Generation of hafnium hydride and its application to chemo- and diastereoselective reactions

Article abstract of DOI:10.1055/s-0029-1216739

Hafnium hydride was generated by the transmetalation between Bu ₃SnH and HfCl₄ using either THF or EtCN as the solvent. This process effectively reduced aldehydes, aldimines, ketones, and esters. In the hafnium hydride reduction of α-alkoxyketones, the diastereoselectivity was dependent on whether THF or EtCN was used as the solvent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216739

LETTER
1495
Generation of Hafnium Hydride and its Application to Chemo- and
Diastereoselective Reactions
Generati
k
on of
H
afniu
u
m
H
ydride ya Shibata,*a Shinji Miyamoto,a Toru Itoh,b Akio Babab
c
Research Center for Environmental Preservation, Osaka University, 2-4 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68798978; E-mail: shibata@epc.osaka-u.ac.jp
d
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 3 February 2009
When the mixture of Bu3SnH and HfCl4 was stirred in tol-
uene at –20 °C, Bu3SnH first appeared after 5 minutes.6
When THF was used as the solvent, both Bu3SnH and
Bu3SnCl were detected. Although the reaction was not
Abstract: Hafnium hydride was generated by the transmetalation
between Bu3SnH and HfCl4 using either THF or EtCN as the sol-
vent. This process effectively reduced aldehydes, aldimines,
ketones, and esters. In the hafnium hydride reduction of a-alkoxy-
ketones, the diastereoselectivity was dependent on whether THF or quantitative, the formation of Bu3SnCl indicated that par-
EtCN was used as the solvent.
tial transmetalation of Bu3SnH with HfCl4 had occurred.
In addition, when the reaction was performed in EtCN,
only Bu3SnCl was detected.4 This result indicated that the
hafnium hydride species formed immediately in EtCN. At
lower reaction temperatures, for example, –40 °C, trans-
metalation did not occur. The generated hafnium hydride
was labile, as evidenced by its decomposition (accompa-
nied by H2 production) concurrent with the generation of
Bu3SnCl.7
Key words: hafnium, hydrides, transmetalation, reduction, selec-
tivity
Hafnium tetrachloride (HfCl4) is a characteristic Lewis
acid, which catalyzes both the hydrometalation of
alkynes1 and esterification.2 Hafnium tetrachloride cata-
lyzes these reactions by activating both the alkynes and
the carbonyl functional groups.
In the next stage, the ability of the hafnium hydride
formed in situ to react with carbonyl derivatives was in-
vestigated. Tri-n-butyltin hydride, HfCl4, and substrate 1
were mixed in either EtCN or THF at –20 °C, and the
reactions were allowed to proceed for 3 hours. Benzalde-
hyde (1a), acetophenone (1b), and aldimine 1c were ef-
fectively reduced to the corresponding alcohols 2a,b and
amine 2c, respectively (Scheme 1, eq 1–3).
By contrast, organotin nucleophiles easily transmetalate
with other acidic metals.3 We previously reported that in-
dium halide (InX3)4 or early transition-metal halides, such
as tantalum halide (TaCl5)5, were easily transmetaled with
tin compounds, such as tin hydride and allylic tins, to gen-
erate active metal species. Thus, an advantage of the orga-
notin-based metal exchange is that the byproducts, such as
the trialkyltin halides, are weak Lewis acids that reduce
decomposition of the generated active metal species.4,5
Regioselective 1,2-reduction of a-enones 3 gave allylic
alcohols 4. Cyclic and acyclic aliphatic enones were ap-
plicable substrates (Scheme 2, eq 4–6). The reaction of ar-
omatic enones, such as chalcone, resulted in complex
mixtures.
In the present study, we examined the transmetalation be-
tween tri-n-butyltin hydride (Bu3SnH) and HfCl4
(Figure 1). We estimated transmetalation by monitoring
the formation of Bu3SnCl using 119Sn NMR.
HfCl4 (1 mmol)
Bu3SnH (1 mmol)
Ph
H
Ph
OH
Bu3SnCl
Bu3SnH
"HHf"
(1)
HfCl4
+
+
–20 °C, 3 h
–20 °C, 5 min
Me4Sn
O
EtCN
THF
2a
2b
84%
Bu3SnCl
(1 mmol)
quant.
1a
HfCl4 (1 mmol)
EtCN
Ph
Bu3SnH (1 mmol)
Ph
(2)
Bu3SnH
–20 °C, 3 h
OH
THF
O
EtCN
THF
85%
92%
1b
(1 mmol)
toluene
Cl
40
20
0
–20 –40 –60 –80 –100
120 100 80
60
–120
[ppm]
HfCl4 (1 mmol)
Bu3SnH (1 mmol)
H
(3)
Cl
–20 °C, 3 h
Figure 1 Generation of Bu3SnCl by transmetalation
NHPh
NPh
2c
EtCN 99%
92%
1c
(1 mmol)
SYNLETT 2009, No. 9, pp 1495–1497
Advanced online publication: 04.05.2009
x
x.
x
x.
2
0
0
9
THF
DOI: 10.1055/s-0029-1216739; Art ID: U01209ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Reduction of carbonyl derivatives

1496
I. Shibata et al.
LETTER
Table 1 Reduction of Estersa
HfCl4 (1 mmol)
Bu3SnH (1 mmol)
t-Bu
Ph
t-Bu
Ph
HfCl4
Bu3SnH
(4)
OH
4a 97%
O
R1
OR2
THF, –20 °C, 1 h
R1
OH
3a (1 mmol)
solvent, –20 °C, 3 h
O
5
6
HfCl4 (1 mmol)
Bu3SnH (1 mmol)
n-C5H11
n-C5H11
Entry R1
R2
Et
Solvent Product
Yield (%)
97
(5)
(6)
O
O
OH
THF, –20 °C, 1 h
4b 61%
3b (1 mmol)
1
BnCH2
EtCN
THF
Ph
6a
6a
OH
HfCl4 (1 mmol)
2
3
0 (48)b
78
HO
Bu3SnH (1 mmol)
BnCH2
t-Bu EtCN
6a
THF, –20 °C, 1 h
56%
4c
(1 mmol)
3c
n-C9H19OH
4
n-C8H17
Et
EtCN
83
Scheme 2 1,2-Reduction of enones
6b
5
6
Ph
Et
EtCN
THF
Ph
6c
Ph
OH
96
99
The reducing ability of this system is so high that the ester
functional groups 5 were effectively reduced to the corre-
sponding alcohols 6 (Table 1). The use of EtCN as solvent
in these reactions gave a greater yield compared with that
obtained using THF (entries 1 and 2). Thus, both aliphatic
and aromatic alkyl esters were applicable substrates.
Bn
Bn
OH
6d
95
Ph
OH
6c
As shown in Scheme 3, the chemoselectivity of the reduc-
tion of the a,b-unsaturated ester 7a was dependent on
which solvent was used to induce either of the active
hafnium species, hafnium hydride or HfCl4. Thus, the
reaction in EtCN afforded predominantly the allylic alco-
hol 8a (eq 7). On the other hand, in toluene, the carbon–
carbon double bond was reduced to give the saturated
ketone 8b (eq 8). In toluene, HfCl4 acted as a Lewis acid,
and no transmetalation occurred.
a Hafnium hydride was generated by the HfCl4/Bu3SnH system. Re-
duction was performed by the reaction of 9 (1 mmol) with HfCl4/
Bu3SnH (3 mmol) in EtCN or THF (2 mL) at –20 °C for 3 h.
b Room temperature.
other hand, the ability of EtCN to coordinate with hafnium
is poor; hence, the reduction with hafnium hydride results
in chelation with the substrate 9 to give the erythro-alco-
hol 11.12
Finally, we performed the reduction of a-alkoxyketones 9
(Table 2).8 Interestingly, the diastereoselectivity of the
reaction was dependent on whether EtCN or THF was
used as the solvent. When the reduction was carried out in
EtCN, predominantly erythro-alkoxy alcohols 11 were
obtained (entries 1 and 3). On the other hand, use of THF
as the solvent increased the ratio of threo-isomers 10 (en-
tries 2 and 6).9
THF
Ph
•
H
Hf
H
OMe
Ph
Ph
OMe
THF
OH
10a threo
Ph
O
Felkin–Anh
OMe
Ph
Scheme 4 explains, in terms of the Lewis acidity of the
hafnium center, why the diastereoselectivity of the hafni-
um hydride reduction of 9 varies with the solvent. Tet-
rahydrofuran coordinates to the hafnium center, and
prevents chelation between hafnium and the oxygen sub-
stituent of 9.10 Hence, the reaction proceeds according to
the Felkin–Anh model11 to give threo-alcohol 10. On the
Ph
Ph
H
Ph
OMe
Ph
O
•
Ph
EtCN
9a
OMe
O
H
OH
11a erythro
Hf
chelation
Scheme 4 Control of diastereoselectivity
HfCl4 (2 mmol)
Ph
OMe
Bu3SnH (2 mmol)
+
Ph
8a
OH
Ph
OH (7)
EtCN, –20 °C, 3 h
O
8c
44%
12%
(1 mmol)
7a
HfCl4 (2 mmol)
Bu3SnH (2 mmol)
Ph
OMe
7a
+
(8)
Ph
OH
toluene, –20 °C, 3 h
(1 mmol)
O
8c 8%
8b 41%
Scheme 3 Reduction of unsaturated esters
Synlett 2009, No. 9, 1495–1497 © Thieme Stuttgart · New York

LETTER
Generation of Hafnium Hydride
1497
Table 2 Reduction of a-Alkoxyketonesa
Michael, D.; Mingos, P., Eds.; Elsevier: Oxford, 2006,
Chap. 8, 341–380.
(4) Miyai, T.; Inoue, K.; Yasuda, M.; Shibata, I.; Baba, A.
Tetrahedron Lett. 1998, 39, 1929.
(5) Shibata, I.; Kano, T.; Kanazawa, N.; Fukuoka, S.; Baba, A.
Angew. Chem. Int. Ed. 2002, 41, 1389.
(6) Hafnium(IV) chloride and Bu3SnH were mixed in NMR
sample tube under the conditions of –20 °C, and the mixture
was immediately introduced NMR instrument and
measured. The obtained chart was the one after 5 minutes
from mixing.
(7) In transmetalated mixture in EtCN over –20 °C, fast
decomposition occurred with quantitative generation of H2,
hence we could not determine exact hafnium species such as
HHfCl3 or H2HfCl2.
(8) Shibata, I.; Yoshida, T.; Kawakami, T.; Baba, A.; Matsuda,
H. J. Org. Chem. 1992, 57, 4049.
OR2
OR2
R3
OR2
R3
HfCl4
R1
Bu3SnH
R1
R1
R3
+
solvent, –20 °C, 3 h
O
OH
10 threo
OH
11 erythro
9
(1 mmol)
Entry
Substrate 9
Solvent
Yield (%) 10/11
OMe
Ph
1
2
EtCN
THF
93
96
15:85
77:23
Ph
O
O
9a
OMe
Me
3
4
Ph
EtCN
THF
85
77
10:90
54:46
(9) Typical Procedure
A 10 mL round-bottom flask charged with HfCl4 (1.0 mmol)
was dried by heating to 110 °C under reduced pressure
(1.33·10–3 bar) for 1 h. After the nitrogen was filled, EtCN
(2 mL) was added to dissolve HfCl4, and the solution was
cooled to –20 °C. To the mixture was added Bu3SnH (1.0
mmol) and after 5 minutes benzoin methyl ether (9a, 1.0
mmol). After stirring for 3 h, the resulting mixture was
quenched by aq MeOH (5 mL) and extracted with Et2O (3 ×
10 mL). The combined organic layer was treated with NH4F,
and then the precipitate was filtered to remove the tin
compound. The organic layer was dried over MgSO4, and
then filtered and evaporated. Yield and ratio of 10a/11a were
determined by NMR. Further purification was performed by
SiO2 column chromatography eluting with hexane–EtOAc =
85:15 afforded 10a and 11a as a mixture.
9b
Oi-Pr
Me
5
6
EtCN
THF
100
94
52:48
86:14
Ph
O
9c
a Hafnium hydride was generated by HfCl4/Bu3SnH system. Reduc-
tion was performed by the reaction of 9 (1 mmol) with HfCl4/Bu3SnH
(1 mmol) in EtCN or THF (2 mL) at –20 °C for 3 h.
In conclusion, hafnium hydride generated in situ demon-
strated consistent reducing ability. In some cases, control
of regio- and diastereoselectivity was achieved by varying
the solvent.
threo-2-Methoxy-l,2-phenylethanol (10a) and erythro-2-
Methoxy-l,2-phenylethanol (11a)
Compound 10a: Mp 84–87 °C. IR (KBr): 3400, 1030, 1045
cm–1. MS: m/z = 228 [M+]. 1H NMR (400 MHz, CDC13):
d = 2.45 (br, 1 H, OH), 3.30 (s, 3 H, OCH3), 4.12 (d, 1 H,
J = 8.3 Hz, CHOMe), 4.65 (d, 1 H, J = 8.3 Hz, CHOH),
7.11–7.28 (m, 10 H, Ph).
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Cul-
ture, the Mizuho-Espec Foundation, the Kurata Memorial-Hitachi
Science and Technology Foundation, and the Naito Foundation.
Compound 11a 1H NMR (400 MHz, CDC13): d = 2.45 (br,
1 H, OH), 3.22 (s, 3 H, OCH3), 4.34 (d, 1 H, J = 5.4 Hz,
CHOMe), 4.88 (d, 1 H, J = 5.4 Hz, CHOH), 7.11–7.28 (m,
10 H, Ph).
References and Notes
(10) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74,
5828.
(11) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
18, 2199.
(12) In the reduction of 9a in MeCN, the addition of ligand such
as Ph3P=O afforded 79% anti selectivity. Hence Ph3P=O
coordinates to hafnium center to prevent the chelate
formation.
(1) Asao, N.; Liu, J.-X.; Sudoh, T.; Yamamoto, Y. J. Org.
Chem. 1996, 61, 4568.
(2) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000,
290, 1140. (b) Ishihara, K.; Nakayama, M.; Ohara, S.;
Yamamoto, H. Tetrahedron 2002, 58, 8179.
(3) Baba, A.; Shibata, I.; Yasuda, M. In Comprehensive
Organometallic Chemistry III, Vol. 9; Crabtree, R. H.;
Synlett 2009, No. 9, 1495–1497 © Thieme Stuttgart · New York

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