Stereochemistry of intermolecular oxypalladation: PdII-catalyzed 1,3-chirality transfer reaction of chiral allylic alcohol with methanol

Article abstract of DOI:10.1021/jo9011464

(Chemical Equation Presented) The intermolecular oxypalladation of chiral nonracemic allylic alcohols (S)-1, (R)-1, and (R)-3 in methanol gave chiral nonracemic methyl allyl ethers (S)-2 and/or (R)-2 with excellent selectivity. The reaction induced the 1,

Full text of DOI:10.1021/jo9011464

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Stereochemistry of Intermolecular Oxypalladation: PdII-Catalyzed
1,3-Chirality Transfer Reaction of Chiral Allylic Alcohol with Methanol
Yogesh S. Vikhe, Sudhir M. Hande, Nobuyuki Kawai, and Jun’ichi Uenishi*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
juenishi@mb.kyoto-phu.ac.jp
Received June 3, 2009
The intermolecular oxypalladation of chiral nonracemic allylic alcohols (S)-1, (R)-1, and (R)-3 in
methanol gave chiral nonracemic methyl allyl ethers (S)-2 and/or (R)-2 with excellent selectivity. The
reaction induced the 1,3-chirality transfer to give syn-SN20 product exclusively through syn
oxypalladation. On the other hand, the anti-SN20 product was produced in 20-33% in THF,
toluene, and CH2Cl2 and predominantly in CH3CN. The π-olefin-Pd complexes I and II are
proposed as important intermediates to explain the syn- and anti-oxypalladation pathways. The
byproduct 9 was formed through the second syn-oxypalladation from the methyl allyl ether 2, though
the rate of this second reaction was far slower than that of allylic alcohol.
Introduction
enol (ketone; R = H, enol ether; R = alkyl) or alkyl allyl
ether.3 The catalytic process of the reaction involves oxypal-
ladation to alkenyl bond by PdII and oxy nucleophiles such
as water, alcohol, or carboxylic acid and β-hydride elimina-
tion from the resulting σ-alkyl Pd complex. However, there
has been a controversy regarding syn or anti stereochemis-
tries of oxypalladtion reaction at the addition step.2b
PdII-catalyzed reactions are used as versatile and valuable
tools in synthetic organic chemistry.1 Oxypalladation reac-
tions including the Wacker oxidation have been in use and a
topic of interest for decades (Scheme 1).2 The reaction gives
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Organic synthesis; Negishi, E.-i., Ed.; John Wiley & Sons: New York, 2002.
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New York, 2002; pp 2141-2192. (b) Henry, P. M. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; John Wiley &
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Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318–5365. (d) Muzart,
J. Tetrahedron 2005, 61, 5955–6008.
€
Backvall and co-workers reported that oxypalladation is
an anti process in the presence of a high chloride ion
concentration.4 Stille and Kurosawa reported that methox-
ypalladation is also an anti process.5,6 Henry and co-workers
˚
€
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(b) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc.
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5174 J. Org. Chem. 2009, 74, 5174–5180
Published on Web 07/02/2009
DOI: 10.1021/jo9011464
r
2009 American Chemical Society

Vikhe et al.
JOCFeatured Article
SCHEME 1. Oxypalladation Reaction of Alkene with Oxynu-
cleophile
SCHEME 2. 1,3-Chirality Transfer in Intra- and Intermolecular
Oxypalladation Reactions
proposed that oxypalladation process depends on the reaction
conditions and oxypalladation is syn at low chloride ion
concentrations, while the process is anti at high chloride ion
concentrations.7 Recently, Pd-catalyzed carboetherification
was reported to proceed through syn addition by Wolf et al.8
In the case of intramolecular oxypalladation reactions, Hayashi
and co-workers, and Stoltz and co-workers performed the
deuterium labeling experiment to establish syn stereochemis-
try.9 However, most of these studies were carried out in the
presence of oxidants such as quinone, CuCl2, or oxygen, which
were essential for the oxidation of Pd0 to PdII in the catalytic
cycle. Recently, we investigated the PdII-catalyzed intramole-
cular oxypalladation reactions of chiral nonracemic allylic
alcohols and demonstrated that the reaction is highly stereo-
specific through the syn oxypalladation pathway to give various
oxaheterocycles.10 The most interesting part of our study was
to use acyclic chiral allylic alcohol with the PdCl2(CH3CN)2
catalyst in organic solvents without reoxidant.
After investigating intramolecular oxypalladation,10 we
turned our attention to intermolecular oxypalladation. If we
carefully selected an appropriate chiral nonracemic allylic
alcohol and an alcoholic nucleophile for the intermolecular
reaction, we would be able to deduce the reaction mechanism
by analyzing the stereochemistry of products produced
through the 1,3-chirality transfer process, as shown in
Scheme 2. Herein, we report an intermolecular PdII-cata-
lyzed oxypalladation with methanol as a nucleophile in
organic solvents under mild reaction conditions and propose
the mechanism with clear stereochemical evidence.
Results and Discussion
We have chosen (R)- and (S)-1-cyclohexyl-5-phenylpent-
2-en-1-ol, (S)-1, (R)-1, and (R)-3 as substrates for the reac-
tion. In fact, the preliminary reaction of racemic 1 with
30 mol % of PdCl2(CH3CN)2 in absolute methanol afforded
1-cyclohexyl-3-methoxy-5-phenylpent-2-ene 2 in 70-85%
yield, as shown in Scheme 3.
SCHEME 3. Intermolecular Oxypalladation of Compound 1
If (R)-1-cyclohexyl-3-methoxy-5-phenylpent-2-ene (R)-2
is obtained from (S)-1, then the syn-SN20 process proceeds
by syn oxypalladation. If (R)-2 is obtained from (R)-1, then
the anti-SN20 process proceeds by anti oxypalladation
(Figure 1). The mechanistic pathway will be further con-
firmed using (R)-3 as a substrate.
(7) (a) Henry, P. M.; Lee, H. B. Can. J. Chem. 1976, 54, 1726–1738.
(b) Zaw, K.; Henry, P. M. J. Org. Chem. 1990, 55, 1842–1847. (c) Francis,
J. W.; Henry, P. M. Organometallics 1991, 10, 3498–3503. (d) Zaw, K.;
Henry, P. M. Organometallics 1992, 11, 2008–2015. (e) Francis, J. W.; Henry,
P. M. Organometallics 1992, 11, 2832–2836. (f) Francis, J. W.; Henry, P. M
J. Mol. Catal. A: Chem. 1996, 112, 317–326. (g) Hamed, O.; Henry, P. M.
Organometallics 1997, 16, 4903–4909. (h) Hamed, O.; Thompson, C.; Henry,
P. M. J. Org. Chem. 1997, 62, 7082–7083. (i) Hamed, O.; Henry, P. M.;
Thompson, C. J. Org. Chem. 1999, 64, 7745–7750.
(8) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620–1621.
(b) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468–16476. (c)
Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893–
2901.
(9) (a) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am.
Chem. Soc. 2004, 126, 3036–3037. (b) Trend, R. M.; Ramtohul, Y. K.; Stoltz,
B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788.
(10) (a) Kawai, N.; Lagrange, J. -M.; Ohmi, M.; Uenishi, J. J. Org. Chem.
2006, 71, 4530–4537. (b) Kawai, N.; Lagrange, J. -M.; Uenishi, J. Eur. J. Org.
Chem. 2007, 2808–2814. (c) Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron:
Asymmetry 2005, 16, 1299–1303. (d) Uenishi, J.; Vikhe, Y. S.; Kawai, N.
Chem. Asian J. 2008, 3, 473–483. (e) Hande, S. M.; Kawai, N.; Uenishi, J. J.
Org. Chem. 2009, 74, 244–253.
FIGURE 1. Structures of precursors (S)-1, (R)-1, and (R)-3 and
expected products (R)-2 and (S)-2.
Synthesis of Precursors of the Reaction. The synthesis of
precursors (S)-1, (R)-1, and (R)-3 are shown in Scheme 4.
The chiral centers of the secondary allylic alcohols (S)-1 and
(R)-1 are constructed by Carreira’s asymmetric alkyny-
lation.11 The addition of 4-phenyl-1-butyne to cyclohexane-
carboxaldehyde in the presence of Zn(OTf)2 and triethyla-
mine with chiral ligand (-)-N-methylephedrine gave (S)-4 in
89% yield with 97% ee, while the same reaction using
(þ)-N-methylephedrine gave (R)-4 in 98% yield with 98% ee.
€
(11) For the asymmetric addition, see: Frantz, D. E.; Fassler, R.;
Carreira, E. M J. Am. Chem. Soc. 2000, 122, 1806–1807.
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SCHEME 4. Asymmetric Synthesis of Precursors (S)-1, (R)-1, and (R)-3
SCHEME 5. Preparation of Authentic Materials (S)-7 and (R)-7
The partial reduction of the triple bond of (S)-4 and (R)-4 was
performed with Red-Al in refluxing THF to afford trans-
alkenes (S)-1 in 89% and (R)-1 in 91% yield, respectively.12
The preparation of (Z)-allylic alcohol (R)-3 was performed in
three steps from (R)-4. Cis hydrogenation of (R)-4 in the
presence of Lindlar’s catalyst under a hydrogen atmosphere
was slow and gave an inseparable mixture of (R)-3 and (R)-4
after 3 days. Therefore, after benzoylation of the mixture
and separation of the corresponding benzoates, allyl ben-
zoate (R)-5 was isolated in 30% yield along with a benzoate
of (R)-4 in 52% yield in two steps. Finally, saponification of
(R)-5 gave pure (R)-3 in 77% yield.
Determination of Absolute Configurations. The absolute
stereochemistry of (R)-2 and (S)-2 could be determined after
converting them to 1,2-dimethoxy-4-phenylbutane (S)-7 and
(R)-7 and comparing them with the authentic optically pure
(R)- and (S)-compounds (S)-7 and (R)-7. The authentic
samples would be prepared in two steps from 4-phenyl-
1-butene, as shown in Scheme 5. The Sharpless asymmetric
dihydroxylation of 4-phenylbutene with AD-mix-R gave
(S)-6 with 78% ee in quantitative yield.13 O-Methylation of
(S)-6 with iodomethane and NaH gave (S)-7 in 83% yield.
Similarly, its enantiomer (R)-7 was obtained with 82% ee in
two steps using AD-mix-β instead of AD-mix-R in the first
step. These enantiomers were separable in chiral HPLC.
Intermolecular Chirality Transfer Reaction. First, (R)-1
(98% ee) was treated with PdCl2(CH3CN2) (30 mol %) in
absolute methanol at room temperature for 12 h to give 2 in
82% yield. Chiral HPLC analysis revealed an enantiomeric
ratio of a 3:97. It was then converted to 7 using the following
two-step reaction sequence: (i) ozonolysis and reduction of
the resulting ozonide with NaBH4; (ii) O-methylation of its
sodium salt with iodomethane (Scheme 6). This conversion
gave 1,2-dimethoxy-4-phenylbutane 7 in 97% yield, of which
the stereochemistry of the major enantiomer was identified
to be (S)-7 by chiral HPLC analysis in comparison with the
authentic materials prepared in Scheme 5. The reaction of
(S)-1 (97% ee) under the same reaction conditions gave (R)-2
(13) (a) Wang, Z. -M.; Zang, X. -L.; Sharpless, K. B. Tetrahedron Lett.
1993, 34, 2267–2270. (b) Wang, F. -D.; Yue, J. -M. Eur. J. Org. Chem. 2005,
2575–2579.
(12) Compound (S)-1 has been reported; see: Ji, J. -X.; Qiu, L. -Q.;
Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68, 1589–1590.
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TABLE 1. PdII-Catalyzed Intermolecular Oxypalladation Reaction in Different Solvents
entry
solvent MeOH (equiv)
MeOH
time
12 h
2, yield a(%)
ratiob (R)-2/(S)-2
9, yield (%)
1
2
82
65
58
40
84
63
3:97
33:67
50:50
66:34
19:81
31:69
3
12
28
12
13
15
THF MeOH (10 equiv)
MeOH LiCl (3 M soln.)
CH3CN MeOH (10 equiv)
Toluene MeOH (10 equiv)
CH2Cl2 MeOH (10 equiv)
DMF MeOH (10 equiv)
26 h
3
4 daysc
2 daysc
22 h
4b
5
6
45 min
3 daysd
7d
a Combined yields of (R)-2 and (S)-2. bThe ratios were determined by chiral HPLC analysis. c The reaction was not complete. dNo reaction occurred.
SCHEME 6. Intermolecular Oxypalladation Reaction of (R)-1
and (S)-1
of (R)-3 in 36% yield (Scheme 7). It is interesting to note that
the oxypalladation reactions of (R)-1 and (R)-3, having a
configurationally different alkenyl unit, produced different
enantiomers (S)-2 and (R)-2 with excellent selectivity. Use
of both the (E)- and/or (Z)-allyl alcohols does not alter
the mode of the oxypalladation reaction, that is, syn-SN20
reaction takes place totally through a highly selective 1,3-
chirality transfer process. It is interesting that Henry et al.
reported that the reactions of both (Z,R)- and (E,R)-allylic
alcohols with water in the presence of K2PdCl4 under a 0.1 M
of chloride ion concentration afforded the same (R)-enan-
tiomer, and the ee values of each of the starting allylic
alcohols (66% and 65%) decreased to 28% and 42% in the
products, respectively.7i In comparison with their results, the
chirality transfer reactions in our study gave syn-SN20 reac-
tion product through the same mode of oxypalladation. This
stereochemical behavior was similar to that of the intramo-
lecular oxypalladation reactions.9,10
Solvent Effect and Stereoselectivity. Next, the reaction of
(R)-1 and methanol was carried out in various solvents with
PdCl2(CH3CN) 2 (30 mol %) at room temperature, and the
results are summarized in Table 1. The result from Scheme 6
is listed in entry 1 for comparison. The reaction in THF
gave (S)-2 as a major isomer in 65% yield with retention of
the configuration the same as in methanol. The selectivity
[(R)-2:(S)-2=33:67] was lower than that (3:97) in methanol,
indicating that two modes of oxypalladation occurred
simultaneously (entry 2). Careful analysis of the product
revealed the formation of methyl ether 9 in 12% yield.
Addition of an excess of LiCl in methanol (3 M solution)
deaccelerated the reaction rate and gave racemic products
(entry 3). No high chloride concentration effect was ob-
served. The result was more interesting when the reaction
was carried out in CH3CN (entry 4). The reaction rate was
slow and gave (R)-2 as a major isomer in a 66:34 ratio,
which was a completely opposite stereochemical outcome
to others. This result suggests that the chirality transfer in
CH3CN and other solvents altered the mode of methox-
ypalladation. The reaction in toluene gave the product in
a satisfactory yield with good selectivity (entry 5). Sur-
prisingly, the reaction in CH2Cl2 was faster than that in
methanol (entry 6 vs entry 1) and was completed in 45 min
with moderate chemical yield in a 31:69 ratio, which was
similar to that in THF. No reaction occurred in DMF even
after 3 days (entry 7).
SCHEME 7. Intermolecular Oxypalladation Reaction of (R)-3
in 70% yield with excellent selectivity in a 94:6 ratio. The
stereochemistry of the major enantiomer was confirmed to
be R using the same analysis as above. Therefore, (S)-2 was
obtained as a syn-SN20 product from (R)-1, and (R)-2 was
obtained as a syn-SN20 product from (S)-1.
Similar to the reactions of (R)-1 and (S)-1, an oxypallada-
tion reaction of (Z)-allyl alcohol (R)-3 (98% ee) was carried
out with PdCl2(CH3CN)2 (30 mol %) in absolute methanol
at room temperature. The reaction was slower than that of
the (E)-allyl alcohols and took 22 h to give (R)-2 in 53% yield
with excellent selectivity (94:6 ratio), along with the recovery
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SCHEME 8. Intermolecular Oxypalladation Reaction of Ethyl Allyl Ether (R)-10
SCHEME 9. Proposed Reaction Mechanism for Intermolecular Oxypalladation Reaction
Compound 9 was isolated in a 3% to 28% yield in all
reactions. The longer the reaction time, the more byproduct
9 was produced, suggesting that 9 might be formed from 2.
One may consider the possibility that π-allyl Pd intermediate
would be generated from 1. However, it is not rational
because the PdII catalyst could not be regenerated from
Pd0 in the absence of an oxidant in the catalytic cycle. Despite
many attempts, the enantiomers of 9 would not be separate
on chiral HPLC. In order to confirm its mechanistic pathway
as well as its stereochemistry, we prepared substrate (R)-10
by ethylation of (R)-1 and subjected it to the reaction as
shown in Scheme 8. When optically pure (R)-10 (98% ee) was
treated with PdCl2(CH3CN)2 (30 mol %) in absolute metha-
nol at room temperature for 24 h, a mixture of (S)-2 and (R)-2
resulted in 30% yield with a 85:15 ratio along with 35%
recovery of the starting material. Therefore, alkyl allyl ether
is not a good substrate for the oxypalldation reaction, but the
reaction surely occurs stereoselectively with 1,3-chirality trans-
fer. This result indicates that the rate of second oxypalladation
of methyl allyl ether 2 is much slower than that of allyl alcohol
in the reaction of 1 in methanol. This reaction mechanism is
discussed in the next section.
π-complex II, which exists in equilibrium with I. Then, a syn
attack of the coordinated methanol in the intermediate II gives
σ-alkyl Pd intermediate III through syn oxypalladation.14
Finally, syn elimination of PdCl(OH) gives the major syn-
SN20 product (S)-2. The minor anti-SN20 product (R)-2 is
formed by the anti oxypalladation with methanol from I.
Thus, a methanol attacks externally from the back side of
π-olefin Pd complex of I to form σ-alkyl Pd intermediate IV
through anti oxypalladation, which undergoes syn elimination
of PdCl(OH) to afford (R)-2. PdCl2 can be regenerated by the
reaction of PdCl(OH) with HCl in its catalytic cycle. These
results suggest that the selectivity depends on the formation of
π-olefin Pd intermediates I or II, and solvents may play an
important role in this process. When the π-olefin Pd complex I
is solvated well with a polar solvent like CH3CN, the nucleo-
philic attack of methanol takes place from the backside of
π-olefin Pd complex I and results in anti oxypalladation to give
IV.15 In methanol, as in THF, toluene, or CH2Cl2, the inter-
mediate II can generate favorably in an equilibrium between I
and II. Syn attack of a methanol to II occurs to give III. Our
experimental results strongly support the hypothesis that the
intermolecular oxypalladation reaction proceeds through syn
oxypalladation.
Proposed Reaction Mechanism. Based on the above results,
we propose the reaction mechanism of PdII-catalyzed inter-
molecular oxypalladation reaction, depicted in Scheme 9.
First, PdCl2 coordinates to form π-olefin Pd complex I syn
selectively on alkene with respect to the chiral allylic alcohol.
Ligand exchange with a methanol occurs to generate another
(14) A migratory attack of coordinated oxy nucleophile on the Pd
complex to olefin was supported by the calculation study; see: Nelson, D.
J.; Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564–1568.
(15) Anti oxypalladation product in CH3CN was also reported in ref 5c.
The result can be explained similarly.
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Vikhe et al.
SCHEME 10. Mechanistic Consideration of Intermolecular Oxypalladation Reaction of Ethyl Allyl Ether (R)-10
JOCFeatured Article
As described, we assumed the formation of 9 from 2 in the
reaction of 1 based on the evidence that the reaction of allyl
ethyl ether (R)-10 with methanol gave (S)-2 predominantly.
The plausible intermediates in the mechanism for the for-
mation of (S)-2 and (R)-2 in a 85:15 ratio were described in
Scheme 10. As shown in the parentheses, there are four
possible intermediates, V-VIII, depending on the combina-
tion of syn and/or anti coordination/oxypalladation pro-
cesses. Syn elimination of PdCl(OEt) from the intermediate
V takes place to give major isomer (S)-2, while syn elimina-
tion of PdCl(OMe) from V reverts back to (R)-10. Syn
elimination of PdCl(OEt) from anti oxypalladation inter-
mediate VI proceeds because of the formation of some (R)-2
in the experimental result. Since no (Z)-allyl ethers such as 11
and 12 were produced, anti elimination did not occur in the
intermediates VI to VIII.
These results clearly indicated that the formation of
(S)-2 occurred from (R)-10 through syn oxypalladation and
syn elimination with excellent selectivity. Therefore, the
formation of methyl allyl ether 9 can be explained similarly
as a second order product from 2 under the reaction condi-
tions. However, it is less stereospecific than allylic alcohol
substrates.
methanol. The results indicate that syn or anti stereochemistry
in the intermolecular oxypalladation process is anticipated
not to be simple. However, at least in methanol, syn oxypalla-
dation occurs with high 1,3-chirality transfer. Similarly, using
(R)-10 as a substrate, we have demonstrated that allyl ether 9
could be formed from allyl ether 2 through syn oxypalladation
and syn elimination. In this study, we successfully answered
questions regarding the mechanisms inherent in intermolecu-
lar oxypalladation and provided clear evidence to support our
conclusions.
Experimental Section
General Conditions for PdII-Catalyzed Reaction in Methanol.
To a solution of 1, 3, or 10 (0.1 mmol) in absolute methanol
(2.5 mL) was added PdCl2(CH3CN)2 (7.8 mg, 30 mol %) at
room temperature. After being stirred for 12-24 h, the reaction
mixture was diluted with ethyl acetate and filtered through a
Celite pad. The solvent was evaporated, and the residue was
purified by column chromatography on silica gel eluted with 3%
EtOAc in hexane to give 2. The chemical yield and reaction time
are indicated below.
The reaction of (R)-1 (98% ee) gave (E,3S)-1-cyclohexyl-
3-methoxy-5-phenylpentene [(S)-2] in 82% yield with 93% ee:
reaction time 12 h; colorless oil; Rf=0.33 (3% EtOAc in hexane);
[R]21 -15.9 (c 0.86, CHCl3); 1H NMR (300 MHz, CDCl3)
D
Conclusions
δ 7.29-7.14 (m, 5H), 5.53 (dd, J=15.5, 6.6 Hz, 1H), 5.25 (ddd,
J=15.5, 8.1, 1.2 Hz, 1H), 3.43 (q, J=6.6 Hz, 1H), 3.24 (s, 3H),
2.65 (td, J =6.9, 1.4 Hz, 2H), 2.03-1.85 (m, 2H), 1.79-1.61
(m, 6H), 1.34-1.02 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 142.2 (ph), 140.6 (C-1), 128.5 (ph),128.3 (ph), 127.4 (C-2),
125.7 (ph), 81.8 (C-3), 55.6 (OMe), 40.4 (C-4), 37.2 (C-5), 33.0
In summary, we have demonstrated that oxypalladation of
the chiral nonracemic allylic substrate with PdCl2(CH3CN)2
catalyst in methanol gives syn-SN20 product stereospecifically
with 1,3-chirality transfer. The reaction can be explained by
syn coordination of the PdII catalyst on alkene directed by the
chiral allylic alcohol, followed by syn oxypalladation and syn
elimination in methanol. A considerable amount of anti-SN20
product can be obtained using solvents such as THF, toluene,
and CH2Cl2. When CH3CN was used as a solvent, anti-SN20
product was formed as a major isomer in a 2:1 ratio. We
proposed that the equilibrium between π-olefin Pd intermedi-
ates IandIIdeterminesthe pathwayofthesyn or anti attack of
(c-hexyl), 31.7 (c-hexyl), 26.1 (c-hexyl), 26.0 (c-hexyl); IR (film, cm-1
)
3025, 2923, 2851, 1603, 1495, 1449, 1349, 1102, 971, 891, 745,
699; MS (EI) m/z 258 (Mþ), 226, 175, 162, 153; HRMS calcd for
C18H26O (Mþ) 258.1984, found m/z 258.1980. Enantiomeric
excess value was determined by chiral HPLC [column: Daicel
Chiralcel ODH, UV detection at 254 nm, solvent: 2-propanol/
hexane (1/99), flow rate 0.5 mL min-1, retention time: (S)-2 tR=
8.3 min and (R)-2 tR=27.2 min].
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The reaction of (S)-1 (97% ee) gave (E,3R)-1-cyclohexyl-
3-methoxy-5-phenylpentene [(R)-2] in 70% yield with 88% ee:
reaction time 14 h; [R]21D þ16.3 (c 0.57, CHCl3). Other physical
and spectroscopic data are the same as described for (R)-2.
The reaction of (R)-3 (98% ee) gave (R)-2 in 53% yield with
89% ee along with a recovery of the starting material in 36%
yield: reaction time 22 h.
The reaction of (R)-10 (98% ee) gave (S)-2 in 30% yield with
69% ee along with a recovery of the starting material in 35%
yield: reaction time 24 h.
with 15% EtOAc in hexane afforded (R)-7 (56.3 mg) in 96% yield.
(R)-1,2-Dimethoxy-4-phenylbutane: colorless oil; [R]25 -4.73
(c 1.14, CHCl3); Rf = 0.38 (20% EtOAc in hexane); H NMR
D
1
(300 MHz, CDCl3) δ 7.30-7.14 (m, 5H), 3.42 (s, 3H), 3.36 (s, 3H),
3.43-3.29 (m, 3H), 2.78-2.60 (m, 2H), 1.89-1.77 (m, 2H); 13C
NMR (75 MHz, CDCl3)δ142.0 (ph), 128.37 (ph), 128.3 (ph), 125.7
(ph), 79.1 (C-2), 74.4 (C-1), 59.1 (OMe), 57.3 (OMe), 33.0 (C-3),
31.5 (C-4); IR (film, cm-1) 3026, 2926, 1603, 1496, 1455, 1358,
1193, 1128, 965, 746, 700; MS (CI) m/z 195 (Mþþ1); HRMS calcd
for C12H19O2 (Mþþ1) 195.1385, found m/z 195.1381. The ee value
was determined to be 82% ee by chiral HPLC analysis [column:
Daicel Chiralcel ODH, 254 nm, solvent: 2-propanol/hexane
(10:90), flow rate: 0.5 mL min-1, (R)-7: 14.6 min and (S)-7:
8.9 min]. The synthesis of (S)-6 was prepared quantitatively in
similar manner as described for preparation of (R)-6 using AD-
mix-R instead of AD-mix-β. The ee value was identified to be 78%.
Compound (S)-7 was prepared from (S)-6 in 83% yield with 77%
ee by the same manner as described for preparation of (R)-7.
Transformation of 2 to 7. Through a solution of 2 (20 mg,
0.077 mmol) in CH2Cl2 (2 mL) was bubbled a dilute stream of O3
in O2 at -78 °C for 2-3 min until a blue color persisted in the
solution. An excess of ozone was removed by bubbling
N2 gas. NaBH4 (11.7 mg, 0.309 mmol) was added, and the
reaction mixture was warmed to room temperature during 1 h.
MeOH (0.5 mL) was added, and the mixture was stirred for an
additional 30 min. After the addition of satd NH4Cl (5 mL), the
mixture was extracted with CH2Cl2 (5 mL ꢀ 3) and dried over
MgSO4. Evaporation of solvent and purification of the residue
on silica gel column chromatography eluted with 60% EtOAc in
hexane afforded 8 (13.8 mg) in quantitative yield. Physical and
spectroscopic data of (S)-8, which was derived from (S)-2. (R)-2-
General Conditions for PdII-Catalyzed Reaction in Other
Organic Solvents. To a solution of (R)-1 (0.1 mmol) and methanol
(40 μL, 1 mmol) in each dry solvent (1.5 mL) (THF, CH3CN,
toluene, CH2Cl2, or DMF) was added [PdCl2(CH3CN)2] (7.8 mg,
30 mol %) at room temperature. The mixture was stirred for
appropriate time listedinTable1, dilutedwithEtOAc, andfiltered
through Celite pad. The solvent was evaporated and the residue
was purified by column chromatography on silica gel eluted with
3% EtOAc in hexane to give 2. All the products including the
side product 9 were separable by HPLC (normal-phase silica
gel column). Their chemical yields are listed in Table 1. (E)-(5-
Cyclohexyl-5-methoxypent-3-enyl)benzene (9): colorless oil; Rf=
0.33 (3% EtOAc in hexane); 1H NMR(300 MHz, CDCl3) δ 7.29-
7.24 (m, 2H), 7.18-7.14 (m, 3H), 5.55 (dt, J=15.4, 6.7 Hz, 1H),
5.26 (ddt, J=15.4, 6.9, 1.2 Hz, 1H), 3.17 (s, 3H), 3.15 (dd, J=7.3,
6.7 Hz, 1H), 1.83-1.78 (m, 1H), 1.72-1.52(m, 4H),1.43-1.30 (m,
1H), 1.25-1.04 (m, 3H), 0.94-0.78 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 141.6 (ph), 133.6 (C-4), 129.8 (C-3), 128.4 (ph), 128.2
(ph), 125.7 (ph), 87.2 (C-5), 56.0 (OMe), 42.4 (C-2), 35.7 (C-1),
34.0 (c-hexyl), 29.2 (c-hexyl), 28.7 (c-hexyl), 26.6 (c-hexyl), 26.14
(c-hexyl), 26.1 (c-hexyl); IR (film, cm-1) 2922, 2850, 2352, 1450,
1096, 962; MS (EI) m/z 258 (Mþ), 175, 153, 143; HRMS calcd for
C18H26O (Mþ) 258.1984, found m/z 258.1991.
Methoxy-4-phenylbutanol: colorless oil; [R]20 þ20.1 (c 0.85,
D
CHCl3); Rf=0.1 (20% EtOAc in hexane); 1H NMR (300 MHz,
CDCl3) δ 7.30-7.15 (m, 5H), 3.70 (dd, J=11.5, 3.4 Hz, 1H), 3.53
(dd, J=11.7, 5.8 Hz, 1H), 3.40 (s, 3H), 3.31-3.23 (m, 1H), 2.67
Preparation of the Standard Compounds (R)-7 and (S)-7.16 To
a stirred solution of AD-mix-β (1.4 g) in a 1:1 mixture of
t-BuOH/H2O (10 mL) was added 4-phenyl-1-butene (132 mg) at
0 °C, and the mixture was stirred overnight at the same
temperature. Then, Na2SO3 (1.5 g) was added to the mixture,
and the stirring was continued at room temperature for 30 min.
The organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layer was
washed with brine and water and dried over MgSO4. Evapora-
tion of the solvent and purification of the residue on silica gel
column chromatography eluted with 15% EtOAc in hexane
afforded (R)-613b in quantitative yield. (R)-4-Phenylbutane-1,2-
diol: colorless oil; Rf=0.27 (80% EtOAc in hexane); 1H NMR
(300 MHz, CDCl3) δ 7.31-7.16 (m, 5H), 3.72-3.64 (m, 2H),
3.47 (dd, J=7.5, 7.8 Hz, 1H), 2.86-2.64 (m, 2H), 2.33 (bs, 1H),
2.12 (bs, 1H), 1.84-1.70 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 141.6 (ph), 128.43 (ph), 128.37 (ph), 125.9 (ph), 71.4 (C-2), 66.7
(C-1), 34.6 (C-3), 31.7 (C-4). The ee value of (R)-6 was deter-
mined to be 82% ee by chiral HPLC analysis [column: Daicel
Chiralcel ODH, 254 nm, solvent: 2-propanol/hexane (20: 80)
flow rate: 1 mL min-1, (R)-6: 7.2 min and (S)-6: 9.4 min]. To a
solution of (R)-6 (50 mg, 0.3 mmol) in THF (1.7 mL) was added
NaH (36 mg, 0.9 mmol) at 0 °C. After the reaction mixture
was stirred for 10 min at the same temperature, MeI (0.25 mL,
1.8 mmol) was added. The reaction mixture was stirred at room
temperature for 3.5 h and then quenched with satd NH4Cl
(5 mL), extracted with EtOAc (10 mL ꢀ 3), washed with water,
and dried over MgSO4. Evaporation of the solvent and purifica-
tion of the residue on silica gel column chromatography eluted
(td, J=7.3, 1.2 Hz, 2H), 2.15 (br s, 1H), 1.97-1.70 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 141.8 (ph), 128.4 (ph), 128.3 (ph),
125.8 (ph), 80.6 C-2), 63.6 (C-1), 57.0 (OMe), 32.1 (C-3), 31.4
(C-4). IR (film, cm-1) 3433 2930 1601 1455 1115 692; MS (EI) m/z
180 (Mþ), 149, 148, 130, 117; HRMS calcd for C11H16O2 (Mþ)
180.1150, found m/z 180.1156. To a solution of 8 (10 mg,
5.5 μmol) in THF (1 mL) at 0 °C was added NaH (5.2 mg,
0.22 mmol), and the mixture was stirred for 10 min at the same
temperature. MeI (83 μL, 0.55 mmol) was then added, and
the mixture was stirred for 24 h at room temperature. Themixture
was quenched with satd NH4Cl (5 mL) and extracted with EtOAc
(10 mL ꢀ 3). The combined extract was dried over MgSO4 and
condensed. The residual oil was purified by column chromato-
graphy on silica gel eluted with 15% EtOAc in hexane to give 7
(10.5 mg) in 98% yield. The ee value was determined by chiral
HPLC analysis under the same conditions described above.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research and in part by the 21st COE
Program from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting Information Available: Synthetic procedures
and physical and characterization data for compounds (R)-1,
(S)-1, (R)-3, (R)-4, (S)-4, (R)-5, and (R)-10, copies of 1H NMR
and 13C NMR spectra for compounds 1, 2, 3, 5-10, and chiral
HPLC charts of racemic and optically active compounds for
1, 2, 6, and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) For racemic 7, see: Norman, R. O. C.; Parr, W. J. E.; Thomas, C. B.
J. Chem. Soc. Perkin Trans. 1 1976, 811–817.
5180 J. Org. Chem. Vol. 74, No. 15, 2009