Reactivity and selectivity in hydrovinylation of strained alkenes

Article abstract of DOI:10.1021/jo1015135

The scope of Ni(II)-catalyzed hydrovinylation has been extended to strained alkenes such as heterobicyclic [2.2.1]heptanes and cylobutenes. Reactions involving the heterobicyclic compounds are rare examples for this class of compounds where the metal-catalyzed C-C bond-forming reactions proceed without a concomitant ring-opening process. While the enantioselectivity in these systems remains modest, hydrovinylation of endo-5,6 - bis-benzyloxymethylbicyclo[2.2.1] hept-2-ene gives excellent yield (>90%) of the product with one of the highest enantioselectivities (95-99% ee) reported for a C-C bond-forming reaction of norbornenes.

Full text of DOI:10.1021/jo1015135

pubs.acs.org/joc
Reactivity and Selectivity in Hydrovinylation of Strained Alkenes
Wang Liu and T. V. RajanBabu*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus,
Ohio 43210, United States
rajanbabu.1@osu.edu
Received August 2, 2010
The scope of Ni(II)-catalyzed hydrovinylation has been extended to strained alkenes such as
heterobicyclic [2.2.1]heptanes and cylobutenes. Reactions involving the heterobicyclic compounds
are rare examples for this class of compounds where the metal-catalyzed C-C bond-forming
reactions proceed without a concomitant ring-opening process. While the enantioselectivity in these
systems remains modest, hydrovinylation of endo-5,6–bis-benzyloxymethylbicyclo[2.2.1]hept-2-ene
gives excellent yield (>90%) of the product with one of the highest enantioselectivities (95-99% ee)
reported for a C-C bond-forming reaction of norbornenes.
Introduction
cant differences in their reactivities. Such differences
might result from either electronic or steric reasons. Proper
choice of a catalyst can augment such differences, and
a number of these dimerization reactions have been
developed.3 Hydrovinylation (addition of ethylene) of al-
kenes (eq 1) is one such reaction where significant progress
has been achieved in several areas including the devel-
opment of enantioselective processes. Codimerization of
ethylene with more reactive partners like vinylarenes and
1,3-dienes has been carried out with excellent overall selec-
tivity, and advances in broadening the scope of this
Heterodimerization of alkenes is a reaction with a huge
potential for the synthesis of valuable intermediates since the
starting materials are often readily available, or can easily be
synthesized.1,2 Advantages of alkenes over other conven-
tional carbon feedstocks such as CO or HCN include their
lack of toxicity and ease of handling while possessing suffi-
cient reactivity to permit activation by transition metal
complexes. In addition, depending on the substitution pat-
tern, an alkene could be prochiral, and thus can serve as a
cheap source for enantiomerically pure intermediates. How-
ever, since the two starting materials and the expected
product(s) in a dimerization necessarily carry the same
functional group, viz., an alkene, finding successful reaction
conditions without concomitant side reactions such as
homodimerizations, oligomerizations, and isomerizations
is more challenging. The success of the reaction depends on
the judicious choice of two alkenes, where there are signifi-
(3) For seminal studies and reviews, see: (a) Hata, G. J. Am. Chem. Soc.
1964, 86, 3903. (b) Wittenberg, D. Angew. Chem., Int. Ed. Engl. 1964, 3, 153.
(c) Alderson, T.; Jenner, E. L.; Lindsey, R. V., Jr. J. Am. Chem. Soc. 1965, 87,
ꢀ
5638. (d) Bogdanovic, B.; Henc, B.; Meister, B.; Pauling, H.; Wilke, G.
Angew. Chem., Int. Ed. Engl. 1972, 11, 1023. (e) Bogdanovic, B. Adv.
ꢀ
€
Organomet. Chem. 1979, 17, 105. (f) Fe: Ehlers, J.; Konig, W. A.; Lutz, S.;
Wenz, G.; tom Dieck, H. Angew. Chem., Int. Ed. Engl. 1988, 27, 1556. (g)
Moreau, B.; Wu, J. Y.; Ritter, T. Org. Lett. 2009, 11, 337. Use of Ni: (h)
Wilke, G. Angew. Chem., Int. Ed. Engl. 1988, 27, 185. (i) RajanBabu, T. V.
Chem. Rev. 2003, 103, 2845. For more recent reports, see: Ru: (j)
Goossen, L. J. Angew. Chem., Int. Ed. Engl. 2007, 46, 7544. (k) Ura, Y.;
Tsujita, H.; Mitsudo, T.-a.; Kondo, T. Bull. Korean Chem. Soc. 2007, 28,
(1) Chauvin, Y.; Olivier, H. Dimerization and Codimerization. In Applied
Homogeneous Catalysis with Organometallic Compounds; Cornils, B.,
Herrmann, W. A., Eds.; VCH: New York, 1996; Vol. 1, pp 258-268.
(2) Su, A. C. L. Adv. Organomet. Chem. 1979, 17, 269.
€
2139. Co: (l) Hilt, G.; du Mesnil, F.-X.; Luers, S. Angew. Chem., Int. Ed.
2001, 40, 387.
7636 J. Org. Chem. 2010, 75, 7636–7643
Published on Web 10/21/2010
DOI: 10.1021/jo1015135
r
2010 American Chemical Society

Liu and RajanBabu
JOCArticle
reaction with respect to substrates and catalysts continue
unabated.4
Results and Discussion
Norbornene represents a class of substrates where the
viability of the reaction depends presumably on the en-
hanced reactivity of the strained bicyclic system as com-
pared to ethylene and the dimerization product (Scheme 1).
Indeed hydrovinylation of norbornene was among the first
metal-catalyzed asymmetric carbon-carbon bond-forming
reactions ever reported,5 even though the enantioselectivity
was unacceptable by current standards. Other reports of
codimerization of norbornene with ethylene include the
use of [Ni(2,4,6-Me3C6H2)(CH3CN)(phosphane)]þ [BF4]-,6
FIGURE 1. Ligands for hydrovinylation of strained alkenes.
in ∼80% ee. Even though this represents one of the highest
enantioselectivities reported for a carbon-carbon bond-
forming reaction of norbornene,10 the generality of this
reaction, or the broader question of whether reactivity
differences brought about by strain can be used to effect a
selective heterodimerization, has not been addressed. In
this paper we disclose the first experiments that deal with
this aspect of hydrovinylation.
SCHEME 1. Ligand Dependence on the Ni-Catalyzed Hydro-
vinylation of Norbornene
Hydrovinylation of Norbornene Derivatives. Our studies
started with a detailed examination of the hydrovinylation of
endo-5,6-bis-5,6-(benzyloxymethyl)bicyclo[2.2.1]hept-2-ene
(3), using the ligands L1-L6. This substrate was chosen as a
prototypical bicyclo[2.2.1]alkene since the enantiomers of
the product can be detected by UV absorption, and thus
directly analyzed on a chiral stationary phase HPLC column.
The choice of ligands for this study is based on several
previous observations from which we concluded that hemi-
labile ligands, when used in conjunction with a highly dis-
sociated counterion (e.g., 3,5-[[(CF3)2C6H3]4B]-, BARF-),
gave the highest selectivity in the reactions of vinylarenes11,12
and 1,3-dienes.13,14 It was also known that in ligands L1-L3
the location of the “hemilabile” oxygen in relation to the
phosphorus atom is crucial for obtaining high regioselec-
tivity for specific classes of substrates. Thus we have shown
that ligand L1 is the most suitable one for the hydrovinyla-
tion of certain classes of 1,3-dienes,13 ligand L2 is best for
vinylarenes,15 and ligand L3 gave low selectivities for all classes
(PCy3)2(CO)RuHCl/HBF4 Et2O,7 and Co(pyridineimine)-
3
Cl2/MAO.8 In 2003 we reported remarkable ligand effects on
the course of the Ni-catalyzed hydrovinylation of norbor-
nene (Scheme 1). It was shown that under our then newly
developed reaction conditions a ligand with a smaller cone
angle (Ph3P, 145°) gave a 2:1 adduct (norbornene:ethylene)
whereas a larger ligand (Cy3P, cone angle 180°) gave a 1:1
adduct.9 Among several chiral ligands examined, a phos-
phoramidite ligand (L4, Figure 1) derived from 1,10-bi-
naphthol gave quantitative yield, giving the 1:1 adduct (1)
(4) For representative examples, see: (a) Jolly, P. W.; Wilke, G. Hydro-
vinylation. In Applied Homogeneous Catalysis with Organometallic Com-
pounds; Cornils, B., Herrmann, W. A., Eds.; VCH: New York, 1996; Vol. 2,
pp 1024-1048. (b) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am.
Chem. Soc. 1998, 120, 459. (c) Goossen, L. J. Angew. Chem., Int. Ed. 2002, 41,
3775. (d) RajanBabu, T. V.; Nomura, N.; Jin, J.; Radetich, B.; Park, H.;
Nandi, M. Chem.;Eur. J. 1999, 5, 1963. (e) He, Z.; Yi, C. S.; Donaldson,
(10) For other related metal-catalyzed C-C bond-forming reactions of
norbornene, see: Hydrocyanation: Hodgson, M.; Parker, D.; Taylor, R. J.;
Ferguson, G. Organometallics 1988, 7, 1761. Baker, M. J.; Pringle, P. G.
J. Chem. Soc., Chem. Commun. 1991, 1292. Hydroformylation: Horiuchi, T.;
Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron: Asymmetry 1997, 8, 57.
Yan, M.; Xu, Q.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 2000, 11, 845.
Hydrosilylation: Hayashi, T. Acta Chem. Scand. 1996, 50, 259. Hydroalk-
enylation: Ozawa, F.; Kobatake, Y.; Kubo, A.; Hayashi, T. J. Chem. Soc.,
Chem. Commun. 1994, 1323. Sakuraba, S.; Awano, K.; Achiwa, K. Synlett
1994, 291. Wu, X.-Y.; Xu, H.-D.; Tang, F.-Y.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2001, 12, 2565. Aufdenblatten, R.; Diezi, S.; Togni, A. Monatsh.
Chem. 2000, 131, 1345.
(11) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121,
9899.
(12) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515.
(13) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 54.
(14) Saha, B.; Smith, C. R.; RajanBabu, T. V. J. Am. Chem. Soc. 2008,
130, 9000.
€
ꢀ
W. A. Org. Lett. 2003, 5, 1567. (f) Diez-Holz, C. J.; Boing, C.; Francio, G.;
Holscher, M.; Leitner, W. Eur. J. Org. Chem. 2007, 2995. (g) Tsujita, H.; Ura,
€
Y.; Matsuki, S.; Wada, K.; Mitsudo, T.; Kondo, T. Angew. Chem., Int. Ed.
2007, 46, 5160. (h) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F. Angew. Chem., Int.
Ed. 2008, 47, 1893. (i) Zhang, Q.; Zhu, S. F.; Qiao, X. C.; Wang, L. X.;
Zhou, Q. L. Adv. Synth. Catal. 2008, 350, 1507. (j) Grutters, M. M. P.;
€
van der Vlugt, J. I.; Pei, Y.; Mills, A. M.; Lutz, M.; Spek, A. L.; Muller, C.;
Moberg, C.; Vogt, D. Adv. Synth. Catal. 2009, 351, 2199. (k) RajanBabu,
T. V. Synlett 2009, 853. (l) Sharma, R. K.; RajanBabu, T. V. J. Am. Chem.
Soc. 2010, 132, 3295.
ꢀ
€
(5) Bogdanovic, B.; Henc, B.; Losler, A.; Meister, B.; Pauling, H.; Wilke,
G. Angew. Chem., Int. Ed. Engl. 1973, 12, 954. Nozaki’s Cu-catalyzed
cyclopropanation of styrene with ethyl diazoacetate is the only other example
of an asymmetric C-C bond-forming reaction that preceeds this discovery.
Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1966,
5239.
(6) Muller, G.; Ordinas, J. I. J. Mol. Catal. A: Chem. 1997, 125, 97.
(7) Yi, C. S.; He, Z.; Lee, D. W. Organometallics 2001, 20, 802.
(8) Bianchini, C.; Giambastiani, G.; Meli, A.; Toti, A. Organometallics
2007, 26, 1303.
(9) Kumareswaran, R.; Nandi, N.; RajanBabu, T. V. Org. Lett. 2003, 5,
4345.
(15) For example, hydrovinylation of styrene with [(allyl)Ni]Br]2/ligand
L2/NaBARF (0.007 equiv catalyst) at room temperature in an atmosphere of
ethylene gave >99% yield of 3-phenyl-1-butene with >99% selectivity for
this isomer. Under these conditions most other ligands lead to extensive
isomerization of the initial product into (Z)- and (E)-2-phenyl-2-butenes.
J. Org. Chem. Vol. 75, No. 22, 2010 7637

Liu and RajanBabu
JOCArticle
TABLE 1. Hydrovinylation of 3a
hydrovinylation of this substrate. Thus ligand L4 and its
enantiomer, ent-L4, and a simplified analogue containing the
biphenyl core (L6) gave the best overall yield and selectivity
(>90% yield, 93-99% ee) for this reaction (entries 5, 6,
and 8). This result represents the highest enantioselectivity
ever observed for an asymmetric catalyzed C-C bond-form-
ing reaction of a norbornene derivative. Surprisingly, the
ligand L5, which gave the highest yields and enantioselectiv-
ities (up to 99% yield and >95% ee) for a wide spectrum of
vinylarenes,21 was only moderately selective (66% ee) for
hydrovinylation of 3, even though the yield of the reaction
was excellent (entry 7). The enantioselectivities of the products
were determined by chiral stationary phase HPLC separation
of the primary products on Chiracel-AD-H column, using
hexane and isopropanol (99.6:0.4) as the mobile phase. The
ratios of enantiomers were further confirmed by conversion
of the dibenzyl ether 4 into a THF derivative 6 (eq 3). The
enantiomers of the THF derivative show baseline resolution in
gas chromatography on a Cyclodex B column. A racemic
authentic sample of 6 was prepared via hydrovinylation with
ligand L3.
conditions (mol % cat./ yield of 4 (%) selec. (% ee)
temp/time h)
entry ligand
sign of [R] for major
1
2
3
4
5
6
7
8
L1
L1
L2
L3
3/-22 °C/3
4/23 °C/2
70b,c/NA
<5/NA
3/23 °C/2
48b,c/NA
72b-d/NA
92/93 (-)
93/95-99 (þ)e
95/66 (-)
92/94 (-)
4/23 °C/2
L4
3/-78 °C/5
3/-78 °C/6
3/-78 °C/6
3/-78 °C/6
ent-L4
L5
L6
aSee eq 2 and the Experimental Secion for details of the procedure.
bProduct isolated as a mixture of 3 and 4. cThe rest of the starting
material. dAfter 10 h, no starting material, only isomerization product, 5
along with other contaminants. eProduct ent-4.
of substrates. The phosphoramidites, popularly known as the
Feringa ligands, are by far the most successful ligands for this
reaction.16-21 In our work the three ligands shown L4-L6
have been found to be broadly applicable for several of the
hydrovinylation reactions.21
Hydrovinylation of Azabicyclo[2.2.1]alkenes. Even though
carbametalation and related reactions of norbornene and
similar [2.2.1]-bicyclic molecules are well documented, reac-
tions of the corresponding heterocyclic analogues where the
bicyclic motif is preserved are rare.22-24 Such metalation
reactions involving Ni, Pd, and Rh intermediates most often
lead to ring-opening reactions.24-31 In earlier work we had
noticed that substrates carrying heteroatoms, especially
nitrogen, are slow to undergo hydrovinylation under mod-
erate conditions.19 In light of this observation it is surprising
that the azabicyclic alkene 7 undergoes hydrovinylation in
very good yields, even though, not unexpectedly, the product
is obtained as a mixture of two regioisomers (Scheme 2,
Table 2). For this reaction, the achiral ligands L1-L3 are
much less effective (entries 1-3) compared to the phosphor-
amidite ligands L4-L6, the Ni-complexes of the former
requiring higher temperatures to get reasonable yields. Yields
up to 89% are obtained by using the latter class of ligands at
-47 °C (entries 4-6). In these hydrovinylations, ligands L2
and L3 are the least reactive. For L1, at temperatures where
full conversion is observed (-10 °C), the primary products are
completely isomerized to the ethylidene derivatives 10-13.
The compounds 12 and 13 were not separable by column
chromatography, and were identified as the ketone 14, pre-
pared by Ru-mediated oxidation of the alkenes 12 and 13.
The Ni(II)-catalyzed hydrovinylation of 3 with the ligands
carrying a hemilabile benzyloxy substituent (L1-L3) paral-
lels our observations in the related reaction with vinylarenes
(Table 1). Nickel complex formed from ligand L1, allyl nickel
bromide dimer, and NaBARF is competent to effect the
hydrovinylation of this substrate at low temperature (entry
1), but at higher temperatures, extensive isomerization of the
product (to give a mixture of 4 and 5) is observed (entry 2).
Ligands L2 and L3, on the other hand, did not isomerize the
initially formed product up to several hours. We had pre-
viously found that L2 was one of the few ligands capable of
effecting hydrovinylation of several vinylarenes at room
temperature with no isomerization of the initially formed
3-aryl-1-butene.15 Compound 5 is formed in varying amounts
(0-10%) depending on the catalyst and reaction conditions
(and its structure is presumed on the basis of 1H NMR, which
shows a distinct olefinic H at δ 5.04 (q, J=6 Hz) and Csp2-CH3
signals at δ 1.81 (d, J=6 Hz). As with the other substrates,
finely tuned phosphoramidites are the best ligands for the
(22) Larock, R. C.; Johnson, P. L. J. Chem. Soc., Chem. Commun. 1989,
1368.
(23) Ozawa, F.; Kobatake, Y.; Kubo, A.; Hayashi, T. J. Chem. Soc.,
Chem. Commun. 1994, 1323.
(24) Menard, F.; Lautens, M. Angew. Chem., Int. Ed. 2008, 47, 2085.
(25) Lautens, M.; Rovis, T. Hydroalumination of Carbon-Carbon
Double Bonds. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 1, pp
337-348.
(26) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122,
1804.
(27) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett.
2002, 4, 1311.
(28) Li, L. P.; Rayabarapu, D. K.; Nandi, M.; Cheng, C. H. Org. Lett.
2003, 5, 1621.
(29) Rayabarapu, D. K.; Cheng, C. H. Acc. Chem. Res. 2007, 40, 971.
(30) McManus, H. A.; Fleming, M. J.; Lautens, M. Angew. Chem., Int.
Ed. 2007, 46, 433.
ꢀ
(16) Francio, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002, 124,
736.
(17) Park, H.; Kumareswaran, R.; RajanBabu, T. V. Tetrahedron 2005,
61, 6352.
(18) Smith, C. R.; Mans, D. J.; RajanBabu, T. V. Org. Synth. 2008, 85,
238.
(19) Smith, C. R.; Lim, H. J.; Zhang, A. B.; RajanBabu, T. V. Synthesis
2009, 2089.
(20) Lassauque, N.; Francio, G.; Leitner, W. Adv. Synth. Catal. 2009,
351, 3133.
(31) Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem.
1999, 64, 3538.
(21) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657.
7638 J. Org. Chem. Vol. 75, No. 22, 2010

Liu and RajanBabu
JOCArticle
TABLE 2. Ni-Catalyzed Hydrovinylation of 7a
entry
ligand
conditions (mol % cat./temp/time, h)
yield of HV (%)
products (%)
enantioselectivity for 8, 9 (% ee)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
14/-10 °C/4
8/20 °C/21
8/20 °C/21
8/-47 °C/5
8/-47 °C/6
8/-47 °C/6
78b
79
70
80
89
89
10 (25), 11 (22) [12 þ 13] (31)
8 (46), 9 (33)
8 (40), 9 (30)
8 (38), 9 (42)
8 (53), 9 (36)
8 (37), 9 (52)
8 (21), 9 (33)
8 (7), 9 (0)
8 (20), 9 (31)
aSee Scheme 2 and the Experimental Section for procedure. bAt -10 °C, 8 and 9 fully isomerized to 10, 11, 12, and 13; at -47 °C, 22% yield of [8 þ 9]
with the rest of the starting material.
SCHEME 2. Hydrovinylation of a [2.2.1]-Heterobicyclic Amide (7)
Finally, the bicyclic heterocycles shown in Figure 2 failed
to undergo the Ni-catalyzed hydrovinylation under a variety
of conditions. The exact reason why these substrates fail to
undergo the reaction is not obvious. One might speculate
that the first two substrates are Lewis basic and probably
form stable Ni(II) intermediates. The third and the fourth
substrates, because of the disposition of the substituents on
N (over the lone double bond), are sterically encumbered.
Recall that a reactive Ni(II)intermidiate, possibly a hydride,
has to initially coordinate with the double bond before the
reaction can take place.
FIGURE 2. Heterocyclic compounds that failed to undergo hydro-
vinylation.
Note that the enantioselectivities of these reactions are among
the lowest we have seen even with the highly successful
phosphoramidite ligands (entries 4-6, column 6).
Two other [2.2.1]-heterobicyclic molecules that undergo
hydrovinylation are shown in eqs 4 and 5. In general, these
substrates react only sluggishly with most ligands, and in-
variably higher temperatures are required to obtain accep-
table conversion to the products. Curiously for both these
substrates ligand L1 works best. Attempts to achieve com-
plete conversion lead to extensive isomerization of the initial
products and other side reactions. The hydrovinylation
reaction of 17 with a Ni(II)-L4 complex gave a poor yield
of the product 18, yet with an unusually high enantioselec-
tivity (>87% ee) as determined by chiral stationary phase
GC, where baseline separation of the enantiomers was
observed. The configuration of the major product has not
been confirmed independently, but the proposed structure
is based on the previous results from hydrovinylation of
norbornene.9
Hydrovinylation of a Cyclobutene (19). Except for a few
notable examples that involve metathesis reactions (Ru)32-36
and rearrangements (Rh),37 activation of the strained double
bond in cyclobutenes for metal-catalyzed carbon-carbon
bond-forming reactions has not been explored.38 We find
that the cyclobutene double bond is sufficiently reactive to
take part in a heterodimerization reaction with ethylene even
at low temperatures. Thus under the standard reaction
conditions described earlier, compound 19 undergoes hydro-
vinylation reactions giving the expected product in moderate
yields (Scheme 3 and Table 3). Attempts to isolate 20 from a
mixture of 19 and 20 were unsuccessful, and this mixture was
subjected to hydroboration in order to isolate the hydro-
vinylation product as a primary alcohol derivative 21. As
with other substrates, the phosphoramidites, in particular
the ligand L6, gave the best selectivities for this substrate.
While the absolute configuration of the product has not been
determined, the relative configuration of 20 was established
by NOE measurements on the hydroboration product 21.
We have not optimized these reactions except for examining
the viability of these ligands.
(32) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 6634.
(33) Tallarico, J. A.; Randall, M. L.; Snapper, M. L. Tetrahedron 1997,
53, 16511.
(34) Limanto, J.; Snapper, M. L. J. Am. Chem. Soc. 2000, 122, 8071.
(35) Bassindale, M. J.; Hamley, P.; Harrity, J. P. A. Tetrahedron Lett.
2001, 42, 9055.
(36) Nicolaou, K. C.; Vega, J. A.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2001, 40, 4441.
(37) Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993, 115,
4895.
(38) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
J. Org. Chem. Vol. 75, No. 22, 2010 7639

Liu and RajanBabu
JOCArticle
TABLE 3. Ni-Catalyzed Hydrovinylation of Cyclobutene 19
entry
ligand
conditions (mol % cat./temp/time, h)
yield of 20 (%); (20:19)a
% ee (20) (sign of [R])
1
L1
L2
L3
L4
L4
L5
L6
14/-30 °C/15
14/43 °C/12
14/23 °C/18
10/-50 °C/8
14/-45 °C/6.5
10/-50 °C/3.5
10/-50 °C/5
32; 20:1
67; 5:1
2b
4
0c
5
6
8
7
47; 4.3:1.0
40; 32:1
46; 1.4:1.0
48; 4.7:1.0
55 (-)
52 (-)
82 (-)
aRatio and yield of product calculated based on 1H NMR of a mixture of 19 and 20. bIn ClCH2CH2Cl. cComplex mixture.
columns (Cyclodex B, 25 m ꢀ 0.25 mm ID, 0.12 mm film
thickness or Cyclosil 30 m ꢀ 0.25 mm ID, 0.25 μm thickness).
Enantiomeric excesses of other compounds were determined
by HPLC using a Chiralcel OJ-H or a Chiralcel AD-H column
with hexane/isopropanol as solvents. Conditions are de-
scribed under specific compounds. Optical rotations were
recorded at the sodium D line in chloroform.
SCHEME 3. Hydrovinylation of a Cyclobutene (19)
Synthesis of endo-5,6-Bis(benzyloxymethyl)bicyclo[2.2.1]hept-
2-ene (3). To a solution of 2,3-bis(hydroxymethyl)bicyclo[2.2.1]-
hept-2-ene42 (1.79 g, 11.6 mmol) in THF (30 mL) was added
NaH (1.39 g, 60 wt % in mineral oil, 34.8 mmol) in one portion
at 0 °C under argon. The resulting suspension was stirred at 0 °C
for 60 min and then benzyl bromide (4.4 mL, 37 mmol) was
added dropwise at 0 °C. The mixture was allowed to warm
to room temperature and stirred for 18 h. Water was added
carefully to quench the reaction, and the mixture was extracted
with ether and the organic layers were combined, washed
with brine, dried, and concentrated. The resulting residue was
purified by column chromatography on silica gel (eluting
with hexanes/ethyl acetate =30/1) to obtain 3.4 g (88%) of 3
Conclusions
An endo-5,6-bis(benzyloxymethyl)bicyclo[2.2.1]hept-2-
ene derivative undergoes Ni(II)-catalyzed asymmetric hy-
drovinylation giving the highest enantioselectivities (∼95%
ee) reported for a C-C bond-forming reaction of norbor-
nene derivatives. Other results reported in this paper clearly
demonstrate that the scope of Ni(II)-catalyzed hydrovinyla-
tion extends to strained alkenes such as heterobicyclic-
[2.2.1]heptenes and cyclobutenes. Reactions involving the
heterobicyclic compounds are rare examples for this class of
compounds where the metal-catalyzed C-C bond-forming
reactions proceed without a concomitant ring-opening pro-
cess. While the enantioselectivity in these systems remains
modest, we hope that these results will stimulate further
work in this area, especially since the products of this reac-
tion can potentially be transformed into highly substituted
cyclohexane derivatives.
1
as an oil: H NMR (500 MHz, CDCl3) δ 1.24 (d, J = 8.2 Hz,
1 H), 1.39 (d, J = 8.2 Hz, 1 H), 2.46-2.47 (m, 2 H), 2.89
(s, 2 H), 2.95-2.99 (m, 2 H), 3.21-3.24 (m, 2 H), 4.32 and 4.38
(AB quartet, J=12.0 Hz, 4 H), 5.96 (s, 2 H), 7.17-7.27 (m, 10
H); 13C NMR (125 MHz, CDCl3) δ 41.6, 45.6, 49.0, 70.5, 73.0,
127.5, 127.6, 128.3, 135.3, 138.7; IR (neat) 2920, 2855, 1496,
1454, 1365, 1095 cm-1; HRMS (ESI) calcd for C23H26O2Na ([M
þ Na]þ) 357.1830, obsd 357.1832.
Typical Procedure for Catalytic Hydrovinylation (Table 1,
entry 8). The precatalyst was prepared as follows in a glovebox:
To di-η-allyl-di-μ-bromonickel(II) (1.0 mg, 0.00278 mmol) in
CH2Cl2 (1 mL) was added a solution of ligand L6 (2.5 mg,
0.0057 mmol) in CH2Cl2 (1 mL) at ambient temperature.
The resulting solution was added to a suspension of NaBARF
(5.0 mg, 0.00564 mmol) in dichloromethane (1 mL) and the
mixture was stirred at ambient temperature in a septum-sealed
25 mL round-bottomed flask for 10 min affording a dark brown
solution containing a small amount of fine particulate (NaBr).
The flask was removed from the glovebox and was then cooled
to -78 °C (acetone-dry ice bath), creating a small vacuum. Dry
ethylene (passed through a 0.5 in. ꢀ 4 in. column of Drierite) was
introduced via needle through the serum stopper and the vessel
atmosphere was slowly evacuated 3 times with a 60 mL syringe.
At 78 °C, a solution of 3 (60 mg, 0.18 mmol) in 1 mL of dry
CH2Cl2 is introduced dropwise into the solution of the preca-
talyst over a 1 min period via a syringe. The vessel was then
maintained at -78 °C for a period of 6 h. At the end of this
period the ethylene line is removed and the reaction was quen-
ched by addition of a saturated aqueous NH4Cl solution. The
product was extracted with ether. The organic layers are com-
bined, dried over MgSO4, and concentrated to obtain a yellow oil.
The resulting residue was purified by column chromatography
Experimental Section
General Methods. Reactions requiring air-sensitive manipu-
lations were conducted under an inert atmosphere of nitrogen
by Schlenk techniques or with the aid of a Vacuum Atmospheres
glovebox. Methylene chloride and 1,2-dichloroethane were dis-
tilled from calcium hydride under a dry atmosphere and stored
over molecular sieves. Tetrahydrofuran was distilled under
nitrogen from sodium/benzophenone ketyl. The ligands L1-
L3,39 L4-L6,40 and Naþ{[3,5-(CF3)2C6H3]4B}- (NaBARF)41
were prepared according to the methods described in the
literature. Ethylene (99.5%) was purchased from Matheson
and passed through Drierite before use. Flash column chro-
matography was carried out on silica gel 40. Enantiomeric
excesses of volatile chiral compounds were determined by
gas chromatographic analysis on chiral stationary phase GC
(39) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 54.
(40) Smith, C. R.; Mans, D. J.; RajanBabu, T. V. Org. Synth. 2008, 85,
238.
(41) Smith, C. R.; Zhang, A.; Mans, D. J.; RajanBabu, T. V. Org. Synth.
2008, 85, 248.
(42) Setzer, W. N.; Brown, M. L.; Yang, X.-j.; Thompson, M. A.;
Whitaker, K. W. J. Org. Chem. 1992, 57, 2812.
7640 J. Org. Chem. Vol. 75, No. 22, 2010

Liu and RajanBabu
JOCArticle
on silica gel (eluting with hexanes/ethyl acetate = 40/1) to
obtain 60 mg (92%) of 4 as an oil.
sponding to the unreacted starting material and one to the
hydrovinylation product, in 13% and 36% yields, respectively.
To an ice-cooled solution of the mixture of diols (27 mg)
and pyridine (27.6 mg, 0.35 mmol) in CH2Cl2 (2 mL) was
added p-TsCl (33.3 mg, 0.17 mmol). The reaction solution was
stirred at room temperature for 21 h before addition of H2O.
The organic solution was separated, washed with 1 M aqueous
HCl solution, saturated aqueous NaHCO3 solution, and brine,
and dried (Na2SO4). After concentration, the residue was
purified by silica gel column chromatography (pentane/ether,
50:1) to obtain 14 mg of a mixture of 6 and THF derivative from
the starting material. The mixture analyzed by chiral stationary
phase GC on the Cyclodex Β column revealed that the product
was nearly racemic (<3% ee).
Hydrovinylation of Substrate 3: Product 4. 1H NMR (500
MHz, CDCl3) δ 1.08-1.12 (m, 1 H), 1.22 (d, J = 9.8 Hz, 1 H),
1.42 (d, J = 9.8 Hz, 1 H), 1.59-1.61 (m, 1 H), 2.14 (s, 1 H), 2.18
(m, 3 H), 2.25 (s, 1 H), 3.30 (t, J = 8.7 Hz, 1 H), 3.37 (t, J=8.7
Hz, 1 H), 3.43-3.46 (m, 1 H), 3.48-3.51 (m, 1 H), 4.35-4.44 (m,
4 H), 4.80-4.85 (m, 2 H), 5.65-5.72 (m, 1 H), 7.17-7.27 (m, 10
H); 13C NMR (125 MHz, CDCl3) δ 30.1, 36.7, 37.6, 39.5, 40.2,
40.7, 45.6, 67.8, 68.5, 73.1, 112.0, 127.5, 127.6, 127.6, 128.3,
138.6, 138.6, 144.0; IR (neat) 2954, 2871, 1634, 1496, 1454, 1366,
1097 cm-1; HRMS (ESI) calcd for C25H30O2Na ([M þ Na]þ)
385.2144, obsd 385.2139. [R]22 -9.1 (c 0.33, CHCl3) (L6 at
-35 °C, 82% ee by HPLC); [R]22DD þ13.1 (c 0.42, CHCl3) (ent-L4
at -78 °C, 95% ee by HPLC; >99% by GC of the correspond-
ing THF derivative 6, see next experiment). HPLC conditions
and retention times (Chiracel AD-H): solvent hexanes:isopro-
panol 99.6:0.4; flow rate 0.3 mL/min, retention times (min):
25.53 (þ)-isomer, 29.54 (-)-isomer. The retention time for
starting material: 32.30 min (see the chromatograms in the
Supporting Information). Chiral stationary phase GC for 6
(Cyclodex B column, programmed run: 10 min at 80 °C, 1 deg
per min to 110 °C, 60 min at 110 °C; retention time: 43.91 min,
(-)-isomer: >99% (only one isomer seen in the gas chromato-
gram). Retention times of authentic mixture (-)-isomer: 43.75
min; (þ)-isomer: 44.45 min.
Conversion of 4 into the THF Derivative 6. To a solution of 4
(131 mg, 0.36 mmol, prepared with L6 at -78 °C) in CH2Cl2
(20 mL) was added a hexane solution of BCl3 (3.6 mL, 1 mol
L-1) dropwise at -20 °C under nitrogen. The resulting solution
was stirred for 2 h and then quenched with MeOH (10 mL) at the
same temperature. The mixture is stirred for 40 min. The
solvent was then removed under reduced pressure. The result-
ing residue was purified by column chromatography on silica
gel (eluting with pentane/ethyl ether = 50/1) to obtain 59 mg
(90%) of 6 as an oil. 1H NMR (500 MHz, CDCl3) δ 1.05-1.09
(m, 1 H), 1.31 (d, J = 10 Hz, 1 H), 1.52 (d, J = 10 Hz, 1 H),
1.76-1.81 (m, 1 H), 1.99-2.00 (m, 1 H), 2.13-2.15 (m, 1 H),
2.38-2.53 (m, 3 H), 3.31 (dd, J = 9.6, 6.8 Hz, 2 H), 3.80 (d, J =
9.5 Hz, 1 H), 3.80 (d, J = 9.5 Hz, 1 H), 4.78 (d, J = 10.4 Hz, 1
H), 4.85 (d, J = 17.1 Hz, 1 H), 5.65-5.72 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ 30.6, 38.5, 39.7, 40.7, 45.4, 46.1, 46.2,
68.6, 69.0, 111.8, 144.1; IR (neat) 2945, 2848, 1636, 1090, 998,
908 cm-1; HRMS (ESI) calcd for C11H16ONa ([M þ Na]þ)
Synthesis of N-(4-Toluensulfonyl)-2-aza-bicyclo[2.2.1]hept-5-
ene (7). This compound was prepared according to a literature
procedure.43 Cyclopentadiene (4 mL, 49.0 mmol) was added to a
solution of NH4C1 (1.325 g, 24.8 mmol), 36% aqueous for-
maldehyde (2.6 mL, 34.0 mmol), and MeOH (5 mL). The
reaction mixture was vigorously stirred for 12 h at room
temperature before diluting with an equal volume of water
and was subsequently washed with diethyl ether (2 ꢀ 10 mL).
The aqueous phase was made basic with saturated NaOH. The
2-azabicyclo[2.2.1]hept-5-ene was isolated by extraction with
ether (3 ꢀ 10 mL). To a mixture of this extract and 10% NaOH
(10 mL) was added a solution of TsCl (4 g, 21.0 mmol) in a mixed
solvent (ether: 6 mL; CH2Cl2: 3 mL) over a period of 5 min at
room temperature. The mixture was stirred for 12 h. The organic
layer was separated, dried with Na2SO4, filtered, and concen-
trated in vacuo. The resulting oil was purified by chromatogra-
phy (EtOAc: hexanes = 1:7) to obtain the product (2.77 g, 53%)
as a white solid: mp 67-70 °C; 1H NMR (500 MHz, CDCl3) δ
1.40-1.46 (m, 2 H), 2.39 (s, 3 H), 2.52 (dd, J = 8.5, 1.3 Hz, 1 H),
3.11 (broad s, 1 H), 3.31 (dd, J = 8.5, 2.8 Hz, 1 H), 4.62 (broad s,
1 H), 5.97-5.99 (m, 1 H), 6.07-6.09 (m, 1 H), 7.25 (d, J = 8 Hz,
2 H), 7.65 (d, J = 8 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ
21.5, 43.8, 47.1, 64.2, 127.7, 129.5, 133.5, 136.3, 136.7, 143.1; IR
1654, 1458, 1330, 1155, 1092, 662 cm-1; HRMS (ESI) calcd for
C13H15NO2SNa ([M þ Na]þ) 272.0716, obsd 272.0715.
187.1099, obsd 187.1104. [R]22 -31.7 (c 0.54, CHCl3). GC
D
(methylsilicone) conditions: 110 °C (isothermal), retention
time: 29.88 min. GC Cyclodex B column, retention times
(min) 43.81 min, confirmed by comparison to authentic pro-
duct (see next experiment)
Synthesis of Racemic 6 via Hydrovinylation of 4 Followed
by THF Formation. A racemic sample was prepared by
hydrovinylation of 4 by using the ligand L3 (4 mol % catalyst,
23 °C, 2 h, 72% yield) followed by the THF formation. GC
retention times (min): 43.76 min (∼50%), 44.45 min (∼50%).
An Alternate Synthesis of THF Derivative 6 via Hydrovinyla-
tion of Cyclopentadiene/Maleic Anhydride Adduct. The general
hydrovinylation procedure was employed for the anhydride
adduct (50 mg, 0.30 mmol) with ligand L4 (13.2 mg, 0.024
mmol, 8 mol % catalyst) at 23 °C over 13 h. The crude product
was passed through a short pad of silica gel and redissolved in
THF (10 mL) at 0 °C, and LiAlH4 (40 mg, 1.05 mmol) was added
to this solution. The reaction mixture was warmed to room
temperature and stirred for 14 h and then quenched with satu-
rated NH4Cl. The aqueous layer was extracted with ether four
times. The organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was purified by column
chromatography (eluting with hexanes/ethyl acetate=1.0/1.2)
to obtain 24 mg of a 1.0:2.8 mixture of two diols, one corre-
Typical Procedure for Catalytic Hydrovinylation of Hetero-
bicyclic Alkenes (Table 2, Entry 4). The precatalyst was prepared
as follows in a glovebox: To di-η-allyl-di-μ-bromonickel(II) (2.9
mg, 0.0080 mmol) in CH2Cl2 (1 mL) was added a solution of
ligand L4 (8.7 mg, 0.016 mmol) in CH2Cl2 (1 mL) at ambient
temperature. The resulting solution was added to a suspension
of NaBARF (14.3 mg, 0.016 mmol) suspended in dichloro-
methane (1 mL) and the mixture was stirred at ambient
(43) Gleim, R. D.; Spurlock, L. A. J. Org. Chem. 1976, 41, 1313.
J. Org. Chem. Vol. 75, No. 22, 2010 7641

Liu and RajanBabu
JOCArticle
temperature in a septum-sealed 25 mL round-bottomed flask for
10 min affording a dark brown solution containing a small
amount of fine particulate (NaBr). The flask was removed from
the glovebox. The flask was then cooled to -47 °C in an
acetonitrile-dry ice bath, creating a small vacuum. Dry ethylene
(passed through a 0.5 in. ꢀ 4 in. column of Drierite) was intro-
duced via needle through the serum stopper and the vessel
atmosphere was slowly evacuated 3 times with a 60 mL syringe.
After the solution was cooled to -47 °C, a solution of 7 (50 mg,
0.20 mmol) in 1 mL of dry CH2Cl2 is introduced dropwise into
the solution of the precatalyst over a 1 min period via syringe.
The vessel was then maintained at -47 °C for a period of 5 h. At
the end of this period the ethylene line was removed and the
reaction was quenched by addition of a saturated aqueous
NH4Cl solution. The product was extracted with ether. The
organic layers are combined, dried over MgSO4, and concen-
trated to give a yellow oil. The resulting residue was purified by
column chromatography on silica gel (eluting with hexanes/
ethyl acetate = 9/1) to obtain 45 mg (80%) of an inseparable
mixture of 8 and 9 as an oil.
To this mixture was added sodium metaperiodate (33.6 mg,
0.157 mmol). To this biphasic solution was added an acetonitrile
solution (1 mL) of ruthenium trichloride hydrate (0.65 mg,
0.0031 mmol). The entire mixture was stirred vigorously for
16 h at room temperature. The phases were separated and the
aqueous phase was extracted 3 times with CH2C12. The com-
bined organic extracts were dried (MgSO4) and concentrated.
The crude product was purified by chromatography (EtOAc:
hexanes =1.0:1.5) to give the product (4.9 mg, 59%) as an oil.
1
The structure was confirmed by comparison of H NMR with
the data reported in the literature.43 1H NMR (500 MHz,
CDCl3) δ 1.46-1.49 (m, 1 H), 1.75 (d, J=10.7 Hz, 1 H), 2.09-
2.35 (ABX system, υa = 2.11, υb = 2.32, JAB=18 Hz, JAX =4.4
Hz, JBX=3 Hz, 2 H), 2.42 (s, 3 H), 2.82 (broad s, 1 H), 3.32-
3.33 (m, 2 H), 4.54 (broad s, 1 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.72
(d, J=8.2 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.6, 36.4,
46.0, 48.4, 50.8, 59.1, 127.4, 130.0, 135.0, 144.0, 211.8; IR (neat)
3352, 2918, 2852, 1708, 1679, 1366, 1161 cm-1; HRMS (ESI)
calcd for C13H15NO3SNa ([M þ Na]þ) 288.0665, obsd 288.0674.
Synthesis of Diisopropyl 2,3-Diazabicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylate (15). The substrate was prepared following a
procedure reported in the literature.44 To a freshly distilled
cyclopentadiene (0.62 mL, 7.60 mmol) solution in CH2Cl2 kept
at 0 °C was added the diisopropyl azodicarboxylate (1 mL, 5.08
mmol). The reaction was allowed to warm to room temperature
and stirred until full consumption of the starting material, as
estimated by TLC. The solvent was evaporated under reduced
pressure. The crude clear oil was purified by silica gel chroma-
tography with 1:3 EtOAc/hexanes as eluent. The diazabicycle
was obtained quantitatively as a white solid: mp 95-98 °C ; 1H
NMR (500 MHz, CDCl3) δ 1.22 (d, J = 6.3 Hz, 12 H), 1.65-
1.70 (m, 2 H), 4.90-4.95 (m, 2 H), 5.10 (broad s, 2 H), 6.46
(broad s, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.9, 47.9, 65.2,
70.1, 134.2, 138.4, 158.5; IR (neat) 3411, 2981, 1743, 1700, 1373,
1307, 1174, 1100 cm-1; HRMS (ESI) calcd for C13H20N2O4Na
([M þ Na]þ) 291.1315, obsd 291.1311.
1
Products of Hydrovinylation of 7 with Ligand L4. H NMR
(500 MHz, CDCl3) (8) δ 0.84-0.86 (m, 1 H), 1.27-1.29 (m, 1 H),
1.35-1.44 (m, 1 H), 1.62-1.77 (m, 1 H), 2.40 (s, 3H), 2.44 (broad
s, 1 H), 2.66-2.70 (m, 1 H), 2.98-3.07 (m, 2 H), 3.96 (broad s,
1 H), 4.89-4.98 (m, 2 H), 5.53-5.60 (m, 1 H), 7.28 (d, J=8.2 Hz,
2 H), 7.68 (d, J=8.2 Hz, 2 H); (9) δ 0.89-0.91 (m, 1 H), 1.29-
1.31 (m, 1 H), 1.35-1.44 (m, 1 H), 2.01-2.06 (m, 1 H), 2.29
(broad s, 1 H), 2.30-2.36 (m, 1 H), 2.40 (s, 3 H), 2.98-3.07 (m, 2
H), 4.15 (broad s, 1 H), 4.89-4.98 (m, 2 H), 5.63-5.69 (m, 1 H),
7.28 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.2 Hz, 2 H); (8 þ 9) 13
C
NMR (125 MHz, CDCl3) δ 21.5, 33.8, 34.0, 34.2, 37.4, 38.4,
43.0, 43.7, 47.0, 53.7, 54.0, 60.2, 64.0, 113.4, 114.8, 127.4, 127.4,
129.6, 135.8, 135.9, 139.8, 141.5, 143.2, 143.2; IR (neat) 3430,
2977, 2880, 1638, 1597, 1457, 1341, 1161, 1093, 818 cm-1
;
HRMS (ESI) calcd for C15H19NO2SNa ([MþNa]þ) 300.1029,
obsd 300.1041. HPLC conditions and retention times (Chiracel
AD-H): solvent (hexanes:isopropanol) 98.5:1.5; flow rate 0.4
mL/min, retention times (min): for 8, 43.06, 57.81; for 9, 53.11,
60.77. (see the chromatograms in the Supporting Information)
Hydrovinylation of 7 with Ligand L1. The products of the
reaction were separated into 10, 11, and a mixture of 12 and 13
by column chromatography on silica gel (eluting with hexanes/
ethyl acetate = 9/1). The mixture of 12 and 13 was identified
after conversion to a ketone 14 (see later).
1
Hydrovinylation of 15. 16: H NMR (500 MHz, CDCl3) δ
1.24 (d, J = 6.3 Hz, 12 H), 1.58 (broad s, 1 H), 1.61-1.64 (m, 2
H), 2.05 (broad s, 1 H), 2.68 (broad s, 1 H), 4.33 (broad s, 1 H),
4.51 (broad s, 1 H), 4.93-4.97 (m, 2 H), 5.02-5.05 (m, 2 H),
5.63-5.70 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 22.0, 35.0,
43.3, 60,3, 64.4, 69.9, 115.3, 139.0, 157.3; IR (neat) 2980, 2937,
2878, 1697, 1468, 1374, 1105, 918, 770 cm-1; HRMS (ESI) calcd
for C15H24N2O4Na ([M þ Na]þ) 319.1628, obsd 319.1627.
Hydrovinylation of 7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-
hept-2-ene (17). The starting material was prepared according to
a procedure reported in the literature.45 18: 1H NMR (500 MHz,
CDCl3) δ 1.35-1.56 (m, 3 H), 1.42 (s, 9 H), 1.64-1.73 (m, 3 H),
2.29-2.33 (m, 1 H), 4.00 (broad s, 1H), 4.22 (broad s, 1 H), 4.88 (d,
J = 10.1 Hz, 1 H), 4.94 (d, J = 17.0 Hz, 1 H), 5.70-5.77 (m, 1 H);
13C NMR (125 MHz, CDCl3) δ 28.3, 29.7, 47.4, 79.3, 113.0, 142.0;
IR (neat) 3365, 2920, 2852, 1704, 1454, 1366, 801 cm-1; HRMS
(ESI) calcd for C13H21NO2Na ([M þ Na]þ) 246.1465, obsd
246.1462; GC (Cyclodex B, programmed run, 5 min at 110 °C,
0.5 deg/min, and finally 5 min at 130 °C). Retention times
(min): 39.6, 40.3. Retention time for starting material 17 (min):
28.7.
10: 1H NMR (500 MHz, CDCl3) δ 1.30 (d, J = 10.1 Hz, 1 H),
1.38 (d, J = 10.1 Hz, 1 H), 1.69 (d, J = 6.9 Hz, 3 H), 1.75 (d, J =
16 Hz, 1 H), 2.14-2.18 (m, 1 H), 2.39 (s, 3H), 2.51 (broad s, 1 H),
2.94 (d, J = 8.8 Hz, 1 H), 3.23-3.26 (m, 1 H), 4.71 (broad s, 1 H),
5.04 (q, J = 6.9 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.67 (d, J =
8.2 H, 2 H); 13C NMR (125 MHz, CDCl3) δ 14.8, 21.5, 35.2,
37.0, 38.0, 53.1, 59.5, 116.8, 127.6, 129.2, 136.1, 138.6, 143.0;
white solid, mp 98-102 °C ; IR (neat) 3448, 2980, 1597, 1452,
1338, 1159, 1094, 667 cm-1; HRMS (ESI) calcd for C15H19NO2-
SNa ([M þ Na]þ) 300.1029, obsd 300.1037.
11: 1H NMR (500 MHz, CDCl3) δ 1.30 (d, J = 6.9 Hz, 3 H),
1.33 (d, J = 10.4 Hz, 1 H), 1.44-1.46 (m, 1 H), 1.51 (d, J = 16.1
Hz, 1 H), 2.07-2.11 (m, 1H), 2.39 (s, 3 H), 2.55 (broad s, 1 H),
2.88 (d, J = 8.8 Hz, 1 H), 3.27-3.30 (m, 1 H), 4.33 (broad s, 1 H),
5.34-5.38 (m, 1 H), 7.22 (d, J = 8 Hz, 2 H), 7.64 (d, J = 8 Hz, 2
H); 13C NMR (125 MHz, CDCl3) δ 13.4, 21.5, 32.5, 37.1, 38.4,
53.2, 64.9, 116.8, 127.9, 129.1, 129.2, 135.7, 138.6, 142.8; white
solid, mp 95-98 °C; IR (neat) 3427, 2921, 1593, 1449, 1323,
1154, 1090, 1052, 668 cm-1; HRMS (ESI) calcd for C15H19NO2-
SNa ([M þ Na]þ) 300.1029, obsd 300.1044.
cis-3,4-Bis(benzyloxymethyl)-3,4-dimethylcyclobutene (19).
To
a solution of cis-1,2-dimethylcyclobut-3-ene-1,2-di-
methanol46 (1.06 g, 7.4 mmol) in THF (30 mL) was added
NaH (888 mg, 60 wt % in mineral oil, 22.2 mmol) in one
portion at 0 °C under argon. The resulting suspension was
(44) (a) Diels, O.; Bolm, J. H.; Knoll, W. Justus Liebigs Ann. Chem. 1925,
443, 242. (b) Menard, F.; Lautens, M. Angew. Chem., Int. Ed. 2008, 47, 2085.
(45) Carroll, F. I.; Liang, F.; Navarro, H. A.; Brieaddy, L. E.; Abraham,
P.; Damaj, M. I.; Martin, B. R. J. Med. Chem. 2001, 44, 2229.
(46) Inoue, M.; Lee, N.; Kasuya, S.; Sato, T.; Hirama, M.; Moriyama,
M.; Fukuyama, Y. J. Org. Chem. 2007, 72, 3065.
Oxidation of 12 and 13. The inseparable mixture of the two
isomers 12 and 13 was oxidized to ketone 14. A flask is charged
with a magnetic stirrer, 1 mL of carbon tetrachloride, 1.5 mL
of water, and 8.7 mg (0.031 mmol) of a mixture of 12 and 13.
7642 J. Org. Chem. Vol. 75, No. 22, 2010

Liu and RajanBabu
JOCArticle
stirred at 0 °C for 60 min and then benzyl bromide (2.83 mL,
23.8 mmol) was added dropwise at 0 °C. The mixture was
allowed to warm to room temperature and stirred for another
18 h. Water was carefully added to quench the reaction and
the mixture was extracted with ether and the organic layers
were combined, washed with brine, dried, and concentrated.
The resulting residue was purified by column chromatogra-
phy on silica gel (eluting with hexanes/ethyl acetate=40/1) to
obtain 2.16 g (90%) of cis-3,4-bis(benzyloxymethyl)-3,4-di-
methylcyclobutene (19) as an oil: 1H NMR (400 MHz,
CDCl3) δ 1.15 (s, 6 H), 3.41 (d, J = 9.3 Hz, 2 H), 3.54 (d,
J = 9.3 Hz, 2 H), 4.40 (d, J = 12.4 Hz, 2 H), 4.44 (d, J = 12.4
Hz, 2H), 6.08 (s, 2 H), 7.21-7.31 (m, 10 H); 13C NMR (100
MHz, CDCl3) δ 19.3, 51.8, 73.2, 75.4, 127.3, 127.5, 128.2,
138.8, 141.1. IR (neat) 3029, 2852, 1496, 1453, 1362, 1094,
1075 cm-1; HRMS (ESI) calcd for C22H26O2Na ([M þ Na]þ)
345.1830, obsd 345.1833.
successively at 0 °C and the resulting mixture was stirred at room
temperature for 30 min. Water was added and the mixture was
extracted with ether. The organic layer was washed with brine,
dried over MgSO4, and concentrated. The residue was purified by
column chromatography (eluting with hexanes/ethyl acetate =
10/1) to afford 35 mg (70%) of 21. 1H NMR (400 MHz,
CDCl3) δ 1.02 (s, 3H), 1.11 (s, 3 H), 1.34-1.42 (m, 1 H),
1.45-1.56 (m, 2 H), 1.63-1.72 (m, 1 H), 1.96-2.06 (m, 1 H),
2.11 (broad s, 1 H), 3.07 (d, J = 9.0 Hz, 1 H), 3.26 (d, J = 9.0 Hz,
1 H), 3.40 (d, J = 9.0 Hz, 1 H), 3.37-3.43 (m, 1 H), 3.50-3.54 (m,
1 H), 3.59 (d, J=9.0 Hz, 1 H), 4.29-4.37 (m, 4 H), 7.17-7.27 (m,
10 H). The configuration of the product is assigned by the strong
NOE observed between the methyl hydrogens and the ring
hydrogen shown. 13C NMR (125 MHz, CDCl3) δ 20.3, 21.1,
33.8, 34.2, 37.7, 40.2, 44.7, 62.4, 72.7, 73.1, 73.4, 76.1, 127.3, 127.4,
127.5, 127.6, 128.2, 128.3, 138.3, 138.9; IR (neat) 3364, 2930, 2866,
1717, 1454, 1361, 1072, 736 cm-1; HRMS (ESI) calcd for
C24H32O3Na ([MþNa]þ) 391.2249, obsd 391.2252; [R]22D -16.9
(c 0.51, CHCl3) (L6); HPLC (chiracel AD-H) conditions: hex-
anes:isopropanol 99:1, 0.3 mL/min, retention time (min):
73.43 (-)-isomer, 77.38 (þ)-isomer. The retention times were
confirmed by comparison to an authentic racemic 21 prepared
using nickel complex of L2 (see the chromatograms in the
Supporting Information).
1
Hydrovinylation of 19. 20: H NMR (400 MHz, CDCl3) δ
1.07 (s, 3 H), 1.20 (s, 3 H), 1.64 (dd, J = 8.3, 11.1 Hz, 1 H), 1.92
(t, J = 10.4 Hz, 1 H), 2.62-2.68 (s, 1H), 3.25 (d, J = 9.0 Hz,
1 H), 3.35 (d, J = 9.0 Hz, 1 H), 3.42 (d, J = 9.0 Hz, 1 H), 3.51 (d,
J = 9.0 Hz, 1 H), 4.37-4.45 (m, 4 H), 4.90-4.94 (m, 2 H),
5.87-5.96 (m, 1 H), 7.24 -7.32 (m, 10 H); 13C NMR (100 MHz,
CDCl3) δ 20.2, 21.1, 32.8, 40.2, 43.7, 46.5, 73.1, 73.6, 76.4, 114.0,
127.2, 127.3, 127.3, 127.4, 128.2, 128.2, 138.7, 138.9, 139.1; IR
(neat) 2959, 2926, 2854, 1454, 1360, 1095 cm-1; HRMS (ESI)
calcd for C24H30O2Na ([M þ Na]þ) 373.2144, obsd 373.2142.
Determination of Configuration and Enantiomeric Excess of
the Hydrovinylation Product 20. To a solution of 20 (48 mg, 0.14
mmol) in THF (4 mL) was added 9-BBN (0.51 mL, 0.5 M, 0.6
mmol) at 0 °C under nitrogen. The mixture was allowed to warm
to room temperature and stirred for 3 h. To the solution were
added 1 mL of 2 M NaOH and 0.4 mL of 30% aqueous H2O2
Acknowledgment. Financial assistance for this research by
NSF (CHE-0610349) and NIH (General Medical Sciences,
R01 GM075107) is gratefully acknowledged.
Supporting Information Available: Spectroscopic and chro-
matographic data for characterization of all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 22, 2010 7643