On the mechanism of oxazoline-directed metalations: Evidence for nitrogen-directed reactions

Article abstract of DOI:10.1021/jo951556l

We recently described a method for the synthesis of ferrocene complexes possessing planar chirality which relies on the asymmetric deprotonation of chiral ferrocenyloxazolines. The unexpected stereochemical outcome of these reactions led us to examine whether the metalation is directed by the oxygen or the nitrogen of the oxazoline. In this paper, we describe the synthesis of a constrained ferrocenyloxazoline (compound 13) in which oxygen- and nitrogen-directed metalations provide different stereochemical outcomes. Our results show that nitrogen is responsible for the directive effects of the oxazoline when alkyllithium reagents are used to deprotonate the ferrocene. The implications of this result on the origin of asymmetric induction in the metalation of the unconstrained ferrocenyloxazolines 19 and 20 are discussed.

Full text of DOI:10.1021/jo951556l

J . Org. Chem. 1996, 61, 1629-1635
1629
On th e Mech a n ism of Oxa zolin e-Dir ected Meta la tion s: Evid en ce
for Nitr ogen -Dir ected Rea ction s
Tarek Sammakia* and Hallie A. Latham
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received August 24, 1995X
We recently described a method for the synthesis of ferrocene complexes possessing planar chirality
which relies on the asymmetric deprotonation of chiral ferrocenyloxazolines. The unexpected
stereochemical outcome of these reactions led us to examine whether the metalation is directed by
the oxygen or the nitrogen of the oxazoline. In this paper, we describe the synthesis of a constrained
ferrocenyloxazoline (compound 13) in which oxygen- and nitrogen-directed metalations provide
different stereochemical outcomes. Our results show that nitrogen is responsible for the directive
effects of the oxazoline when alkyllithium reagents are used to deprotonate the ferrocene. The
implications of this result on the origin of asymmetric induction in the metalation of the
unconstrained ferrocenyloxazolines 19 and 20 are discussed.
The use of ferrocene derivatives possessing planar
1
chirality in asymmetric synthesis is well-known. The
preparation of these compounds in nonracemic form has
2
typically relied on classical resolution; however, more
practical and versatile methods for their asymmetric
synthesis have recently been developed.3 We have
described one such method which relies on the diastereo-
F igu r e 1.
topic group selective deprotonation of chiral ferrocenyl-
metalation. Oxazoline-directed metalations can, in prin-
oxazolines (eq 1).4 The magnitude of the asymmetric
ciple, occur via nitrogen or oxygen coordination. In our
system, in order to produce the observed stereochemical
outcome via a nitrogen-directed reaction, the oxazoline
must adopt a rotomer in which the alkyl group of the
oxazoline is placed in the more hindered position at the
transition state (toward the iron and other cyclopenta-
dienyl ring, see structure C, Figure 1). However, if the
metalation is directed by oxygen, the oxazoline assumes
a rotomer in which the alkyl group points in the less
hindered direction (structure D, Figure 1). Surprisingly,
there is little data on the mechanism of oxazoline-directed
lithiations in the literature, and both nitrogen and oxygen
have been suggested to direct metalations.5 Recent
studies by Collum suggest that oxygen can compete
(1)
induction observed with our process depends to a large
extent on the conditions employed in the metalation (e.g.,
solvent, additive, base) and to a lesser extent on the size
of the substituent attached to the oxazoline. Larger
substituents lead to higher selectivity, and no change is
observed in either the sense (which is as shown in eq 1)
or magnitude of asymmetric induction upon introducing
oxygen or sulfur heteroatoms into the alkyl substituent
of the oxazoline.
favorably with nitrogen for coordination to some orga-
nolithium species6 and, consequently, that it is not
unreasonable to consider an oxygen-directed reaction. We
have therefore prepared a ferrocenyloxazoline in which
the conformation of the oxazoline is restricted such that
the heteroatoms are directed toward different ortho
protons of the cyclopentadienyl ring. Metalation of this
species and trapping with an electrophile provides dif-
ferent products depending on which heteroatom is direct-
ing the reaction, thereby enabling us to distinguish
between these modes of coordination. This paper de-
scribes our synthesis of this compound, as well as our
metalation studies which show that in the case of
metalations using alkyllithium reagents it is the nitrogen
of the oxazoline that directs the incoming base.
The stereochemical results of this study prompted us
to investigate the origin of asymmetry operating in the
X
Abstract published in Advance ACS Abstracts, February 1, 1996.
(
1) For leading references, see: Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993.
2) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.
(
J . Am. Chem. Soc. 1970, 92, 5389. Battelle, L. F.; Bau, R.; Gokel, G.
W.; Oyakawa, R. T.; Ugi, I. K. J . Am. Chem. Soc. 1973, 95, 482.
The desired conformational constraint was achieved via
the bridged ferrocenyloxazoline derivative 13, which
contains a tether linking the oxazoline to the other
(
3) (a) Riant, O.; Samuel, O.; Kagan, H. B. J . Am. Chem. Soc. 1993,
1
15, 5835. (b) Rebiere, F.; Riant, O.; Ricard, L.; Kagan, H. Angew.
Chem., Int. Ed. Engl. 1993, 32, 568. (c) Richards, C. J .; Damalidis, T.;
Hibbs, D. E.; Hursthouse, M. B. Synlett 1995, 74. (d) Nishibayashi,
Y.; Uemura, S. Synlett 1995, 79. (e) Ratajczak, A.; Misterkiewicz, B.
J . Organomet. Chem. 1975, 91, 73. (f) Hayashi, T.; Mise, T.; Kumada,
M. Tetrahedron Lett. 1976, 48, 4351. (g) Wang, Y.-F.; Lalonde, J . J .;
Momongan, M.; Bergbreiter, D. E.; Wong, C.-H. J . Am. Chem. Soc.
(5) Meyers, A. I.; Lutomsky, K. J . Org. Chem. 1979, 44, 4464.
Meyers, A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297. For related
examples, see: Elworth, T. R.; Meyers, A. I. Tetrahedron 1994, 50,
6089. Meyers, A. I.; Slade, J . J . Org. Chem. 1980, 45, 2785.
(6) Collum, D. B. Acc. Chem. Res. 1992, 25, 448. Collum, D. B. Acc.
Chem. Res. 1993, 26, 227. These articles review the work of the author
as well as others in this field.
1
988, 110, 7200. (h) Boaz, N. W. Tetrahedron Lett. 1989, 30, 2061.
4) (a) Sammakia, T.; Latham, H. A. J . Org. Chem. 1995, 60, 6002.
b) Sammakia, T.; Latham, H. A.; Schaad, D. R. J . Org. Chem. 1995,
0, 10. For similar studies, see refs 3c and 3d.
(
(
6
0
022-3263/96/1961-1629$12.00/0 © 1996 American Chemical Society

1
630 J . Org. Chem., Vol. 61, No. 5, 1996
Sammakia and Latham
fore hydrogenated and the primary alcohol selectively
activated as the tosylate (12), setting the stage for the
macrocyclization. This reaction proved difficult to ac-
complish in high yield, and a variety of conditions were
examined. The optimum conditions involved treatment
of 12 with NaH and 18-crown-6 in DMSO at room
temperature. In this way, a 30% yield of the desired
product was obtained.
F igu r e 2.
cyclopentadienyl ring of the ferrocene (Figure 2).7 Many
Compound 13 was metalated with sec-butyllithium in
THF at -78 to 0 °C and trapped with iodomethane or
TMSCl to provide the corresponding substituted products
attempts to prepare this compound by further function-
alization of a suitable ferrocenyloxazoline failed. We
therefore chose to synthesize this compound from
ferrocene, a strategy which requires the differential
substitution of the two cyclopentadienyl rings and elabo-
ration of these substituents to an oxazoline on one ring
and the linking chain on the other. This was ac-
complished by preparing the 1,1′-bis(tributylstannyl)
derivative followed by sequential transmetalation of the
(14 and 15) in 70% and 82% yields, respectively. In each
case, only one isomer was detected by NMR and HPLC,
indicating that the metalation proceeds with a very high
level of diastereoselectivity (>100:1).11 The structure of
the product of alkylation with iodomethane was deter-
mined by X-ray crystallography and was found to contain
the methyl group proximal to the nitrogen of the oxazoline,
consistent with a nitrogen-directed reaction (Figure 3).
This result indicates that metalation of our uncon-
8
tributyltin groups and trapping with suitable precursors
for the oxazoline or linking chain (Scheme 1). Thus, bis-
4
strained oxazolines (e.g., 19 and 20) proceeds by nitrogen
lithiation of ferrocene using 3 equiv of n-butyllithium and
TMEDA in ether at room temperature9 followed by
coordination via the rotomer where the alkyl group of
the oxazoline is pointing toward the more hindered side
of the ferrocene (structure C, Figure 1).12 The predomi-
nance of this transition state cannot be due to an intrinsic
preference of the alkyl group on the oxazoline to be in
the more hindered position but must be due to some other
interaction forcing it to adopt that conformation. We
speculate that this interaction involves the incoming
alkyllithium reagent and the substituent on the oxazo-
line. A model for the transition structure which would
lead to the major and minor products is shown in Figure
trapping with tributyltin chloride provided 1,1′-bis(tri-
butyltin)ferrocene (1) in 80% yield. Treatment of 1 with
n-butyllithium in THF provided the monolithio species
which was trapped with acrolein to provide allylic alcohol
2
in 60% yield. Compound 2 underwent isomerization
to the conjugated allylic alcohol upon treatment with
Amberlyst-15 in wet THF. The hydroxyl group was then
protected as a tert-butyldimethylsilyl ether to provide 4
in 71% overall yield from 2. Treatment of 4 with
n-butyllithium in THF provided the corresponding lithio-
ferrocene derived from transmetalation of the remaining
tributyltin moiety, which was trapped with methyl
chloroformate to provide the carbomethoxy-substituted
ferrocene 5 in 73% yield. This sequence enables us to
synthesize gram quantities of a ferrocene derivative with
an oxazoline precursor (carbomethoxy group) on one ring
and a three-carbon tether on the other. Hydrolysis of
methyl ester 5 proved difficult, largely because the
product is sensitive to oxidative decomposition. However,
we found that if the hydrolysis is performed in the
presence of sodium borohydride, a reducing environment
is maintained and the reaction provides an 87% yield of
acid 6. Activation of the carboxylate was accomplished
by preparation of the pentafluorophenyl ester, which
upon treatment with (S)-2-amino-3-methyl-1,3-butane-
4
. In this model, butyllithium13 is coordinated to the
nitrogen of the oxazoline and is undergoing what is
formally a σ-bond metathesis reaction14 with the C-H
of the cyclopentadienyl ring. This mechanism allows the
lithium to interact with the cyclopentadienyl carbon
during deprotonation, thereby avoiding the formation of
a free carbanion, a species which we feel is unlikely in
(10) (S)-2-Amino-3-methyl-1,3-butanediol (18) was prepared in three
steps from L-serine methyl ester by protecting the nitrogen as the CBZ
derivative, followed by addition of MeLi to the ester and finally
deprotecting the nitrogen by hydrogenation:
1
0
diol provided amide 8 in 91% yield from 6. Conversion
of 8 to oxazoline 9 was accomplished by selective activa-
tion of the primary alcohol via the tosylate followed by
in situ cyclization to the oxazoline in 90% yield. The
allylic alcohol was then unmasked by treatment with
TBAF. Attempted tosylation of the allylic alcohol re-
sulted in extensive decomposition, presumably due to the
propensity of the allylic, ferrocenyl tosylate to ionize to
the conjugated ferrocenyl cation. The olefin was there-
(
11) Similar results were obtained using tert-butyllithium in THF.
(12) We do not feel that the oxygen on the tether is playing a
significant role in the reaction. If any chelate structure were formed,
we would expect to see a difference in the stereochemical outcome of
the metalation of unconstrained oxazolines containing heteroatoms at
this position as compared to those that do not. However, we have
prepared five different oxazolines with an oxygen in the corresponding
position and they behave analogously to their nonoxygenated coun-
terparts (i.e., no change in either the sense or magnitude of asymmetric
induction). See ref 4b for details.
(13) We have chosen to ignore the aggregation state of the butyl-
lithium because it is difficult to know with certainty what the reactive
aggregate is, especially in coordinating solvents such as THF. In
hexanes in the presence of TMEDA, we speculate that it is a monomer.
(7) For examples of directed metalation of ferrocene compounds,
see: (a) Slocum, D. W.; Rockett, B. W.; Hauser, C. R. J . Am. Chem.
Soc. 1965, 87, 1241. (b) Bolton, E. S.; Pauson, P. L.; Sandhu, M. A.;
Watts, W. E. J . Chem. Soc. C 1969, 17, 2260. (c) Marr, G. J . Organomet.
Chem. 1967, 9, 141. (d) Schmitt, G.; Klein, P.; Ebertz, W. J . Organomet.
Chem. 1982, 234, 63. For reviews of directed metalation of aryl
compounds, see: (e) Gilman, H.; Morton, J . W., J r. Org. React. 1954,
8
, 258. (f) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. (g)
0
Gschwend, H.; Rodriguez, H. R. Org. React. 1979, 26, 1. (h) Snieckus,
V. Chem. Rev. 1990, 90, 879.
(14) This type of reaction is well known for d early transition metal
complexes. For a discussion, see: Collman, J . P.; Hegedus, L. S.; Norton,
J . R.; Finke, R. G. Principles and Applications of Organotransition
Metal Chemistry; University Science Books: Mill Valley, CA, 1987;
pp 295-298.
(
8) Wright, M. E. Organometallics 1990, 9, 853.
(9) Rausch, M. D.; Ciappenelli, D. J . J . Oraganomet. Chem. 1967,
1
0, 127.

Mechanism of Oxazoline-Directed Metalations
J . Org. Chem., Vol. 61, No. 5, 1996 1631
Sch em e 1
F igu r e 3.
should increase. To test this prediction, we have meta-
lated oxazolines 19 and 20 with n-BuLi, s-BuLi, and
t-BuLi in THF at -78 °C and measured the diastereo-
selectivity. In the case of oxazoline 19, we observe that
the selectivity increases as the alkyl group of the base
increases in size (Table 1). This trend is also observed
with substrate 20 for n-BuLi- and s-BuLi-promoted
reactions, but not with t-BuLi. We suspect that this is
due to severe steric hindrance between the tert-butyl
group of the oxazoline and the alkyllithium preventing
reaction via a nitrogen-directed pathway, resulting in
reaction via an undirected or an oxygen-directed path-
F igu r e 4.
nonpolar solvents at -78 °C.15 Furthermore, it is rea-
sonable to assume that the metalating agent approaches
the cyclopentadienyl ring away from the iron and the
bulk of the ferrocene molecule. In the transition state
leading to the minor diastereomer, there is a steric
interaction between the alkyl group on the oxazoline and
the butyllithium. This interaction is relieved in the
transition state leading to the major diastereomer since
the alkyl group points toward the iron and away from
the incoming base. The stereoselectivity of the reaction
is therefore not governed by an interaction between the
oxazoline substituent and the ferrocene but by the
18
way.
In conclusion, this study provides evidence that reac-
tions involving alkyllithium reagents and oxazolines
proceed via a nitrogen-directed pathway. This indicates
that the metalation of our unconstrained oxazolines (e.g.,
1
9 and 20) proceeds by a rotamer in which the alkyl
group of the oxazoline is pointing toward the iron and
the bottom cyclopentadienyl ring. This conformation is
adopted because it minimizes the interaction between the
alkyl group of the oxazoline and the incoming alkyl-
lithium reagent, as confirmed by the selectivities ob-
interaction of this substituent with the metalating
agent.1
6,17
This model predicts that as this interaction
becomes more severe, the selectivity in the metalation
(
15) For example, metalation of the valine-derived oxazoline with
(17) For a related transition structure hypothesis in an addition
reaction, see: Kundig, E. P.; Ripa, A.; Liu, R.; Amurrio, D.; Bernardelli,
G. Organometallics 1993, 12, 3737.
sec-butyllithium in hexanes containing 1 equiv of TMEDA proceeds
in excellent yields and stereoselectivities. See ref 4a.
(16) For a related transition structure proposal, see ref 3c.
(18) For further evidence of this, see ref 4a.

1
632 J . Org. Chem., Vol. 61, No. 5, 1996
Sammakia and Latham
Ta ble 1
1.1 equiv) was added to the reaction mixture, which was then
warmed to room temperature and diluted with pentane (100
mL) and water (150 mL). The organic phase was washed with
brine (150 mL), dried over MgSO
under reduced pressure. Purification by flash chromatography
hexanes and then 15:1 hexanes:ethyl acetate) provided 12.5
g of 2 (60%). 1H NMR (400 MHz, CDCl ): δ 6.08 (ddd, J )
7.0 Hz, 10.3 Hz, 6.0 Hz, 1H), 5.32 (dt, J ) 17.0 Hz, 1.4 Hz,
4
, filtered, and concentrated
(
3
1
1
2
2
H), 5.16 (dt, J ) 10.3 Hz, 1.4 Hz, 1H), 4.84 (m, 1H), 4.35 (br,
H), 4.16 (br, 1H), 4.14 (br, 1H), 4.09 (br, 2H), 4.04 (br, 2H),
.05 (br, 1H), 1.56 (m, 6H), 1.36 (m, 6H), 1.02 (m, 6H), 0.91
(
m, 9H). 13C NMR (100 MHz, CDCl
3
): δ 139.60, 114.87, 91.49,
7
6
3
4.84, 74.70, 70.72, 70.72, 70.71, 69.60, 68.23, 68.18, 66.44,
6.39, 29.13, 27.35, 13.67, 10.18. IR (thin film): 3413.7 (br),
-
1
086.4 cm . R
E)-3-[1′-(Tr ibu tylstan n yl)fer r ocen yl]-2-pr open -1-ol (3).
Amberlyst-15 ion-exchange resin (3.0 g) was added to a
solution of 2 (8.5 g, 16.0 mmol, 1.0 equiv) in 3:1 THF:H O (32
f
) 0.4 (5:1 hexanes:ethyl acetate).
(
2
mL), and the reaction was allowed to stir for 11 h. The
reaction mixture was filtered, and the filtrate was diluted with
ether, washed with brine, dried over MgSO , filtered, and
4
concentrated. Purification by flash chromatography (hexanes
served upon metalating 19 and 20 with alkyllithium
species bearing different sized alkyl groups.
and then 20:1 hexanes:ethyl acetate) provided 6.4 g of 3 (75%).
1
H NMR (400 MHz, CDCl ): δ 6.33 (d, J ) 15.7 Hz, 1H), 5.93
3
(
dt, J ) 15.7 Hz, 6.0 Hz, 1H), 4.26 (br, 4H), 4.15 (d, J ) 6.0
Hz, 2H), 4.13 (br, 2H), 3.92 (br, 2H), 1.56 (m, 6H), 1.36 (m,
6
Exp er im en ta l Section
1
3
3
H), 1.03 (m, 6H), 0.91 (m, 9H). C NMR (100 MHz, CDCl ):
Gen er a l. All reactions were conducted under a nitrogen
δ 129.47, 125.76, 82.19, 75.39, 75.39, 72.04, 72.04, 69.19, 68.73,
atmosphere in oven-dried glassware using solvents purified
68.73, 66.72, 66.72, 63.97, 29.15, 27.38, 13.69, 10.21. IR (thin
1
-1
according to standard procedures. H NMR spectra were
film): 3329.7 (br), 3086.6 cm . R ) 0.2 (5:1 hexanes:ethyl
f
1
3
obtained at 400 MHz and C NMR spectra at 100 MHz in
acetate).
chloroform-d, with chemical shifts reported in ppm referenced
(E)-3-[1′-(Tr ib u t ylst a n n yl)fer r ocen yl]-1-(ter t-b u t yld i-
m eth ylsiloxy)-2-p r op en e (4). tert-Butyldimethylsilyl chlo-
ride (7.24 g, 48.1 mmol, 1.05 equiv) and imidazole (7.24 g, 106.3
mmol, 2.3 equiv) were added to a solution of 3 (24.3 g, 45.8
mmol, 1.0 equiv) in dichloromethane (90 mL) at room tem-
perature. The reaction mixture was allowed to stir for 0.5 h
and then diluted with pentane (100 mL) and water (150 mL).
The organic phase was washed with water (150 mL), 1 M
copper sulfate solution (2 × 150 mL), and brine (150 mL), dried
1
13
to residual chloroform (7.24 ppm for H and 77.0 ppm for C).
Representative NMR spectra are included in the supporting
information. Infrared spectra were recorded as thin films on
NaCl plates. Optical rotations were obtained at 589 nm.
Concentrations for optical rotations are reported in g/mL. FAB
mass spectra were obtained using a matrix of 3-nitrobenzyl
alcohol. Melting points are uncorrected. Elemental analyses
were performed by Supersun Technology Analytical Labora-
tory, Stony Brook, NY. The diastereomeric excesses of the
metalation reactions were determined by integration of the
downfield cyclopentadienyl ortho-proton resonances, which
over MgSO , filtered, and concentrated at reduced pressure
4
to give 27.8 g of 4 (94%) which was used without further
1
purification. H NMR (400 MHz, CDCl ): δ 6.31 (br d, J )
3
1
were base-line resolved in the H NMR spectra. Spectroscopic
15.6 Hz, 1H), 5.89 (dt, J ) 15.6 Hz, 5.4 Hz, 1H), 4.29 (br, 2H),
4.28 (br, 2H), 4.23 (dd, J ) 5.4 Hz, 1.4 Hz, 2H), 4.14 (br, 2H),
3.96 (br, 2H), 1.60 (m, 6H), 1.40 (m, 6H), 1.05 (m, 6H), 0.98 (s,
data are provided for the major diastereomer only.
1
,1′-Bis(tr ibu tylsta n n yl)fer r ocen e (1). n-Butyllithium
1.58 M in hexanes, 306 mL, 0.484 mol, 3.0 equiv) was added
to a solution of TMEDA (distilled over CaH , 73.0 mL, 0.484
1
3
(
9H), 0.96 (m, 9H), 0.14 (s, 6H). C NMR (100 MHz, CDCl ):
3
δ 127.39, 126.45, 82.84, 75.28, 75.28, 71.91, 71.91, 68.98, 68.48,
68.48, 66.60, 66.60, 64.15, 29.16, 27.38, 25.97, 18.38, 13.71,
2
mol, 3.0 equiv) in ether (150 mL) at room temperature, and
the resulting solution was allowed to stir for 5 min. This
solution was then added to a suspension of ferrocene (30.0 g,
-
1
10.19, -5.06. IR (thin film): 3088.1 cm
hexanes:ethyl acetate).
. Rf ) 0.9 (5:1
0
.161 mol, 1.0 equiv) in ether (150 mL) at room temperature,
(E)-1′-[3-(ter t-Bu tyld im eth ylsiloxy)-2-p r op en yl]fer r o-
cen e 1-Meth yl Ester (5). n-Butyllithium (1.42 M in hexanes,
20.3 mL, 28.8 mmol, 1.5 equiv) was added dropwise to a
solution of 4 (12.4 g, 19.2 mmol, 1.0 equiv) in tetrahydrofuran
(100 mL) cooled to -78 °C. The reaction mixture was allowed
to warm to room temperature and then recooled to -78 °C.
Methyl chloroformate (14.8 mL, 192 mmol, 10 equiv) was
added, and the reaction mixture was warmed to room tem-
perature and diluted with pentane (100 mL) and water (150
mL). The organic phase was washed with brine (150 mL),
and the reaction mixture was allowed to stir for 12 h. The
reaction mixture was then cooled to -78 °C, and tributyltin
chloride (91.9 mL, 0.339 mol, 2.1 equiv) was added via cannula.
The reaction mixture was allowed to warm to room temper-
ature, and the reaction was quenched with water (200 mL).
The organic phase was washed with 1 M HCl (2 × 200 mL),
water (200 mL), a saturated aqueous solution of sodium
bicarbonate (200 mL), and brine (200 mL),and was then dried
over MgSO
sure. Purification by flash chromatography on silica gel
hexanes) followed by Kugelrohr distillation (230 °C at 0.01
4
, filtered, and concentrated under reduced pres-
1
9
dried over MgSO
4, filtered, and concentrated under reduced
(
pressure. Purification by flash chromatography (hexanes, then
40:1 hexanes:ethyl acetate, and then 20:1 hexanes:ethyl
1
mmHg) provided 99.6 g of 1 (81%). H NMR (400 MHz,
CDCl
1
3
): δ 4.28 (br, 4H), 4.01 (br, 4H), 1.62 (m, 12H), 1.40 (m,
acetate) provided 5.8 g of 5 (73%).
1
H NMR (400 MHz,
1
3
2H), 1.07 (m, 12H), 0.96 (m, 18H).
C NMR (100 MHz,
CDCl ): δ 6.16 (d, J ) 15.7 Hz, 1H), 5.87 (dt, J ) 15.7 Hz, 5.2
3
CDCl
3
): δ 74.21, 70.46, 67.89, 29.24, 27.45, 13.73, 10.25. IR
Hz, 1H), 4.71 (br, 2H), 4.30 (br, 4H), 4.19 (br, 4H), 3.76 (s,
-
1
13
(thin film): 3087.5 cm . R
f
) 0.7 (hexanes).
3
C NMR (100 MHz, CDCl ):
3
H), 0.91 (s, 9H), 0.08 (s, 6H).
1
-[1′-(Tr ibu tylsta n n yl)fer r ocen yl]-2-p r op en -1-ol (2). n-
δ 171.38, 128.31, 125.02, 84.84, 72.20, 72.20, 72.09, 70.90,
Butyllithium (1.58 M in hexanes, 29 mL, 45.3 mmol, 1.1 equiv)
was added dropwise to a solution of 1 (30.0 g, 39.3 mmol, 1.0
equiv) in tetrahydrofuran (80 mL) cooled to -78 °C. The
reaction mixture was allowed to warm to -55° C and then
recooled to -78° C. Freshly distilled acrolein (3.0 mL, 44.9,
70.90, 70.06, 70.06, 67.98, 67.98, 63.91, 51.42, 25.96, 18.41,
-5.14. IR (thin film): 1717.0 cm-1. R ) 0.4 (10:1 hexanes:
f
ethyl acetate). Anal. Calcd for C H FeO Si: C, 60.87; H,
2
1
30
3
7.3. Found: C, 60.83; H, 7.29.
E)-1′-[3-(ter t-Bu tyld im eth ylsiloxy)-2-p r op en yl]fer r o-
cen e-1-ca r boxylic Acid (6). Methyl ester 5 (0.050 g, 0.121
mmol, 1.0 equiv) was dissolved in 10:1 tert-butyl alcohol:H
(
(19) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
2
O

Mechanism of Oxazoline-Directed Metalations
J . Org. Chem., Vol. 61, No. 5, 1996 1633
0.29 g of 9 (90%). 1H NMR (400 MHz, CDCl
): δ 6.20 (d, J )
(1 mL). Concentrated NaOH (50% by wt, 0.158 g, 1.98 mmol,
3
1
6.4 equiv) and NaBH (0.011 g, 0.30 mmol, 2.5 equiv) were
4
6.2 Hz, 1H), 5.86 (dt, J ) 15.7 Hz, 5.1 Hz, 1H), 4.67 (br, 1H),
4.65 (br, 1H), 4.32 (m, 3H), 4.26 (br, 2H), 4.19 (m, 5H), 4.05
(dd, J ) 9.9 Hz, 8.1 Hz, 1H), 2.00 (br, 1H), 1.30 (s, 3H), 1.15
added, and the reaction mixture was heated to reflux for 5 h.
The reaction mixture was then cooled to room temperature
and diluted with pentane (10 mL), and the reaction was
quenched with water (5 mL). The aqueous phase was isolated,
then neutralized with 3 M HCl (10 mL), and extracted with
dichloromethane (3 × 15 mL). The combined organic extracts
1
3
(s, 3H), 0.91 (s, 9H), 0.08 (s, 6H).
CDCl
C NMR (100 MHz,
3
): δ 167.14, 127.87, 125.46, 84.78, 75.61, 71.51, 71.45,
71.25, 70.79, 70.04, 70.04, 70.04, 69.81, 68.34, 67.99, 67.91,
64.02, 26.96, 25.98, 24.92, 18.44, -5.11. IR (thin film): 3409.9
-
1
24
were washed with brine (50 mL), dried over MgSO
4
, filtered,
(br), 1651.6 cm . [R]
D
) 1.9° (c 0.01345 g/mL, ethanol). R
f
and concentrated under reduced pressure. Purification by
flash chromatography (hexanes and then 5:1 hexanes:ethyl
) 0.4 (1:1 hexanes:ethyl acetate).
(E)-(S)-2-[1′-(3-Hyd r oxy-1-p r op en yl)fer r ocen yl]-4,5-d i-
h yd r o-4-(1-h yd r oxy-1-m eth yleth yl)oxa zole (10). Tetrabu-
tylammonium fluoride hydrate (0.46 g, 1.75 mmol, 3 equiv)
was added to a solution of 9 (0.282 g, 0.58 mmol, 1.0 equiv) in
THF (1.2 mL) at room temperature. The reaction mixture was
allowed to stir for 1 h and then was diluted with ether, and
the reaction was quenched with a saturated aqueous solution
of sodium bicarbonate. The organic phase was washed with
1
acetate) provided 0.042 g of 6 (87%). H NMR (400 MHz,
CDCl
3
): δ 8.71 (br, 1H), 6.16 (d, J ) 15.7 Hz, 1H), 5.90 (dt, J
)
15.7 Hz, 5.6 Hz, 1H), 4.78 (br, 2H), 4.37 (br, 4H), 4.24 (br,
H), 4.19 (d, J ) 5.6 Hz, 2H), 0.92 (s, 9H), 0.09 (s, 6H).
1
3
2
C
NMR (100 MHz, CDCl ): δ 178.26, 127.83, 125.88, 84.06,
3
7
6
2.68, 72.68, 71.40, 70.41, 70.41, 68.24, 68.24, 64.27, 64.27,
4.27, 25.99, 18.47, -5.16. IR (thin film): 2928.6 (br) cm-1
.
Rf ) 0.6 (1:1 hexanes:ethyl acetate). Anal. Calcd for
C
4
brine, dried over MgSO , filtered, concentrated under reduced
pressure, and purified by flash chromatography (hexanes and
20
H
28FeO
3
Si: C, 60.0; H, 7.05. Found: C, 60.54; H, 7.03.
(
E)-1′-[3-(ter t-Bu tyld im eth ylsiloxy)-2-p r op en yl]fer r o-
then 5:1 ethyl acetate:triethylamine) to provide 0.193 g of 10
1
cen e-1-P en ta flu or op h en yl Ester (7). To a solution of 6
0.95 g, 2.37 mmol, 1.0 equiv) in THF (5 mL) at room
(90%). H NMR (400 MHz, CDCl
1H), 5.94 (dt, J ) 15.7 Hz, 5.8 Hz, 1H), 4.64 (br, 1H), 4.63 (br,
1H), 4.27 (m, 5H), 4.19 (m, 3H), 4.06 (m, 3H), 3.58 (br, 1H),
3
): δ 6.22 (d, J ) 15.7 Hz,
(
temperature was added a solution of pentafluorophenol (0.655
g, 3.56 mmol, 1.5 equiv) in THF (5 mL) followed by a solution
of dicyclohexylcarbodiimide (0.539 g, 2.61 mmol, 1.1 equiv) in
THF (5 mL). The reaction mixture was allowed to stir for 0.5
h, and the solution was then concentrated. The residue was
dissolved in hexanes (5 mL), and the dicyclohexylurea that
precipitated was filtered. The filtrate was washed with 1 M
NaOH (5 mL), water (5 mL), and brine (5 mL), dried over
1
3
2.59 (br, 1H), 1.29 (s, 3H), 1.15 (s, 3H). C NMR (100 MHz,
CDCl ): δ 167.43, 127.82, 126.92, 84.29, 75.42, 71.25, 71.16,
71.16, 70.81, 70.33, 70.25, 69.96, 69.87, 68.45, 68.20, 68.16,
3
-
1
63.33, 26.93, 25.03. IR (thin film): 3353.7 (br), 1643.9 cm
[R]24
) -3.6° (c 0.0111 g/mL, ethanol). R ) 0.1 (1:1 hexanes:
ethyl acetate).
.
D
f
(S)-2-[1′-(3-Hydr oxy-1-pr open yl)fer r ocen yl]-4,5-dih ydr o-
4-(1-h yd r oxy-1-m eth yleth yl)oxa zole (11). A mixture of 10
(0.082 g, 0.217 mmol, 1.0 equiv) and Pd / C (10% Pd, 0.5 g) in
ethyl acetate (2 mL) was allowed to stir for 1.5 h under an
MgSO
.32 g of 7 (98%) which was used without further purification.
4
, and concentrated under reduced pressure to provide
1
1
H NMR (400 MHz, CDCl ): δ 6.25 (d, J ) 15.7 Hz, 1H), 5.94
3
(
(
(
1
7
dt, J ) 15.7 Hz, 5.1 Hz, 1H), 4.85 (br, 2H), 4.50 (br, 2H), 4.42
2
atmosphere of H (balloon pressure) and was then filtered
br, 2H), 4.34 (br, 2H), 4.17 (dd, J ) 5.1 Hz, 1.7 Hz, 2H), 0.91
through Celite and concentrated. The crude product was
purified by flash chromatography (hexanes and then 1:1 ethyl
1
3
s, 9H), 0.08 (s, 6H). C NMR (100 MHz, CDCl ): δ 167.73,
3
1
43 (m), 140 (m), 139 (m), 137 (m), 128.99, 124.90, 85.62, 74.07,
1.94, 70.98, 68.68, 67.42, 63.79, 25.92, 18.40, -5.18. IR (thin
acetate:triethylamine) to provide 0.075 g of 11 (93%). H NMR
(400 MHz, CDCl ): δ 4.65 (br, 2H), 4.32 (dd, J ) 10.1 Hz, 8.5
3
-
1
film): 1756.2 cm . R
E)-(S)-N-[1-(Hyd r oxym eth yl)-2-h yd r oxy-2-m eth ylp r o-
pyl]-1′-[3-(ter t-bu tyldim eth ylsiloxy)-2-pr open yl]fer r ocen e-
-ca r boxa m id e (8). Triethylamine (443 µL, 3.2 mmol, 4.0
f
) 0.7 (5:1 hexanes:ethyl acetate).
Hz, 1H), 4.28 (br, 2H), 4.21 (t, J ) 8.5 Hz, 1H), 4.06 (m, 5H),
3.63 (t, J ) 6.2 Hz, 2H), 2.66 (br, 1H), 2.36 (dd, J ) 8.0 Hz,
(
1
3
7.5 Hz, 2H), 1.74 (m, 2H), 1.31 (s, 3H), 1.15 (s, 3H). C NMR
1
(100 MHz, CDCl
70.26, 69.71, 69.71, 69.57, 68.77, 68.72, 68.38, 62.15, 33.68,
3
): δ 167.80, 90.03, 75.55, 71.19, 70.87, 70.82,
equiv) was added via syringe to a solution of 7 (0.450 g, 0.794
mmol, 1.0 equiv) and (S)-2-amino-3-methyl-1,3-butanediol10
-1
27.02, 25.07, 24.80. IR (thin film): 3355.7 (br), 1646.0 cm
.
[R]24
ethyl acetate). Anal. Calcd for C19
) 53.1° (c 0.01185 g/mL, ethanol). R
) 0.1 (1:1 hexanes:
(
0.347 g, 2.9 mmol, 3.7 equiv) in dimethylformamide (4 mL)
at room temperature. The reaction mixture was warmed to
5° C over a period of 50 min and then cooled to room
D
f
H
3
25FeNO : C, 61.47; H,
8
6.79; N, 3.77. Found: C, 61.25; H, 7.03; N, 3.90.
temperature and concentrated at reduced pressure. Purifica-
tion by flash chromatography (hexanes and then 2:1 hexanes:
ethyl acetate) provided 0.370 g of 8 (93%). 1H NMR (400 MHz,
(S)-2-[1′-[4-(p -Tolylsu lfon yl)-4-oxa b u t yl]fer r ocen yl]-
4,5-dih ydr o-4-(1-h ydr oxy-1-m eth yleth yl)oxazole (12). Com-
pound 11 (0.075 g, 0.202 mmol, 1.0 equiv), p-toluenesulfonyl
chloride (0.042 g, 0.222 mmol, 1.1 equiv), and a catalytic
amount of 4-(dimethylamino)pyridine were dissolved in dichlo-
romethane (2.0 mL) at room temperature. Triethylamine (84.5
µL, 0.606 mmol, 3 equiv) was added, and the reaction mixture
was allowed to stir 5 h. At this time the reaction mixture was
diluted with pentane (5 mL), ethyl acetate (5 mL), and water
(10 mL). The organic phase was washed with brine (10 mL),
CDCl
3
): δ 6.62 (d, J ) 7.7 Hz, 1H), 6.25 (d, J ) 15.8 Hz, 1H),
.87 (dt, J ) 15.8 Hz, 5.3 Hz, 1H), 4.66 (br, 1H), 4.54 (br, 1H),
.32 (br, 1H), 4.30 (br, 2H), 4.27 (br, 2H), 4.21 (br, 1H), 4.19
5
4
(
3
6
8
d, J ) 5.3 Hz, 2H), 4.03 (m, 1H), 3.84 (m, 2H), 3.65 (br, 1H),
.54 (br, 1H), 1.36 (s, 3H), 1.24 (s, 3H), 0.91 (s, 9H), 0.10 (s,
1
3
3
H). C NMR (100 MHz, CDCl ): δ 170.61, 127.85, 126.06,
4.58, 73.13, 73.13, 71.56, 71.39, 70.33, 70.01, 69.42, 69.28,
8.74, 67.86, 64.19, 63.32, 56.86, 27.72, 27.31, 25.98, 18.53,
6
dried over MgSO
4
, filtered, and concentrated at reduced
pressure. The crude product was purified by flash chroma-
-
1
-
5.12, -5.15. IR (thin film): 3382.0, 1634.0, 1538.2 cm
.
2
4
[R]
D
) 2.0° (c 0.0069 g/mL, ethanol). R
f
) 0.1 (5:1 hexanes:
tography (hexanes and then ethyl acetate) to provide 0.087 g
1
ethyl acetate).
of 12 (82%). H NMR (400 MHz, CDCl
3
): δ 7.76 (d, J ) 8.2
(
E)-(S)-2-[1′-[3-(ter t-Bu tyld im eth ylsiloxy)-1-p r op en yl]-
Hz, 2H), 7.32 (d, J ) 8.2 Hz, 2H), 4.63 (br, 1H), 4.62 (br, 1H),
4.31 (A of ABX, J ) 10.0 Hz, 8.5 Hz, 1H), 4.24 (br, 2H), 4.20
(X of ABX, J ) 8.5 Hz, 1H), 4.06 (B of ABX, J ) 10.0 Hz, 8.5
Hz, 1H), 4.03 (br, 2H), 3.98 (m, 4H), 2.42 (s, 3H), 2.31 (m, 2H),
fer r ocen yl]-4,5-d ih yd r o-4-(1-h yd r oxy-1-m eth yleth yl)ox-
a zole (9). p-Toluenesulfonyl chloride (0.165 g, 0.87 mmol, 1.3
equiv), a catalytic amount of 4-(dimethylamino)pyridine (0.8
mg, 6.7 µmol, 1%), and 8 (0.334 g, 0.67 mmol, 1.0 equiv) were
dissolved in dichloromethane (3.3 mL) at room temperature.
Triethylamine (0.28 mL, 2.0 mmol, 3 equiv) was then added,
and the reaction mixture was allowed to stir for 12 h. The
reaction mixture was diluted with ether (10 mL), and the
reaction was quenched with a saturated aqueous solution of
sodium bicarbonate (10 mL). The organic phase was washed
1
3
1.77 (m, 2H), 1.30 (s, 3H), 1.15 (s, 3H). C NMR (100 MHz,
CDCl ): δ 167.23, 144.72, 132.99, 129.81, 127.84, 88.42, 75.54,
3
71.20, 70.85, 70.81, 70.47, 69.86, 69.61, 69.56, 69.53, 69.53,
68.98, 68.96, 68.32, 30.20, 26.88, 25.04, 24.50, 21.59. IR (thin
-
1
24
film): 3380.6, 1651.4, 1358.8, 1175.9 cm . [R]
0.00525 g/mL, ethanol). R ) 0.4 (ethyl acetate). Anal. Calcd
for C26 31FeNO S: C, 59.43; H, 5.95; N, 2.67. Found: C,
D
) 25.0° (c
f
H
5
with brine (10 mL), dried over MgSO
4
, filtered, and concen-
59.71; H, 6.01; N, 2.67.
trated at reduced pressure. Purification by flash chromatog-
raphy (hexanes and then 2:1 hexanes:ethyl acetate) provided
(S)-1-[2-(4,5-Dih yd r o-4,1′-(1,1-d im et h yl-2-oxa -1,5-p en -
ta n ed iyl)oxa zolyl)][8]fer r ocen op h a n e (13). Dry sodium

1
634 J . Org. Chem., Vol. 61, No. 5, 1996
Sammakia and Latham
hydride powder (6.8 mg, 0.284 mmol, 1.5 equiv), 18-cr-6 (75.1
mg, 0.284 mmol, 1.5 equiv), and 12 (99.5 mg, 0.189 mmol, 1.0
equiv) were dissolved in DMSO (1.9 mL), and the reaction
mixture was allowed to stir at room temperature for 24 h. The
reaction mixture was then diluted with ethyl acetate (10 mL)
and washed with brine (10 mL). The aqueous phase was
washed with ethyl acetate (2 × 10 mL), and then the combined
organic phases were washed with brine (10 mL), dried over
1654.6 cm-1. [R]24
0.9 (ethyl acetate).
S)-N-(Ca r boben zyloxy)-L-ser in e Meth yl Ester (16). A
saturated solution of sodium bicarbonate adjusted to pH 9 by
the addition of solid sodium carbonate (65 mL) was added to
a solution of L-serine methyl ester hydrochloride (8.0 g, 51.4
mmol, 1.0 equiv) in THF (130 mL). Benzyl chloroformate (7.7
mL, 54.0 mmol, 1.05 equiv) was added, and the reaction
mixture was allowed to stir for 22 h. The aqueous phase was
then extracted with dichloromethane (2 × 200 mL), and the
combined organic phases were washed with brine, dried over
D
) 257.0° (c 0.00875 g/mL, ethanol). R
f
)
(
MgSO
4
, filtered, and concentrated under reduced pressure.
Purification by flash chromatography (hexanes and then 15:1
1
hexanes:ethyl acetate) provided 20 mg of 13 (30%). H NMR
(
400 MHz, CDCl
3
): δ 4.79 (br, 1H), 4.60 (X of ABX, J ) 7.8
MgSO , filtered, and concentrated under reduced pressure. The
4
Hz, 1H), 4.60 (br, 1H), 4.30 (br, 1H), 4.28 (br, 1H), 4.26 (A of
crude product was purified by Kugelrohr distillation (170 °C
ABX, J ) 10.3 Hz, 7.8 Hz, 1H), 4.20 (br, 1H), 4.14 (br, 1H),
at 0.01 mmHg) to provide 10.7 g of 16 (82%).
1
H NMR (400
4
.03 (br, 1H), 3.99 (br, 2H), 3.97 (B of ABX, J ) 10.3 Hz, 7.8
MHz, CDCl ): δ 7.32 (m, 5H), 5.69 (d, J ) 6.3 Hz, 1H), 5.11
3
Hz, 1H), 3.85 (m, 2H), 3.54 (m, 2H), 2.56 (m, 2H), 2.13 (m,
H), 1.82 (m, 2H), 1.63 (m, 2H), 1.52 (s, 3H), 1.09 (s, 3H). 13
NMR (100 MHz, CDCl ): δ 165.40, 91.61, 76.38, 74.31, 72.40,
9.92, 69.46, 69.17, 68.82, 68.61, 67.79, 67.76, 66.82, 66.71,
(s, 2H), 4.44 (m, X of ABX, 1H), 3.99 (A of ABX, J ) 11.1 Hz,
3.2 Hz, 1H), 3.91 (B of ABX, J ) 11.1 Hz, 2.8 Hz, 1H), 3.77 (s,
2
C
1
3
3
3H), 2.18 (s, 1H).
C NMR (100 MHz, CDCl ): δ 170.98,
3
6
6
156.20, 135.99, 128.52, 128.23, 128.10, 67.19, 63.21, 55.99,
52.73. IR (thin film): 3398.3 (br), 1718.4, 1522.3 cm . [R]
) -13.2° (c 0.00605 g/mL, ethanol). R ) 0.7 (ethyl acetate).
-
1
-1
24
3.61, 28.64, 28.37, 22.54, 22.19. IR (thin film): 1656.1 cm
.
D
2
4
[
R]
acetate). Anal. Calcd for C19
.97. Found: C, 64.41; H, 6.49; N, 4.05.
S,S)-1-[2-(4,5-Dih yd r o-4,1′-(1,1-d im eth yl-2-oxa -1,5-p en -
D
) 526.9° (c 0.0089 g/mL, ethanol).
R
f
) 0.7 (ethyl
23FeNO : C, 64.6; H, 6.56; N,
f
H
2
(
S)-N-(Ca r boben zyloxy)-2-a m in o-3-m eth yl-1,3-bu ta n e-
3
d iol (17). A solution of 16 (8.0 g, 31.6 mmol, 1.0 equiv) in
THF (60 mL) was cooled to -78 °C, and methyllithium (1.4 M
in ether, 113.0 mL, 157.9 mmol, 5.0 equiv) was added via
cannula. The reaction mixture was allowed to warm to room
temperature and was then diluted with ether (60 mL), and
the reaction was quenched with water (100 mL). The organic
phase was washed with brine (100 mL), dried over MgSO4,
filtered, concentrated under reduced pressure, and purified by
Kugelrohr distillation (155-175 °C at 0.01 mmHg) to provide
(
2
0
tan ediyl)oxazolyl)]-2-m eth yl[8]fer r ocen oph an e (14). sec-
Butyllithium (40.0 µL, 46.4 µmol, 2.0 equiv) was added to a
solution of 13 (8.2 mg, 23.2 µmol, 1.0 equiv) in tetrahydrofuran
(0.5 mL) cooled to -78 °C. The reaction was allowed to proceed
for 2 h at -78 °C, at which time the reaction mixture was
warmed to 0 °C and allowed to stir for 5 min, and then the
reaction was quenched with MeI (5 µL, 80.3 µmol, 3.5 equiv).
The resulting reaction mixture was allowed to warm to room
temperature and then diluted with ether (5 mL), and the
reaction was quenched with a saturated aqueous solution of
sodium bicarbonate (10 mL). The organic phase was washed
3.5 g of 17 (44%). 1H NMR (400 MHz, CDCl ): δ 7.30 (m, 5H),
3
5.71 (d, J ) 8.6 hz, 1H), 5.09 (s, 2H), 4.00 (A of ABX, J ) 11.4
Hz, 3.1 Hz, 1H), 3.79 (B of ABX, J ) 11.4 Hz, 2.9 Hz, 1H),
3.50 (X of ABX, J ) 8.6 Hz, 3.1 Hz, 2.9 Hz, 1H), 2.74 (br, 2H),
1
3
with brine (10 mL), dried over MgSO
4
, filtered, and concen-
1.32 (s, 3H), 1.21 (s, 3H).
C NMR (100 MHz, CDCl ): δ
3
trated under reduced pressure to give an orange solid which
was purified by flash chromatography (hexanes and then 15:1
hexanes:ethyl acetate) to provide 6.0 mg of 14 (70%). Recrys-
tallization by the slow evaporation of a 10:1 hexanes:ethyl
156.76, 136.32, 128.52, 128.14, 128.02, 73.62, 66.89, 63.30,
-
1
58.12, 27.50, 27.42. IR (thin film): 3397.9 (br), 1701.5 cm
[R]24
) 24.9° (c 0.0191 g/mL, ethanol). R ) 0.5 (ethyl acetate).
S)-2-Am in o-3-m eth yl-1,3-bu ta n ed iol (18). A mixture of
7 (3.35 g, 13.2 mmol, 1.0 equiv) and Pd/C (10%, 1.5 g) in ethyl
acetate (12 mL) was allowed to stir for 12 h under 1.2 atm of
and then filtered through Celite. The solids were washed
.
D
f
(
acetate solution provided crystals suitable for X-ray diffraction.
1
1
Mp ) 116-120 °C. H NMR (400 MHz, CDCl
3
): δ 4.55 (X of
ABX, J ) 7.6 Hz, 1H), 4.55 (br, 1H), 4.23 (br, 1H), 4.17 (A of
ABX, J ) 10.4 Hz, 7.6 Hz, 1H), 4.12 (br, 1H), 4.11 (br, 1H),
H
2
with methanol, and the filtrate was concentrated. The crude
4
.08 (br, 1H), 4.02 (B of ABX, J ) 10.4 Hz, 7.6 Hz, 1H), 3.95
product was purified by Kugelrohr distillation (100-120 °C
(br, 1H), 3.86 (m, 1H), 3.73 (br, 1H), 3.54 (m, 1H), 2.61 (m,
1
at 0.01 mmHg) to provide 0.275 g of 18 (17%). H NMR (400
1
1
1
6
2
H), 2.33 (s, 3H), 2.15 (m, 1H), 1.79 (m, 1H), 1.65 (m, 1H),
MHz, CDCl
3
7
3
): δ 3.74 (A of ABX, J ) 10.7 Hz, 3.7 Hz, 1H),
.55 (B of ABX, J ) 10.7 Hz, 7.6 Hz, 1H), 2.68 (X of ABX, J )
.6 Hz, 3.7 Hz, 1H), 2.12 (br, 4H), 1.21 (s, 3H), 1.18 (s, 3H).
1
3
.54 (s, 3H), 1.10 (s, 3H).
3
C NMR (100 MHz, CDCl ): δ
65.53, 92.07, 85.20, 76.68, 74.34, 71.95, 70.69, 70.34, 69.33,
8.01, 67.15, 66.93, 66.81, 66.45, 63.40, 28.77, 28.36, 22.45,
13
C NMR (100 MHz, CDCl
5.64. IR (thin film): 3354.2 (br) cm . [R]
g/mL, ethanol). R ) 0.1 (ethyl acetate).
-F er r ocen yl-4,5-d ih yd r o-4-isop r op yloxa zole (19). p-
3
): δ 71.77, 63.30, 59.99, 27.12,
1.98, 14.76. R
f
) 0.9 (ethyl acetate). FAB calcd for C20
(M ) 367, found 367.
S,R)-1-[2-(4,5-Dih ydr o-4,1′-(1,1-dim eth yl-2-oxa -1,5-p en -
H
25
-
-1
24
2
D
) -14° (c 0.0019
+
FeNO
2
f
(
2
t a n e d i y l ) o x a z o l y l ) ] -2 -( t r i m e t h y l s i l y l ) [ 8 ] ) f e r r o -
cen op h a n e (15). This material was prepared from 13 (0.0191
g, 0.054 mmol) following the same procedure as for 14. The
red oil obtained was purified by flash chromatography (hex-
Toluenesulfonyl chloride (0.82 g, 4.29 mmol, 1.3 equiv), a
catalytic amount of 4-(dimethylamino)pyridine (0.004 g, 0.03
mmol, 1%), and (2S)-N-(1-hydroxy-3-methylbutyl)ferrocen-
4b
amide (1.0 g, 3.3 mmol, 1.0 equiv) were dissolved in dichlo-
anes and then 20:1 hexanes:ethyl acetate) to provide 0.0188 g
romethane (16 mL) at room temperature. Triethylamine (1.38
mL, 9.9 mmol, 3 equiv) was added, and the reaction mixture
was allowed to stir overnight. The reaction mixture was
diluted with ether (15 mL), and the reaction was quenched
with a saturated aqueous solution of sodium bicarbonate (15
mL). The organic phase was washed with brine (15 mL), dried
1
of 15 (82%). H NMR (400 MHz, CDCl
(
4
3
): δ 4.81 (br, 1H), 4.48
t, J ) 7.9 Hz, 1H), 4.38 (br, 1H), 4.26 (br, 1H), 4.18 (br, 1H),
.15 (m, 2H), 3.94 (m, 4H), 3.54 (m, 1H), 2.55 (m, 1H), 2.15
(
m, 1H), 1.67 (m, 2H), 1.55 (s, 3H), 1.08 (s, 3H), 0.33 (s, 9H).
1
3
C NMR (100 MHz, CDCl ): δ 164.95, 91.78, 77.51, 77.39,
3
7
6
6.07, 74.04, 73.64, 73.25, 70.94, 68.96, 68.25, 66.86, 66.71,
6.48, 63.63, 28.98, 28.17, 22.88, 22.12, 0.59. IR (thin film):
4
over MgSO , filtered, and concentrated at reduced pressure,
producing a red solid which was purified by flash chromatog-
raphy (hexanes and then 10:1 hexanes:ethyl acetate) to provide
1
0
1
J
.75 g of 19 (80%). H NMR (400 MHz, CDCl
3
): δ 4.73 (br,
(
20) In the stereochemical designation (R, S), the first descriptor
H), 4.70 (br, 1H), 4.29 (br 2H), 4.25 (A of ABX, J AX ) 10 Hz,
(
in this example, “R”) refers to the stereochemistry of the oxazoline
substituent while the second descriptor (in this example, “S”) refers
to the stereochemistry of the disubstituted ferrocene. See: Marquard-
ing, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J . Am. Chem.
Soc. 1970, 92, 5389. The author has deposited atomic coordinates for
this structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
AB ) 8 Hz, 1H), 4.16 (s, 5H), 4.03 (B of ABX, J BX ) 8 Hz, 1H),
3.95 (X of ABX, 1H), 1.82 (m, 1H), 0.97 (d, J ) 7 Hz, 3H), 0.90
13
(
7
1
d, J ) 7 Hz, 3H). C NMR (100 MHz, CDCl
3
): δ 165.56,
2.25, 70.57, 70.10, 70.06, 69.51, 69.25, 68.94, 68.90, 32.26,
-
1
8.92, 17.75. IR (thin film): 1659.1 cm
19FeNO: C, 64.67; H, 6.44; N,
4.71. Found: C, 64.72; H, 6.27; N, 4.53.
f
. R ) 0.7 (ethyl
acetate). Anal. Calcd for C16
H

Mechanism of Oxazoline-Directed Metalations
S,S)-2-(2-Tr im eth ylsilyl)fer r ocen yl)-4,5-d ih yd r o-4-iso-
J . Org. Chem., Vol. 61, No. 5, 1996 1635
Anal. Calcd for C17 21FeNO: C, 65.61; H, 6.8; N, 4.5.
(
H
p r op yloxa zole (19A). Gen er a l P r oced u r e. The alkyl-
lithium reagent (1.2 equiv) was added to a solution of 19 (0.1-
Found: C, 65.49; H, 6.81; N, 4.38.
(S,S)-2-(2-(Tr im et h ylsilyl)fer r ocen yl)-4,5-d ih yd r o-4-
ter t-bu tyloxa zole (20A). Gen er a l P r oced u r e. The alky-
llithium reagent (1.2 equiv) was added to a solution of 20 (0.1-
0.25 g, 0.34-0.84 mmol, 1.0 equiv) in tetrahydrofuran (2-5
mL) cooled to -78 °C. The reaction was allowed to proceed
for 2 h at -78 °C, at which time the reaction mixture was
warmed to 0 °C and allowed to stir for 5 min, and then the
0
.2 g, 0.35-0.7 mmol, 1.0 equiv) in tetrahydrofuran (2-5 mL)
cooled to -78 °C. The reaction was allowed to proceed for 2 h
at -78 °C, at which time the reaction mixture was warmed to
0
°C and allowed to stir for 5 min, and the reaction was then
quenched with TMSCl (distilled over CaH
2
under an atmo-
sphere of N , 1.3 equiv). The resulting reaction mixture was
2
allowed to warm to room temperature and was then diluted
with ether (5 mL), and the reaction was quenched with a
saturated aqueous solution of sodium bicarbonate (10 mL). The
organic phase was washed with brine (10 mL), dried over
reaction was quenched with TMSCl (distilled over CaH
2
under
an atmosphere of N , 1.3 equiv). The resulting reaction
2
mixture was allowed to warm to room temperature and was
then diluted with ether (5 mL), and the reaction was quenched
with a saturated aqueous solution of sodium bicarbonate (10
mL). The organic phase was washed with brine (10 mL), dried
over MgSO , filtered, and concentrated under reduced pressure
4
to give a viscous red oil which was purified by flash chroma-
4
MgSO , filtered, and concentrated under reduced pressure to
give a viscous red oil which was purified by flash chromatog-
raphy (hexanes and then 15:1 hexanes:ethyl acetate) to provide
1
a 3:1-16:1 mixture of diastereomers (85-95%). H NMR (400
MHz, CDCl
3
): δ 4.88 (br, 1H), 4.41 (br, 1H), 4.25 (br, 1H), 4.25
tography (hexanes and then 15:1 hexanes:ethyl acetate) to
1
(
A of ABX, J AX ) 9 Hz, J AB ) 8 Hz, 1H), 4.16 (s, 5H), 3.98 (B
provide a 6:1-36:1 mixture of diastereomers (80-90%).
H
of ABX, J BX ) 8 Hz, 1H), 3.92 (X of ABX, 1H), 1.73-1.85 (m,
NMR (400 MHz, CDCl
3
): δ 4.87 (br, 1H), 4.41 (br, 1H), 4.25
1
9
7
0
H), 1.01 (d, J ) 7 Hz, 3H), 0.91 (d, J ) 7 Hz, 3H), 0.31 (s,
(br, 1H), 4.18 (A of ABX, J AX ) 8 Hz, J AB ) 10 Hz, 1H), 4.16
(s, 5H), 4.07 (X of ABX, 1H), 3.86 (B of ABX, J BX ) 8 Hz, 1H),
1
3
H).
3
C NMR (100 MHz, CDCl ): δ 165.63, 76.90, 75.35,
1
3
3.12, 72.89, 72.83, 71.46, 69.39, 69.27, 32.52, 19.08, 18.02,
0.94 (s, 9H), 0.31 (s, 9H).
3
C NMR (100 MHz, CDCl ): δ
-1
.47. IR (thin film): 1651.5 cm . R
27FeNOSi: C, 61.78; H, 7.37;
N, 3.79. Found: C, 62.04; H, 7.37; N, 3.72.
S)-2-F er r ocen yl-4,5-d ih yd r o-4-ter t-bu tyloxa zole (20).
f
) 0.5 (5:1 hexanes:ethyl
165.54, 77.15, 76.68, 75.23, 73.21, 73.04, 71.40, 69.38, 67.82,
33.59, 26.00, 0.53. IR (thin film): 1658.1 cm . R
hexanes:ethyl acetate). Anal. Calcd for C20 29FeNOSi: C,
-
1
acetate). Anal. Calcd for C19
H
f
) 0.6 (5:1
H
(
62.66; H, 7.62; N, 3.65. Found: C, 62.91; H, 7.64; N, 3.62.
p-Toluenesulfonyl chloride (0.55 g, 2.87 mmol, 1.3 equiv), a
catalytic amount of 4-(dimethylamino)pyridine (0.003 g, 0.02
mmol, 1%), and (2S)-N-(1-hydroxy-3,3-dimethylbutyl)ferro-
cenamide (0.70 g, 2.21 mmol, 1.0 equiv) were dissolved in
dichloromethane (11 mL) at room temperature. Triethylamine
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM48498), the Camille and Henry
Dreyfus Foundation, and the Petroleum Research Fund,
administered by the American Chemical Society, for
financial support of the research. T.S. is a recipient of
an American Cancer Society J unior Faculty Develop-
ment Award. We are grateful to Martin Berliner for
assistance in the NMR determination of the structure
of the alkylated oxazoline and to NSC Technologies, a
Unit of Monsanto, for a gift of tert-leucine.
4
b
(0.92 mL, 6.62 mmol, 3 equiv) was added, and the reaction
mixture was allowed to stir overnight. The reaction mixture
was diluted with ether (10 mL), and the reaction was quenched
with a saturated aqueous solution of sodium bicarbonate (15
mL). The organic phase was washed with brine (15 mL), dried
over MgSO , filtered, and concentrated at reduced pressure,
4
producing a red solid which was purified by flash chromatog-
raphy (hexanes and then 10:1 hexanes:ethyl acetate) to provide
1
0
1
5
.63 g of 20 (96%). H NMR (400 MHz, CDCl
3
): δ 4.74 (br,
Su p p or tin g In for m a tion Ava ila ble: Selected 1H and 13C
H), 4.67 (br, 1H), 4.27 (br, 2H), 4.19 (X of ABX, 1H), 4.15 (s,
NMR spectra (9 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
H), 4.10 (A of ABX, J AX ) 9 Hz, J AB ) 8 Hz, 1H), 3.85 (B of
1
3
ABX, J BX ) 10 Hz, 1H), 0.92 (s, 9H). C NMR (100 MHz,
CDCl
8.81, 68.13, 33.46, 25.85. IR (thin film): 1663.8 cm . [R]
-150° (c 0.021 g/mL, CH Cl ). ) 0.8 (ethyl acetate).
3
): δ 165.30, 75.96, 70.71, 69.95, 69.89, 69.35, 68.86,
-
1 24
6
)
D
2
2
R
f
J O951556L