Directed hydrozirconation of homopropargylic alcohols

Article abstract of DOI:10.1016/j.tet.2008.03.052

Homopropargylic alcohols undergo directed hydrozirconation with Schwartz reagent (Cp₂ZrHCl) to generate vinyl-metal species in which the metal fragment is proximal to the alkoxide. Electrophilic trapping yields tri-substituted olefins in good y

Full text of DOI:10.1016/j.tet.2008.03.052

Tetrahedron 64 (2008) 6955–6960
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Directed hydrozirconation of homopropargylic alcohols
*
Xiaofeng Liu, Joseph M. Ready
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Homopropargylic alcohols undergo directed hydrozirconation with Schwartz reagent (Cp2ZrHCl) to
generate vinyl-metal species in which the metal fragment is proximal to the alkoxide. Electrophilic
trapping yields tri-substituted olefins in good yields with good control of regio- and stereochemistry.
Experiments with a homopropargylic ether confirmed the role of the hydroxyl group in the directed
hydrometalation.
Received 19 January 2008
Received in revised form 11 March 2008
Accepted 14 March 2008
Available online 21 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
favored kinetically. Furthermore, this kinetic selectivity can be
enhanced through an equilibration process (Scheme 1). Thus, in the
Olefin synthesis remains a challenging and important endeavor.
Olefins are building blocks for organic synthesis and components
of natural products, pharmaceuticals, and functional molecules. Of
the many strategies to generate alkenes, those based on coupling a
nucleophile, an electrophile, and an alkyne offer substantial ver-
satility (Eq. 1).1 The ready availability of alkynes from commercial
sources and standard preparations2 adds to the attractiveness of
these methods. To synthesize olefins from alkynes in a practical
manner, however, three challenges must be addressed. In particu-
lar, the modest reactivity of alkynes must be overcome, and both
the regiochemistry and stereochemistry of the alkene product must
be controlled.
presence of excess Cp2ZrHCl, hydrozirconation of a vinyl zirconium
intermediate can generate a vicinal dimetallic species. Subsequent
b-hydride elimination provides a means to interconvert regioiso-
meric vinyl zirconium products.5 Of note, hydrozirconation is ste-
reospecific, so cis-addition of H–Zr is almost always observed.6
The identification of factors other than steric bulk for controlling
the regioselectivity of hydrozirconation could create new oppor-
tunities and applications for hydrozirconation in organic synthe-
sis.7 If the normal regioselectivity of hydrozirconation could be
reversed it might provide access to olefins with substitution pat-
terns that are difficult to access by other methods. In this context,
we have demonstrated an alkoxide-directed hydrozirconation of
terminal propargylic alcohols (Eq. 2).8 We found that under stan-
dard conditions propargylic alcohols undergo hydrozirconation
with the expected sense of regioselectivity. However, in the pres-
ence of ZnCl2, the lithium alkoxides of terminal propargylic alco-
hols react to yield the branched products exclusively.9 As part of
a broader program to exploit directing groups in alkyne function-
alization reactions,10,11 this result encouraged us to explore the
hydrozirconation of homopropargylic alcohols.12 In this regard, it is
Nucleophile (Nu-)
Electrophile (El+)
Nu
R
El
R'
R
R'
ð1Þ
Among reagents that react with alkynes, the Schwartz reagent
(Cp2ZrHCl) is notable for its utility. The Schwartz reagent reacts
with internal and terminal alkynes with predictable regiose-
lectivity and stereospecificity to provide vinyl zirconium species.3
This reagent is ideally suited for the synthesis of alkenes (Eq. 1,
Nu¼H) because the vinyl zirconium intermediates can participate
in cross-coupling reactions, conjugate and nucleophilic additions,
and can undergo carbonylation, halogenation or transmetalation.
The wide applicability of vinyl zirconium reagents is reflected by
their frequent appearance in the literature of synthetic chemistry.4
The regioselectivity of hydrozirconation is usually controlled by
steric effects. Indeed, early elegant studies from the Schwartz group
established that the least-hindered vinyl zirconium species is
RS
H
RL
Cp2ZrHCl
RS
RL
ZrCp2Cl
Cp2ZrHCl
Cp2ZrHCl
- Cp2ZrHCl
RS
ClCp2Zr
RL
H
RS
RL
Cp2ZrHCl
H
ZrCp2Cl
H
- Cp2ZrHCl
ClCp2Zr
* Corresponding author.
Scheme 1. Hydrozirconation of alkynes with Schwartz reagent. RS and RL represent
E-mail address: joseph.ready@utsouthwestern.edu (J.M. Ready).
small and large substituents, respectively.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.052

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X. Liu, J.M. Ready / Tetrahedron 64 (2008) 6955–6960
noteworthy that Hoveyda and co-workers found that homoallylic
alcohols could modulate the regioselectivity of Cp2ZrCl2-catalyzed
carobometalation.13
product distribution (entries 2 and 3). As a control experiment, we
omitted CH3Li and ZnCl2 and were surprised to find that hydro-
zirconation still proceeded with good regioselectivity. Additionally,
the formation of Z-olefin was suppressed (entry 4). Incremental
improvements in yield were observed when the iodination was
carried out at a warmer temperature (entry 5), when the hydro-
zirconation/trapping occurred in CH2Cl2 (entry 6), and when I2 was
replaced with N-iodosuccinimide (entry 7). Compared to terminal
propargylic alcohols, internal homopropargylic alcohols react more
slowly, thus requiring higher concentrations of Schwartz reagent.21
This rate difference is not surprising given the increased steric
hindrance that accompanies substitution on the alkyne. However,
while increased substitution decreases the reaction rate, it in-
creases the effectiveness of the alcohol as a directing group.
Accordingly, high regioselectivity is observed with homo-
propargylic alcohol 1a in the absence of additives, whereas termi-
nal propargylic alcohols require the inclusion of ZnCl2 and initial
generation of a lithium alkoxide (Eq. 2).
To better understand the origin of regioselectivity, we compared
homopropargylic alcohol 1a to its methyl ether, 1b (Scheme 2A).
These experiments revealed that converting the free alcohol to a
methyl ether substantially attenuated the kinetic regioselectivity of
the hydrozirconation. Thus alcohol 1a provided a 9:1 ratio of
regioisomers while the methyl ether 1b showed only a modest bias
for the same regioisomer. Neither ratio changed substantially upon
prolonged reaction time. These results appear most easily accom-
modated by a model involving intramolecular hydrozirconation
with an alkoxy-zirconium hydride (5, Scheme 2B).7 The strong O–Zr
interaction accounts for the high kinetic selectivity. The stability of
We were especially interested in the reactivity and selectivity
observed with homopropargylic alcohols because these substrates
can be prepared easily and in optically active form through prop-
argylation of aldehydes14 or addition of terminal alkynes to epox-
ides.15 As described below, our studies resulted in the discovery of
a simple method for directed hydrometalation of homopropargylic
alcohols (Eq. 3). These transformations introduce a hydride and an
electrophile cis with respect to the new olefin, with the electrophile
proximal to the directing group. In this regard, both cis- and trans-
selective hydrosilylations have been reported.16,17 Similar to the
protocols disclosed here, these reductions introduce the silyl group
proximal to the alcohol. In contrast, hydroalumination of homo-
propargylic alcohols generally yields organometallic reagents with
the metal fragment distal to the alcohol moiety; both cis- and trans
addition of Al–H to the alkyne are possible.18,19 Finally, hydro-
stannylation with Bu2Sn(OTf)H provides (Z)-g-stannylated allylic
alcohols with good selectivity.20
Cp2ZrHCl (2 equiv)
THF, 23 °C
OH
OH
OH
Additive;
Electrophile (El+)
El
+
R
ð2Þ
R
El
R
linear
branched
Additive
linear : branched
none
>50 : 1
1 : >50
CH3Li (1 equiv); ZnCl2 (6 equiv)
OH El
OH
R''
R1
R1
A
Cp2ZrHCl, CH2Cl2;
I2
C4
OR
Cp2ZrHCl;
Electrophile (El+)
C10
H
C10
I
ð3Þ
R
R
+
OR
OR
C10
R'
R''
R'
I
H
1
C10 = n-C10H21
C4 = n-C4H9
2
3
2. Results and discussion
Substrate
1a: R = H
Product distribution
2a : 3a 9 : 1
=
Initial experiments were performed with simple homo-
propargylic alcohol 1a. Following conditions we found optimal for
the branched-selective hydrozirconation of terminal propargylic
alcohols,8 1a was deprotonated (CH3Li) and treated with a solution
of ZnCl2 and Cp2ZrHCl in THF. Encouragingly, the regioselectivity
was greater than 20:1, but conversion was modest (Table 1, entry 1).
Of greater concern was the observation of substantial quantities of
non-iodinated material (4a) and the Z-olefin (Z-2a) (see below).
Performing the hydrozirconation at elevated temperatures or with
more Schwartz reagent had only modest effects on conversion and
2b : 3b 1.6 : 1
1b: R = CH3
=
B
R'
R'
R'
OH
2 Cp2ZrHCl
R
O
O
R
-H2, -Cp2ZrCl2
R
Zr
H
Zr
Cp2
H
Cp2
5
6
Scheme 2. Directed hydrozirconation of homopropargylic alcohols.
Table 1
Hydrozirconation/iodination of homopropargylic alcohol 1aa
nC4H9
nC4H9
nC4H9
nC4H9
OH
nC4H9
1. Hydrozirconation
conditions
nC10H21
H
H
nC10H21
nC10H21
+
+
+
nC10H21
OH
OH
OH
OH
2. [I] trap
nC10H21
I
Z-2a
I
H
3a
H
H
4a
I
1a
E-2a
Entry
Additive
Cp2ZrHCl (equiv)
Solvent
[I]b/temp (ꢀC)
NMR yields (%)
Isolated yield (2a)
E-2a
Z-2a
3a
4a
1
2
3
4
5
6
7
MeLi (1 equiv)/ZnCl2 (6 equiv)
MeLi (1 equiv)/ZnCl2 (6 equiv)
MeLi (1 equiv)/ZnCl2 (9 equiv)
d
d
d
d
2
THF
THF
THF
THF
THF
CH2Cl2
CH2Cl2
I2/ꢁ78
I2/ꢁ78
I2/ꢁ78
I2/ꢁ78
I2/rt
58
59
65
56
70
74
75
9
13
17
d
d
d
d
Trace
Trace
Trace
8
12
10
14
14
11
23
11
12
8
d
d
d
d
61
64
74
2 (40 ꢀC)
3
3
3
3
3
I2/rt
NISc/rt
8
a
Reactions carried out on a 0.4 mmol scale. Hydrozirconation reaction time¼3 h.
b
c
Two equivalents.
N-Iodosuccinimide.

X. Liu, J.M. Ready / Tetrahedron 64 (2008) 6955–6960
6957
Table 2
and even O-alkyl (entry 5) substituents are tolerated on the alkyne.
Furthermore, alkyl (entry 7) and silyl (entry 8) ethers as well as
tertiary amines (entry 6) are accommodated by the method. In
contrast to the results tabulated above, homopropargylic alcohols
featuring a terminal alkyne do not provide synthetically useful
yields of the vinyl iodides. Under various conditions, poor conver-
sion, over-reduction or poor regioselectivity compromise the yield
of the desired products.
Electrophilic trapping is not limited to iodination. For example,
after quenching the remaining Cp2ZrHCl with acetonitrile, trans-
metalation from Zr to Zn facilitated a Negishi coupling with iodo-
benzene (Eq. 4).23 The coupled product was isolated as a single
olefin stereoisomer in good yield.
Hydrozirconation/iodination of homopropargylic alcoholsa
Cp2ZrHCl (3 equiv),
R1
CH2Cl2, 23 °C, 3h;
NIS (2 equiv)
R1
OH
R2
H
OH
R2
I
1
2
Entry
1
Product
Yieldb (%)
74
C4H9
C10H21
H
2a
OH
I
CH3
C10H21
2
3
2c
75
79
Cp2ZrHCl (3 equiv) CH2Cl2;
OH
I
CH3CN;
TIPSO
CH3
H
ZnCl2, THF;
PhI, Pd(PPh3)4 (10 mol%)
CH3
OH
C6H13
OH
ð4Þ
2d
OH
I
OTIPS
H
Ph
7
79% yield
CH3
4
2e
72
OH
I
All of the substrates in Table 2 feature a methylene between the
alkyne and the carbinol. Introducing a methyl group on the
propargylic carbon expands the potential structural diversity of
accessible products. However, hydrozirconation of this class of
homopropargylic alcohols proved less regioselective than the re-
actions described above. The increased steric bulk at the prop-
argylic position appears to counterbalance the directing effect of
the hydroxyl group. In particular, treating alkynol 1k under the
conditions optimized for 1a returned a nearly statistical distribu-
tion of regioisomers (Table 3, entry 1). In contrast and consistent
with the results obtained with terminal propargylic alcohols, initial
deprotonation with CH3Li and the inclusion of ZnCl2 in the reaction
mixture substantially improved the regioselectivity (>38:1). Ac-
cordingly, the desired vinyl iodide was isolated in good yield (entry
2). The same procedure was found optimal for hindered homo-
propargylic alcohols (Table 2, entry 9).
H
C12H25
EtO
H
5
6
7
8
2f
70
74
66
76
OH
I
CH3
OH
Bn2N
PMB
2g
2h
2i
H
I
O
O
CH3
OH
H
I
I
TIPS
CH3
OH
H
The generation of small amounts of Z-vinyl iodides in the
presence of Li and Zn salts (Table 1, entry 1 and Table 3, entry 2)
contrasts with the usual behavior of the Schwartz reagent. Indeed,
the stereospecificity of hydrozirconation contributes to its broad
application in organic synthesis. This unusual loss of stereochem-
ical integrity may result from the hydrozirconation of a vinyl zinc
intermediate. In this context, Knochel and co-workers reported the
hydrozirconation of vinyl zinc reagents to yield geminal hetero-
bimetallic species.24 In reactions of homopropargylic alcohols,
directed hydrozirconation followed by transmetalation could yield
a vinyl zinc intermediate (E-8, Scheme 3). Subsequent hydro-
zirconation would lead to a heterobimetallic compound such as 9.
Critically, b-hydride elimination could now provide either the E or Z
olefin. Consistent with this proposal, the E/Z ratio was found to
(p-BrPh)
OH
Ph
9c
2j
68
H
I
a
Reactions carried out on a 0.4 mmol scale; see Section 4 for details.
b
c
Isolated yield of E-olefin.
Hydrozirconation performed on the lithium alkoxide in the presence of 9 equiv
ZnCl2.
the five-membered chelate likely contributes to the resistance of
the oxazirconacycle (6) to isomerization to the distal product.22
The scope of the directed hydrozirconation displays several
noteworthy features (Table 2). Both primary and secondary alcohols
effectively direct the hydrometalation. Aryl (entries 4 and 9), alkyl,
Table 3
Hydrozirconation/iodination of homopropargylic alcohol 1j
H3C
Cp2ZrHCl (3 equiv)
Conditions;
H3C
OH
H3C
OH
H3C
OH
H3C
OH
H
R
R
I
OH
CH3
R
H
R
H
+
CH3
+
CH3
CH3
+
CH3
[I] trap
R
I
H
I
H
-
R = Br-(CH2)4
( )-Z-2k
NMR yields (%)
( )-3k
( )-4k
( )-1k
( )-E-2k
Entry
Additive
Solvent
[I]/temp (ꢀC)
Isolated yield (E-2k)
E-2k
Z-2k
3k
4k
1
d
CH2Cl2
THF
NIS (2 equiv)/23
I2 (2 equiv)/ꢁ78
43
77
d
33
<2
16
6
d
2a
CH3Li (1 equiv); ZnCl2 (9 equiv)
7
69
a
Reaction carried out on a 1.0 mmol scale; see Section 4 for details.

6958
X. Liu, J.M. Ready / Tetrahedron 64 (2008) 6955–6960
R
R
R
R
4.3. General procedure for hydrozirconation/iodination of
homopropargylic alcohols with a propargylic methylene
(Table 2)
CH3Li;
Cp2ZrHCl
R
R
H
R
H
ZnCl2
R
O
O
R
Zr
Cp2
Zn
HO
E-8
6
A solution of homopropargylic alcohol (0.40 mmol) in CH2Cl2
(1.0 mL) was added in one portion to a stirred suspension of
Cp2Zr(H)Cl (310 mg, 1.2 mmol) in CH2Cl2 (2.0 mL) at room tem-
perature, followed by rinsing with CH2Cl2 (1.0 mL). The mixture
was stirred for 3 h and formed a clear yellow solution. A solution of
N-iodosuccinimide (180 mg, 0.80 mmol) in THF (2.0 mL) was
added. After 0.5 h at room temperature, a mixed aqueous solution
of saturated Na2S2O3 (5 mL) in saturated aqueous NaHCO3 solution
(5 mL) was added to quench the reaction. After dilution with ether,
the reaction mixture was separated and the aqueous layer was
extracted with ether. The combined organic phases were dried over
Na2SO4, concentrated and purified by chromatography on silica gel.
Cp2ZrHCl
R
R
R
R
R
R
H
R
R
R
- Cp2ZrHCl
H
O
O
H
O
Zr
ZrCl
Zn
Z-8
H
Zn
H
ZrCp2Cl
9
10: Zr = ZrCp2
Scheme 3. Olefin isomerization in the presence of ZnCl2.
deteriorate as the reaction progressed. The fact that single olefin
stereoisomers were formed in the absence of ZnCl2 indicates that
hydrozirconation to yield the dizirconium species 10 is prevented,
likely due to steric effects.
4.3.1. (E)-7-Iodooctadec-7-en-5-ol (E-2a)
Light yellow oil, 74% yield. 1H NMR (CDCl3) d¼0.87 (t, J¼6.8, 3H),
0.92 (t, J¼6.8, 3H), 1.18–1.56 (m, 22H), 1.64 (d, J¼2.8, 1H), 2.00–2.16
(m, 2H), 2.40 (ddd, J¼0.4, 3.6, 14.4, 1H), 2.62 (dd, J¼8.8, 14.4, 1H),
3.83–3.93 (m, 1H), 6.36 (t, J¼7.6, 1H). 13C NMR (CDCl3) d¼14.0, 14.1,
22.7, 27.9, 29.1, 29.1, 29.3, 29.4, 29.5, 29.6, 31.3, 31.9, 35.7, 46.3, 70.4,
98.0,144.9. HRMS (EIþ): m/z calcd for [C18H35IO]þ: 394.1733; found:
394.1730. Regiochemical assignment was based on COSY spectra;
J-coupling was observed between the C8 vinyl proton and the C9
allylic protons. Stereochemical assignment was based on an NOE
between the C6 and C9 allylic protons and the absence of an NOE
between the C8 vinyl proton and the C6 allylic proton (see Z isomer
below). Further support is provided by comparison to a similar
compound.26
3. Conclusion
We have developed two procedures for hydrozirconation
of homopropargylic alcohols. Substrates with a methylene group
between the alkyne and the alcohol undergo stereospecific hydro-
zirconation with good control of regioselectivity. The reaction con-
ditions are simple and require no additives. For more challenging
substrates, such as those with substitution on the propargylic car-
bon, the addition of CH3Li and ZnCl2 to the reaction mixture mark-
edly increases the regioselectivity of hydrozirconation. Coupled
with prior results,8,7 the present study suggests that factors other
than sterics can dictate regioselectivity in hydrozirconation re-
actions. This observation should present new opportunities for
organozirconium reagents in organic synthesis.
4.3.1.1. (Z)-7-Iodooctadec-7-en-5-ol (Z-2a). Light yellow oil, 1H
NMR (CDCl3) d¼0.81 (t, J¼7.2, 3H), 0.85 (t, J¼7.2, 3H), 1.10–1.52 (m,
22H), 2.14 (q, J¼6.8, 2H), 2.52 (dd, J¼8.4, 14.0, 1H), 2.63 (dm, J¼14.0,
1H), 3.86–3.96 (m, 1H), 5.62 (t, J¼6.4, 1H). 13C NMR (CDCl3) d¼14.1,
14.1, 22.7, 27.8, 28.3, 29.2, 29.3, 29.5, 29.6, 29.6, 31.9, 35.6, 36.5, 52.9,
69.5, 104.5, 138.7. HRMS (EIþ): m/z calcd for [C18H35IO]þ: 394.1733;
found: 394.1732. Stereochemical assignment based on an NOE
between the C8 vinyl proton and the C6 allylic proton and com-
parison to related compounds.27
4. Experimental
4.1. General
Unless otherwise stated, reactions were performed under ni-
trogen atmosphere with a positive pressure using freshly purified
solvents. Solvents were purified using solvent purification columns
purchased from Glass Contour, Laguna Beach, CA. All reactions were
monitored by 1H NMR or thin layer chromatography with E. Merck
silica gel 60 F254 pre-coated plates (0.25 mm). Gas chromatography
(GC) was performed on an HP 6890N autosampling GC with an
HP-5 capillary column and equipped with a FID detector. Flash
chromatography was performed using silica gel (particle size 40–
63 mm) purchased from Sorbent Technologies. 1H and 13C NMR
spectra were recorded on Varian Inova-400 or Mercury-300 spec-
trometer. Chemical shift are reported relative to internal chloro-
form (CDCl3: 1H, d¼7.26, 13C, d¼77.0). Coupling constants are in
hertz and are reported as d (doublet), t (triplet), q (quartet), quin
(quintet). Mass spectra were acquired on a Shimadzu QP5000 GC/
MS using the indicated ionization method.
4.3.1.2. (E)-8-Iodooctadec-7-en-5-ol (E-3a). Light yellow oil, 1H
NMR (CDCl3) d¼0.88 (t, J¼7.2, 3H), 0.91 (t, J¼7.2, 3H), 1.16–1.56 (m,
22H), 2.21 (t, J¼7.2, 2H), 2.32–2.45 (m, 2H), 3.65–3.70 (m, 1H), 6.24
(t, J¼7.6, 1H). 13C NMR (CDCl3) d¼14.1, 14.1, 22.7, 22.8, 27.8, 28.4,
29.3, 29.3, 29.5, 29.6, 29.7, 29.6, 31.9, 36.5, 38.7, 71.0, 106.4, 137.0.
HRMS (EIþ): m/z calcd for [C18H35IO]þ: 394.1733; found: 394.1734.
Stereochemical assignment is based on an NOE between the C6 and
C9 allylic protons.
4.3.2. (E)-4-Iodopentadec-4-en-2-ol (E-2c)
Light yellow oil, 75% yield. 1H NMR (CDCl3) d¼0.88 (t, J¼7.2, 3H),
1.18–1.42 (m, 19H), 1.65 (d, J¼3.6, 1H), 2.02–2.18 (m, 2H), 2.42 (dd,
J¼3.6, 14.4, 1H), 2.65 (dd, J¼8.0, 14.4, 1H), 4.05–4.15 (m, 1H), 6.37
(t, J¼8.0,1H).13C NMR (CDCl3) d¼14.1, 21.9, 22.6, 29.1, 29.1, 29.3, 29.4,
29.5, 29.5, 31.3, 31.9, 47.7, 66.8, 97.6,144.8. HRMS (EIþ): m/z calcd for
[C15H29IO]þ: 352.1263; found: 352.1261. Stereochemical assign-
ment supported by an NOE between the C3 and C6 allylic protons.
4.2. Materials
4.3.3. (E)-3-Iododec-3-en-1-ol (E-2d)
Cp2Zr(H)Cl was purchased from Strem Chemicals Inc. and used
within 2 months. All homopropargylic alcohols were prepared by
addition of appropriate terminal alkynes to epoxides,15b except 1d
(Table 2, entry3, Aldrich)and1g(Table 2, entry6, fromtheaminolysis
of the corresponding 1-chloro-alkynol with dibenzyl amine25).
Light yellow oil, 79% yield. 1H NMR (CDCl3) d¼0.72 (t, J¼7.2, 3H),
1.02–1.27 (m, 8H), 1.25 (t, J¼6.0, 1H), 1.93 (q, J¼7.6, 2H), 2.50 (t,
J¼6.0, 2H), 3.59 (q, J¼6.0, 2H), 6.21 (t, J¼7.2, 1H). 13C NMR (CDCl3)
d¼14.0, 22.5, 28.7, 29.1, 31.1, 31.6, 41.4, 61.2, 97.3, 144.8. EIMS (m/z):
HRMS (EIþ): m/z calcd for [C10H19IO]þ: 282.0481; found: 282.0480.

X. Liu, J.M. Ready / Tetrahedron 64 (2008) 6955–6960
6959
Stereochemical assignment supported by an NOE between the C2
and C5 allylic protons.
(3.0 mL) at ꢁ78 ꢀC. After 20 min, the solution was warmed up to
room temperature. Meanwhile, Cp2Zr(H)Cl (770 mg, 3.0 mmol) and
THF (2.0 mL) were added sequentially to freshly fused ZnCl2 (1.2 g,
9.0 mmol). The resulting mixture was stirred until all Cp2Zr(H)Cl
dissolved (about 3 min; solid ZnCl2 remained suspended). The
prepared solution of alkoxide was then transferred into the mixture
of ZnCl2 and Cp2Zr(H)Cl in THF, followed by rinsing with THF
(2.0 mL). The resulting clear solution was stirred for 6 h and gave
a mixture with gray precipitate. Anhydrous CH3CN (0.52 mL,
10 mmol) was then added. After 10 min, the reaction was cooled to
ꢁ78 ꢀC and a solution of I2 (510 mg, 2.0 mmol) in 3.0 mL of THF was
added. After 1 h at this temperature, a mixed aqueous solution of
saturated Na2S2O3 (15.0 mL) and saturated aqueous NaHCO3 solu-
tion (15.0 mL) was added to quench the excess I2. After dilution with
ether, the reaction mixture was separated and the aqueous layer
was extracted with ether. The combined organic phases were dried
over Na2SO4, concentrated, and purified by repetitive chromatog-
raphy on silica gel to provide 2k as a light yellow oil (247.4 mg, 69%
yield). 1H NMR (CDCl3) d¼0.93 (d, J¼6.4, 3H), 1.26 (d, J¼6.4, 3H),
1.46–1.64 (m, 2H), 1.77 (d, J¼2.4, 1H), 1.80–2.00 (m, 3H), 2.10–2.28
(m, 2H), 3.41 (t, J¼6.4, 2H), 3.55–3.66 (m, 1H), 6.40 (t, J¼7.2, 1H).
13C NMR (CDCl3) d¼18.3, 19.4, 27.6, 30.5, 31.9, 33.3, 45.8, 70.7,
111.5, 143.0. MS (EIþ) (m/z): 360, 362 [M]þ. HRMS (EIþ): m/z calcd
for [C10H18IOBr]þ: 359.9586; found: 359.9585.
4.3.4. (E)-4-Iodo-5-phenylpent-4-en-2-ol (E-2e)
Light yellow oil, 72% yield. 1H NMR (CDCl3) d¼1.26 (d, J¼6.4, 3H),
1.71 (d, J¼4.0, 1H), 2.51 (ddd, J¼1.2, 4.0, 14.4, 1H), 2.91 (dd, J¼8.8,
14.4, 1H), 4.19–4.30 (m, 1H), 7.24–7.40 (m, 5H), 7.49 (s, 1H). 13C NMR
(CDCl3) d¼22.2, 47.8, 67.5, 103.9, 127.5, 128.3, 128.4, 137.2, 143.7.
HRMS (EIþ): m/z calcd for [C11H13IO]þ: 288.0011; found: 288.0012.
Stereochemical assignment supported by an NOE between the C3
allylic proton and the aromatic ring.
4.3.5. (E)-1-Ethoxy-2-iodohexadec-1-en-4-ol (E-2f)
Light yellow oil, 70% yield. 1H NMR (CDCl3) d¼0.88 (t, J¼6.8, 3H),
1.18–1.40 (m, 24H), 1.41–1.58 (m, 4H), 1.79 (d, J¼3.6, 1H), 2.41 (dd,
J¼3.6, 14.4, 1H), 2.74 (dd, J¼8.4, 14.4, 1H), 3.73–3.92 (m, 3H), 6.57 (s,
1H). 13C NMR (CDCl3) d¼14.1, 15.3, 22.7, 25.6, 29.4, 29.6, 29.7, 29.7,
31.9, 36.3, 42.3, 68.4, 70.7, 75.1, 151.3. HRMS (EIþ): m/z calcd for
[C18H35IO2]þ: 410.1682; found: 410.1680.
4.3.6. (E)-9-(Dibenzylamino)-4-iodonon-4-en-2-ol (E-2g)
Yellowoil, 74%yield.1HNMR(CDCl3)d¼1.22 (d, J¼6.0, 3H),1.37 (q,
J¼7.6, 2H),1.50 (quin, J¼7.6, 2H),1.58 (br s,1H), 2.00 (ddd, J¼2.4, 7.2,
14.8, 2H), 2.34 (dd, J¼4.4,14.4,1H), 2.40 (t, J¼7.2, 2H), 2.56 (dd, J¼8.4,
14.4,1H), 3.54 (s, 4H), 4.02–4.12 (m,1H), 6.29 (t, J¼7.2,1H), 7.18–7.42
(m, 10H). 13C NMR (CDCl3) d¼22.0, 26.3, 26.5, 30.9, 47.6, 52.8, 58.3,
66.7, 97.8, 126.8, 128.1, 128.7, 139.7, 144.5. HRMS (EIþ): m/z calcd for
[C23H30INO]þ: 463.1372; found: 463.1373. Stereochemical assign-
ment supported by an NOE between the C3 and C6 allylic protons.
4.5. Hydrozirconation of homopropargylic alcohols/Negishi
cross-coupling. Synthesis of 7
Hydrozirconation was carried out as described in the general
procedure for substrates in Table 2. After hydrozirconation, CH3CN
(0.052 mL, 1.0 mmol) and phenyl iodide (0.140 mL, 1.2 mmol) were
added. After 10 min, Pd(PPh3)4 (46 mg, 0.040 mmol) in THF
(1.0 mL) was added and the reaction was stirred overnight. The
reaction was quenched with aqueous NaHCO3 and extracted with
ether. The combined organic phases were dried over MgSO4, con-
centrated, and purified by repetitive chromatography on silica gel
to give 115 mg of product as light yellow oil (79% yield). 1H NMR
(CDCl3) d¼1.00–1.15 (m, 21H), 1.17 (d, J¼6.0, 3H), 1.90 (d, J¼3.6,
1H), 2.43–2.53 (m, 1H), 2.53–2.63 (m, 1H), 2.65 (dd, J¼4.4, 14.0, 1H),
2.76 (dd, J¼8.0, 14.0, 1H), 3.71–3.85 (m, 1H), 3.82 (t, J¼6.4, 2H), 5.84
(t, J¼7.6, 1H), 7.19–7.36 (m, 5H). 13C NMR (CDCl3) d¼12.0, 18.0, 23.0,
32.6, 39.8, 63.0, 66.5, 126.5, 126.9, 128.3, 128.6, 138.5, 143.0 HRMS
(EIþ): m/z calcd for [C22H38O2Si]þ: 362.2641; found: 362.2642.
4.3.7. (E)-4-Iodo-7-(4-methoxybenzyloxy)hept-4-en-2-ol (E-2h)
Light yellow oil, 66% yield. 1H NMR (CDCl3) d¼1.24 (d, J¼6.0,
3H), 2.19–2.30 (m, 1H), 2.41 (dd, J¼3.2, 14.4, 1H), 2.46–2.59 (m, 1H),
2.62 (d, J¼3.2, 1H), 2.73 (dd, J¼8.8, 14.4, 1H), 3.36–3.50 (m, 2H), 3.81
(s, 3H), 4.02–4.13 (m, 1H), 4.42 (d, J¼12.0, 1H), 4.47 (d, J¼12.0, 1H),
6.33 (dd, J¼6.4, 9.2, 1H), 6.86–6.93 (m, 2H), 7.20–7.32 (m, 2H). 13
C
NMR (CDCl3) d¼22.3, 31.7, 48.3, 55.2, 66.2, 67.6, 72.6, 100.0, 113.7,
129.4, 129.8, 140.8, 159.2. EIMS (m/z): 332 [MꢁCH3CHO]þ. HRMS
(CIþ): m/z calcd for [C15H20IO3ꢁH]þ: 375.0458; found: 375.0459.
Stereochemical assignment supported by an NOE between the C3
and C6 allylic protons.
4.3.8. (E)-4-Iodo-7-(triisopropylsilyloxy)hept-4-en-2-ol (E-2i)
Light yellow oil, 76% yield.1H NMR (CDCl3) d¼1.00–1.16 (m, 21H),
1.25 (d, J¼6.4, 3H), 2.12 (d, J¼3.2, 1H), 2.25–2.36 (m, 1H), 2.38–2.50
(m, 2H), 2.74 (dd, J¼8.4, 14.4, 1H), 3.73 (t, J¼6.0, 2H), 4.02–4.13 (m,
1H), 6.40 (t, J¼7.2, 1H). 13C NMR (CDCl3) d¼11.9, 17.9, 22.1, 34.6, 48.4,
62.0, 66.4, 99.3, 141.3. HRMS (EIþ): m/z calcd for [C16H32IO2SiꢁH]þ:
411.1217; found: 411.1212. Stereochemical assignment supported
by an NOE between the C3 and C6 allylic protons.
Acknowledgements
We thank Donghui Zhang (UTSW) for key initial experiments.
Financial support was provided by the Welch Foundation (I-1612)
and the NIH (NIGMS, R01-GM074822).
4.3.9. (E)-1-(4-Bromophenyl)-3-iodo-4-phenylbut-3-en-1-ol (E-2j)
Reaction was preformed following the procedure for 2k. Light
yellow viscous oil, 68% yield. 1H NMR (CDCl3) d¼2.06 (d, J¼3.2, 1H),
2.74 (ddd, J¼1.2, 4.8, 14.4, 1H), 3.12 (ddd, J¼0.8, 8.8, 14.4, 1H), 5.05–
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