Lewis acid-promoted conjugate addition of dienol silyl ethers to nitroalkenes: Synthesis of 3-substituted azepanes

Article abstract of DOI:10.1021/jo071126i

(Chemical Equation Presented) A novel γ-selective conjugate addition of 1-silyl-substituted dienol ethers to nitroalkenes activated by Lewis acids has been developed. The resulting α,β-unsaturated acylsilanes undergo photoinduced protodesilylation to affo

Full text of DOI:10.1021/jo071126i

or reductive amination processes effect direct construction of
7-membered rings.6 Recently, an asymmetric synthesis of
polysubstituted azepanes was reported by Beak and co-workers
that employs an enantioselective conjugate addition of a lithiated
allylamine followed by lactamization.9 Despite these important
advances, a general approach for the synthesis of azepanes with
a variety of substituents from easily accessible starting materials
remains a challenge.
Nitroalkenes are readily available and are versatile building
blocks for efficient C-C and C-N bond-formation reactions.
Over the past two decades we have extensively investigated
and developed the Lewis acid-promoted cycloaddition of enol
ethers and nitroalkenes for the construction of monocyclic, fused
and spirocyclic nitrogen-containing compounds, notably pyr-
rolidines and piperidines.10 Herein we report a novel construction
of azepanes that takes advantage of the reactivity of nitroalkenes
toward dienol ethers (Scheme 1).
Lewis Acid-Promoted Conjugate Addition of
Dienol Silyl Ethers to Nitroalkenes: Synthesis of
3-Substituted Azepanes
Scott E. Denmark* and Min Xie
Department of Chemistry, Roger Adams Laboratory,
UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed May 28, 2007
SCHEME 1
A novel γ-selective conjugate addition of 1-silyl-substituted
dienol ethers to nitroalkenes activated by Lewis acids has
been developed. The resulting R,â-unsaturated acylsilanes
undergo photoinduced protodesilylation to afford the corre-
sponding enals, which can be conveniently transformed into
azepanes under appropriate reductive conditions.
For this strategy to succeed, the addition reaction between
dienol ethers and nitroalkenes must provide the 1,6-relationship
between the nitro and carbonyl functional groups in the adducts,
which can be further transformed into azepanes. Because dienol
ethers possess two nucleophilic sites, the desired γ-selective
nucleophilic addition is not guaranteed. Fortunately, it has been
demonstrated that in the presence of Lewis acid activators,
dienol ethers undergo Mukaiyama-type vinylogous aldol reac-
tions.11,12
To develop an efficient synthesis of azepane precursors,
studies commenced with an investigation of the effects of differ-
ent Lewis acids on the reactivity and selectivity of nitroalkenes
toward dienol ethers. Previous studies from this group have
already demonstrated that Me3Al, Ti(Oi-Pr)2Cl2 and SnCl4 are
effective Lewis acid promotors for the cycloaddition reactions
of nitroalkenes with enol ethers.10c Thus, pentadienol ether 213
was prepared as a mixture of (E)- and (Z)-isomers and was em-
ployed in the reaction with nitroalkene 1 (Scheme 2). Although
the relatively mild Lewis acid Me3Al promoted the addition of
dienol ether 2 to nitroalkene 1, the formation of only Diels-
Alder product 3 was observed. SnCl4 afforded the same product
with higher efficiency. Interestingly, Ti(Oi-Pr)2Cl2 effected the
formation of both cyclohexene 3 and R-adduct 4. Unfortunately,
the desired γ-adduct was not obtained in any case.
Azepanes, 7-membered nitrogen-containing heterocycles are
an important structural motif found in a variety of medicinal
compounds.1 These heterocycles have attracted much interest,
and their synthesis has been the subject of intensive study. A
classic method for the construction of azepanes is the reduction
of the corresponding caprolactams which are in turn available
from Beckmann rearrangement of cycloalkanone oximes2 or
from the Schmidt reaction of cycloalkanone (which offers com-
plementary regioselectivity).3 Unfortunately, these two methods,
although generally efficient, often generate a mixture of consti-
tutional isomers.4 Other ring-expansion5 or rearrangement6 reac-
tions allow for the formation of 7-membered nitrogen-containing
heterocycles from 3-, 4-, 5-, 6-, and 8-membered rings.
Ring-formation processes provide alternative strategies to
construct azepanes and their unsaturated analogues. For example,
the combination of azadienes with Fischer carbene complexes
allows for the asymmetric construction of highly substituted
7-membered heterocycles.7 Ring-closing metathesis has also
been applied in azepane synthesis.8 In addition, numerous
cyclization reactions including nitrogen alkylation, lactamization,
(7) Barluenga, J. J. Pure Appl. Chem. 2002, 74, 1317-1325.
(8) Li, H.; Ble´riot, Y.; Chantereau, C.; Mallet, J.; Sollogoub, M.; Zhang,
Y.; Rodr´ıguez-Garc´ıa, E.; Vogel, P.; Jime´nez-Barbero, J.; Sinay¨, P. Org.
Biomol. Chem. 2004, 2, 1492-1499.
* To whom correspondence should be addressed. E-mail: denmark@
scs.uiuc.edu.
(1) Proctor, G. R.; Redpath, J. Monocyclic Azepines: The Synthesis and
Chemical Properties of the Monocyclic Azepines; John Wiley & Sons: New
York, 1996.
(2) Fernandez, F.; Perez, C. Heterocycles 1987, 26, 2411-2417.
(3) Georg, G. I.; Guan, X.; Kant, J. Bioorg. Med. Chem. Lett. 1991, 1,
125-128.
(4) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131-9166.
(5) Schmitz, E.; Ohme, R.; Schramm, S.; Striegler, H.; Heyne, H.;
Rusche. J. J. Prakt. Chem. 1977, 319, 195-200.
(6) Newkome, G. R. ComprehensiVe Heterocyclic Chemistry II, Vol.
9: SeVen Membered and Larger Rings and All Fused DeriVatiVes; Perga-
mon: NewYork, 1996.
(9) Lee, S. J.; Beak, P. J. Am. Chem. Soc. 2006, 128, 2178-2179.
(10) (a) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137-
165. (b) Denmark, S. E.; Cottell, J. J. Nitronates. In Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural
Products; John Wiley & Sons: New Jersey, 2003; Chapter 2. (c) Denmark,
S. E.; Seierstad, M. J. Org. Chem. 1999, 64, 1610-1619.
(11) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 319-322.
(12) (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682-4698. (b) Heemstra, J. R., Jr.; Denmark,
S. E. J. Am. Chem. Soc. 2006, 128, 1038-1039.
(13) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994,
116, 2812-2820.
10.1021/jo071126i CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/03/2007
7050
J. Org. Chem. 2007, 72, 7050-7053

TABLE 1. Lewis Acid Promoted Conjugate Addition of 10 to
Nitroalkenes
SCHEME 2
entry
R
product
yield,a %
1
2
3
4
5
6
7
8
9
C6H5
1-naphthyl
2-furyl
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
n-hexyl
11a
11b
11c
11d
11e
11f
11g
11h
11i
75
76
70
92
90
70
64
55
15
Previous studies in these laboratories have shown that vinyl
ketene acetals 512a and 812b undergo vinylogous aldol addition
reactions and therefore could potentially effect the desired γ-site
selectivities in the addition to nitroalkenes. Unfortunately, when
the ester-derived dienol ether 5 was combined with nitroalkene
1 in the presence of Me3Al, only the R-cycloadduct 6 was
formed (Scheme 3). Exclusive R-site-selectivity was again
observed in the addition of 8 to nitrostyrene 7 to produce 9 in
good yield (Scheme 3). To effect the desired γ-site nucleophilic
attack while preventing both the R addition and the Diels-Alder
pathway, dienol ethers bearing a bulky substituent at C(1) were
considered. The acylsilane-derived dienol ether 10 bearing a
silyl substituent at C(1) represents this structural characteristic
and can be conveniently synthesized from allyltrimethylsilane.14
Although addition reactions of this 1,1-disubstituted dienol ether
find no precedent, we decided to test its behavior in reactions
with nitroalkenes. Gratifyingly, 10 underwent addition to
2-nitrostyrene in the presence of TiCl2(Oi-Pr)2 with exclusive
γ-selectivity, to afford the nitroacylsilane product 11a. Ulti-
mately, SnCl4 was found to be an effective promotor for
generating the conjugate adduct 11a in good yield (Scheme 3).
a Yield of analytically pure materials.
1). The shortest reaction times and most consistent yields could
be achieved by the addition of a solution of SnCl4 to the
precooled solution of reactants over 40 s. Both electron-neutral
and electron-rich nitroalkenes (entries 1-5) were consumed in
10 min at -70 °C and afforded the desired products in good
yields. Yields for electron-poor nitroalkenes (entries 6-9)
decreased under the standard conditions, and unreacted nitroal-
kenes were recovered. This incomplete conversion was likely
due to the nonproductive consumption of dienol ether 10. A
control experiment established that, when 10 was combined with
SnCl4 under the same conditions, the dienol ether decomposed
completely within minutes, at a rate comparable to that of the
productive addition to less reactive nitroalkenes. It was also
observed that an undesired product arose from the addition of
10 to the acylsilane product.15 This side reaction, unfortunately,
thwarts the use of a large excess of dienol ether.
SCHEME 3
During a survey of Lewis acids, Me2AlCl was found to be
the only suitable reagent to activate aliphatic nitroalkene 7i
(Scheme 4). Unfortunately, under a variety of conditions, the
nitroalkene was never consumed. 1H NMR and 13C NMR
analysis of the reaction mixture confirmed that Me2AlCl reacted
with nitroalkene 7i to afford the corresponding chloride adduct
12,16 which was not susceptible toward further nucleophilic
attack by the dienol ether 10. Slow addition of a CH2Cl2 solution
of Me2AlCl to the mixture of 7i and 10 at -40 °C over 4 h,
however, afforded 11i in 45% yield. After quenching the
reaction with a methanolic solution of Et3N followed by aqueous
workup, unreacted 7i and 10 were recovered. Thus, a novel,
SCHEME 4
Optimized conditions for the SnCl4-promoted addition of
dienol ether 10 were applied for a variety of nitroalkenes (Table
(14) Ryu, I.; Yamamoto, H.; Sonoda, N.; Murai, S. Organometallics
1996, 15, 5459-5461.
(15) A side product was isolated from the reaction of 7a and 10, which
was not stable after isolation and therefore was not fully characterized. It
could possibly be accounted for by a structure such as
1
which was suggested by H NMR analysis.
J. Org. Chem, Vol. 72, No. 18, 2007 7051

Lewis acid-promoted vinylogous conjugate addition to nitroal-
kenes affords nitroacylsilanes which are potential precursors to
azepanes.
accomplished by a photoinduced protiodesilylation21 in a protic
solvent to afford the corresponding enals in generally good
yields (Table 2). From this success, a streamlined Pd-C-
catalyzed hydrogenation followed by Al-Hg reduction process
conveniently converted the nitroaldehydes to 3-susbtituted
azepanes. The tosyl-protected derivatives were prepared to
facilitate isolation and purification.
The elaboration of nitroacysilanes into azepanes was expected
to be straightforward. Acylsilanes are aldehyde equivalents and
are highly susceptible toward nucleophilic attack.17 To develop
an effective process to convert nitroacylsilanes into azepanes,
11a was chosen as the test substrate. The trans double bond in
11a was easily saturated through catalytic hydrogenation (1 atm)
with Pd/C (10 wt %) in quantitative yield. Among a number of
methods investigated for the reduction of nitro group and the
concomitant reductive amination, Al-Hg was found to effect
the clean conversion of 13a into a cyclized product (Scheme
5). However, spectroscopic data indicated that a mixture of
lactam 14a and azepane 15a was obtained. Unfortunately,
variation of solvent, pH, or temperature exerted little effect upon
the product distribution.
TABLE 2. Elaboration of r,â-Unsaturated Acylsilanes into
N-Tosylazepanes
enal,
N-tosylazepane,
yield, b
SCHEME 5
entry
R
yield, a
%
%
1
2
3
4
5
6
7
8
9
C6H5
1-naphthyl
2-furyl
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
3-BrC6H4
n-hexyl
22a, 78
22b, 72
22c, 60
22d, 74
22e, 75
22f, 72
22g, 76
22h, 70
22i, 75
23a, 82
23b, 85
23c, 72
23d, 92
23e, 89
23f, 76
23g, 70
23h, 55
23i, 72
a Yield of chromatographically homogeneous products. b Yield of ana-
lytically pure products.
In summary, a novel, vinylogous conjugate addition of an
acylsilane-derived dienol ether to aryl and alkyl substituted
nitroalkenes was developed. The nitroacylsilane products were
obtained in good to moderate yields. Nitroacylsilanes could be
easily converted into the corresponding enals, which were
efficiently elaborated into N-tosylazepanes in good yield through
a streamlined three-step process involving catalytic hydrogena-
tion, reductive amination, and tosylation.
A plausible mechanism for the formation of the two products
is illustrated in Scheme 5. Reduction of the nitro group affords
the hydroxylamine 16a, which undergoes intramolecular nu-
cleophilic attack onto the acylsilane moiety to afford a zwitterion
intermediate 17a and then eliminates Me3SiOH (Peterson
elimination18) and tautomerizes to lactam 14a. Alternatively,
intermediate 17 may undergo a [1,2]-silyl shift (Brook re-
arrangement19) followed by extrusion of Me3SiOH to afford
nitrone 21a that can be further reduced to azepane 15a.20
To eliminate some of these mechanistic pathways in the
tandem reduction/reductive amination sequence, the acylsilane
was transformed into an aldehyde. This conversion is easily
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
Representative Procedure for SnCl4-Promoted Conjugate
Addition of Acylsilane-Derived Dienol Ether (10) to Nitrostyrene
(7a). Preparation of Acylsilane 11a. To a cold (-70 °C, internal
temperature) solution of nitrostyrene 7a (175 mg, 1.17 mmol, 1.0
equiv) and dienol ether 10 (515 mg, 1.40 mmol, 1.2 equiv) in dry
CH2Cl2 (4.0 mL) in a 50-mL, round-bottomed, two-necked flask
under nitrogen was added a CH2Cl2 solution of SnCl4 (0.50 M,
2.58 mL, 1.29 mmol, 1.1 equiv) dropwise via syringe through a
septum over 40 s. The resulting yellow solution was allowed to
stir at -70 °C for 10 min. With vigorous stirring, a MeOH solution
of Et3N (1.0 M, 5.7 mL, 5.7 mmol, 4.9 equiv) was rapidly added
to the reaction mixture, followed by H2O (1 mL). The mixture was
warmed to ambient temperature and passed through a silica gel
plug (3 cm × 2 cm) and then was eluted with CH2Cl2 (40 mL).
The organic eluent was dried (Na2SO4) and concentrated in vacuo.
In a dark environment, the organic residue was purified by column
chromatography (SiO2, 30 mm × 20 cm, hexane/EtOAc, 10/1, 8/1,
3/1) to afford 248 mg (73%) of 11a as a heavy, yellow oil. Data
for 11a: 1H NMR (500 MHz, CDCl3): δ 7.38-7.29 (m, 3 H,
(16) For spectroscopic data for the chloride adduct, see Supporting
Information.
(17) (a) Patroc´ınio, A. F.; Mora, P. J. S. J. Braz. Chem. Soc. 2001, 12,
7-31. (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. ReV. 1990,
19, 147-195. (c) Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647-660.
(18) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784.
(19) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84.
(20) The formation of a lactam (amide) from an acylsilane and a
hydroxylamine appears to be unprecedented. However, the analogy to the
recently reported peptide ligation of hydroxylamines with R-keto acids is
noteworthy. Bode, J. W.; Fox. R. M.; Baucom, K. D. Angew. Chem., Int.
Ed. 2006, 45. 1248-1252.
(21) Brook, A. G.; Duff, J. M. J. Am. Chem. Soc. 1967, 89, 454-455.
7052 J. Org. Chem., Vol. 72, No. 18, 2007

H-phenyl), 7.21-7.18 (m, 2 H, H-phenyl), 6.43 (dt, J ) 16.1, 7.1,
1 H, HC(3)) 6.30 (dt, J ) 16.1, 1.2, 1 H, HC(2)), 4.61 (d, J ) 7.5,
2 H, HC(6)), 3.66, (m, 1 H, HC(5)), 2.66, (m, 2 H, HC(4)), 0.12
(s, 9 H, (H3C)3Si); 13C NMR (126 MHz, CDCl3): δ 236.5 (C(1)),
142.7 (C(3)), 138.3 (C(2)), 137.9 (C(7)), 129.2 (C(9)), 128.4
(C(10)), 127.4 (C(8)), 79.9 (C(6)), 43.5 (C(5)), 36.2 (C(4)), -2.2
(C(11)); IR (neat): cm-1 3065 (w), 3032 (m), 2959 (m), 2917 (m),
2896 (m), 2361 (w), 2342 (w), 1953 (w), 1876 (w), 1809 (w), 1639
(m), 1590 (s), 1553 (s), 1496 (m), 1455 (m), 1434 (m), 1379 (s),
1259 (s), 1190 (m), 1153 (m), 1089 (w), 980 (m), 846 (s), 762
(m), 701 (m); MS (FI): 291.2 (M+, 100), 292.2 (24); TLC Rf 0.28
(hexane/EtOAc, 3/1) [silica gel, UV, I2, CAM]; Anal. Calcd for
C15H21NO3Si: C, 61.40; H, 7.90; N, 4.77. Found: C, 61.21; H,
7.87; N, 4.91.
Representative Procedure for Photoinduced Protiodesilyla-
tion of r,â-Unsaturated Acylsilane 11a. Preparation of Enal 22a.
R,â-Unsaturated acylsilane 11a (473 mg, 1.62 mmol) was dissolved
in MeOH (60 mL) in a 250-mL, round-bottomed flask, and water
(20 mL) was added with stirring. The flask was sealed with a septum
and was cooled in a cold bath of 2-propanol to maintain an internal
temperature at -10 °C by an immersion cooler. The solution was
irradiated with light generated from a 250-W bulb 10 cm away
from the top of the solution. After irradiation for 12 h, the yellow
color of the solution faded. The solution was then concentrated
under vacuo to 30 mL and was then extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with brine (50
mL), dried over Na2SO4, and were then passed through a silica gel
plug (3 cm × 3 cm), eluting with CH2Cl2 (60 mL). The organic
eluent was concentrated, and the residue was purified by column
chromatography (SiO2, 30 mm × 20 cm, hexane/EtOAc, 10/1, 8/1,
6/1, 4/1, 3/1) to afford 267 mg (75%) of 22a as a colorless, heavy
oil. Data for 22a: 1H NMR (500 MHz, CDCl3): δ 9.40 (d, J )
7.8, 1H, HC(1)), 7.38-7.29 (m, 3 H, H-phenyl), 7.22-7.18 (m, 2
H, H-phenyl), 6.60 (dt, J ) 15.6, 7.1, 1 H, HC(3)) 6.08 (ddq, J )
15.6, 7,8, 1.4, 1 H, HC(2)), 4.61 (t, J ) 7.9, 2 H, HC(6)), 3.70, (m,
1 H, HC(5)), 2.77 (m, 2H, HC(4)); 13C NMR (100 MHz, CDCl3):
δ 193.2 (C(1)), 152.5 (C(3)), 137.5 (C(2)), 135.2 (C(7)), 129.3
(C(9)), 128.3 (C(8)), 127.3 (C(10)), 79.9 (C(6)), 43.1 (C(5)), 35.9
(C(4)); IR (neat): cm-1 3358 (w), 3064 (m), 3031 (m), 3007 (m),
2920 (m), 2747 (m), 1858 (w), 1884 (w), 1812 (w), 1691 (vs),
1639 (m), 1604 (m), 1552 (vs), 1495 (m), 1455 (m), 1434 (s), 1380
(s), 1340 (w), 1314 (w), 1203 (w), 1177 (m), 1132 (s), 1087 (m),
1012 (m), 978 (s), 950 (w), 917 (w), 882 (w), 847 (w), 764 (s),
736 (m), 702 (s), 651 (w); TLC Rf 0.14 (hexane/EtOAc, 3/1) [silica
gel, UV, I2, CAM].
equipped with a magnetic stir bar. Pd-C (10 wt %, 45 mg) was
added. The flask was hooked up to a hydrogenation manifold and
the solution stirred vigorously at ambient temperature under an
atmosphere of H2 for 1 h. The reaction mixture was filtered through
a silica gel plug (10 mm × 2 cm) with a short pad of Celite on
top, eluting with THF (30 mL). H2O (7 mL) was added to the eluate.
The resulting homogeneous solution was transferred to a 100-mL,
round-bottomed flask, which was then cooled in a water bath.
Aluminum amalgam (300 mg) was freshly prepared based upon a
literature procedure22 and was added right away to the precooled
solution of saturated aldehyde. The resulting suspension was stirred
vigorously for 1 h at ambient temperature. The reaction mixture
was then filtered through a Celite pad (3 cm × 1 cm) with a filter
paper on top, eluting with MeOH (50 mL). All the solvent was
removed under vacuo. The organic residue was redissolved in CH2-
Cl2. TsCl (295 mg, 1.55 mmol, 1.5 equiv) was then added, followed
by Et3N (215 µL, 1.55 mmol, 1.5 equiv). The solution was allowed
to stand at ambient temperature for 1 h and then concentrated under
vacuo. The residue was purified by column chromatography (SiO2,
30 mm × 20 cm, hexane/EtOAc, 10/1, 4/1) to give 311 mg of 23a
as a colorless, heavy oil. The product was crystallized from EtOH
to afford 269 mg (82%) of an analytically pure white solid. Data
1
for 23a: mp (sealed tube) 99.5-100.5 °C. H NMR (500 MHz,
CDCl3): δ 7.68 (m, 2 H, HC(12)), 7.34-7.18 (m, 7 H, aromatic
H’s), 3.68 (m, 1 H, HC(1)), 3.58 (m, 1 H, HC(6)), 3.15 (m, 1 H,
HC(6′)), 2.96 (m, 2 H, HC(1′), HC(2)), 2.41 (s, 3 H, HC(15)), 2.05-
1.92 (m, 2 H, HC(3), HC(5)), 1.91 (m, 1 H, HC(4)), 1.79-1.61
(m, 3 H, HC(3′), HC(4′), HC(5′)); 13C NMR (126 MHz, CHCl3):
δ 144.3 (C(7)), 142.9 (C(11)), 136.4 (C(20)), 129.6 (C(13)), 128.6
(C(9)), 127.2 (C(8)), 126.9 (C(12)), 126.5 (C(10)), 54.5 (C(1)), 48.2
(C(6)), 47.7 (C(2)), 35.0 (C(3)), 28.8 (C(5)), 25.4 (C(4)), 21.5
(C(15)); IR (CDCl3): cm-1 3156 (w), 2937 (m), 2360 (s), 2342
(s), 1794 (w), 1600 (m), 1459 (m), 1382 (w), 1336 (s), 1159 (s),
1092 (m), 1047; TLC Rf 0.36 (hexane/EtOAc, 3/1) [silica gel, UV,
I2, CAM]. Anal. Calcd for C19H23NO2S: C, 69.27; H, 7.04; N, 4.25.
Found: C, 69.17; H, 7.20; N, 4.38.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (GM R01-30938).
Supporting Information Available: Full experimental proce-
dures and characterization data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO071126I
Representative Procedure for the Synthesis of N-Tosyl
Azepane, 23a. Enal 22a (226 mg, 1.03 mmol) was dissolved in 21
mL of THF-H2O (20/1) in a 50-mL, round-bottomed flask
(22) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-
1353.
J. Org. Chem, Vol. 72, No. 18, 2007 7053