Enantioselective hydrogenation of diaryl-substituted α,β-unsaturated nitriles

Article abstract of DOI:10.1016/j.tetlet.2006.03.115

α,β-Unsaturated nitriles can be hydrogenated with enantioselectivities up to 88% ee using chiral ruthenium-diphenylphosphino bisaryl and bisheteroaryl complexes such as ruthenium(II)-BINAP and ruthenium(II)-BINP. Mechanistic investigations indicate that conversion is accelerated by electron-rich ligands and that an additional coordinative group needs be present in order to promote conversion. The chiral products are useful building blocks for the synthesis of histamine H₂ agonists of the arpromidine type.

Full text of DOI:10.1016/j.tetlet.2006.03.115

Tetrahedron Letters 47 (2006) 3733–3736
Enantioselective hydrogenation of diaryl-substituted
a,b-unsaturated nitriles
Tobias C. Wabnitz,a Simona Rizzo,b Carsten Go¨tte,c Armin Buschauer,c
Tiziana Benincorid,* and Oliver Reisera,*
aInstitut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040 Regensburg, Germany
bIstituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, via Golgi, 19, 20133-Milano, Italy
cInstitut fu¨r Pharmazie, Universita¨t Regensburg, D-93040 Regensburg, Germany
`
Dipartimento di Scienze Chimiche ed Ambientali, Universita dell’Insubria, via Valleggio 11, 22100-Como, Italy
d
Received 7 March 2006; accepted 20 March 2006
Available online 17 April 2006
Abstract—a,b-Unsaturated nitriles can be hydrogenated with enantioselectivities up to 88% ee using chiral ruthenium-
diphenylphosphino bisaryl and bisheteroaryl complexes such as ruthenium(II)-BINAP and ruthenium(II)-BINP. Mechanistic inves-
tigations indicate that conversion is accelerated by electron-rich ligands and that an additional coordinative group needs be
present in order to promote conversion. The chiral products are useful building blocks for the synthesis of histamine H2 agonists
of the arpromidine type.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Enantioselective hydrogenation has evolved into a pow-
erful tool in synthetic chemistry and a diverse array of
chiral compounds can now be accessed in enantiopure
form through hydrogenation of carbon–carbon or car-
bon–heteroatom double bonds.1 Although a wide range
of prochiral substrates can be used as substrates, in the
majority of the cases, enantioselectivity is greatly
increased when a suitable coordination site is present,
normally containing heteroatom functionalities as, for
example, seen with acrylic acid derivatives, aminoalk-
enes, enol esters and other compound classes. The enan-
tiodifferentiating hydrogenation of compounds lacking
such moieties is substantially more difficult.2
tional challenge.3 Only recently, a chemoselective cata-
lytic conjugate reduction of a,b-unsaturated nitriles,
that is, not employing stoichiometric metal hydride
reductants, was reported as a non asymmetric variant
by Yun et al.4 Apart from isolated cases such as the rho-
dium diphospine-mediated hydrogenation of a,b-unsat-
urated nitriles bearing additional carboxylate or
phthalimido substituents,5 there are no reports on the
asymmetric hydrogenation of acrylonitrile derivatives.
In our studies towards developing a general enantio-
selective methodology for the preparation of optically
active nitriles, we initially focused on b,b-diaryl acrylo-
nitriles as the hydrogenation products can serve as
building blocks for the synthesis of chiral arpromidines,
a class of highly active histamine H2 receptor agonists.
These compounds are currently investigated for their
use as positive inotropic and vasodilatory drugs.6 The
results of the catalyst screening for the asymmetric
hydrogenation of E-3-(3,4-difluorophenyl)-3-(2-pyr-
idyl)propenenitrile (E-1), which can be converted to 3
being one of the most potent H2-agonists known to date
(Scheme 1), are summarized in Table 1.
a,b-Unsaturated nitriles are valuable and easily accessi-
ble building blocks in organic synthesis. However, a gen-
eral methodology for the asymmetric hydrogenation of
a,b-unsaturated nitriles has not yet been developed.
Due to their electronic structure, nitriles prefer end-on
coordination of metal ions, which is not suitable for
hydrogenation of a conjugated double bond. Further-
more, chemoselection between the olefinic double bond
and the nitrile group in hydrogenation poses an addi-
Due to the polarized nature of the olefinic double bond,
we initially studied chiral hydride reagents such as
BINAL-H for this conjugate reduction process.7
*
Corresponding authors. Tel.: +49 941 943 4631; fax: +49 941 943
4121 (O.R.); e-mail: oliver.reiser@chemie.uni-regensburg.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.115

3734
T. C. Wabnitz et al. / Tetrahedron Letters 47 (2006) 3733–3736
Scheme 1. Hydrogenation of acrylonitrile E-1 as a key step for the synthesis of arpromidine analog 3.
Table 1. Catalytic enantioselective hydrogenation of the a,b-unsaturated nitrile E-1a
Entry
Catalystb
E0ligand [V]
Solvent
T [ꢁC]
p(H2) [bar]
t [h]
Conversion (%)c
ee (%)
1
2f
3
4
5
6
7
8
9
Li[Al(H)((+)-(R)-BINOLate)(OEt)]d
[Rh((+)-(R)-BINAP)(COD)]ClO4
[Ru((+)-(R)-BINAP)Cl2Ædmfn]
[Ru((+)-(R)-TolBINAP)Cl2Ædmfn]
[Ru((+)-(S)-tetraMe-BITIANP)Cl2Ædmfn]
[Ru(( )-BIMIP)Cl2Ædmfn]
[Ru((+)-(S)-tetraMe-BITIOP)Cl2Ædmfn]
[Ru((ꢀ)-(S)-N-Me-2-BINP)Cl2Ædmfn]
[Ru((ꢀ)-(S)-N-Me-2-BINP)Cl2Ædmfn]
[Ru((ꢀ)-(S)-N-Me-2-BINP)Cl2Ædmfn]
n.d.
THF
ꢀ78 to 0
—
50
12
144
48
48
48
60
48
24
72
48
Decomp.e
rac
+0.63
+0.63
+0.65
+0.83
+1.15
+0.57
+0.52
+0.52
+0.52
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
50
50
50
50
50
50
50
37
0
100
100
60
—
100
100
100
100
100
100
25
51 (S)g
52 (S)
52 (S)
h
27
–
100
100
55
53 (R)
80 (R)
81 (R)
88 (R)
10
100
70
a For a general procedure, see Ref. 16. Unless otherwise noted, there were no side reactions, and products could be isolated quantitatively according
to conversion.
b 2 mol % catalyst was used (except in entry 1).
c Conversion was determined by 1H NMR of the crude mixture.
d Used as a reagent (3 equiv).
e Decomposition of the starting material, 9% isolated yield of 2.
f Both in the presence and absence of Et3N (2 mol %); COD = 1,5-cycloctadiene.
g Configuration of the major enantiomer being indicated, see Ref. 17.
h Racemic ligand.
Unfortunately, this approach furnished only racemic
products and suffered from side reactions even at low
temperatures (entry 1). Similarly, chiral rhodium diphos-
phine complexes such as [Rh((+)-(R)-BINAP)(COD)]-
ClO4, which are extremely effective catalysts for the
enantioselective hydrogenation of acetamidoacrylates
and related compounds,1,8 turned out to be unsuitable
catalysts for this transformation. Even after prolonged
periods, no conversion was observed (entry 2). In con-
trast, ruthenium-based catalysts exhibited high activities
in this reaction. The ruthenium-BINAP system [Ru((+)-
(R)-BINAP)Cl2Ædmfn] developed by Noyori9,10 led to
complete conversion of the acrylonitrile 1 and furnished
the chiral product in 51% ee (entry 3). BINAP and Tol-
BINAP performed very similarly in this process (entries
3,4). In order to improve the enantioselection, a series
of other chiral diphosphine ligands were investigated.
bisaryl systems,11 were also tested as ligands for this
transformation. These ligands offer the possibility of
fine-tuning the electron-donor properties at the phos-
phorous atoms. Normally, electronic-rich diphosphines
are superior ligands in terms of both conversion and
enantioselectivity in ruthenium and rhodium-catalyzed
hydrogenations of olefins and carbonyl compounds.12
Variation of the electron density of the biheteroaryl
diphosphines revealed a similar correlation in case of
the hydrogenation of a,b-unsaturated nitriles. The elec-
tron-poor ligands (as determined by their electrochemi-
cal oxidation peak potential E0)(+)-(S)-tetraMe-
BITIANP and ( )-BIMIP led to poor conversions and
no improvement of enantioselectivity was observed (en-
tries 5 and 6 in Table 1). In contrast, smooth conversion
was observed with electron-rich ligands such as (+)-(S)-
tetraMe-BITIOP and (ꢀ)-(S)-N-Me-2-BINP (entries
7,8). In the latter case, the enantiomeric excess could
be raised to 81%. Reducing the hydrogenation pressure
led to a decreased reaction rate, but left the enantioselec-
Diphenylphosphino biheteroaryls (Fig. 1), which are
synthetically more easily accessible than the carbocyclic
N
S
S
PPh2
N
N
PAr2
PPh2
PPh2
PPh2
2
2
2
2
2
Ar = Ph
BINAP
Ar = p-Tolyl TolBINAP
tetraMe-BITIANP
BIMIP
tetraMe-BITIOP
N-Me-2-BINP
Figure 1. Bisaryl- and bisheteroaryl diphosphine ligands for asymmetric hydrogenations.

T. C. Wabnitz et al. / Tetrahedron Letters 47 (2006) 3733–3736
3735
tivity unaffected. In contrast, through lowering the reac-
tion temperature, the level of enantioselectivity was fur-
ther increased to 88% ee (entries 9 and 10).
theless, the influence of the pyridyl substituent as a pos-
sible coordinative site for the ruthenium catalysts was
investigated through hydrogenation of 5 and 6. In these
constitutional isomers with very similar electronic prop-
erties, only 5 contains the nitrogen in the ortho-position
of the pyridyl substituent. Whilst the expected result
(100% conversion and +39% ee with (+)-(R)-BINAP
as a ligand, ꢀ81% ee with (ꢀ)-(S)-N-Me-2-BINP) was
obtained when E-5 was subjected to hydrogenation,
the isomer E-6 could not be converted at all (entries
5–7). Similarly, the b,b-diphenyl acrylonitrile 7 did not
undergo any conversion (entry 6). An analogous obser-
vation was made when a-substituents were present as in
the nitriles 8–10. In these cases, the ortho-nitrogen of 8
was a requirement for conversion (entries 9–11). In
contrast, Z-cinnamonitrile (11) was readily converted
into the saturated achiral product (entry 12). These
results demonstrate the difficulties inherent to the hydro-
genation of a,b-unsaturated nitriles and the need for
additional coordinative sites when acrylonitriles bearing
more than one substituent are used.15
In order to gain insights into the reaction mechanism,
the Z-isomer of 1 and compounds 4–10 were synthesized
and subjected to hydrogenation using the established
[Ru((R)-BINAP)Cl2Ædmfn] catalyst (Scheme 2). The
results are summarized in Table 2. The hydrogenation
of Z-1 proceeded much slower than with the E-isomer,13
furnishing the product in low ee and opposite configura-
tion (entries 1 and 2). In addition, traces of E-1 were de-
tected in the reaction mixture after hydrogenation. As
the reaction products are stable under hydrogenation
conditions, this implies that ruthenium catalysts are able
to isomerize the E/Z-isomers of a,b-unsaturated nitriles,
similarly to the Ru-catalyzed isomerization of a,b-unsat-
urated carbonyl compounds investigated by Takaya
et al.14 Furthermore, this result also indicates that the
configuration at the nitrile-bearing a-carbon atom plays
a crucial role in the selection of the enantiofaces. Never-
In conclusion, the ruthenium diphosphine-mediated
enantioselective hydrogenation of a,b-unsaturated nitr-
iles has been achieved with up to 88% ee,16,17 offering a
new access to chiral arpromidine precursors. Mechanis-
tic investigations revealed that electron-rich diphosphine
ligands accelerate conversion of these transforma-
tions. Furthermore, the stereoselection observed with
Scheme 2. Asymmetric hydrogenation of various a,b-unsaturated
nitriles.
Table 2. Catalytic hydrogenation of di- and monoaryl-substituted a,b-unsaturated nitriles with [Ru((+)-(R)-BINAP)Cl2Ædmfn] according to Scheme
2a
Entry
Substrate
Conversion (%)b ee (%)
Entry
Substrate
Conversion (%)b ee (%)
X
X
X
X
51 (S)c
53 (R)e
39 (S)
2
4
Z-1
Z-4
70
26
8d (R)
race
CN
1
3
5
6
E-1: X = F
E-4: X = Cl
E-5: X = H
E-5: X = H
100
90
100
100
CN
81 (R)f
N
N
CN
CN
Ph
Ph
7
E-6
0
—
8
7
0
—
Ph
N
H
CN
CN
CN
g
Ph
Ph
Ph
Ph
N
9
8
100
—
10
12
9
0
—
H
H
N
CN
11
10
0
—
11
100
N/A
H
H
a For a general procedure, see Ref. 16. Unless otherwise noted, there were no side reactions, and products could be isolated quantitatively according
to conversion.
b Conversion was determined by 1H NMR of the crude mixture.
c Configuration of the major enantiomer being indicated, see Ref. 17.
d Traces of E-1 were formed during the reaction.
e (ꢀ)-(S)-BINAP was used as the ligand.
f (ꢀ)-N-(S)-Me-2-BINP was used as a ligand.
g HPLC-measurements not reproducible (stereocenter not stable).

3736
T. C. Wabnitz et al. / Tetrahedron Letters 47 (2006) 3733–3736
12. For recent discussions of electronic effects in asymmetric
hydrogenations, see: (a) Dubrovina, N. V.; Tararov, V. I.;
Monsees, A.; Spannenberg, A.; Kostas, I. D.; Bo¨rner, A.
Tetrahedron: Asymmetry 2005, 16, 3640; (b) Jeulin, S.; de
Paule, S. B.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43,
320; (c) Jones, Z. A.; Ph.D. Dissertation, University of
Cambridge, 2005.
E/Z-isomers outlined the importance of the configura-
tion at the a-carbon. A strong dependence on the
presence and position of further heteroatoms, probably
serving as coordination sites, emphasizes the intrinsic
difficulties of these conversions. A comprehensive
study along these lines is now in progress in our
laboratories.
13. The formation of stable seven-membered chelate rings of
the ruthenium catalyst and the Z-isomer cannot be ruled
out as it was observed that ruthenium(II) in these
solutions was considerably less sensitive to oxygen than
the corresponding systems containing the E-isomer.
14. Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.;
Takaya, H. J. Org. Chem. 1995, 60, 357.
15. Using pyridine as a stoichiometric or catalytic additive did
not increase conversion with unreactive substrates. There-
fore, pyridine substituents most likely serve as coordina-
tion sites.
Acknowledgements
This work was supported by the DFG (Graduiertenkol-
leg 760 Medizinische Chemie), the Vigoni Programm
(DAAD) and the Fonds der Chemischen Industrie.
T.C.W. thanks the Studienstiftung des deutschen Volkes
for a fellowship. T.B. thanks the Dipartimento di
`
Chimica Organica e Industriale dell’Universita di
Milano for hospitality.
16. Representative procedure: All substrates were prepared
according to the literature procedures and E/Z-isomers
were separated by column chromatography. The ruthe-
nium catalyst was prepared according to the general
procedure by Noyori (Ref. 10). The catalyst (2 mol %) was
added to a degassed solution of the substrate in dichlo-
romethane (approx. 0.01 M) in a stainless steel autoclave.
The autoclave was immediately sealed, flushed with
hydrogen (3·) before setting pressure and temperature.
After the reaction, the mixture was condensed in vacuo
and conversion was determined by 1H NMR. Unless
otherwise indicated, no side reactions were observed and
the products could be isolated quantitatively according to
conversion. The enantiomeric excess was determined by
chiral GC using a Restek Rt-bDEXcst colum (30 m). The
product was analyzed after isolation by column chroma-
tography. Analytical data for 2 (100% conversion, 95%
isolated yield, 51% ee): IR (film): m = 3059, 2932, 2248
References and notes
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Buschauer, A.; Friese-Kimmel, A.; Baumann, G.; Schu-
nack, W. Eur. J. Med. Chem. 1992, 27, 321; (c) Dove, S.;
Elz, S.; Seifert, R.; Buschauer, A. Mini-Rev. Med. Chem.
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7. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J.
Am. Chem. Soc. 1984, 106, 6717.
8. For detailed mechanistic studies of this reaction, see:
Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109,
1746.
1
(C„N), 1609, 1591, 1433, 1284, 1119, 751, 622 cmꢀ1. H
NMR (250 MHz, CDCl3) d = 3.09 (dd, J = 16.7, 8.3 Hz,
1H, CH2), 3.31 (dd, J = 16.7, 7.1 Hz, 1H, CH2), 4.39 (br t,
J = 7.9 Hz, 1H, CHCH2), 7.03–7.24 (m, 5H, aryl-H), 7.63
(ddd, J = 7.9, 7.5, 1.6 Hz, 1H, pyridyl-H), 8.61 (ddd,
J = 4.8, 1.6, 0.8 Hz, 1H, pyridyl-H). 13C{1H} NMR
(62.9 MHz, CDCl3) d = 22.4 (d, J(C,F) = 1.0 Hz,
CH2CN), 48.4 (d, J(C,F) = 1.6 Hz, Ar2CHCH2), 116.9
(dd, J(C,F) = 18.4, 0.8 Hz, aryl-C), 117.7 (dd,
J(C,F) = 17.8, 1.1 Hz, aryl-C), 118.4 (CN), 122.6 (pyr-
idyl-C), 123.3 (pyridyl-C), 124.0 (dd, J(C,F) = 6.4, 3.2 Hz,
aryl-C), 137.0 (pyridyl-C), 137.7 (dd, J(C,F) = 5.1, 3.8 Hz,
aryl-C), 149.5 (pyridyl-C), 149.9 (dd, J(C,F) = 248.0,
12.7 Hz, C-F), 150.5 (dd, J(C,F) = 248.6, 12.7 Hz, C-F),
158.7 (d, J(C,F) = 0.8 Hz, pyridyl-C). MS (EI(70 eV)): m/z
(%) = 244 (100) [M+], 243 (54) [M+ꢀH], 216 (12)
[M+ꢀHCNꢀH], 204 (85) [M+ꢀCH2CN]. GC (30 m
Rt-bDEXcst, 0.7 bar H2, 170 ꢁC): tr((+)-2) = 33.7 min,
tr((ꢀ)-2) = 34.6 min. Elemental analysis: C14H10F2N2
(244.3) calcd C 68.83%, H 4.13%, N 11.47%; found: C
68.66%, H 4.13%, N 11.31%. Optical rotation (51% ee)
9. Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
10. For efficient preparation of Ru-BINAP catalysts, see: (a)
Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R.
Tetrahedron Lett. 1991, 32, 4163; (b) Takaya, H.; Ohta, T.;
Inoue, S.-i.; Tokunaga, M.; Kitamura, M.; Noyori, R.
Org. Synth. 1994, 72, 74.
24
½aꢁD +53.9 (c 1.02, CHCl3).
17. Determination of absolute configuration of the products:
The hydrogenation product of E-4 (X = Cl) was reduced
with LiAlH4 to the corresponding amine (80%, no
racemization observed), being previously described in
enantiomerically pure form: (a) Zabel, M.; Breu, J.; Rau,
F.; Range, K.-J.; Krey, A.; Uffrecht, A.; Buschauer, A.
Acta Cryst. 2000, C56, 250; (b) Schuster, A.; Go¨tte, C.;
Bernhardt, G.; Buschauer, A. Chirality 2001, 13, 285. The
configuration of all other products was assigned in
analogy to these results.
`
11. (a) Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J.
Org. Chem. 1996, 61, 6244; (b) Benincori, T.; Cesarotti, E.;
`
Piccolo, O.; Sannicolo, F. J. Org. Chem. 2000, 65, 2043; (c)
`
Benincori, T.; Rizzo, S.; Sannicolo, F. J. Heterocycl.
Chem. 2002, 39, 471.