Tunable phosphoramidite ligands for asymmetric hydrovinylation: Ligands par excellence for generation of all-carbon quaternary centers

Article abstract of DOI:10.1055/s-0029-1216826

α-Alkylstyrenes undergo efficient hydrovinylation (addition of ethene) in the presence of a nickel catalyst prepared from [(allyl)NiBr] ₂, Na⁺[BAr₄]^- [Ar = 3,5-bis(trifluoromethyl)phenyl], and a phosphoramidite ligand giving products in excellent yields and enantioselectivities. In many cases phosphoramidites derived from achiral 2,2′-biphenol are almost as good as ligands derived from the more expensive enantiopure 1,1′-bi(2-naphthol)s. The hydrovinylation products, which carry two versatile latent functionalities, an aryl and a vinyl group, are potentially useful for the synthesis of several important natural products containing benzylic all-carbon quaternary centers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216826

SPECIAL TOPIC
2089
Tunable Phosphoramidite Ligands for Asymmetric Hydrovinylation:
Ligands par excellence for Generation of All-Carbon Quaternary Centers
All-Carbon
Q
uate
r
rnary
C
a
e
nters via
H
i
ydrovi
g
nylation R. Smith, Hwan Jung Lim, Aibin Zhang, T. V. RajanBabu*
Department of Chemistry, The Ohio State University, 100 W. 18th Ave, Columbus, OH 43210, USA
Fax +1(614)2921685; E-mail: rajanbabu.1@osu.edu
Received 20 April 2009
employed in the discovery of many new asymmetric cata-
lytic processes that involve the use of carbon feedstocks
for selective C–C bond-forming reactions.2,3 Phosphor-
amidites, originally introduced by Feringa4a,b for the asym-
Abstract: a-Alkylstyrenes undergo efficient hydrovinylation (ad-
dition of ethene) in the presence of a nickel catalyst prepared from
[(allyl)NiBr]2, Na+[BAr4]– [Ar = 3,5-bis(trifluoromethyl)phenyl],
and a phosphoramidite ligand giving products in excellent yields
and enantioselectivities. In many cases phosphoramidites derived metric copper-catalyzed conjugate addition of dialkylzinc
from achiral 2,2¢-biphenol are almost as good as ligands derived
from the more expensive enantiopure 1,1¢-bi(2-naphthol)s. The hy-
drovinylation products, which carry two versatile latent functional-
Recently we5 and the Zhou group6 have described the use
ities, an aryl and a vinyl group, are potentially useful for the
synthesis of several important natural products containing benzylic
reagents to enones, are among the most versatile and tun-
able ligands for C–C and C–H bond-forming reactions.4c–i
of phosphoramidite ligands derived from different sourc-
es for the asymmetric hydrovinylation reactions of (1-
alkylvinyl)arenes leading to useful intermediates with all-
carbon quaternary centers (Equation 1).7 In this paper we
disclose the full details of our efforts, including results of
more recent studies aimed at exploring the scope and lim-
itations of this reaction.
all-carbon quaternary centers.
Key words: alkenes, asymmetric catalysis, hydrovinylation, phos-
phoramidite ligands, nickel
Catalytic asymmetric C–C bond-forming reactions con-
tinue to attract great interest among synthetic chemists.1
Among these, a subclass of reactions that depend on the
activation and subsequent stereoselective incorporation of
small molecules such as CO, CO2, HCN, acetylene, and
ethene into prochiral substrates, are among the most chal-
lenging.2 Ideally, new reactions must accomplish the re-
quisite transformations under nearly ambient conditions
with high turnover frequencies, high regio- and stereo-
selectivities, all the while generating only little or no side
products. Further, the newly installed functionality must
be amenable to further transformations leading to valu-
able end products. Research in this area could lead to new
breakthroughs in fundamental science, and under the most
optimistic scenario, will add to our repertoire of methods
for economically viable syntheses of valuable chemical
intermediates.
C2H4 (1 bar)
R
H
[Ni(allyl)L]+ X–
R
+
R
Ar
*
(catalyst)
Ar
Ar
Me
2
3
1
Equation 1
Asymmetric Hydrovinylation
Hydrovinylation,8 the addition of ethene as a hydrogen
and a vinyl group across an activated olefin (Equations 1
and 2), has received much renewed attention9 since we
disclosed new protocols for this prototypical heterodimer-
ization reaction.10 During the past decade the scope of the
reaction has also been considerably broadened.8b Since
ethene is an inexpensive, abundantly available feedstock
carbon source, and the vinyl group in the resulting product
readily transformed into a variety of other common func-
tionalities, this reaction has huge potential to be a scal-
able, environmentally benign method for the preparation
of valuable chemical intermediates. Application of old
(Figure 1, 5,8a 610) and new (7,7c,11 8,3f 9,7 106) ligands
have enabled successful asymmetric hydrovinylation of
vinylarenes, 1,3-dienes and strained bicyclic olefins such
as norbornene. Asymmetric hydrovinylation of vinyl-
arenes (Equation 2) has been the most developed, and the
resulting 3-arylbut-1-enes 4 have been converted into a
number of synthetically useful derivatives such alco-
hols,3b,12 halides, aldehydes, carboxylic acids, and chiral
1-ethylarylamines.13
In developing new metal-catalyzed reactions, the ligand is
a major factor as efficiency (turnover frequency), selectiv-
ity, and catalytic stability are often dependent on the prop-
erties of the ligand. In the area of asymmetric catalysis,
success often depends on the availability of enantiomeri-
cally pure ligands that are amenable to fine tuning for op-
timum performance. Once the essential features of the
catalytic system are identified, systematic modifications
in the ligand scaffolding, especially, those affecting the
steric and electronic environment around the chelating at-
oms, are often required to achieve acceptable levels of cat-
alytic efficiency and selectivity. Such a strategy has been
SYNTHESIS 2009, No. 12, pp 2089–2100
Advanced online publication: 14.05.2009
x
x.
x
x
.
2
0
0
9
DOI: 10.1055/s-0029-1216826; Art ID: C01309SS
© Georg Thieme Verlag Stuttgart · New York

2090
C. R. Smith et al.
SPECIAL TOPIC
We chose a-ethylstyrene (11b, Equation 3) as a prototyp-
ical substrate for the initial studies. A racemic sample of
the expected product 12b was conveniently prepared by
carrying out the reaction under conditions described in
Equation 4, using [2-(benzyloxy)phenyl]diphenylphos-
phine (13)7c as a ligand. This was followed by studies us-
ing 6–8, a set of ligands we had used with varying degree
of success in the asymmetric hydrovinylation of mono-
substituted vinylarenes and 1,3-dienes. The results of
these scouting experiments are listed in Table 1.
C2H4 (1 bar)
[(allyl)NiBr]2, L, NaBARF (0.7 mol%)
CH2Cl2, low temp.
R
R
4
> 95% yield
> 95% ee
Equation 2
Me
R
R
O
R
Me
Me
P
R
Me
C2H4 (1 bar)
Ph
Me
Bn
Me
*
H
O
Me
O
[(allyl)NiBr]2/L/NaBAr4
•
OBn
•
N
(1 mol% cat.)
N
PPh2
S
H
P
Ph
CH2Cl2
P
•
PPh2
•
Me
Me
S
11b R = Et
12b R = Et
13
Ar = 3,5-(CF3)2C6H3
6
7
(R,R)-5
Equation 4
Me
Me
S
H
O
Ph
Catalysts derived from the MOP ligand 6 (entry 2)10 and
the phosphinite 83f (entry 6) showed no reactivity while
R
N
P
Ph
R
Ph
N
S
Ph
Ph
O
HN
O
P
O
O
O
O
OBn
Ac
O
P
Table 1 Hydrovinylation of a-Ethylstyrene (Ligand Scouting)
Ra
Entry
Ligand
(mol%)
Temp
(°C)
Time
(h)
Conversion eea
(%)
(%)
Sa
1
2
3
4
5
6
13 (5)
6 (5)
7 (5)
7 (5)
7 (5)
8 (5)
25
48
74
rac
10
8
9
b
b
–
–
low
67
–
Figure 1 Assorted ligands for asymmetric hydrovinylation
–10
0
16
19
22
27 (R)
27 (R)
25 (R)
–
76
Ligand Tuning for the Generation of All-Carbon
Quaternary Centers via Asymmetric Hydrovinyla-
tion
25
72
b
b
–
–
low
The search for new methods for stereoselective generation
of all-carbon quaternary centers is a subject of consider-
able topical interest.14 Several important pharmaceutically
relevant compounds, among them, analgesic (–)-eptazo-
cine,15 protein kinase C activator lyngbyatoxin and related
structures like teleocidin B4,16 and cognitive enhancing
agent (–)-phenserine,17 contain an all-carbon quaternary
center at the benzylic position. The viability of hydroviny-
lation of a-alkylstyrene as a method for generating an all-
carbon quaternary benzylic center was initially discov-
ered during the scouting phase of our studies of hydrovi-
nylation (Equation 3, 11a → 12a), even though the
conversions were only modest under the highly catalytic
reaction conditions.3e
a Determined by GC analysis on Cyclodex-B column. Configuration
assigned by GC retention times of the known compound.18
b Various.
Table 2 Asymmetric Hydrovinylation of a-Ethylstyrene (11b) Us-
ing Ligand 9
Entry
Ligand
(mol%)
Temp
(°C)
Time
(h)
Conversion eea (%)
(%)
1
2
3
4
5
6
7
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (1)
9 (2)
–10
21
17
19
17
4
>99
>99
>99
>99
>99
>99
79 (R)
77 (R)
88 (R)
93 (R)
96 (R)
95 (R)
97.6 (R)b
–30
–55
–70
R
R
–70
Me
C2H4 (1 bar)
[(allyl)Ni([PPh3)]/AgOTf (0.007 equiv)
–70
4
CH2Cl2, 0 °C
–70 to –65
4
99.7
11a R = Me
11b R = Et
12a R = Me (42%)
12b R = Et
a Determined by GC analysis on Cyclodex-B column, for authentic
product see ref.18
b Reaction was performed on a 50-mmol scale.
Equation 3
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

SPECIAL TOPIC
All-Carbon Quaternary Centers via Hydrovinylation
2091
those derived from the phospholane ligand 7, which gave as 10 °C difference can bring about a deterioration of the
very high enantiomeric excess and turnover numbers in selectivity (entries 2–4). We also noticed that the hydrovi-
the hydrovinylation of a number of styrene derivatives,11 nylation reaction, even at –70 °C, is exothermic and care-
and 1,3-dienes,7c showed only moderate reactivity under ful control of the reaction conditions (<–70 °C) is
similar conditions (entries 3–5). At this point we turned essential for obtaining high enantioselectivities. Under
our attention to phosphoramidite ligands, starting with these conditions, no isomerization [to (Z)- and (E)-2-aryl-
one of the ‘original’ Feringa ligands 9 derived from (R)- but-2-enes] or oligomerization of starting alkenes was de-
binaphthol and bis[(S)-a-methylbenzyl]amine.19 The re- tected, as judged by careful GC analysis and H NMR
1
sults of these experiments on the asymmetric hydroviny- spectroscopy. The surprisingly high yields and selectivi-
lation of a-ethylstyrene (11b) using the ligand 9 are ties are highly reproducible and are independent of the
shown in Table 2. In a typical experiment, the phosphora- catalyst loading (entries 5–7), indicating the total absence
midite ligand was treated with allylnickel bromide dimer of nonselective reactions for this substrate. The reaction
[(allyl)NiBr]2 and sodium tetrakis[3,5-bis(trifluorometh- can be performed on a 50-mmol scale using 0.02 equiva-
yl)phenyl]borate {Na+[BARF]–, BARF
=
[3,5- lents of the nickel catalyst (entry 7).
(CF3)2C6H3]4B} in dichloromethane and was subsequent-
ly placed under an ethene atmosphere at –70 °C for a few
minutes.20 The ethene line was removed, and the styrene
dissolved in dichloromethane was added while maintain-
ing the reaction mixture at –70 °C. After all the starting
material had been consumed, the product was isolated af-
ter workup by simple filtration through a silica gel col-
umn. Optimization of reaction conditions revealed that the
enantioselectivity of the reaction depends critically on the
temperature at which the reaction is carried out. As little
Hydrovinylation of several a-alkylstyrene derivatives
were attempted under the optimal conditions and the re-
sults are tabulated in Table 3. While the 4-methylstyrene
14 gave excellent selectivity for the formation of the ex-
pected product 21 (entry 1), the 4-chloro derivative 15
gave up to 5% isomerization of the starting olefin to a
mixture of (Z)- and (E)-a,b-disubstituted styrenes (entry
2). A similar minor side reaction was also observed for the
substrate 17. An isopropyl group at the a-position of the
styrene 16 retards the reaction (entry 3), and it is best ac-
Table 3 Asymmetric Hydrovinylation of a-Alkylstyrenes Using Ligand 9a
Entry
Vinylarene
Product
Temp (°C) Time (h)
Yield (%)
>90
ee (%)b
90
1
14
21
–60
–70
12
11
2
15
22
>90c
90
Cl
Cl
3
4
5
16d
17
23
24
25
20
8
60e
93c
>95
>50f
93
24
–70
C5H11
C5H11
18
–70
14
>98
6
7
19
20
–
–
–70
–70
14
14
0
0
–
–
Ph
a See Equation 4 for details.
b Determined by GC, the (R)-isomer was assigned by analogy to 12b.
c The remainder was isomerized product from the starting material.
d 10 mol% catalyst used.
e The remainder was starting material.
f Determined via Mosher esters of hydroboration product.
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

2092
C. R. Smith et al.
SPECIAL TOPIC
complished at 24 °C with 10 mol% catalyst. Even though bearing quaternary center at the benzylic position.22 We
the yield of the reaction is only moderate, very high enan- reasoned that asymmetric hydrovinylation on a highly
tiomeric excess (~97%) was observed for the isolated functionalized styrene of generic structure 29 would give
product. The 2-naphthyl derivative 18 gave excellent 30, from which it should be possible to reach the target
yield (>98%) and selectivity (93%) for the expected prod- molecule(s) (Scheme 1). Asymmetric hydrovinylation of
uct 25. 2-(1-Naththyl)but-1-ene (19) failed to undergo the these substrates would also test additional functional
reaction (entry 6) and (E)-1-phenyl-3-ethylbuta-1,3-diene group compatibility of this demanding reaction.
(20) gave a nearly racemic product.
In the event, a number of new styrene derivatives 29a–g
Asymmetric hydrovinylation of functionalized vinyl- were prepared by Stille coupling of a suitable (tributyl-
arenes with and without a 1-substituent on the vinyl group stannyl)alkene and the appropriate aryl iodide partner.23
of the arene is a key reaction in a number of on-going total Results of asymmetric hydrovinylation of these com-
synthesis efforts in our group. Some limitations in the use pounds using different phosphoramidite ligands, starting
of ligand 9 have been noted in the previous paragraph, and with 9 are shown in Table 4. As seen from entries 1–3,
others have become apparent as our studies continued. tert-butyldimethylsiloxy and azido substituents on the
This applies to asymmetric hydrovinylations of even sim- alkyl tether are detrimental to the reaction and no products
ple vinylarenes where we had made the most progress. For are formed even when high catalyst loading (10 mol%) is
example, 4-isobutylstyrene and 3-fluoro-4-phenylstyrene, used. Surprisingly, the phthalimido group is tolerated (en-
precursors of ibuprofen and flurbiprofen, gave only 90% tries 5–10) and gives products 30d and 30g (Table 4) from
and 86% ee using 9 as a ligand. In an attempt to improve the respective precursors. However, an ortho-substituent
the selectivity we decided to take advantage of the versa- (e.g., 29e and 29f) prevents the reaction from taking place
tility of the phosphoramidite ligands, especially the ease (entries 11 and 12). Ligand 9 gave marginally better enan-
with which the biaryl and the amine moieties can be mod- tioselectivity in the asymmetric hydrovinylation of 29g
ified.21 Figure 2 shows a selection of the modified phos- (entry 6 vs 9), compared to 26, prepared from achiral 2,2¢-
phoramidites 26–28 that were found to be especially biphenol and (S,S)-bis(a-methylbenzyl)amine; the latter
useful in early studies for the asymmetric hydrovinylation was found to give a quantitative yield of the product (entry
of simple vinyl arenes. We have since examined the scope 9), especially under slightly elevated pressure. Ligand 27
of these ligands for the generation of all-carbon benzylic gave 68% yield and 50% ee under comparable conditions.
quaternary centers and the results are described in the fol- We had earlier found that ligand 28 gave low enantiose-
lowing paragraphs.
lectivities in the hydrovinylation of even simpler sub-
strates such as a-ethylstyrene. In terms of the overall
efficiency (10 mol% catalyst) and selectivity (best: 61%
ee) of hydrovinylations, these highly functionalized mol-
ecules are among the worst substrates we have examined.
One early application of the modified phosphoramidites
has been in our approach to pyrrolidinoindolines like phy-
sostigmine and related compounds that carry a methyl-
O
O
O
*
Bn
O
O
P
N
P
N
P
N
O
*
9
Ra,S,S binaphthyl
ent-9 Sa,R,R binaphthyl
26 S,S biphenyl
28 (Ra,S,S)
27 (Ra,S)
ent-26 R,R biphenyl
rac-26 R,R/S,S (1:1)
Figure 2 Selected phosphoramidite ligands
Me
RO
Y
RO
RO
N
Y
Me
N
H
Z
Z
Me
(pyrrolidinoindolines)
29
30
R = MeNHC(O)-, (–)-physostigmine
R = PhNHC(O)-, (–)-phenserine
Scheme 1 a-Alkylstyrene precursors for pyrrolidinoindolines
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

SPECIAL TOPIC
All-Carbon Quaternary Centers via Hydrovinylation
2093
Table 4 Asymmetric Hydrovinylation of 29 Using Phosphoramidite Ligands
C2H4
[allylNiBr]2 (1 mol%)
L, NaBARF (2 mol%)
CH2Cl2
RO
RO
Y
Y
Z
Z
29
30
Entry
1
Styrene
29a
29a
29b
29c
R
Z
Y
Ligand (mol%) Conditions
Product Yield (%) eea (%)
Me
Me
Me
Me
Me
Bn
Me
Bn
Bn
Bn
Me
Me
H
H
OTBS
OTBS
9 (10)
9 (10)
C2H4 (1 bar), r.t., 12 h
–
0
0
–
2
C2H4 (1 bar), 35 °C, 12 h
C2H4 (1 bar), r.t., 12 h
–
–
3
N(Boc)Me N3
9 (10)
–
0
–
4
H
NPhth
9 (5)
C2H4 (1 bar), r.t., 12 h
–
<5
47
69b
81b
76b
>95
68b
0
–
5
29d
29g
29d
29g
29g
29g
29e
H
NPhth
NPhth
NPhth
NPhth
NPhth
NPhth
NPhth
NPhth
9 (10)
C2H4 (1 bar), 35 °C, 12 h
C2H4 (1 bar), 35 °C, 48 h
C2H4 (1 bar), 35 °C, 12 h
C2H4 (1 bar), 35 °C, 48 h
C2H4 (8.07 bar), 25 °C, 0.5 hc
C2H4 (1 bar), 35 °C, 12 h
C2H4 (8.07 bar), 25 °C, 0.5 hc
C2H4 (8.07 bar), 25 °C, 0.5 hc
30d
30g
30d
30g
30g
30g
–
–
6
H
9 (10)
61
–
7
H
26 (10)
26 (10)
26 (10)
27 (10)
26 (10)
26 (10)
8
H
53d
55
50
–
9
H
10
11
12
H
NO2
Br
29f
–
0
–
a Determined by 19F NMR of the N-MTPA derivative of the hydrovinylation product.
b Isomerization of the double bond (~15% to 31, see Figure 3) observed, the configuration of 31 was established by NOE studies.
c Carried out in a Fischer–Porter tube.
d Analyzed as a g-lactam after oxidative degradation of the alkene and cyclization.
Notice that the higher pressure of ethene, in addition to ceptable for the planned synthesis of pyrrolidinoindolines,
having a decidedly beneficial effect on the overall yield of we turned our attention to other substrates that could serve
the reaction, also prevents isomerization of the starting that role. One such class of compounds, more readily ac-
alkene to 31 (entries 8 and 9).24
cessible compared to 29, is represented by the 1-methyl-
enetetralin derivatives 32a–c shown in Scheme 2. We
reasoned that these alkenes would be sterically less de-
manding for the nickel coordination in the hydrovinyla-
tion reaction, and, without the phthalimido group, would
possibly be less Lewis basic, leading to larger turnovers in
the catalyst. After hydrovinylation (to give 33), the prod-
ucts would still carry either a relatively reactive benzylic
position, or a functionalized aromatic carbon suitable for
further elaboration into the desired compounds. For exam-
ple, when X = CH2, benzylic oxidation followed by some
variation of the Beckmann or Schmidt rearrangement
would place the nitrogen at the correct position.
The low turnover and enantioselectivity notwithstanding,
one notable feature of these ligands is the small difference
in the selectivities imparted by the more elaborate (and
expensive) (R)-1,1¢-bi(2-naphthol)-derived phosphora-
midite 9 and the simpler (and less expensive) 2,2¢-biphe-
nol-derived ligand 26, and this may have practical
consequences in terms of the cost of ligands.25 Besides,
the use of such ligands for the synthesis of racemic inter-
mediates is not without some value since hydrovinylation
represents a new method for the generation of quaternary
centers.
Since the enantioselectivity in the asymmetric hydroviny-
Nickel-catalyzed asymmetric hydrovinylation of 32a–c
using ligands 9, 26, and 27 were carried out under opti-
mized reaction conditions (Equation 5) and the results are
shown in Table 5. Most gratifyingly, these substrates un-
dergo efficient (<2 mol% catalyst) hydrovinylation at low
temperature, giving excellent enantioselectivities (up to
99% ee) for the expected product. Apart from a minor
isomerization of the double bond in the starting materials
to give more stable internal alkenes (34a or 34b), this is
lation of the alkene precursor 29g was found to be unac-
H
N-phth
H
BnO
NPHT
BnO
H
NOE
31
Figure 3
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

2094
C. R. Smith et al.
SPECIAL TOPIC
HO
C2H4 (1 bar)
O
R
[(allyl)NiBr] , L, NaBARF (0.7–2.0 mol%)
R
2
R
R
R
X = CH2
CH2Cl2, low temp.
X
X
X
X
33a X = CH2, R = H
33b X = CH2, R = OMe
33c X = O, R = H
32a X = CH2, R = H
32b X = CH2, R = OMe
32c X = O, R = H
O
32a X = CH2, R = H
32b X = CH2, R = OMe
32c X = O, R = H
33
CO2H
R
O
pyrrolidinoindolines
O
N
*
R
Scheme 2 Exomethylene precursors for pyrrolidinoindolines
X
O
35
34a X = CH2, R = H
34b X = CH2, R = OMe
34c X = O, R = H
an exceptionally clean reaction to give the highly valued
products. There is very little of this isomerization in the
oxygenated substrate 32c, but it undergoes a competitive
dimerization (to give 35 in ~15% yield) in addition to the
hydrovinylation product. Compounds like 33a and 33b
have been used in the syntheses of analgesic (–)-eptazo-
cine, narcotic (–)-aphanorphine and related com-
pounds.15b,26,27 The minor detraction of the isomerization
notwithstanding, the asymmetric hydrovinylation signifi-
cantly shortens the synthesis of these compounds carrying
a benzylic all-carbon quaternary center. For example, 33b
has been previously synthesized via stoichiometic oxazo-
line directed alkylation (12 steps, 35% overall yield, 99%
ee)26 or an enzyme-catalyzed desymmetrization of a chiral
malonate (13 steps, 31% overall yield, 97% ee).27 A close-
ly related compound has been prepared by using asym-
metric intramolecular Heck reaction (~10 steps, 37%
overall yield, 93% ee) in a key step.15b For comparison,
asymmetric hydrovinylation yields the product 33b in
80% yield and ~99% ee in two steps from 3-methoxyte-
tralone! Attempts to convert these adducts into pyrrolidi-
noindolines, and intermediates for lyngbyatoxin and
teleocidins, are currently underway. Incidentally, we also
found that the modified phosphoramidite ligands also give
very high yields and selectivities in the asymmetric hy-
drovinylation of our model substrate, 11b (entry 4).
Equation 5
diastereomeric phosphoramidites. Upon examination of
Table 5, entry 3, it is clear that the chirality of the product
is determined by the axial chirality of the biaryl moiety of
the ligand, not by the chirality of the amine. Thus both
(Ra,S,S)-ligand 9 and a diastereomer with (Ra,R,R)-config-
uration gave the (R)-product in comparable enantiomeric
excess (94% and 89%). The (Sa,R,R)-ligand (ent-9) as ex-
pected gave the (S)-product. Since the phosphoramidite
26 (S,S), a ligand derived from flexible biphenyl scaffold-
ing, also gives the R-configuration in the product, it
should be presumed that the chirality of the bis-amine
(S,S) induces R-configuration in the biphenyl unit, a be-
havior that was previously recorded by Alexakis and co-
workers.28 Further support in the present context comes
from the solid state structure of a catalytically active (al-
lyl)Ni(26)(Br) complex. These results will be reported in
due course.
In this study, we have reported the details of a new cata-
lytic method for the generation of all-carbon quaternary
centers starting from relatively simple vinylarene deriva-
tives. Fine-tuning of the phosphoramidite ligands sug-
gests that in the construction of these ligands, inexpensive
2,2¢-biphenol can effectively replace the more expensive
We briefly examined the origin of asymmetric induction
in the 3,4-dihydro-2H-1-benzopyran product 33c using
Table 5 Asymmetric Hydrovinylation of Exomethylene Compoundsa
Entry
Substrate
Product
Ligand
9
26
27
Yield (%)
eeb (%)
99
Yield (%)
eeb (%)
>95
–
Yield (%)
eeb (%)
1
2
3
4
32a
32b
32c
11b
33a
33b
33c
12b
71c
82c
68c
–
64c
–
99
–
99
70d
94e
66c
95
84
–
–
>97
>97
92
92
94
a See Equation 5 and experimental section for details.
b Determined by GC, (R)-isomer of products. Configurations assigned by comparison of [a]D25 to an authentic sample.26
c The remainder was isomerized product 34 from starting material.
d Also contains 15% dimeric product 35 (configuration not established).
e A diastereomer of this ligand with (Ra,R,R)-configuration also gave (R)-adduct in ~70% yield and 89% ee.
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

SPECIAL TOPIC
All-Carbon Quaternary Centers via Hydrovinylation
2095
13C NMR (100 MHz, CDCl3): d = 150.1, 150.0, 149.5, 139.3,
136.52, 136.46, 133.9, 123.8, 132.5, 131.5, 131.4, 130.5, 130.2,
129.9, 128.8, 128.7, 128.4, 128.3, 128.1, 128.0, 127.02, 126.96,
126.9, 126.0, 125.6, 125.4, 125.3, 124.9, 124.8, 124.4, 124.1, 124.0,
123.8, 122.3, 122.2, 121.7, 52.0, 47.2, 21.7.
enantiopure 1,1¢-bi(2-naphthol)s. Expansion of the scope
of this reaction to dienes and strained bicyclic molecules,
and applications in natural product synthesis will be re-
ported in due course.
31P NMR (101 MHz, CDCl3): d = 145.5.
HRMS (ESI): m/z [M + Na]+ calcd for C39H30NNaO2P: 598.1906;
Reactions requiring air-sensitive manipulations were conducted un-
der an inert atmosphere of N2 by using Schlenk techniques or a
Vacuum Atmospheres glovebox. CH2Cl2 was distilled from CaH2
under N2 and stored over molecular sieves. THF was distilled under
N2 from Na/benzophenone ketyl. Unless specified other wise, vinyl-
arenes were made via Wittig reaction of the corresponding alde-
hydes or ketones with methyltriphenylphosphonium bromide using
BuLi in hexane soln in THF as a base to generate the ylide.
found: 598.1907.
Asymmetric Hydrovinylation, Synthesis of (R)-3-Methyl-3-phe-
nylpent-1-ene (12b);20 Typical Procedure
Precatalyst preparation: In a glovebox, a 100-mL, pear-shaped
Schlenk flask with one side-arm fitted with a rubber septum and
equipped with a magnetic stirrer bar was evacuated, flame-dried,
and purged with argon. The flask was charged with anhyd CH2Cl2
(50 mL) and was transferred into a glovebox. To the flask was
quickly added [(allyl)NiBr]2 (180 mg, 0.50 mmol, 0.01 equiv),
[(R)-1,1¢-binaphthyl-2,2¢-diyldioxy]{bis[(S)-(1-phenylethyl)]ami-
no}phosphine (9, 539 mg, 1.00 mmol, 0.02 equiv), and NaBARF
(886 mg, 1.00 mmol, 0.02 equiv) in the order mentioned. The result-
ing suspension was stirred at r.t. for 2 h to afford a dark-brown soln
containing a small amount of fine particles (NaBr).
Ligands4b,21b 9, ent-9, 26, ent-26, 27, and 28, Na+[3,5-
20,30
(CF3)2C6H3]4B]– (NaBARF),20,29 and [(allyl)NiBr]2
were pre-
pared according to the literature. Ethene (99.5%) was purchased
from Matheson Inc., and passed through Drierite before use. Ana-
lytical TLC was performed on E. Merck precoated (0.25 mm) silica
gel 60 F254 plates. Flash column chromatography was carried out
on silica gel 40 (Scientific Adsorbents Incorporated, Microns
Flash). Enantiomeric excesses of chiral compounds 12b, 21, 22, 23,
25, and 33a–c were determined by GC analyses on chiral stationary
phase, which were performed on a Hewlett-Packard 5890 equipped
with Cyclodex-B (25 m × 0.25 mm, 0.12 mm film thickness) capil-
lary GC column purchased from Chrompack; He was used as the
carrier gas. The ee of 24 was determined by 19F NMR using the cor-
responding Mosher ester of the alcohol derived from hydroboration
of 24. For determining the ee of 30g, the free amine was liberated
from the phthalimide, and was converted into the Mosher amide. 19F
NMR analysis of the diastereomeric amides reveals the ee of the
original HV product 30g. Optical rotations were recorded on a
Perkin-Elmer Model 241 polarimeter at the Na D line in CHCl3.
Asymmetric hydrovinylation: A 1-L, three-necked, round-bottomed
flask equipped with a rubber septum, a Teflon-taped flow-con-
trolled argon inlet, a thermometer, and a magnetic stir bar was
flame-dried and purged with argon. The flask was then charged with
anhyd CH2Cl2 (150 mL). The catalyst soln prepared above, now re-
moved from the dry box, was introduced to the vessel via cannula.
The flask containing the catalyst soln was further rinsed with
CH2Cl2 (10 mL), and this soln was also transferred to the mixture.
Upon completion of precatalyst transfer, the system closed at the
flow-controlled stopcock and then was cooled to –70 °C in a dry ice/
acetone bath, creating a small vacuum. A strong flow of dry ethene
was introduced through a needle through the serum stopper to re-
lieve the vacuum and then was adjusted to maintain a pressure of 1
mbar by releasing excess gas through an oil bubbler. The introduc-
tion of the ethene caused the internal temperature to rise. Within ca.
5 min, the internal temperature increased by 5 °C and the ethylene
line was removed. The soln was cooled back to –70 C with vigor-
ous stirring. A soln of 2-phenylbut-1-ene (11b, 6.60 g, 50.0 mmol)
in anhyd CH2Cl2 (30 mL) was introduced as a weak stream into the
soln of precatalyst over a 2-min period via syringe followed by a
rinse with CH2Cl2 (10 mL). Ethene was introduced again through a
needle, first as a strong flow and then regulated to maintain a pres-
sure of 1 atm. Under an ethene atmosphere, the internal temperature
of the mixture was then maintained between –65 °C and –70 °C for
a period of 4 h. At the end of this period the ethene line was removed
and the mixture was slowly poured into an Erlenmeyer flask con-
taining pentane (500 mL) and was combined with a pentane rinse
(50 mL) of the reaction vessel. After warming to r.t., the resulting,
cloudy soln was filtered through a plug of silica gel [Merck, grade
9385, mesh 230–400, 60 Å, 4 cm × 5 cm, (d × h)], which was eluted
with pentane (100 mL). The combined eluates were concentrated by
rotary evaporation (20 °C/26.7 mbar) to afford 12b (7.99 g, 99.7%)
as clear liquid; 97.6% ee.
The following phosphoramidites were prepared using our recent
modifications21b of the previously reported methods.4
(Biphenyl-2,2¢-diyldioxy){bis[(R)-1-phenylethyl]amino}phos-
phine (ent-26)
(Biphenyl-2,2¢-diyldioxy)chlorophosphine (125 mg, 0.5 mmol) was
treated with (–)-bis[(R)-1-phenylethyl]amine (102 mg, 0.454
mmol) in THF to afforded ent-26; yield: 94%; Rf = 0.49 (pentane–
CH2Cl2, 3:1).
1H NMR (400 MHz, CDCl3): d = 7.48–7.44 (m, 2 H), 7.36–7.31 (m,
2 H), 7.30–7.27 (m, 2 H), 7.20–7.19 (m, 2 H), 7.14–7.09 (m, 10 H),
4.61–4.56 (m, 2 H), 1.72 (d, J = 7.20 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 151.9, 151.0, 142.9, 131.2, 129.8,
129.0, 127.9, 126.6, 124.3 (d, J = 256.0 Hz), 122.2 (d, J = 192.0 Hz),
52.6, 22.1.
31P NMR (101 MHz, CDCl3): d = 146.4 (Lit.28 147.0).
HRMS (ESI): m/z [M + Na]+ calcd for C28H26NNaO2P: 462.1593;
found: 462.1591.
{Benzyl[(S)-1-(1-naphthyl)ethyl)]amino}[(R)-1,1¢-binaphthyl-
2,2¢-diyldioxy]phosphine (27)
The coupling of (–)-[(R)-1,1¢-binaphth-2,2¢-diyldioxy]chlorophos-
phine (175 mg, 0.5 mmol) with (S)-N-benzyl-1-(1-naphthyl)ethyl-
amine (119 mg, 0.45 mmol) gave 27; yield: 90%; Rf = 0.48
(pentane–CH2Cl2, 2:1).
1H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 8.8 Hz, 1 H), 7.86–
7.84 (m, 3 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.8 (d, J = 8.2 Hz, 1 H), 7.66
(d, J = 8.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1
H), 7.48 (t, J = 7.4 Hz, 2 H), 7.43–7.37 (m, 2 H), 7.33–7.28 (m, 3
H), 7.25–7.16 (m, 7 H), 6.96 (d, J = 8.8 Hz, 1 H), 5.40–5.33 (m, 1
GC (HP methylsilicone column, 25 m × 0.25 mm, conditions: 5 min
at 100 °C, 5 °C/min, 5 min at 200 °C): tR = 10.61 min.
GC (Cyclodex-B, 40 min at 70 °C, 5 °C/min, 10 min at 90 °C): tR =
53.90 (R), 55.65 min (S).
[a]D22 –22.3 (c 1.05, CHCl3) {Lit.31 [a]D20 –12.5 (c 0.8, CHCl3, 92%
ee)}.
IR (neat): 3083, 3058, 2966, 2877, 1636, 1600, 1493, 1446, 1030,
913, 760, 700 cm–1.
H), 3.95–3.36 (dAB q, nA = 4.21, nB = 3.11, JAB = 15.3 Hz, JH-P
2.1 Hz, 2 H), 1.69 (d, J = 6.8 Hz, 3 H).
=
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2096
C. R. Smith et al.
SPECIAL TOPIC
(R)-3-Methyl-3-(2-naphthyl)pent-1-ene (25)
GC (120 °C isothermal): tR = 130.79, 132.86 min; 93% ee.
[a]D20 –22.9 (c 1.43, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.85–7.75 (m, 3 H), 7.73 (s, 1 H),
7.50–7.40 (m, 3 H), 6.12 (dd, J = 17.5, 11 Hz, 1 H), 5.16 (d, J = 11.0
Hz, 1 H), 5.09 (d, J = 11.0 Hz, 1 H), 2.00–1.90 (m, 1 H), 1.90–1.80
(m, 1 H), 1.46 (s, 3 H), 0.80 (t, J = 7.5 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): d = 147.0, 145.0, 133.5, 132.0,
128.1, 127.6, 127.5, 126.0, 125.9, 125.5, 125.0, 112.2, 44.9, 33.4,
24.5, 9.1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.27 (m, 4 H), 7.19–7.15 (m,
1 H), 6.02 (dd, J = 17.6, 10.8 Hz, 1 H), 5.10 (dd, J = 10.8, 1.2 Hz, 1
H), 5.03 (dd, J = 17.6, 1.2 Hz, 1 H), 1.88–1.70 (ABX3, nA = 1.83,
nB = 1.75, JAB = 13.8 Hz, JAX = 7.4 Hz, JBX = 7.4 Hz, 2 H), 1.34 (s,
3 H), 0.76 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 147.4, 146.9, 128.0, 126.7, 125.7,
111.7, 44.5, 33.4, 24.4, 8.9.
HRMS (ESI): m/z [M]+ calcd for C12H16: 160.1252; found:
160.1257.
Other compounds in the Tables 3– 5 were prepared by appropriate
modifications in the amount of catalyst, reaction temperature, and
reaction time as indicated therein.
HRMS (LCT ESI): m/z [M + Na]+ calcd for C16H18Na: 233.1306;
found: 233.1310.
(R)-3-Methyl-3-(4-methylphenyl)pent-1-ene (21)
GC (85 °C isothermal): tR = 53.69, 55.96 min; 90% ee.
[a]D20 –22.1 (c 1.28, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.21 (d, J = 7.5 Hz, 2 H), 7.11 (d,
J = 7.5 Hz, 2 H), 6.01 (dd, J = 17.5, 11.0 Hz, 1 H), 5.09 (d, J = 11.0
Hz, 1 H), 5.03 (d, J = 17.5 Hz, 1 H), 2.32 (s, 3 H), 1.90–1.70 (m, 2
H), 1.34 (s, 3 H), 0.77 (t, J = 6.5 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): d = 147.2, 144.6, 135.2, 128.9,
126.7, 111.7, 44.3, 33.5, 24.5, 21.0, 9.1.
HRMS (LCT ESI): m/z [M + Na]+ calcd for C13H18Na: 197.1306;
found: 197.1302.
Synthesis of Alkenes 29a–f via Stille Coupling; General Proce-
dure
A flask was charged with the aryl iodide (100 mol%, 1–5 mmol
scale), vinyltin (120 mol%), PdCl2(PPh3)2 (5 mol%), K2CO3 (100
mol%), Et4NCl (100 mol%), and deoxygenated DMF (5 mL), and
the resulting mixture was stirred at 110 °C overnight. After the re-
action was completed, the mixture was cooled to r.t. and then was
filtered through Celite to remove solid impurities. The soln was di-
luted with H2O and the crude product was extracted with EtOAc,
dried (MgSO4), and purified by column chromatography.
1-[4-(tert-Butyldimethylsiloxy)but-1-en-2-yl]-3-methoxyben-
zene (29a)
Following the general procedure, 29a was obtained in 70% isolated
yield as a colorless oil.
3-(4-Chlorophenyl)-3-methylpent-1-ene (22)
GC (105 °C isothermal): tR = 57.68, 62.15 min; 90% ee.
1H NMR (400 MHz, CDCl3): d = 7.31–7.27 (t, J = 7.8 Hz, 1 H, Ar),
7.09–7.02 (m, 2 H, Ar), 6.89–6.86 (m, 1 H, Ar), 5.40 (s, 1 H, =CH2),
5.17 (s, 1 H, =CH2), 3.85 (s, 3 H, ArOMe), 3.80–3.77 (t, J = 7.2 Hz,
2 H, CH2OTBS), 2.81–2.78 (m, 2 H, CH2CH2OTBS), 0.98 (s, 9 H,
t-Bu), 0.09 [s, 6 H, Si(t-Bu)Me2].
13C NMR (100 MHz, CDCl3): d = 159.8, 145.4, 142.8, 129.4, 118.8,
114.2, 112.9, 112.2, 62.6, 55.3, 39.1, 26.1, 18.5, –5.2.
[a]D20 –21.5 (c 1.25, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.35–7.20 (m, 4 H), 6.00 (dd, J =
17.5, 11.0 Hz, 1 H), 5.14 (d, J = 11.0 Hz, 1 H), 5.05 (d, J = 17.5 Hz,
1 H), 1.90–1.70 (m, 2 H), 1.36 (s, 3 H), 0.78 (t, J = 7.5 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): d = 146.6, 146.1, 131.6, 128.4,
128.2, 112.4, 44.5, 33.6, 24.6, 9.0.
3,4-Dimethyl-3-phenylpent-1-ene (23)
GC (60 min at 70 °C, 0.5 °C/min, 60 min at 90 °C): tR = 101.39,
102.99 min; 97% ee.
1H NMR (500 MHz, CDCl3): d = 7.40–7.25 (m, 3 H), 7.25–7.10 (m,
2 H), 6.19 (dd, J = 17.5, 11.0 Hz, 1 H), 5.19 (d, J = 11.0 Hz, 1 H),
5.06 (d, J =17.5 Hz, 1 H), 2.25–2.15 (m, 1 H), 1.35 (s, 3 H), 0.86 (d,
J = 7.0 Hz, 3 H), 0.78 (d, J = 7 Hz, 3 H).
1-[(tert-Butoxycarbonyl)(methyl)amino]-2-[4-(tert-butyldi-
methylsiloxy)but-1-en-2-yl]-4-methoxybenzene (29b)
Following the general procedure, 29b was obtained in 56% isolated
yield as a pale yellow solid.
1H NMR (400 MHz, CDCl3): d = 6.95–6.93 (d, J = 7.6 Hz, 1 H, Ar),
6.75–6.69 (m, 2 H, Ar), 5.15 (s, 1 H, vinyl), 5.02 (s, 1 H, vinyl), 3.78
(s, 3 H), 3.60–3.55 (m, 2 H), 3.03 (s, 3 H), 2.52–2.50 (m, 2 H), 1.32
(s, 9 H), 0.84 (s, 9 H), –0.02 (s, 6 H).
13C NMR (125.7 MHz, CDCl3): d = 148.4, 144.9, 128.1, 126.8,
125.7, 113.3, 47.6, 36.3, 20.7, 18.3, 17.9.
13C NMR (100 MHz, CDCl3): d = 157.9, 155.3, 129.3, 114.9, 113.1,
79.7, 61.6, 55.4, 39.4, 28.3, 27.8, 26.8, 25.9, 18.2, –4.5.
3-Methyl-3-phenyloct-1-ene (24)
50–55% ee by Mosher method.
[a]D20 –6.9 (c 1.06, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.40–7.28 (m, 4 H), 7.25–7.15 (m,
1 H), 6.05 (dd, J = 17.5, 10.5 Hz, 1 H), 5.10 (d, J = 10.5 Hz, 1 H),
5.04 (d, J = 17.5 Hz, 1 H), 1.85–1.65 (m, 2 H), 1.37 (s, 3 H), 1.35–
1.10 (m, 6 H), 0.88 (t, J = 7.5 Hz, 3 H).
1-(4-Azidobut-1-en-2-yl)-3-methoxybenzene (29c)
To a stirred soln of 29a (50 mg, 0.17 mmol) in EtOH (2 mL) was
added 1 M HCl (0.1 mL) and the resulting soln was stirred at r.t. for
1 h. When the deprotection was complete, the mixture was diluted
with H2O (3 mL) and the product was extracted CH2Cl2 (3 × 3 mL).
The combined organic layers were dried (MgSO4), filtered, and
evaporated. The crude alcohol was dissolved in CH2Cl2 (3 mL) and
Et3N (59 mL, 0.042 mmol), and methanesulfonyl chloride (16 mL,
0.021 mmol) were added in succession at 0 °C. The resulting mix-
ture was stirred at r.t. for 2 h after which the solvent was evaporated.
The residue was dissolved in DMF (2 mL) and NaN3 (23 mg, 0.034
mmol) was added. The mixture was heated to 60 °C for 12 h. The
soln was diluted with H2O (5 mL), and the product was extracted
with EtOAc (3 × 5 mL). The crude product was purified by prepar-
ative TLC to give 29c (28 mg, 82%) as a colorless oil.
13C NMR (125.7 MHz, CDCl3): d = 147.9, 147.4, 128.2, 126.7,
125.8, 111.7, 44.4, 41.3, 32.7, 25.1, 24.3, 22.7, 14.2.
Mosher ester
19F NMR (376.5 MHz, CDCl3): d = –71.30 (diastereomer 1), –71.31
(diastereomer 2).
13C NMR (125.7 MHz, CDCl3): d = 24.10 (diastereomer 1), 24.04
(diastereomer 2).
HRMS (LCT ESI): m/z [M + Na]+ calcd for C15H22Na: 225.1619;
found: 225.1618.
1H NMR (400 MHz, CDCl3): d = 7.33–7.29 (t, J = 8.0 Hz, 1 H, Ar),
7.03–6.98 (m, 2 H, Ar), 6.90–6.88 (dd, J = 4.0, 2.4 Hz, 1 H, Ar),
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

SPECIAL TOPIC
All-Carbon Quaternary Centers via Hydrovinylation
2097
5.44 (s, 1 H, =CH2), 5.22 (s, 1 H, =CH2), 3.86 (s, 3 H, ArOMe),
3.42–3.38 (t, J = 7.2 Hz, 2 H, CH2N3), 2.85–2.81 (t, J = 7.0 Hz, 2 H,
CH2CH2N3).
13C NMR (100 MHz, CDCl3): d = 159.9, 144.8, 141.8, 129.6, 118.7,
Ar), 7.20–7.18 (t, J = 8.0 Hz, 1 H, Ar), 7.05–7.01 (m, 2 H, Ar),
6.81–6.78 (m, 1 H, Ar), 5.33 (s, 1 H, =CH2), 5.12 (s, 1 H, =CH2),
5.06 (s, 2 H, OCH2Ph), 3.83–3.79 (t, J = 7.4 Hz, 2 H, CH2NPhth),
2.88–2.85 (t, J = 7.2 Hz, 2 H, CH2CH2NPhth).
13C NMR (125.7 MHz, CDCl3): d = 168.2, 158.8, 144.8, 141.6,
137.1, 133.8, 132.1, 129.4, 128.6, 128.0, 127.6, 123.2, 118.9, 114.9,
114.0, 112.7, 70.0, 37.4, 34.0.
115.1, 113.1, 112.3, 55.4, 49.9, 35.2.
1-Methoxy-3-(4-phthalimidobut-1-en-2-yl)benzene (29d)
Following the general Stille procedure, 29d was obtained in 63%
isolated yield as pale yellow oil.
HRMS: m/z [M + H]+ calcd for C25H22NO3: 384.1600; found:
384.1583.
IR (neat): 3072, 2941, 2835, 1770. 1712, 1598, 1576, 1488, 1466,
1434, 1394, 1359, 1328, 1287, 1231, 1187, 1120, 1087, 1047, 1001
cm–1.
Asymmetric Hydrovinylation of Substrates 29a–g; General
Procedure
In a N2-charged drybox, a two-necked Schlenk tube was charged
with [(allyl)NiBr]2 (1 mol%), ligand (2 mol%), and NaBARF (2
mol%), and the mixture was dissolved in anhyd CH2Cl2 (5–7 mL/
mmol of olefin). This precatalyst was stirred at r.t. for 10 min, and
then taken out of the drybox. After the ethene line was connected to
the reaction vessel, the line was evacuated 3 times to remove oxy-
gen in the line, and then ethene was introduced to the vessel. Into
the activated catalyst, starting olefin in anhyd CH2Cl2 (1–2 mL/
mmol of olefin) was added, and the resulting mixture was stirred at
r.t. under the atmospheric pressure of ethene. After the reaction, the
solvent was evaporated, and the crude product was purified by col-
umn chromatography.
1H NMR (400 MHz, CDCl3): d = 7.80–7.78 (dd, J = 3.0, 2.4 Hz, 2
H, Ar), 7.69–7.66 (dd, J = 3.0, 2.4 Hz, 2 H, Ar), 7.22–7.18 (t, J =
8.0 Hz, 1 H, Ar), 7.04–7.02 (d, J = 7.6 Hz, 1 H, Ar), 6.99 (s, 1 H,
Ar), 6.75–6.73 (dd, J = 8.0, 2.4 Hz, 1 H, Ar), 5.37 (s, 1 H, =CH2),
5.16 (s, 1 H, =CH2), 3.85–3.79 (m, 5 H, ArOMe, RCH2NPhth),
2.91–2.88 (t, J = 7.2 Hz, 2 H, CH2CH2NPhth).
13C NMR (100 MHz, CDCl3): d = 168.1, 159.6, 144.9, 141.6, 133.8,
132.1, 129.3, 123.0, 118.6, 114.7, 113.1, 111.7, 55.2, 37.5, 34.0.
HRMS: m/z [M + H]+ calcd for C19H18NO3: 308.1287; found
308.1272.
4-Methoxy-1-nitro-2-(4-phthalimidobut-1-en-2-yl)benzene
(29e)
Following the general procedure, purification by column chroma-
tography (25% EtOAc–hexane) [Rf = 0.5 (50% EtOAc–hexanes)]
gave 29e (39% yield) as a colorless oil.
(R)-3-(3-Methoxyphenyl)-3-methyl-5-phthalimidopent-1-ene
(30d)
Following the general procedure using (allyl)Ni(26)(BARF) (10
mol%) at 35 °C for 12 h gave 30d (81% isolated yield) as a pale yel-
low oil.
IR (neat): 3085, 2943, 2848, 1770, 1722, 1601, 1574, 1514, 1393,
1337, 1249, 1187, 1097, 1065, 1027 cm–1.
IR (neat): 3072, 2930, 2837, 1772, 1707, 1601, 1484, 1396, 1366,
1284, 1249, 1173, 1049 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01–7.99 (d, J = 9.2 Hz, 1 H, Ar),
7.81–7.79 (m, 2 H, Ar), 7.70–7.66 (m, 2 H, Ar), 6.86–6.80 (m, 2 H,
Ar), 5.16 (s, 1 H, =CH2), 4.99 (s, 1 H, =CH2), 3.89 (s, 3 H, ArOMe),
3.80–3.77 (t, J = 7.0 Hz, 2 H, CH2NPhth), 2.80–2.76 (t, J = 6.8 Hz,
2 H, CH2CH2NPhth).
13C NMR (125.7 MHz, CDCl3): d = 168.4, 163.2, 144.9, 140.7,
134.3, 131.9, 127.5, 126.2, 123.4, 118.2, 116.6, 116.3, 113.7, 56.2,
37.0, 35.2.
1H NMR (400 MHz, CDCl3): d = 7.74–7.72 (m, 2 H, Ar), 7.67–7.63
(m, 2 H, Ar), 7.15–7.11 (t, J = 8.0 Hz, 1 H, Ar), 6.92–6.87 (m, 2 H,
Ar), 6.59–6.56 (dd, J = 8.0, 2.4 Hz, 1 H, Ar), 6.09–6.02 (dd, J =
11.2, 6.0 Hz, 1 H, CH=CH2), 5.15 (s, 1 H, CH=CH2), 5.12–5.10 (d,
J = 8.0 Hz, 1 H, CH=CH2), 3.76 (s, 3 H, OMe), 3.64–3.60 (t, J = 8.0
Hz, 2 H, CH2NPhth), 2.24–2.18 (m, 1 H, CH2CH2NPhth), 2.10–
2.05 (m, 1 H, CH2CH2NPhth), 1.46 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 168.4, 159.6, 147.9, 145.9, 133.9,
132.4, 129.4, 123.2, 119.1, 112.9, 112.7, 111.2, 55.3, 43.5, 38.6,
34.8, 25.2.
HRMS: m/z [M + H]+ calcd for C19H17N2O5: 353.1137; found:
353.1120.
1-Bromo-4-methoxy-2-(4-phthalimidobut-1-en-2-yl)benzene
(29f)
Following the general procedure, 29f was obtained in 40% isolated
yield as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 7.79–7.77 (m, 2 H, Ar), 7.68–7.65
(m, 2 H, Ar), 7.35–7.33 (d, J = 8.8 Hz, 1 H, Ar), 6.81–6.80 (d, J =
2.8 Hz, 1 H, Ar), 6.63–6.60 (dd, J = 8.8, 3.2 Hz, 1 H, Ar), 5.21 (s, 1
H, =CH2), 5.00 (s, 1 H, =CH2), 3.76–3.73 (m, 5 H, ArOMe,
CH2NPhth), 2.85–2.82 (t, J = 7.0 Hz, 2 H, CH2CH2NPhth).
(R)-3-[3-(Benzyloxy)phenyl]-3-methyl-5-phthalimidopent-1-
ene (30g)
Following the general procedure using (allyl)Ni(26)(BARF) (10
mol%) under 35 °C for 48 h gave 30g (76%, isolated yield) as a pale
yellow oil.
[a]D22 +1.87 (c 1.03, CHCl3, 53% ee).
IR (neat): 3084, 3025, 2942, 2872, 1772, 1707, 1601, 1437, 1390,
1360, 1243, 1084, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.76–7.74 (m, 2 H, Ar), 7.66–7.63
(m, 2 H, Ar), 7.44–7.30 (m, 5 H, Ar), 7.16–7.12 (t, J = 8.0 Hz, 1 H,
Ar), 6.96–6.92 (m, 2 H, Ar), 6.67–6.65 (m, 1 H, Ar), 6.08–6.01 (dd,
J = 10.8, 6.0 Hz, 1 H, CH=CH2), 5.15 (s, 1 H, CH=CH2), 5.12–5.10
(d, J = 8.0 Hz, 1 H, CH=CH2), 5.01 (s, 2 H, OCH2Ph), 3.63–3.59 (t,
J = 8.0 Hz, 2 H, CH2NPhth), 2.25–2.18 (m, 1 H, CH2CH2NPhth),
2.13–2.04 (m, 1 H, CH2CH2NPhth), 1.46 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 168.4, 158.9, 148.1, 145.8, 137.4,
133.9, 132.4, 129.4, 128.7, 128.4, 128.1, 127.8, 126.6, 123.2, 119.3,
113.9, 112.7, 112.2, 70.1, 43.5, 38.6, 34.8, 25.2, 21.3.
13C NMR (100 MHz, CDCl3): d = 168.3, 158.8, 146.6, 143.7, 134.0,
133.5, 132.2, 123.3, 117.8, 116.2, 114.9, 112.3, 55.6, 36.9, 34.9.
1-(Benzyloxy)-3-(4-phthalimidobut-1-en-2-yl)benzene (29g)
Following the general procedure, 29g was obtained and further pu-
rified by column chromatography [10% EtOAc–hexane, Rf = 0.3
(15% EtOAc–hexane)] to give 29g (63% isolated yield) as a pale
yellow oil.
IR (neat): 3062, 3031, 2945, 2869, 1771, 1713, 1597, 1574, 1488,
1435, 1395, 1360, 1288, 1224, 1121, 1087, 1026, 1001 cm–1.
HRMS: m/z [M + H]+ calcd for C27H26NO3: 412.1913; found:
412.1916.
1H NMR (400 MHz, CDCl3): d = 7.79–7.77 (dd, J = 5.4, 3.2 Hz, 2
H, Ar), 7.67–7.65 (dd, J = 5.4, 3.2 Hz, 2 H, Ar), 7.45–7.31 (m, 5 H,
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

2098
C. R. Smith et al.
SPECIAL TOPIC
3-[3-(Benzyloxy)phenyl]-1-phthalimidobut-2-ene (31)
J = 17.60, 1.20 Hz, 1 H), 2.84 (d, J = 7.6 Hz, 2 H), 1.90–1.83 (m, 3
H), 1.76–1.71 (m, 1 H), 1.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 148.8, 142.3, 135.8, 129.1, 128.5,
125.7, 125.6, 112.0, 40.9, 37.6, 34.1, 28.3, 22.4.
HRMS (ESI): m/z [M]+ calcd for C13H16: 172.1247; found:
172.1245.
1H NMR (400 MHz, CDCl3): d = 7.90–7.69 (m, 4 H, phthalimido),
7.49–7.29 (m, 5 H, Ar), 7.19 (t, J = 6.4 Hz, 1 H, Ar), 7.05–6.85 (m,
2 H, Ar), 6.84–6.79 (m, 1 H, Ar), 5.85 [t, J = 7.0 Hz, 1 H,
Ar(CH3)C=CHCH2NPhth], 5.03 (s, 2 H, OCH2Ph), 4.50 [d, J = 7.5
Hz, 2 H, Ar(CH3)C=CHCH2NPhth, E], 4.22 [d, J = 6.5 Hz, 2 H,
Ar(CH3)C=CHCH2NPhth,
Ar(CH3)C=CHCH2NPhth,
Z],
E],
2.23
2.01
[s,
[s,
3
3
H,
H,
1-Methyl-3,4-dihydronaphthalene (34a)
Ar(CH3)C=CHCH2NPhth, Z]; the configuration of the major prod-
uct was established by NOE studies (Figure 3).
13C NMR (100 MHz, CDCl3): d = 168.4, 144.5, 139.4, 137.3, 134.1,
132.5, 129.6, 128.1, 127.8, 123.4, 121.6, 119.1, 113.7, 113.1, 70.2,
36.5, 16.4.
1H NMR (400 MHz, CDCl3): d = 7.23–7.17 (m, 2 H), 7.15–7.10 (m,
2 H), 5.85–5.83 (m, 1 H), 2.75 (t, J = 8.0 Hz, 2 H), 2.26–2.20 (m, 2
H), 2.04 (dd, J1 = 3.2 Hz, J2 = 1.6 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): d = 136.3, 135.9, 132.3, 127.3,
126.7, 126.3, 125.4, 122.8, 28.3, 23.2, 19.3.
HRMS: m/z [M + Na+] calcd for C25H21NNaO3: 406.1419; found:
406.1400.
(R)-7-Methoxy-1-methyl-1-vinyl-1,2,3,4-tetrahydronaphtha-
lene (33b)
(R)-3-[3-(Benzyloxy)phenyl]-3-methyl-5-phthalimidopent-1-
ene (30g)
Following the general procedure, using
4 mol% of (al-
lyl)Ni(9)(BARF) as the catalyst, 7-methoxy-1-methylene-1,2,3,4-
tetrahydronaphthalene (32b, 0.30 g, 1.72 mmol) was reacted at –70
°C for 6 h. Purification by column chromatography gave the product
(0.30 g, >99%) as a mixture of the hydrovinylation product 33b
(82%, >99% ee by chiral GC), isomerized starting material 34b
(15%), and unconverted starting material 32b (3%). The ratios of
these compounds were determined by integration of the diagnostic
peaks in the 1H NMR spectrum.
Under Elevated Pressure of Ethene (Table 4, entry 9): In an N2-
charged drybox, (allyl)Ni(26)(BARF) precatalyst (10 mol%) in
CH2Cl2 (1.5 mL) was prepared, and then the soln was added to a
Fisher–Porter tube. After 10 min of stirring at r.t., starting material
29g (20 mg, 0.0487 mmol) in CH2Cl2 (1.5 mL) was added to the
precatalyst soln. The tube was tightly closed, and then taken out
from a drybox. After the tube was connected to an ethene line, the
line was evacuated (3 ×), and then ethene gas was introduced to the
tube, and pressurized to 17 psi. During the reaction, internal pres-
sure decreased, so the system was recharged (3 ×). The soln was
stirred for 30 min and then concentrated. The crude product was pu-
rified by preparative TLC to give ~20 mg (>95%) of the product 30g
identified in the previous experiment.
GC (Cyclodex-B, isothermal, 120 °C): tR = 56.09 (R-isomer), 57.10
min (S-isomer, obtained using ent-9); 99% ee.
[a]D22 –14.5 (c 0.142, CHCl3) {Lit.26 [a]D20 –21.1 (c 3.8, CHCl3)}.
IR (neat): 2958, 2829, 1722, 1637, 1606, 1580, 1488, 1443, 1368,
1322, 1223, 1190, 1121, 1064 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.01–6.96 (m, 2 H, Ar), 6.68–6.65
(m, 1 H, Ar), 5.95–5.88 (dd, J = 17.2, 10.4 Hz, 1 H, CH=CH2), 5.85
(br s, 1 H, isomerized product’s vinyl-H), 5.02–4.99 (dd, J = 10.4,
1.2 Hz, 1 H, CH=CH2), 4.87–4.82 (dd, J = 17.6, 1.2 Hz, 1 H,
CH=CH2), 3.75 (s, 3 H, OMe), 2.71–2.68 (t, J = 6.2 Hz, 2 H,
ArCH2R), 1.85–1.73 (m, 4 H, ArCH2CH2CH2, ArCH2CH2CH2),
1.36 (s, 3 H, CqCH3).
Determination of the Enantiomeric Excess of 30g by Mosher’s
Method
The phthalimide protecting group in hydrovinylation product 30g
(15 mg, 0.036 mmol) was removed by refluxing this material with
hydrazine hydrate (500 mol%), and EtOH (3 mL) for 12 h. The
crude amine was purified by acid–base workup, and subsequent ex-
traction with CH2Cl2. A soln of the amine in CH2Cl2 (2 mL) was
treated with Et3N (300 mol%), followed by MTPA-Cl (110 mol%).
The enantiomeric excess was determined by the integration of 19F
NMR peaks in the diastereomers [19F NMR d (C6D6): Mosher
amides from the racemic product: 68.61, and 68.57]. The diastereo-
meric ratio using ligand 26 was 1.0:3.5 corresponding to an ee of
~55% in the asymmetric catalyzed reaction. For both reactions per-
formed under 1 atmosphere of ethene at 35 °C for 48 h (Table 4, en-
try 8), and under 17 psi of ethene at 25 °C for 0.5 h (Table 4, entry
9), the selectivity was approximately same, within experimental er-
ror. The enantioselectivities for reactions using other ligands were
estimated the same way.
13C NMR (125.7 MHz, CDCl3): d = 157.7, 148.8, 143.7, 130.0,
129.0, 113.8, 112.2, 111.9, 55.4, 41.4, 37.7, 29.6, 28.4, 19.6.
(R)-4-Methyl-4-vinyl-3,4-dihydro-2H-1-benzopyran (33c)
Following the general procedure using 10 mol% of (al-
lyl)Ni(9)(BARF) and 32c (0.2 g, 1.37 mmol) at 35 °C for 12 h, the
desired product 33c (0.167 g, 70%) was obtained as a pale yellow
oil after purification. In addition to the expected product, a head-to-
tail dimer 35 was also obtained.
GC (Cyclodex-B, isothermal 100 °C): tR = 47.03 (S-isomer, ob-
tained from ligand ent-9), 48.76 min (R-isomer); 94% ee;
Ligand 9 (Table 4, entry 6): d.r. 1.0:4.1, ~61% ee.
Ligand 27 (Table 4, entry 10): d.r. 1.0:3.0 (~50% ee).
IR (neat): 2959, 2830, 1722, 1637, 1605, 1579, 1487, 1443, 1368,
1321, 1223, 1190, 1121, 1064 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.15–7.07 (m, 2 H, Ar), 6.88–6.84
(m, 1 H, Ar), 6.81–6.79 (dd, J = 8.2, 1.2 Hz, 1 H, Ar), 5.92–5.87 (dd,
J = 17.5, 10.5 Hz, 1 H, CH=CH2), 5.12–5.10 (dd, J = 10.5, 1.5 Hz,
1 H, CH=CH2), 4.87–4.82 (dd, J = 12.2, 1.2 Hz, 1 H, CH=CH2),
4.18–4.13 (m, 2 H, OCH2), 1.89–1.86 (m, 2 H, OCH2CH2), 1.43 (s,
3 H, CH3).
(R)-1-Methyl-1-vinyl-1,2,3,4-tetrahydronaphthalene (33a)
Yield of 33a: 71% contaminated with ~28% 1-methyl-3,4-dihy-
dronaphthalene (34a).
GC (HP methylsilicone, 5 min at 100 °C, 5 °C/min, 5 min at 200
°C): tR = 13.10 min.
GC (Cyclodex-B, 75 min at 90 °C): tR = 62.85 (S), 63.69 min (R);
>99% ee.
[a]D20 –35.4 (c 1.15 CHCl3).
3C NMR (100 MHz, CDCl3): d = 154.3, 147.5, 128.9, 127.9, 127.7,
120.4, 117.1, 114.2, 62.9, 37.9, 36.1, 27.9.
4-[(3,4-Dihydro-2H-1-benzopyran-4-yl)methyl]-4-methyl-
1,2,3,4-dihydro-2H-1-benzopyran (35)
Isolated yields of dimer 35 as a pale yellow oil, from HV using
ligand 9 and 26, were ~15%.
1H NMR (400 MHz, CDCl3): d = 7.21–7.13 (m, 4 H), 6.01 (dd, J =
17.60, 10.40 Hz, 1 H), 5.10 (dd, J = 10.40, 1.20 Hz, 1 H), 4.89 (dd,
Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York

SPECIAL TOPIC
All-Carbon Quaternary Centers via Hydrovinylation
2099
IR (neat): 3058, 2927, 2856, 1725, 1590, 1578, 1487, 1450, 1347,
1266, 1221, 1165, 1090 cm–1.
M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
For representative examples of the use of finely tuned
phosphoramidites from various research groups, see:
(c) Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org.
Chem. 2004, 69, 5660. (d) Bernsmann, H.; van den Berg,
M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.;
De Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943.
(e) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky, G.;
Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957.
(f) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 15506. (g) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 12370. (h) Du, H.; Yuan, W.;
Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
(i) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
T.; Carreira, E. M. Angew. Chem. Int. Ed. 2004, 43, 5971.
(5) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128,
5620.
(6) Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.;
Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 2780.
(7) For other reports of phosphoramidite ligands in asymmetric
hydrovinylation see: (a) Franció, G.; Faraone, F.; Leitner,
W. J. Am. Chem. Soc. 2002, 124, 736. (b) Kumareswaran,
R.; Nandi, N.; RajanBabu, T. V. Org. Lett. 2003, 5, 4345.
(c) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006,
128, 54.
(8) For recent reviews, see: (a) Jolly, P. W.; Wilke, G. In
Applied Homogeneous Catalysis with Organometallic
Compounds, Vol. 2; Cornils, B.; Herrmann, W. A., Eds.;
VCH: New York, 1996, 1024–1048. (b) RajanBabu, T. V.
Synlett 2009, 853.
(9) Hydrovinylation is one of the first metal-catalyzed
asymmetric C–C bond-formation reactions reported, even
though the selectivities were poor compared to today’s
standards: (a) Bogdanović, B.; Henc, B.; Meister, B.;
Pauling, H.; Wilke, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 1023. (b) Bogdanović, B.; Henc, B.; Lösler, A.; Meister,
B.; Pauling, H.; Wilke, G. Angew. Chem., Int. Ed. Engl.
1973, 12, 954.
1H NMR (400 MHz, CDCl3): d = 7.16–7.02 (m, 4 H, Ar), 6.84–6.76
(m, 4 H, Ar), 5.42–5.40 (t, J = 3.8 Hz, 1 H, vinyl), 4.63–4.62 (d, J =
3.6 Hz, 2 H), 4.21–4.18 (m, 1 H, OCH2CH2), 4.14–4.11 (m, 1 H,
OCH2CH2), 2.89–2.86 (d, J = 14.0 Hz, 1 H, CH2C), 2.71–2.67 (d,
J = 14.0 Hz, 1 H, CH2C), 2.00–1.97 (m, 1 H, OCH2CH2), 1.75–1.69
(m, 1 H, OCH2CH2), 1.29 (s, 3 H, CH3). The assignments were fur-
ther confirmed by COSY and NOESY experiments.
13C NMR (100 MHz, CDCl3): d = 154.1, 128.9, 127.7, 127.5, 124.1,
122.8, 121.2, 120.5, 117.2, 116.4, 65.3, 63.0, 42.4, 34.9, 34.5, 29.7.
Acknowledgment
Financial assistance for this research by NSF (CHE-0610349) and
NIH (General Medical Sciences, R01 GM075107) is gratefully
acknowledged. We also thank the ACS Organic Division for a
graduate fellowship sponsored by The Schering Plough
Corporation to Craig Smith.
References
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(23) Details of the synthesis of these compounds will be reported
separately.
(24) We have since observed such isomerization reaction in a
number of alk-1-enes, which undergo highly selective
isomerization to isomeric alk-2-enes under conditions
reminiscent of the hydrovinylation reaction under catalysis
of Ni(II) or Pd(II): Lim, H. J.; Smith, C. R.; RajanBabu, T.
V. J. Org. Chem. 2009, 74, in press.
(25) Biphenol-derived phosphoramidites have been used with
excellent results in copper-catalyzed conjugate additions:
see ref. 4c.
(18) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877.
(19) For the use of phosphoramidites derived from bis-phenols of
spirobisindane in related asymmetric hydrovinylations, see
reference 6.
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(27) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371.
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F.; Benhaim, C. Synlett 2001, 1375.
(20) For a detailed procedure, see: Smith, C. R.; Mans, D. J.;
Zhang, A.; RajanBabu, T. V. Org. Synth. 2008, 85, 248.
(21) (a) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10,
1657. (b) Smith, C. R.; Mans, D. J.; RajanBabu, T. V. Org.
Synth. 2008, 85, 238.
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Synthesis 2009, No. 12, 2089–2100 © Thieme Stuttgart · New York