Pd(II)-catalyzed aliphatic Claisen rearrangements of acyclic allyl vinyl ethers

Article abstract of DOI:10.1016/j.tet.2008.04.056

Palladium (II)-catalyzed [3,3] sigmatropic rearrangement of acyclic allyl vinyl ethers delivers 2,3-anti disubstituted pentenal Claisen adducts with high diastereoselectivity. Reaction conditions for circumventing allyl vinyl ether cleavage that had previ

Full text of DOI:10.1016/j.tet.2008.04.056

Tetrahedron 64 (2008) 6863–6869
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-catalyzed aliphatic Claisen rearrangements of acyclic allyl vinyl ethers
*
Nessan J. Kerrigan, Christopher J. Bungard, Scott G. Nelson
University of Pittsburgh Center for Chemical Methodologies and Library Development University of Pittsburgh, Department of Chemistry, Pittsburgh, PA 15260, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium (II)-catalyzed [3,3] sigmatropic rearrangement of acyclic allyl vinyl ethers delivers 2,3-anti
Received 31 January 2008
Received in revised form 11 April 2008
Accepted 14 April 2008
disubstituted pentenal Claisen adducts with high diastereoselectivity. Reaction conditions for circum-
venting allyl vinyl ether cleavage that had previously plagued catalyzed rearrangement of
a-un-
substituted vinyl ether substrates are described. Merging Pd(II) catalysis with the facile access to the
Claisen substrates afforded by Ir(I)-catalyzed olefin isomerization provides an expedient procedure for
realizing asymmetric anti-selective Claisen rearrangements.
Available online 18 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Background
Activating
p
-bonds through coordination to transition metal
Transition metal catalysis offers a strategy for accessing [3,3]
sigmatropic rearrangements that are stereochemically comple-
mentary to their thermal counterparts. Nakai demonstrated that
complexes constitutes one of the most fundamental mechanisms in
catalysis. As a result, catalyzed additions to alkenes are most
commonly associated with late transition metal–olefin co-
ordination leading to an activated, electrophilic h2 complex.1 This
analysis has undoubtedly contributed to the development of [3,3]
sigmatropic rearrangements catalyzed by complexation-induced
activation of the olefin residues in the ubiquitous 1,5-diene sub-
strates (Fig. 1).2,3 The ability of Pd(II) complexes to activate olefins
toward nucleophilic attack has proven especially useful in
developing catalyzed Cope,4 Claisen,5 and hetero-Claisen rear-
rangements.6 The complementary stereoselectivity exhibited by
Pd(II)-catalyzed Claisen variants relative to their thermal counter-
parts affords unique opportunities to execute syn- or anti-selective
rearrangements from a common substrate. Unfortunately, extend-
ing Pd(II) catalysis to diene substrates yielding aldehyde-containing
Claisen adducts has yielded limited success.5a In pursuit of gener-
ally useful, operationally simple aliphatic Claisen rearrangements,
we were interested in circumventing these difficulties to realize
anti-selective Claisen rearrangements to complement the syn-se-
lective thermal variants. Toward this goal, this account describes
the development of efficient Pd(II)-catalyzed aliphatic Claisen
rearrangements of acyclic allyl vinyl ethers affording 2,3-anti 4-
pentenal products with uniformly high diastereoselection (anti/
synꢀ95:5).
Pd(II)-catalyzed Claisen rearrangements of a-substituted allyl vinyl
ethers proceed with high anti diastereoselection presumably due to
the boat-type transition state enforced by bidentate substrate–
catalyst coordination (Eq. 1).5b However, van der Baan had pre-
viously observed that attempted Pd(II)-catalyzed rearrangement of
a-unsubstituted allyl vinyl ethers afforded minor amounts of
Claisen adduct 1 and significant quantities of allylic alcohol 2 (Eq.
2).5a We have been interested in merging catalyzed olefin isomer-
ization with thermal [3,3] sigmatropic rearrangements as a strategy
for developing operationally simple, aliphatic Claisen rearrange-
ments.7,8 Engaging the allyl vinyl ethers emerging from the Ir(I)-
catalyzed olefin isomerization in Pd(II)-catalyzed [3,3] sigmatropic
rearrangement offered an attractive strategy for obtaining the
stereochemically complementary anti Claisen adducts, provided
the competing ‘hydrolysis’ pathway could be circumvented.
R1
OHC
10 mol % (iPrCN)2PdCl2
O
R1
i
5 equiv PrCN, tol
R3
R2
R3
anti:syn ≥ 95:5
(71-84%)
R2
40 °C
2 mol %
[Ir(PCy3)3]+
O
R1
R3
R2
* Corresponding author. Tel.: þ1 412 624 4290; fax: þ1 412 624 8611.
E-mail address: sgnelson@pitt.edu (S.G. Nelson).
Figure 1. Pd(II)-catalyzed Claisen rearrangements of acyclic allyl vinyl ethers.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.056

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N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
Useful reaction catalysts were generally limited to nitrile com-
O
O
Me
10 mol %
H
plexes of palladium(II) dihalide complexes; the corresponding
bis(phosphine) or bis(amine) complexes expressed little or no
catalytic activity. Complexes possessing weakly- or non-co-
ordinating counterions (e.g., PdI2, Pd(OTf)2, Pd(NO2)Cl) afforded
extensive substrate decomposition or Claisen adducts with little
diastereoselectivity. We had observed a similar phenomenon in
thermal Claisen rearrangements where Lewis acidic contaminants
(MeCN)2PdCl2
(78%)
Me
ð1Þ
ð2Þ
88:12
(syn:anti)
Nakai Tetrahedron Lett. 1987, 28, 5879.
5 mol %
(MeCN)2PdCl2
promote epimerization of the chiral a-substituted aldehyde Claisen
Me
Me
OHC
Me
adduct.7a Using 7.5–10 mol % of the optimized catalyst system
afforded the highest reaction yields; using 5 mol % catalyst led to
a measurable decrease in reaction efficiency (Table 1, entry e).
Palladium-catalyzed Claisen rearrangements are generally
interpreted according to the mechanism originally enumerated by
Nakai (Fig. 2).5b,d To rationalize the anti diastereoselection emerg-
ing from Pd(II)-catalyzed Claisen rearrangements, a Pd(II)–diolefin
complex 6 was implicated as an operative intermediate. Substrate
chelation of the Pd(II) catalyst favors the boat-type conformation 6
relative to the higher energy chair-type chelate 7. While this model
provides an explanation for the observed anti distereoselection, the
process by which these Pd(II)-templated diolefin complexes ulti-
mately arrive at the Claisen adduct has not been explicitly defined.
O
OH
+
Me
Me
1 (18%)
2
van der Baan Tetrahedron Lett.1986,27, 6267.
3. Results and discussion
Allyl vinyl ether 3a served as a representative test substrate for
evaluating the Pd(II)-catalyzed aliphatic Claisen rearrangements. In
accord with van der Baan’s observation, reacting 3a with 5–
10 mol % (MeCN)2PdCl2 afforded a mixture of Claisen adduct 4a and
the allylic alcohol 5 (Eq. 3).5a Evaluating reaction efficiency as
a function of catalyst structure revealed a strong correlation be-
tween product distribution and ligand addend. Specifically, the
Presumably, 6 exists in equilibrium with the s-bound Pd(II) com-
plex 8 obtained by addition of the electron-rich vinyl ether to the
Pd(II) center. Ensuing migratory insertion would deliver oxo-
carbenium ion 9, an intermediate common to related transition
metal-catalyzed [3,3] sigmatropic rearrangements proceeding
via the cyclization-induced rearrangement mechanism.6 Collapse
Pd(II)-catalyzed Claisen rearrangement of
a-unsubstituted allyl
vinyl ether 3a proved to be especially responsive to alkyl nitrile
additives. Using acetonitrile as solvent or cosolvent in the Claisen
rearrangements decreased reaction rates dramatically, presumably
due to saturation of the Pd(II) coordination sphere. Nitriles having
electronically- or sterically-diminished competency as ligands rel-
ative to acetonitrile, however, effectively mitigated the putative
hydrolysis side reaction.
of 9 via
b-elimination of the oxocarbenium ion regenerates the
Pd(II) catalyst in delivering the 2,3-anti Claisen rearrangement
product 10.
This mechanistic analysis provides a guide for interpreting the
ligand-dependent product distribution observed for the Pd(II)-
catalyzed rearrangements of aliphatic allyl vinyl ethers.11 We
speculate that addition of an adventitious nucleophile to oxo-
carbenium ion 9 yields the organopalladium species 11 (Fig. 3,
5 mol %
(MeCN)2PdCl2
Me
Me
OHC
Me
Me
O
OH
+
nBu
nBu
Me
nBu
0
pathway a). Collapse of 9 by C2 –C3 bond fragmentation would
3a
4a
5
generate the allylic alcohol 12 and provide a viable pathway for the
apparent substrate hydrolysis observed by van der Bann. Support
for this hypothesis was derived from the observation that vinyl
ether 13 and allylic ether 14, substrates that cannot undergo cy-
clization to generate an oxocarbenium ion intermediate, were im-
mune to ether hydrolysis under the catalyzed Claisen conditions
(Eq. 4). This analysis suggested that accelerating the collapse of
oxocarbenium ion 9 via C1–O fragmentation would minimize the
putative bimolecular addition believed responsible for allylic al-
cohol formation (pathway b). Partitioning the competing reaction
mechanisms accordingly required Lewis basic additives expressing
poor nucleophilicity toward the oxocarbenium ion yet representing
strong ligands for Pd(II). The increased electron density at palla-
dium accompanying Lewis base coordination was expected to
labilize the Pd–C bond and accelerate the desired collapse of
4a:5
67:33
85:15
% yield 4a
Additive
none
PhCN (1 equiv)
43
58
PhCN (5 equiv)
95:5
69
ð3Þ
i
Thus, adding 1 equiv of PhCN or PrCN to the Pd(II)-catalyzed
rearrangement of 3a further increased the percentage of Claisen
adduct (4a/5¼85:15); adding up to 5 equiv of the nitrile affords 4a
contaminated with only 5% of the allylic alcohol (4a/5¼95:5).9,10
The nitrile additive was also revealed to have an ancillary ben-
efit beyond limiting allylic alcohol production (Table 1). Claisen
rearrangement could be conducted at 40 ꢁC without significant
catalyst decomposition and no detectable thermal background re-
action leading to significantly decreased reaction times (w96 h at
23 ꢁC/w24 h at 40 ꢁC) (entries a and b).5f Reactions conducted at
elevated temperature without the nitrile additive led to rapid Pd(0)
formation and correspondingly decreased reaction efficiency.
R1
R1
R2
PdL2
R1
R2
L
O
O
L
L
Pd
R2
L
O
Pd
O
Table 1
6
7
Effect of reaction variables on Claisen rearrangement efficiencya (3a/4a)
Entry
Catalyst
Temperature (ꢁC)
Time (h)
4a (% yield)
R1
R1
R1
R2
R2
1
2
3
4
5
10 mol % (iPrCN)2PdCl2
10 mol % (iPrCN)2PdCl2
10 mol % (iPrCN)2PdBr2
7.5 mol % (iPrCN)2PdCl2
5 mol % (iPrCN)2PdCl2
23
40
40
40
40
48
24
24
34
48
55
74
70
68
50
R2
Pd
H
O
L
H
O
PdL
10
9
8
a
Toluene was used as the reaction solvent (0.02 M).
Figure 2. Postulated mechanism for Pd(II)-catalyzed Claisen rearrangements.

N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
6865
Nu
concentrations of the Pd(II)–olefin complex leading to cyclization-
induced rearrangement and allowing lower catalyst loadings
(5 mol %) to be used. In this instance, the Pd(II)-catalyzed Claisen
rearrangement is substantially more efficient than the thermal al-
ternative that proceeds in only modest chemical yield and with
eroded olefin geometry control.
1'
2
R1
R2
R1
R2
R1
R2
2'
3
Pd(II)
(a)
O
O
O
1
Nu:
R3
R3
R3
PdCl
PdCl
9
11
Me
n
Bu
2 mol %
L
OHC
Me
[Ir(PCy3)3]+
39 °C
Conditions
n
n
O
O
Bu
Bu
(ligand)
H
R1
R2
R1
R2
(R)-19
OH
17
Ph (99% ee)
18
(b)
O
R3
O
n
Ph
Ph
Bu
Me
R3
12
Conditions
Result
Pd
10
Cl
L
i
84% (R)-19
(93% ee)
5 mol % (BuCN)PdCl2
15
i
5 equiv BuCN, tol
Figure 3. Proposed mechanism for ligand-dependent product distribution in Pd(II)-
catalyzed Claisen rearrangements.
75°C
50% (S)-19 (95% ee)
(+ 8% Z olefin)
ð5Þ
oxocarbenium ion 15 (pathway b). Among the Lewis bases satis-
fying this criterion, alkyl nitriles and alkenes represented good
ligands for palladium while offering negligible nucleophilicity.12
The Pd(II)-catalyzed Claisen rearrangement protocol provides
a highly diastereoselective route to anti-2,3-disubstituted-pentenal
derivatives. Merging these reactions with Ir(I)-catalyzed isomeri-
zation of di(allyl) ethers provides an operationally simple strategy
for accessing Claisen rearrangements that are stereochemically
complementary to their syn-selective thermal counterparts.
Me
OMe
OH
O
OH
Me
Conditions: 10 mol % (MeCN)2PdCl2, CH2Cl2, 23 °C
nBu
nBu
Me
Me
Ph
Me
Ph
13
14
ð4Þ
4. Experimental
To maximize efficiency and operational simplicity in the Pd(II)-
4.1. General information
catalyzed Claisen rearrangements, a reaction sequence was de-
veloped that utilized easily obtained di(allyl) ethers as precursors
to the requisite allyl vinyl ether substrates. The di(allyl) ethers 16
participated in Ir(I)-catalyzed isomerization to the Claisen sub-
strates 3a–h according to the published procedure (Table 2).7 Allyl
vinyl ether products free of metal contaminants were conveniently
obtained by filtering hexane (or pentane) solutions of the crude
product mixture through Florisil (62–93%). Subjecting the resulting
allyl vinyl ethers to the optimized Claisen rearrangement condi-
tions (10 mol % catalyst, 0.1 M toluene, 40 ꢁC) afforded Claisen
adducts incorporating various linear or branched alkyl sub-
stituents at the allylic (R2) or vinyl (R3) positions with uniformly
high anti diastereoselection (ꢀ95:5).13 Unlike their thermal
counterparts, rigorous control of vinyl ether geometry is not
a prerequisite for high diastereoselection in the Pd(II)-catalyzed
Claisen rearrangements. Allyl vinyl ethers 3e and 3f produced as
E/Z vinyl ether mixture afford the anti Claisen adduct with ex-
ceptionally high diastereoselectivity (>97:3) with product yields
similar to the homogeneous E,E-allyl vinyl ethers.14 This obser-
vation reveals that vinyl ether geometry is subject to in-
terconversion under the Claisen reaction conditions. The 3-phenyl
substrate 3e suggests that some branching at the R2 position is
tolerated, however, this is not general as substrates incorporating
isopropyl or trimethylsilyl substituents at this position are
unreactive. Enantioenriched allyl vinyl ethers 3f–h participate in
the Pd(II)-catalyzed Claisen rearrangement with only minor ero-
sion of optical purity (entries f–h).
Unless otherwise stated, all reactions were performed in dry
glassware under an atmosphere of oxygen-free nitrogen using
standard inert atmosphere techniques for the manipulation of
solvents and reagents. Anhydrous solvents were obtained by pas-
sage through successive alumina-packed columns on a solvent
purification system. Acetone was distilled from Drierite and stored
under dry nitrogen. Isobutyronitrile was distilled from CaH2. The
di(allyl) ethers 16 used in preparing 3a–h and 19 were prepared
according to the published procedures.7 (S)-5-Phenylpent-1-en-3-
ol (>99% ee) was prepared using the published procedure.16
17
[(cC8H14)2IrCl]2 and PCy3 were stored and weighed out in a ni-
trogen-filled glove box. Temperatures for the catalyzed Claisen
rearrangements were controlled using an IkaÒ Werke hotplate/
stirrer. Chemical shifts are reported relative to residual CHCl3
(7.26 ppm) for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR spectra.
Flash chromatography was performed as previously described on
Iatrobeads 6RS-8060 (pH 7 silica gel), purchased from Shell-USA, or
EM silica gel 60 (230–240 mesh).18,19 Analytical high performance
liquid chromatography (HPLC) was performed on a Hewlett Pack-
ard 1100 liquid chromatograph equipped with a variable wave-
length UV detector (deuterium lamp, 190–600 nm), using Daicel
ChiracelÔ columns (250ꢂ4.6 mm) (Daicel Inc.).
4.2. General procedure A for isomerization7a
A solution of [(cC8H14)2IrCl]2 (0.5 mol %, 0.01 equiv Ir) and PCy3
(3 mol %, 0.03 equiv) in anhydrous CH2Cl2 was added to a solution
of NaBPh4 (1 mol %, 0.01 equiv) in CH2Cl2/acetone (25:1) (0.67 M
final concentration in substrate 1) and the resulting yellow solution
Quaternary carbon stereocenters are also accessible from the
Pd(II)-catalyzed Claisen rearrangements. Catalyzed olefin isomeri-
zation of the di(allyl) ether precursor 17 proceeds to afford the Z
vinyl ether 18 without competing isomerization of the terminal
olefin (Eq. 5).15 Reacting 18 with 5 mol % (iPrCN)PdCl2 afforded (R)-
19 in excellent yield and with faithful chirality transfer (84%). Steric
bulk about the vinyl ether is believed to minimize unproductive Pd
coordination at this position, thereby increasing equilibrium
stirred for 5 min at ambient temperature. Di(allyl) ether
1
(1.0 equiv) was added and the reaction stirred for 10–60 min at
ambient temperature or 0 ꢁC after which the solvent was removed
in vacuo. In some cases, PPh3 (0.03 equiv) was added and the
resulting solution stirred for 5 min prior to solvent removal.

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N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
Table 2
Olefin isomerization–Claisen rearrangement of 1,1-disubstituted and trisubstituted allyl ethers
R1
R2
2 mol %
10 mol %
OHC
[Ir(PCy3)3]+
(RCN)2PdCl2
O
R1
O
R1
i
PrCN/tol
40 °C
then filter
(Florisil )
R3
R3
R2
R3
R2
16
3a-h
4a-h
Entry
a
3 (% yield)a
4 (% yield)b
Diastereomer ratio (% ee)c,d
OHC
Me
Me
Me
Me
O
95:5 anti/syn
n
n
Bu
Bu
(93)
Me
(74)
OHC
Me
CH2CH2OTBDPS
O
CH2CH2OTBDPS
b
93:7 anti/syn
Ph
Ph
(93)
(70)
OHC
Me
Me
O
TBDPSO
TBDPSO
O
c
94:6 anti/syn
96:4 syn/anti
n
n
Bu
Bu
(87)
(71)
OHC
Me
Ph
d
Ph
(69)
(71)
OHC
Et
Me
Et
O
e
f
>97:3 anti/syn
n
n
Bu
Me
Bu
(92; 1.9:1 E:Z)
(71)
c
OHC
O
C6H11
c
C6H11
Et
Me
>97:3 anti/syn (84)
Et
Me
(70)
OHC
(92; 2.6:1 E:Z)
(86% ee)
Me
Me
O
g
97:3 anti/syn (86)
97:3 anti/syn (92)
n
n
Et
C5H11
Et
C5H11
(82, 88% ee)
(71)
OHC
Me
Me
O
OBn
h
OBn
Et
Et
(53, 93% ee)
(59)
a
Allyl vinyl ethers possess E,E olefin stereochemistry except as noted in entries e and f.
Yields reported for chromatographically purified materials; minor stereoisomers are, generally, inseparable. The major product diastereomers are depicted in the table.
Diastereomer ratios (dr) determined by 1H NMR of crude product mixtures.
b
c
d
Product enantiomeric purity reported in parentheses for reactions employing enantioenriched di(allyl) ethers 16.
Pentane or hexane was added to the residue and the resulting
suspension was loaded onto a 6ꢂ2 cm plug of Florisil and eluted
with the solvent indicated. Removal of the solvent in vacuo afforded
the vinyl ethers as indicated below.
resulting yellow solution stirred for 5 min at ambient temperature.
Di(allyl) ether 16 (1.0 equiv) was added and the reaction stirred for
6–12 h at ambient temperature whereupon the solvent was re-
moved in vacuo. Pentane or hexanes was added and the resulting
suspension was loaded onto a 6ꢂ2 cm plug of Florisil and eluted
with the solvent indicated. Removal of the solvent in vacuo afforded
the vinyl ethers as indicated below.
4.3. General procedure B for isomerization7a
A solution of [(cC8H14)2IrCl]2 (1.0 mol %, 0.02 equiv Ir) and PCy3
(6.0 mol %, 0.06 equiv) in anhydrous CH2Cl2 (1.5 ml) was added to
a solution of NaBPh4 (2.0 mol %, 0.02 equiv) in CH2Cl2/acetone
(25:1) (1.5 ml, 0.67 M final concentration in substrate 16) and the
4.3.1. (2E)-4-[(E)-Prop-1-enyloxy]-2-octene (3a)
General procedure A was followed employing 1.48 g of (E)-4-
allyloxy-2-octene (8.80 mmol). Purification by filtration through

N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
6867
Florisil (eluting with pentane) gave 1.37 g (93%) of the title com-
pound as a colorless oil. IR (thin film): 3034, 2933, 2861, 1674, 1657,
title compound as a colorless oil and a 1.9:1 E/Z mixture of butenyl
group isomers. IR (thin film): 3035, 2960, 2861, 1669, 1456,
1456, 1170 cmꢃ1
;
1H NMR (300 MHz, CDCl3):
d
6.08 (dq, J¼12,
1170 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
6.08 (dt, J¼12, 1.4 Hz, 1H),
1.6 Hz, 1H), 5.63 (dq, J¼15, 6.4 Hz, 1H), 5.36 (ddq, J¼15, 6.8, 1.6 Hz,
1H), 4.88 (dq, J¼6.7, 12 Hz, 1H), 3.92 (q, J¼6.8 Hz, 1H), 1.72 (dd,
J¼6.7,1.6 Hz, 3H),1.53 (dd, J¼6.8,1.6 Hz, 3H),1.4–1.7 (m, 2H),1.2–1.4
5.63 (dqd, J¼15, 6.4, 0.8 Hz, 1H), 5.36 (ddq, J¼14, 7.6, 1.6 Hz, 1H),
4.91 (dt, J¼12, 7.1 Hz, 1H), 3.92 (dt, J¼14, 7.6 Hz, 1H), 1.92 (ddq,
J¼15, 7.3, 1.4 Hz, 2H), 1.71 (ddd, J¼6.4, 1.5, 0.4 Hz, 3H), 1.38–1.75 (m,
2H), 1.30 (m, 4H), 0.95 (t, J¼7.4 Hz, 3H), 0.88 (m, 3H); signals
observed for the (Z)-isomer: 5.94 (dt, J¼6.3, 1.4 Hz, 1H), 4.30 (dt,
J¼13, 7.1 Hz, 1H), 3.88 (dt, J¼14, 7.0 Hz, 1H), 2.10 (m, 2H); 13C NMR
(m, 4H), 0.90 (m, 3H); 13C NMR (75 MHz, CDCl3):
d 145.3, 131.6,
128.2,100.3, 81.4, 35.0, 27.4, 22.6, 17.7, 14.0, 12.5; MS (EI, 70 eV): m/z
111 (MþꢃC3H5O), 69, 55; HRMS m/z calcd for C8H15 (MþꢃC3H5O):
111.1174, found: 111.1171.
(75 MHz, CDCl3): d 144.3, 142.96 (Z), 131.9 (Z), 131.7, 128.0, 127.9 (Z),
108.4 (Z), 108.0, 82.2 (Z), 81.2, 35.0, 27.3, 22.6, 21.0, 17.5, 17.4 (Z), 15.1,
14.4 (Z), 13.9; MS (EI, 70 eV): m/z 154 (MþꢃC2H5), 139, 125, 110, 81,
69, 55; HRMS m/z calcd for C12H22O (Mþ): 182.1671, found:
182.1676.
4.3.2. (3E)-1-(tert-Butyl)diphenylsilyloxy-5-[(E)-prop-1-enyloxy]-
7-phenyl-3-heptene (3b)
General procedure
A was followed employing 0.399 g of
((E)-5-(allyloxy)-7-phenylhept-3-enyloxy)(tert-butyl)diphenylsilane
(0.822 mmol) at 0 ꢁC for 1 h. After this time, PPh3 (6.5 mg,
0.025 mmol) was added. Purification by filtration through Florisil
(eluting with 5% EtOAc/hexane) gave 0.372 g (93%) of the title
compound as a colorless oil. IR (thin film): 3027, 2930, 2858, 1673,
4.3.6. (3R,4E)-3-[(E)-3-Cyclohexyl-1-prop-1-enyloxy]-4-hexene (3f)
General procedure B was followed employing 0.704 g of ((1E)-3-
((R,E)-hex-4-en-3-yloxy)prop-1-enyl)cyclohexane
(3.16 mmol).
Purification by filtration through Florisil (eluting with pentane)
gave 0.648 g (92%) of the title compound as a colorless oil and
a 2.6:1.0 E/Z mixture of cyclohexyl-1-propenyl group isomers. IR
1657, 1428, 1157 cmꢃ1 1H NMR (300 MHz, CDCl3):
; d 7.68 (m, 4H),
7.40 (m, 6H), 7.28 (m, 2H), 7.19 (m, 3H), 6.08 (dq, J¼12, 1.5 Hz, 1H),
5.68 (dt, J¼16, 6.8 Hz, 1H), 5.45 (dd, J¼16, 7.3 Hz, 1H), 4.91 (dq, J¼12,
6.7 Hz, 1H), 3.96 (dt, J¼6.1, 7.0 Hz, 1H), 3.72 (t, J¼6.5 Hz, 2H), 2.60–
2.76 (m, 2H), 2.32 (dt, J¼6.5, 6.5 Hz, 2H), 1.74–2.03 (m, 2H), 1.52 (dd,
(thin film): 3036, 2921, 2852,1670,1448,1288,1164 cmꢃ1; [
a
]
D ꢃ7.9
(c 3.16, CHCl3); 1H NMR (300 MHz, CDCl3):
d
6.03 (dt, J¼12.3, 1.1 Hz,
1H), 5.99 (dt, J¼6.4, 1.4 Hz, 1H, Z-isomer), 5.57–5.72 (m, 1H), 5.31–
5.41 (m, 1H), 4.86 (dt, J¼12.3, 7.8 Hz, 1H, E-isomer), 4.31 (dt, J¼7.4,
6.4 Hz, 1H, Z-isomer), 3.87 (dt, J¼7.0, 6.7 Hz, 1H, E-isomer), 3.82 (dt,
J¼7.8, 6.7 Hz, 1H, Z-isomer), 1.94–2.00 (m, 1H), 1.45–1.78 (m, 11H),
1.07–1.28 (m, 4H), 0.79–0.98 (m, 5H); 13C NMR (75 MHz, CDCl3):
J¼6.8, 1.5 Hz, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 145.2,
141.8, 135.5, 133.9, 132.0, 130.3, 129.6, 128.5, 128.3, 127.6, 125.7, 100.8,
80.1, 63.5, 36.9, 35.6, 31.4, 26.9, 19.2, 12.5; MS (ESI): m/z 507
(MþþNa); HRMS (ESI) m/z calcd for C32H40O2Si (MþþNa): 507.2695,
found: 507.2719.
d
145.2, 143.8 (Z), 131.5 (Z), 131.2, 128.5, 128.2 (Z), 105.0 (Z), 104.6,
83.5 (Z), 82.5, 38.6, 38.3, 35.5, 33.1, 33.0, 32.9, 32.9, 31.7, 28.2, 28.1,
26.6, 26.4, 26.3,17.7, 9.6; MS (EI, 70 eV): m/z 222 (Mþ), 204,193,179,
140, 126, 122, 111, 96, 83; HRMS (EI) m/z calcd for C15H26O (Mþ):
222.1984, found: 222.1988.
4.3.3. (3E)-1-(tert-Butyl)diphenylsilyloxy-2-[(E)-prop-1-enyloxy]-
3-octene (3c)
A modification of general procedure A was followed employing
0.218 g of ((E)-2-(allyloxy)oct-3-enyloxy)(tert-butyl)diphenylsilane
(0.515 mmol). The substrate was added at 0 ꢁC and stirred at this
temperature for 1 h followed by addition of PPh3 (4.1 mg, 6 mol %).
Purification by filtration through Florisil (eluting with 5% Et2O/
pentane) gave 0.189 g (87%) of the title compound as a colorless oil.
4.3.7. (3S,4E)-3-[(E)-Prop-1-enyloxy]-4-decene (3g)
General procedure A was followed employing 0.900 g of (3S)-
(E)-3-(allyloxy)dec-4-ene (4.59 mmol) for 15 min at ambient tem-
perature. Purification by filtration through Florisil (eluting with
pentane) gave 0.738 g (82%) of the title compound as a colorless oil.
1H NMR (300 MHz, CDCl3):
d 7.65–7.72 (m, 4H), 7.33–7.45 (m, 6H),
6.12 (dq, J¼12, 1.5 Hz, 1H), 5.67 (dtd, J¼16, 6.7, 0.7 Hz, 1H), 5.35 (ddt,
J¼16, 7.1, 1.4 Hz, 1H), 4.87 (dq, J¼13, 6.2 Hz, 1H), 4.11 (dt, J¼6.0,
6.3 Hz, 1H), 3.74 (dd, J¼11, 6.4 Hz, 1H), 3.63 (dd, J¼11, 5.1 Hz, 1H),
2.03 (dt, J¼6.5, 6.6 Hz, 2H), 1.51 (dd, J¼6.8, 1.5 Hz, 3H), 1.25–1.40 (m,
IR (thin film): 3038, 2960, 2927, 2858, 1675, 1657, 1459, 1173 cmꢃ1
;
[
a
]
þ0.66 (c 2.13, CHCl3); 1H NMR (300 MHz, CDCl3):
d 6.09 (dq,
D
J¼12.3, 1.6 Hz, 1H), 5.61 (dt, J¼15.4, 6.4 Hz, 1H), 5.31 (ddt, J¼15.4,
7.6, 1.4 Hz, 1H), 0.88 (t, J¼7.5 Hz, 3H), 4.87 (dq, J¼12.3, 6.8 Hz, 1H),
3.86 (dt, J¼6.9, 6.8 Hz, 1H), 2.04 (dt, J¼6.8, 6.5 Hz, 2H), 1.44–1.71 (m,
2H), 1.52 (dd, J¼6.8, 1.6 Hz, 3H), 1.22–1.43 (m, 6H), 0.88 (t, J¼6.9 Hz,
4H), 1.05 (s, 9), 0.88 (m, 3H); 13C NMR (75 MHz, CDCl3):
d 145.7,
135.7, 135.0, 133.6, 133.5, 129.6, 127.6, 126.9, 100.3, 81.7, 66.5, 32.0,
31.1, 26.8, 22.2, 19.2, 13.9, 12.5; MS (EI, 70 eV): m/z 422 (Mþ), 365,
307, 267, 239, 199, 183, 135, 109, 75, 67; HRMS m/z calcd for
3H); 13C NMR (75 MHz, CDCl3):
d 145.2, 134.1, 129.9, 100.4, 82.7,
32.2, 31.3, 28.8, 28.2, 22.4, 14.0, 12.5, 9.6; MS (EI, 70 eV): m/z 196
C
27H38O2Si (Mþ): 422.2641, found: 422.2628.
(Mþ), 167, 138, 109, 97, 83, 69; HRMS (EI) m/z calcd for C13H24
O
(Mþ): 196.1827, found: 196.1820.
4.3.4. (E)-3-[(E)-Prop-1-enyloxy]propenylbenzene (3d)
General procedure A was followed employing 0.800 g of E-3-
allyloxypropenylbenzene (4.59 mmol) for 1 h. Purification by fil-
tration through Florisil (gradient elution with pentane to 2.5% Et2O/
pentane) gave 0.549 g (69%) of the title compound as a colorless oil.
4.3.8. (4S,2E)-1-Benzyloxy-4-[(E)-prop-1-enyloxy]-2-hexene (3h)
General procedure A was followed employing 0.431 g of (4S)-
(E)-4-allyloxy-1-benzyloxyhex-2-ene (1.75 mmol) for 10 min at
ambient temperature. After this time, PPh3 (13.8 mg, 0.053 mmol)
was added. Purification by filtration through Florisil (gradient elu-
tion with hexane to 2.5% Et2O/pentane) gave 0.228 g (53%) of the
title compound as a colorless oil. IR (thin film): 3031, 2933, 2857,
IR (thin film): 3027, 2923, 2858, 1675, 1656, 1267, 1174 cmꢃ1
;
1H
NMR (300 MHz, CDCl3):
d
7.24–7.44 (m, 5H), 6.66 (d, J¼16.0 Hz, 1H),
6.28–6.38 (m, 2H), 4.85–4.96 (m, 1H), 4.36 (dd, J¼5.9, 1.2 Hz, 2H),
1.61 (dd, J¼6.7,1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
146.0,136.4,
1674, 1656, 1454, 1170 cmꢃ1; [
(300 MHz, CDCl3):
a
]
ꢃ3.8 (c 2.16, CHCl3); 1H NMR
D
132.5, 128.4, 127.7, 126.4, 124.9, 99.3, 69.7, 12.4; MS (EI, 70 eV): m/z
d
7.26–7.35 (m, 5H), 6.10 (dq, J¼12.3, 1.6 Hz, 1H),
174 (Mþ), 131, 118, 117, 115, 104, 91, 89; HRMS (EI) m/z calcd for
5.78 (dt, J¼15.7, 5.5 Hz, 1H), 5.64 (dd, J¼15.7, 6.7 Hz, 1H), 4.90 (dq,
J¼12.3, 6.8 Hz,1H), 4.05 (dd, J¼5.5, 0.5 Hz, 2H), 4.52 (s, 2H), 3.97 (dt,
J¼6.5, 6.4 Hz, 1H), 1.57–1.75 (m, 2H), 1.53 (dd, J¼6.8, 1.5 Hz, 3H),
C
12H14O (Mþ): 174.1045, found: 174.1041.
4.3.5. (2E)-4-[(E)-But-1-enyloxy]-2-octene (3e)
0.92 (t, J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 145.3, 138.1,
General procedure B was followed employing 0.995 g of (2E)-4-
((E)-but-2-enyloxy)oct-2-ene (5.46 mmol). Purification by filtration
through Florisil (eluting with pentane) gave 0.918 g (92%) of the
133.0, 128.9, 128.3, 127.7, 127.5, 100.8, 81.6, 71.9, 69.9, 28.0, 12.4 9.5;
MS (EI, 70 eV): m/z 246 (Mþ), 189, 171, 91, 77, 69; HRMS (EI) m/z
calcd for C16H22O2 (Mþ): 246.1620, found: 246.1619.

6868
N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
4.3.9. (3R)-3-[(Z)-2-Methylhex-1-enyloxy]-5-phenyl-1-
pentene (13)
4.4.3. (E)-anti-3-n-Butyl-2-methyl-6-(tert-butyldiphenyl-
silyloxy)hex-4-enal (4c)
General procedure B was followed employing 0.500 g of (3R)-
[3-(2-butyl-allyloxy)-pent-4-enyl]-benzene (1.94 mmol) for 11 h.
Purification by filtration through Florisil (elution with hexane) gave
0.225 g (45%) of the title compound as a colorless oil. IR (thin film):
General procedure C (10 mol % catalyst, 40 ꢁC, 15 h) was fol-
lowed employing 0.177 g of ether 3c (0.420 mmol). Purification by
flash chromatography (5% Et2O/pentane) on Iatrobeads gave
0.125 g (71%) of the title compound as a colorless oil (anti/
3027, 2956, 2858, 1682, 1455, 1152 cmꢃ1; [
a]
D 5.4 (c 2.29, CHCl3); 1H
7.15–7.32 (m, 5H), 5.72–5.83 (m, 2H), 5.15–
syn¼94:6). 1H NMR (300 MHz, CDCl3):
9.60 (d, J¼2.2 Hz, 1H), 7.67
d
NMR (300 MHz, CDCl3):
d
(dd, J¼7.0, 1.0 Hz 4H), 7.33–7.45 (m, 6H), 5.58 (dt, J¼15, 4.6 Hz, 1H),
5.42 (ddt, J¼15, 9.0, 1.4 Hz, 1H), 4.17 (dd, J¼4.6, 1.4 Hz, 2H), 2.46 (m,
1H), 2.33 (dqd, J¼14, 6.9, 2.2 Hz, 1H), 1.15–1.45 (m, 6H), 1.05 (s, 9H),
1.01 (d, J¼6.9 Hz, 3H), 0.89 (m, 3H); 13C NMR (75 MHz, CDCl3):
5.27(m, 2H), 3.92(dt, J¼6.7, 6.2 Hz,1H), 2.63–2.81 (m, 2H), 2.07–2.20
(m, 2H), 1.78–2.03 (m, 2H), 1.53 (d, J¼1.4 Hz, 3H), 1.30–1.44 (m, 4H),
0.93 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 141.9,138.7,138.6,
128.4, 128.3, 125.8, 116.5, 114.4, 81.0, 36.8, 31.3, 29.6, 28.7, 22.5, 17.3,
14.0; MS (EI, 70 eV): m/z 258 (Mþ), 144, 129, 114, 91, 71; HRMS (EI)
m/z calcd for C18H26O (Mþ): 258.1984, found: 258.1979.
d 205.0, 135.4, 133.7, 131.3, 130.2, 129.6, 127.6, 64.0, 50.2, 42.7, 32.4,
29.5, 26.7, 22.5, 19.2, 14.0, 10.1; MS (ESI): m/z 445 (MþþNa); HRMS
(ESI) m/z calcd for C27H38O2Si (MþþNa): 445.2539, found: 445.2555.
4.3.10. Preparation of (iBuCN)2PdCl2
4.4.4. (E)-anti-2-Methyl-3-phenylpent-4-enal (4d)
A suspension of 2.00 g of PdCl2 (11.3 mmol) in iBuCN (20 ml) was
heated at 100 ꢁC overnight. The resulting solution was filtered
while warm and rinsed through the filter with a small amount of
CH2Cl2. Hexane was added to the filtrate and the resulting pre-
cipitate was filtered, washed with hexanes, and dried under vac-
uum for 30 min to afford 3.44 g (96%) of the catalyst as a yellow/
orange solid, which was stored in a desiccator.
General procedure C (10 mol % catalyst, 50 ꢁC, 38 h) was fol-
lowed employing 0.200 g of ether 3d (1.148 mmol). Purification by
flash chromatography (gradient elution with hexane to 2.5% Et2O/
pentane) on Iatrobeads gave 0.142 g (71%) of the title compound as
a colorless oil (anti/syn¼96:4). IR (thin film): 2978, 2932, 1724,
1724, 1493, 1453, 994, 920 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d 9.54
(d, J¼2.4 Hz, 1H), 7.20–7.41 (m, 5H), 5.91–6.02 (m, 1H), 5.16 (s, 1H),
5.12 (d, J¼5.5, 1H), 3.59 (app t, J¼8.7 Hz, 1H), 2.77–2.86 (m, 1H), 1.13
(d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 204.0, 141.3, 138.0,
4.4. General procedure C for palladium-catalyzed Claisen
rearrangements
128.7, 127.7, 126.7, 116.8, 51.4, 50.4, 11.8; MS (EI, 70 eV): m/z 174
(Mþ), 159, 145, 117, 91; HRMS m/z calcd for C12H14O (Mþ): 174.1045,
found: 174.1039.
The vinyl ether 2 (1.0 equiv) was added to a solution of
(iBuCN)2PdCl2 (0.05–0.10 equiv) in toluene/iBuCN (5 equiv) (0.1 M
final concentration of substrate) and the reaction stirred at 40 or
50 ꢁC. After the indicated time, hexane was added to the reaction
mixture and the resulting mixture was purified by flash chroma-
tography on Iatrobeads 6RS-8060 silica gel.21 The column was ini-
tially flushed with 150–200 ml hexane prior to elution of desired
product with pentane/diethyl ether as specified below.
4.4.5. (E)-anti-2-Ethyl-3-methylnon-4-enal (4e)
General procedure C (10 mol % catalyst, 40 ꢁC, 24 h) was fol-
lowed employing 0.200 g of ether 3e (1.10 mmol). Purification by
flash chromatography (2.5% Et2O/pentane) on Iatrobeads gave
0.142 g (71%) of the title compound as a colorless oil (anti/
syn¼>97:3). IR (thin film): 2961, 2873, 2703, 1724, 1460, 1380,
971 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
9.56 (d, J¼3.7 Hz, 1H), 5.44
(dtd, J¼15, 6.6, 0.7 Hz, 1H), 5.25 (ddt, J¼15, 8.1, 1.3 Hz, 1H), 2.45 (m,
1H), 1.92–2.07 (m, 2H), 1.47–1.65 (m, 2H), 1.22–1.37 (m, 4H), 1.00 (d,
J¼6.9 Hz, 3H), 0.90 (m, 3H), 0.87 (t, J¼7.4 Hz, 3H); 13C NMR
4.4.1. (E)-anti-2,3-Dimethylnon-4-enal (4a)
General procedure C (10 mol % catalyst, 40 ꢁC, 24 h) was fol-
lowed employing 0.20 g of ether 3a (1.19 mmol). Purification by
flash chromatography (2.5% Et2O/pentane) on Iatrobeads gave
0.148 g (74%) of the title compound as a colorless oil (anti/
syn¼95:5). IR (thin film): 2961, 2929, 2873, 1728, 1456, 1378,
(75 MHz, CDCl3):
d 205.7, 132.2, 131.3, 59.0, 36.9, 32.1, 31.6, 22.1,
19.8, 18.6, 13.9, 11.9; MS (EI, 70 eV): m/z 182 (Mþ), 167, 153, 126, 111,
97, 81, 69, 55; HRMS m/z calcd for C12H22O (Mþ): 182.1671, found:
182.1667.
971 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
9.63 (d, J¼2.3 Hz, 1H), 5.46
(dt, J¼15, 6.7 Hz, 1H), 5.25 (dd, J¼15, 7.9 Hz, 1H), 2.57 (m, 1H), 2.26
(dqd, J¼14, 6.8, 2.2 Hz, 1H), 2.00 (m, 2H), 1.2–1.4 (m, 4H), 1.06 (d,
J¼6.9 Hz, 3H), 1.03 (d, J¼7.0 Hz, 3H), 0.89 (t, J¼7.1 Hz, 3H); 13C NMR
4.4.6. (E,2S,3S)-anti-2-Cyclohexylmethyl-3-methylhept-4-enal (4f)
General procedure C (10 mol % catalyst, 50 ꢁC, 24 h) was fol-
lowed employing 0.200 g of ether 3f (84% ee; 0.899 mmol). Puri-
fication by flash chromatography (gradient elution with pentane to
1.5% Et2O/pentane) on Iatrobeads gave 0.140 g (70%) of the title
compound as a colorless oil (anti/syn¼>97:3). Separation of the
enantiomers of the derived p-tosylhydrazones by chiral HPLC Dai-
(75 MHz, CDCl3): d 205.3, 131.5, 131.4, 51.5, 37.4, 32.1, 31.5, 22.1, 18.4,
13.8, 10.4; MS (EI, 70 eV): m/z 168 (Mþ), 153, 139,127, 111, 83, 69, 55;
HRMS m/z calcd for C11H20O (Mþ): 168.1514, found: 168.1512.
i
4.4.2. (E)-anti-3-(tert-Butyldiphenylsilyloxyethyl)-2-methyl-7-
phenylhept-4-enal (4b)
cel ChiracelÔ OD-H column, flow rate 1.0 ml/min, 3% PrOH, 97%
hexanes, tR 15.7 and 19.2 provided the enantiomer ratio: 90.6:9.4
General procedure C (10 mol % catalyst, 50 ꢁC, 26 h) was followed
employing 0.10 g of ether 3b (0.206 mmol). Purification by flash
chromatography (gradient elution with hexane to 5% EtOAc/hex-
anes) on Iatrobeads gave 0.070 g (70%) of the title compound as
a colorless oil (anti/syn¼93:7). IR (thin film): 2930,1726,1454,1428,
(84% ee). IR (thin film): 2963, 2924, 2852, 1726 cmꢃ1; [
a
]
D ꢃ26.3 (c
2.05, CHCl3); 1H NMR (300 MHz, CDCl3):
d
9.54 (d, J¼3.9 Hz, 1H),
5.48 (dt, J¼15, 6.3 Hz, 1H), 5.23 (ddt, J¼15, 8.1, 1.4 Hz, 1H), 2.40 (m,
1H), 2.22 (m, 1H), 2.01 (m, 2H), 1.58–1.78 (m, 6H), 1.50 (m, 1H), 1.26
(m, 1H), 1.18 (m, 4H), 1.00 (d, J¼6.8 Hz, 3H), 0.97 (t, J¼7.4 Hz, 3H),
1390,1111, 973 cmꢃ1; 1H NMR (300 MHz, CDCl3):
d
9.53 (d, J¼2.1 Hz,
0.72–1.00 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 205.8, 132.8, 131.2,
1H), 7.65 (m, 5H), 7.35–7.45 (m, 5H), 7.1–7.3 (m, 5H), 5.42 (dt, J¼15,
6.7 Hz, 1H), 5.06 (dd, J¼15, 9.2 Hz, 1H), 3.64 (m, 2H), 2.67 (m, 2H),
2.60 (m, 2H), 2.23 (m, 3H), 1.43–1.73 (m, 2H), 1.05 (s, 9H), 0.94 (d,
54.7, 37.4, 35.6, 34.2, 34.0, 32.6, 26.4, 26.2, 26.0, 25.4, 18.4, 13.8; MS
(EI, 70 eV): m/z 221 (Mþ), 204, 193, 179, 165, 125, 111, 95, 93, 67, 55;
HRMS m/z calcd for C15H26O2 (Mþ): 222.1984, found: 222.1981.
J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 205.2, 141.7, 135.5, 133.8,
132.5, 129.9, 129.6, 128.4, 128.2, 127.6, 125.8, 61.5, 50.2, 39.3, 35.8,
35.4, 34.2, 26.8, 19.2, 10.1; MS (ESI): m/z 507 (MþþNa); HRMS (ESI)
m/z calcd for C32H40O2Si (MþþNa): 507.2695, found: 507.2715.
4.4.7. (E,2R,3R)-anti-2-Methyl-3-pentylhept-4-enal (4g)
General procedure C (8 mol % catalyst, 50 ꢁC, 24 h) was followed
employing 0.247 g of ether 3g (88% ee; 1.258 mmol). Purification by

N.J. Kerrigan et al. / Tetrahedron 64 (2008) 6863–6869
6869
flash chromatography (elution with 2.5% Et2O/pentane) on Iatro-
beads gave 0.175 g (71%) of the title compound as a colorless oil
(anti/syn¼97:3). Separation of the enantiomers of the derived p-
tosylhydrazones by chiral HPLC Daicel ChiracelÔ AD column, flow
stereochemistry of 4g and 4h was assigned based on comparison
to the corresponding syn diastereomers.7b The relative stereo-
chemistry for all other compounds was assigned by analogy to the
above examples.
i
rate 1.0 ml/min, 3% PrOH, 97% hexanes, tR 23.2 and 25.7 provided
the enantiomer ratio: 93.2:6.8 (86% ee). IR (thin film): 2960, 2928,
Acknowledgements
2857, 2699, 1728, 1458, 1377, 971 cmꢃ1; [
a
]
ꢃ23.8 (c 4.10, CHCl3);
D
1H NMR (300 MHz, CDCl3):
d
9.59 (d, J¼2.2 Hz, 1H), 5.47 (dt, J¼15.2,
Support from the National Science Foundation (CHE 0718467),
the National Institutes of Health (P50 GM067082) for the University
of Pittsburgh Center for Chemical Methodologies and Library De-
velopment (UPCMLD), and the Merck Research Laboratories is
gratefully acknowledged.
6.3 Hz, 1H), 5.09 (ddt, J¼15.3, 9.0, 1.4 Hz, 1H), 2.34–2.48 (m, 1H),
2.34–2.24 (m, 1H), 2.08–1.93 (m, 2H), 1.16–1.43 (m, 8H), 1.00 (d,
J¼6.9 Hz, 3H), 0.95 (t, J¼7.4 Hz, 3H), 0.87 (t, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3):
d 205.5, 134.7, 128.7, 50.4, 43.1, 32.8, 31.6, 26.9,
25.5, 22.5, 14.0, 13.9, 10.0; MS (EI, 70 eV): m/z 196 (Mþ), 181, 167,
153, 139, 125, 111, 97, 83, 69; HRMS m/z calcd for C13H24O (Mþ):
196.1827, found: 196.1823.
References and notes
4.4.8. (E,2R,3R)-anti-3-Benzyloxymethyl-2-methylhept-4-enal (4h)
General procedure C (10 mol % catalyst, 50 ꢁC, 30 h) was fol-
lowed employing 0.10 g of ether 3h (93% ee; 0.406 mmol). Purifi-
cation by flash chromatography (elution with 2.5% Et2O/pentane)
on Iatrobeads gave 0.059 g (59%) of the title compound as a color-
less oil (anti/syn¼97:3). Separation of the enantiomers by chiral
HPLC Daicel ChiracelÔ OD-H column, flow rate 0.8 ml/min, 0.2%
iPrOH, 99.8% hexanes, tR 12.9 and 15.1 provided the enantiomer
ratio: 4.2:95.8 (92% ee). IR (thin film): 2963, 2932, 2872, 1724, 1454,
1. For recent reviews: (a) Michalak, A.; Ziegler, T. Top. Organomet. Chem. 2005, 12,
145–186; (b) Hahn, C. Chem.dEur. J. 2004, 10, 5888–5899.
2. (a) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579–586; (b) Lutz, R. P.
Chem. Rev. 1984, 84, 205–247.
3. For reviews of Lewis acid-catalyzed Claisen rearrangements, see: (a) Maruoka,
K. In Lewis Acid Reagents: A Practical Approach; Yamamoto, H., Ed.; Oxford
University Press: New York, NY, 1999; pp 5–29; (b) Hiersemann, M.; Abraham,
L. Eur. J. Org. Chem. 2002, 1461–1471; (c) Nubbemeyer, U. Synthesis 2003, 961–
1008; (d) Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
4. (a) Overman, L. E.; Knoll, F. M. J. Am. Chem. Soc. 1980, 102, 865–867; (b)
Overman, L. E.; Jacobsen, E. J. J. Am. Chem. Soc. 1982, 104, 7225–7231; (c)
Overman, L. E.; Renaldo, A. E. Tetrahedron Lett. 1983, 24, 3757–3760; (e)
Overman, L. E.; Renaldo, A. E. J. Am. Chem. Soc. 1990, 112, 3945–3949.
5. (a) van der Bann, J. L.; Bickelhaupt, F. Tetrahedron Lett. 1986, 27, 6267–6270; (b)
Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, 28, 5879–5882; (c)
Hayashi, T.; Yamamoto, A.; Ito, Y. Synth. Commun. 1989, 19, 2109–2115; (d)
Sugiura, M.; Yanagisawa, M.; Nakai, T. Synlett 1995, 447–448; (e) Sugiura, M.;
Nakai, T. Tetrahedron Lett. 1996, 37, 7991–7994; (f) Akiyama, K.; Mikami, K.
Tetrahedron Lett. 2004, 45, 7217–7220.
6. (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910; (b) Overman, L. E.;
Campbell, C. B.; Knoll, F. M. J. Am. Chem. Soc. 1978, 100, 4822–4834; (c) Kwart,
H.; Miles, W. H.; Horgan, A. G.; Kwart, L. D. J. Am. Chem. Soc. 1981, 103, 1757–
1760; (d) Schenk, T. G.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2058–2066; (e)
Auburn, P. R.; Whelan, J.; Bosnich, B. Organometallics 1986, 5, 1533–1537.
7. (a) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003, 125, 13000–
13001; (b) Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233.
8. Other examples of olefin isomerization–Claisen rearrangements: (a) Reuter,
J. M.; Salomon, R. G. J. Org. Chem. 1977, 42, 3360–3364; (b) Swenton, J. S.;
Bradin, D.; Gates, B. D. J. Org. Chem. 1991, 56, 6156–6163; (c) Wille, A.;
Tomm, S.; Frauenrath, H. Synthesis 1998, 305–308; (d) Higashino, T.;
Sakaguchi, S.; Ishii, Y. Org. Lett. 2000, 2, 4193–4195; (e) Ben Ammar, H.; Le
1363, 1100, 972 cmꢃ1; [
CDCl3):
a]
D 11.8 (c 2.58, CHCl3); 1H NMR (300 MHz,
d
9.62 (d, J¼2.2 Hz, 1H), 7.25–7.50 (m, 5H), 5.59 (dt, J¼15.4,
6.3 Hz, 1H), 5.18 (ddt, J¼15.4, 8.8, 1.5 Hz, 1H), 4.48 (s, 2H), 3.50 (dd,
J¼9.3, 5.2 Hz, 1H), 3.39 (app t, J¼8.5 Hz, 1H), 2.75–2.87 (m, 1H),
2.50–2.60 (m, 1H), 1.96–2.06 (m, 2H), 1.01 (d, J¼7.0 Hz, 3H), 0.96 (t,
J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 204.7, 138.1, 136.0, 128.3,
127.6 (2C overlap), 125.3, 73.0, 71.7, 47.9, 43.6, 25.6, 13.7, 10.1; MS
(EI, 70 eV): m/z 247 (Mþ1), 246 (Mþ), 188, 158, 125, 91; HRMS m/z
calcd for C16H22O2 (Mþ): 246.1620, found: 246.1613.
4.4.9. (E,2R)-2-Butyl-2-methyl-7-phenylhept-4-enal (R-14)
To a solution of (iPrCN)2PdCl2 (5.5 mol %, 17 mg, 55
m
mol) and
iPrCN (5 equiv to 6, 5 mmol, 31
ml) in toluene (10 ml, 0.1 M final
concentration of 12) was added vinyl ether 12 (259 mg, 1 mmol;
99% ee). The resulting solution was stirred at 40 ꢁC for 12.5 h. After
cooling to ambient temperature, the reaction mixture was trans-
ferred directly to a Iatrobeads (neutral silica gel)-packed flash col-
umn and eluted with 100% hexanes (100 ml) then 2% Et2O in
pentane to afford 217 mg (84%) of the title compound as a colorless
ˆ
Notre, J.; Salem, M.; Kaddachi, M. T.; Dixneuf, P. H. J. Organomet. Chem. 2002,
662, 63–69; (f) Le Noˆtre, J.; Brissieux, L.; Se´meril, D.; Bruneau, C.; Dixneuf, P.
H. Chem. Commun. 2002, 1772–1773; (g) Schmidt, B. Synlett 2004, 1541–
1544; (h) Nevado, C.; Echavarren, A. M. Tetrahedron 2004, 60, 9735–9744; (i)
Trost, B. M.; Zhang, T. Org. Lett. 2006, 8, 6007–6010.
9. (a) Overman, L. E.; Renaldo, A. E. Tetrahedron Lett. 1983, 24, 2235–2238;
Overman, L. E.; Renaldo, A. E. J. Am. Chem. Soc. 1990, 112, 3945–3949. See also
Ref. 4–6.
10. Rigorous efforts were made to eliminate or scavenge water and/or halide ions
from the reaction mixtures.
11. Palladium(II) complexes incorporating phosphine- or amine-based ligands
(both mondentate and bidentate) exhibited uniformly poor reactivity relative to
PdX2(RCN)2 complexes.
12. Isobutyronitrile was generally used in preference to benzonitrile since it could
be easily removed from crude reaction mixtures under vacuum.
13. Reaction efficiency decreased considerably at concentrations exceeding 0.2 M.
14. Allyl vinyl ethers incorporating Z-enol ether moieties have been demonstrated
to afford the same Claisen diastereomer as the corresponding E-enol ether
isomers, albeit with substantially lower yields. See Ref. 5d.
15. Wang, K.; Bungard, C. J.; Nelson, S. G. Org. Lett. 2007, 9, 2325–2328.
16. Takagi, Y.; Teramoto, J.; Kihara, H.; Itoh, T.; Tsukube, H. Tetrahedron Lett. 1996,
37, 4991–4992.
i
oil. The enantiomers of the primary alcohol obtained by Bu2AlH
reduction of R-13 were separated by chiral HPLC (Daicel ChiracelÔ
AD column, flow rate 1.0 ml/min, 2% iPrOH, 98% hexanes, tR 11.1 and
12.2) to provide the enantiomer ratio: 3.7:96.3 (93% ee). [
1.35, CHCl3); IR (film): 2958, 2931, 2859, 1726, 1454, 971 cmꢃ1
NMR (300 MHz, CDCl3): 9.42 (s, 1H), 7.16–7.31 (m, 5H), 5.50 (dt,
a]
D ꢃ1.2 (c
;
1H
d
J¼15.2, 6.6 Hz, 1H), 5.31 (dt, J¼15.1, 7.3 Hz, 1H), 2.68 (t, J¼7.3 Hz,
2H), 2.34 (dt, J¼7.6, 7.1 Hz, 2H), 2.08–2.22 (m, 2H), 1.07–1.55 (m,
6H), 0.97 (s, 3H), 0.90 (t, J¼7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
206.6, 141.7, 133.4, 128.4, 128.2, 125.7, 125.1, 49.1, 38.5, 35.8, 34.9,
34.2, 26.1, 23.3, 18.3, 13.9; MS (EI, 70 eV): m/z 258 (Mþ), 240, 202,
183, 167, 154, 98, 91; HRMS m/z calcd for C12H14O (Mþ): 258.1984,
found: 258.1979.
17. Onderdelinden, A. L.; van der Ent, A. Inorg. Chim. Acta 1972, 6, 420–426.
18. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
19. Using neutral Iatrobeads silica gel limits epimerization of the
aldehyde that can accompany purification on standard silica gel.
a-substituted
4.5. Proof of stereochemistry
20. Nonoshita, K.; Maruoka, K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1992, 65, 541–
The relative stereochemistry of 4a20 and 4d21 was assigned
545.
based on correlation to literature compounds. The relative
21. Wipf, P.; Waller, D. L.; Reeves, J. T. J. Org. Chem. 2005, 70, 8096–8102.