Synthesis of sulfoximine-derived P,N ligands and their applications in asymmetric quinoline hydrogenations

Article abstract of DOI:10.1002/adsc.200800068

A series of naphthalene-bridged P,N-type sulfoximine ligands and their iridium complexes have been synthesized. They were applied in the enantioselective hydrogenation of quinoline derivatives, and enantioselectivities up to 92% ee have been achieved in the hydrogenation of 2-methylquinoline.

Full text of DOI:10.1002/adsc.200800068

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DOI: 10.1002/adsc.200800068
Synthesis of Sulfoximine-Derived P,N Ligands and their
Applications in Asymmetric Quinoline Hydrogenations
Sheng-Mei Lua and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax : (+49)-241-809-2391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Received: January 30, 2008; Published online: April 15, 2008
Dedicated to Prof. Dr. Andreas Pfaltz on occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Aseries of naphthalene-bridged P,N-type
been achieved in the hydrogenation of 2-methylqui-
sulfoximine ligands and their iridium complexes noline.
have been synthesized. They were applied in the
enantioselective hydrogenation of quinoline deriva- Keywords: asymmetric catalysis; enantioselectivity;
tives, and enantioselectivities up to 92% ee have hydrogenation; iridium; quinolines; sulfoximines
Introduction
pared from 1,8-diaminonaphthalene[8]) with n-BuLi
(À788C, 1 h) followed by addition of ClPAr2 (À788C,
Ligands which bear phosphorus and nitrogen as the 30 min, then 258C, 16 h) led to diarylphosphine deriv-
donor atoms are among the most important and atives, which could be oxidized by H2O2 (258C, 2 h)
widely used heterodentate ligands in asymmetric affording phosphinoylnaphthalenes 2–7 in moderate
metal catalysis.[1] Best known are phosphinooxazo- yield (51–63% over two steps). No aqueous work-up
lines, which proved highly useful for various enantio- was required after the phosphorylation, and it was
selective transformations including allylic substitu- possible to simply evaporate the solvent after the first
tions, conjugate enone additions and olefin hydroge- step and change to acetone in the second. Then, using
nations.[2] Sulfoximine-based compounds of this type a copper-catalyzed cross-coupling reaction,[9] com-
are rare. This is surprising considering that related pounds 8a–i were obtained in yields ranging from 50
N,N- and N,O-type sulfoximines proved widely appli- to 86%. Subsequent reductions of the phosphine
cable as chiral ligands in a number of asymmetric cat- oxides using HSiCl3/Et3N afforded naphthalene-bridg-
alyses leading to products with high enantiomeric ex- ed phosphanylsulfoximines 9a–i in 34–74% yield
cesses. Examples include (hetero)-Diels–Alder, Mu- (Scheme 1). Unfortunately, the commonly used
kaiyama-type aldol and carbonyl-ene reactions as well method for the preparation of iridium complexes
as additions of diorganozinc reagents to carbonyl and {mixing of the P,N ligand with [Ir(COD)Cl)]2 in di-
N
heterocarbonyl compounds.[3,4] Just recently benzene- chloromethane followed by the addition of NaBARF
bridged P,N ligands with sulfoximidoyl substituents and water}[10] proved sluggish, giving inseparable mix-
were synthesized and their application in asymmetric tures of the desired complexes and impurities (ac-
hydrogenations of acyclic ketimines yielded amines cording to 31P NMR). Following Zhouꢀs protocol,[11]
with up to 98% ee.[5] Encouraged by these results, we however, complexes 10a–i were accessible in high
decided to synthesize naphthalene-bridged P,N-type yields (69–92%; Scheme 1).
sulfoximines[6] and to test their efficacy as ligands in
asymmetric hydrogenation reactions.
With the goal to investigate the effect of the alkyl
substituent at the sulfoximine moiety on the catalytic
activity, complexes 10a–d were synthesized. Based on
the results of the hydrogenation of 2-methylquinoline
(11a), complexes 10e–i bearing various aryl substitu-
ents at the phosphorus atom were prepared. All of
Results and Discussion
Following methodology developed earlier in our these complexes were stable to oxygen and moisture
group,[6,7] treatment of 1,8-diiodonaphthalene (1, pre- allowing purifications by flash column chromatogra-
Adv. Synth. Catal. 2008, 350, 1101 – 1105
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Scheme 1. Syntheses of sulfoximine-based P,N ligands and their iridium complexes.
phy on silica gel and handling in the laboratory at- 20 h (Table 1, entry 1). However, when toluene was
mosphere. used as the solvent under the same conditions, 45%
Next, asymmetric hydrogenations of quinolines conversion of 11a was achieved and 12a was formed
were investigated using complexes 10a–i as cata- with 88% ee (entry 2). After increasing the hydrogen
lysts.[12] The first reaction was carried out with 1 pressure to 60 bar, the reaction temperature and time
mol% of complex 10a in CH2Cl2 at room temperature were optimized, and the results of those studies are
under 40 bar of H2 pressure using 2-methylquinoline listed in Table 1 (entries 3–7).
(11a) as the model substrate. Disappointingly, only a
trace of product could be detected by H NMR after to 3 days led to an improved conversion of 11a (92%)
Extending the reaction time at room temperature
1
and an enantioselectivity of 92% ee for 12a (Table 1,
entry 3). Prolonging the reaction time to 6 days gave
Table 1. Asymmetric hydrogenation of 2-methylquinoline
full conversion but a product with slightly lower ee
(11a) to give 12a under various conditions with complex
(90%; entry 4). If the reaction was carried out at 40
10a.[a]
or 508C and for a shorter time, a trace of substrate re-
mained (entries 5 and 6). Finally at 608C after 20 h,
complete conversion and good enantioselectivity
(87% ee) were achieved (entry 7).
In order to improve the asymmetric quinoline hy-
drogenation further, the effects of additives[13] were
Entry Solvent H2
[bar]
Temp.
[8C]
Time Conv.
[%][b]
ee
[%][c]
investigated under the optimal conditions. Iodine,
which is a commonly used additive and essential in
other hydrogenations of quinolines,[12] had a negative
effect, leading to incomplete conversion and very low
ee (Table 2, entry 1). Other compounds such as NIS
and NBS gave >90% conversions of 11a, but the ee
of 12a was <10% (entries 2 and 3). Surprisingly, the
absolute configuration of the product was reversed in
the presence of I2 and NIS. When Bu4NBr and Bu4NI
were added to the reaction mixture, no product was
detected (entries 5 and 6). The same result was ob-
served (with or without iodine) in attempts to pro-
duce an efficient in situ catalyst {by combining the
1
2
3
4
5
6
7
CH2Cl2 40
r.t.
r.t.
r.t.
r.t.
40
20 h <5
20 h 45
-
toluene 40
toluene 60
toluene 60
toluene 60
toluene 60
toluene 60
88
92
90
90
90
87
3 d
6 d
2 d
92
>95
90
50
60
20 h 88
20 h >95
[a]
Reactions conditions: 11a (0.5 mmol), catalyst 10a (1
mol%), solvent (1.5 mL). All the reactions were carried
out under argon.
[b]
[c]
1
Conversions were determined by H NMR.
Enantiomer ratios were determined by HPLC using a
Chiralcel OD-H column. The S enantiomer of 12a was
formed in excess.
P,N ligand and [Ir
start}.
A
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Synthesis of Sulfoximine-Derived P,N Ligands and their Applications
Table 2. Effect of additive on the hydrogenation of 2-methylquinoline (11a) to give 12a (see Table 1 for Scheme).[a]
FULL PAPERS
Entry
Additive
Conv. [%][b]
ee [%][c]
Entry
Additive
Conv. [%][b]
ee [%][c]
1
2
3
I2
NIS
NBS
93
>95
92
À8
À8
5
4
5
6
KI
Bu4NBr
Bu4NI
>95
<5
<5
77
-
-
[a]–[c] As in Table 1; at 608C, 20 h reaction time . Anegative sign under ee indicates the reversed absolute configuration of the
product.
Next, complexes 10b–i were evaluated in the hydro-
genation of 2-methylquinoline (11a) under the opti-
mized conditions (Table 3).
Table 4. Hydrogenation of quinoline derivatives 11 using
complex 10a.[a]
Increasing the steric bulk of the alkyl substituent of
the sulfoximidoyl moiety lowered the enantioselectivi-
ty of the resulting catalyst. Thus, using 10b, 10c and
10d bearing an ethyl, isobutyl or a phenethyl group at
the sulfur atom resulted in the formation of 12a with
only 76, 41 and 35% ee, respectively (Table 3, en-
tries 1–3; compared to 87% ee achieved with methyl-
substituted 10a). Substitutions of the phenyl group at
the phosphorus atom had no obvious effect on the
performance of the resulting catalysts. Thus, similar
conversions (93–>95%) and enantioselectivities (64–
78% ee) were obtained with complexes bearing either
electron-donating (MeO-, Me-, 3,5-diMe) or electron-
withdrawing (CF3-) groups (Table 3, entries 4–7). A
significant deviation in conversion and ee was ob-
served in the reaction with complex 10i having a 5-
methyl-2-furyl substituted P,N ligand. There, the con-
version of 11a was only 84% and 12a had 23% ee.
31P NMR studies confirmed the difference between
complexes 10e–h and 10i. Whereas the former
showed very similar chemical shifts (around 17.5–
19.7 ppm), the latter had a 31P NMR chemical shift of
À10.2 ppm, indicating that this phosphorus atom was
much more electron-rich.
Entry R1
R2
Compd. Time Conv. ee [%][c] Abs.
[h]
[%]
Conf.[d]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
F
Me 11a
Et
Et
i-Bu 11c
i-Bu 11c
20
24
48
24
48
24
48
24
24
24
>95
62
69
53
71
62
90
>95
43
>95
87 (S)
77 (S)
70 (S)
75 (R)
55 (R)
80 (S)
65 (S)
75 (S)
64 (S)
78 (S)
11b
11b
Pr
11d
Pent 11e
Me 11f
Me 11g
9
10
MeO Me 11h
[a]
Reaction conditions: 11 (0.5 mmol), catalyst 10a (1
mol%), toluene (1.5 mL), 608C. All the reactions were
carried out under argon.
As in Table 1
As in Table 1.
Determined by comparison of rotation sign with the liter-
ature data[14a] or assuming analogous reaction pathways
(for entries 4 and 5).
[b]
[c]
[d]
To assess the substrate scope, a variety of substitut-
ed quinoline derivatives were hydrogenated under the
optimized conditions using complex 10a as catalyst.
As shown in Table 4, both reactivity and enantioselec- conversions remained incomplete and, surprisingly,
tivity depended on the substitution pattern of the sub- the enantioselectivites were lower (entries 3 and 5).
strate. When the substituent at the 2-position of the For the 2,6-disubstituted quinolines the reaction pro-
quinoline was changed from methyl to ethyl, n- ceeded well, when the substituents at the 6-position
propyl, isobutyl or n-pentyl groups, both conversion were electron-donating groups such as Me or MeO
and enantioselectivity decreased (entries 2–7). Even (full conversions of 11f and 11h after 24 h; entries 8
after a prolonged reaction time of 48 h, the quinoline and 10). In contrast, the hydrogenation reaction was
Table 3. Hydrogenation of 2-methylquinoline (11a) to give 12a using complexes 10b–i (see Table 1 for Scheme).[a]
Entry
Complex
Conv. [%][b]
ee [%][c]
Entry
Complex
Conv. [%][b]
ee [%][c]
1
2
3
4
10b
10c
10d
10e
95
61
91
93
76
41
35
78
5
6
7
8
10f
10g
10h
10i
94
96
>95
84
76
66
64
23
[a]–[c] As in Table 1; at 608C, 20 h reaction time.
Adv. Synth. Catal. 2008, 350, 1101 – 1105
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1103

Sheng-Mei Lu and Carsten Bolm
FULL PAPERS
for 16 h, the reaction mixture was cooled to room tempera-
ture under argon and degassed water (30 mL) was added.
Then, the mixture was filtered through celite and washed
three times with CH2Cl2. The aqueous layer was extracted
with CH2Cl2 (3”20 mL) and the combined organic extracts
were dried over Na2SO4, filtered and concentrated under re-
duced pressure. The product was then purified by flash chro-
matography (silica gel, pentane/EtOAc, 10:1–3:1).
slow with substrate 11g having an electron-withdraw-
ing group at C-6 (Table 4, entry 9).
Conclusions
We have described the synthesis of naphthalene-
bridged P,N-type sulfoximine ligands and demonstrat-
ed their catalytic potential in the enantioselective iri-
dium-catalyzed hydrogenation of quinolines. Further
applications of this class of ligands in asymmetric cat-
alysis are under investigation.
General Procedure for the Preparation of Complexes
10a–i
Under an argon atmosphere,
charged with (S)-N-[8-(diphenyl-phosphanyl)naphthyl]-S-
methyl-S-phenylsulfoximine (47 mg, 0.1 mmol), [Ir-
(COD)Cl]2 (34 mg, 0.05 mmol), NaBARF (133 mg,
a dry Schlenk-tube was
AHCTREUNG
Experimental Section
0.15 mmol) and dry CH2Cl2 (3 mL). After stirring at room
temperature for 2 h, the product was purified by flash chro-
matography (silica gel, pentane/CH2Cl2, 1:1–1:2) to afford
the complexes as orange-yellow foaming solids.
The detailed characterization data of compounds 2–7, 8a–i,
9a–i, 10a–i and the HPLC conditions for compounds 12a–h
are given in the supporting information.
General Procedure for Hydrogenation
General Procedure for the Preparation of
Compounds 2–7
Amixture of complex 10a (8.1 mg, 0.005 mmol) and quino-
lines 11 (0.5 mmol) was placed in a 5-mL vial equiped with
a stirrer bar. Then this vial was put into an argon-filled steel
autoclave. To the mixture was added toluene (1.5 mL) under
an argon atmosphere. Finally the autoclave was closed and
purged three times with hydrogen (less than the pressure
needed) and finally pressurized to 60 bar. The reaction mix-
ture was stirred for the indicated period of time. Then, the
hydrogen gas was released slowly. The conversion of the re-
action was determined by 1H NMR spectroscopy of the
crude reaction mixture, and the product was purified by
chromatography with pentane/EtOAc (10:1). Enantiomer
ratios were analyzed with HPLC using a Chiralcel OD-H
column. All the products were known compounds. The spec-
To a solution of 1,8-diiodonaphthalene (1, 1.9 g, 5.0 mmol)
in anhydrous THF (20 mL) was added n-BuLi (3.2 mL,
1.6M in hexane, 5.0 mmol) at À788C under an argon atmos-
phere. The mixture was stirred at À788C for 1 h, and then
Ar2PCl (5.0 mmol) was added dropwise. After stirring for
30 min, the cooling bath was removed, and the reaction mix-
ture was stirred overnight at room temperature. Then, the
solvent was removed under vacuum. To the residue dis-
solved in acetone (10 mL) was added an excess amount of
H2O2 (30%, 2.0 equiv.) in an ice bath. After stirring at room
temperature for 2 h, the solvent was removed and the resi-
due was directly purified by flash chromatography (silica
gel, pentane/EtOAc, 1:1–1:5 as the eluent) yielding the
target compound as a solid.
1
tra data of H NMR and 13C NMR were accordance with the
literature reports.[14]
General Procedure for the Preparation of
Compounds 8a-i
Acknowledgements
Under an argon atmosphere, a 50-mL of Schlenk-flask was
charged with the (S)-sulfoximine (5.5 mmol), 2–7
(5.0 mmol), CuI (0.5 mmol), and Cs2CO3 (12.5 mmol). The
mixtures were dissolved in distilled toluene (20 mL). Then
DMEDA(1.0 mmol) was added. After being heated to
1108C overnight, the mixture was cooled to room tempera-
ture and neutralized with an aqueous solution of HCl (2M).
The aqueous layer was extracted with CH2Cl2 (3”20 mL)
and the combined organic extracts were dried over Na2SO4,
filtered and concentrated under reduced pressure. The resi-
due was purified by flash chromatography (silica gel, pen-
tane/EtOAc, 1:1–1:5).
We are grateful to the Fonds der Chemischen Industrie for
the financial support, and S. Lu thanks the Alexander von
Humboldt Foundation for a postdoctoral fellowship.
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Synthesis of Sulfoximine-Derived P,N Ligands and their Applications
FULL PAPERS
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