Catalytic asymmetric hydrogenation of heterocyclic ketone-derived hydrazones, pronounced solvent effect on the inversion of configuration

Article abstract of DOI:10.1016/j.tetlet.2011.05.017

An enantioselective hydrogenation of hydrazones derived from heterocyclic ketones was developed with up to 85% ee. The enantiomeric purity was enriched to >99% ee by crystallization from EtOAc in >80% yield. Optimization studies have revealed a notable so

Full text of DOI:10.1016/j.tetlet.2011.05.017

Tetrahedron Letters 52 (2011) 3718–3722
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic asymmetric hydrogenation of heterocyclic ketone-derived
hydrazones, pronounced solvent effect on the inversion of configuration
a
a
c
a
b
Nizar Haddad a, , Bo Qu , Sonia Rodriguez , Lars van der Veen , Diana C. Reeves , Nina C. Gonnella ,
Heewon Lee a, Nelu Grinberg a, Shengli Ma a, Dhileepkumar Krishnamurthy a, Tobias Wunberg c,
Chris H. Senanayake a
⇑
a Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, USA
b Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, USA
c Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective hydrogenation of hydrazones derived from heterocyclic ketones was developed with
up to 85% ee. The enantiomeric purity was enriched to >99% ee by crystallization from EtOAc in >80%
yield. Optimization studies have revealed a notable solvent effect that resulted in inversion of enantiose-
lectivity from 85% ee in MeOH to ꢀ27% ee in DCE. The hydrazone geometry and possible hydrogenation
via endocyclic alkene were examined as possible factors for the inversion of enantioselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 February 2011
Revised 26 April 2011
Accepted 5 May 2011
Available online 20 May 2011
Keywords:
Hydrazones
Chiral hydrazenes
Asymmetric hydrogenation
Reversed enantioselectivity
1. Introduction
enantioselectivity. To the best of our knowledge, hydrogenations
of hydrazones derived from cyclic ketones of the current work
Chiral hydrazines are integral substructures of many clinically
relevant pharmaceutical compounds.1 Despite the advances in
asymmetric hydrogenation of imines,2 limited attention was given
to asymmetric hydrogenation of hydrazones. Several publications
were reported since the detailed study by Burk et al.3 in 1994 on
the asymmetric hydrogenation of N-benzoyl hydrazones of
acetophenone derivatives. While high enantioselectivity was
obtained in the case of these substrates, low selectivity (43% ee)
has been reported for alkyl hydrazones derived from 2-butanone.
Yoshikawa et al.3e reported recent studies focused on the asym-
metric hydrogenation of N-alkoxycarbonyl hydrazones of aceto-
phenone derivatives, ligand screening was required to obtain
high enantioselectivity. The optimized conditions provided 64%
ee in the hydrogenation of bis-alkylhydrazone derived from
benzylacetone.
and inversion of enantioselectivity in the asymmetric hydrogena-
tion of hydrazones have not been previously reported.
2. Results and discussion
The asymmetric hydrogenations of N-benzoylhydrazones and
Boc-hydrazones were expected to provide different enantioselec-
tivities,3e therefore, hydrazones 1a and 1b were prepared4 and
studied.
Variety of chiral ligands (Fig. 1) were examined for substrates
1a and 1b, using 3% Rh(NBD)2BF4 in MeOH under 300 psi of H2 at
30 °C. Representative results (Table 1) identified Mandyphos ligand
4 as optimal; it provided complete conversion of the Boc protected
substrate 1a with 85% ee. Interestingly, under the same conditions,
the hydrogenation of benzoyl protected substrate 1b, gave poor
reactivity and low enantioselectivity (entry 2). Conversely, the
use of Et-Duphos as ligand provided higher enantioselectivity
(60% ee) with the benzoyl protected hydrazone 1b and poor selec-
tivity with substrate 1a. In general, high conversions were
obtained in most cases of alkylphosphine as well as arylphosphine
ligands.
Herein, we describe our studies on the enantioselective hydro-
genation of hydrazones of heterocyclic ketones A (Scheme 1),
where an unexpected solvent effect resulted in the inversion of
⇑
Corresponding author.
E-mail address: nizar.haddad@boehringer-ingelheim.com (N. Haddad).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.017

N. Haddad et al. / Tetrahedron Letters 52 (2011) 3718–3722
3719
Table 1
H
N
H
N
R
Selected ligand screening experiments for substrates 1a and 1b
HN
(S)
R
N
H
H2
H
N
H
H2, Rh(NBD)2BF4
N
N
R
N
Bz
NH
Boc
NH
300 psi, 30 o
MeOH,
C
or
R = Bz, Boc
(R)
Ref. 2
(R)
O
O
O
Chiral Ligand
H
N
H
N
3 mol%
R
N
a:
2a
2b
1
R = Boc
H2
R
NH
b: R = Bz
Up to 85%ee
(R)
R = Bz, Boc
n = 1,2
O
A
Entry
Ligand
2a
2b
n
O
B
n
% Conv.a
% eeb
% Conv.
% eec
This work
1
2
3
4
5
6
7
8
9
(S,S)-Et-DuPhos 3
(R,S)-MandyPhos 4
(S)-Binaphane 5
(R)-PhanePhos 6
(R,S)-JosiPhos 7
(R,R,S,S) DuanPhos 8
(R,R)-WalPhos 9
(S,R,R)-TunePhos 10
(S,S)-Et-FerroTane 11
(R)-BINAP 12
100
100
100
100
100
100
100
45
<5
30
42
28
2
100
60
0
100
70
100
100
100
100
40
60
14
n/a
14
34
54
10
20
35
21
—
Scheme 1. Substrates
hydrogenation.
A (R = Bz, Boc) pose a challenge for asymmetric
85
36
44
44
28
63
28
N/A
8
NMe2
Ph
PCy2
Cy2P
Ph
Et
Et
Fe
P
P
P
P
10
11
12
(R,R)-Quinox P 13
(S,S)-NorPhos 14
12
9
—
—
NMe2
Et Et
—
4
(R,S)-MandyPhos
5
3
(S)-Binaphane
H
(S,S)-Et-DuPhos
a
b
c
Conversions were determined by NMR and HPLC.
ee was determined by GC.
ee was determined by HPLC.
PtBu2
H
CH3
Ph2P
Cy2P
Fe
Ph2P
Table 2
Solvent screening using (R,S)-MandyPhos 4 (3 mol %) under 300 psi H2, 30 °C for 20 h
P
P
H
tBu
tBu
7
(R,S)- JosiPhos
(R)-PhanePhos
6
8
(R,R,S,S)-DuanPhos
Entry
Substrate
Solvent
Conversion
% ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
MeOH
EtOH
1-Pentanol
3-pentanol
THF
100
80
100
20
100
50
90
85
54
26
4
32
ꢀ24
ꢀ14
ꢀ27
ꢀ12
26
8
26
14
ꢀ14
PXyl2
Fe
PXyl2
P
O
O
PPh2
PPh2
Fe
Me
DCM
DCM
P
1,2-DCE
1,2-DCE
CF3CH2OH
Toluene
MeOH/H2O
MeOH
50
(R,R)- WalPhos
9
(S,R,R)-C3-TunePhos 10
(S,S)-Et-FerroTane 11
100
100
5
100
60
t-Bu
H
N
P
P
PPh2
PPh2
PPh2
1,2-DCE
100
N
H
PPh2
t-Bu
(S,S)-NorPhos 14
(R,R)-Quinox P 13
(R)-BINAP 12
major product when the hydrogenation was carried out in the
nonco-ordinating solvents dichloromethane or 1,2-dichloroeth-
ane7 (enries 6–9). While unexpected inversions in asymmetric
reactions are documented,8,9 inversion of chirality under homoge-
neous Rh catalyzed hydrogenation of hydrazones or imines as a
result of solvent effect is unprecedented.
Similar inversion of enantioselectivity as a factor of solvent was
obtained with substrate 1b (Table 2, entry 14). This result suggests
minor or no effect of the nature of the hydrazone protecting group.
The inversion of configuration in nonco-ordinating solvents could
indicate co-ordination effect of the oxygen heteroatom.
Hydrazone 15 was prepared and tested for similar inversion.
Hydrogenation under the optimized conditions, using (R,S)-Man-
dyPhos 4 as ligand in MeOH, provided 16 in high enantioselectivity
(Table 3).
Hydrogenation of 15 in dichloromethane provided lower
enantioselectivity compared to methanol or 1,2-dichloroethane.
Interestingly, no inversion of the configuration of the major prod-
uct was obtained with this substrate. In order to adequately
address the possibility that other factors such as hydrazone
geometry or hydrogenation via possible endocyclic eneamine
Figure 1. Selected ligands tested in this study.
The hydrogenation of substrate 1a with ligand 4 was examined
at 0 °C when a minor increase of enantioselectivity was observed.
Additional testing with ligand kits of MandyPhos, JosiPhos and
WallPhos series of ferrocene based ligands5 with substrate 1a,
did not provide us with a more effective catalyst than Mandyphos
ligand 4.
In an attempt for further optimization on N-Boc-hydrazone 1a,
different solvents were examined with Mandyphos ligand 4. Meth-
anol emerged as the solvent of choice with this ligand. As described
in Table 2, the tested alcohols indicated a large effect on the con-
version and enantioselectivity of the reaction, the bulkier alcohols
yielding a diminished enantioselectivity and lower conversion
(MeOH > EtOH > n-pentanol > 3-pentanol),6 presumably due to
increased steric constraints at the metal center via solvent ligation.
Water was found to play a detrimental role on the enantioselectiv-
ity, 5% water in methanol reduced the enantioselectivity from 85%
ee to 26% ee. More notable is the inverted configuration of the

3720
N. Haddad et al. / Tetrahedron Letters 52 (2011) 3718–3722
Table 3
H
N
H
H
N
H
N
N
Solvent effect using (R,S)-Mandyphos 4 under 300 psi H2, rt for 20 h
Boc
Boc
D
Boc
Boc
HN
n
HN
n
N
HN
D
D2
H2
D
Boc
HN
Boc
HN
Rh(NBD)2BF4
Rh(NBD)2BF4
MandyPhos 4
NH
N
O
O
O
18a:
18b: n=1
O
n
300 psi, 30 oC
MeOH,
(R,S)-MandyPhos
n
n=2 17a: n=2
1a: n=2
15:
19a: n=2
(R)
Formed
in >98%
17b: n=1
n=1
19b:
n=1
4
O
O
Not detected by 1H-NMR
15
16
Scheme 2. Deuterium labeling did not result in the formation of 18a or 18b at a
Entry
Solvent
Conversion
% ee
detectable limit.
1
2
3
MeOH
DCM
1,2-Dichloroethane
100
30
100
72
12
71
H
N
H
N
H
NH2
H
Boc
H2/Ligand 4, MeOH
300 psi, 30 o
Rh(NBD)2BF4,
87% isolated yield
Boc
N
HN
HN
HCl/Dioxane
(R)
C
O
O
O
16
15
20
H2,
Raney Ni
O
H
O
N
O
H
O
N
O
O
H
O
O
H
Bz
NH
(R)
NH2
NH2
H
N
N
N
N
H
H
BzCl
THF
BzCl
THF
N
N
(R)
O
22
O
O
21
21
Authentic Sample
O
O
O
O
Major enantiomer
n
n
n
n
E-cis
E-trans
Z-cis
Z-trans
Scheme 3. Assignment of absolute configuration of 16.
1a : n=1
15
Major
Minor
: n=2
isomerization contributes to the reversed enantioselectivity de-
tected in substrates 1.
Figure 2. Possible geometrical isomers of hydrazones 1a and 15.
The enantiomeric purity of 1a was enriched from 85% ee to
>99% ee by crystallization from EtOAc in >80% yield. The absolute
configuration of hydrazine 16 was determined by comparison to
an authentic sample of 22 with known (R)-configuration
(Scheme 3). A 300 mg sample of 15 was reduced under the opti-
mized conditions, using 0.5 mol % catalyst. Sample of hydrazine
16 (67% ee) was deprotected with 4 N HCl/Dioxane followed by
reductive cleavage of the N–N bond of 20 under 300 psi of H2 with
Raney Ni3b,12 to the corresponding amine 21 which then was trea-
ted with benzoyl chloride to give the known compound13 22 with
67% ee. Chiral GC comparison of this sample with an authentic
sample of (R)-22, prepared from (R)-(+)-3-aminotetrahydrofuran,
indicated an overlap with the major enantiomer of the reaction
mixture, confirming (R)-configuration in compound 16. The (R)-
configuration of hydrazene 2a was assigned based on optical
rotation sign and order of GC elution in comparison with 16.
intermediate contribute to this difference between five- and six-
membered ring heterocycles, we compared the geometry of hydra-
zones 1a and 15 in different solvents by NMR and tested their pos-
sible hydrogenation via endocyclic isomer.
The geometry of hydrazones, namely the ratio of cis/trans amide
conformers, is known to be affected by the nature of the solvent.10
The effect of solvents on Z/E geometrical isomerization was
reported on N-acyl and N-aroylhydrazones compounds with pre-
ferred Z configuration stabilized by intramolecular hydrogen bond-
ing.11 We examined the geometry and isomeric ratios of substrates
1 and 15 in CD3OD and CD2Cl2 by NMR. NOE experiments con-
firmed E-geometry of the major isomers of 1a and 15 at 0 °C and
25 °C. Four isomers were detected for compound 15 in CD2Cl2 at
0 °C (Fig. 2). NOESY data show two sets of NOE between the NH
protons and the C4-methylene protons, consistent with E-cis,
E-trans, Z-cis and Z-trans possible conformers.
3. Conclusion
One set of geometrical isomers was detected at 25 °C with E/Z
ratio of 1/0.15. A similar ratio of 1/0.18 was obtained in CD3OD.
Similar E/Z ratio for substrate 15, 1/0.25 in CD2Cl2 and 1/0.18 in
CD3OD was determined. These results indicate that the initial con-
figurations of hydrazones 1a and 15 in both solvents (MeOH,
CH2Cl2) do not play a key role in reversing the enantioselectivity
(Table 2).
Hydrogenation via isomerization of the hydrazone double bond
to the endocyclic ene-hydrazone 17a is another possible factor that
might contribute to reversed enantioselectivity in 1a. This was
examined for the five- and six-membered ring systems in metha-
nol and for 1a in CH2Cl2 as described in Scheme 2.
We have developed practical enantioselective hydrogenation of
hydrazones of five- and six-membered ring heterocyclic ketones
with up to 85% ee that was enriched to >99% ee after crystallization
in good yield. Optimization studies revealed an unexpected solvent
effect on the inversion of enantioselectivity in the six-membered
ring compounds 1, while retention of configuration was found in
the five-membered ring compound 15. Detailed studies ruled out
the hydrazone geometry or hydrogenation via endocyclic alkene
as possible factors for the inversion of configuration.
4. Experimentals
Hydrogenation of hydrazones 1 and 15 with deuterium under
the optimized conditions, revealed single deuterium incorporation
at the tertiary carbon in both compounds 19a and 19b as con-
firmed by LCMS and NMR data. The results consequently are con-
sistent with hydrogenation of the exocyclic C@N bond in both
substrates with no effective hydrogenation via isomerization to
the corresponding endocyclic double bond 17. To this end, neither
the initial hydrazone configuration nor endocyclic double bond
1H and 13C chemical shifts were calibrated versus TMS. 1H and
13C spectra observe frequencies were 1H: 600 or 400 MHz; 13C:
150 or 100 MHz; HRMS were performed on a Time of Flight mass
spectrometer (LC/MSD TOF). Enantiomeric excess was determined
by GC (Chiralsil-L-Val, 25 m, 0.25 mm) or HPLC (Chiralcel OD-H,
4.6 ꢁ 250 mm column) with detection at 220 nm, isocratic 92/8
Heptane/IPA with 1.5 mL/min flow rate for 20 min. (R)-(+)-3-amin-

N. Haddad et al. / Tetrahedron Letters 52 (2011) 3718–3722
3721
otetrahydrofuran-4-toluene sulfonate was purchased from Fluka.
4.2.2. (R)-tert-butyl-2-(3-deuteriotetrahydro-2H-pyran-3-yl)
All reagents were used as received unless stated otherwise.
hydrazinecarboxylate (19a)
Hydrazone 1a (100 mg, 0.45 mmol) was hydrogenated follow-
ing the typical procedure described above, under 300 psi of D2.
The compound was isolated in 93% yield as a white solid; 1H
NMR (400 MHz, CDCl3) d: 6.18 (bs, 1H), 3.89 (bs, 1H), 3.60 (d, J
=11.2 Hz, 1H), 3.75 (dt, J1 = 4.4, J2 = 11.2 Hz, 1H), 3.45 (dt, J1 = 2.8,
J2 = 10.6 Hz, 1H), 3.28 (d, J =11.2 Hz, 1H), 1.85 (m, 1H), 1.75 (m,
1H), 1.55 (m, 1H), 1.44 (s, 9H), 1.40 (m, 1H);
4.1. Typical procedure for the hydrazones synthesis
4.1.1. Tert-butyl-2-(2H-pyran-3(4H,5H,6H)-ylidene)hydrazine-
carboxylate (1a)
A 100 mL 3-neck flask with inert gas valve and septum was
charged with (6.50 g, 49.04 mmol) tert-butylhydrazinecarboxylate
and 30 mL MeOH. (4.91 g, 49.04 mmol) dihydro-2H-pyran-3(4H)-
one was syringed into the flask. The mixture was stirred at rt for
2 h to observe the disappearance of tert-butylhydrazinecarboxylate
monitored by LC–MS. The mixture was then dried over Na2SO4 and
the solution was filtered and the solvent removed under reduced
pressure to yield 10.4 g of white solid (99% yield). The compound
was further purified by passing through a short silica pad using
50% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3) d: 7.77 (br s, 1H),
4.20 (s, 2H), 3.78 (t, J = 5.38 Hz, 2H), 2.43 (t, J = 6.60 Hz, 2H), 1.85
(m, 2H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) d: 153.08, 149.49,
81.31, 71.51, 67.30, 28.24, 24.83, 23.19; HRMS for [2
4.2.3. (R)-N0-(2H-pyran-3(4H,5H,6H)-ylidene)benzohydrazide
(2b)
Hydrazene 2b was prepared and isolated in 91% yield; 1H NMR
(400 MHz, CDCl3) d: 7.86 (dd, J1 = 2.4, J2 = 11.3 Hz, 1H), 3.66 (m,
1H), 3.57 (m, 2H), 3.25 (b s, 1H), 1.95 (m, 1H), 1.82 (m, 1H), 1.69
(m, 1H), 1.54 (m, 1H); 13C NMR (100 MHz, CDCl3) d: 167.4, 132.3,
131.7, 128.7, 127.4, 69.5, 68.2, 56.1, 26.6, 23.3; HRMS for
[C12H16N2O2+H+]: observed 221.1302, calculated 221.1284; 60%
ee; ½a 2D0
ꢂ
= ꢀ6.2o (c 1.11, CHCl3).
C
10H18N2O3+H+]: observed 429.2706, calculated 429.2707.
4.2.4. (R)-tert-butyl-2-(dihydrofuran-3-(2H)-ylidene)hydrazine
carboxylate (16)
4.1.2. N0-(2H-pyran-3(4H,5H,6H)-ylidene)benzohydrazide (1b)
Following the typical procedure for 1a, the mixture was heated
to 60 °C for 7 h until benzohydrazide detected at <2% by LC-MS.
The product was isolated as white solid in 82% yield. 1H NMR
(400 MHz, CDCl3 d: 7.56 (br s, 1H), 7.80–7.82 (m, 2H), 7.52–7.56
(m, 1H), 7.44–7.48 (m, 2H), 4.31 (br s, 2H), 3.79–3.85 (t,
J = 5.2 Hz, 2H), 2.54–2.57 (t, J = 6.6 Hz, 2H), 1.89–1.95 (quint,
J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d: 164.24, 156.49,
133.33, 131.92, 128.68, 127.26, 71.40, 67.14, 24.96, 24.22; HRMS
for [C12H14N2O2+H+]: observed 219.1142, calculated 219.1128.
Hydrazene 16 was prepared and isolated in 87% yield; 1H NMR
(400 MHz, CDCl3) d: 6.41 (br s, 1H), 3.98 (br s, 1H), 3.92 (m, 2H),
3.80–3.68 (m, 4H), 2.00 (m, 1H), 1.76 (m, 1H), 1.46 (s, 9H); 13C
NMR (100 MHz, CDCl3) d: 157.0, 80.7, 71.8, 67.1, 60.3, 31.0, 28.3;
HRMS for [2 C9H18N2O3+H+]: observed 405.2716, calculated
405.2707; 72% ee; ½a D20
ꢂ
= +10.5o (c 1.14, CHCl3).
4.2.5. (R)-tert-butyl-2-(3-deuteriotetrahydrofuran-3-yl)
hydrazine carboxylate (19b)
Hydrazene 19b was prepared under 300 psi of D2. The com-
pound was isolated in 85% yield; 1H NMR (400 MHz, CDCl3) d:
6.20 (br s, 1H), 3.92 (dd, J1 = 7.6, J2 = 15.7 Hz, 1H), 3.78 (six,
J1 = 4.8, J2 = 8.3, J3=13.2 Hz, 1H), 3.73 (d, J = 9.6 Hz, 1H), 3.69 (d,
J = 9.6 Hz, 1H), 2.00 (m, 1H), 1.75 (m, 1H), 1.45 (s, 9H).
Procedures related to the assignment of absolute configuration
described at the Supplementary data.
4.1.3. Tert-butyl-2-(dihydrofuran-3(2H)-ylidene)hydrazine-
carboxylate (15)
Following the typical procedure for1a, hydrazone 15 was pre-
pared in 85% yield as a white solid; 1H NMR (400 MHz, CDCl3) d:
7.69 (br s, 1H), 4.22 (s, 2H), 4.01 (t, J = 6.96 Hz, 2H), 2.45
(t, J = 6.92 Hz, 2H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d:
156.30, 152.78, 81.54, 69.41, 67.78, 28.24, 27.43; HRMS for [2
C9H16N2O3+H] +: observed 401.2407, calculated 401.2394.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data; 1H and 13C spectra for new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.05.017.
4.2. Typical procedure for asymmetric hydrogenations
4.2.1. (R)-tert-butyl-2-(tetrahydro-2H-pyran-3-yl)hydrazine-
carboxylate (2a)
The catalyst solution was prepared in a 10 mL flask in the glove
box by addition of ligand 4 (25.35 mg, 0.03 mmol) to Rh(NBD)2BF4
(11.25 mg, 0.03 mmol) in degassed methanol (1 mL). The mixture
was stirred for 20 min at rt. Hydrazone 1a (320 mg, 1.5 mmol)
was placed in a 10 mL autoclave under N2 followed by addition
of 3 mL methanol. The catalyst solution was transferred to the
hydrazone solution then the mixture purged three times with N2
followed by two times with H2. The reaction was stirred under
300 psi H2 at 30 °C for 20 h. LCMS and 1H-NMR confirmed com-
plete conversion. The product was purified by column chromatog-
raphy to provide 556 mg product of 85% ee in 87% isolated yield as
a white solid. Crystallization from ethylacetate provided 80% of the
product in 99.4% ee. 1H NMR (400 MHz, CDCl3) d: 6.10 (bs, 1H),
3.90 (bs, 1H), 3.87 (dd, J1 = 2.4, J2 = 11.2 Hz, 1H), 3.75 (dt, J1 = 5.3,
J2 = 11.2 Hz, 1H), 3.46 (dt, J1 = 2.8, J2 = 11.9 Hz, 1H), 3.3 (dd,
J1 = 7.9, J2 = 11.3 Hz, 1H), 3.9 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H),
1.59 (m, 1H), 1.47 (s, 9H), 1.44 (m, 1H); 13C NMR (100 MHz, CDCl3)
References and notes
1. (a) Coteron, J. M.; Catterick, D.; Castro, J.; Chaparro, M. J.; Diaz, B.; Fernandez, E.;
Ferrer, S.; Gamo, F. J.; Gordo, M.; Gut, J.; de las, H. L.; Legac, J.; Marco, M.;
Miguel, J.; Munoz, V.; Porras, E.; de la Rosa, J. C.; Ruiz, J. R.; Sandoval, E.;
Ventosa, P.; Rosenthal, P.; Fiandor, J. M. J. Med. Chem. 2010, 53, 6129; (b)
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H.-U.; Spinder, F. In Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
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3. For selected representative publications see: (a) Burk, M. J.; Feaster, J. E. J. Am.
Chem. Soc. 1992, 114, 6266; (b) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford,
N. Tetrahedron 1994, 50, 4399; (c) Tappe, K.; Knochel, P. Tetrahedron:
Asymmetry 2004, 15, 91; (d) Ireland, T.; Tappe, K.; Grossheimann, G.;
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J. C.; Ramasamy, D.; Sheppard, R. Org. Lett. 2010, 12, 276.
4. Hydrazones were prepared with minor modification of literature procedure
(Ref. 3e).
5. Ligands kit available from Solvias.
6. In contrast to low solubility of substrate 1b in IPA (Ref. 3e), hydrazone 1a is
highly soluble in the tested alcohols.
d
C
:
154.3, 84.2, 68.1, 66.43, 57.3, 28.1, 23.8, 22.5; HRMS for [2.
10H20N2O3+H+]: observed 433.3015, calculated 433.3020; 99.4%
ee; ½a 2D0
ꢂ
= +33.7o (c 0.78, CHCl3).

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N. Haddad et al. / Tetrahedron Letters 52 (2011) 3718–3722
7. For studies on solvent effect of Rh catalyzed hydrogenations see (a) Crabtree, R.
H.; Demou, P. C.; Eden, D.; Mihelcic, J. M.; Parnell, C. A.; Quirk, J. M.; Morris, G.
E. J. Am. Chem. Soc. 1982, 104, 6994; (b) Crabtree, R. H.; Felkin, H.; Morris, G. E. J.
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3649.
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Am. Chem. Soc. 2003, 125, 113; (c) Jenkins, R$. L.; Dummer, N.; Li, X.; Bawaked,
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1993, 1074; (b) Kapron, J. T.; Santarsiero, B. D.; Vederas, J. C. J. Chem. Soc., Chem.
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13. Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. compound 2b0
in Supplementary data of this reference.