Design, reactivities, and practical application of dialkylzinc hydride ate complexes generated in Situ from dialkylzinc and metal hydride. A new methodology for activation of NaH and LiH under mild conditions

Article abstract of DOI:10.1021/ja9718477

We designed various dialkylzinc hydride 'ate' complexes, prepared from dialkylzinc and metal hydride, and investigated the reactivities (and the transference aptitude of ligands) of these zincates toward benzophenone. The results clearly reveal that dimethylzinc hydrides are the most powerful and selective zincates for the reduction of the carbony1 group. This complex reagent turned out to be effective for the reduction of esters and amides as well as aldehydes and ketones to the corresponding alcohols and amines with good to excellent yields under mild conditions. Furthermore, the method was successfully used for the highly selective 1,2-reduction of α,β-unsaturated carbonyl compounds, the regioselective ring-opening reduction of epoxides, and the chemoselective reduction of aldehydes in the presence of ketones. We also discuss and clarify the active species and the mechanism of this reduction using the diastereoselective reductions of some carbonyl compounds with an adjacent chiral center. Also, this reducing system was found to constitute a powerful tool for the stereoselective synthesis of syn- and anti-1,2-diols. Moreover, we developed the catalytic version of this reducing system. The LiH-Me₂Zn-ultrasound system proved to be effective not only for the catalytic reduction of the carbonyl compounds and epoxides but also for the partial reduction (the conversion) of carboxylic acids to aldehydes. This system is a very attractive method for several reasons (good availability, low cost, and easy operation) and would be particularly useful for large- scale reductions.

Full text of DOI:10.1021/ja9718477

J. Am. Chem. Soc. 1997, 119, 11425-11433
11425
Design, Reactivities, and Practical Application of Dialkylzinc
Hydride Ate Complexes Generated in Situ from Dialkylzinc and
Metal Hydride. A New Methodology for Activation of NaH
and LiH under Mild Conditions
Masanobu Uchiyama,* Shozo Furumoto, Mariko Saito, Yoshinori Kondo, and
Takao Sakamoto*
Contribution from the Faculty of Pharmaceutical Sciences, Tohoku UniVersity, Aobayama,
Aoba-ku, Sendai 980-77, Japan
ReceiVed June 5, 1997X
Abstract: We designed various dialkylzinc hydride “ate” complexes, prepared from dialkylzinc and metal hydride,
and investigated the reactivities (and the transference aptitude of ligands) of these zincates toward benzophenone.
The results clearly reveal that dimethylzinc hydrides are the most powerful and selective zincates for the reduction
of the carbonyl group. This complex reagent turned out to be effective for the reduction of esters and amides as
well as aldehydes and ketones to the corresponding alcohols and amines with good to excellent yields under mild
conditions. Furthermore, the method was successfully used for the highly selective 1,2-reduction of R,â-unsaturated
carbonyl compounds, the regioselective ring-opening reduction of epoxides, and the chemoselective reduction of
aldehydes in the presence of ketones. We also discuss and clarify the active species and the mechanism of this
reduction using the diastereoselective reductions of some carbonyl compounds with an adjacent chiral center. Also,
this reducing system was found to constitute a powerful tool for the stereoselective synthesis of syn- and anti-1,2-
diols. Moreover, we developed the catalytic version of this reducing system. The LiH-Me2Zn-ultrasound system
proved to be effective not only for the catalytic reduction of the carbonyl compounds and epoxides but also for the
partial reduction (the conversion) of carboxylic acids to aldehydes. This system is a very attractive method for
several reasons (good availability, low cost, and easy operation) and would be particularly useful for large-scale
reductions.
Introduction
Organometallic reagents having Lewis acidity (vacant orbital)
often form complexes with anion species, such as carboanions
and alkoxy anions, to generate metallic anion complexes defined
as ate complexes.1 Ate complexes, being bimetallic compounds,
are known to show unique reactivities that metallic reagents
themselves do not possess. Such unique reactivities of ate
complexes have also been reported in recent studies on
organozinc reagents. For example, while organozinc halides
(Reformatsky-type, symbolized as RZnX) and diorganozincs
(R2Zn) exhibit different reactivities, triorganozincs (R3Zn-Metal+)
are known to produce 1,4-conjugated additions toward R,â-
unsaturated carbonyl compounds2 and the metallation of aro-
matic halides3 or vinyl halides.4 Lithium trialkylzincates, one
of the organozincates,5 is a complex arising from dialkylzinc
having Lewis acidity and alkyllithium having Lewis basicity.
Figure 1. Classification of reactivities of triorganozincates.
Since all of alkyl ligands coordinated to Zn are usually the same,
these reactivities, i.e., the magnitude of the transference aptitude
of alkyl groups, are essentially equivalent. However, the
reactivities of the alkyl groups should be nonequivalent, if
different alkyl groups do coordinate to Zn (Figure 1). Namely,
when different alkyl groups coordinating triorganozincates react
with electrophilic reagents, a problem is which alkyl group
transfer occurs first. Such transference aptitude of alkyl groups
on Zn has been discussed in 1,4-conjugated additions toward
R,â-unsaturated carbonyl compounds2b-d and 1,2-additions to
X Abstract published in AdVance ACS Abstracts, November 1, 1997.
(1) (a) Wittig, G. Quart. ReV. 1966, 191-210. (b) Tochtermann, W.
Angew. Chem., Int. Ed. Engl. 1966, 5, 351-375.
(2) (a) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977,
679-682. (b) Tuckmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber. 1986,
119, 1581-1593. (c) Jansen, J. F. G. A.; Ferringa, B. L. Tetrahedron Lett.
1988, 29, 3593-3596. (d) Kjonas, R. A.; Hoffer, R. K. J. Org. Chem.
1988, 53, 4133-4135.
(3) (a) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T. J. Org.
Chem. 1994, 59, 4717-4718. (b) Kondo, Y.; Matsudaira, T.; Sato, J.;
Murata, N.; Sakamoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 736-
738. (c) Kondo, Y.; Takazawa, N.; Yoshida, A.; Sakamoto, T. J. Chem.
Soc., Perkin Trans. 1 1995, 1207-1208. (d) Kondo, Y.; Fujinami, M.;
Uchiyama, M.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1997, 799-
800.
(4) (a) Harada, T.; Katsuhira, K.; Hattori, K.; Oku, A. J. Org. Chem.
1993, 58, 2958-2965. (b) Harada, T.; Katsuhira, K.; Hara, D.; Kotani,
Y.; Maejima, K.; Kaji, R.; Oku, A. J. Org. Chem. 1993, 58, 4897-4907.
(5) (a) We recently reported unique reactivities of new “highly coordi-
nated” ate complexes of organozinc derivatives as a new type of orga-
nozincates: Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.; Sakamoto,
T. J. Am. Chem. Soc. 1996, 118, 8733-8734. (b) More recently, “highly
coordinated” zincates were used as a reactive intermediates for asymmetric
1,2-migration reaction: McWilliams, J. C.; Armstrong, J. D., III; Zheng,
N.; Bhupathy, M.; Volante, R. P.; Reider, P. L. J. Am. Chem. Soc. 1996,
118, 11970-11971.
S0002-7863(97)01847-7 CCC: $14.00 © 1997 American Chemical Society

11426 J. Am. Chem. Soc., Vol. 119, No. 47, 1997
Uchiyama et al.
Table 1 Reactivities of Dialkylzinc Hydride Ate Complexes
aldehydes.3d We are interested in the transference aptitude
between alkyl and hydride groups above Zn, not between alkyl
and alkyl groups as usually occurs, because the magnitude of
the former is considered to be larger than that of the latter. If a
hydride was selectively transferred compared with alkyl group
from the dialkylzinc hydride ate complex, this complex would
be a new reducing (hydrometallating) reagent.
yield
(%)a
Since the nature of the zinc-hydride bond is between that
of saline hydrides, metallic hydrides, and molecular hydrides,6
the structure and reactivities as a nucleophile or base7 have been
extensively studied in compounds of H2Zn,8 H3ZnM (M ) Li,
Na, etc.),9 H4ZnM′ (M′ ) Li2, Na2, Mg, etc.),9 and related
compounds.10 However, these hydride reagents have scarcely
been used as a practical hydride donor for the reduction of
carbonyl compounds in organic synthesis, because their dif-
ficulty of their preparations, low reactivity, and low selectivity.
However, if the environment, i.e., ligands coordinated to Zn, is
altered, the nature of the compound as a hydride source should
be changed. We designed dialkylzinc hydride ate complexes
made with dialkylzinc as the Lewis acid and metal hydrides as
the Lewis base. In 1970, Kubas and Shriver reported that
various kinds of dialkylzinc formed complexes with LiH or NaH
in THF, Et2O, or DMF.11 However, the structure and reactivities
of the complex have received little attention. On the other hand,
although LiH and NaH have the advantages of good availability,
low cost, and easy operation, they are known as essentially inert
hydrides toward the reduction of carbonyl compounds. In this
paper, we report the design and reactivities of dialkylzinc
hydride ate complexes, prepared in situ from a metal hydride
and dialkylzinc, toward carbonyl compounds and the practical
applications of this system as a hydride source for chemose-
lective, stereoselective, and catalytic reductions. We also
discuss the active species and the mechanism of this reduction
using the diastereoselective reductions of some carbonyl com-
pounds with an adjacent chiral center.12
entry
preparations of 1
R
metal+
solvent
3
4
1
2
3
LiH
NaH
THF
THF
THF
0
0
16
NaH + ZnCl2
4
5
LiH + Me2Zn
NaH + Me2Zn
Me Li+
Me Na+
THF
THF
32 <1
99 <1
6
7
NaH + Et2Zn
Et Na+
THF
56 43
4 18
NaH + ZnCl2 + 2tBuLi
tBu Na+ or Li+ THF
8
9
LiH + ZnCl2 + 2MeLi
NaH + ZnCl2 + 2MeLi
Me Li+
Me Na+ or Li+ THF
THF
36 <1
92 <1
10 NaH + Me2Zn
11 NaH + Me2Zn
12 LiH + Me2Zn + sonication Me Li+
Me Na+
Et2O
CH2Cl2 93 <1
88 <1
Me Na+
THF
96 <1
a Isolated yield based on the amount of 2.
toward carbonyl compounds using benzophenone (2) as a model
substrate were investigated. These results are summarized in
Table 1. Very interestingly, use of the methyl group as a ligand
on Zn produced benzhydrol (3) as the sole product; dimethylzinc
hydrides selectively transferred the hydride compared with the
methyl group from the zincate to 2 (entries 4 and 5, 8 and 9).
Particularly, when sodium hydride was used as the metal
hydride, a hydride adduct was obtained in high yield without
the formation of any detectable amount of the methyl adduct 4
(entries 5 and 9). In diethyl ether (Et2O) and dichloromethane
(CH2Cl2), these activations and selectivities were also observed
without any problems (entries 10 and 11). A noteworthy fact
is that no methylation product was obtained in all cases!
However, when ethyl (primary alkyl) and tert-butyl (tertiary
alkyl) groups, being more bulky and anionic alkyl groups, were
used instead of the methyl group, a large amount of alkylated
product (4) was obtained and accompanied by the hydride adduct
(entries 6 and 7). Judging from the results that the reduction
of 2 with LiH, NaH, and H2Zn did not or scarcely proceeded
(entries 1-3), we can assume that LiH or NaH was activated
as a hydride source by ate complexation with Me2Zn.
On the other hand, the low yield of 3 when the LiH-Me2Zn
system was used (entry 4) was attributed to the slower ate
complexation reaction in comparison with the NaH-Me2Zn
system (entry 5),11 not an effect of the countercation of the
dimethylzinc hydride ate complexes, because reactivities, i.e.,
the yield of 3, were found to be similar in both the NaH-Me2-
Zn system (entry 5) and NaH-ZnCl2-2MeLi system (entry 9).
Indeed, the reaction of 2 with the LiH-Me2Zn system under
sonication dramatically proceeded to give 3 in 96% yield (entry
12). This result indicates that LiH was activated by sonication
and the ate complexation reaction was accelerated.13 Since the
methyl group was found to be excellent as an activating and
nontransfer group, the wide applicability of this new reducing
system is demonstrated by the reduction of other carbonyl
compounds using the NaH-Me2Zn system which exhibited the
best reactivities and selectivities toward 2.
Results and Discussion
Reactivities of Dialkylzinc Hydride Ate Complexes. Ini-
tially, the reactivities and transference aptitude of ligands above
Zn in various kinds of dialkylzinc hydride ate complexes (1)
(6) For a review see: Shriver, D. F.; Atkins, P. W.; Langford, C. H. In
Inorganic Chemistry, 2nd ed.; Oxford University Press: Oxford, 1994; Part
1, Chapter 9.
(7) Ashby, E. C.; Boone, J. R. J. Org. Chem. 1976, 41, 2890-2903.
(8) (a) Barbaras, G. D.; Dillard, C.; Finholt, A. E.; Wartik, T.; Wilzbach,
K. E.; Schlesinger, H. I. J. Am. Chem. Soc. 1951, 73, 4585-4590. (b)
Watkins, J. J.; Ashby, E. C. Inorg. Chem. 1974, 13, 2350-2354.
(9) (a) Ashby, E. C.; Watkins, J. J. J. Chem. Soc., Chem. Commun. 1972,
998-999. (b) Ashby, E. C.; Watkins, J. J. Inorg. Chem. 1973, 12, 2493-
2503. (c) Ashby, E. C.; Nainan, K. C.; Prasad, H. S. Inorg. Chem. 1977,
16, 348-353.
(10) (a) Shriver, D. F.; Kubas, G. J.; Marshall, J. A. J. Am. Chem. Soc.
1971, 93, 5076-5079. (b) Ashby, E. C.; Watkins, J. J. Inorg. Chem. 1977,
16, 1445-1451. (c) Watkins, J. J.; Ashby, E. C. Inorg. Chem. 1977, 16,
2075-2081. (d) Ashby, E. C.; Goel, A. B. J. Organomet. Chem. 1977,
139, C89-C91. (e) Ashby, E. C.; Goel, A. B. Inorg. Chem. 1981, 20,
1096-1101.
(11) Kubas, G. J.; Shriver, D. F. J. Am. Chem. Soc. 1970, 92, 1949-
1954.
(12) Although there are some reports on using ZnX2 (X ) Cl or OSO2-
Me) or Zn(0) as activator of the reductiVe silylation, no papers of a method
for direct activation of LiH or NaH as a zinc ate complex using dialkylzinc
have been published. For examples using NaH-Cl(CH3)3Si-ZnCl2 mixed
system, see: (a) Caube´re, P.; Vanderesse, R.; Fort, Y. Acta Chem. Scand.
1991, 45, 742-745. (b) Nordahl, A° .; Carson, R. Ibid. 1990, 44, 274-278.
For examples using NaH-Cl(CH3)3Si-NaOCH2C(CH3)3-ZnCl2 (Zn-
CRASi) mixed system, see: (c) Brunet, J.-J.; Besozzi, D.; Caube´re, P.
Synthesis 1982, 721-723. (d) Caube´re, P. Pure Appl. Chem. 1985, 57,
1875-1882. For examples using LiH-Cl(CH3)3Si-ZnX2 (X ) Cl or
OSO2Me) or Zn(0) mixed system, see: (e) Ohkuma, T.; Hashiguchi, S.;
Noyori, R. J. Org. Chem. 1994, 59, 217-221.
Reduction of Other Carbonyl Compounds with NaH-Me2-
Zn System. The metal hydride reduction of carbonyl com-
(13) For a review, see: Steven, V. L.; Caroline, M. R. L. Ultrasound in
Synthesis, 1st ed.; Springer-Verlag Berlin Heidelberg: Berlin, 1989.

Dialkylzinc Hydride Ate Complexes
J. Am. Chem. Soc., Vol. 119, No. 47, 1997 11427
Table 2. Reduction of Carbonyl Compounds and Epoxide with NaH-Me2Zn Reducing Systema
a Unless otherwise noted, the reaction was carried out using NaH (1.2 equiv), Me2Zn (1.1 equiv), and substrate (1 equiv) in THF at room
temperature for 12 h. b Isolated yield. Value in parentheses are yield of reduction using NaBH4 under the same conditions. c The reaction was
carried out at 0 °C for 1 h. d The reaction was carried out using NaH (2.2 equiv) and Me2Zn (2.0 equiv) at 0 °C for 6 h. e No conjugate reduction
product was obtained. f 4-Phenyl-2-butanone was also obtained in 25% yield. g The reaction was carried out using NaH (3.0 equiv) and Me2Zn (3.0
equiv). h 4-Chloroacetanilide was recovered in 28% yield.
pounds such as aldehydes, ketones, esters, and enones to the
corresponding alcohols is one of the most fundamental processes
in organic synthesis.14 Successful methods for accomplishing
this transformation with metal hydrides or metal ate hydrides
containing boron,15 aluminum,16 silicon,17 and tin18 have been
reported. Unfortunately, however, many of these reagents also
have some significant disadvantages: low reactivity, low
chemoselectivity, the requirement of strict reaction conditions,
and the cost of reagents especially on an industrial level. Thus,
the development of a new, simple, and practical method for
the highly selective reduction of various carbonyl compounds
is still desirable.
The NaH-Me2Zn “ate” complex proved effective for the
reduction of other carbonyl compounds (Table 2). The reduction
of an aromatic aldehyde gave alcohols in quantitative yield
(entry 1). Interestingly, aliphatic aldehydes, particularly eno-
lizable aldehydes, were also reducible in high yields and no
aldol products were obtained (entries 2 and 3). This indicates
that NaH completely eliminates the intrinsic basicity and
dramatically increases the nucleophilicity by ate complexation
with Me2Zn. Furthermore, the reduction of esters and lactones,
as well as aldehydes and ketones, also proceeded well to afford
the corresponding alcohols in high yields (entries 4-8).
These remarkable reducing abilities of the NaH-Me2Zn “ate”
complex prompted us to further survey whether this reducing
system could be used for chemoselective reduction. During the
reduction of the R,â-unsaturated ketones by metal hydrides, two
possible products can be obtained on the basis of the reaction
direction of the hydrides, i.e., addition to the carbonyl group
(1,2-addition) to give the allylic alcohols or addition to the
conjugated double bond (1,4-addition) to give the saturated
ketones.19 This complex reducing reagent proved effective for
the highly selective 1,2-reduction of the enone (entry 9). No
conjugate reduction products was isolated. Under the same
conditions, the reduction using NaBH4 gave 1,2-reduction and
1,4-reduction products in 73 and 25% yields, respectively. The
ring opening reaction of the monosubstituted epoxide by metal
hydrides can follow two pathways: the addition to the R-carbon
(with respect to the substituent group) to give a primary alcohol
or the addition to the â-carbon (less-hindered site) to give a
secondary alcohol.20 The NaH-Me2Zn reducing reagent styrene
oxide and 1-phenethyl alcohol was obtained in 92% yield with
perfect regioselectivity (entry 10). On the other hand, the
reduction of styrene oxide with NaBH4 did not proceed at all
under the same conditions.21 Moreover, this reducing system
proved effective in the reduction of the amide groups.14 The
reduction of the N-monoalkylamide proceeded normally to
afford the corresponding dialkylamine, namely 4-chloroacet-
anilide, was converted to N-ethyl-4-chloroaniline in 68% yield,
and 28% of the starting material was recovered (entry 11).
However, the reduction of N,N-dimethylbenzamide, the N,N-
dialkylamide, proceeded to give an abnormal product, benzyl
(14) For a review on the metal hydride reduction of carbonyl compounds,
see: (a) Greeves, N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 1.1 and references
cited therein. (b) Hajo´s, A. Complex Hydrides; Elsevier: Amsterdam, 1979.
(15) (a) Brown, H. C.; Schlesinger, H. I.; Burg, A. B. J. Am. Chem.
Soc. 1939, 61, 673-680. (b) Schlesinger, H. I.; Brown, H. C.; Hoekstra,
H. R.; Rapp, L. R. J. Am. Chem. Soc. 1953, 75, 199-204. (c) Nystrom, R.
F.; Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 3245-
3246. (d) Brown, C. A. J. Am. Chem. Soc. 1973, 95, 4100-4102. (e)
Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1973, 95, 1669-1671.
(f) Brown, H. C.; Krishnamurthy, S.; Hubbard, J. L. J. Am. Chem. Soc.
1978, 100, 3343-3349. (g) Brown, H. C.; Krishnamurthy, S. Tetrahedron
1979, 35, 567-607.
(16) (a) Doukas, H. M.; Fontaine, T. D. J. Am. Chem. Soc. 1951, 73,
5917-5918. (b) Doukas, H. M.; Fontaine, T. D. J. Am. Chem. Soc. 1953,
75, 5355-5356. (c) Zieglar, K.; Geller, H. G.; Lehmkuhl, H.; Pfohl, W.;
Zosel, K. Liebigs Ann. Chem. 1960, 629, 1-13. (d) Eisch, J. J.; Kaska,
W. C. J. Am. Chem. Soc. 1966, 88, 2213-2220. (e) Gensler, W. J.; Bruno,
J. J. J. Org. Chem. 1963, 28, 1254-1259.
(17) (a) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5405-5415.
(b) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5415-5421. (c)
Semmelhack, M. F.; Misra, R. N. J. Org. Chem. 1982, 47, 2469-2471. (d)
Yang, D.; Tanner, D. D. J. Org. Chem. 1986, 51, 2267-2270. (e) Kira,
M.; Sato, K.; Sakurai, H. J. Org. Chem. 1987, 52, 948-949. (f) Reding,
M. T.; Buchwald, S. L. J. Org. Chem. 1995, 60, 7884-7890.
(18) (a) Fung, N. Y. M.; de Mayo, P.; Schauble, J. H.; Weedon, A. C.
J. Org. Chem. 1978, 43, 3977-3979. (b) Neumann, W. P. Synthesis, 1987,
665-683. (c) Degueil-Castaing, M.; Rahm, A.; Dahan, N. J. Org. Chem.
1986, 51, 1672-1676.
(19) For the regioselective reduction of R,â-unsaturated carbonyl com-
pounds, see: Keinan, E.; Greenspoon, N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter
3.5 and references cited therein.
(20) For the regioselective reduction of epoxides, see: Murai, S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 8, Chapter 4.4 and references cited therein.
(21) For activation of NaBH4 using a mixed solvent, see: (a) Soai, K.;
Ookawa, A.; Oyamada, H.; Takase, M. Heterocycles 1982, 19, 1371-1374.
(b) Ookawa, A.; Hiratsuka, H.; Soai, K. Bull. Chem. Soc. Jpn. 1987, 60,
1813-1818.

11428 J. Am. Chem. Soc., Vol. 119, No. 47, 1997
Uchiyama et al.
Figure 2. Possible mechanism for reduction of carbonyl compounds with metal hydride-Me2Zn reducing system.
Figure 3. Diastereoselective reductions of carbonyl compounds with an adjacent chiral center.
alcohol, in 88% yield (entry 12). The scope and limitation of
this amide reduction, in combination with the mechanism, are
currently under investigation. Next, the wide applicability of
this new reducing system is demonstrated by the selective
reduction of more reactive aldehydes in the presence of ketone.22
In the competitive reaction of 2-naphthaldehyde (5, 1 equiv)
and benzophenone (2, 1 equiv) with NaH-Me2Zn (1 equiv),
the reduction of 5 was performed with more than 98%
selectivity.
Finally, the complex reagent prepared in situ from NaH and
Me2Zn has proved to be a powerful (for reduction of esters,
lactones, epoxides, and amides) and highly chemoselective (for
reduction of R,â-unsaturated carbonyl compounds, monosub-
stituted epoxide, and amides) reducing reagent.
Active Species of This Complex Reducing System: Dias-
tereoselective Reduction of â-Hydroxy Carbonyl Com-
pounds. During the reduction of carbonyl compounds with this
complex reducing system, the following two possible pathways
can be considered, although we suppose the active species of
this system is the dimethylzinc hydride “ate” complex (Figure
2): (1) In the initial step, dimethylzinc hydride “ate complexes”
are generated from metal hydrides and Me2Zn. Following the
formation of the ate complexes, the carbonyl compounds are
reduced to the corresponding metal alkoxides by the hydride
ate complexes (path A). (2) Me2Zn activates the carbonyl
compounds as a Lewis acid, and the metal hydrides directly
reduced them (path B).
Only a slight difference in reactivities due to the two possible
mechanisms is observed in the reduction of the usual carbonyl
compounds. However, in the reduction of carbonyl compounds
with an adjacent chiral center, the reactivities or diastereose-
lectivities should differ based on the two possible mechanisms.23
In particular, the reduction of â-hydroxy carbonyl compounds
would give important information (Figure 3). For example,
when a syn-diol was selectively obtained, the reduction was
proved to proceed by attack of an external hydride on a six-
membered chelate transition state such as 7, the conformation
of which was governed by the substituent at the alcohol center.24
On the other hand, the anti-diol was produced by attack of an
internal hydride above the metal complexes bound to the
alcohol.25 Therefore, it is helpful to distinguish between the
(23) For the diastereoselective reductions using metal hydrides, see: (a)
Davis, A. P. In Methods of Organic Chemistry; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
1995; Vol. E 21d, Chapter 2.3.3.1 and references cited therein. (b) Miha´ly,
N. In StereoselectiVe Synthesis, 2nd ed.; VCH: Weinheim, 1995. (c)
Reference 14a.
(22) For the selective reduction of more reactive aldehyde in the presence
of ketone by metal hydrides, see: ref 14a.

Dialkylzinc Hydride Ate Complexes
J. Am. Chem. Soc., Vol. 119, No. 47, 1997 11429
Table 3. Diastereoselective Reduction of â-Hydroxy Ketones
Table 4. Diastereoselective Reduction of R-Substituted Ketones
yield (%)
(anti + syn)
ratio
(anti:syn)
entry
1
“hydride”
NaH + Me2Zn
yield (%)
(anti + syn)
ratio
(anti:syn)
entry
R
“hydride”
65
83:17
2
3
LiH + Me2Zn + sonication
NaBH4
57
91
59:41
50:50
1
2
H
H
NaH + Me2Zn
99
72
99:1
(99:1)
(8:1)
LiH + Me2Zn +
sonication
LiAlH4
89:11
3
4
5
H
H
92a
96
70
87:13
92:8
4:96
(7:1)a
(12:1)
(1:24)
NaBH4
b
Si(iPr)3 NaH + Me2Zn
b
6
Si(iPr)3 LiH + Me2Zn +
85
22:78
(1:4)
sonication
b
7
Si(iPr)3 NaBH4
64
23:77
(1:4)
a In THF at -78 °C. Taken from ref 40. b Yields and ratios of
products were determined after desilylation.
Figure 4. Possible mechanism for reduction of â-hydroxy ketones with
metal hydride-Me2Zn reducing system.
dialkylzinc hydride mechanism and the Lewis acid mechanism.
Namely, when the active species of this reduction is dimeth-
ylzinc hydride, the anti-diols should be selectively obtained
(Figure 2, path A). When Me2Zn activates the carbonyl
compounds as a Lewis acid and metal hydrides reduce them
directly, the syn-diols should be selectively obtained (Figure 2,
path B).
The reduction of 3-hydroxy-1,3-diphenyl-1-propanone (9) by
various metal hydrides was investigated. The results are
summarized in Table 3. In the reduction using this reducing
system, the anti-diol was favored over the syn-diol. However,
reduction with NaBH4 exhibited no selectivity under the same
conditions. Judging from the relation between diastereoselec-
tivity and the reaction mechanism, the reduction using this
reducing system was considered to proceed by attack of an
internal hydride above the metal complexes bound to the alcohol
Via a chair transition state (12) to preferentially give the anti-
diol (Figure 4, O-coordinated model). This result strongly
supports the fact that the active species of this complex reducing
system is dimethylzinc hydride “ate” complex. However,
another path is also slightly possible. Residual Me2Zn, Li+, or
Na+ was chelated by â-hydroxy ketones to form a six-membered
transition state (13), allowing attack of an external hydride to
reduce the carbonyl group with syn-selectivity (Figure 4, Cram
chelation model26). Therefore, the anti-selectivity was consid-
ered to be slightly lower (mismatched model27).
Figure 5. R-Hydroxy carbonyl compounds reduction model.
Figure 6. R-Substituted carbonyl compounds reduction model.
Diastereoselective Reduction of r-Hydroxy Carbonyl
Compounds. The reduction of 2-hydroxy-1-phenyl-1-propane
(14a) with various metal hydrides was investigated (Table 4,
entries 1-4).28 Although the yields and ratios of the products
depend to some degree on the reducing reagent, the anti-diol is
favored in all cases. The reduction of 2-hydroxypropiophenone
with NaH + Me2Zn system was found to exhibit a remarkably
high anti-selectivity (compared with LiAlH4 or NaBH4). Next,
the reduction of R-triisopropylsilyloxy carbonyl compounds
(14b) was also investigated (Table 4, entries 5-7).29 Triiso-
(24) (a) Anwar, S.; Davis, A. P.; Fort, Y. Tetrahedron. 1988, 44, 3761-
3770. (b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 112, 3560-3578. (c) Evans, D. A.; Hoveyda, A. Ibid. 1990,
112, 6447-6449. (d) Sarco, C. R.; Collibee, S. E.; Knorr, A. L.; DiMare,
M. J. Org. Chem. 1996, 61, 868-873.
(25) (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233-2238. (b)
Chen, K.-M.; Gunderson, K. G.; Hardtmann, G.-E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Chem. Lett. 1987, 1923-1926. (c) Chen, K.-M.; Hardtmann,
G.-E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron. Lett. 1987, 28,
155-158.
(26) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74,
5828-5835. (b) Still, W. C.; McDonald, J. H., III Tetrahedron. Lett. 1980,
21, 1031-1034. (c) Corcoran, R. C.; Ma, J. J. Am. Chem. Soc. 1992, 114,
4536-4542.
(27) The term “mismatched model” is used to refer to the main two
mechanisms (O-coordinated model and cram chelation model) exhibiting
the same diastereoselectivities.
(28) (a) Cram, D. J.; Greene, F. D. J. Am. Chem. Soc. 1953, 75, 6005-
6010. (b) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 21,
2199-2204. (c) Che´rest, M.; Prudent, N. Tetrahedron 1980, 21, 1599-
1606. (d) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61. (e) Anh,
N. T. Top. Curr. Chem. 1980, 88, 145.
(29) For the diastereoselective reduction of R-alkoxy carbonyl com-
pounds, see: (a) Overmann, L. E.; McCready, R. J. Tetrahedron. Lett. 1982,
23, 2355-2358. (b) Takahashi, T.; Miyazawa, M.; Tsuji, I. Ibid. 1985,
26, 5139-5142. (c) Samuels, W. D.; Nelson, R. T.; Hallen, R. T. Ibid.
1986, 27, 3091-3094. (d) Davis, F. A.; Haque, M. S.; Przeslawski, R. M.
J. Org. Chem. 1989, 54, 2021-2024. (e) Ko, K.-Y.; Eliel, E. L. Ibid. 1986,
51, 5353-5362.

11430 J. Am. Chem. Soc., Vol. 119, No. 47, 1997
Table 5. Diastereoselective Reduction of 1,2-Diketones
Uchiyama et al.
Table 6. Dimethylzinc-Catalyzed Reduction of Benzophenone (2)a
entry
Me2Zn (mol %)
yield (%)
1
2
3
50
20
10
99
98
89
yield (%)
(anti + syn)
ratio
(anti:syn)
entry
1
“hydride”
NaH + Me2Zn
61
98:2
(49:1)
4
5
56
2
3
4
LiH + Me2Zn + sonication
LiAlH4
NaBH4
45
95:5
72:28
67:33
(19:1)
(3:1)a
(2:1)
a Unless otherwise noted, the reaction was carried out using NaH
(1.2 equiv), Me2Zn (cat.), and benzophenone (2) (1 equiv; 1 mmol) in
THF at room temperature for 12 h. b Isolated yield based on the amount
of 2.
98a
98
a In THF at -78 °C. Taken from ref 40.
Diastereoselective Reduction of 1,2-Dicarbonyl Com-
pounds. This reducing system was proved effective for the
reduction of 1,2-diketones (Table 5).14 Although the anti-diol
is favored over the syn-diol in all cases, this dimethylzinc
hydride complex exhibited higher anti-selectivities in compari-
son to the usual reducing reagents such as LiAlH4 or NaBH4.
This reduction using dimethylzinc hydride complexes is attrac-
tive from a synthetic viewpoint, not only because high diaste-
reoselectivity was obtained but also because two chiral centers
are constructed at the same time.
Reaction Mechanism for the Reduction of Carbonyl
Compounds with This Complex Reducing System and These
Catalytic Reductions. On the basis of the result that no
methylation product was obtained during the reduction of
carbonyl compounds with this reducing system, we considered
this reaction mechanism as follows (Figure 7). The proposed
reaction mechanism involves an initial ate complexation reaction
to generate the dimethylzinc hydride ate complexes 23. Follow-
ing the formation of 23, the carbonyl compound 24 is reduced
to the corresponding sodium alkoxide (26), and Me2Zn (21) is
regenerated at the same time. Therefore, this reduction possibly
proceeds catalytically. Indeed, the reduction of benzophenone
(2) with NaH in the presence of catalytic amounts of Me2Zn
proceeded smoothly to give benzhydrol (3) in high yields (Table
6). Although the reduction of 2 (1 mmol) using 5 mol % Me2-
Zn gave 3 in 56% yield (entry 4), the reaction using 10 mol %
Me2Zn afforded the product in 89% yield (entry 3).
Reaction Condition-Dependent Catalytic Efficiency of
This Reducing System. The catalytic efficiency of the reduc-
tion of benzophenone (2) with various metal hydrides was
investigated (Figure 8). During the reduction of 2 with LiH,
the yield of benzhydrol (3) was not much more than 100% even
after 48 h, i.e., the turnover number (TON, defined as moles of
the product per mole of the catalyst) of the reduction was about
1 (Figure 8, solid line). However, when NaH in place of LiH
was used, the reaction dramatically proceeded to give rise to 2
in 1000% yield after 6 h (TON ) 10) and subsequently became
saturated (Figure 8, dashed line). Furthermore, during the reduc-
tion with LiH under sonication, the yield of 3 reached 1700%
after 2 h (TON ) 17) and gradually rises thereafter (Figure 8,
dotted line). Taking into account an amount (20 equiv) of metal
hydride and 2 recently used, we can assume that the Me2Zn-
catalyzed LiH reduction system under sonication should intrinsi-
cally exhibit higher catalytic activities. Also, the initial com-
plexation of Me2Zn and metal hydride are considered to allow
the existence of a certain amount of free (uncomplexed) metal
Figure 7. Possible mechanism for the catalytic reduction of carbonyl
compounds.
propylsilyl moiety is known as the group which is deprived of
the Lewis basicity of the oxygen atom. Yields and ratios of
these reductions were determined after desilylation of the
reduction products by treatment with tetra-n-butylammonium
fluoride. In contrast to the case of 14a, the syn-diol is favored
over the anti-diol in these reductions. The NaH-Me2Zn system
was also found to exhibit high diastereoselectivity. These results
indicate that this reducing system constitutes a powerful tool
for the stereoselective synthesis of syn- and anti-1,2-diols.
The dimethylzinc hydride “ate complex” mechanism can
successfully interpret these selectivities (Figure 5). Namely,
for the reduction of R-hydroxy carbonyl compounds, the anti-
diol was selectively produced by attack of an internal hydride
above the dimethylzinc hydride ate complexes bound to the
alcohol Via an O-coordinated transition state such as 17 (Figure
5, O-coordinated model). Moreover, because the anti-diol was
also supported by a chelation model in addition to this internal
hydride path (matched model27), an extraordinarily high selec-
tivity was obtained (Figure 5, Cram chelation model). On the
other hand, for the reduction of R-triisopropylsilyloxy carbonyl
compounds, the syn-diol supported by Felkin-Anh model was
favored over the anti-diol (Figure 6, Felkin-Anh model). In
the absence of a neighboring chelationable heteroatom, asym-
metric induction from the remote center is generally ineffective
during reductions of acyclic ketones.30 Therefore, the dimeth-
ylzinc hydride ate complex turned out to be a highly selective
reducing reagent.
(30) (a) Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94,
7159-7161. (b) Brown, H. C.; Hubbard, J. L.; Singaram, B. Tetrahedron
1981, 37, 2359-2362. (c) Suzuki, K.; Katayama, E.; Tsuchihashi, G.-i.
Tetrahedron. Lett. 1984, 25, 2479-2482. (d) Oishi, T.; Nakata, T. Acc.
Chem. Res. 1984, 17, 338-344.

Dialkylzinc Hydride Ate Complexes
J. Am. Chem. Soc., Vol. 119, No. 47, 1997 11431
Table 7. Catalytic Reduction Using LiH-Me2Zn-Sonication Systema
a Unless otherwise noted, the reaction was carried out using LiH (1.2 equiv), Me2Zn (20 mol %), and substrate (1 equiv) in THF at room
temperature for 12 h. b Isolated yield. c The reaction was carried out at 0 °C for 1 h. d The reaction was carried out using LiH (3.0 equiv) and
Me2Zn (30 mmol %) at 0 °C for 6 h. f The reaction was carried out using LiH (3.0 equiv) and Me2Zn (30 mol %) at room temperature for 48 h.
N-Ethyl-4-chloroaniline was the sole product, and 4-chloroacetanilide was recovered in 32% yield. e Values in parentheses are ratio of 1,2-reduction
and 1,4-reduction. g Values in parentheses are ratio of 1-phenethyl alcohol and 2-phenethyl alcohol. h The reaction was carried out using LiH (3.0
equiv) and Me2Zn (100 mol %) at room temperature for 24 h.
Figure 9. Possible mechanism for the partial reduction of carboxylic
acids.
an aromatic aldehyde were reducible in excellent yields without
the formation of any detectable amount of aldol products,
although there are free metal hydrides in plenty during the initial
step of this reaction (entries 1-3). Ketones, esters, and amides
are also reductively converted to the corresponding alcohols and
amines in THF under mild conditions (entries 4-6). Further-
more, this method was successfully used for the highly selective
Figure 8. Reaction condition-depependent catalytic efficiency of
reduction of benzophenone (1). The reaction was carried out using
metal hydride (20 equiv), Me2Zn (1 equiv; 1mmol), and benzophenone
(2) (20 equiv) in THF at room temperature. Isolated yield is based on
the amount of Me2Zn.
1,2-reduction of R,â-unsaturated carbonyl compounds and
regioselective ring opening reduction of epoxides (entries 7 and
8).
The reduction of carboxylic acids using a metal hydride is
generally known to be difficult and proceeds to the correspond-
ing alcohols.32 However, this catalytic reduction turned out to
be an effective method for the partial reduction of aromatic and
aliphatic carboxylic acids to the corresponding aldehydes (entries
9 and 10). The best solvent for the reduction was THF; the
rate of the reduction was slower in Et2O and CH2Cl2. It seems
difficult to explain this partial reduction using the ordinary
accepted hydride reduction mechanisms.33 A plausible mech-
anism for this partial reduction is shown in Figure 9, although
hydride. Therefore, LiH is seemed to be superior to NaH in
several respects such as (lower) basicity and (lower) reactivity.31
Finally, the LiH-Me2Zn-ultrasound catalytic reduction
system was found to be an effective method for the catalytic
reduction of carbonyl compounds on the basis of the catalytic
efficiency, cost, low basicity, and ease of operation.
Catalytic Reduction of Carbonyl Compounds with LiH-
Me2Zn-Ultrasound System. As we succeeded in optimizing
the conditions for the catalytic reduction with the dimethylzinc
hydride ate complex, we turned our interest to the catalytic
reduction of other carbonyl compounds and epoxides with the
LiH-Me2Zn-ultrasound system (Table 7). Interestingly, ali-
phatic aldehydes, particularly enolizable aldehydes as well as
(32) For the complete reduction of carboxylic acids to alcohols, see:
Barrett, A. G. M. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 8, Chapter 1.10 and references cited
therein.
(33) For the partial reduction of carboxylic acids to aldehydes, see: (a)
Johnstone, R. A. W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 1.11 and references
cited therein. (b) Davis, A. P. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 1.12 and
references cited therein.
(31) Cotton, F. A.; Willkinson, G.; Langford, C. H. AdVanced Inorganic
Chemistry, 4th ed.; John Wiley & Sons: New York, 1980; Part 2, Chapter
7.

11432 J. Am. Chem. Soc., Vol. 119, No. 47, 1997
Uchiyama et al.
hexane (1:5) as eluent to give benzhydrol (3) (183.7 mg, 99%): mp
65-67 °C (recrystallized from n-hexane/ethyl acetate, colorless plates)
(lit.35 mp 68 °C).
that is highly speculative. The reduction of the carbonyl group
would proceed by attack of an internal hydride above the
dimethylzinc hydride ate complexes bound to the hydroxy group
Via an O-coordinated transition state such as 31 which rapidly
produces the Me2Zn-acetal complex intermediate (32). Since
32 was very stable, this reduction was considered to stop at
this stage. Although further investigation is needed to determine
the mechanism, the present procedure provides a new convenient
partial reduction of carboxylic acids to aldehydes.
Procedure for Chemoselective Reduction of 2-Naphthaldehyde
(5) in the Presence of Benzophenone (2). Under Ar atmosphere,
commercial dimethylzinc (1.1 mL, 1.1 mmol; 1.0 M hexane solution)
was added to a mixture of dry THF (3 mL) and NaH (44.3 mg, 1.1
mmol; 60% in oil) at 0 °C, and the solution was stirred for 30 min at
this temperature. To the mixture was successively added benzophenone
(2) (183.5 mg, 1.0 mmol) and 2-naphthaldehyde (5) (156.2 mg, 1.0
mmol) in THF at -78 °C under Ar atmosphere. The mixture was
stirred for 6 h at -20 °C. A saturated aqueous NH4Cl solution (30
mL) was added to the mixture, and the aqueous layer was extracted
with CHCl3 (30 mL × 3). The combined CHCl3 layer was dried over
MgSO4, and the CHCl3 was removed under reduced pressure. The
residue was purified by SiO2 column chromatography using AcOEt/
hexane (1:5) as eluent to give a mixture of 2-naphthalenemethanol (6)
and benzhydrol (2). The ratio of the two products were determined
through analysis of the 1H NMR spectrum of the mixture in comparison
to those of authentic samples.
Conclusion
We have shown the reactivities of various dialkylzinc hydride
“ate” complexes prepared from a metal hydride and dialkylzinc;
dimethylzinc hydride proved to be the most effective zincate
for the reduction of the carbonyl groups based on reactivities
and selectivities. We have also revealed that the active species
of this complex reagent is the dimethylzinc hydride “ate”
complex by using the diastereoselective reductions of some
carbonyl compounds with an adjacent chiral center. This system
was successfully used for chemoselective, diastereoselective,
and catalytic reductions. These results suggest a possible way
to develop catalytic asymmetric reduction using optically active
diorganozincs as activating catalysts. The theoretical approach
with the help of ab initio calculations for this new reduction,
i.e., reactivities, selectivities, nontransferability of alkyl group,
mechanisms of unprecedented reductions, and the asymmetric
version of this reducing system are currently under investigation.
On the basis of simplicity, good availability, low cost, and ease
of operation, the present work provides a new practical method
for the reduction of carbonyl compounds.
Preparation of 3-Hydroxy-1,3-diphenyl-1-propanone (9).36 To
n
a cold (-78 °C) solution of (iPr)2NLi [from 6.0 mmol of BuLi (1.37
M hexane solution; 4.4 mL) and (iPr)2NH (6.1 mmol)] in THF (8 mL)
was added acetophenone (609 mg, 5.0 mmol) in THF (3 mL) under
Ar atmosphere, and the mixture was stirred for 10 min at this
temperature. To the resulting solution was added PhCHO (0.64 mL,
6.0 mmol). The solution was stirred for 30 min at this temperature.
The solvent was removed under reduced pressure, and the residue was
treated with aqueous NH4Cl (10 mL) followed by extraction with CHCl3
(10 mL × 3). The CHCl3 layer was dried over MgSO4, and the CHCl3
was removed under reduced pressure. The residue was purified by
SiO2 column chromatography using AcOEt/hexane (1:5) as eluent to
give 3-hydroxy-1,3-diphenyl-1-propanone (9) (667 mg, 59%): mp 51-
1
52 °C (recrystallized from n-hexane, colorless needles); 300 MHz H
NMR (CDCl3/TMS) δ (ppm) 7.96 (d, 2H, J ) 7.1 Hz), 7.62-7.28
(8H, m), 5.35 (2H, dt, J ) 3.0, 6.0 Hz), 3.57 (1H, d, J ) 3.0 Hz), 3.38
(2H, d, J ) 6.0 Hz).
Experimental Section
General Methods. Melting points were determined with a Yazawa
micro melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a Varian Gemini 2000 using tetramethylsilane as an
internal standard. Chemical shifts are expressed in δ (ppm) values,
and coupling constants (J) are expressed in hertz (Hz). The following
abbreviations are used: s ) singlet, d ) doublet, t ) triplet, q ) quartet,
m ) multiplet, and brs ) broad singlet. Mass spectra were recorded
on a JEOL JMS-O1SG-2 spectrometer. NaH (60% in oil) and LiH
Preparation of 2-Hydroxy-1-phenyl-1-propane (14a).37 A solution
of propiophenone (2.0 g, 15.0 mmol), C6H5I(OAc)2 (5.0 g, 15.1 mmol),
and NaOH (6.0 g, 150 mmol) in 30 mL of MeOH was stirred for 4 h
at 0 °C under sonication. After neutralization by aqueous HCl, the
solution was extracted with CHCl3 (30 mL × 3). The CHCl3 layer
was dried over MgSO4, and the CHCl3 was removed under reduced
pressure. The residue was purified by SiO2 column chromatography
using AcOEt/hexane (1:5) as eluent to give 2-hydroxy-1-phenyl-1-
t
were obtained from Wako Chemicals Co., Ltd. MeLi in Et2O, BuLi
1
in pentane, Me2Zn (1.0 M solution in hexane), and Et2Zn (1.0 M
solution in hexane) were obtained from Kanto Chemical Co., Ltd. ZnCl2
(0.5 M solution in THF) was obtained from Aldrich Chemical Co. The
concentration of MeLi and tBuLi were determined by titration prior to
use.34
Preparation of Dimethylzinc. Under Ar atmosphere, MeLi (1.02
M Et2O solution, 2.0 mL, 2.0 mmol) was added to the mixture of dry
THF (3 mL) and ZnCl2 (1M THF solution; 1.0 mL, 1.0 mmol) at 0 °C,
and the mixture was stirred for 30 min at this temperature.
Preparation of Di-tert-butylzinc. Under Ar atmosphere, tBuLi (1.46
M pentane solution, 1.4 mL, 2.0 mmol) was added to the mixture of
dry THF (3 mL) and ZnCl2 (1M THF solution; 1.0 mL, 1.0 mmol) at
0 °C, and the mixture was stirred for 30 min at this temperature.
General Procedure for Reduction of Benzophenone (2). Under
Ar atmosphere, commercial dimethylzinc (1.1 mL, 1.1 mmol; 1.0 M
hexane solution) was added to a mixture of dry THF (3 mL) and NaH
(44.3 mg, 1.1 mmol; 60% in oil) at 0 °C, and the solution was stirred
for 30 min at this temperature. To the mixture was successively added
benzophenone (2) (183.5 mg, 1.0 mmol) in THF at 0 °C. After the
solution was allowed to warm to room temperature, the mixture was
stirred for 12 h. The solvent was removed under reduced pressure,
and the residue was treated with aqueous NH4Cl (30 mL) followed by
extraction with CHCl3 (30 mL × 3). The CHCl3 layer was dried over
MgSO4, and the CHCl3 was removed under reduced pressure. The
residue was purified by SiO2 column chromatography using AcOE/
propane (14a) (1.46 g, 63%) as a colorless oil: 300 MHz H NMR
(CDCl3/TMS) δ (ppm) 7.94 (2H, d, J ) 7.1 Hz), 7.62 (1H, t, J ) 7.6
Hz), 7.51 (2H, t, J ) 7.6 Hz), 5.17 (1H, q, J ) 7.1 Hz), 3.82 (1H, br),
1.46 (3H, d, J ) 6.9 Hz).
Preparation of 2-((Triisopropylsilyl)oxy)-1-phenyl-1-propane
(14b).38 A solution of 14a (260 mg, 1.69 mmol), imidazole (288 mg,
4.23 mmol), and triisopropylsilyl chloride (392 mg, 2.03 mmol) in DMF
(5 mL) was stirred for 12 h at room temperature. The solution was
treated with aqueous NH4Cl (10 mL) followed by extraction with Et2O
(10 mL × 2). The Et2O layer was dried over MgSO4, and the Et2O
was removed under reduced pressure. The residue was purified by
SiO2 column chromatography using AcOEt/hexane (1:25) as an eluent
to give 2-((triisopropylsilyl)oxy)-1-phenyl-1-propane (14b) (449 mg,
1
87%) as a colorless oil: 300 MHz H NMR (CDCl3/TMS) δ (ppm)
8.11 (2H, d, J ) 7.1 Hz), 7.55 (1H, t, J ) 6.9 Hz), 7.44 (2H, t, J ) 8.2
Hz), 4.98 (1H, q, J ) 6.9 Hz), 1.56 (3H, d, J ) 6.9 Hz), 1.16-0.74
(18H, m).
General Procedure for Diastereoselective Reduction of 3-Hy-
droxy-1,3-diphenyl-1-propanone (9) Using NaH-Me2Zn System.
Under Ar atmosphere, commercial dimethylzinc (1.1 mL, 1.1 mmol;
(35) Wiselogle, F. Y.; Sonneborn, H., III Organic Synthesis; Wiley: New
York, 1941; Collect. Vol. I, p 90.
(36) (a) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H.
D. J. Am. Chem. Soc. 1973, 95, 3310-3324. (b) Reference 25a.
(37) (a) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.
Soc. 1992, 114, 1778-1784. (b) Moriarty, R. M.; Hu, H.; Gupta, S. C.
Tetrahedron. Lett. 1981, 22, 1283-1286.
(34) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 46, 1879.
Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
(38) Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797-4798.

Dialkylzinc Hydride Ate Complexes
J. Am. Chem. Soc., Vol. 119, No. 47, 1997 11433
1.0 M hexane solution) was added to the mixture of dry THF (3 mL)
and NaH (88.7 mg, 2.2 mmol; 60% in oil) at 0 °C, and the solution
was stirred for 30 min at this temperature. To the mixture was
successively added 9 (220.0 mg, 0.97 mmol) in THF (3 mL) at 0 °C.
After the solution was allowed to warm to room temperature, the
mixture was stirred for 12 h. The solution was treated with aqueous
NH4Cl (30 mL) followed by extraction with CHCl3 (10 mL × 3). The
CHCl3 layer was dried over MgSO4, and the CHCl3 was removed under
reduced pressure. The residue was purified by SiO2 column chroma-
tography using AcOEt/hexane (1:2) as eluent to give a mixture of
stereoisomers of the diol (145.1 mg, 65%). The ratios of the
diastereomeric diols were determined by integration of the proton
signals in the 1H NMR spectra.39 rel-(1S,3S)-1,3-Diphenyl-1,3-
propanediol (anti-diol) (10): 300 MHz 1H NMR (CDCl3/TMS) δ (ppm)
4.99 (2H, dd, J ) 9.9, 5.8 Hz), 2.78 (2H, d, J ) 3.8 Hz), 2.19 (2H, t,
J ) 5.2 Hz). rel-(1S,3R)-1,3-Diphenyl-1,3-propanediol (syn-diol)
the standard manner.38 The solution was treated with NH4Cl (30 mL)
followed by extraction with CHCl3 (10 mL × 3). The CHCl3 layer
was dried over MgSO4, and CHCl3 was removed under reduced
pressure. The residue was purified by SiO2 column chromatography
using AcOEt/hexane (1:4) as eluent to give a mixture of stereoisomers
of the diol (42.5 mg, 70%). The ratios of the diastereomeric diols were
determined by integration of the proton signals in the 1H NMR spectra.40
General Procedure for Diastereoselective Reduction of 1-Phenyl-
1,2-propanedione (20). Under Ar atmosphere, commercial dimeth-
ylzinc (2.2 mL, 2.2 mmol; 1.0 M hexane solution) was added to the
mixture of dry THF (3 mL) and NaH (88.9 mg, 2.2 mmol; 60% in oil)
at 0 °C, and the solution was stirred for 30 min at the temperature. To
the mixture was successively added 20 (147.4 mg, 1.00 mmol) in THF
(3 mL) at 0 °C. After the solution was allowed to warm to room
temperature, the mixture was stirred for 12 h. The solution was treated
with aqueous NH4Cl (30 mL) followed by extraction with CHCl3 (10
mL × 3). The CHCl3 layer was dried over MgSO4, and the CHCl3
was removed under reduced pressure. The residue was purified by
SiO2 column chromatography using AcOEt/hexane (1:4) as an eluent
to give a mixture of stereoisomers of the diol (92.6 mg, 61%). The
ratios of the diastereomeric diols were determined by integration of
1
(11): 300 MHz H NMR (CDCl3/TMS) δ (ppm) 5.05 (2H, d, J ) 11
Hz), 3.21 (2H, s), 2.26-1.93 (2H, m).
General Procedure for Diastereoselective Reduction of 2-Hy-
droxy-1-phenyl-1-propane (14a). Under Ar atmosphere, commercial
dimethylzinc (0.5 mL, 0.5 mmol; 1.0 M hexane solution) was added
to the mixture of dry THF (3 mL) and NaH (40.3 mg, 1.0 mmol; 60%
in oil) at 0 °C, and the solution was stirred for 30 min at the temperature.
To the mixture was successively added 14a (59.9 mg, 0.40 mmol) in
THF (3 mL) at 0 °C. After the solution was allowed to warm to room
temperature, the mixture was stirred for 12 h. The solution was treated
with aqueous NH4Cl (30 mL) followed by extraction with CHCl3 (10
mL × 3). The CHCl3 layer was dried over MgSO4, and the CHCl3
was removed under reduced pressure. The residue was purified by
SiO2 column chromatography using AcOEt/hexane (1:4) as eluent to
give a mixture of stereoisomers of the diol (60.0 mg, 99%). The ratios
of the diastereomeric diols were determined by integration of the proton
signals in the 1H NMR spectra.40 rel-(1S,2R)-1-Phenyl-1,2-propanediol
(anti-diol) (15): 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 7.37-
7.28 (5H, m), 4.38 1 H, d, J ) 7.7 Hz), 3.87 (1H, quint, J ) 7.6 Hz),
2.88 (1H, br), 2.71 (1H, br), 1.00 (3H, d, J ) 7.4 Hz). rel-(1S,2S)-
1-Phenyl-1,2-propanediol (anti-diol) (16): 300 MHz 1H NMR (CDCl3/
TMS) δ (ppm) 7.35-7.25 (5H, m), 4.66 (1H, d, J ) 4.1 Hz), 3.99
(1H, dq, J ) 4.1, 6.3 Hz), 3.17 (2H, br), 1.05 (3H, d, J ) 6.3 Hz).
General Procedure for Diastereoselective Reduction of 2-((Tri-
isopropylsilyl)oxy)-1-phenyl-1-propane (14b). Under Ar atmosphere,
commercial dimethylzinc (0.5 mL, 0.5 mmol; 1.0 M hexane solution)
was added to the mixture of dry THF (3 mL) and NaH (40.6 mg, 1.0
mmol; 60% in oil) at 0 °C, and the solution was stirred for 30 min at
the temperature. To the mixture was successively added 14b (118.5
mg, 0.38 mmol) in THF (3 mL) at 0 °C. After the solution was allowed
to warm to room temperature, the mixture was stirred for 12 h. The
solution was treated with aqueous NH4Cl (30 mL) followed by
extraction with CHCl3 (10 mL × 3). The CHCl3 layer was dried over
MgSO4, and the CHCl3 was removed under reduced pressure. The
residue was hydrolyzed to the corresponding diols with (nBu)4NF in
1
the proton signals in the H NMR spectra.40
General Procedure for Catalytic Reduction. Under Ar atmo-
sphere, commercial dimethylzinc (0,2 mL, 0.2 mmol; 1.0 M hexane
solution) was added to the mixture of dry THF (3 mL) and LiH (10.0
mg, 1.2 mmol; 95%) at 0 °C, and the solution was stirred for 30 min
at the temperature under sonication. To the mixture was successively
added the carbonyl compound (1.0 mmol) in THF (3 mL) at 0 °C.
After the solution was allowed to warm to room temperature, the
mixture was stirred for 12 h under sonication. The solvent was removed
under reduced pressure, and the residue was treated with aqueous NH4-
Cl (30 mL) followed by extraction with CHCl3 (30 mL × 3). The
CHCl3 layer was dried over MgSO4, and the CHCl3 was removed under
reduced pressure. The residue was purified by SiO2 column chroma-
tography to give product.
General Procedure for Partial Reduction of Carboxylic Acids
to Aldehyde. Under Ar atmosphere, commercial dimethylzinc (1.0
mL, 1.0 mmol; 1.0 M hexane solution) was added to the mixture of
dry THF (3 mL) and LiH (25.2 mg, 1.2 mmol; 95%) at room
temperature, and the solution was stirred for 30 min at the temperature
under sonication. To the mixture was successively added the carboxylic
acid (1.0 mmol) in THF (3 mL) at 0 °C. After the solution was allowed
to warm to room temperature, the mixture was stirred for 24 h under
sonication. The solvent was removed under reduced pressure, and the
residue was treated with NH4Cl (30 mL) followed by extraction with
CHCl3 (30 mL × 3). The CHCl3 layer was dried over MgSO4, and
the CHCl3 was removed under reduced pressure. The residue was
purified by SiO2 column chromatography to give the corresponding
aldehyde.
Acknowledgment. This work has been supported in part
by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan (no. 09771893).
(39) Todesko, R.; Bockstaele, D. V.; Gelan, J.; Martens, H.; Put, J.;
DeSchryver, F. C. J. Org. Chem. 1983, 48, 4963-4968.
(40) Bowlus, S. B.; Katzenelenbogen, J. A. J. Org. Chem. 1974, 39,
3309-3314.
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