The development of double axially chiral phosphoric acids and their catalytic transfer hydrogenation of quinolines

Article abstract of DOI:10.1002/anie.200703925

(Chemical Equation Presented) Building a better scaffold: Low loadings (0.2-1 mol%) of new double axially chiral phosphoric acid catalysts 1 based on bisbinol scaffold were used for asymmetric transfer hydrogenation. 2-Aryl- and 2-alkyl-substituted quinolines gave tetrahydroquinolines in excellent yields and with up to 98% ee and 2,3-disubstituted tetrahydroquinolines were prepared in high diastereo- and enantioselectivities (up to > 20:1 and 92% ee).

Full text of DOI:10.1002/anie.200703925

Angewandte
Chemie
DOI: 10.1002/anie.200703925
Asymmetric Catalysis
The Development of Double Axially Chiral Phosphoric Acids and
Their Catalytic Transfer Hydrogenation of Quinolines**
Qun-Sheng Guo, Da-Ming Du,* and Jiaxi Xu
The design of novel chiral catalysts for asymmetric synthesis is
an active field of modern organic chemistry.[1] Chiral phos-
phoric acid catalysts, pioneered by Akiyama et al. and Terada
and co-workers,[2] have been recently applied to a wide range
of asymmetric organic transformations.[3] Brønsted acids are
used in these asymmetric reactions, mainly to protonate the
electrophile, which is thereby activated and ready for attack
by a corresponding nucleophile. To
achieved compared to the mono axially chiral phosphoric acid
catalysts based on the same scaffold. For the synthesis of the
new catalyst, we removed the middle axial chirality of I to
give the simplified compound II. Then for convenience, we
further rationally modified II to obtain compound (R,R)-1
(Scheme 1) as the target catalysts. (R,R)-1 has double axial
chirality and can be recognized as a “dimeric” form of (R)-
our knowledge, the previously
reported chiral phosphoric acid cata-
lysts are based on a limited number
of backbone scaffolds, namely 3,3’-
substituted binol (1,1’-bi-2-naph-
thyl),[4] 3,3’-substituted H8-binol,[5]
taddol
(a,a,a’,a’-tetraaryl-2,2-
dimethyl-1,3-dioxolan-4,5-dimetha-
nol),[6] vanol (3,3’-diphenyl-[2,2’-
binaphthalene]-1,1’-diol), and vapol
(2,2’-diphenyl-[3,3’-biphenanthrene]-
4,4’-diol).[7] The development of new
chiral phosphoric acids with tunable
backbones and the expansion of their
Scheme 1. Rational design of new double axially chiral phosphoric acids.
application to other useful asymmet-
ric organic transformations is still a
great challenge for chemists. Herein, the design, synthesis,
and application of novel double axially chiral phosphoric acid
catalysts are reported.
alkoxy-binol phosphate. (R,R)-1 has a larger chiral pocket
than those of previously developed phosphoric acid catalysts.
The requisite chiral phosphoric acid catalysts (R,R)-1a–d
were conveniently synthesized from MOM-protected alkoxy
The rationale for our design of new chiral phosphoric acid
catalysts originated from the observation that substitutents at
the 3,3’-positions of binol are very important for achieving
high selectivity. The use of 3,3’-nonsubstituted binol phos-
phate as a catalyst always gave low or even no enantioselec-
(R)-binol
2 in a five-step sequence as illustrated in
Scheme 2.[8] MOM-monoprotected alkoxy (R)-binol 2 was
iodonated to afford 3, and then coupled with the correspond-
ing mono boric acid intermediate 4 to give the bis-binol
derivatives 5 in 79–92% yield. Cleavage of the MOM groups
afforded the corresponding alkoxy-substituted bis-binol 6 in
88–94% yield. The double axially chiral phosphoric acid
catalysts 1a–d were obtained after treatment with POCl3, and
subsequent hydrolysis (93–96% yield).
c]
tivity.[4b, We assumed that if the substitutents at the 3,3’-
positions of binol phosphate I possess a stable double axial
chirality, then better performance in organocatalysis may be
[*] Q.-S. Guo, Prof. D.-M. Du, Prof. J. Xu
Beijing National Laboratory for Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education
College of Chemistry and Molecular Engineering
Peking University
The catalytic efficiency of our chiral phosphoric acid
catalysts was examined for the asymmetric transfer hydro-
genation of quinolines. Although a variety of chiral Rh, Ru,
and Ir complexes have been demonstrated to be highly
efficient and enantioselective in the hydrogenation of pro-
chiral olefins, ketones, and imines, most of these catalysts
failed to give satisfactory results in the asymmetric hydro-
genation of heteroaromatic compounds.[9] A few successful
examples of the asymmetric hydrogenation of quinolines have
recently been reported.[10] Chiral phosphoric acids as organo-
catalysts can provide excellent enantioselectivities in the
transfer hydrogenation of imines, quinolines, and a-imino
esters.[4a–f] Rueping et al.[10b] reported the asymmetric transfer
Beijing 100871 (China)
Fax: (+86)10-62751708
E-mail: dudm@pku.edu.cn
[**] This project was partially supported by the National Natural Science
Foundation of China (grant numbers 20572003, 20772006, and
20521202), the Program for New Century Excellent Talents in
University (NCET-07-0011), and Peking University.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Screening of the new phosphoric acid catalysts.[a]
Entry
Catalyst
R
Yield [%]
ee [%][b]
1
2
3
4
1a
1b
1c
1d
Me
iPr
nBu
98
70
93
85
95
>99
>99
>99
cyclohexanyl
[a] Reaction conditions: 7 (0.1 mmol), 9 (2.4 equiv), and 1 (2 mol%) in
toluene (3 mL) at 358C for 20 h. [b] Determined by HPLC on a chiral
stationary phase using a Chiracel-OD-H column.
95% ee, respectively). The higher enantioselectivity is prob-
ably due to the increased steric effects of 1d. It is interesting
to note that the enantioselectivity was slightly improved from
95 to 96% ee when the loading of catalyst 1d was varied from
2 to 0.2 mol%.
The influence of the solvent on the catalyzed transfer
hydrogenation of 2-phenylquinoline was examined in CH2Cl2,
CHCl3, benzene, toluene, and Et2O (Table 2); in all cases
excellent enantioselectivities (94–96% ee) were obtained.
The hydrogenation of 2-butylquinoline resulted in excellent
enantioselectivity (93% ee) when the reaction was conducted
in Et2O. A slight increase in the enantioselectivity (from 93to
94% ee) was observed when Hantzsch ester 10 was used.
The scope of the Brønsted acid catalyzed transfer hydro-
genation was further explored by testing a wide range of 2-
substituted quinolines under the optimized reaction condi-
tions (namely, 2.4 equiv 10 and either 0.2 or 1 mol% 1d in
Et2O at 3 58C for 20 h). High enantioselectivities and good
yields for a series of tetrahydroquinolines were observed
(Table 3). In the transfer hydrogenation of 2-aryl-substituted
quinolines, our catalyst loading (0.2 mol%) was lower than
that reported by Rueping et al. (2 mol%).[10b] In the same
reaction for 2-alkyl-substituted quinolines, our new chiral
phosphoric catalyst 1d gave higher enantioselectivity (up to
95% ee) than the previously reported method (up to
91% ee).[10b]
Scheme 2. Synthesis of new double axially chiral phosphoric acids.
MOM=methoxymethyl.
hydrogenation of quinolines using 3,3’-bis(9-phenanthryl)-
binol phosphate. A variety of 2-aryl-substituted tetrahydro-
quinolines were synthesized with excellent enantioselectiv-
ities (> 99% ee), but 2-alkyl-substituted tetrahydroquinolines
had lower enantioselectivities (87–91% ee). Herein, we
report that a low catalyst loading (0.2 mol%) is sufficient in
the asymmetric transfer hydrogenation of quinolines when
catalyzed by our chiral phosphoric acid catalysts 1. By using
this new catalyst we obtain excellent enantioselectivities of up
to 98% ee for 2-aryl- and 2-alkyl-substituted quinolines.
With the new Brønsted acids (1a–1d) in hand, we first
investigated which chiral phosphoric acid would be most
effective for the catalyzed transfer hydrogenation of quino-
lines (Table 1). When the phosphoric acid catalysts were
present at 2 mol% in toluene at 358C, both 1a and 1c could
catalyze the hydrogen transfer with good enantioselectivities
(70 and 85% ee, respectively). Whereas 1b and 1d showed
improved catalytic properties for the same reaction (93and
The reduction of 2,3-disubstituted quinolines 11a–c were
also examined under the optimized reaction conditions using
1d (1 mol%). The tetrahydroquinolines 12a–c were obtained
in high yields with excellent diastereoselectivities (up to
> 20:1) and high enantioselectivities (up to 92% ee; Table 4).
Interestingly, 12a was obtained in the cis configuration, while
12b and 12c had trans configurations. A rational mechanism
for this transformation is not clear at present.
In summary, we have synthesized a series of novel chiral
phosphoric acid catalysts based on the bis-binol scaffold. In
760
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Table 2: Influence of the solvents on the new phosphoric acid catalyzed
Table 4: Catalytic asymmetric hydrogenation of 2,3-disubstituted quino-
transfer hydrogenation of quinolines.[a]
lines.[a]
Entry
1
Product
Yield [%]
d.r.[b]
ee [%][c]
Entry
Solvent
R=Ph
yield [%]
R=nBu
yield [%]
ee [%][b]
ee [%][b]
>99
>20:1(cis/trans)
82
1
2
3
4
5
6
7
8
9
CCl4
CH2Cl2
CHCl3
benzene
toluene
THF
Et2O
dioxane
Et2O
92
98
97
>99
>99
88
>99
95
80
95
94
96
96
92
96
88
96[c]
85
98
97
>99
98
91
>99
48
>99
8
85
65
82
85
80
93
16
94[c]
2
3
>99
>20:1(trans/cis)
94:6(trans/cis)
92
91
93
>99
[a] Reaction conditions: 7 (0.1 mmol), 9 (2.4 equiv), and 1d (1 mol%) in
solvent (3 mL) at 358C for 20 h. [b] Determined by HPLC on a chiral
stationary phase using a Chiracel-OD-H column. [c] Using Hantzsch
ester 10 (2.4 equiv).
[a] Reaction conditions: 11 (0.1 mmol), 9 (2.4 equiv), and 1d (1 mol%)
in Et2O (3 mL) at 358C for 12 h. [b] Determined by H NMR spectros-
copy. [c] Determined by HPLC on a chiral stationary phase using a
Chiracel-OD-H column.
1
Table 3: Catalytic asymmetric hydrogenation of quinoline derivatives.[a]
alkyl-substituted quinolines. Low catalyst loadings (0.2–
1 mol%) was sufficient to afford tetrahydroquinoline deriv-
atives with excellent enantioselectivities (up to 98% ee) and
yields. Furthermore, 2,3-disubstituted quinolines were also
hydrogenated with excellent diastereoselectivities and high
enantioselectivities (up to 92% ee). Further exploration of
this new type of Brønsted acid in other asymmetric trans-
formations is currently underway within our research group.
Entry
R
Product Yield [%] ee [%][b] Config[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5
4-BrC6H4
4-ClC6H4
4-FC6H4
8a
8b
8c
8d
8e
8 f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
>99
>99
96
>99
>99
52[c]
>99
>99
>99
>99
>99[c]
>99[c]
>99[c]
>99[c]
>99[c]
>99[c]
96
97
98
97
94
86
95
97
98
97
88
94
94
92
90
93
S
S
S
S
S
S
S
S
S
S
R
R
R
R
R
R
4-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
2-naphthyl
4-CF3C6H4
1,1’-biphenyl-4-yl
CH3
CH3CH2CH2
CH3(CH2)2CH2
CH3(CH2)3CH2
cyclohexyl
C6H5CH2CH2
Experimental Section
Representative example of the asymmetric hydrogenation of quino-
lines. The quinoline 7a (0.1 mmol), catalyst 1d (0.2 mol%), Hantzsch
dihydropyridine 10 (0.24 mmol), and Et2O (3mL) were added to a
vial and the mixture was exposed to an argon atmosphere. The
resulting yellow solution was stirred at 358C for 20 h. The solvent was
evaporated in vacuo, and the crude product was purified by column
chromatography on silica gel to afford the (S)-2-phenyl-1,2,3,4-
tetrahydroquinoline (8a) in quantitative yield (> 99%). 1H NMR
(300 MHz, CDCl3): d = 1.88–2.11 (m, 2H), 2.69 (dt, J = 16.2, 4.8 Hz,
1H), 2.82–2.91 (m, 1H), 3.95 (s, 1H), 4.37 (dd, J = 9.3, 3.3 Hz, 1H),
6.48 (d, J = 7.5 Hz, 1H), 6.62 (td, J = 7.5, 0.9 Hz, 1H), 6.95–7.00 (m,
2H), 7.24–7.37 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 26.3,
30.9, 56.1, 113.9, 117.0, 120.7, 126.4, 126.8, 127.3, 128.5, 129.2, 144.6,
144.7 ppm; [a]D20 = À34.8 degcm3 gÀ1 dmÀ1 (c = 0.011 gcmÀ3, CHCl3,
96% ee). The ee value of the product was determined by HPLC on a
chiral stationary phase (Chiracel-OD-H; hexanes:iPrOH 95:5 at
0.6 mLminÀ1), major isomer: tr = 16.31 min, minor isomer: tr =
17
18
8q
8r
>99[c]
90
95
R
R
>99[c]
[a] Reaction conditions:
7 (0.1 mmol), 10 (2.4 equiv), and 1d
21.04 min. Lit.[10b] [a]DRT = À37.7 degcm3 gÀ1 dmÀ1 (c = 0.011 gcmÀ3
CHCl3, 97% ee).
,
(0.2 mol%) at 358C in Et2O (3 mL) for 20 h. [b] Determined by HPLC
on a chiral stationary phase using a Chiracel-OD-H column. [c] Using 1d
(1 mol%) at 358C for 12 h. [d] Determined by comparison of the optical
rotation sign with literature data or by analogy.
Received: August 26, 2007
comparison to the chiral phosphoric acids based on the 3,3’-
substituted binol scaffold, our catalysts show higher efficiency
in the asymmetric transfer hydrogenation of 2-aryl- and 2-
Keywords: asymmetric synthesis · Brønsted acid ·
hydrogenation · organocatalysis · tetrahydroquinolines
.
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Communications
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762
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