Diastereoselective addition of zincated hydrazones to alkenylboronates and stereospecific trapping of boron/zinc bimetallic intermediates by carbon electrophiles

Article abstract of DOI:10.1021/ja806258v

Zincated hydrazones possessing a tert-butyl group on the zinc atom undergo addition to (E)- or (Z)-alkenylboronic acid pinacol esters to produce α-alkylated-γ-boryl-γ-zinciohydrazone intermediates with good to excellent diastereoselectivity (ds). The 1,1 -organodimetallic intermediate possessing a boron atom and a zinc atom in the position γ to the hydrazone group undergoes further C-C bond formation with a carbon electrophile to give a γ-boryl hydrazone possessing several contiguous stereogenic centers with up to 99% ds. The (S)-1-amino-2-methoxymethylpyrrolidine hydrazone shows a high level of asymmetric induction in the addition/trapping sequence. Density functional theory calculations on the pathways of the addition reaction revealed a metallo-ene mechanism consisting of the formation of a π complex between a zincated hydrazone and a vinylborane followed by a six-centered bond reorganization of a highly ordered boat conformation transition state. The calculations indicated that the use of the zinc atom together with the imine or hydrazone is the key for the success of the olefinic variant of the aldol reaction that has long been considered not to take place because of the endothermicity of the reaction and has never been examined with any seriousness by chemists. The steric repulsion caused by the bulky tert-butyl ligand on the zinc atom and the pinacol moiety of the vinylboronate substrates in the highly ordered transition structures gives rise to the observed high ds of the present carbozincation reaction.

Full text of DOI:10.1021/ja806258v

Published on Web 10/25/2008
Diastereoselective Addition of Zincated Hydrazones to
Alkenylboronates and Stereospecific Trapping of Boron/Zinc
Bimetallic Intermediates by Carbon Electrophiles
Takuji Hatakeyama,† Masaharu Nakamura,† and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received August 9, 2008; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Abstract: Zincated hydrazones possessing a tert-butyl group on the zinc atom undergo addition to (E)- or
(Z)-alkenylboronic acid pinacol esters to produce R-alkylated-γ-boryl-γ-zinciohydrazone intermediates with
good to excellent diastereoselectivity (ds). The 1,1-organodimetallic intermediate possessing a boron atom
and a zinc atom in the position γ to the hydrazone group undergoes further C-C bond formation with a
carbon electrophile to give a γ-boryl hydrazone possessing several contiguous stereogenic centers with
up to 99% ds. The (S)-1-amino-2-methoxymethylpyrrolidine hydrazone shows a high level of asymmetric
induction in the addition/trapping sequence. Density functional theory calculations on the pathways of the
addition reaction revealed a metallo-ene mechanism consisting of the formation of a π complex between
a zincated hydrazone and a vinylborane followed by a six-centered bond reorganization of a highly ordered
boat conformation transition state. The calculations indicated that the use of the zinc atom together with
the imine or hydrazone is the key for the success of the olefinic variant of the aldol reaction that has long
been considered not to take place because of the endothermicity of the reaction and has never been
examined with any seriousness by chemists. The steric repulsion caused by the bulky tert-butyl ligand on
the zinc atom and the pinacol moiety of the vinylboronate substrates in the highly ordered transition structures
gives rise to the observed high ds of the present carbozincation reaction.
Scheme 1. Addition of Metal Enolates to Carbonyls and Olefins
Introduction
Stereocontrol in the construction of multiple stereogenic
centers has been a central issue of organic synthesis for a long
time, and those in acyclic systems remain a challenge. We
considered over a decade ago that the addition of a metal enolate
to an unactivated olefin might be a potentially powerful method
to achieve stereocontrol of multiple stereogenic centers during
formation of new C-C bonds (Scheme 1, middle). The
γ-metalated carbonyl or imine compounds are the homologues
of metal enolates1 and metal homoenolates (ꢀ-metalated car-
bonyl compounds),2,3 in which we have had a longstanding
interest. Such a reaction, however, did not exist in the literature.
In fact, quantum-mechanical calculations of any kind would
indicate that the addition of the enolate anion of acetone to
ethylene is highly endothermic and will hardly take place. This
reaction is electronically equivalent to the aldol reaction that
has long served as a prototype of acyclic stereocontrol (Scheme
1, top). The olefinic variant (Scheme 1, middle), however, is
potentially much more interesting in that one can use the initial
addition product for possible further C-C bond formation. It
should be noted that such reactions are different both mecha-
nistically and synthetically from Michael addition reactions.
The initial success of our exploration was limited to a strained
olefin4 and intermolecular cyclization,5 but we quickly discov-
ered that these limitations can readily be removed. Thus, we
† Present address: International Research Center for Elements Science,
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(1) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181–187.
(2) (a) Kuwajima, I.; Nakamura, E. J. Am. Chem. Soc. 1977, 99, 7360–
7361. (b) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1983, 105,
651–652. (c) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I.
J. Am. Chem. Soc. 1988, 110, 3296–3298.
(4) Nakamura, E.; Kubota, K. J. Org. Chem. 1997, 62, 792–793.
(5) (a) Nakamura, E.; Sakata, G.; Kubota, K. Tetrahedron Lett. 1998, 39,
2157–2158. (b) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem.
1998, 63, 2442–2450. (c) Karoyan, P.; Chassaing, G. Tetrahedron Lett.
1997, 38, 85–88.
(3) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368–
3370.
9
15688 J. AM. CHEM. SOC. 2008, 130, 15688–15701
10.1021/ja806258v CCC: $40.75
2008 American Chemical Society

Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Scheme 2. Stereocontrolled Construction of Multiple Stereogenic
Centers by an Addition/Trapping Sequence
on the zinc(II) atom, as well as careful control of the trapping
conditions, allowed us to achieve up to 99% diastereoselectivity
(ds) in the coupling of three components overall (Scheme 1,
bottom).
We now present a full account of the diastereoselective
carbometalation of zincated hydrazones to alkenylboronates,
stereoselective trapping of the resulting zinc/boron organodi-
metals, including the construction of the fourth stereogenic
center derived from the electrophile, and application of an
optically active hydrazone for the asymmetric construction of
multiple stereogenic centers. Density functional theory (DFT)
studies of the pathways of the addition reaction indicated a six-
centered boat transition state, which accounts for the sense and
degree of the diastereoselectivity.
Scheme 3. Addition of a Zincated Hydrazone Possessing an Alkyl
Dummy Ligand to (E)- or (Z)-Hexenylboronate
Results and Discussion
Experimental Studies of the Feasibility and Stereoselectiv-
ity of the Reaction. The procedure for sequential three-
component coupling of zincated hydrazones, alkenylboronates,
and electrophiles is outlined in Scheme 2. Treatment of a starting
hydrazone A with 2 equiv of tert-butyllithium10 (t-BuLi; 1 equiv
for deprotonation and 1 equiv as a ligand on the zinc atom)
followed by addition of 1 equiv of anhydrous zinc chloride in
ether produces a zincated hydrazone B.11 Solvent is removed
in vacuo, and then an (E)- or (Z)-alkenylboronate C and hexane
are added. It should be noted that the addition reaction was much
slower without removal of the ether.12 The zincated hydrazone
B adds to the (E)- or (Z)-alkenylboronate C at 0 °C for 12-48
h to give a B/Zn dimetallic species D, which upon electrophilic
trapping gives a γ-borylhydrazone E in good to high overall
yield. To achieve the excellent ds, a careful choice of workup
conditions is mandatory, as hydrolysis of the hydrazone moiety
under strongly acidic workup often resulted in 5-15% epimer-
ization of the R-carbon center. Therefore, we hydrolyzed the
γ-borylhydrazone E with aqueous propionic acid to minimize
the epimerization (1-3% in most cases).
Table 1. Effect of Dummy Ligands on ds and Reactivity
Effect of a Dummy Ligand on the Reactivity and ds of the
Zincated Hydrazone. We first examined the reaction between
hexenylboronates (3E and 3Z) and the N,N-dimethylhydrazone
of 3-pentanone to investigate the effect of a nontransferable
dummy ligand (R) on the zinc atom (Scheme 3). Each of the
zincated hydrazones 2a-2c was prepared by sequential treat-
ment with t-BuLi (1 equiv), anhydrous ZnCl2 (1 equiv), and
the corresponding alkyllithium (1 equiv). The nature of the
dummy ligand showed a significant impact on both the
stereoselectivity and the reaction rate (Table 1). The reaction
of zincated hydrazone 2a bearing a tert-butyl ligand with (E)-
hexenylboronate 3E gave what we call here the syn adduct 4syn
in excess (95.2:4.8) of the alternative anti adduct in 88% yield
(entry 1). On the other hand, the reactions of 2b and 2c with
(E)-hexenylboronate 3E gave the anti adduct 4anti as the major
diastereomer (45.0:55.0 and 32.9:67.1, respectively) in moderate
a Bpin ) 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. b Diastereoselecti-
vities were determined by GC analyses of the crude product. c Isolated
yield. d Yield was determined by 1H NMR spectroscopy. e Zincated
hydrazone 2d was prepared via two steps: (1) deprotonation with t-BuLi
and (2) transmetalation with ZnCl2.
discovered that zincated hydrazones and imines [M1 ) Zn(II)]
readily add to ethylene6 (Y ) H) and vinylmagnesium halide7
(Y ) M2 ) MgBr), and the resulting organozinc intermediates
can be trapped by one- or two-carbon electrophiles.
After considerable experimentation, we found that the addition
of (E)- and (Z)-zincated hydrazones [M1 ) Zn(II)] to (E)- and
(Z)-alkenylboronates8 (Y ) BOR2) takes place with high
stereoselectivity.9 A proper choice of the nontransferable ligand
(10) When we used LDA in THF for deprotonation, the subsequent addition
reaction was very slow. We assume that the diisopropylamine or THF
slowed down the addition reaction through coordination to the zinc
atom.
(6) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997, 36,
2491–2493.
(7) Nakamura, E.; Kubota, K.; Sakata, G. J. Am. Chem. Soc. 1997, 119,
5457–5458.
(11) The X-ray structure of the lithiated hydrazone has been reported (s-
trans, as in SM6 in Figure 8). See: Collum, D. B.; Kahne, D.; Gut,
S. A.; Depue, R. T.; Mohamadi, F.; Wanat, R. A.; Clardy, J.; Duyne,
G. V. J. Am. Chem. Soc. 1984, 106, 4865–4869.
(8) (a) Nakamura, M.; Hara, K.; Hatakeyama, T.; Nakamura, E. Org. Lett.
2001, 3, 3137–3140. (b) Cooke, M. P., Jr. J. Org. Chem. 1994, 59,
2930–2931. (c) Cooke, M. P., Jr.; Widener, R. K. J. Am. Chem. Soc.
1987, 109, 931–933.
(12) The rate of the addition reaction increased in the order THF < Et2O
< hexane. We assume that coordinative solvents prevent π-complex
formation between the zincated hydrazone and alkenylboronates, such
as in CP3 and CP4 in Figure 8.
(9) Preliminary communication: (a) Nakamura, M.; Hatakeyama, T.; Hara,
K.; Fukudome, H.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 14344–
14345.
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A R T I C L E S
Hatakeyama et al.
Table 3. Stereoselective Addition of Cyclic Substrates
Table 2. Diastereoselective Addition of Zincated Hydrazones to
(E)- or (Z)-Alkenylboronates
a Addition reactions were carried out in hexane at room temperature
(entry 1) or 0 °C (entries 2-4) for 48 h. b Zincated hydrazones 17, 19,
and 21 were prepared as in Scheme 2. c The reactions used 1.25 equiv
of 17, 19, or 21. d Isolated yield. e Diastereoselectivity was determined
by GC analyses of the crude product. f Diastereoselectivity was
determined from the 1H NMR spectrum of the crude product.
also described). We found that the N-alkyl- and N-arylimines
used in our earlier studies13 are less effective in the present
reaction. We consider the zincated acyclic hydrazone 2 to be a
(Z)-isomer in light of the stereochemistry of the addition of the
zincated cyclic hydrazones, which is discussed later (see
Theoretical Studies).
Diastereoselective Addition of Zincated Hydrazones to
Alkenylboronates. Having established the conditions for the
highly diastereoselective addition of zincated hydrazone 2a, we
studied the substrate scope on both the alkenylboronates and
hydrazone substrates. Table 2 summarizes the results of the
addition reactions of various acyclic zincated hydrazones with
alkenylboronates. The reaction of 2a with (E)-styrylboronate
5E [99.6% (E)] gave syn adduct 6syn in 92% yield with 97.5%
ds (entry 1). Zincated hydrazone 7 prepared from 1-cyclohexy-
lpropan-1-one N,N-hydrazone reacted with (E)-propenylboronate
8E [99.3% (E)] to give syn adduct 10syn, which possesses two
stereogenic centers, in 93% yield with 99.2% ds (entry 2). Also,
the reactions of 7 with (E)-octenylboronate 9E and (E)-
styrylboronate 5E proceeded with 99.5 and 99.6% ds, respec-
tively (entries 3 and 4). The reaction of 7 with (Z)-propenyl-
boronate 8Z [99.1% (Z)] gave an alternative anti diastereomer
10anti as the major product (82% ds, entry 5). Zincated
hydrazone 13 prepared from 2-methylheptan-3-one reacted with
8E and 8Z to give adducts 14syn (99.2% ds) and 14anti (92.5%
ds), respectively (entries 6 and 7). The reactions of zincated
a Addition reactions were carried out in hexane at 0 °C for 12-48 h.
b Zincated hydrazones 2a, 7, and 13 were prepared as in Scheme 2, and
zincated hydrazone 15 was prepared as in Scheme 3. c The reactions
used 1.05 equiv of 2a or 7 or 1.25 equiv of 13 or 15. d Bpin )
4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. e Isolated yield. f Diastereosele-
ctivities were determined by GC analyses of the crude product. g Yield
was determined by 1H NMR spectroscopy.
yields (entries 2 and 3). Without any alkyl dummy ligand (i.e.,
ligand ) Cl), the reaction did not take place at all (entry 4). As
shown in entries 5-7, the reactions of 2a-2c with (Z)-
hexenylboronate 3Z proceeded smoothly to give the anti adduct
4anti as the major diastereomer. The zincated hydrazone 2a
showed slightly higher ds (25.6:74.4) than 2b and 2c (33.8:
66.2 and 28.0:72.0, respectively). The relative stereochemistry
of 4 was determined by X-ray and NMR analyses of the isolated
compounds, as described in the Supporting Information (the
stereochemical assignment of other products in Tables 2-4 is
(13) (a) Nakamura, M.; Hatakeyama, T.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 11820–11825. (b) Nakamura, M.; Hatakeyama, T.; Hara,
K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 6362–6363.
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Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Table 4. Stereoselective Synthesis of γ-Boryl Hydrazones E via
the Addition/Trapping Sequence
18syn with 98.5% ds (entry 2). Six- and eight-membered-ring
substrates 19 and 21 gave the corresponding products 20syn and
22syn with comparable chemical yields and selectivities (entries
3 and 4). The inversion of the ds between the acyclic (2a, 7,
13, and 15) and cyclic (17, 19, and 21) hydrazones strongly
suggests that the addition reactions of the acyclic hydrazones
proceed from (Z)-isomers. The observed ds can be explained
with the six-centered boat transition state (TS) model obtained
from DFT calculations as described later.
Stereoselective Trapping of the Zn/B Organodimetals. When
the addition of a zincated hydrazone to (E)- and (Z)-alkenyl-
boronates is stereospecific and the stereogenic center bearing
zinc and boron is configurationally stable, we should be able to
create additional contiguous stereogenic centers by trapping the
B/Zn intermediate D with a carbon electrophile, as shown in
Scheme 4. The reaction of 7 and 8E followed by treatment with
allyl bromide (2.4 equiv) in the presence of CuCl (1 equiv) in
Et2O gave γ-borylhydrazone 23 in 86% yield with an overall
ds of 99.2% (Table 4, entry 1). When THF was used as the
solvent, the stereoselectivity dropped to 71.5% because of
epimerization of the carbon center to which the Zn and B atoms
are bonded. The stereochemistry of the third stereogenic center,
along with the syn-addition nature of the first carbozincation,
indicates that the electrophilic trapping occurred with overall
retention of the stereochemistry of the B/Zn organodimetals (see
below). This addition/trapping sequence starting from substrate
13 gave the corresponding adduct 24 with >99% ds (entry 2).14
The B/Zn intermediate D undergoes epimerization at the
dimetalated stereogenic carbon center under these reaction
conditions. The production of compounds possessing the same
relative stereochemistry (i.e., 23 and 25) starting from either
(E)- or (Z)-alkenylboronate (entries 1 and 3) must be the
consequence of such stereomutation of the dimetallic stereo-
center. On the basis of the observed reduction in the ds in THF
(entries 1, 3, and 4), we assume that the configuration of the
B/Zn stereocenters is controlled by the conformation of the six-
membered chelate structure of the product D (Figure 1).
Trapping of the B/Zn intermediate D produced by the reaction
of 15 and 3E gave adduct 26 possessing the same stereochem-
istry as 23, 24, and 25 (97.6% ds, entry 4). On the other hand,
the reaction of 15 and 3Z followed by trapping with allyl
bromide in Et2O gave mainly the other diastereomer 26′ with
63.3% ds (entry 5). As shown in Figure 1, the B/Zn intermediate
D might favor the anti configuration at the ꢀ- and γ-carbons
because of the conformational stability of the six-centered
chelate structure, in which the boryl group and the substituent
on the ꢀ-carbon of the anti configuration can occupy the less-
hindered equatorial positions. Interestingly, trapping of the
intermediate D prepared from 15 and 3Z in THF gave the adduct
26′ with a better ds of 83.0%.
a Addition reactions were carried out in hexane at 0 °C for 12-48 h.
b Zincated hydrazones 7 and 17 were prepared as in Scheme 2, and
zincated hydrazone 15 was prepared as in Scheme 3. c The reactions
used 1.05 equiv of 7 or 13 or 1.25 equiv of 15 or 17. d Bpin )
4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. e Electrophilic trapping was
carried out in Et2O with 1-2 equiv of CuCl and 2-4 equiv of
electrophile. f Solvent in the trapping step. g Isolated yield.
h Diastereoselectivities were determined by GC analyses of the crude
product. i The yields were determined by 1H NMR spectroscopy using
pyridine as the internal standard. j This number refers to the percentage
of the major isomer over all others as determined by 1H NMR
spectroscopy.
The three-component coupling protocol can create four
stereogenic centers in a highly stereocontrolled fashion. Thus,
the B/Zn intermediate D produced by the reaction of 7 and 8E
underwent 1,4-addition with 2-cyclohexen-1-one in the presence
of Me3SiCl3 and CuCl to produce the three-component coupling
product 27 in 69% overall yield with >95% overall ds (entry
6). We can understand the stereochemistry of the 1,4-addition
in terms of the reported TS of the conjugate addition of an
organocopper compound to cyclohexenone15 (Figure 2).
hydrazone 15 derived from an aryl alkyl ketone proceeded in a
similar manner: the reactions with 3E and 3Z gave syn adduct
16syn (98.0% ds) and anti adduct 16anti (95.2% ds), respectively
(entries 8 and 9).
Addition of Zincated Cyclic Hydrazones to Alkenylboronates.
The reactions of cyclic hydrazone substrates and (E)- and (Z)-
alkenylboronates are shown in Table 3. The reaction of
cycloheptanone hydrazone 17 with (E)-propenylboronate 8E
gave anti adduct 18anti with 81% ds at room temperature (entry
1). On the other hand, the reaction with (Z)-propenylboronate
8Z was much faster (even at 0 °C) and gave the syn diastereomer
(14) (a) Hupe, E.; Calaza, M. I.; Knochel, P. Chem.sEur. J. 2003, 9, 2789–
2796. (b) Boudier, A.; Knochel, P. Tetrahedron Lett. 1999, 40, 687–
690.
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Scheme 4. Stereocontrolled Trapping of the B/Zn Organodimetal D with Carbon Electrophiles
Asymmetric Construction of Three Contiguous Stereogenic
Centers. We examined the asymmetric version of the three-
component coupling using optically active (S)-1-amino-2-
methoxymethylpyrrolidine (SAMP) hydrazone16 28. The cor-
responding chiral zincated hydrazone 29 was prepared accordingly
and allowed to react with 3E at room temperature for 72 h.
Successive trapping with allyl bromide gave adduct 30 in 63%
yield with 95% overall ds (>99% ds, >99% ee after recrys-
tallization) (eq 1). The stereochemistry of the product was
group can be reduced stereoselectively with BH3 ·THF. The Bpin
group was converted stereospecifically to a hydroxy group (the
terminal double bond was hydrogenated before the reduction
to avoid hydroboration). The diol 32 was obtained with 85%
ds, with other minor diastereomers accounting for the rest.
Esterification of the diol and recrystallization gave diester 33
with 99% ds (eq 2), and the stereochemistry was assigned by
X-ray crystallography.
determined by X-ray crystallography. It is noteworthy that the
absolute configuration of the R-carbon is opposite to that of
the R-carbon in the products obtained by the alkylation reaction
of lithiated SAMP hydrazones with alkyl halides.17
Hydrolysis of the Hydrazone and Oxidative Cleavage of the
Bpin Group. γ-Borylhydrazones such as 25 can be used for
further synthetic transformations in a stereoselective manner.
Hydrolysis of the hydrazone moiety can be achieved readily
(albeit with slightly less stereochemical control), and the ketone
Theoretical Studies of the Addition of Zincated Hydra-
zones to Alkenylboronates. To gain mechanistic insights into
the origin of the high diastereoselectivities, we conducted a
series of theoretical/computational studies of the addition of zinc
Figure 1. Conformational stability of the organozinc intermediate.
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Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Figure 2. A possible transition structure for the 1,4-addition of B/Zn dimetallic species.
Figure 3. Energy profiles for the isomerization of the zinc enamides and their isomers. Relative free energies (∆G, kcal/mol) with respect to SM2 are
shown in parentheses.
enamides and zincated hydrazones to alkenylboronates (or
ethylene). Details of the theoretical methods are described in
the Experimental Section. We first examined the structure of a
zincated N-methylenamide of acetone and its addition to
ethylene (eq 3) as a simplified model at the B3LYP/631A level.
3.5 kcal/mol lower in free energy than SM1. The TS of the
rotation TS1 (C2-C1-N-Zn dihedral angle ) 94.3°, C2-Zn
distance ) 3.682 Å) lies 9.8 kcal/mol above SM1.
The R-metallo imines SM3 and SM4 are geometrical isomers
with respect to the C1-N double bond and interconvert with
each other through SM1 and SM2. In the (E)-isomer SM3, the
nitrogen atom is coordinated to the zinc atom (N-Zn distance
) 2.398 Å). In SM4, which is 4.6 kcal/mol higher in free
energy, there is no such coordination, and the C-Zn bond is
perpendicular to the imine plane, as previously found in the
crystal structure of a dimeric Reformatsky reagent.18 TS2, the
TS separating SM3 and SM1, has an aza-π-allyl zinc structure,
in which the N-Zn (1.976 Å) and C1-Zn (2.334 Å) bond
lengths are intermediate between those of SM1 and SM3; this
is also true of TS3 (N-Zn and C1-Zn distances of 2.133 and
2.422 Å, respectively). The energy barriers separating
SM1-SM4 are low enough to suggest that all of them may
also be in equilibrium with each other under the reaction
conditions (hexane as solvent). However, we were able to locate
reaction pathways for the addition to ethylene only for the zinc
enamides SM1 and SM2.
Addition of Acetone Imine to Ethylene. We located a single
reaction pathway each for SM1 and SM2 that takes place via
a metallo-ene-type [4 + 2] TS,19 as shown in Figures 5 and 6,
respectively (Paths A and B). The mechanism is similar to the
one discussed in the aldol reaction except for the important point
that the boat TS (Path A) is favored over the half-chair TS (Path
B). In both paths, the zinc enamide and ethylene first form a π
complex, which then goes through a metallo-ene-type TS on
Structural Analysis of Zincated Imines. We found as station-
ary points four equilibrium structures arising from tautomerism
and geometric isomerism of the C-N double bond: zinc
enamides SM1 and SM2 and R-zincio imines SM3 and SM4.
SM1 isomerizes to SM2 via TS1 (Figure 3, Path 1; numbers in
parentheses represent free energies relative to SM2). SM1
isomerizes to SM3 via TS2 (Path 2). SM2 isomerizes to SM4
via TS3 (Path 3). These structures have free-energy differences
of at most 23.4 kcal/mol.
The structures are shown in Figure 4. The zinc enamides SM1
and SM2 are conformational isomers with respect to rotation
around the C1-N bond. SM1 is an s-cis conformer
(C2-C1-N-Zn dihedral angle ) 27.8°, C2-Zn distance )
3.033 Å), and SM2 is an s-trans conformer (C2-C1-N-Zn
dihedral angle ) 180.0°, C2-Zn distance ) 4.155 Å) that is
(15) (a) Yamanaka, Y.; Nakamura, E. Organometallics 2001, 20, 5675–
5681. (b) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc.
1997, 119, 4900–4910.
(16) (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253–2329. (b) Enders, D.; Wortmann, L.;
Peters, R. Acc. Chem. Res. 2000, 33, 157–169.
(18) Dekker, J.; Budzelaar, P. H. M.; Boersma, J.; Van der Kerk, G. J. M.;
(17) Enders, D. Chem. Scr. 1985, 25, 139–147.
Spek, A. J. Organometallics 1984, 3, 1403–1407.
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Hatakeyama et al.
Figure 4. Isomerization pathway for the starting zinc enamide, as obtained from DFT calculations (B3LYP/631A). Free-energy changes (kcal/mol) and
bond lengths (Å) are given. Relative free energies (∆G, kcal/mol) with respect to SM2 are shown in parentheses.
Figure 5. Energy profiles for the reaction pathways for addition of a zinc enamide to ethylene (B3LYP/631A). Relative free energies (∆G, kcal/mol) with
respect to SM2 + ethylene are shown in parentheses.
its way to the product, in which zinc is covalently bonded in
hand and coordinated to the imine group.
of 1.335 Å in ethylene)]. Formation of the C-C and C-Zn
bonds in the next state takes place synchronously via TS4 with
a very low free energy of activation (∆Gq ) 10.8 kcal/mol) to
form a nitrogen-chelated γ-zincio imine PD1 with a stabilization
energy of 27.6 kcal/mol.
In Path A, SM1 interacts with ethylene to form a π complex
CP1, which is 9.1 kcal/mol higher in free energy than SM1 +
ethylene because of the entropy contribution.20The geometrical
parameters indicate only a weak electrostatic interaction between
the zinc center and the ethylene π electrons [N-Zn-Me angle
) 169.2°, C3-Zn distance ) 3.178 Å, C4-Zn distance ) 3.078
Å, C3-C4 distance ) 1.339 Å (compare to the CdC distance
TS4 is a six-centered boat transition state. The zinc enamide
moiety still retains the original s-cis structure (C2-C1-N-Zn
dihedral angle ) 22.0°). The C2-C3 and C4-Zn bond lengths
indicate synchronous formation of these bonds, although the
latter may be slightly more advanced. The imine in the product
PD1 is an (E)-imine, which was found in the product obtained
after hydrolysis in the experiments (see above). The overall
process of converting SM1 and ethylene to PD1 is exothermic
(∆G ) -4.2 kcal/mol).
(19) (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000,
122, 11791–11798. (b) Hirai, A.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 1999, 121, 8665–8666. (c) Marek, I.; Schreiner, P. R.;
Normant, J. F. Org. Lett. 1999, 1, 929–931. (d) Endo, K.; Hatakeyama,
T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264–
5271.
In Path B, CP2 is 6.8 kcal/mol higher in free energy than
(20) CP1 is 1.8 kcal/mol lower in total electronic energy than SM1 +
ethylene.
SM2 + ethylene.21 The C-C and C-Zn bonds form via TS5,
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Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Figure 6. Reaction pathways for addition of a zinc enamide to ethylene, as obtained from DFT calculations (B3LYP/631A). Free-energy changes (kcal/
mol) and bond lengths (Å) are given. Relative free energies (∆G, kcal/mol) with respect to SM2 + ethylene are shown in parentheses.
Figure 7. Natural localized molecular orbitals (NLMOs) of TS4 (4a, LMO45; 4b, LMO46; 4c, LMO47) and TS5 (5a, LMO46′; 5b, LMO47′; 5c, LMO45′).
Nucleus-independent chemical shifts (NICS) values are shown in brackets at the left. Points labeled Cp are the center points of the [4 + 2] transition
structures.
with a free energy of activation ∆Gq ) 22.5 kcal/mol, followed
by formation of the γ-zincio imine PD2 with a stabilization
energy of 27.4 kcal/mol. TS5 represents a half-chair conformer
because of the s-trans conformation of the starting zinc enamide
SM2. The C2-C1-N-Zn dihedral angle (106.0°) in TS5 is
larger than that in TS4, reflecting this conformation of SM2.
The C2-C3 bond (2.240 Å) and the C4-Zn bond (2.262 Å) are
much shorter than those in TS4, indicating that TS5 is reached
later than TS4, which reflects the much higher free energy of
activation for Path B than for Path A.
C1dN double bond; as a result, the reaction is endothermic (∆G
) 1.9 kcal/mol). Upon consideration of the whole scheme, TS5
in Path B is 5.9 kcal/mol higher in free energy than TS4 in
Path A. We therefore conclude that the reaction takes place via
Path A. The following analysis of the diastereoselectivities of
the reactions is entirely consistent with this conclusion.
Two types of theoretical analysis were carried out to
characterize the transition structures of the reaction: aromaticity
analysis and orbital analysis. The aromaticity of the metallo-
ene transition structures TS4 and TS5 was examined using
GIAO calculations22 at the B3LYP/631A level (Figure 7, left).
Negative nucleus-independent chemical shift (NICS)23 values
(-10.13 and -17.32 for TS4 and TS5, respectively) were
Path B produces a (Z)-imine, which does not agree with the
experimental facts. In addition, the (Z)-geometry of the C1dN
double bond forces the zinc atom to be π-coordinated to the
(21) CP2 is 1.1 kcal/mol lower in total electronic energy than SM2 +
(22) Wolinski, K.; Hilton, J. F.; Pulay, P. J. J. Am. Chem. Soc. 1990, 112,
ethylene.
8251–8260.
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Figure 8. Reaction pathways for the addition of a zincated hydrazone to a vinylboronate, as obtained from DFT calculations (B3LYP/631A). Relative free
energies (∆G, kcal/mol) with respect to SM6 + vinylboronate are shown in parentheses.
obtained at the center points (labeled as Cp in Figure 7) of the
six heavy atoms included in the bond reorganization. These
values are larger than those obtained likewise for the other
stationary points on each reaction pathway (CP1, CP2, PD1,
and PD2). This trend follows those found for pericyclic reactions
in general, such as ene reactions,23b 1,3-dipolar cycloadditions,24
and Diels-Alder reactions.25
Addition of Acetone Hydrazone to Vinylboronate. We next
used the same B3LYP/631A theoretical model to examine a
more realistic case: the addition of the enolate form of a zincated
acetone hydrazone to a vinylboronate (eq 4). As in the enamide
Natural localized molecular orbital (NLMO) analysis26 using
the SCF Kohn-Sham orbitals of TS4 and TS5 provides insight
into the molecular-orbital interactions between the zinc enamide
and ethylene (Figure 7, right).27 The in-phase orbital overlaps
of the forming C-Zn and C-C bonds, respectively, are found
in LMO45 (4a) and LMO46 (4b) for the boat TS4 and in
LMO46′ (5a) and LMO47′ (5b) for TS5. The LMOs 4a and
5a, consisting of the π orbital of ethylene and the zinc 4p orbital,
are related to the C4-Zn bond formation. The π* orbital of
ethylene and the π orbital of zinc enamide compose the LMOs
4b and 5b, which are responsible for the formation of the C2-C3
bond.
case, we located two types of pathway, one going through an
energetically favorable boat TS (Paths C and D) and the other
through an unfavorable half-chair TS (Paths E and F); in each
case, the two paths involve diastereomers of similar energies
arising because of the presence of the boryl group (Figure 8).
The pathways involve the π complexes CP3-CP6 and the six-
centered TSs TS6-TS9 and lead to the γ-zincio hydrazones
PD3-PD6.
The two zincated hydrazones SM5 (s-cis) and SM6 (s-trans)
are conformational isomers, separated from each other by TS10,
the TS for rotation around the C1-N bond (∆Gq ) 11.2 kcal/
mol, which is much smaller than the free energy of activation
for the addition reaction, ∆Gq ) 19.5 kcal/mol). SM5 and SM6
each interact with the vinylboronate to form two diastereomeric
π complexes (CP3 and CP4 from SM5, CP5 and CP6 from
SM6).
Whereas these orbital interactions are found equally in TS4
and TS5, a striking difference is found in an in-phase secondary
orbital interaction in LMO47 (4c), consisting of the nitrogen
2p orbital, the zinc 4s-4p hybrid orbital, and the forming C-C
σ orbital. This orbital interaction is not found in TS5. Although
the quantitative discussion of a secondary orbital interaction is
always a matter of controversy, we think that this secondary
orbital interaction in TS4 may be a reason for the stability of
TS4 with respect to TS5.
Transition structures are shown in Figure 9. TS6 and TS7
are the boat conformers. The six-centered core structures
resemble each other and TS4 and TS5 of the zincated enamide.
The boryl group of TS6 occupies an axial position and that of
TS7 an equatorial position, yet the free-energy difference in
this simplest model is negligibly small (∆G ) 0.2 kcal/mol).
TS8 and TS9 are half-chair conformers. They are much less
stable than TS6 and TS7 (by over 8.0 kcal/mol) and represent
a later transition state, as was found previously for the zincated
enamide counterparts. The lengths of the cleaving double bond
C3-C4 (1.409 Å in TS8 and 1.408 Å in TS9 vs 1.390 Å in
TS6 and 1.389 Å in TS7) also suggest the advanced nature
of TS8 and TS9. The boryl group occupies an axial position in
TS8 and an equatorial position in TS9. TS8 is less stable than
TS9 by only a small amount (∆G ) 0.4 kcal/mol).
(23) (a) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes,
N. J. R. v. E. J. Am. Chem. Soc. 1996, 118, 6317–6318. (b) Chen, Z.;
Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R. Chem.
ReV. 2005, 105, 3842–3888.
(24) Coss´io, F. P.; Morao, I.; Jiao, H.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1999, 121, 6737–6746.
(25) Jiao, H.; Schleyer, P. v. R. J. Phys. Org. Chem. 1998, 11, 655–662.
(26) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1995, 83, 1739–1740.
(27) For MO analyses of organozinc reactions using localized molecular
orbital (LMO) and natural bond orbital (NBO) methods, see: (a) Mori,
S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56,
2804. (b) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem.
Soc. 2002, 124, 7181–7192. (c) Hratchian, H. P.; Chowdhury, S. K.;
Gutie´rrez-Garc´ıa, V. M.; Amarasinghe, K. K. D.; Heeg, M. J.; Schlegel,
H. B.; Montgomery, J. Organometallics 2004, 23, 4636–4646.
The products PD3 and PD4 have an (E) C1dN double bond,
in which the sp2 nitrogen lone pair coordinates to the zinc atom.
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Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Figure 9. Transition structures TS6-TS9 obtained from DFT calculations (B3LYP/631A). Relative free energies (∆G, kcal/mol) with respect to SM6 +
vinylboronate are shown in parentheses. Bond lengths (Å) are also given.
In PD5 and PD6, which possess a (Z) C1dN double bond, the
zinc atom is p-coordinated to the imine group. These products
are less stable than PD3 and PD4 (∆G ) 4.9-7.9 kcal/mol).
Detailed structural parameters for the stationary points are
reported in the Supporting Information.
Analysis of Diastereoselectivity. With the conclusion that the
boat transition state is overwhelmingly favored in the present
reactions, we studied a series of additions of zincated hydrazones
to (E)- and (Z)-propenylboronates via such boat transition states,
to examine the origin of the high experimental diastereoselec-
tivities.
We first studied three chemical models: the addition reactions
of an (E)-propenylboronate with the zincated hydrazones derived
from 3-pentanone N,N-dimethylhydrazone that possess methyl
and tert-butyl groups on the zinc atom (denoted here as models
1 and 2, respectively) and with the one derived from 2-methyl-
3-pentanone N,N-dimethylhydrazone that possesses a tert-butyl
group on the zinc atom (denoted here as model 3). All of the
diastereomeric transition structures of the boat conformation
were fully optimized for these model reactions, and their relative
electronic energies (∆E) were compared.
Model 1 serves as a model for the addition to (E)-hexenyl-
boronate of the zincated hydrazone derived from a 3-pentanone
N,N-dimethylhydrazone that possesses a butyl group on the zinc
atom (denoted here as exp-1), which gave the anti adduct as
the major diastereomer (syn:anti ) 32.9:67.1, as shown in entry
3 of Table 1). Model 2 serves as a model for the addition to
(E)-hexenylboronate of the zincated hydrazone derived from a
3-pentanone N,N-dimethylhydrazone that possesses a tert-butyl
group on the zinc atom (denoted here as exp-2), which gave
the syn adduct as the major diastereomer (syn:anti ) 95.2:4.8,
as shown in entry 1 of Table 1). Model 3 serves as a model for
the addition to (E)-propenylboronate of the zincated hydrazone
derived from a 1-cyclohexylpropan-1-one N,N-dimethylhydra-
zone possessing a tert-butyl group on the zinc atom (denoted
here as exp-3), which gave the syn adduct as the major
diastereomer (syn:anti ) 99.2:0.8, as shown in entry 2 of Table
2).
and found that the relative energies are in very good agreement
with each other. We also carried out polarizable continuum
model (PCM) calculations on model 2 and found that the relative
stabilities (∆E) of each TS in the solvent (heptane) differ from
those in the gas phase by less than 0.15 kcal/mol.28 As shown
in Figure 10, four isomeric transition structures of the boat
conformation were obtained for each model (TSA1-TSD1 for
model 1, TSA2-TSD2 for model 2, and TSA3-TSD3 for
model 3).
TSB1 is the most stable transition structure for model 1 and
lies 0.16 kcal/mol lower in electronic energy (this ∆E corre-
sponding to a syn:anti ratio of 42.7:57.3 at 273 K) than the
second most stable structure (TSD1). The small energy differ-
ence agrees with the poor selectivity (syn:anti ) 32.9:67.1)
observed in exp-1. TSA2 is the most stable transition structure
for model 2. The second most stable structure (TSC2) is ∆E )
1.38 kcal/mol higher in electronic energy than TSA2. TSB2
and TSD2 are even higher in energy because of the steric
repulsion between the tert-butyl group on the zinc atom and
the pinacol moiety of the boryl group, which occupies an
equatorial position. The relative energies (corresponding to a
syn:anti ratio of 92.7:7.3 at 273 K) agree with the high
diastereoselectivity obtained in the real system (syn:anti ) 95.2:
4.8).
For model 3, TSA3 is the most stable, lying 3.64 kcal/mol
lower in energy than the next most stable structure (TSC3).
The low stability of TSC3 is attributed to the additional steric
repulsion between the isopropyl group and the methyl group
on the enamide terminal. Accordingly, TSB3 and TSD3 are
much higher in energy than TSA3 and TSC3 because of the
steric repulsion between the isopropyl group and the methyl
group on the boronate group. The relative electron energies
(which yield a syn:anti ratio of 99.9:0.1 at 273 K) agree very
well with the selectivity obtained in exp-3 (syn:anti ) 99.2:
0.8).
Overall, the computational results gave full support to the
beneficial use of a tert-butyl group on the zinc atom and the
effects of bulky substituents on the ketone skeleton. Such effects
of the substituents on the metal and the substrates parallel the
The calculations on models 1 and 2 were performed at the
B3LYP/631A level, while calculations on models 2 and 3 were
performed at the B3LYP/631A//2 L-ONIOM level. To check
the results obtained by the B3LYP/631A//2 L-ONIOM method,
we performed the calculations on model 2 using both methods
(28) We used the heptane polarity for the PCM calculation. The relative
energies of TSA2-TSD2 obtained from the PCM calculation (B3LYP/
631A) are 0, 2.37, 1.38, and 2.76 kcal/mol, respectively.
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Figure 10. Transition structures for the addition of zincated hydrazones to an (E)-propenylboronate, as obtained from calculations at the B3LYP/631A and
B3LYP/631A//2 L-ONIOM levels. Relative electronic energies (∆E, kcal/mol) from the B3LYP/631A and B3LYP/631A//2 L-ONIOM methods are shown
without and in parentheses, respectively. Diastereoselectivities calculated from the ∆E values at T ) 273 K are shown in bold and those obtained experimentally
in italics. The green squares in the model 2 and model 3 structures show the boundaries between the first and second layers used in the two-layered ONIOM
calculations.
Figure 11. Transition structures for the addition of the zincated hydrazone derived from 2-methyl-3-pentanone to (Z)-propenylboronate, as obtained from
calculations at the B3LYP/631A//2 L-ONIOM level. Relative electronic energies (∆E, kcal/mol) are shown in parentheses. Diastereoselectivities calculated
from the ∆E values at 273 K are shown in bold and those obtained experimentally in italics. The green square in the model 4 structure shows the boundary
between the first and second layers used in the two-layered ONIOM calculations.
substituent effects known for the aldol reaction, except for the
fundamental difference that the present reaction prefers boat
transition states instead of chair transition states.
We then studied (at the B3LYP/631A//2 L-ONIOM level)
the addition reaction between (Z)-propenylboronate and the
zincated hydrazone derived from a 2-methyl-3-pentanone N,N-
dimethylhydrazone possessing a tert-butyl group on the zinc
atom (denoted here as model 4). Model 4 serves as a model for
the addition to (Z)-propenylboronate of the zincated hydrazone
derived from a 1-cyclohexylpropan-1-one N,N-dimethylhydra-
zone possessing a tert-butyl group on the zinc atom (denoted
here as exp-4). As shown in Figure 11, the relative electronic
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Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
Figure 12. Transition structures for the addition of the zincated hydrazone derived from cycloheptanone to (E)- and (Z)-propenylboronate, as obtained from
calculations at the B3LYP/631A//2 L-ONIOM level. Relative electronic energies (∆E, kcal/mol) are shown in parentheses. Diastereoselectivities calculated
from the ∆E values at 298 K for model 5 and 273 K for model 6 are shown in bold and those obtained experimentally in italics. The green squares in the
models show the boundaries between the first and second layers used in the two-layered ONIOM calculations.
energies ∆E and corresponding calculated syn:anti ratios agree
with the modest selectivity observed in exp-4 (syn:anti ) 18.0:
82.0, as shown in entry 5 of Table 2). The favored transition
structure TSA4 is only 0.78 kcal/mol lower in electronic energy
than TSB4 because of the steric repulsion between the isopropyl
group and the methyl group on the boronate.
intermediate. The carbometalation/trapping sequence achieved
the three-component coupling of a zincated hydrazone, an
alkenylboronate, and an electrophile, producing a γ-boryl
hydrazone with contiguous stereogenic centers. The ds may
exceed 99%. The γ-boryl hydrazones obtained by the multi-
component coupling are amenable to further synthetic elabora-
tions, which would allow introduction of a variety of functional
groups or additional stereogenic centers in a stereoselective
fashion. In addition, the SAMP hydrazone shows a high level
of asymmetric induction without loss of diastereomeric control
in the addition/trapping sequence. We expect that the present
method will be useful for the synthesis of optically active
molecules possessing multiple stereogenic centers.
Through extensive computational and theoretical analyses,
we have elucidated the reaction pathways of the present reaction;
they feature the boat transition state as well as the origin of
such a preference. Most importantly, the calculations indicated
that the use of the zinc atom together with the imine or
hydrazone has effectively lowered the activation energy and
made the overall reaction exothermic and that this combination
is the key to the success of the olefinic variant of the aldol
reaction, which has long been considered not to take place
because of the endothermicity of the reaction and has never
been examined with any seriousness by chemists.
The high diastereoselectivity is the result of the mutual face
selection between the nucleophilic sp2 carbon and electrophilic
sp2 carbon dictated by the steric repulsion between the tert-
butyl group on zinc and the pinacol moiety. Without any
sterically hindered substituents, there would appear to be little
selectivity. This is also true for the aldol reaction between a
simple ketone enolate and a simple aldehyde. The mechanistic
information described above will increase the reliability of the
new synthetic strategy, which features stereocontrolled C-C
bond formation by means of stereospecific olefin carbometala-
tion reactions of metal enolates and their congeners.
We also carried out B3LYP/631A//2 L-ONIOM calculations
on the addition of the zincated hydrazone of cycloheptanone
N,N-dimethylhydrazone to (E)- and (Z)-propenylboronate (mod-
els 5 and 6, respectively). Two transition structures were located
for each model reaction (Figure 12). TSD5 is 1.67 kcal/mol
higher in electronic energy than TSC5 because of the steric
repulsion between the tert-butyl group and the pinacol moiety
of the boryl group. TSD6 is 2.02 kcal/mol higher in electronic
energy than TSC6 for the same reason. The larger energy
difference between TSC6 and TSD6 than between TSC5 and
TSD5 may be attributed to the steric repulsion between the
methyl group on the boronate and the hydrazone side chain in
TSD5 and TSC5. The relative energies yield syn:anti ratios that
agree well with the selectivities obtained experimentally (syn:
anti ) 19.0:81.0 for model 5 and syn:anti ) 98.5:1.5 for model
6, as shown in entries 1 and 2, respectively, of Table 3).
The mechanistic studies showed that the high diastereose-
lectivity with respect to CR atom and Cꢀ arises from the steric
repulsion between the tert-butyl group on zinc and the pinacol
moiety of the alkenylboronate in the six-centered boat transition
structure. (E)- and (Z)-Alkenylboronates accordingly show the
opposite selectivity. The cyclic zinc enamides (or zincated
hydrazones) are by definition (E)-isomers, and the opposite
selectivity observed for the acyclic substrates suggests that the
acyclic zincated enamides are (Z)-isomers.
Conclusions
Zincated hydrazones possessing a tert-butyl dummy ligand
on the zinc atom reacted with (E)- and (Z)-alkenylboronates
with high diastereoselectivities in a stereospecific manner. The
B/Zn organodimetallic intermediates produced by the aza-zincio-
ene reaction were trapped in high yields by various carbon
electrophiles in a stereoselective manner. The latter selectivity
largely reflected the stereochemistry of the C-Zn bond in the
Experimental Section
General. All of the reactions dealing with air- or moisture-
sensitive compounds were carried out in a dry reaction vessel under
a positive pressure of argon or nitrogen. Air- and moisture-sensitive
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liquids and solutions were transferred via syringe or stainless-steel
cannula. Analytical thin-layer chromatography was performed on
glass plates coated with 0.25 mm, 230-400 mesh silica gel
containing a fluorescent indicator (Merck, no. 1.05715.0009). Thin-
layer chromatography plates were visualized by exposure to
ultraviolet light (254 nm) and/or by immersion in an acidic staining
solution of p-anisaldehyde followed by heating on a hot plate.
Organic solutions were concentrated by rotary evaporation at ∼30
mmHg. Flash column chromatography was performed on Kanto
silica gel 60 (spherical, neutral, 140-325 mesh, pretreated with
N,N-dimethylaniline for purification of hydrazones) as described
by Still et al.29
Computational Methods. All of the calculations were performed
with the Gaussian 03 package.30 The DFT method was employed
using the B3LYP hybrid functional.31 Structures were optimized
with a basis set (denoted here as 631A) consisting of Ahlrichs’
SVP all-electron basis set32 for the zinc atom and the 6-31G* basis
set33 for other atoms. In some reactions, geometry optimizations
were performed using the two-layered ONIOM method (first layer,
B3LYP/631A; second layer, HF/3-21G), and then energies were
reevaluated by a single-point calculation with B3LYP/631A (this
method is denoted here as B3LYP/631A//2 L-ONIOM). Each
stationary point was adequately characterized by normal-coordinate
analysis (no imaginary frequencies for an equilibrium structure and
one imaginary frequency for a transition structure) using the same
method as for the geometry optimization. Intrinsic reaction
coordinate (IRC) analyses34 were carried out throughout the reaction
pathways using the same method as for the geometry optimization
in order to confirm that all of the stationary points were smoothly
connected to each other. NICS values were evaluated by using the
gauge-invariant atomic orbital (GIAO) approach with B3LYP/631A
(denoted here as GIAO-B3LYP/631A).
Solvents. Anhydrous diethyl ether (Et2O) and hexane were
purchased from Kanto Chemical Co. and degassed and dried over
molecular sieves in a storage flask. The eluent for column
chromatography (a 0:100 to 40:60 mixture of Et2O and hexane)
was dried over molecular sieves in a bottle. The water content of
the solvent was confirmed with a Karl Fischer Moisture Titrator
(MKC-210, Kyoto Electronics Company) to be less than 10 ppm.
Anhydrous tetrahydrofuran (THF) was purchased from Kanto
Chemical and distilled from benzophenone ketyl at 760 mmHg
under argon immediately before use.
Materials. Unless otherwise noted, materials were purchased
from Tokyo Kasei Kogyo Co., Aldrich Inc., and other commercial
suppliers and were used after appropriate purification. ZnCl2
(anhydrous, beads) was purchased from Aldrich. CuCl was
purchased from Wako Co, and t-BuLi was purchased from Kanto
Chemical and titrated before use. Florisil (100-200 mesh) was
purchased from Yoneyama Yakuhin Kogyo Co., Ltd.
Typical Procedure for an Addition Reaction (Procedure A):
(2R*,3R*)-1-Cyclohexyl-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1-butanone N,N-Dimethylhydrazone (10syn). t-
BuLi (1.59 M in pentane, 1.26 mL, 2.0 mmol) was slowly added
to a solution of the N,N-dimethylhydrazone of 1-cyclohexylpropan-
1-one (0.182 g, 1.0 mmol) in hexane (1.0 mL) at -78 °C. The
mixture was stirred at 0 °C for 1.5 h, and then ZnCl2 (0.5 M in
Et2O, 2.0 mL, 1.0 mmol) was added at that temperature. After 15
min, the solvents were removed in vacuo (10 min, 0 °C, 0.1 mmHg).
(E)-Propenylboronate 8E [0.160 g, 0.95 mmol, 99.3% (E)] and
hexane (0.4 mL) were slowly added at 0 °C. After 12 h, saturated
aqueous NaHCO3 (4.0 mL) was added at 0 °C. The aqueous layer
was extracted with hexane (twice) and Et2O (twice). The combined
organic extracts were filtrated with a pad of Florisil using Et2O as
an eluent, and the ds (99.2%) was determined by GC analysis. The
solvents were removed in vacuo, and the resulting crude product
was purified by column chromatography on silica gel (15, 30%
Et2O in hexane) to give the title compound (0.309 g, 93% yield)
as a colorless oil. Rf ) 0.39 (20% AcOEt in hexane). IR (neat):
2813, 2769, 1625 (CdN), 1314, 1144, 959, 847. 1H NMR: δ 0.64
(dd, J ) 9.8, 15.5 Hz, 1H, CHHB), 0.87 (d, J ) 7.0 Hz, 3H,
CH(CH3)CH2B), 1.03 (d, J ) 7.0 Hz, 3H, CCHCH3), 1.06 (dd, J
) 2.3, 15.5 Hz, 1H, CHHB), 1.15-1.20 (m, 1H, CH(CH2)2CHH),
1.25 (s, 12H, C(CH3)2C(CH3)2), 1.31-1.40 (m, 4H, (CHH)2CH2-
(CHH)2), 1.51-1.58 (m, 2H, CHH(CH2)3CHH), 1.67-1.76 (m, 3H,
CH2(CHH)3CH2), 1.99-2.03 (m, 1H, CHCH2B), 2.12 (dq, J ) 7.0,
9.0 Hz, 1H, CCHCH3), 2.37 (s, 6H, N(CH3)2), 3.27 (tt, J ) 3.0,
11.5 Hz, 1H, (CH2)2CH). 13C NMR: δ 19.2, 21.3, 24.7 (2C), 24.9
(2C), 26.1, 26.1, 26.2, 29.2, 29.8, 33.7, 39.8, 42.5, 47.9 (2C), 82.7
(2C), 178.6. The NMR signal of the carbon R to the boron was not
found. APCI-HRMS: calcd for C20H40BN2O2 [M + H]+, 351.31865;
found, 351.31917.
Instrumentation. Proton nuclear magnetic resonance (1H NMR)
and carbon nuclear magnetic resonance (13C NMR) spectra were
recorded with a JEOL AL-400 (400 MHz), JEOL ECX-400 (400
MHz), or JEOL ECA-500 (500 MHz) NMR spectrometer. Chemi-
cal-shift values (δ scale) for protons are reported in parts per million
downfield from tetramethylsilane and are referenced to the residual
proton of CDCl3 (δ 7.26). 13C NMR spectra were recorded at 125
or 100 MHz; chemical shifts for carbons (δ scale) are reported in
parts per million downfield from tetramethylsilane and are refer-
enced to the carbon resonance of CDCl3 (δ 77.0). Data are presented
as follows: chemical shift, multiplicity (s ) singlet, d ) doublet,
t ) triplet, q ) quartet, quint ) quintet, sext ) sextet, sept ) septet,
m ) multiplet and/or multiplet resonances, br ) broad), coupling
constant in hertz, signal area integration in natural numbers, and
assignment (italic). IR spectra recorded on an FT/IR-420 (JASCO)
or a React IR 1000 Reaction Analysis System equipped with
DuraSample IR (ASI Applied System) are reported in cm-1
.
Characteristic IR absorptions are reported except for normal
aliphatic C-H absorptions (2980-2840 and 1470-1350 cm-1).
High-resolution mass spectra (HRMS) were obtained using the
electron impact (EI) method with a JEOL GC-mate II instrument
or the atmospheric pressure chemical ionization (APCI) or elec-
trospray ionization (ESI) method with a JEOL JMS-T100LC
instrument.
Typical Procedure for the Addition/Trapping Sequence:
(2R*,3R*,4S*)-1-Cyclohexyl-2,3-dimethyl-4-[(3S*)-3-oxocyclo-
hexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-1-
one N,N-Dimethylhydrazone (27). The addition reaction was
carried out according to procedure A on a 2.0 mmol scale. The
solvents were removed in vacuo, and then Et2O (1.0 mL) was added.
The mixture of 2-cyclohexen-1-one (0.78 mL, 8.0 mmol), Me3SiCl
(1.02 mL, 8.0 mmol), and CuCl (0.396 g, 4.0 mmol) was added
via a cannula at 0 °C. After 2 h, the reaction mixture was warmed
to 20 °C and stirred for 2 h. Saturated aqueous NaHCO3 (12 mL)
and 10% aqueous ammonia (12 mL) were added at 0 °C. After the
copper salts had dissolved, the aqueous layer was extracted with
Et2O (five times). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and then filtered. The solvents
were removed in vacuo, and the resulting crude product was purified
by column chromatography on silica gel (20, 40% Et2O in hexane)
to give the title compound (0.555 g, 69% yield, >95% ds as
determined by 1H NMR spectra) as a white solid. Recrystallization
from pentane gave crystals suitable for X-ray diffraction (>99%
ds). Rf ) 0.13 (20% AcOEt in hexane). IR (neat): 2814, 2768, 1714
(29) Still, W. C.; Klahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2924.
(30) Frisch, M. J.; et al. Gaussian 03, revision C.02; Gaussian, Inc.:
Pittsburgh, PA, 2003.
(31) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(32) Schafer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571–
2577.
(33) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; John Wiley & Sons: New York, 1986. and
references cited therein.
(34) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368. (b) Gonzalez, C.;
Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161. (c) Gonzalez,
C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
9
15700 J. AM. CHEM. SOC. VOL. 130, NO. 46, 2008

Diastereoselective Addition of Zincated Hydrazones
A R T I C L E S
(CdO), 1623 (CdN), 1311, 1144, 962, 846, 717. 1H NMR: δ 0.80
(d, J ) 6.8 Hz, 3H, CH(CH3)CHB), 1.06-1.13 (m, 4H, CCHCH3,
(CH2)2CHH(CH2)2), 1.15-1.41 (m, 18H, (CHH)2CH2(CHH)2, BCH,
C(CH2)2CHH, C(CH3)2C(CH3)2), 1.51-1.63 (m, 3H, CHH(CH2)3-
CHH, CCH2CHH), 1.68-1.77 (m, 3H, CH2(CHH)3CH2), 1.97-2.14
(m, 5H, CH(CH3)CHB, CHHC(O)CH2(CHH)2CH), 2.18-2.27 (m,
2H, CCHCH3, CCHHCH2), 2.33-2.41 (m, 8H, CHHC(O)CHH,
N(CH3)2), 3.40 (brt, J ) 11.0 Hz, 1H, CH-(CH2)5-). 13C NMR:
δ 15.3, 20.0, 25.0 (2C), 25.1, 25.3 (2C), 25.7, 25.9, 26.2, 29.1,
29.8, 30.1, 33.0 (brs, R to the boron), 36.4, 38.1, 39.4, 39.9, 41.5,
47.8 (2C), 49.1, 83.0 (2C), 178.5, 211.8. Anal. Calcd for
C26H47BN2O3: C, 69.94; H, 10.61; N, 6.27. Found: C, 69.95; H,
10.64; N, 6.17.
Acknowledgment. We thank the Ministry of Education, Culture,
Sports, Science, and Technology of Japan for financial support and
are grateful for a Grant-in-Aid for Scientific Research (S, E.N.,
18105004), a Grant-in-Aid for Scientific Research on Priority Areas
“Synergistic Effects for Creation of Functional Molecules” from
MEXT (M.N., 18064006), and a Grant-in-Aid for Young Scientists
from JSPS (T.H., 19750077).
Supporting Information Available: Experimental procedures,
characterization data, and complete ref 30. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA806258V
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