Stereocontrol in hydride addition to ketone-derived chiral N-acylhydrazones

Article abstract of DOI:10.1016/S0040-4020(03)01091-3

Chiral N-acylhydrazones derived from various aldehydes and N-amino-4-benzyl-2-oxazolidinone have previously been shown to be effective for acyclic stereocontrol of intermolecular radical and allylsilane additions. Treatment of the propionaldehyde hydrazone with tributyltin hydride in the presence of boron trifluoride etherate led to rapid chemoselective reduction of the imine bond in high yield. Preparation of similar hydrazones from ketones led to E/Z isomer mixtures, usually in ratios of 4:1 or greater. Geometry of the C=N bond was assigned by steric compression shifts in ¹³C NMR spectra. Reduction with tributyltin hydride and boron trifluoride etherate afforded diastereomer mixtures in ratios very similar to the original E/Z isomer ratios. The chiral auxiliary blocked the opposite face of the C=N bond relative to a related process using a chelated Lewis acid. A stereocontrol model involving monodentate interaction of the N-acylhydrazone and boron trifluoride is consistent with the observed stereochemical outcome.

Full text of DOI:10.1016/S0040-4020(03)01091-3

Tetrahedron 59 (2003) 6393–6402
Stereocontrol in hydride addition to ketone-derived chiral
N-acylhydrazones
*
Jun Qin and Gregory K. Friestad
Department of Chemistry, University of Vermont, Cook Physical Sciences Building, Burlington, Vermont 05405 USA
Received 6 May 2003; revised 3 July 2003; accepted 10 July 2003
Abstract—Chiral N-acylhydrazones derived from various aldehydes and N-amino-4-benzyl-2-oxazolidinone have previously been shown to
be effective for acyclic stereocontrol of intermolecular radical and allylsilane additions. Treatment of the propionaldehyde hydrazone with
tributyltin hydride in the presence of boron trifluoride etherate led to rapid chemoselective reduction of the imine bond in high yield.
Preparation of similar hydrazones from ketones led to E/Z isomer mixtures, usually in ratios of 4:1 or greater. Geometry of the CvN bond
was assigned by steric compression shifts in 13C NMR spectra. Reduction with tributyltin hydride and boron trifluoride etherate afforded
diastereomer mixtures in ratios very similar to the original E/Z isomer ratios. The chiral auxiliary blocked the opposite face of the CvN bond
relative to a related process using a chelated Lewis acid. A stereocontrol model involving monodentate interaction of the N-acylhydrazone
and boron trifluoride is consistent with the observed stereochemical outcome.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(1).3 During the development of the radical addition
reactions, we discovered that boron trifluoride etherate
promoted an extremely rapid and quantitative reduction of
chiral N-acylhydrazones by tributyltin hydride. Specifically,
we found that in the presence of BF3·OEt2, N-acylhydrazone
2 was reduced by Bu3SnH to afford amine 3 in quantitative
yield within 5 min (Scheme 1). Naito et al. recently reported
quite similar BF3-promoted racemic hydrostannation reac-
tions involving achiral N-heteroatom-substituted aldimines
and ketimines.4
Chiral amines are important substructures in biologically
active materials of both natural and synthetic origin, and
methods for their asymmetric synthesis are an important
current objective. Asymmetric reduction of the CvN bond
of ketone-derived imines is a convenient method for the
synthesis of chiral amines, and a variety of chiral auxiliaries
have been shown to be effective in this process.1
Additionally, several excellent catalytic enantioselective
approaches have been developed recently.2 Often, high
selectivity is limited to substrates derived from aryl alkyl
ketones, where the two carbonyl substituents are easily
distinguished. When both substituents of a ketimine have
similar steric properties, low E/Z isomer ratios with respect
to the CvN bond geometry and/or poor discrimination of
enantiotopic faces of the imine can present difficult
problems. Chiral auxiliaries offer a practical advantage
under these circumstances, because in principle E/Z
mixtures of the starting imine could be separated prior to
use, or mixtures of diastereomeric products could be
resolved before removal of the auxiliary.
In the context of the radical additions, hydridic behavior by
the stannane reagent was undesirable. In that study, the
reduction could be avoided by the use of ZnCl2 or InCl3 as
Lewis acids, whereupon the chiral auxiliary afforded high
stereoselectivity in the radical addition. A model involving
Lewis acid chelation was invoked to explain the selectivity
(Fig. 1).
Considered apart from the radical addition study, the
reduction reaction raised some interesting questions which
are summarized in Figure 1: could the chiral N-acyl-
hydrazone stereocontrol element provide for stereoselective
reduction of CvN bond of ketone N-acylhydrazones? Was
We have previously described non-basic tin-mediated
intermolecular radical addition reactions for construction
of chiral a-branched amines using chiral N-acylhydrazone
auxiliaries derived from N-amino-4-benzyl-2-oxazolidinone
Keywords: asymmetric synthesis; amines; imines; chiral hydrazones;
reduction; boron trifluoride; tributyltin hydride.
*
Corresponding author. Tel.: þ1-8026561042; fax: þ1-8026568705;
e-mail: gregory.friestad@uvm.edu
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01091-3

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J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
Figure 1. Complementary C–C or C–H bond constructions for chiral amine synthesis.
Scheme 2.
BF3·OEt2 acting as a non-chelating or chelating Lewis acid
in the reduction? Could the same stereocontrol model be
applied to predict the outcome of the selectivity?
N-amino-4-benzyl-2-oxazolidinone (1)5 under standard
conditions.
The choice of ketones was constrained by the desire to
correlate the reductive amination products to known
compounds which had previously been prepared in
diastereomerically pure form by radical addition.3 This
required a series of ethyl ketones and phenyl ketones, some
of which were commercially available. tert-Butyl ethyl
ketone was prepared by oxidation of the corresponding
alcohol (PCC, CH2Cl2). Others were prepared by direct
coupling reactions with acyl chlorides 4a–4d (Scheme 2).
There are many methods available for direct coupling of
carboxylic acid derivatives with organometallic reagents to
afford ketones.8 We found that, for preparation of the ethyl
ketones, reaction of tetraethylsilane with the appropriate
acid chloride9 proved practical for ketones 5b and 5c. These
The very rapid reduction reaction of Scheme 1 seemed to
offer some advantages in operational simplicity, along with
potential for complementary chemoselectivity relative to
asymmetric hydrogenation. Furthermore, hydride additions
to ketone hydrazones could help lay a foundation for
synthesis of quaternary carbon centers by analogous
additions of carbon nucleophiles. For these reasons, and
because of the synthetic value of alternative general
approaches to asymmetric amine synthesis, we examined
the sequence exemplified by Scheme 1 in greater detail in
order to define its scope, examine the potential for
stereoselectivity, and develop an understanding of the
roles of the Lewis acid and chiral auxiliary. Here we
present the full details of this study.
Table 1. Preparation of ketone hydrazones (Scheme 2)
Entry R1
R2
Ketone (yield) Hydrazone (yield) E/Z ratio
2. Results
1
2
3
4
5
6
7
8
Et
Et
Et
Et
iPr
cC5H9
5aa
5bb
7a (84%)
7b (49%)
7c (64%)
7d (67%)
8a (55%)
8b (59%)
8c (55%)
8d (73%)
77:23
79:21
85:15
.98:2
19:81
26:74
13:87
,2:98
2.1. Synthesis of ketone N-acylhydrazones
cC6H11 5cb
tBu
Ph iPr
5db
As a starting point for testing the configurational control in
hydride additions of N-acylhydrazones such as that
indicated in Scheme 1, prochiral ketimine substrates were
required. It is now well-documented that N-aminooxa-
zolidinones are reliably condensed with aldehydes to afford
the corresponding N-acylhydrazones (i.e. hydrazides).5–7 It
was expected that various ketones would condense with
6a (72%c)
6b (88%c)
Ph cC5H9
Ph cC6H11 6ca
Ph tBu
6d (82%c)
a
b
c
Commercially available ketone was employed.
Ketone was prepared and used directly without purification.
Isolated yield of ketone based on 1.

J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
6395
Figure 2. Ketimine steric compression shifts from literature sources (13C NMR, CDCl3).11
were used directly in the subsequent condensation reaction
with 1. On the other hand, an organovanadium-mediated
method10 proved convenient for the phenyl ketones.
Reaction of phenylmagnesium bromide with vanadium(III)
chloride at 2788C, followed by addition of the acyl chloride
and warming to ambient temperature afforded ketones 6a,
6b, and 6d in good yield.
may be obtained by comparison of E and Z isomers. In
2-butanone oxime (iii), E/Z¼77:23, the steric compression
shifts of C1 (a), C3 (a0) and C4 (b) are 6.0, 5.9 and 1.2 ppm,
respectively.11a,b Finally, the effect has been used to assign
the E/Z isomers of acetophenone N-benzoylhydrazone (iv);
the methyl 13C NMR chemical shifts for E and Z isomers are
25.01 and 26.54 ppm, respectively (Dd¼1.53 ppm).11d In all
these examples, the a-carbon with a cis relationship to the
N-substituent is found upfield from the same a-carbon
having a trans relationship to the N-substituent, usually by
several ppm.
Condensation of ketones 5 and 6 with N-aminooxazolidi-
none 1 in the presence of a catalytic amount of
p-toluenesulfonic acid in refluxing toluene afforded ketone
N-acylhydrazones 7 and 8 (Scheme 2, Table 1). Mixtures of
E/Z isomers were obtained in the cases of 7a–c and 8a–c.
Unfortunately, attempts to separate these isomers by
flash chromatography were unsuccessful. Ketone N-acyl-
hydrazones 7d and 8d, which have highly branched
tertiary butyl (tBu) substituents, were formed as single
For ketone N-acylhydrazones obtained as mixtures of E/Z
isomers, steric compression shifts (Dd) could be observed
clearly for one or both of the a-carbons. The key data used
for assignment of CvN bond geometries of the hydrazones
are found in Table 2.
t
isomers, presumably due to steric repulsion from the Bu
substituent.
Upon assignment of structures 7a–7c and 8a–8c by 13C
chemical shifts according to the literature precedents noted
1
2.2. Determination of E/Z isomer ratio by NMR analysis
above, the H chemical shifts of the a-hydrogen within R2
were also found to be reliable indicators of a cis or trans
relationship of R2 with the N-substituent on the CvN bond
(i.e. the oxazolidinone). The trans methine (relative to the
oxazolidinone) was found upfield of the cis methine in all
compounds, with the differences in chemical shifts ranging
from 0.45 to 0.84 ppm. Structures of hydrazones (E)-7d and
(Z)-8d were assigned by analogy with the others, and also by
consideration of the stereochemical outcome of the
reduction reactions (vide infra).
Assignment of CvN bond geometry was achieved through
comparison of 13C NMR chemical shifts of the a-carbon of
the E and Z isomers. Steric compression shifts are observed
when a ketone is converted to ketone oxime or ketone
hydrazone.11 Steric compression shifts in 13C NMR
spectroscopy arise from steric perturbations of carbon
nuclei, and have been utilized in the studies of diverse
organic compounds.12 Of relevance for this study is the
ability of steric compression shifts to distinguish between
carbons which have cis and trans relationships to the
N-substituent of a CvN bond.
Table 2. Key NMR data for (E)- and (Z)-hydrazones in CDCl3 at 500 MHz
(1H) or 125 MHz (13C)
Hydrazone
a-Carbon of R2 (d, ppm)
a-Hydrogen of R2
(d, ppm)
Four examples of steric compression shifts in assignment of
CvN bond geometry are presented in Figure 2. First, the
2 equivalent methyl resonances in the 13C NMR spectrum of
acetone (30.7 ppm) become non-equivalent upon conver-
sion to the oxime (i) (21.5 and 14.7 ppm). The cis a-carbon
resonance is upfield from the trans a-carbon, and the
difference of these chemical shifts (subtracting cis from
trans), Dd¼6.8 ppm, is the steric compression shift. A
similar effect was also observed in the guanylhydrazone
derived from cyclohexanone (ii), which exhibits a signifi-
cant steric compression shift (Dd¼8.6 ppm) for the
a-carbon.11c For CvN bonds which have non-equivalent
C-substituents, steric compression shift Dd for each carbon
R2-transa
R2-cisa
Dd (ppm) R2-transa
R2-cisa
7a
7b
7c
8a
8b
8c
34.2 (E)
45.4 (E)
44.3 (E)
37.3 (Z)
48.5 (Z)
47.5 (Z)
30.9 (Z)
42.2 (Z)
41.9 (Z)
31.3 (E)
42.5 (E)
42.9 (E)
3.3
3.2
2.4
6.0
6.0
4.6
2.68b (E)
2.85 (E)
2.36c (E)
2.99b (Z)
3.12 (Z)
2.62c (Z)
3.24 (Z)
3.30 (Z)
3.13 (Z)
3.52 (E)
3.54 (E)
3.46 (E)
The designations trans and cis refers to the relationship between R2 and
the N-substituent. Therefore (E)-7a–7c and (Z)-8a–8c are designated
here as trans.
cf. corresponding aldehyde hydrazone (E): d 2.60.
cf. corresponding aldehyde hydrazone (E): d 2.34.
a
b
c

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J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
Table 3. Stereoselectivity and yield in reduction of N-acylhydrazones
N-Acylhydrazone (E/Z ratio)
Hydrazide (yield)
dra
(E)-7a (77:23)
(E)-7b (79:21)
(E)-7c (85:15)
(E)-7d (.98:2)
(Z)-8a (19:81)
(Z)-8b (26:74)
(Z)-8c (13:87)
(Z)-8d (,2:98)
(S)-9a (89%)
(S)-9b (82%)
(S)-9c (76%)
(S)-9d (94%)
(R)-10a (92%)
(R)-10b (78%)
(R)-10c (94%)
(R)-10d (94%)
80:20
76:24
85:15
89:11
19:81
26:74
18:82
12:88
a
Ratio of diastereomers S/R (configurations of new stereogenic center).
2.3. Reduction of ketone N-acylhydrazones by Bu3SnH
the configuration of the CvN bond participate to define the
configuration of the newly formed stereocenter.
With structural assignments in place, the stereochemical
results of reduction reactions could give meaningful
information regarding the hypothesis set forth in Figure 1.
First, some variations to the conditions of Scheme 1 were
explored. Changing reducing reagent from Bu3SnH to less
toxic Et3SiH resulted in recovery of the unchanged starting
material. Although reduction could be observed in some
cases with other Lewis acids during the previous radical
addition study, those reactions were not as reliable and
smooth as the BF3-mediated reduction. We employed the
original conditions discovered for aldehyde hydrazones
(Scheme 1) for the remainder of the study.
The hydride additions appear to be quite stereospecific; the
diastereomeric ratios of products were similar to the E/Z
isomer ratios of the hydrazones, in some cases identical. For
example, reduction of 7c as 85:15 E/Z mixture afforded
hydrazine 9c with a diastereomer ratio (S/R) 85:15. This
suggests a stereospecific process in which both E and Z
isomers are reduced with good stereocontrol. The stereo-
specificity is not complete, however: The reductions of
hydrazones 7d and 8d, employed as single isomers, gave
89:11 and 88:12 diastereomeric ratios, respectively. These
latter two examples have lower stereospecificity compared
to the complementary radical addition to aldehyde N-acyl-
hydrazones (generally dr.13:1) favoring the diastereo-
meric products.3
Ketone hydrazones were reduced to diastereomeric
mixtures of N-acylhydrazines (i.e. hydrazides), and the
1
diastereomer ratios were measured by H NMR or HPLC
(Table 3). In the presence of BF3·OEt2 (1.5–2.0 equiv.) as
Lewis acid, reductions of ketone N-acylhydrazones 7 and 8
by Bu3SnH (1.5–2.5 equiv.) at 2788C afforded hydrazides
9 and 10 as diastereomer mixtures in good-to-excellent
yield. In each case, the major isomer is that arising from
addition of hydride from the a-face (as drawn in Table 3).
Assignment of configuration rests on evidence from
chemical correlation of 9a to (S)-valinol and X-ray crystal-
lography of the N-benzoyl derivative of 10d, as described
previously.3
In considering possible binding modes for the Lewis acid
with the N-acylhydrazones, the question of chelation versus
non-chelation demanded some attention. There has been
some interesting discussion in the literature regarding the
proposed bidentate binding to boron trifluoride. Widely
used as a Lewis acid in organic synthesis,13 BF3·OEt2 is
generally presumed to involve the formation of tetracoordi-
nate complexes LBF3 with binding of the ligand L at a
single Lewis basic atom.14 Although bidentate binding of
BFþ2 is well-known,15 few examples of pentacoordinate
complexes of the general formula L2BX3 have been
postulated, and chelate structures are rarely invoked with
boron trifluoride.16 On the other hand, chelation should be
an important consideration with the combination BF3·OEt2/
Bu3SnH in view of the very interesting studies on the
reactions of B(C6F5)3 with stannanes16d and silanes17 which
have implicated hydride or allyl transfer from tin (or silicon)
to boron, leaving Bu3Snþ available to serve as a chelating
Lewis acid.
When the reduction of 8a was conducted with a sub-
stoichiometric amount (0.5 equiv.) of stannane, the dia-
stereomer ratio of 10a (38% yield, 74% yield based on
stannane) was 17:83, with the same configuration (R)
favored. Determination of the E/Z ratio of the remaining
hydrazone was not possible due to complications by
BF3·OEt2-promoted hydrolysis during workup.
The diastereoface selectivity observed in these hydride
additions to ketone N-acylhydrazones is opposite that of
radical3 or allylsilane6 additions using Zn(II) or In(III) salts
as Lewis acids. The latter give product configurations
3. Discussion
The foregoing results show that both the chiral auxiliary and

J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
6397
libration of CvN bond isomers having differential rates of
reduction.18 Evidence of relevance to this issue may be seen
in the close correlations of initial E/Z ratio with product
diastereomer ratios across several different examples. This
evidence makes the equilibration hypothesis highly
unlikely, since it would require a scenario where all
examples of Table 3 have the concentrations of equilibrat-
ing hydrazone·BF3 isomers balanced with the reduction
rates in such a way as to give product ratios which are
coincidentally similar to that of the hydrazone E/Z ratio.
Such a remarkable coincidence can be considered even
more unlikely in light of the experiment with substoichio-
metric stannane, where it is reasonable to assume that the
precise balance might be altered by the different stannane
concentration.19 In fact, an almost identical ratio is obtained
regardless of the concentration of stannane. Various
literature precedents also seem to indicate that N-acyl-
hydrazone isomers may not be prone to equilibration under
these conditions: (1) it has been suggested previously that
CvN bond isomerization of N-acylhydrazones may be
slower than Rh-mediated reduction;11d (2) complexation of
E/Z isomeric mixtures of imines with B(C6F5)3 preserves
the CvN geometry at 2408C (i.e. higher temperature than
that employed in this study), and excess B(C6F5)3 inhibits
isomerization even at higher temperatures;20 (3) Inter-
conversion of imine CvN isomers occurs only to a small
extent at 658C during hydrogenation in the presence of a
titanocene catalyst, even over 2–3 days.21 These precedents
argue against CvN isomer equilibration of N-acylhydra-
zones during the reductions by BF3·OEt2/Bu3SnH,
especially considering the low temperatures employed in
the present study.
Figure 3.
consistent with chelated Lewis acids and addition from the
face opposite the benzyl group of the oxazolidinone (Fig. 1).
In contrast, if the same N–N bond dihedral angle (A, Fig. 3)
is assumed in these reductions, the hydride addition would
be required to preferentially take place from the face
proximal to the benzyl group, a prospect which seems
unlikely.
A non-chelated model of the hydrazone geometry can be
invoked in the present case which is consistent with the
outcome of the reduction reaction, and which may explain
its stereochemical difference from the radical3 and allyl-
silane6 additions. It is important to note that Lewis acid
activation of CvN bonds was necessary, since no reaction
was observed without BF3·OEt2. A tetracoordinate BF3
complex with boron bound only to the imino nitrogen would
lack rotational restriction of the N–N bond. Steric
repulsions between R1/R2 and the benzyl stereocontrol
element would be expected to destabilize conformer A
(Fig. 3), in which the benzyl group blocks the a-face.
Furthermore, the interactions of B–F and CvO bond
dipoles would be expected to further disfavor A. The
alternative conformer B appears more favorable; this places
the benzyl stereocontrol element on the b-face of the CvN
bond relative to A. Hydride addition on the more exposed
a-face of B, opposite the benzyl substituent of the auxiliary,
is consistent with all the observed results.
4. Conclusion
Clean and efficient reduction of ketone N-acylhydrazones
by BF3·OEt2/Bu3SnH gave hydrazine products in good yield
and good stereospecificity. A non-chelating stereocontrol
model is proposed to be involved in the reactions, wherein
BF3 activates the CvN bond toward hydride addition by the
stannane, although an intervening hydride exchange has not
been excluded. The products of the overall reductive
amination process were obtained with complementary,
albeit lower, stereoselectivity compared to their preparation
by radical addition to aldehyde N-acylhydrazones. For
synthetic applications, the possibility of resolving the
diastereomers before removal of the auxiliary is a distinct
advantage. In conjunction with known methods for N–N
bond cleavage,22 reduction of chiral N-acylhydrazones
offers a complementary alternative to other reductive
amination methods.
The key difference between this proposed model and the
radical addition model is that with a non-chelating Lewis
acid, a different N–N bond rotamer is preferred. Further
support for this model is offered by the lower stereo-
selectivity in comparison to the radical additions; this is
consistent with conformer B because the stereocontrol
element is farther away from the CvN carbon in the non-
chelated N–N bond rotamer.
Finally, it is worth noting that rate of reduction appears to be
independent of the CvN bond geometry. In the control
experiment with substoichiometric stannane, where the
reduction of 15a was incomplete, the ratio of the products
(17:83) was almost the same as in the reaction with
complete conversion (19:81). Unfortunately, the hydrolytic
instability of the hydrazone in the presence of boron
trifluoride prevented the complementary analysis of the E/Z
ratio of the recovered starting material. Nevertheless, the
result of this competition experiment implies that both E and
Z isomers were reduced at nearly the same rate.
5. Experimental
5.1. Materials and methods
Reactions employed oven- or flame-dried glassware under
nitrogen unless otherwise noted. Tetrahydrofuran (THF)
and toluene were distilled from sodium/benzophenone ketyl
under argon. Benzene, triethylamine and CH2Cl2 were
distilled from CaH2 under argon or nitrogen. Nitrogen was
Interconversion of CvN bond isomers under the reaction
conditions has not been rigorously ruled out. Thus, a
conceivable alternative hypothesis involves rapid equi-

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J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
passed successively through columns of anhydrous CaSO4
and R3-11 catalyst (Schweizer-Hall, South Plainfield, NJ)
for removal of water and oxygen, respectively. All other
materials were used as received from Aldrich or purified by
standard procedures. Thin layer chromatography (TLC)
employed glass 0.25 mm silica gel plates with UV indicator.
Flash chromatography columns were packed with 230–400
mesh silica gel as slurry in the initial elution solvent.
Gradient flash chromatography was conducted by adsorp-
tion of product mixtures on silica gel, packing over a short
pad of clean silica gel as a slurry in hexane, and eluting with
a continuous gradient from hexane to the indicated solvent.
Radial chromatography refers to centrifugally accelerated
thin-layer chromatography performed using a Chromatotron
(Harrison Research, Palo Alto CA) with precast rotors
supplied by Analtech (Newark, DE). Melting points were
determined on a Meltemp apparatus and are uncorrected.
Proton and carbon NMR data were obtained with a Bruker
ARX 500 spectrometer. Infrared spectra were recorded with
a Perkin–Elmer 2000 FT-IR spectrophotometer. Optical
rotations were determined using a Rudolph Research
Autopol IV polarimeter. Low resolution mass spectra were
obtained with a Finnegan 4610 quadrupole spectrometer or
a Hewlett Packard 5988 GCMS. Combustion analyses were
performed by Atlantic Microlab (Norcross, GA) or
Robertson Laboratories (Madison, NJ). Diastereomer ratios
(100 mg, 0.52 mmol) and 2-methyl-3-pentanone (0.13 mL,
1.04 mmol) by General Procedure A was obtained 7a
1
(120 mg, 0.44 mmol, 84% yield, E:Z¼3.4:1 by H NMR
analysis) as colorless oil. IR (film) 3029, 2935, 2970, 1764,
1631, 1454, 1393, 1354, 1214, 1103, 1067, 1036, 756,
1
699 cm21; H NMR (500 MHz, CDCl3), E isomer d 7.30
(dd, J¼7.5, 7.5 Hz, 2H), 7.24 (dd, J¼7.2, 7.2 Hz, 1H), 7.15
(dd, J¼7.5, 7.5 Hz, 2H), 4.34–4.20 (m, 2H), 4.02 (dd,
J¼8.3, 8.3 Hz, 1H), 3.16–3.05 (m, 1H), 2.77–2.64 (m, 2H),
2.54–2.44 (m, 1H), 2.41–2.31 (m, 1H), 1.22–1.10 (m, 9H);
Z isomer d 7.35–7.10 (m, 5H), 4.34–4.20(m, 2H), 4.06–
3.99 (m, 1H), 3.24 (m, apparent sextet, J¼6.8 Hz, 1H),
3.16–3.05 (m, 1H), 2.77–2.64 (m, 1H), 2.41–2.31 (m, 2H),
1.22–1.10 (m, 6H), 1.06 (d, J¼7.2 Hz, 3H) (multiplicity for
some resonances could not be determined due to overlap
with E isomer); 13C NMR (125 MHz, CDCl3), E isomer d
184.9, 154.7, 135.8, 129.0, 128.7, 127.0, 66.6, 60.9, 38.4,
34.2, 24.5, 20.7, 20.1, 10.6; Z isomer d 185.3, 155.2, 129.0,
66.8, 38.6, 30.9, 24.0, 19.7, 19.2, 11.1 (some resonances
were not reported due to overlap with E isomer); MS (CI)
m/z (relative intensity) 275 ([MþH]þ, 100%). Anal. calcd
for C21H24N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C,
69.91; H, 8.20; N, 10.23.
5.2.2. 1-Cyclopentyl-1-propanone N-acylhydrazone 7b.
1-Cyclopentyl-1-propanone was prepared according to the
known method9 from cyclopentanecarbonyl chloride
(1.22 mL, 10 mmol) and tetraethylsilane (1.88 mL,
10 mmol), and AlCl3 (1.33 g, 10 mmol). To a solution of
the unpurified 1-cyclopentyl-1-propanone in CH2Cl2
(30 mL) was added 1 (150 mg, 0.780 mmol) and MgSO4
(2 g), and the mixture was stirred at ambient temperature for
2 days. Concentration and flash chromatography (3:1
hexanes/ethyl acetate) afforded 7b (116 mg, 0.387 mmol,
1
were determined by integration of H NMR spectra, or by
HPLC using a Varian HPLC system equipped with dual
ProStar 210 pumps and a ProStar 320 single-wavelength UV
detector.
5.1.1. Isobutyrophenone (6a). According to the known
method,10 a suspension of VCl3 (1.57 g, 10 mmol) in
CH2Cl2 (20 mL) was added phenylmagnesium bromide
(3.3 mL, 3.0 M in diethyl ether, 11 mmol) dropwise at
2788C. After 20 min, isobutyryl chloride (1.05 mL,
10 mmol) was added, and the mixture was allowed to
warm slowly to ambient temperature. After ca. 16 h,
concentration and gradient flash chromatography (20:1 to
7:1 hexane/EtOAc) afforded 6a (1.2 g, 82% yield).
1
49% yield, E:Z¼3.8:1, H NMR analysis) as colorless oil.
IR (film) 3063, 3028, 2955, 1759, 1627, 1497, 1454, 1394,
1
1212, 1072, 1028, 755, 699 cm21; H NMR (500 MHz,
CDCl3), E isomer d 7.38–7.22 (m, 3H), 7.15 (d, J¼7.2 Hz,
2H), 4.35–4.22 (m, 2H), 4.03 (dd, J¼7.9 Hz, 1H), 3.11 (dd,
J¼13.9, 4.15 Hz, 1H), 2.85 (m, apparent quartet,
J¼7.91 Hz, 1H), 2.73 (dd, J¼13.9, 9.1 Hz, 1H), 2.53–
2.32 (m, 2H), 1.98–1.52 (m, 8H), 1.14 (dd, J¼7.5, 7.5 Hz,
3H); Z isomer d 7.37–7.11 (m, 5H), 4.36–4.22 (m, 2H),
4.07–3.99 (m, 1H), 3.28 (m, apparent quartet, 9.0 Hz, 1H),
3.15–3.06 (m, 1H), 2.77–2.68 (m, 1H), 2.43–2.30 (m, 2H),
2.08–1.98 (m, 1H), 1.97–1.41 (m, 6H), 1.52–1.42 (m, 1H),
1.19–1.11 (m, 3H) (multiplicity for some resonances could
not be determined due to overlap with E isomer); 13C NMR
(125 MHz, CDCl3), E isomer d 183.5, 154.8, 135.8, 129.0,
128.7, 126.9, 66.6, 60.9, 45.4, 38.4, 30.8, 30.2, 25.5, 25.3
(2C), 10.7; Z isomer d 184.3, 155.2, 135.8, 66.6, 42.2, 38.5,
30.3, 25.9, 25.2, 11.6 (some resonances were not reported
due to overlap with E isomer); MS (CI) m/z (relative
intensity) 301 ([MþH]þ, 100%). Anal. calcd for
C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 71.81;
H, 8.05; N, 9.20.
5.1.2. Cyclopentyl phenyl ketone (6b). By the procedure
described for 6a, from cyclopentanecarbonyl chloride
(1.22 mL, 10 mmol) was obtained 6b (1.25 g, 72% yield).
5.1.3. 2,2-Dimethyl-1-phenyl-1-propanone (6d). By the
procedure described for 6a, from 2,2-dimethylpropionyl
chloride (1.23 mL, 10 mmol) was obtained 6d (1.4 g, 88%
yield).
5.2. Preparation of N-acylhydrazones, general
procedure A
To a solution of (S)-3-amino-4-phenylmethyl-2-oxazolidi-
none 15 in CH2Cl2, toluene or benzene (0.2 M) was added
TsOH·H2O (cat.) and ketone (5–10 equiv.) at ambient
temperature or reflux temperature of the solvent (if
necessary to complete the reaction). When the reaction
was complete (TLC) the mixture was concentrated and
purified by gradient flash chromatography (hexane to 1:1
hexane/EtOAc) to afford the hydrazone.
5.2.3. 1-Cyclohexyl-1-propanone N-acylhydrazone 7c.
1-Cyclohexyl-1-propanone was prepared according to the
known method9 from cyclohexanecarbonyl chloride
(1.34 mL, 10 mmol) and tetraethylsilane (1.88 mL,
10 mmol), and AlCl3 (1.33 g, 10 mmol). To a solution of
the unpurified 1-cyclohexyl-1-propanone in CH2Cl2
5.2.1. 2-Methyl-3-pentanone N-acylhydrazone 7a. From 1

J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
6399
(30 mL) was added 1 (190 mg, 0.989 mmol) and MgSO4
(2 g), and the mixture was stirred at ambient temperature for
2 days. Concentration and flash chromatography (3:1
hexanes/ethyl acetate) afforded 7c (200 mg, 0.637 mmol,
64% yield, E:Z¼5.6:1, 1H NMR analysis) as a colorless oil.
IR (film) 3028, 2930, 2853, 1764, 1628, 1498, 1451, 1394,
127.1, 126.7, 66.0, 59.8, 37.4, 37.4, 20.4, 20.1; E isomer d
67.0, 61.2, 39.0, 31.3, 20.2, 19.6 (some resonances were not
reported due to overlap with Z isomer); MS (CI) m/z
(relative intensity) 323 ([MþH]þ, 100%). Anal. calcd for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.68;
H, 6.90; N, 8.62.
1353, 1211, 1075, 1030, 754, 700 cm21
;
1H NMR
(500 MHz, CDCl3), E isomer d 7.35–7.27 (m, 2H), 7.27–
7.22 (m, 1H), 7.20–7.11 (m, 2H), 4.35–4.20 (m, 2H), 4.03
(dd, J¼8.7, 8.7 Hz, 1H), 3.11 (dd, J¼13.6, 4.1 Hz, 1H), 2.72
(dd, J¼13.6, 8.7 Hz, 1H), 2.51–2.42 (m, 1H), 2.41–2.30
(m, 2H), 2.00–1.78 (m, 10H), 1.12 (dd, J¼7.5 Hz, 3H); Z
isomer d 7.37–7.09 (m, 5H), 4.35–4.22 (m, 2H), 4.05 (dd,
J¼8.7, 8.7 Hz, 1H), 3.15–3.11 (m, 1H), 2.95–2.85 (m, 1H),
2.69 (dd, J¼13.9, 9.1 Hz, 1H), 2.42–2.32 (m, 2H), 2.00–
1.18 (m, 10H), 1.15 (dd, J¼7.2, 7.2 Hz, 3H) (multiplicity for
some resonances could not be determined due to overlap
with E isomer); 13C NMR (125 MHz, CDCl3), E isomer d
184.5, 154.7, 135.8, 129.0, 128.7, 127.0, 66.6, 60.9, 44.3,
38.4, 31.1, 30.5, 26.2, 26.1, 26.0, 24.7, 10.6; Z isomer d
184.6, 155.2, 66.7, 41.9, 38.6, 29.8, 29.1, 26.0, 25.9, 25.5,
11.1 (some resonances were not reported due to overlap
with E isomer); MS (CI) m/z (relative intensity) 315
([MþH]þ, 100%). Anal. calcd for C19H26N2O2: C, 72.58;
H, 8.33; N, 8.91. Found: C, 72.88; H, 8.43; N, 8.83.
5.2.6. Cyclopentyl phenyl ketone N-acylhydrazone 8b.
From 1 (70 mg, 0.365 mmol) and cyclopentyl phenyl ketone
(190 mg, 1.09 mmol) by General Procedure A was obtained
1
8b (78 mg, 0.224 mmol, 59% yield, Z:E¼2.9:1, H NMR
analysis) as a colorless oil. IR (film) 3027, 2955, 2869,
1
1764, 1603, 1454, 1392, 1213, 1086, 1029, 699 cm21; H
NMR (500 MHz, C6D6), Z isomer d 7.38–7.34 (m, 2H),
7.29–7.00 (m, 6H), 6.80 (d, J¼6.8 Hz, 2H), 3.85–3.75 (m,
1H), 3.38 (dd, J¼8.7, 7.5 Hz, 1H), 3.26 (dd, J¼8.7, 8.7 Hz,
1H), 3.01 (dddd, apparent quintet, J¼7.9 Hz, 1H), 2.95 (dd,
J¼13.2, 4.9 Hz, 1H), 2.33 (dd, J¼13.2, 9.4 Hz, 1H), 2.10–
1.40 (m, 8H); E isomer d 7.54–7.50 (m, 2H), 7.41–7.00 (m,
6H), 6.85 (d, J¼7.9 Hz, 2H), 4.08–4.00 (m, 1H), 3.65–3.53
(m, 2H), 2.91 (dd, J¼4.5, 3.6 Hz, 1H), 2.50 (dd, J¼13.9,
8.7 Hz, 1H), 2.43–2.33 (m, 1H), 2.10–1.40 (m, 8H)
(multiplicity for some resonances could not be determined
due to overlap with Z isomer); 13C NMR (125 MHz,
CDCl3), Z isomer d 178.8, 155.1, 137.4, 135.7, 129.0, 128.8,
128.6, 128.1, 127.0, 126.5, 66.0, 59.8, 48.5, 37.5, 30.7, 30.3,
25.1 (2C); E isomer d 181.7, 155.0, 136.8, 135.6, 129.1,
128.6, 127.9, 66.9, 61.2, 42.5, 38.8, 30.6, 30.5, 25.6, 25.6
(some resonances were not reported due to overlap with Z
isomer); 13C NMR (125 MHz, C6D6), Z isomer d 179.2,
155.0, 138.6, 136.4, 129.5, 129.2, 128.8, 127.1, 127.0, 65.9,
60.6, 48.9, 38.3, 30.9, 30.8, 25.4 (2C) (one resonance was
overlap with solvent peaks); E isomer d 179.7, 155.1, 137.8,
136.3, 66.3, 61.4, 42.9, 38.8, 26.02, 25.95 (some resonances
were not reported due to overlap with Z isomer); MS (CI)
m/z (relative intensity) 349 ([MþH]þ, 100%). Anal. calcd
for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C,
75.67; H, 6.74; N, 7.68.
5.2.4. 2,2-Dimethyl-3-pentanone N-acylhydrazone 7d.
From 1 (70 mg, 0.37 mmol) and 2,2-dimethyl-3-pentanone
(208 mg, 1.82 mmol) by General Procedure A was obtained
1
7d (70 mg, 0.24 mmol, 67% yield, E:Z .98:2, H NMR
analysis) as a colorless oil. [a]2D4¼247.58 (c 2.5, CHCl3). IR
(film) 3029, 2970, 1763, 1625, 1455, 1394, 1352, 1201,
1
1171, 1081, 1042, 756, 703 cm21; H NMR (500 MHz,
CDCl3) d 7.31 (dd, J¼7.2, 7.2 Hz, 2H), 7.25 (d, J¼7.5 Hz,
1H), 7.20 (d, J¼7.2 Hz, 2H), 4.31–4.21 (m, 2H), 4.09–4.01
(m, 1H), 3.14 (dd, J¼13.6, 4.2 Hz, 1H), 2.73 (dd, J¼13.6,
8.3 Hz, 1H), 2.59–2.49 (m, 1H), 2.45–2.35 (m, 1H), 1.20
(s, 9H), 1.13 (dd, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 187.1, 154.6, 136.0, 128.9, 128.7, 127.0, 66.8,
61.3, 39.9, 38.4, 28.0, 22.3, 11.4; MS (CI) m/z (relative
intensity) 289 ([MþH]þ, 100%). Anal. calcd for
C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.81;
H, 8.54; N, 9.56.
5.2.7. Cyclohexyl phenyl ketone N-acylhydrazone 8c.
From 1 (120 mg, 0.625 mmol) and cyclohexyl phenyl
ketone (235 mg, 1.25 mmol) by General Procedure A was
obtained 8c (125 mg, 0.345 mmol, 55% yield, Z:E¼6.5:1,
1H NMR analysis) as a colorless oil. IR (film) 3061, 3028,
2929, 2853, 1764, 1621, 1496, 1444, 1392, 1213, 1086,
1029, 755, 699 cm21; 1H NMR (500 MHz, C6D6), Z isomer
d 7.34 (d, J¼8.3 Hz, 2H), 7.27–7.01 (m, 6H), 6.83 (d,
J¼6.8 Hz, 2H), 3.86–3.76 (m, 1H), 3.39 (dd, J¼8.3, 8.3 Hz,
1H), 3.28 (dd, J¼8.3, 8.3 Hz, 1H), 2.95 (dd, J¼13.9, 4.5 Hz,
1H), 2.62 (m, J¼11.3, 3.4 Hz, 1H), 2.36 (dd, J¼13.6,
9.4 Hz, 1H), 2.08–1.99 (m, 1H), 1.97–1.88 (m, 1H), 1.78–
1.65 (m, 2H), 1.62–1.52 (m, 2H), 1.25–1.08 (m, 3H), 0.32
(s, 1H); E isomer d 7.50–7.44 (m, 2H), 7.42–6.75 (m, 8H),
4.11–4.00 (m, 1H), 3.64–3.53 (m, 2H), 3.49–3.42 (m, 1H),
3.00–2.91 (m, 1H), 2.52 (dd, J¼13.6, 9.0 Hz, 1H), 2.47–
2.42 (m, 1H), 1.88–1.83 (m, 1H), 1.82–0.90 (m, 8H)
(multiplicity for some resonances could not be determined
due to overlap with Z isomer); 13C NMR (125 MHz, C6D6),
Z isomer d 179.8, 154.7, 137.7, 136.1, 128.9, 128.5, 128.2,
126.9, 126.7, 65.6, 60.2, 47.0, 37.8, 30.6, 30.5, 26.1, 26.0
(2C) (one resonance was overlap with solvent peaks); E
isomer d 180.3, 154.9, 138.0, 136.0, 129.1, 128.3, 66.1,
61.2, 42.7, 38.5, 30.2, 29.6, 26.2, 25.8 (some resonances
5.2.5. Isobutyrophenone N-acylhydrazone 8a. From 1
(150 mg, 0.780 mmol) and isobutyrophenone (1.15 g,
7.80 mmol) by General Procedure A was obtained 8a
(136 mg, 0.422 mmol, 54% yield, Z:E¼4.3:1, 1H NMR
analysis) as a colorless oil. IR (film) 3061, 3028, 2931,
2969, 2873, 1765, 1604, 1443, 1392, 1351, 1213, 1029,
1
701 cm21; H NMR (500 MHz, CDCl3), Z isomer d 7.45–
7.21 (m, 8H), 7.10 (d, J¼7.2 Hz, 2H), 4.00–3.92 (m, 1H),
4.01 (dd, J¼7.9, 7.9 Hz, 1H), 3.84 (dd, J¼7.9, 6.4 Hz, 1H),
3.10 (dd, J¼13.6, 4.1 Hz, 1H), 2.99 (m, apparent septet,
J¼6.8 Hz, 1H), 2.58 (dd, J¼13.6, 9.0 Hz, 1H), 1.20 (dd,
J¼8.7, 7.2 Hz, 6H); E isomer d 7.46–7.06 (m, 10H), 4.48–
4.39 (m 1H), 4.30 (dd, J¼7.5, 7.5 Hz, 1H), 4.10 (dd, J¼8.7,
8.7 Hz, 1H), 3.52 (m, apparent septet, J¼6.8 Hz, 1H), 3.22
(dd, J¼13.6, 4.9 Hz, 1H), 2.79 (dd, J¼13.6, 9.4 Hz, 1H),
1.25 (d, J¼6.8 Hz, 3H), 1.15 (d, J¼7.2 Hz, 3H) (multiplicity
for some resonances could not be determined due to overlap
with Z isomer); 13C NMR (125 MHz, CDCl3), Z isomer d
180.4, 155.1, 136.7, 135.7, 129.0, 128.8, 128.7, 128.1,

6400
J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
were not reported due to overlap with Z isomer); MS (CI)
m/z (relative intensity) 363 ([MþH]þ, 100%). Anal. calcd
for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found: C,
75.93; H, 7.24; N, 7.56.
5.3.2. (4S,30S)-3-(20-Methyl-30-pentylamino)-4-phenyl-
methyl-2-oxazolidinone [(S,S)-9a]. Reduction of 7a by
General Procedure B (39 mg, 0.142 mmol) gave dia-
stereomeric mixture 9a (35 mg, 0.127 mmol, 89% yield,
(S,S):(S,R)¼4.0:1) as a colorless oil. (S,S)-9a: HPLC
retention time 11.8 min, Si C8 MICROSORB-MVe
5.2.8. 2,2-Dimethyl-1-phenyl-1-propanone N-acylhydra-
zone 8d. From 1 (95 mg, 0.49 mmol) and 2,2-dimethyl-1-
phenyl-1-propanone (160 mg, 1.0 mmol) by General
Procedure A was obtained 8d (120 mg, 0.36 mmol, 73%
t
˚
100 A column, gradient elution (hexane to PrOH/hexane
1
1:9, 0–20 min); H NMR (500 MHz, CDCl3) d 7.33 (dd,
J¼7.1, 7.1 Hz, 2H), 7.25 (dd, J¼7.4, 7.4 Hz, 1H), 7.16 (dd,
J¼7.1, 1.4 Hz, 2H), 4.13 (dd, J¼8.2, 8.2 Hz, 1H), 4.05–
4.00 (m, 2H), 3.92–3.87 (m, 1H), 3.36 (dd, J¼13.4, 3.5 Hz,
1H), 2.82–2.77 (m, 1H), 2.61 (dd, J¼13.4, 10.1 Hz, 1H),
1.93–1.83 (m, 1H), 1.54–1.46 (m, 1H), 1.39–1.31 (m, 1H),
1.04 (dd, J¼7.5, 7.5 Hz, 3H), 0.99 (d, J¼6.9 Hz, 3H), 0.94
(d, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 158.4,
136.1, 129.1, 128.9, 127.0, 66.2, 65.5, 59.7, 36.8, 28.6, 20.8,
18.5, 16.9, 10.9. Diastereomer mixture 9a: IR (film) 3304,
3028, 2961, 2874, 1758, 1604, 1498, 1454, 1397, 1238,
1089, 1029, 743, 702 cm21; MS (CI) m/z (relative intensity)
277 ([MþH]þ, 100%), 193(58%). Anal. calcd for
C16H24N2O2: C, 69.53; H, 8.75; N, 10.14. Found: C,
69.52; H, 8.78; N, 9.98.
1
yield, Z:E . 98:2, H NMR analysis) as a colorless oil.
[a]2D3¼2132.58 (c 2.0, CHCl3). IR (film) 3062, 3029, 2931,
2972, 2868, 1765, 1617, 1442, 1394, 1359, 1214, 1200,
1077, 1030, 753, 702 cm21; 1H NMR (500 MHz, CDCl3) d
7.41–7.10 (m, 10H), 3.88–3.78 (m, 1H), 3.33 (dd, J¼8.3,
8.3 Hz, 1H), 3.15 (dd, J¼8.7, 8.7 Hz, 1H), 2.91 (dd, J¼13.6,
4.52 Hz, 1H), 2.30 (dd, J¼13.6, 9.42 Hz, 1H), 1.25 (s, 9H);
13C NMR (125 MHz, CDCl3) d 185.2, 154.8, 136.2, 135.8,
128.9, 128.8, 128.0, 127.4, 127.1, 127.0, 66.2, 60.1, 39.6,
37.8, 28.5; 13C NMR (125 MHz, C6D6) d 184.8, 154.6,
136.7, 136.2, 128.8, 128.5, 127.2, 126.7, 65.7, 60.4, 39.3,
38.2, 28.3; MS (CI) m/z (relative intensity) 337 ([MþH]þ,
100%). Anal. calcd for C21H24N2O2: C, 74.97; H, 7.19; N,
8.33. Found: C, 74.79; H, 7.20; N, 8.30.
5.3.3. (4S,10S)-3-(10-Cyclopentyl-10-propylamino)-4-
phenylmethyl-2-oxazolidinone [(S,S)-9b]. Reduction of
7b by General Procedure B (57 mg, 0.19 mmol) gave
diastereomeric mixture 9b (47 mg, 0.156 mmol, 82% yield,
(S,S):(S,R)¼3.1:1) as a colorless oil. (S,S)-9b: HPLC
retention time 10.2 min, Chiralcel OD 250£0.46 mm
5.3. Reduction of N-acylhydrazones, general procedure
B
In a solution of the N-acylhydrazone in CH2Cl2 (ca. 0.1 M)
was added BF3·OEt2 (1.5–2 equiv.) at 2788C and stirred for
15 min. Then Bu3SnH (1.5–2.5 equiv.) was added and the
reaction mixture was allowed to warm up to room
temperature. Stannanes were removed by dilution with
EtOAc, stirring overnight with excess KF, and filtration
through a short pad of silica gel. Concentration and gradient
flash chromatography (hexane to 3:1 hexane/EtOAc)
afforded N-acylhydrazine 3 and N-acylhydrazines 9a–9d
and 10a–10d as mixtures of diastereomers. Diastereomer
ratios were determined by HPLC (9) or a combination of
t
1
(L£I.D.) column, PrOH/hexane 1:9; H NMR (500 MHz,
CDCl3) d 7.32 (dd, J¼7.2, 7.2 Hz, 2H), 7.26 (dd, J¼7.2,
7.2 Hz, 1H), 7.16 (d, J¼7.1 Hz, 2H), 4.12 (dd, J¼8.7,
8.7 Hz, 1H), 4.04–4.00 (m, 2H), 3.93–3.88 (m, 1H), 3.34
(dd, J¼13.4, 3.6 Hz, 1H), 2.86 (m, apparent quintet,
J¼4.6 Hz, 1H), 2.62 (dd, J¼13.4, 10.0 Hz, 1H), 1.99 (m,
apparent sextet, J¼7.9 Hz, 1H), 1.86–1.80 (br m, 1H),
1.79–1.72 (br m, 1H), 1.69–1.44 (br m, 6H), 1.37–1.24 (br
m, 2H), 1.00 (dd, J¼7.4, 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 158.7, 136.1, 129.1, 128.9, 127.1, 65.9, 64.1, 59.0,
41.2, 37.0, 29.3, 29.1, 25.6 (2C), 23.0, 9.3. Diastereomer
mixture 9b: IR (film) 3299, 3062, 3027, 2954, 2868, 1759,
1604, 1497, 1454, 1397, 1362, 1237, 1089, 1029, 912, 744,
702 cm21; MS (CI) m/z (relative intensity) 303 ([MþH]þ,
84%), 193 (100%). Anal. calcd for C18H26N2O2: C, 71.47;
H, 8.67; N, 9.26. Found: C, 71.73; H, 8.67; N, 9.17.
1
GCMS and H NMR (10). Major isomers of N-acylhydra-
zines 10 were separated from the diastereomeric mixtures
by radial chromatography for full characterization, but
N-acylhydrazines 9 required characterization within the
diastereomeric mixture. Characterization data for the minor
diastereomers (obtained through a different method) have
been reported previously.3
5.3.1. (S)-3-(10-Propylamino)-4-phenylmethyl-2-oxa-
zolidinone (3). Reduction of aldehyde N-acylhydrazone 23
(71 mg, 0.31 mmol) by General Procedure B gave 3 (73 mg,
0.31 mmol, 100% yield) as a colorless oil; [a]2D3¼þ42.68 (c
0.15, CHCl3). IR (film) 3293, 3028, 2961, 1757, 1604, 1497,
5.3.4. (4S,10S)-3-(10-Cyclohexyl-10-propylamino)-4-
phenylmethyl-2-oxazolidinone [(S,S)-9c]. Reduction of
7c by General Procedure B (92 mg, 0.290 mmol) gave
diastereomeric mixture 9c (70 mg, 0.222 mmol, 76% yield,
(S,S):(S,R)¼5.6:1) as a colorless oil. (S,S)-9c: HPLC
retention time 9.1 min, Chiralcel OD 250£0.46 mm
1402, 1093 cm21 1H NMR (500 MHz, CDCl3) d 7.30
;
t
1
(dddd, J¼7.0, 7.0, 1.1, 1.1 Hz, 2H), 7.24 (dddd, J¼7.3, 7.3,
1.2, 1.2 Hz, 1H), 7.15 (ddd, J¼6.8, 1.4, 1.4 Hz, 2H), 4.13
(dd, J¼8.6, 7.7 Hz, 1H), 4.02–3.97 (m, 2H), 3.96–3.90 (m,
1H), 3.30 (dd, J¼13.6, 3.7 Hz, 1H), 3.00–2.93 (m, 1H),
2.91–2.85 (m, 1H), 2.64 (dd, J¼13.5, 9.7 Hz, 1H), 1.53 (m,
apparent sextet, J¼7.3 Hz, 2H), 0.97 (dd, J¼7.4, 7.4 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 158.4, 135.9, 129.0,
128.9, 127.0, 66.2, 58.9, 52.7, 37.7, 21.3, 11.4; MS (CI) m/z
(relative intensity) 235 ([MþH]þ, 100%). Anal. calcd for
C13H18N2O2: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.39;
H, 7.72; N, 11.75.
(L£I.D.) column, PrOH/hexane 1:9; H NMR (500 MHz,
CDCl3) d 7.31 (m, 2H), 7.26–7.23 (m, 1H), 7.15 (m, 2H),
4.13 (m, apparent quartet, J¼8.6 Hz, 1H), 4.03 (dd, J¼8.9,
4.4 Hz, 1H), 3.99 (d, J¼4.1 Hz, 1H), 3.90–3.84 (m, 1H),
3.35 (dd, J¼13.2, 3.2 Hz, 1H), 2.78–2.71 (m,1H), 2.60 (dd,
J¼13.4, 9.8 Hz, 1H), 1.85–1.78 (m, 3H), 1.72–1.64 (m,
2H), 1.56–1.44 (m, 2H), 1.42–1.32 (m, 1H), 1.28–1.06 (m,
5H), 1.02 (dd, J¼7.4, 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 158.4, 136.2, 129.1, 128.9, 127.0, 65.8, 65.6, 59.7,
39.5, 36.9, 29.2, 27.9, 26.8, 26.7 (2C), 21.5, 10.9.
Diastereomer mixture 9c: IR (film) 3303, 3063, 3027,

J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
6401
2926, 2852, 1759, 1604, 1497, 1452, 1398, 1363, 1238,
1198, 1088, 1029, 958, 743, 702 cm21; MS (CI) m/z
(relative intensity) 317 ([MþH]þ, 100%), 193 (39%). Anal.
calcd for C19H28N2O2: C, 72.12; H, 8.92; N, 8.85. Found: C,
72.27; H, 9.00; N, 8.82.
1H), 3.92–3.90 (m, 2H), 3.75–3.70 (m, 2H), 2.77 (dd,
J¼13.6, 3.1 Hz, 1H), 2.24 (m, apparent sextet, J¼9.3 Hz,
1H), 2.02–1.94 (m, 1H), 1.74–1.66 (m, 2H), 1.64–1.49 (m,
3H), 1.47–1.40 (m, 1H), 1.39–1.31 (m, 1H), 1.09–1.01 (m
1H); 13C NMR (125 MHz, CDCl3) d 159.4, 141.7, 136.2,
129.0, 128.8, 128.7, 128.1, 127.7, 126.9, 69.4, 66.8, 59.1,
43.9, 37.6, 30.6, 30.3, 25.7, 24.9; MS (CI) m/z (relative
intensity) 351 ([MþH]þ, 37%), 350 (M, 46%), 193 (100%);
HRMS (FABþ) calcd for C22H26N2O2Li: 357.2154. Found:
357.2119.
5.3.5. (4S,30S)-3-(20,20-Dimethyl-30-pentylamino)-4-
phenylmethyl-2-oxazolidinone [(S,S)-9d]. Reduction of
7d by General Procedure B (55 mg, 0.191 mmol) gave
diastereomeric mixture 9d (52 mg, 0.179 mmol, 94% yield,
(S,S):(S,R)¼7.8:1) as a colorless oil. (S,S)-9d: HPLC
retention time 8.3 min, Chiralcel OD 250£0.46 mm
5.3.8. (4S,10R)-3-(10-Cyclohexyl-10-phenylmethylamino)-
4-phenylmethyl-2-oxazolidinone [(S,R)-10c]. Reduction
of 8c by General Procedure B (20 mg, 0.055 mmol) gave
diastereomeric mixture 10c (19 mg, 0.052 mmol, 94%
yield, (S,R):(S,S)¼4.7:1). Radial chromatography gave
(S,R)-10c as a colorless solid. (S,R)-10c: GCMS retention
time 10.1 min, 15 m£0.25 mm£0.25 m (L£I.D.£F.T.) 5%-
phenyl-95%-dimethylsiloxane column, Helium; mp 103–
1048C; [a]2D6¼þ26.98 (c 0.95, CHCl3). IR (film) 3503, 3321,
3062, 2928, 1767, 1603, 1496, 1453, 1367, 1214, 1029, 954,
t
1
(L£I.D.) column, PrOH/hexane 1:9; H NMR (500 MHz,
CDCl3) d 7.32 (dd J¼7.6, 7.6 Hz, 2H), 7.25 (dd, J¼7.3,
7.3 Hz, 1H), 7.16 (d, J¼6.9 Hz, 2H), 4.15–4.02 (m, 2H),
3.96–3.91 (m, 2H), 3.35 (dd, J¼13.4, 3.3 Hz, 1H), 2.60 (dd,
J¼13.5, 10.0 Hz, 1H), 2.54–2.51 (m, 1H), 1.75–1.67 (m,
1H), 1.46–1.37 (m, 1H), 1.09 (dd, J¼7.6, 7.6 Hz, 3H), 0.99
(s, 9H); 13C NMR (125 MHz, CDCl3) d 158.4, 136.1, 129.1,
128.9, 127.0, 70.1, 65.2, 58.6, 36.1, 34.5, 27.0, 23.4, 13.4.
Diastereomer mixture 9d: IR (film) 3308, 3063, 3028, 2959,
2873, 1758, 1604, 1498, 1478, 1394, 1237, 1216, 930, 745,
702 cm21; MS (CI) m/z (relative intensity) 291 ([MþH]þ,
77%), 193 (100%). Anal. calcd for C17H26N2O2: C, 70.31;
H, 9.02; N, 9.65. Found: C, 70.38; H, 9.00; N, 9.62.
1
841, 755, 701 cm21; H NMR (500 MHz, CDCl3) d 7.33–
7.21 (m, 8H), 7.05 (d, J¼7.1 Hz, 2H), 4.43 (d, J¼2.6 Hz,
1H), 3.99–3.95 (m, 2H), 3.86–3.81 (m, 2H), 3.01 (dd,
J¼13.9, 3.8 Hz, 1H), 2.10–2.04 (m, 1H), 1.93 (d,
J¼12.7 Hz, 1H), 1.78 (d, J¼13.3 Hz, 1H), 1.75–1.62 (m,
3H), 1.56 (d, J¼11.0 Hz, 1H), 1.32–1.23 (m, 1H), 1.20–
1.00 (m, 3H), 0.89–0.80 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 158.7, 140.1, 136.2, 128.9 (2C), 128.8, 127.9,
127.6, 127.0, 68.9, 66.3, 58.9, 41.3, 37.5, 30.5, 28.9, 26.4,
26.2, 26.1; MS (CI) m/z (relative intensity) 365 ([MþH]þ,
18%), 193 (100%). Anal. calcd for C23H28N2O2: C, 75.79;
H, 7.74; N, 7.69. Found: C, 75.63; H, 7.87; N, 7.66.
5.3.6. (4S,10R)-3-(20-Methyl-10-phenyl-10-propylamino)-
4-phenylmethyl-2-oxazolidinone [(S,R)-10a]. Reduction
of 8a by General Procedure B (13 mg, 0.040 mmol) gave
diastereomeric mixture 10a (12 mg, 0.037 mmol, 92%
yield, (S,R):(S,S)¼4.2:1). Radial chromatography afforded
(S,R)-10a as a colorless solid. (S,R)-10a: GCMS retention
time 6.9 min, 15 m£0.25 mm£0.25 m (L£I.D.£F.T.) 5%-
phenyl-95%-dimethylsiloxane column, Helium; mp 110–
1128C; [a]2D6¼þ32.08 (c 0.45, CHCl3). IR (film) 3311, 3289,
3084, 3062, 2959, 2869, 1778, 1603, 1491, 1453, 1388,
1292, 1029, 948, 762, 742, 703 cm21; 1H NMR (500 MHz,
CDCl3) d 7.35–7.20 (m, 8H), 7.04 (d, J¼7.4 Hz, 2H), 4.38
(d, J¼1.9 Hz, 1H), 3.98 (dd, J¼8.0, 8.0 Hz, 1H), 3.93 (dd,
J¼6.7, 2.4 Hz, 1H), 3.87–3.80 (m, 2H), 3.01 (dd, J¼13.9,
3.5 Hz, 1H), 2.12–2.01 (m, 2H), 1.00 (d, J¼6.6 Hz, 3H),
0.79 (d, J¼6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
158.7, 139.7, 136.1, 129.0, 128.9 (2C), 127.9, 127.6, 127.0,
69.6, 66.3, 59.0, 37.4, 31.2, 19.9, 18.4; MS (CI) m/z (relative
intensity) 325 ([MþH]þ, 15%), 193 (100%). Anal. calcd for
C20H24N2O2: C, 74.04; H, 7.46; N, 8.63. Found: C, 73.75;
H, 7.48; N, 8.38.
5.3.9. (4S,10R)-3-(20,20-Dimethyl-10-phenyl-10-propyl-
amino)-4-phenylmethyl-2-oxazolidinone
[(S,R)-10d].
Reduction of 8d by General Procedure B (20 mg,
0.060 mmol) gave diastereomeric mixture 10d (19 mg,
0.057 mmol, 94% yield, (S,R):(S,S)¼7.4:1). Radial
chromatography gave (S,R)-10d as a colorless solid. (S,R)-
10d: GCMS retention time 6.7 min, 15 m£0.25 mm£0.25 m
(L£I.D.£F.T.) 5%-phenyl-95%-dimethylsiloxane column,
Helium; mp 129–1318C; [a]2D6¼þ61.38 (c 0.5, CHCl3). IR
(film) 3325, 3062, 3025, 2972, 2957, 1760, 1492, 1478,
1399, 1296, 1204, 1101, 962, 876, 742, 702 cm21; 1H NMR
(500 MHz, CDCl3) d 7.37 (d, J¼6.8 Hz, 2H), 7.29 (dd,
J¼6.9, 6.9 Hz, 4H), 7.26–7.22 (m, 2H), 7.08 (d, J¼7.4 Hz,
2H), 4.45 (d, J¼3.6 Hz, 1H), 3.88–3.78 (m, 4H), 3.05
(dd, J¼13.3, 3.3 Hz, 1H), 2.19 (dd, J¼13.6, 8.8 Hz, 1H),
0.97 (s, 9H); 13C NMR (125 MHz, CDCl3) d 158.5, 139.4,
136.2, 129.6, 128.9 (2C), 127.5 (2C), 127.0, 72.5, 66.2,
57.5, 37.8, 34.4, 27.2; MS (CI) m/z (relative intensity) 339
([MþH]þ, 19%), 193 (100%). Anal. calcd for C21H26N2O2:
C, 74.52; H, 7.74; N, 8.28. Found: C, 74.35; H, 7.87; N,
8.32.
5.3.7. (4S,10R)-3-(10-Cyclopentyl-10-phenylmethyl-
amino)-4-phenylmethyl-2-oxazolidinone
[(S,R)-10b].
Reduction of 8b by General Procedure B (27 mg,
0.077 mmol) gave diastereomeric mixture 10b (21 mg,
0.060 mmol, 78% yield, (S,R):(S,S)¼2.9:1). Radial chro-
matography gave (S,R)-10b as a colorless solid. (S,R)-10b:
GCMS retention time 5.9 min, 15 m£0.25 mm£0.25 m
(L£I.D.£F.T.) 5%-phenyl-95%-dimethylsiloxane column,
Helium; mp 105–1078C; [a]2D6¼þ50.18 (c 0.3, CHCl3). IR
(film) 3290, 3061, 3028, 2953, 2867, 1758, 1603, 1496,
1398, 1219, 1086, 956, 913, 761, 744, 701 cm21; 1H NMR
(500 MHz, CDCl3) d 7.34 (ddd, J¼6.9, 1.5, 1.5 Hz, 2H),
7.29 (dddd, J¼7.1, 7.1, 1.5, 1.5 Hz, 2H), 7.23 (dddd, J¼7.4,
7.4, 1.5, 1.5 Hz, 3H), 7.18 (dddd, J¼7.2, 7.2, 1.4, 1.4 Hz,
1H), 6.95 (ddd, J¼6.9, 1.4, 1.4 Hz, 2H), 4.44 (d, J¼2.2 Hz,
Acknowledgements
We thank NIGMS (RO1 GM67187-01) and NSF Vermont
EPSCoR (Graduate Research Fellowship to J. Q.) for
generous support.

6402
J. Qin, G. K. Friestad / Tetrahedron 59 (2003) 6393–6402
89, 6612. (c) Grutzner, J. B.; Jautelat, M.; Dence, J. B.; Smith,
References
R. A.; Roberts, J. D. J. Am. Chem. Soc. 1970, 92, 7107.
13. (a) Bednarski, M. D.; Lyssikatos, J. P. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 2, p 661. (b) Yamaguchi, M. Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, p 325.
1. Review: (a) Martens, J. Methods of Organic Chemistry
(Houben-Weyl); Helmchen, G., Ed.; Thieme: New York,
1995; Vol. E21d, pp 4199–4238. For recent examples using
various chiral auxiliaries, see: (b) N-sulfinylimines: Kochi, T.;
Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124,
6518–6519. 1-arylethylamines: (c) Cayuela, E. M.; Xiao, L.;
Sturm, T.; Manzano, B. R.; Jalon, F. A.; Weissensteiner, W.
Tetrahedron: Asymmetry 2000, 11, 861–869. (d) Roland, S.;
Mangeney, P. Eur. J. Org. Chem. 2000, 611–616. phenyl-
glycinol: (e) Stalker, R. A.; Munsch, T. E.; Tran, J. D.; Nie,
X. P.; Warmuth, R.; Beatty, A.; Aakeroy, C. B. Tetrahedron
2002, 58, 4837–4849.
14. (a) Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in
Organic Synthesis; CRC: Boca Raton, 1995. (b) Guryanova,
E. N.; Goldshtein, I. P.; Romm, I. P. Donor–Acceptor Bond;
Wiley: New York, 1975. (c) Reetz, M. T. Angew. Chem., Int.
Ed. Engl. 1984, 23, 556.
15. (a) For some examples of BFþ2 chelates formed from
BF3·OEt2, see: Plazuk, D.; Klys, A.; Zakrzewski, J.;
Rybarczyk-Pirek, A.; Olszak, T. A. Organometallics 2001,
20, 4448–4450. (b) Borle, F.; Fehr, F.; Nesvadba, P.;
Gossauer, A. Photochem. Photobiol. 1997, 65, 949–956.
(c) Five-membered BFþ2 chelates form more readily than six-
membered: Hartman, J. S.; Shoemaker, J. A. W. Can. J. Chem.
2001, 79, 426–436.
2. Reviews: (a) Spindler, F.; Blaser, H.-U. Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999; Vol. 1, p 248. (b) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094. (c) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994. Selected recent examples: (d) Mao, J. M.; Baker,
D. C. Org. Lett. 1999, 1, 841–843. (e) Hansen, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 713–715. (f) Abe, H.;
Amii, H.; Unemaya, K. Org. Lett. 2001, 3, 313–315. (g) Xiao,
D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425–3428.
(h) Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura,
S.; Hidai, M. Chem. Commun. 2001, 2360–2361. (i) Xie,
Y. N.; Mi, A. Q.; Jiang, Y. Z.; Liu, H. Synth. Commun. 2001,
31, 2767–2771. (j) Blaser, H.-U. Adv. Synth. Catal. 2002, 344,
17–31. (k) Chen, Y. C.; Wu, T. F.; Deng, J. G.; Liu, H.; Cui,
X.; Zhu, J.; Jiang, Y. Z.; Choi, M. C. K.; Chan, A. S. C. J. Org.
Chem. 2002, 67, 5301–5306. (l) Jiang, X. B.; Minnaard, A. J.;
Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.; Andrien, J. G.
O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5,
1503–1506.
16. Ground-state pentacoordinate boron intermediates have
generated some controversy. (a) Maruyama, K.; Ishihara, Y.;
Yamamoto, Y. Tetrahedron Lett. 1981, 22, 4235–4238.
(b) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett.
1984, 25, 729–732. (c) Lee, D. Y.; Martin, J. C. J. Am. Chem.
Soc. 1984, 106, 5745–5746. (d) Ooi, T.; Uraguchi, D.;
Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1998, 120,
5327–5328. (e) Maruoka, K.; Ooi, T. Chem. Eur. J. 1999, 5,
829–833. (f) Blackwell, J. M.; Piers, W. E.; Parvez, M. Org.
Lett. 2000, 2, 695–698. (g) Blackwell, J. M.; Piers, W. E.;
McDonald, R. J. Am. Chem. Soc. 2002, 124, 1295–1306.
(h) Aubrecht, K. B.; Winemiller, M. D.; Collum, D. B. J. Am.
Chem. Soc. 2000, 122, 11084–11089. (i) Cardillo, G.;
Gentilucci, L.; Gianotti, M.; Tolomelli, A. Org. Lett. 2001,
3, 1165–1167. (j) Marshall, J. A.; Gill, K. J. Organomet.
Chem. 2001, 624, 294–299.
3. Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122,
8329–8330.
4. (a) Ueda, M.; Miyabe, H.; Namba, M.; Nakabayashi, T.; Naito,
T. Tetrahedron Lett. 2002, 43, 4369–4371. For related
reactions, see: (b) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3,
1745–1748. (c) Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.;
Piers, W. E. Org. Lett. 2000, 2, 3921–3923. (d) Suwa, T.;
Shibata, I.; Nishino, K.; Baba, A. Org. Lett. 1999, 1,
1579–1581.
17. (a) Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.;
Yamamoto, Y. J. Org. Chem. 2000, 65, 6179–6186.
(b) Blackwell, J. M.; Morrison, D. J.; Piers, W. E. Tetrahedron
2002, 58, 8247–8254. (c) Parks, D. J.; Blackwell, J. M.; Piers,
W. E. J. Org. Chem. 2000, 65, 3090–3098, See also Ref. 4c.
18. Enhancement of the diastereomer or enantiomer ratio versus
the initial E/Z ratio has been previously observed in reductions
of imines. (a) Borg, G.; Cogan, D. A.; Ellman, J. A.
Tetrahedron Lett. 1999, 40, 6709–6712. (b) Verdaguer, X.;
Lange, U. E. W.; Buchwald, S. L. Angew. Chem. Int. Ed. 1998,
37, 1103–1107.
5. Synthesis of oxazolidinone-derived N-acylhydrazones: Shen,
Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236–6239.
6. Friestad, G. K.; Ding, H. Angew. Chem. Int. Ed. 2001, 40,
4491–4493.
7. Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123,
9922–9923.
19. The effect of stannane concentration on the rate of reduction
has not been determined.
8. Dieter, R. K. Tetrahedron 1999, 55, 4177–4236.
9. Olah, G. A.; Ho, T.-L.; Prakash, G. K. S.; Gupta, B. Synthesis
1977, 677–678.
20. Blackwell, J. M.; Piers, W. E.; Parvez, M.; McDonald, R.
Organometallics 2002, 21, 1400–1407.
21. Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 8952–8965.
10. Hirao, T.; Misu, D.; Yao, K.; Agawa, T. Tetrahedron Lett.
1986, 27, 929–932.
22. For numerous examples, see footnotes 21–28 within Ref. 22a.
(a) Friestad, G. K. Tetrahedron 2001, 57, 5461–5496. See
also: (b) Ghelfi, F.; Parsons, A. F. J. Org. Chem. 2000, 65,
6249–6253. (c) Luna, A. P.; Ceschi, M.-A.; Bonin, M.;
Micouin, L.; Husson, H.-P.; Gougeon, S.; Estenne-Bouhtou,
G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002,
67, 3522–3524. (d) Chandrasekhar, S.; Reddy, C. C.; Rao, R. J.
Synlett 2001, 1561–1562.
11. (a) Levy, G. C.; Nelson, G. L. J. Am. Chem. Soc. 1972, 94,
4897–4901. (b) Hawkes, G. E.; Herwig, K.; Roberts, J. D.
´
¨
J. Org. Chem. 1974, 39, 1017–1028. (c) Gyorgydeak, Z.;
Holzer, W. Heterocycles 1998, 48, 1395–1406. (d) Burk,
M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron
1994, 50, 4399–4428.
12. (a) Grant, D. M.; Cheney, B. V. J. Am. Chem. Soc. 1967, 89,
5315. (b) Dalling, D. K.; Grant, D. M. J. Am. Chem. Soc. 1967,