
trophilic Si atom could make nucleophilic activation of these
silanes more challenging. Although fluoride ion is perhaps the
most obvious choice of activator for this purpose, there are
surprisingly few examples of simple fluoride-promoted addition
of allylsilanes to CdN bonds (aza-Sakurai reaction, eq 1).23-25
It was our hope that the dual activation concept, employing a
mild Lewis acid together with fluoride in an aza-Sakurai
reaction, would overcome this lack of reactivity. Thus this
concept would require two separate, mutually compatible
activators; the difficulty in identifying an effective Lewis acid
that is compatible with fluoride was anticipated to be a
significant obstacle in the initial stages of method development.
Turning to the issue of stereoselectivity, we chose to exploit
chiral N-acylhydrazones (Figure 1) wherein Lewis acid activa-
tion and restriction of rotamer populations were key design
elements.26,27 These had previously proved to be excellent
acceptors for stereoselective radical addition,28,29 hydride reduc-
tion,30 and other reactions.31 The stereocontrol is quite simple
and predictable, and is easily understood by considering the
spatial relationship between the oxazolidinone substituent and
the CdN π system (Figure 2). In N-acylhydrazone A, chelation
of a Lewis acid exposes the si face to addition, while
(21) Related concepts of dual activation using separate nucleophilic and
Lewis acidic species have been rarely reported. (a) Myers, J. K.; Jacobsen,
E. N. J. Am. Chem. Soc. 1999, 121, 859-8960. (b) Yanagisawa, A.;
Nakatsuka, Y.; Asakawa, K.; Kageyama, H.; Yamamoto, H. Synlett 2001,
69-72. (c) Saito, S.; Yamazaki, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2001, 40, 3613-3617. France, S.; Wack, H.; Hafez, A. M.; Taggi, A. E.;
Witsil, D. R.; Lectka, T. Org. Lett. 2002, 4, 1603-1605. (d) Kobayashi,
S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640-5641. (e)
Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed. 2003, 42,
3927-3930.
(22) Two related (but mechanistically distinct) dual activation approaches
have been explored more extensively: (a) A nucleophile may be activated
by deprotonation (Bronsted base approach) in the presence of a Lewis acid;
for discussion and leading references, see: Kanemasa, S.; Ito, K. Eur. J.
Org. Chem. 2004, 4741-4753. (b) Lewis acids and bases may react with
each other to form a single species that achieves dual activation (bifunctional
catalyst approach); for selected seminal examples, see: Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. Corey,
E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-5553.
Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc.
1991, 113, 4247-4252. Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993,
34, 4001-4004. Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2363-2365. Denmark, S. E.; Coe, D. M.; Pratt, N. E.;
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K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333-2334. Krueger,
C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284-
4285. For more recent references and extensive discussion, see ref 15.
(23) Reviews of activation of allylsilanes: (a) Chuit, C. C.; Corriu, R.
J. P.; Reye, C.; Young, J. C. Chem. ReV. 1993, 93, 1371-1448. (b) Also
see ref 18.
(13) For a recent review of allyl organometallic addition to CdN bonds,
see ref 1. Also see: Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-
2293. Kleinman, E. F.; Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 2, pp 975-1006.
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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.
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1895-1946. Denmark, S. E.; Nicaise, O. J.-C. J. Chem. Soc., Chem.
Commun. 1996, 999-1004.
(15) (a) Sluggish reactivity of allylsilanes toward neutral imines has been
noted: see refs 1 and 13. (b) Though allylsilane addition to iminium ions
is effective, a strong Lewis acid such as TiCl4 or BF3‚Et2O is often required.
For a review, see: Fleming, I.; Dunogus, J.; Smithers, R. Org. React. 1989,
37, 57-575. Recent examples: Schaus, J. V.; Jain, N.; Panek, J. S.
Tetrahedron 2000, 56, 10263-10274. Akiyama, T.; Sugano, M.; Ka-
goshima, H. Tetrahedron Lett. 2001, 42, 3889-3892.
(16) Review: Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed.
2003, 42, 4732-4739.
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Chem. Soc. 2004, 126, 5686-5687.
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6942-6943. (b) Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S.
J. Am Chem. Soc. 2001, 123, 9493-9499. (c) Kobayashi, S.; Ogawa, C.;
Konishi, H.; Sugiura, M. J. Am Chem. Soc. 2003, 125, 6610-6611.
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738. (b) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 14133-14139. (c) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai,
M.; Shibasaki, M. J. Am Chem. Soc. 2002, 124, 6536-6537.
(20) For a review of dual activation, see: Ma, J.-A.; Cahard, D. Angew.
Chem., Int. Ed. 2004, 43, 4566-4583.
(24) (a) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844-4849. (b) Wang, D.-
K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 1999, 64,
4233-4237. (c) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901-
6905.
(25) Ding, H.; Friestad, G. K. Synthesis 2004, 2216-2221.
(26) (a) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329-
8330. (b) Friestad, G. K.; Draghici, C.; Soukri, M.; Qin, J. J. Org. Chem.
2005, 70, 6330-6338.
(27) Review of chiral N-acylhydrazones: Friestad, G. K. Eur. J. Org.
Chem. 2005, 3157-3172.
(28) Review of radical addition to CdN bonds: Friestad, G. K.
Tetrahedron 2001, 57, 5461-5496.
(29) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922-9923.
(30) Qin, J.; Friestad, G. K. Tetrahedron 2003, 59, 6393-6402.
(31) (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.
282 J. Org. Chem., Vol. 71, No. 1, 2006

Allylsilane Addition to Chiral N-Acylhydrazones
SCHEME 2
FIGURE 1. Application of chiral N-acylhydrazones for asymmetric
amine synthesis via addition and N-N bond cleavage.
tion with enantiopure hydrazone 1a at ambient temperature to
afford the allyl adduct 2a in 56% yield (dr 5:1) in 1 h. A catalytic
amount of TBAF (10 mol %) afforded slightly lower yield (45%)
and the same diastereomeric ratio in 2 h. Under these catalytic
TBAF conditions, a slight improvement in yield and diastereo-
selectivity was observed at 0 °C (60% yield, dr 6:1), although
at -78 °C there was virtually no reaction (<2% yield).
Switching the solvent to noncoordinating methylene chloride
slowed the reaction. Control experiments showed no reaction
occurred without TBAF, even under refluxing conditions, and
other fluoride sources such as CeF3 or CsF did not promote the
allyl addition.
FIGURE 2. Stereocontrol models involving chiral N-acylhydrazones-
Lewis acid combinations.
SCHEME 1
Encouraged by the promising preliminary results showing
nucleophilic activation with fluoride, we tested the dual activa-
tion hypothesis by incorporating various Lewis acids, including
ZnCl2, TiCl4, SnCl4, Sc(OTf)3, Yb(OTf)3, or indium(III) tri-
fluoromethanesulfonate [In(OTf)3]. Our concerns about their
mutual compatibilities were not unwarranted; upon addition of
a Lewis acid to the mixture of hydrazone, allylsilane, and TBAF
in THF there was no reaction. Attributing this to incompatibility
of Lewis acid with fluoride ion, we selected a new experimental
protocol. Thus, two CH2Cl2 solutions were prepared separately,
one consisting of hydrazone 1a with Lewis acid and the other
of allyltrimethylsilane with TBAF. After 4 h, these two solutions
were combined at ambient temperature. With this protocol, the
allyl addition did occur, but inefficiently. For example, the yield
of 2a was 28% with SnCl4, 20% with TiCl4, and 14% with
In(OTf)3.
Eventually, we found that the soluble, air-stable, nonhygro-
scopic fluoride source tetrabutylammonium triphenyldifluoro-
silicate (TBAT)35 could effectively promote allyltrimethylsilane
addition to the complex formed by mixing 1a with a Lewis
acid, providing 2a with good stereoselectivity. From a broad
range of Lewis acids screened, including SnCl4 and InCl3
(Scheme 2), In(OTf)3 was chosen; no reaction was observed in
the presence of numerous other Lewis acids.36 The striking
difference between InCl3 and In(OTf)3 suggests the importance
of a nonnucleophilic counterion under these conditions. Use of
0.2 equiv of In(OTf)3 led to no reaction. Despite their previously
documented utility in radical additions to hydrazones,26,37 ZnCl2
and Cu(OTf)2 led to no change of hydrazone 1a.
monodentate interaction of N-acylhydrazone B with BF3 induces
addition to the re face. The complementary selectivities presum-
ably originate from preferential population of different N-N
bond rotamers.
Finally, we anticipated merging the allylsilane addition with
application of a recently disclosed TFA-activated N-N bond
cleavage method,32 ultimately generating homoallylic N-tri-
fluoroacetamides as synthetically useful building blocks. To
establish broader utility, brief exploration of alkene oxidation
and metathesis transformations of these building blocks was
envisioned.
The hypotheses outlined above offered fertile territory for
new reaction development. Here we disclose complete details
of development of convenient, highly stereoselective allylsilane
additions using dual activation by fluoride and indium(III)
trifluoromethanesulfonate.33 In this study, mechanistic insights
have been gained through comparison with other allylmetal
additions, and expanded scope was demonstrated, including the
merger of allylsilane addition with oxidation and metathesis
reactions.
Results and Discussion
Variations to the substituents on silicon were examined next
(Table 1). Although allyltrialkoxysilanes and various allyl-
Method Development. Our initial studies examined the aza-
Sakurai reaction of allyltrimethylsilane with chiral hydrazone
1a34 (Scheme 1), using tetrabutylammonium fluoride (TBAF)
as a fluoride source for nucleophilic activation. With 1 equiv
of TBAF in THF, allyltrimethylsilane underwent smooth reac-
(35) (a) In comparison to TBAF, the nucleophilicity and basicity of F-
are moderated by the covalent Si-F linkage in TBAT. (b) Pilcher, A. S.;
Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995, 117, 5166-5167.
Handy, C. J.; Lam, Y.-F.; DeShong, P. J. Org. Chem. 2000, 65, 3542-
3543.
(36) There was no reaction in the presence of the following Lewis
acids: InF3, ZnCl2, TiCl4, Sc(OTf)3, Yb(OTf)3, Hf(OTf)4, Zr(OTf)4,
Cu(OAc)2, Cu(OTf)2, TMSOTf, NiF2, NiI2, and In(OAc)3.
(37) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed.
2003, 42, 5061-5063.
(32) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637-640.
(33) Portions of this work appeared in a preliminary communication:
Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40, 4491-4493.
(34) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236-6239.
J. Org. Chem, Vol. 71, No. 1, 2006 283

Friestad et al.
TABLE 1. Variation of Silicon Substituents in TBAT/
In(OTf)3-Promoted Addition of Allylsilanes to Hydrazone 1a
(Scheme 2)a
SCHEME 3
[Si] of allylsilane
yield of 3a,b %
drc
SiMe3
58
94:6
SiPh3
Si(OMe)3
SiCl3
SiMeCl2
SiMe2Cl
SiMe2N(iPr)2
Si(allyl)3
0 (nr)
0 (nr)
0 (nr)
0 (nr)
0 (nr)
81
95:5
>99:1
78
a Reaction conditions: A solution of allylsilane (3 equiv) and TBAT (3
equiv), and a solution of In(OTf)3 (1.3 equiv) and hydrazone 2a, each in
CH2Cl2 (0.1 M), were prepared separately. After 4 h at ca. 25 °C, the
allylsilane/TBAT mixture was transferred by syringe to the hydrazone-
In(OTf)3 mixture. After 2 d at ca. 25 °C, the reaction mixture was washed
with water, dried (anhydrous MgSO4), concentrated, and purified by flash
chromatography. b Isolated yields of purified diastereomer mixtures (nr:
no reaction). c Diastereomer ratio by HPLC (Microsorb-MV C8, 2-PrOH/
hexane).
the yield. The R,â-unsaturated hydrazone (E)-2f underwent
chemoselective addition to the CdN bond; here the adduct offers
further potential for functionalization of the olefinic moiety from
cinnamaldehyde. Although propionaldehyde hydrazone 2g26 also
participated in the reaction, stereoselectivity was modest.
Improved selectivity has been reported for saturated substrates
by using indium(0)-promoted allyl addition.31b
To compare the reactivity of the TBAT/allylsilane system
with a strongly basic allylmetal reagent, allylmagnesium
bromide addition to hydrazone 1a was performed in CH2Cl2.
Allyl adduct 2a was obtained in 47% yield after 18 h, with the
predominant configuration (S) at the new stereogenic center (dr
86:14). A complex mixture of byproducts was also obtained,
which appeared by NMR analysis to result from allyl addition
to the oxazolidinone moiety. On the other hand, allyltributyltin
(70% yield) or tetraallyltin (43% yield) gave better stereo-
selectivity (dr 93:7 and 97:3, respectively), although no reaction
occurred in the absence of In(OTf)3.
Configurational Assignment and N-N Bond Cleavage.
Assignment of configuration of 2a, derived from allyl addition
to the benzaldehyde hydrazone, was accomplished by chemical
correlation. Lithiation (n-BuLi) and acylation with benzoic
anhydride, followed by reductive removal of the auxiliary with
samarium(II) iodide (SmI2), afforded known benzamide (S)-
439 (Scheme 3), with the configuration identified by optical
rotation in comparison with material of known configuration.40
The stereochemical outcome of addition was found to be the
same in the major product from allyl addition to the propion-
aldehyde hydrazone: Hydrogenation of 2g gives 5, a derivative
of (R)-3-aminohexane,41 which was identical with the known
compound obtained from n-propyl radical addition to 1g
(Scheme 3).29
TABLE 2. Preparation of Various Aldehyde Hydrazones 1 and
TBAT/In(OTf)3-Promoted Addition of Tetraallylsilanea
R
hydrazoneb
allyl adductc
drd
phenyl
p-tolyl
m-nitrophenyl
2-naphthyl
2-furyl
1a, 80%
1b, 94%
1c, 91%
1d, 92%
1e, 92%
1f, 97%
1g, 92%
1h, 98%
2a, 78%
2b, 94%
2c, 71%
2d, 82%
2e, 58%
2f, 60%
2g, 51%
2h, 54%e
>99:1
98:2
>99:1
98:2
96:4
95:5
82:18
96:4
-CHdCHPh (E)
-CH2CH3
3,4-dimethoxyphenyl
a Reaction conditions for hydrazone formation: aldehyde (0.4 mmol), 3
(0.25 mmol), anhydrous MgSO4 (200 mg), p-toluenesulfonic acid (ca. 5
mol %) in toluene (10 mL), reflux 10 min. For allyl addition conditions
see Table 1. b Isolated yield. c Isolated yields of purified diastereomer
mixtures. d Diastereomer ratio by HPLC (see Table 1). e Reaction scale:
4.5 mmol of hydrazone.
chlorosilanes were ineffective under these conditions, allyl-
(diisopropylamino)dimethylsilane led to significant improve-
ment, providing 2a in high yield and stereoselectivity. A superior
allyl donor proved to be commercially available tetraallylsilane,
which gave 2a in 78% yield with excellent stereocontrol (dr
>99:1). The improved yield and selectivity of tetraallylsilane
versus allyltrimethylsilane may be attributable to a slightly more
electrophilic silicon atom, leading to greater fluoride ion affinity,
increased hypervalent silicate population, and a later transition
state.38
Reaction Scope. With effective reaction conditions at hand,
a brief survey of the scope of the reaction was undertaken with
a series of aldehyde hydrazones (Table 2). Aromatic aldehyde
hydrazones 1b-h generally gave homoallylic amines in good
yield with excellent stereoselectivity. Stereocontrol varied only
slightly with the electronic properties of the aromatic system,
although electron-rich 2-furyl and veratryl groups diminished
Although the reductive N-N bond cleavage with SmI2 could
succeed in preserving the synthetically useful alkene functional-
ity in the allyl adducts (in contrast to hydrogenolysis), related
studies indicated that a N-benzoyl group was required to
facilitate the process.42 To access the primary amines after N-N
(39) (a) Wang, X.; Li, J.; Zhang, Y. Synth. Commun. 2003, 33, 3575-
3581. (b) Katritzky, A. R.; Koeditz, J.; Lang, H. Inorg. Chim. Acta 1994,
220, 67-72. (c) Also see ref 31b.
(40) (a) Specific optical rotation of 4, [R]20D -20 (c 0.34, CHCl3), was
within experimental error of an authentic sample, [R]20 -22 (c 0.34,
D
CHCl3), prepared from the known homoallylic amine. Basile, T.; Bocoum,
A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766-7773.
(b) The specific rotations of several compounds (including 4) were recorded
erroneously in the preliminary report (ref 33); corrected data are provided
in the Supporting Information.
(41) The difference in R/S nomenclature between 4 and 5 reflects the
different priorities of substituents, not a difference in mechanism.
(42) Substituting the benzoyl with other acyl groups such as methoxy-
carbonyl resulted in no reaction. See ref 26b.
(38) Similar explanations have been advanced regarding enhanced
reactivity of bis(allyl)silanes. Shibato, A.; Itagaki, Y.; Tayama, E.; Hokke,
Y.; Asao, N.; Maruoka, K. Tetrahedron 2000, 56, 5373-5382.
284 J. Org. Chem., Vol. 71, No. 1, 2006

Allylsilane Addition to Chiral N-Acylhydrazones
SCHEME 4
bond cleavage would then still require a difficult benzamide
hydrolysis. Fortunately, an alternative N-N bond cleavage
method based on the activating effect of a trifluoroacetamide
(N-TFA) group leaves a more functional TFA protecting
group.43,44 After N-trifluoroacetylation, the SmI2-mediated N-N
bond cleavage of hydrazines 2a and 2h occurs smoothly
(Scheme 4) to afford the trifluoroacetamides 6a and 6h.45 As
in other N-N bond cleavages of this type with SmI2, the
oxazolidinone component may also be recovered in high yield.
Furthermore, as expected from ample precedent,46 removal of
the TFA protecting group from 6h was achieved under mild
basic conditions, affording free amine 7 in 91% yield.32
Mechanistic Studies. With the basic reaction method estab-
lished, questions regarding the mechanism warranted further
attention. A series of control experiments with 1a gave some
mechanistic insight to better understand the roles of the reactants.
First, the importance of In(OTf)3 and TBAT was assessed by
carrying out reactions in their absence. Without In(OTf)3 a lower
yield (15%) was found due to incomplete conversion, which
was accompanied by lower stereoselectivity (dr 67:33). Without
TBAT, the yield was also lowered (30%), but the diastereo-
selectivity remained high (dr 94:6). Thus, both In(OTf)3 and
TBAT are required for good reactivity, while In(OTf)3 also is
important for stereocontrol. If both In(OTf)3 and TBAT are
omitted, no reaction occurs.
FIGURE 3. 1H NMR spectra (500 MHz, CD2Cl2, 27 °C) of a mixture
of 1a and In(OTf)3 (1.2 equiv): top, hydrazone 1a; middle, 1a +
In(OTf)3, 15 min; bottom, 1a + In(OTf)3, 18 h. Arrows denote the
peaks assigned to the CHdN proton of the hydrazone-Lewis acid
complex.
SCHEME 5
The configuration of the adduct shows that addition occurred
on the si face, consistent with all other available evidence
involving chelation-controlled additions to related N-acyl-
hydrazones in the presence of Lewis acids capable of chelation
(e.g., ZnCl2, InCl3, and In(OTf)3). Since previous studies of
closely related N-acylhydrazones showed that monodentate
interaction (BF3‚OEt2) leads to addition on the re face (Figure
2B),30 the stereochemical outcome here is significant evidence
in support of a model involving Lewis acid chelation by the
N-acylhydrazone.
For the nucleophilic component, two alternative types of
allylic nucleophiles may be considered, depending on whether
the allylsilicate undergoes transmetalation with In(III). An
allylsilicate intermediate C (formed by addition of F- to the
allylsilane) could react directly with the N-acylhydrazone
(Scheme 5, path a), or alternatively, its reaction with In(OTf)3
could result in transmetalation to afford an allylindium species
D as the active nucleophilic agent (path b).47
The results of these control experiments were consistent with
our working hypothesis based on dual activation of both the
nucleophilic and electrophilic components. For the electrophilic
interaction, a chelation model is envisioned, where two-point
binding of a Lewis acid activates the N-acylhydrazone toward
nucleophilic attack. Nucleophilic activation would involve
addition of fluoride ion to the allylsilane, generating a hyper-
valent silicate. Several experimental tests were carried out to
further examine this working hypothesis.
Coordination of the Lewis acid to the imine nitrogen is
1
supported by H NMR spectroscopy experiments (Figure 3);
significant downfield shift of the hydrazone proton was observed
upon mixing In(OTf)3 (1.2 equiv) and 1a. A new set of peaks
appears in the spectrum, highlighted by a new hydrazone peak
above 10.5 ppm (arrows in Figure 3). Two species persist even
after 18 h.
Further experiments garnered evidence to distinguish the
alternative hypotheses of Scheme 5. Including additional
In(OTf)3 in the TBAT/allylsilane mixture led to 66% yield and
dr >99:1, results which are very similar to those with the
optimized conditions of Table 1. This suggests that any
interaction of F- with In(OTf)3 under these conditions is slow,
if it occurs at all. However, increasing the reaction time for
(43) Details including the scope of this reaction are reported elsewhere
(ref 32).
(44) Chelation of SmI2 by neighboring fluorines increases its reducing
power. Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2002, 124, 6357-
6361.
(45) Enantiomeric purities of chiral hydrazines are unchanged during
N-N bond cleavage according to this method. See ref 32.
(46) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; pp 353-354.
(47) Addition of allylindium species to imino compounds is known. (a)
Jin, S.-J.; Araki, S.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1993, 66, 1528-
1532. (b) Also see ref 31b and references therein.
J. Org. Chem, Vol. 71, No. 1, 2006 285

Friestad et al.
TABLE 3. Allyl Addition with Use of a Grignard Reagent in the
SCHEME 6
a
Presence of In(OTf)3
R1
phenyl
hydrazoneb
allyl adductc
drd
reaction observed. The same result was found with use of InI3
in THF. Again the reactivities observed in the aza-Sakurai
reactions of Tables 1 and 2 were not reproduced, adding further
evidence against transmetalation and the intermediacy of
allylindium species in the allylsilane addition reactions.
Two additional observations are inconsistent with the trans-
metalation hypothesis: The allylsilane addition fails in 10:1
CH2Cl2/water, although water is known to be compatible with
allylindium addition.48,50 Also, variation of reactivity and
selectivity upon changing the silicon ligands (Table 1) implies
the presence of silicon at the transition state.
1a
1b
1c
1d
1e
1f
2a, 76%
2b, 53%
2c, 9%
2d, 65%
2e, 56%
2f, 64%
2g, 28%
86:14
82:18
93:7
80:20
93:7
p-tolyl
m-nitrophenyl
2-naphthyl
2-furyl
-CHdCHPh
-CH2CH3
86:14
63:37
1g
a Reaction conditions: see text. b Isolated yield. c Isolated yields of
purified diastereomer mixtures. d Diastereomer ratio by HPLC (see Table
1).
Taken together, these results show that the transmetalation
is not likely to play a key role in the dual activation method of
allylsilane addition to chiral N-acylhydrazones. Addition of a
hypervalent allylsilicate to the Lewis acid-complexed N-
acylhydrazone appears to best explain the observations. Stereo-
chemical results are consistent with the chelate structure in
Figure 2A, wherein restriction of rotamer populations facilitates
steric blocking of the re face.
Synthetic Elaborations of the Homoallylic Amines. With
the synthetic methodology having been established for allyl
addition to chiral N-acylhydrazones, it became interesting to
consider the most effective approach to broaden the scope of
potential applications. For this purpose, oxidation and cross-
coupling of the alkene moiety were attractive options, and we
briefly explored these transformations to highlight the synthetic
utility of the allylsilane addition methodology.
such a mixture of In(OTf)3, TBAT, and allylsilane to >12 h
prior to combining it with the In(OTf)3-hydrazone complex
led to a pronounced diminution of reactivity and selectivity (22%
yield, dr 95:5). This suggests that, over time, the In(OTf)3 may
react with the active allyl donor, leading either to a less reactive
allylindium donor species by a slow transmetalation or to some
other decomposition product of the allylsilane. Accordingly, 1H
NMR experiments (500 MHz, CD2Cl2, 27 °C) showed that
tetraallylsilane is essentially unchanged after 4 h in the presence
of TBAT, and when In(OTf)3 is added, consumption of the
tetrallylsilane requires at least a further 14 h. These experiments
indicate that transmetalation to an allylindium species (if it
occurs at all under these conditions) is slow, and even if
sufficient time is allowed for complete consumption of the
allylsilane, the resulting species does not duplicate the results
of Tables 1 and 2.
In the course of ongoing synthetic objectives, we had occasion
to attempt conversion of homoallylic amines to the correspond-
ing methyl ketones by Wacker oxidation.51 Amide 4h, obtained
in 78% yield from 2h by the two-step procedure of Scheme 3,
was oxidized successfully to afford 88% of the desired methyl
ketone 8 under modified Wacker oxidation conditions52 employ-
ing 20 mol % of PdCl2 (Scheme 6). Similarly, Wacker oxidation
of racemic TFA-amide rac-6h53 furnished methyl ketone 9 in
69% yield. Although free base 10 was oxidized to the methyl
ketone, elimination of the amino substituent consumed the
desired product.54 Acylated â-aminoketones 8 and 9 did not
suffer this decomposition, and were easily isolated and purified.
We also sought to couple our homoallylic amine synthesis
with the ubiquitous olefin metathesis,55 a strategic intersection
Next we experimentally tested whether transmetalation, if
carried out intentionally by an alternative method, could
reproduce the results of allylsilane addition in the presence of
TBAT and In(OTf)3. For this purpose, In(OTf)3 was incorpo-
rated into the allylmagnesium bromide addition to 1a, with the
intent to reproduce in situ the Mg-In transmetalation reported
by Whitesides et al.48 When a preformed complex of 1a (1
equiv) and In(OTf)3 (1.3 equiv) was used, allylmagnesium
bromide (3 equiv) addition required 2 days to complete and
76% yield of 2a was obtained, with 86:14 dr (Table 3). This
same method was then applied to hydrazones 1b-g. Decom-
position of 1c became a serious side reaction, and the yields
and selectivities of the reactions were significantly lower,
revealing that these conditions are clearly distinguished from
the allylsilane conditions.49
(50) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149-11176. Kumar,
H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S. Tetrahedron Lett. 2000,
41, 9311-9314. Chan, T. H.; Lu, W. Tetrahedron Lett. 1998, 39, 8605-
8608.
For allylmagnesium bromide addition to 1a, more control
experiments on transmetalation were performed. When the order
of addition was changed,48 so that allylmagnesium bromide was
allowed to react with In(OTf)3 in CH2Cl2 prior to addition of
1a (either alone or with additional In(OTf)3), there was no
(51) Reviews: Takacs, J. M.; Jiang, X.-T. Curr. Org. Chem. 2003, 7,
369-396. Tsuji, J. Synthesis 1984, 369-384.
(52) Smith, A. B., III; Cho, Y.-S.; Friestad, G. K. Tetrahedron Lett. 1998,
39, 8765-8768.
(48) Whitesides et al. have reported that allylmagnesium bromide and
InCl3 gives allylindium(III) dichloride. Kim, E.; Gordon, D. M.; Schid, W.;
Whitesides, G. M. J. Org. Chem. 1993, 58, 5500-5507.
(49) The allylmagnesium bromide additions in the presence of In(OTf)3
are also clearly distinguished from known allylindium addition reactions.
Stereoselectivity is low in the former, while Cook’s allylindium addition
to these chiral N-acylhydrazones was fast (3 h) and highly diastereoselective
(>99: 1 dr, see ref 31b).
(53) Racemic homoallylic amine was readily prepared by a convenient
catalytic allylsilane addition procedure: see ref 24.
(54) Benzylamine 10 was oxidized to a complex mixture containing the
known alkene ArCHdCHCOCH3 (Ar ) 3,4-dimethoxyphenyl). Jitoe, A.;
Masuda, T.; Nakatani, N. Phytochemistry 1993, 32, 357-364.
(55) For reviews of olefin metathesis, see: (a) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. (b) Deiters,
A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238.
286 J. Org. Chem., Vol. 71, No. 1, 2006

Allylsilane Addition to Chiral N-Acylhydrazones
TABLE 4. Cross Metathesis of Homoallylic Trifluoroacetamides
SCHEME 7
SCHEME 8
a Mixture of alcohol diastereomers was obtained (dr 3:2). b Veratryl )
3,4-dimethoxyphenyl.
that would offer greatly expanded synthetic potential. Exploiting
this tactic, a wide range of homoallylic amines could be easily
prepared from the parent homoallylic trifluoroacetamide, of-
fering potential access to numerous highly functionalized
building blocks for synthesis. Whereas ring-closing metathesis
had been reported with trifluoroacetamide precursors in a few
isolated cases,56 it was a surprise to find that cross-metathesis
reactions of N-TFA-protected homoallylic amines had not been
previously reported.
Cross-metathesis reactions of TFA-protected homoallylic
amines were examined by using 5% mol of second generation
Grubbs catalyst (21a) in refluxing methylene chloride (Table
4). These reactions proved to be no exception to precedent.
Under these conditions, cross-metathesis between the protected
homoallylic amine rac-6a or rac-6h and a number of function-
alized alkenes proceeded effectively. Allyltrimethylsilane was
coupled with rac-6a to afford 11 in good yield; further
elaboration with the allylic silane moiety can be envisioned.
Cross-metathesis with various oxygen-containing alkenes in-
cluding alcohol, ketone, and ester functionality was also
effective; methyl acrylate gave excellent yields of R,â-unsat-
urated δ-aminoesters 13 and 17. Racemic allylic alcohols 16
and 19 were employed in the cross-metathesis with rac-6a and
rac-6h, respectively, affording 15 and 18 as inseparable
diastereomeric mixtures. Together, these functionalized cross-
metathesis partners yield products with broad synthetic potential.
Piperidine and quinolizidine alkaloids may be constructed
through a tactic combining allylic amination (i.e., N-allylation)
with metathesis. For example, N-allylation of trifluoroacetamide
rac-6h (Scheme 7) and ring-closing metathesis of the resulting
diene 20 with the first-generation Grubbs catalyst (21b)
smoothly provided unsaturated piperidine 22 in 54% yield for
two steps.
from 7 (Scheme 8). Subjection of this material to intramolecular
Pd-catalyzed allylic amination57 gave piperidine 25 in high yield.
With triphenylphosphine as the ligand, the R-vinyl diastereomer
(2R)-25 was preferred.58
A preformed TsOH salt5 of the tertiary amine 25 (dr 1:1)
was treated with second-generation Grubbs catalyst (21a) to
afford ring-closing metathesis product 26 (dr 1:1) as an easily
separated mixture of diastereomers in 85% yield (Scheme 8).
This established the quinolizidine framework, wherein the
relative configuration was determined by observation of Bohl-
mann bands59 in the infrared spectrum of (9aS)-26.
Conclusions
Highly stereoselective allylsilane addition to chiral N-
acylhydrazones occurs in the presence of stoichiometric amounts
of easily handled, air-stable TBAT and In(OTf)3. To our
knowledge these are the first examples of useful auxiliary acyclic
stereocontrol in allylsilane addition to stable, isolable imino
derivatives. Diastereomer ratios ranged upward from 95:5 for
(57) Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano, J. Tetrahedron
Lett. 1998, 39, 1713-1716. Trost, B. M.; Lee, C. B. J. Am. Chem. Soc.
2001, 123, 3671-3686.
(58) Improvement in the diastereoselectivity of this allylic amination step
was briefly examined, substituting PPh3 with the (+)- or (-)-enantiomer
of Trost’s N,N′-bis(2′-diphenylphosphinobenzoyl)-1,2-diaminocyclohexane
ligand, or its naphthoyl-substituted analogue. These reactions were all
nonselective (dr 1:1), despite the general utility of these important ligands.
Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
114, 9327-9343. Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 99-102.
For the quinolizidine skeleton, a simple nucleophilic substitu-
tion with tosylate 23 delivers secondary amine 24 in 68% yield
(56) (a) Fu, G. C.; Nguyen, S. B.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856-9857. (b) Schuster, M.; Pernerstorfer, J.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1979-1980. (c) Huwe, C. M.;
Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376-
2378. (d) Maier, M. E.; Lapeva, T. Synlett 1998, 891-893.
(59) Bohlmann, F. Chem. Ber. 1958, 91, 2157-2167.
J. Org. Chem, Vol. 71, No. 1, 2006 287

Friestad et al.
Hz, 1H), 5.10 (d, J ) 10.2 Hz, 1H), 4.45 (br s, 1H), 4.24 (dd, J )
7.1, 7.1 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.80-3.79 (m, 2H),
3.21-3.15 (m, 2H), 2.51 (dd, J ) 13.1, 9.5 Hz, 1H), 2.46-2.43
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 157.6, 149.1, 148.7, 135.9,
134.5, 134.3, 129.0, 128.8, 126.9, 120.3, 118.3, 111.1, 110.8, 65.8,
62.4, 58.1, 56.0, 55.9, 40.3, 36.8; MS (APCI) m/z (rel intensity)
383 ([M + H]+, 7%). Anal. Calcd for C22H26N2O4: C, 69.10; H,
6.85; N, 7.32. Found: C, 68.91; H, 6.75; N, 7.30. Minor dia-
all unsaturated hydrazones examined, while propionaldehyde
hydrazone gave a ratio of 82:18. All evidence is consistent with
a mechanism involving dual activation in which the nucleophilic
component is a hypervalent allylfluorosilicate and the electro-
philic component is a chiral N-acylhydrazone-In(III) chelate.
A trifluoroacetyl substituent enables clean and efficient
reductive cleavage of the N-N bond in the adducts with SmI2
in the presence of MeOH, conditions which are compatible with
alkene functionality. These reactions furnish chiral homoallylic
amines which bear a convenient TFA protecting group. Synthetic
potential is demonstrated in combination with Wacker oxida-
tion60 and metathesis transformations. Considering the synthetic
versatility of the allyl group, the allylsilane addition described
here offers potentially useful methodology for highly stereo-
selective access to complex targets.
stereomer (1′R)-2h: colorless oil; [R]23 +28 (c 0.1, CHCl3); IR
D
(film) 3281, 2934, 2836, 1754, 1593, 1516, 1455, 1419, 1263, 1141,
1
1092, 1027 cm-1; H NMR (500 MHz, CDCl3) δ 7.27-7.03 (m,
5H), 6.95 (d, J ) 1.9 Hz, 1H), 6.89 (d, J ) 8.2 Hz, 1H), 6.80 (d,
J ) 8.2 Hz, 1H), 5.71 (dddd, J ) 16.3, 13.8, 7.3, 6.1 Hz, 1H),
5.14-5.12 (m, 1H), 5.07-5.02 (m, 1H), 4.40-4.25 (br, 1H), 4.20
(dd, J ) 7.0, 7.0 Hz, 1H), 4.01 (dd, J ) 7.3, 7.3 Hz, 1H), 3.88-
3.82 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.00 (dd, J ) 13.9, 3.8
Hz, 1H), 2.52-2.43 (m, 2H), 2.14 (dd, J ) 13.0, 10.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 158.7, 149.0, 148.8, 136.0, 134.6,
133.4, 128.9, 128.8, 127.0, 120.5, 117.9, 111.3, 111.0, 66.4, 62.5,
58.9, 56.0, 55.9, 39.7, 37.6; MS (APCI) m/z (rel intensity) 341 ([M
- allyl]+, 100%). Anal. Calcd for C22H26N2O4: C, 69.10; H, 6.85;
N, 7.32. Found: C, 68.83; H, 6.84; N, 7.08.
Experimental Section61
Representative Procedure for the Preparation of Enantiopure
N-Acylhydrazones (1a-h): (S)-3-(Benzylidene)amino-4-phenyl-
methyl-2-oxazolidinone (1a). A procedure based on the literature
method34 was employed. To a solution of (S)-3-amino-4-phenyl-
methyl-2-oxazolidinone (60 mg, 0.31 mmol) in toluene (10 mL)
was added anhydrous MgSO4 (200 mg), a catalytic amount of
p-TsOH (ca. 5 mol %), and benzaldehyde (0.05 mL, 0.49 mmol).
After the solution was heated at reflux for 10 min, concentration
and flash chromatography (5:1 hexane/ethyl acetate) gave 1a (70
mg, 81%) as a colorless solid, the properties of which matched the
published data.26
Representative Procedure for Wacker Oxidation (8 and 9):
(S)-N-[1-(3,4-Dimethoxyphenyl)-3-oxobutyl]benzamide (8). A
mixture of benzamide 4h (622 mg, 2.0 mmol), PdCl2 (72 mg, 0.40
mmol), and Cu(OAc)2 (148 mg, 0.80 mmol) in H2O/DMF (1:7, 16
mL) was stirred under oxygen (1 atm) for 2 d. To the brownish
mixture was added 1% HCl solution. The resulting clear solution
was extracted with CH2Cl2. The organic phase was washed with
saturated NaHCO3 solution and brine. It was dried over anhydrous
MgSO4, concentrated, and purified by flash chromatography (1:1
hexanes-EtOAc). Methyl ketone 8 (576 mg, 88%) was obtained
as a colorless solid: mp 139-140 °C; [R]21D -9.5 (c 0.39, CHCl3);
IR (film) 3329, 3064, 2997, 2940, 2837, 1715, 1636, 1516, 1462,
1418, 1359, 1261, 1142, 1026 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.78 (d, J ) 7.0 Hz, 2H), 7.50-7.40 (m, 3H), 7.29 (d, J ) 7.8
Hz, 1H), 6.88-6.80 (m, 3H), 5.55-5.49 (m, 1H), 3.85 (s, 3H),
3.83 (s, 3H), 3.20 (d, J ) 16.5 Hz, 1H), 3.00 (d, J ) 16.5 Hz, 1H),
2.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 208.1, 166.6, 149.3,
148.1, 134.3, 133.6, 131.6, 128.6, 127.0, 118.4, 111.4, 110.4, 56.0,
55.9, 50.0, 48.1, 31.0; MS (APCI) m/z (rel intensity) 327 ([M +
1]+, 46%). Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28.
Found: C, 69.51; H, 6.36; N, 4.17.
Representative Procedure for Addition with Tetraallylsilane
and TBAT (2a-h): (4S,1′S)-3-(1′-Allyl-1′-phenylmethylamino)-
4-phenylmethyl-2-oxazolidinone (2a). A mixture of 1a (56 mg,
0.2 mmol) and indium triflate (0.26 mmol) in CH2Cl2 (2.2 mL)
was stirred at room temperature. Meanwhile, a mixture of TBAT
(0.6 mmol) and tetraallylsilane (0.6 mmol) in CH2Cl2 (0.8 mL) was
stirred in another flask. After 4 h, the TBAT mixture was added to
the hydrazone mixture. The resulting reaction mixture was stirred
at room temperature for 2 d, and then 2 mL of water was added.
The organic phase was separated, dried over anhydrous MgSO4,
concentrated and purified by flash chromatography to give 2a (50
mg, 78%) as a colorless oil: [R]23 -19.5 (c 0.43, CHCl3); IR
D
(film) 3290, 3028, 2927, 1754, 1699, 1653, 1558, 1497, 1456, 1399,
1
1093, 918 cm-1; H NMR (500 MHz, CDCl3) δ 7.39-7.13 (m,
Representative Procedure for Cross Metathesis (11-15, 17-
18): (E)-2,2,2-Trifluoro-N-(1-phenyl-4-trimethylsilylbut-3-enyl)-
acetamide (11). To a Schlenk tube containing rac-6a (40 mg, 0.164
mmol) was added CH2Cl2 (2.7 mL), allyltrimethylsilane (80 µL,
0.492 mmol), and second-generation Grubbs catalyst 21a (5% mol)
under argon, then the mixture was heated at reflux. When the
reaction was complete (TLC, ca. 3 h), the mixture was concentrated
and passed through a short plug of silica gel, eluting with EtOAc.
Concentration and purification by flash chromatography gave 11
as a mixture of alkene isomers (43 mg, 80%, E/Z ) 2:1). Further
chromatography (20:1 petroleum ether-methyl tert-butyl ether)
gave (E)-11 as a colorless oil: IR (film) 3309, 3085, 3036, 2947,
2907, 1715, 1698, 1653, 1557, 1539, 1453, 1416, 1317, 1248, 1183
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 6.47 (br
s, 1H), 5.53 (ddd, J ) 16.2, 8.1, 8.1 Hz, 1H), 5.10-5.05 (m, 1H),
4.98 (ddd, J ) 7.0, 7.0, 7.0 Hz, 1H), 2.60-2.55 (m, 2H), 1.41 (d,
J ) 8.1 Hz, 1H), -0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
156.4 (2JCF ) 36.9 Hz), 139.6, 132.1, 128.9, 128.0, 126.4, 122.0,
115.9 (1JCF ) 286.4 Hz), 53.8, 39.1, 23.1, -2.1; MS (MALDI)
m/z (rel intensity) 330 ([M + 1]+, 8%); HRMS-CI (m/z) [M +
H]+ calcd for C16H23F3NOSi, 330.1501, found 330.1500.
8H), 6.91 (dd, J ) 7.2 Hz, 2H), 5.74 (dddd, J ) 10.2, 10.2, 7.8,
6.1 Hz, 1H), 5.13 (dd, J ) 17.1, 1.4 Hz, 1H), 5.05 (dd, J ) 10.3,
1.0 Hz, 1H), 4.43 (s, 1H), 4.23 (ddd, J ) 7.9, 1.3, 1.3 Hz, 1H),
3.77-3.70 (m, 2H), 3.16 (dd, J ) 13.4, 3.4 Hz, 1H), 3.06-3.04
(m, 1H), 2.45-2.40 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 157.7,
142.1, 135.99, 135.98, 134.2, 129.1, 128.8, 128.5, 127.98, 127.93,
126.9, 118.4, 65.8, 62.9, 58.2, 40.3, 36.8; MS (EI) m/z (rel intensity)
323 ([M + H]+, 40%); Anal. Calcd for C20H22N2O2: C, 74.50; H,
6.88; N, 8.69. Found: C, 74.40; H, 6.89; N, 8.59. Diastereomer
ratios of 2a-h were determined by HPLC comparison with
authentic mixtures (see the Supporting Information).
(4S,1′S)-3-(1′-(3,4-Dimethoxyphenyl)but-3′-enylamino)-4-
phenylmethyl-2-oxazolidinone (2h). With use of the procedure
described above for the preparation of 2a, from 1h (1.53 g, 4.5
mmol) was obtained 2h (920 mg, dr 96:4, 54% yield) as a colorless
oil. Major diastereomer (1′S)-2h: [R]23D -75 (c 0.08, CHCl3); IR
(film) 3286, 2934, 2835, 1753, 1593, 1516, 1455, 1262, 1237, 1141,
1
1092 cm-1; H NMR (500 MHz, CDCl3) δ 7.25-7.18 (m, 7H),
6.83 (d, J ) 8.1 Hz, 1H), 5.81-5.75 (m, 1H), 5.17 (d, J ) 17.0
(60) During preparation of this manuscript a related homoallylic amide
Wacker oxidation approach was reported in a total synthesis of quinolizidine
alkaloid abresoline. Atobe, M.; Yamazaki, N.; Kibayashi, C. Tetrahedron
Lett. 2005, 46, 2669-2673.
(61) A statement of general experimental procedures is provided in the
Supporting Information.
(S)-2,2,2-Trifluoro-N-allyl-N-(1-(3,4-dimethoxyphenyl)-1-
butenyl)acetamide (20). To a solution of trifluoroacetamide
rac-6h (53 mg, 0.175 mmol) in THF (1 mL) was added lithium
hexamethyldisilazide (0.18 mL, 1 M in THF, 0.87 mmol) and allyl
iodide (0.02 mL, 0.2 mmol). Monitoring by TLC showed no
288 J. Org. Chem., Vol. 71, No. 1, 2006

Allylsilane Addition to Chiral N-Acylhydrazones
reaction. Additional allyl iodide (0.2 mL, 2 mmol) and HMPA (0.1
mL) were added at ambient temperature, and the mixture was stirred
in the dark for 16 h. Concentration and flash chromatography gave
N-allyl product 20 (35 mg, 58%) as a colorless liquid followed by
unreacted 6h (17 mg, 32%). Complicated NMR spectra were
observed for 20 as a result of hindered rotation. IR (film) 3056,
2982, 2939, 2834, 2300, 1686, 1604, 1521, 1477, 1265, 1208, 1152
chromatography. (2R)-25: pale yellow oil; [R]22 +1.2 (c 0.6,
D
CHCl3); IR (film) 3074, 2931, 2851, 2795, 1639, 1590, 1514, 1463,
1
1416, 1322, 1255, 1235, 1145, 1030 cm-1; H NMR (500 MHz,
CDCl3) δ 6.95 (s, 1H), 6.89-6.75 (m, 2H), 5.93 (ddd, J ) 18.0,
9.5, 9.5 Hz, 1H), 5.65 (dddd, J ) 17.0, 10.0, 6.5, 6.5 Hz, 1H),
5.21 (d, J ) 17.5 Hz, 1H), 5.10 (d, J ) 10.0 Hz, 1H), 4.98 (dd, J
) 17.0, 1.5 Hz, 1H), 4.90 (d, J ) 10.0 Hz, 1H), 3.96-3.90 (m,
1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.19 (dd, J ) 6.5, 6.5 Hz, 1H),
2.63-2.41 (m, 3H), 2.16 (dd, J ) 10.0, 10.0 Hz, 1H), 1.80-1.15
(m, 6H); 13C NMR (125 MHz, CDCl3) δ 148.6, 147.7, 141.6, 137.0,
135.2, 120.7, 115.9, 115.4, 112.6, 110.4, 62.8, 62.7, 55.92, 55.87,
45.2, 34.0, 30.4, 26.2, 23.7; MS (APCI) m/z (rel intensity) 302 ([M
+ 1]+, 48%). Anal. Calcd for C19H27NO2: C, 75.71; H, 9.03; N,
4.65. Found: C, 75.84; H, 9.17; N, 4.34. (2S)-25: pale yellow oil;
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.92-6.80 (m, 3H), 5.79-
5.66 (m, 2.5H), 5.60-5.48 (m, 4.5H), 3.93-3.67 (m, 8H), 2.93-
2.61 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 157.4 (2JCF ) 35.3
Hz), 149.1, 134.2, 134.0, 133.1, 132.2, 129.8, 128.8, 120.7, 120.1,
118.8, 118.0, 117.8, 116.6 (1JCF ) 287 Hz), 112.0, 111.5, 110.8,
110.7, 59.5, 59.4, 55.9, 55.8, 47.3, 46.1, 35.9, 35.2; MS (EI) m/z
(rel intensity) 343.01 ([M]+, 14%). Anal. Calcd for C17H20F3NO3:
C, 59.47; H, 5.87; N, 4.08. Found: C, 59.49; H, 5.90; N, 4.03.
(S)-2-(3,4-Dimethoxyphenyl)-N-2,2,2-trifluoroacetyl-1,2,3,6-
tetrahydropyridine (22). To a solution of N-allyltrifluoroacetamide
20 (25 mg, 0.072 mmol) in CH2Cl2 (36 mL) was added Grubbs
catalyst 21b (5.9 mg, 0.0072 mmol). After 16 h at ambient
temperature, concentration and flash chromatography gave 22 (21
mg, 92.5%) as a colorless liquid. Complicated NMR spectra were
observed for 22 as a result of hindered rotation (two rotamers, ratio
3:2). IR (film) 2929, 2851, 1687, 1518, 1451, 1257, 1188, 1143,
[R]22 +20 (c 0.15, CHCl3); IR (film) 3073, 2931, 2835, 2801,
D
2713, 1734, 1640, 1589, 1514, 1463, 1418, 1261, 1146, 1029 cm-1
;
1H NMR (500 MHz, CDCl3) δ 6.85-6.70 (m, 3H), 5.88 (ddd, J )
17.5, 8.5, 8.5 Hz, 1H), 5.74 (dddd, J ) 17.0, 10.5, 7.0, 7.0 Hz,
1H), 5.19-5.11 (m, 2H), 4.98 (dd, J ) 17.0, 1.5 Hz, 1H), 4.94-
4.88 (m, 1H), 3.98 (dd, J ) 7.5, 7.5 Hz, 1H), 3.85 (s, 3H), 3.83 (s,
3H), 2.93-2.84 (m, 1H), 2.72-2.46 (m, 2H), 1.85-1.02 (m, 8H);
13C NMR (125 MHz, CDCl3) δ 148.1, 147.7, 143.8, 136.9, 130.3,
121.1, 115.5, 115.1, 112.9, 110.4, 63.7, 62.7, 55.9, 55.8, 45.5, 37.2,
34.8, 26.3, 24.1; MS (MALDI) m/z (rel intensity) 302 ([M + 1]+,
27%); HRMS-CI (m/z) [M + H]+ calcd for C19H28NO2 302.2107,
found 302.2112.
1
1027 cm-1; H NMR (300 MHz, CDCl3) δ 6.90-6.78 (m, 3H),
6.06-5.90 (m, 1H), 5.98 (d, J ) 6.6 Hz, 0.6H), 5.66-5.61 (m,
1H), 5.30 (d, J ) 5.7 Hz, 0.4H), 4.61 (br d, J ) 18.1 Hz, 0.4H),
4.14 (br d, J ) 17.8 Hz, 0.6H), 3.86 (s, 3H), 3.83 (s, 3H), 3.56-
3.49 (m, 0.6H), 3.24 (br d, J ) 18.9 Hz, 0.4H), 2.78-2.65 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 156.2 (2JCF ) 35.3 Hz), 155.7
(J ) 35.5 Hz), 149.1, 148.8, 130.6, 129.8, 124.7, 123.9, 123.4,
122.7, 119.5, 119.2, 116.7 (1JCF ) 286 Hz), 111.0, 110.9, 110.1,
56.0, 55.9, 53.5, 50.1, 40.9, 39.7, 28.2, 26.9; MS (EI) m/z (rel
intensity) 315.2 ([M]+, 42%). Anal. Calcd for C15H16F3NO3: C,
57.14; H, 5.12; N, 4.44. Found: C, 57.32; H, 5.09; N, 4.40.
7-((S)-1-(3,4-Dimethoxyphenyl)but-3-enylamino)hept-1-en-3-
yl Methyl Carbonate (24). To a solution of amine 7 (187 mg,
0.903 mmol), tosylate 2362 (257 mg, 0.750 mmol), and Et3N (0.11
mL, 0.825 mmol) in acetonitrile (9.0 mL) was added sodium iodide
(169 mg, 1.12 mmol) in one portion under argon. The resulting
white suspension was refluxed for 4 d. Basic brine (2 M NaOH
saturated with NaCl) was added to the cooled reaction mixture and
the mixture was extracted with CH2Cl2 and dried over anhydrous
MgSO4. Concentration and flash chromatography (1:1 hexanes-
EtOAc to 30:1 CH2Cl2-MeOH to 5:1 CH2Cl2-MeOH) afforded
unreacted amine 7 (48 mg) and 24 (183 mg, 65%, dr 1:1) as a pale
yellow oil. IR (film) 3427, 3243, 3049, 2985, 2929, 1724, 1652,
(1S,2S)-6-(3,4-Dimethoxyphenyl)-1,3,4,6,6,7,9a-hexahydro-
2H-quinolizine (26). A diastereomeric mixture of 2-vinylpiperidines
(2R)-25 and (2S)-25 (114 mg, 0.378 mmol, dr ) 1:1) and TsOH‚
H2O (78 mg, 0.40 mmol) in CH2Cl2 (170 mL) was stirred at ambient
temperature for 3 h. Second-generation Grubbs catalyst 21b (50
mg, 0.0588 mmol) was added in one portion under argon. After 2
d at ambient temperature, a second portion of 21b (20 mg, 0.024
mmol) was added. After another 36 h, the mixture was concen-
trated, acidified with 2 M HCl, and washed with EtOAc to re-
move the catalyst. The acidic aqueous phase was adjusted to pH
10 (2 M NaOH), extracted with CH2Cl2, and concentrated to afford
26 as a diastereomeric mixture (dr 1:1). Flash chromatography (2:1
hexanes-EtOAc to 20:1 EtOAc-MeOH to 8:1 EtOAc-MeOH)
furnished the two separated diastereomers (88 mg in total, 85%)
(9aR)-26 and (9aS)-26. (9aR)-26: pale yellow oil; [R]25 -60 (c
D
0.8, CHCl3); IR (film) 2927, 2850, 2739, 1589, 1511, 1460, 1323,
1
1260, 1144, 1029 cm-1; H NMR (500 MHz, CDCl3) δ 6.86 (s,
1H), 6.82-6.74 (m, 2H), 5.90-5.84 (m, 1H), 5.57 (dd, J ) 10.0,
1.5 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.88-2.79 (m, 1H), 2.72
(d, J ) 11.5 Hz, 1H), 2.66 (d, J ) 11.0 Hz, 1H), 2.26 (dd, J )
18.0, 1.5 Hz, 1H), 2.12-1.08 (m, 8H); 13C NMR (125 MHz, CDCl3)
δ 148.5, 148.1, 138.4, 130.9, 124.2, 121.1, 111.8, 110.4, 61.0, 55.88,
55.82, 54.6, 52.5, 32.2, 31.9, 25.3, 24.7; HRMS-EI (m/z) [M]+ calcd
for C17H23NO2 273.1729, found 273.1724. (9aS)-26: pale yellow
1
1537, 1483, 1455, 1385, 1355, 1334, 1150, 907 cm-1; H NMR
(500 MHz, CDCl3) δ 6.86 (s, 1H), 6.80-6.77 (m, 2H), 5.77-5.63
(m, 2H), 5.23 (d, J ) 17.0 Hz, 1H), 5.15 (d, J ) 10.5 Hz, 1H),
5.09-4.96 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H), 3.53
(dd, J ) 7.5, 6.0 Hz, 1H), 2.44-2.27 (m, 4H), 1.68-1.22 (m, 8H);
13C NMR (125 MHz, CDCl3) δ 155.3, 149.1, 148.0, 136.8, 136.0,
135.6, 119.4, 117.4 (2C), 111.0, 110.0, 79.0, 78.97, 62.4, 55.9, 54.6,
47.4, 43.2, 34.1, 29.9, 22.7. Anal. Calcd for C21H31NO5: C, 66.82;
H, 8.28; N, 3.71. Found: C, 66.82; H, 8.26; N, 3.91.
(R)-1-((S)-1-(3,4-Dimethoxyphenyl)but-3-enyl)-2-vinylpiperi-
dine (2R-25) and (S)-1-((S)-1-(3,4-Dimethoxyphenyl)but-3-enyl)-
2-vinylpiperidine (2S-25). To a solution of amine 24 (dr 1:1, 84.0
mg, 0.22 mmol), triphenylphosphine (35 mg, 0.13 mmol), and
allylpalladium chloride dimer (13 mg, 0.036 mmol) was added Et3N
(80 µL, 0.57 mmol) via a microsyringe. The resulting solution was
stirred at room temperature for 3 d, then concentrated. The residue
was taken up by 3:1 hexanes-EtOAc and filtered. The filtrate was
concentrated and purified by flash chromatography (5:1 to 1:1
hexanes-EtOAc) to give 25 (60 mg, 89%, (2R):(2S) ) 1.6:1) as a
pale yellow oil. The mixture was used in the next step without
separation. Pure diastereomers were obtained by further flash
oil; [R]25 -58 (c 0.42, CHCl3); IR (film) 2930, 2878, 2783 and
D
2728 (Bohlmann bands), 1698, 1648, 1516, 1260, 1233, 1134, 1029
cm-1; 1H NMR (500 MHz, CDCl3) δ 6.88 (s, 1H), 6.83-6.75 (m,
2H), 5.76-5.69 (m, 1H), 5.88 (d, J ) 9.5 Hz, 1H), 3.86 (s, 3H),
3.84 (s, 3H), 3.22 (dd, J ) 10.5, 3.5 Hz, 1H), 2.67 (d, J ) 11.0
Hz, 2H), 2.45-2.38 (m, 1H), 2.25-1.15 (m, 8H); 13C NMR (125
MHz, CDCl3) δ 149.3, 148.1, 136.3, 130.7, 124.6, 120.4, 110.8,
110.6, 66.1, 63.21, 56.1, 55.9, 52.5, 36.5, 32.7, 26.3, 25.1; MS
(APCI) m/z (rel intensity) 274 ([M + 1]+, 100%); HRMS-ESI (m/
z) [M + H]+ calcd for C17H24NO2,274.1807, found 274.1804.
Acknowledgment. We thank NIH (NIGMS, GM-67187) and
NSF (Vermont EPSCoR Graduate Research Fellowship to H.D.)
for generous support of this work.
Supporting Information Available: Characterization data and
selected experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
(62) For preparation of 23, see the Supporting Information.
JO052037D
J. Org. Chem, Vol. 71, No. 1, 2006 289