Tandem Sakurai-aldol addition reactions as a route to structurally complex carbocycles

Article abstract of DOI:10.1021/jo050225y

Tandem intramolecular Sakurai-aldol reactions provide a concise and highly diastereoselective route to substituted cyclohexenone derivatives. The cyclization substrates are readily obtained using olefin isomerization-Claisen rearrangement (ICR) reactions

Full text of DOI:10.1021/jo050225y

Tandem Sakurai-Aldol Addition Reactions as a Route to
Structurally Complex Carbocycles
Benjamin D. Stevens and Scott G. Nelson*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
sgnelson@pitt.edu
Received February 4, 2005
Tandem intramolecular Sakurai-aldol reactions provide a concise and highly diastereoselective route
to substituted cyclohexenone derivatives. The cyclization substrates are readily obtained using olefin
isomerization-Claisen rearrangement (ICR) reactions to prepare the key chiral allyl silane
precursors. The Claisen reaction products are elaborated to the chiral Sakurai-aldol substrates by
an efficient two-step sequence involving vinyl organometallic-aldehyde addition and oxidation of
the resulting alcohol. The reaction of the resulting enones with TiCl4 elicits a highly stereoselective
allyl silane conjugate addition to produce a trichlorotitanium enolate as the reaction intermediate;
intermolecular trapping of the enolate with an aldehyde provides pentasubstituted cyclohexanone
derivatives in which the annulation reaction establishes four stereocenters and two new C-C bonds.
A fully intramolecular variant of the Sakurai-aldol reaction that creates four stereocenters, two
new C-C bonds, and establishes two new carbocyclic rings is also described.
Introduction
The potential for rapidly generating molecular com-
plexity in the form of C-C bond networks, cyclic struc-
tures, or complex stereochemical relationships routinely
characterizes the most salient organic synthesis meth-
odologies.1 Indeed, the enduring utility of Diels-Alder
cycloadditions can be traced to their ability to rapidly and
selectively generate structural complexity in the form of
two new C-C σ-bonds and a new carbocyclic ring
decorated with up to four contiguous stereocenters.
Efforts to mimic similar efficiency in generating struc-
tural complexity have resulted in synthesis strategies
that merge multiple transformations into a single opera-
tion becoming increasingly important in both target-
directed and diversity-oriented synthesis activities.2 We
were attracted to the chiral allylic silanes 1 as templates
for tandem reaction development (Figure 1) with the goal
FIGURE 1. Allyl silane templates for stereochemically rich
carbocycle construction.
of developing new methodologies providing similar op-
portunities for multiple stereocontrolled C-C bond con-
(1) For a review, see: Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551-564.
10.1021/jo050225y CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/27/2005
J. Org. Chem. 2005, 70, 4375-4379
4375

Stevens and Nelson
structions, carbocyclic ring formation, or establishing
multiple stereogenic centers. The elaboration of these
aldehydes to the corresponding enone 2 would present
intramolecular allyl silane conjugate addition as a con-
duit to structurally complex and stereochemically rich
carbocyclic products. Herein, we describe the facile access
to the stereodefined allyl silane templates using olefin
isomerization-Claisen rearrangement (ICR) reactions
and the utility of these intermediates as platforms for
the stereocontrolled synthesis of tri-, tetra-, and penta-
substituted carbocycles.3
Our interest in the allyl silane-based strategy for
complex carbocycle construction originated from the
ready availability of the requisite chiral allyl silanes from
the catalyzed olefin ICR methodology developed in our
laboratories. The ICR methodology makes easily pre-
pared di(allyl) ether 3 the direct progenitor of aliphatic
Claisen rearrangements producing 2,3-disubstituted 4-pen-
tenal derivative 1 with high syn diastereoselection.
Moreover, the aliphatic Claisen rearrangements accessed
through the ICR sequence produce aldehyde functional-
ities that can be readily transformed to the targeted
enone annulation precursors.
FIGURE 2. Sakurai annulation process.
SCHEME 1
allylation proceeded by Pd(0)-catalyzed O-allylation of the
corresponding zinc alkoxide to produce the di(allyl) ether
ICR substrates (()-5a-c (52-93%).7,8 The di(allyl) ethers
(()-5a-c were subjected to the standard ICR reaction
After elaborating the ICR-derived allyl silanes to the
enone annulation precursor 2, we anticipated that the
ensuing allyl silane conjugate addition would proceed
through a synclinal boatlike transition state orienting the
C2/C3 substituents in the pseudoequatorial positions
(Figure 2).4,5 As a result, the C2 and C3 stereocenters
established in the preceding Claisen rearrangement
would be effectively translated to the incipient stereo-
centers arrayed about the trans,trans,cis-tetrasubstituted
cyclohexanone product 3.6 Further functionalization of
the putative carbocycles could then be accomplished by
derivatization of the cyclohexanone-derived enolate or
nucleophilic addition to the ketone functionality.
+
conditions (1 mol % Ir(PCy3)3 and then 3 mol % PPh3,
∆) which produced the desired syn-2,3-disubstituted
pentenals 7a-c (98-100% unpurified).9,10 In each case,
the crude Claisen-derived aldehydes were sufficiently
pure to use directly in subsequent transformations after
filtration to remove the isomerization catalyst.
Homologating the ICR-derived allyl silanes to the
enone annulation precursors exploited the electrophilicity
of the aldehyde function emerging from the aliphatic
Claisen rearrangement (Scheme 2). Enones 8a and 8b
were obtained by vinylmagnesium bromide addition to
aldehydes 7a and 7b followed by oxidation (SO3‚pyr or
Dess-Martin periodinane (DMP)) of the intervening
allylic alcohol (43-45% from 7). The â-methyl-substituted
Results and Discussion
The di(allyl) ether ICR substrates were prepared from
allylic alcohols (()-4a-c which differ in the identity of
the â substituent (R1 ) Me, iPr, Ph) (Scheme 1). Alcohol
(7) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369-4371.
(8) The attempted allylation under typical Williamson etherification
conditions (NaH or KH then allyl bromide) resulted in considerable
Peterson elimination of the â-silyl alkoxide intermediates. See: Peter-
son, D. J. J. Org. Chem. 1968, 33, 780-784.
(2) For reviews, see: (a) Neuschuetz, K.; Velker, J.; Neier, R.
Synthesis 1998, 227-255. (b) Wipf, P. Pharm. News 2002, 9, 157-
169.
(3) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003,
125, 13000-13001.
(9) The Ir(I) isomerization catalyst was prepared by reacting [IrCl-
(C8H14)2]2, NaBPh4 (2 equiv), and PCy3 (6 equiv) (see Supporting
Information for full procedural details). The resulting catalyst is
(4) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673-1675.
(5) For reviews of intramolecular allyl silane additions, see: (a)
Hosomi, A. Acc. Chem. Res. 1988, 21, 200-206. (b) Schinzer, D.
Synthesis 1988, 263-273. (c) Sakurai, H. Synlett 1989, 1-8. (d)
Schinzer, D.; Langkopf, E. Chem. Rev. 1995, 95, 1375-1408. (e)
Majetich, G.; Defauw, J. Tetrahedron 1988, 44, 3833 and references
therein.
+
formulated as the Ir(PCy)3 complex on the basis of reaction stoichi-
ometry and is not necessarily intended to represent the reactive
catalyst complex that may be accessed by reversible phosphine
dissociation. See ref 3.
(10) For certain substrates, Claisen reaction times were accelerated
considerably by conducting the thermal sigmatropic rearrangement
under microwave irradiation (see Supporting Information for full
procedural details).
(6) For a related cyclization of Claisen-derived allyl silanes, see:
Wilson, S. R.; Price, M. F. J. Am. Chem. Soc. 1982, 104, 1124-1126.
4376 J. Org. Chem., Vol. 70, No. 11, 2005

Tandem Sakurai-Aldol Addition Reactions
SCHEME 2
The relative stereochemistry about Sakurai-derived
cyclohexanone 11 was consistent with annulation pro-
ceeding through a synclinal transition state 12 with the
C2 and C3 alkyl substituents occupying pseudoequatorial
orientations.12 Adherence to this transition state was
predicted to be independent of allyl silane geometry;13
thus, minor amounts of the Z allyl silane converge with
the same cyclohexanone diastereomer derived from the
predominant E allyl silane. In accordance with this
model, the diastereoselectivity in the remaining enone
cyclizations reflected the original Claisen diastereomer
ratios and proved to be independent of any allyl silane
isomers. Thus, acryloyl enones 8a [syn/anti ) 90 (6.5:1
E/Z):10] and 8b [syn/anti ) 92 (10.5:1 E/Z):8] produced
the trans,trans-2,3,4-trisubstituted cyclohexanones 13a
(major/Σothers ) 90:10, 59%) and 13b (major/Σothers ) 93:
7, 82%), respectively (eq 3).
enones 9a-c were obtained by allylmagnesium bromide
addition to aldehydes 7a-c followed by Ir(I)-catalyzed
olefin isomerization to the epimeric E allylic alcohols
10a-c (50-59% from 7). The resulting mixture of dia-
stereomeric allylic alcohols was oxidized to the requisite
enone cyclization precursors 9a-c (62-86%).
Access to the enone annulation templates provided the
opportunity to evaluate the ability of the C2 and C3
stereocenters established in the Claisen rearrangement
and to define stereoselectivity during the allyl silane
conjugate addition. The efficiency of the Lewis acid-
promoted enone cyclizations proved to be strongly de-
pendent on the identity of the requisite Lewis acid.
Reacting enone 9a with TiCl4 (1.2 equiv) at -78 °C
promoted rapid conjugate addition to produce the tetra-
substituted cyclohexanone 11 in a 67% yield (major/Σothers
) 92:8) (eq 2).11 Other Lewis acid promoters possessing
attenuated Lewis acidity relative to TiCl4 eroded cycliza-
tion efficiency considerably; rapid enone cyclization medi-
ated by a strong Lewis acid is believed to eliminate
competing reaction pathways such as enone oligomer-
ization. Sakurai annulation diastereoselection is directly
reflective of the diastereomer ratio emerging from the
ICR sequence used to prepare the cyclization substrates;
this suggests that stereocontrol derived from preexisting
enone chirality is complete. The veracity of this assertion
was unambiguously established by the TiCl4-mediated
cyclization of diastereometrically pure 9a, obtained by
HPLC separation, that produced cyclohexanone 11 as a
single diastereomer.
The E enones 9b [syn/anti ) 92 (4.3:1 E/ZC7-8):8] and 9c
[syn/anti ) 91 (8.1:1 E/ZC7-8):9] also cyclized to the trans,-
trans,cis-tetrasubstituted cyclohexanones 14b (major/
Σothers ) 95:5, 82%) and 14c (major/Σothers ) 89:11, 87%),
respectively, with faithful translation of chirality (eq 4).
Analyzing the Lewis acid-promoted Sakurai reaction
mechanisms revealed an opportunity for accessing fully
substituted cyclohexanone derivatives by merging the
annulation process with the ensuing stereoselective eno-
late functionalization. Provided that the putative Ti(IV)
cyclohexanone enolate 15, emerging from the conjugate
(11) Huang, X.; Pi, J. Synlett 2003, 481-484.
(12) Related allyl silane-enone additions exhibit a similar preference
for reaction via the synclinal transition state. The competing anti-allyl
silane-enone orientation in 12 suffers
a developing syn-pentane
interaction. For a discussion of competing transition states in related
intramolecular Hosomi-Sakuari reactions, see: (a) Schinzer, D.; Soly-
om, S.; Becker, M. Tetrahedron Lett. 1985, 26, 1831-1834. (b) Majetich,
G.; Hull, K.; Defauw, J.; Desmond, R. Tetrahedron Lett. 1985, 26,
2747-2750.
(13) Tokoroyama, T.; Tsukamoto, M.; Asada, T.; Iio, H. Tetrahedron
Lett. 1987, 28, 6645-6648.
J. Org. Chem, Vol. 70, No. 11, 2005 4377

Stevens and Nelson
SCHEME 3a
addition, was sufficiently long-lived, the addition of a
suitable electrophile should lead to stereoselective C6
bond construction (eq 5).14,15
Indeed, the reaction of the enone cyclization substrates
with TiCl4 (CH2Cl2, -78 °C) was accompanied by the
appearance of a red-orange color, characteristic of Ti(IV)-
enolates, that persisted until the reaction was quenched.
Considering the utility of Ti(IV) enolates in aldol addition
reactions, we elected to examine the potential for devel-
oping a tandem Sakurai annulation-aldol sequence for
stereodefined pentasubstituted cyclohexanone 16. Thus,
enone 9a was reacted with TiCl4 (1 equiv) to generate
cyclohexanone enolate 17; the addition of benzaldehyde
quenched the resulting red-orange color and, after work-
up, provided the pentasubstituted cyclohexanone deriva-
tive 18a in a 52% yield (89:11 syn/anti aldol diastereo-
selectivity) (eq 6).
a (a)(i) Cp2Zr(H)Cl, (ii) 5 mol % AgAsF6, 9a; (b) (i) NaOH, (ii)
Dess-Martin periodinane; (c) TiCl4, CH2Cl2, -78 °C; and (d)
i
4-BrC6H4COCl, DMAP, Pr2NEt.
confirmed by X-ray structure determination of the p-
bromobenzoate ester 19 derived from 18a, thereby con-
firming the predictive value of the proposed transition
states for both the Sakurai annulation and aldol addition
events.
The potential strategic value of the tandem Sakurai-
aldol reactions became apparent when we considered the
potential for executing the tandem reactions in a fully
intramolecular manifold. Tethering the aldehyde elec-
trophile to the allyl silane provided an opportunity for a
tandem Sakurai-aldol annulation process establishing
two new C-C σ-bonds, four new stereocenters, and two
new carbocycles in a single operation (eq 7).
To investigate the feasibility of the proposed bicycliza-
tion reaction, we required efficient access to the aldehyde-
tethered enone, preferably via a synthesis sequence
paralleling that previously developed for preparing the
simple enones (Scheme 3). Thus, the benzoate ester of
5-pentynol was subjected to alkyne hydrozirconation,16
and the resulting alkenyl zirconium complex 20 was
directly engaged in AgAsF6-catalyzed17 addition to the
Claisen-derived aldehyde 9a to produce the allylic alcohol
21 as an inconsequential mixture of alcohol epimers
(81%). After the benzoate protecting group was removed,
the Dess-Martin periodinane oxidation of the resulting
diol provided the tandem cyclization precursor in the
form of keto aldehyde 22 [64%, syn/anti ) 94 (14.7:1
E/ZC9,10):6]. In accordance with previous results, the
TiCl4-induced cyclization of enone 22 led to the hydrin-
dane derivative 23 (52%, major/Σothers ) 83:17) resulting
from intramolecular allyl silane conjugate addition and
the ensuing intramolecular aldol annulation (90:10 anti/
syn aldol diastereoselectivity). The relative stereochem-
istry of the major cycloadduct diastereomer was con-
As expected, the intrinsic Sakurai diastereoselection
was retained in these tandem reactions with enolate
facial selectivity ensured by chirality established during
the allyl silane addition. While the Ti(IV) enolate ex-
pressed a strong facial bias in establishing the C6
stereocenter, some erosion in aldehyde facial selectivity
was observed which resulted in an 89:11 syn/anti mixture
of aldol adducts. The use of isobutyraldehyde to trap the
intervening Ti(IV) enolate similarly leads to the penta-
substituted cyclohexanone 18b as a 92:8 syn/anti mixture
of aldol products (52%). The relative stereoselection of
the tandem Sakurai-aldol reactions was unambiguously
(14) For a related tandem annulation-enolate derivatization reac-
tion, see ref 11.
(15) For aldol additions involving chlorotitanium enolates, see:
Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(16) Schwartz, J.; Labinger, J. A. Angew. Chem. 1976, 88, 402-409.
(17) Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba, S.
Tetrahedron 1995, 51, 4483-4494.
4378 J. Org. Chem., Vol. 70, No. 11, 2005

Tandem Sakurai-Aldol Addition Reactions
NH4Cl, and the resulting mixture was warmed to ambient
temperature. The aqueous layer was extracted with CH2Cl2
(3×), and the combined organic extracts were dried (Na2SO4)
and filtered through a fine glass frit; the filter cake was washed
with Et2O. The evaporation of the solvents produced the crude
product mixture that was purified by flash chromatography
on SiO2 (5:1 hexanes/EtOAc) to yield 26 mg of 18b (52%) as a
clear oil. The diastereomer ratio was determined by 500 MHz
1H NMR (CHOH): 85% (18b, δ 3.88), 8% (18b anti aldol, δ
3.98), 7% (Sakurai minor diastereomer/syn aldol, δ 3.32); IR
firmed by X-ray structure determination of the C7
p-bromobenzoate ester 24.
Conclusion
Merging the ICR methodology with the tandem Saku-
rai-aldol annulation process provides a concise and highly
stereoselective entry to highly substituted cyclohex-
anones. Considerable structural complexity emerges from
the tandem annulation process with two new C-C bonds,
one or two new carbocyclic rings, and up to four new
stereocenters established in a single transformation. The
ability to elaborate simple precursors to structurally
complex and stereochemically rich carbocycles provided
by the tandem Sakurai-aldol process is expected to be
useful in both diversity- and target-oriented synthesis.
(thin film) 3454, 3076, 2965, 1704, 1639, 999, 914 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 5.67 (ddd, J ) 16.8, 10.4, 9.0 Hz,
1H), 5.10 (dm, J ) 10.3 Hz, 1H), 5.07 (dm, J ) 16.8 Hz, 1H),
3.92-3.86 (m, 1H), 2.38-2.28 (m, 3H), 2.12 (qdd, J ) 7.1, 4.3,
3.1 Hz, 1H), 1.90 (pd, J ) 6.9, 3.5 Hz, 1H), 1.63-1.52 (m, 1H),
1.51 (d, J ) 7.8 Hz, 1H), 1.08 (d, J ) 6.5 Hz, 3H), 1.04 (d, J )
6.9 Hz, 3H), 1.01 (d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 7.2 Hz, 3H),
0.85 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 12.4,
14.7, 15.1, 19.2, 20.1, 30.5, 37.9, 38.6, 48.1, 48.4, 61.2, 75.7,
116.4, 140.4, 214.7; MS (EI) m/z 220 (M+ - H2O), 205, 195,
166, 98, 68; HRMS (EI) m/z calcd for C15H24O (M+ - H2O)
220.1827, found 220.1835.
Experimental Section
Representative Procedure for Sakurai Annulation
Reactions. Preparation of R*-(2S,3R,4S,5S)-2,3,5-Tri-
methyl-4-vinylcyclohexanone (11). A solution of 0.10 g
(0.42 mmol) of enone 9a (82.5:7.9:9.7 syn/anti/Z) in 10 mL of
CH2Cl2 was slowly added to 1.2 mL (1.2 mmol) of a vigorously
stirred solution of TiCl4 in CH2Cl2 (1.0 M) at -78 °C to produce
a deep red reaction mixture. The syringe and flask were
washed with an additional 1 mL of CH2Cl2, and this rinse was
added to the reaction vessel. After the mixture was stirred for
15 min at -78 °C, the reaction was quenched with saturated
aqueous NH4Cl, and the resulting mixture was warmed to
ambient temperature. The aqueous layer was extracted with
CH2Cl2 (3×), and the combined organic extracts were dried
(Na2SO4) and filtered through a fine glass frit; the filter cake
was washed with Et2O. The evaporation of the solvents
produced the crude product mixture that was purified by flash
chromatography on SiO2 (20:1 pentane/Et2O) to yield 46 mg
of 11 (67%) as a colorless volatile oil. The separation of the
diastereomers by GC-MS [HP-1 (12 m × 0.20 mm), pressure
21 kPa, 70 °C for 2.00 min, ramp at 10 °C/min to 300 °C, hold
for 60 min] provided the diastereomer ratio: 91.7% (trans,
trans, cis Tr ) 6.49), 8.3% (Tr ) 6.99); IR (thin film) 3076, 2969,
Tandem Intramolecular Sakurai-Aldol Reactions. R*-
(3aS,5S,6R,7R,7aR)-Octahydro-3-hydroxy-5,6-dimethyl-
7-vinylinden-4-one (23). A 1.0 M CH2Cl2 solution of TiCl4
(0.28 mL, 0.28 mmol) was added to a -78 °C solution of 65
mg (23 mmol) of keto aldehyde 22 (87.8:6.1:6.1 syn/anti/Z) in
4.6 mL of CH2Cl2. After the mixture was stirred for 20 min at
-78 °C, the reaction was quenched with 5 mL of saturated
aqueous NH4Cl, and the biphasic mixture was warmed to
ambient temperature. The aqueous layer was extracted with
CH2Cl2 (3×), and the combined organic extracts were dried
(Na2SO4) and filtered through a fine glass frit; the filter cake
was washed with Et2O. The solvent was evaporated, and the
resulting crude product mixture was purified by flash chro-
matography on SiO2 (2:1 hexanes/EtOAc) to yield 25 mg of 23
(52%) as a clear viscous oil. The diastereomeric ratio was
determined by GC-MS [HP-1 (12 m × 0.20 mm), pressure 21
kPa, 70 °C for 2.00 min, ramp at 10 °C/min to 300 °C, hold for
60 min]: 5.8% (Tr ) 10.15), 6.1% (23 syn aldol, Tr ) 10.42),
5.3% (Tr ) 11.63), 83% (23, Tr ) 11.95); IR (thin film) 3400,
3075, 2969, 1706, 1639, 998, 913 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.59 (dt, J ) 17.1, 9.8 Hz, 1H), 5.12 (dd, J ) 17.0,
1.9 Hz, 1H), 5.09 (dd, J ) 9.9, 1.9 Hz, 1H), 4.83 (dd, J ) 6.4,
2.3 Hz, 1H), 2.85-2.73 (m, 2H), 2.48 (td, J ) 10.3, 4.7 Hz,
1H), 2.20-2.09 (m, 2H), 1.81-1.71 (m, 1H), 1.58-1.40 (m, 3H),
1.26-1.09 (m, 1H), 1.03 (d, J ) 6.5 Hz, 3H), 0.99 (d, J ) 6.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 11.7, 18.7, 23.7, 33.1,
39.4, 46.6, 49.2, 50.1, 61.2, 72.3, 116.2, 140.5, 212.2; MS (EI)
m/z 208 (M+), 190, 140, 122, 68; HRMS (EI) m/z calcd for
C13H20O2 208.1463, found 208.1468.
1
1713, 1638, 915 cm-1; H NMR (300 MHz, CDCl3) δ 5.67 (dt,
J ) 18.0, 9.3 Hz, 1H), 5.11-5.06 (m, 2H), 2.63 (dd, J ) 13.0,
5.0 Hz, 1H), 2.37-2.18 (m, 3H), 2.02 (dqd, J ) 12.9, 6.5, 0.7
Hz, 1H), 1.60-1.46 (m, 1H), 1.04 (d, J ) 6.5 Hz, 3H), 0.98 (d,
J ) 6.5 Hz, 3H), 0.83 (d, J ) 6.9 Hz. 3H); 13C NMR (75 MHz,
CDCl3) δ 11.8, 13.9, 19.2, 36.9, 38.8, 48.6, 50.6, 52.2, 116.2,
140.6, 212.2; MS (EI) m/z 166 (M+), 138, 96, 68; HRMS (EI)
m/z calcd for C11H18O 166.1358, found 166.1357.
General Procedure F for Tandem Intermolecular
Sakurai-Aldol Reactions. Preparation of R*-(2R,3R,4R,-
5R,6S)-2-((S)-1-Hydroxy-2-methylpropyl)-3,5,6-trimethyl-
4-vinylcyclohexanone (18b). A solution of 0.050 g (0.21
mmol) of enone 9a (82.5:7.9:9.7 syn/anti/Z) in 5 mL of CH2Cl2
was slowly added to 0.6 mL (0.6 mmol) of a vigorously stirred
solution of TiCl4 in CH2Cl2 (1.0 M) at -78 °C to produce a deep
red reaction mixture. The syringe and flask were washed with
an additional 0.5 mL of CH2Cl2, and this rinse was added to
the reaction vessel. After the mixture was stirred for 15 min
at -78 °C, 23 µL (18 mg, 0.25 mmol) of isobutyraldehyde was
added, and the reaction mixture was stirred for 60 min at
-78 °C. The reaction was quenched with saturated aqueous
Acknowledgment. Support from the National In-
stitutes of Health (P50 GM067082) for the University
of Pittsburgh Center for Chemical Methodologies and
Library Development, the Merck Research Laboratories,
and Eli Lilly & Co. is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, proton and carbon NMR spec-
tra, and X-ray diffraction data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO050225Y
J. Org. Chem, Vol. 70, No. 11, 2005 4379