Planar chiral [2.2]paracyclophane-based phosphine-Bronsted acid catalysts bearing exceptionally high reactivity for aza-Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2012.11.021

Several new planar chiral bifunctional phosphine compounds based on the [2.2]paracyclophane backbone with a pseudo-ortho substitution pattern have been synthesized and applied to the aza-Morita-Baylis-Hillman reaction. An enantiopure phosphine-phenol cata

Full text of DOI:10.1016/j.tetlet.2012.11.021

Tetrahedron Letters 54 (2013) 384–386
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Planar chiral [2.2]paracyclophane-based phosphine-Brønsted acid catalysts
bearing exceptionally high reactivity for aza-Morita–Baylis–Hillman reaction
⇑
,
Shinji Kitagaki , Yuu Ohta, Ryohei Takahashi, Mika Komizu, Chisato Mukai
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Several new planar chiral bifunctional phosphine compounds based on the [2.2]paracyclophane backbone
with a pseudo-ortho substitution pattern have been synthesized and applied to the aza-Morita–Baylis–
Hillman reaction. An enantiopure phosphine-phenol catalyst bearing an aryl group as a spacer connected
to a phosphino group exhibited an exceptionally high reactivity (rt, 2–40 min) and good enantioselectivity
(up to 85% ee).
Received 20 September 2012
Revised 1 November 2012
Accepted 5 November 2012
Available online 14 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Morita–Baylis–Hillman reaction
Cyclophanes
Organocatalysis
Planar chirality
The substituted [2.2]paracyclophanes have attracted considerable
attention as a new type of planar chiral ligand1,2 since [2.2]PHANE-
PHOS, the pseudo-ortho-bis(diphenylphosphino)[2.2]paracyclophane
ligand, realized the highly enantioselective hydrogenation of olefins
or ketones catalyzed by a rhodium or ruthenium complex.3 However,
there are a few examples using the cyclophane derivative as an
organocatalyst,4–12 among which only two catalysts with an
additional chiral source, such as a sugar or oxazoline unit, have been
proven to show a high enantioselectivity.6,8 Thus, potential of the
[2.2]paracyclophane asa planar chiral backboneoftheorganocatalyst
has not yet been demonstrated.
m
We have been interested in the development of bifunctional13
organocatalysts14 based on the planar chiral pseudo-ortho-substi-
tuted aryl[2.2]paracyclophane that has no additional chiral source
and that is expected to construct an efficient asymmetric environ-
ment different from the known functionalized cyclophanes. Our
design concept is as follows: (1) Two functional groups (R1 and
R2 in Fig. 1) are located, respectively, on the [2.2]paracyclophane
backbone and the meta position of a spacer aryl group, connected
to the pseudo-ortho position of the backbone. (2) The [2.2]paracy-
clophane backbone would provide the inherent conformational
rigidity. (3) The spacer would offer not only a steric or electronic
element based on the aryl group itself and/or its characteristic sub-
stituents, R3, which interacts with the substrate and/or reactant,
Figure 1. Design concept.
but also the conformational flexibility that makes the distance be-
tween the two functional groups suitable for performing the dual
activation of the substrate and reactant. The synthesis of similar
aryl[2.2]paracyclophanes, which have a functional group at the
ortho position of the aryl group, and their application as chiral li-
gands or a reagent have already been reported by the Rozenberg
group.2,15,16
We have recently developed a concise and efficient synthetic
method for the chiral [2.2]paracyclophanes based on the above
mentioned concept, which includes the stepwise successive palla-
dium-catalyzed cross-coupling for the [2.2]paracyclophane bear-
ing two different leaving groups in a pseudo-ortho relationship.17
We now report the synthesis of several phosphine-Brønsted acid
catalysts by the developed method and the evaluation of their cat-
alytic reactivities based on the aza-Morita–Baylis–Hillman (aza-
MBH) reaction.
⇑
Corresponding author. Tel.: +81 52 839 2657; fax: +81 52 834 8090.
E-mail address: skitagak@meijo-u.ac.jp (S. Kitagaki).
Current address: Faculty of Pharmacy, Meijo University, 150 Yagotoyama,
Tempaku-ku, Nagoya 468-8503, Japan.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.021

S. Kitagaki et al. / Tetrahedron Letters 54 (2013) 384–386
385
We designed the planar chiral [2.2]paracyclophanylphosphines
3a–e containing the m-hydroxy-, amido-, thioureido-, or carboxy-
phenyl group at the pseudo-ortho position and the cyclophane 8
bearing a phosphino group and an acid functionality in the
opposite way to the above mentioned one. 3,5-Dimethoxyphenyl-
and 3-aminophenyl-[2.2]paracyclophanylphosphine oxide 2b and
2c were prepared from bromo[2.2]paracyclophanyl triflate 1 by
the Suzuki–Miyaura coupling/phosphinylation sequence since
3-siloxyphenyl one 2a was obtained in lower yield by the reverse
order method (Scheme 1).17 The one-pot installation of the aryl
group and phosphinyl group was accomplished with 51% yield
for the cyclophane 2d bearing a methoxycarbonyl group on the
spacer aryl group. The cyclophanylphosphine 3a or 3b17 with one
or two hydroxy groups on the spacer was obtained by the depro-
tection of 2a or 2b and subsequent reduction of the phosphinyl
group using trichlorosilane. The treatment of 2c with trichlorosi-
lane produced the amide 3c or thiourea 3d after acetylation or
the thiourea-forming reaction. The phosphine-carboxylic acid 3e
was prepared from 2d by the reduction/hydrolysis sequence. The
phosphine 3f having no acid functionality was also prepared. The
phosphine-alcohol 5, which contained no spacer in its structure,
was synthesized by the alkaline hydrolysis of phosphinylcyclopha-
nyl triflate 417 and subsequent trichlorosilane reduction.
The cyclophane 8a bearing a phosphino group and a hydroxy
functionality in the opposite way to 3a was synthesized from the
bromocyclophanol 618 via the Suzuki–Miyaura coupling using the
phosphinylboronic ester 7a19 (Scheme 2).
With several bifunctional cyclophanylphosphines in hand, we
turned our attention to their application in organocatalytic asym-
metric reactions. The aza-MBH reaction20 using the N-tosylaldi-
mine 9a and methyl vinyl ketone (MVK) 10 was selected and the
results of the reaction in THF at room temperature are summarized
in Table 1.
Scheme 2. Preparation of 8a from 6.
Table 1
Cyclophanylphosphine-catalyzed aza-MBH reaction
Entry Catalyst (Y,Z)
Solvent
Time
Yield
(%)
ee (%)
(conf.)a,b
1
2
3
4
5
6
(Sp)-3a (OH,H)
(Sp)-3b (OH,OH)
(Rp)-3b (OH,OH)
(Sp)-3f (OMe,OMe)
rac-3c (NHAc,H)
rac-3d
THF
THF
THF
THF
THF
THF
12 d
5 d
5 d
15 d
7 d
12 d
81
96
61 (S)
70 (S)
69 (R)
0
—
—
91
34c
23c
24c
(NHCSNHAr,H)
rac-3e (COOH,H)
(Rp)-5
7
THF
THF
THF
7 d
2 d
2 h
22c
99
99
—
8
18 (R)
34 (S)
48 (S)
66 (S)
75 (S)
67 (S)
40 (S)
9d
(Sp)-8a
(Sp)-8a
(Sp)-8b
(Sp)-8c
10d
11d
12d
13d,e
14
Toluene 10 min 99
Toluene 15 min 89
Toluene 10 min 99
Toluene 15 min 88
(Sp)-8c
(Sp)-3g (OH,OH)
THF
3.4 d
89
a
b
c
Determined by HPLC analysis using Daicel Chiralpak AS-H.
Determined by the sign of the specific rotation.
Reaction was not completed.
Used 5 mol % of the catalyst.
Reaction was performed at 0 °C.
d
e
Among the cyclophanylphosphines 3a–e bearing a different
Brønsted acid functionality on the spacer aryl group, only the phos-
phine-phenol catalysts 3a and 3b gave the desired MBH adduct
11a in good to excellent yields, although the reaction time was
long (5–12 days) at the catalyst loading of 10 mol %. In addition,
the chiral, non-racemic 3a and 3b exhibited good asymmetric
induction abilities, and (Sp)-3b produced (S)-11a in 70% ee (entries
1 and 2). The use of (Rp)-3b also provided (R)-11a with 69% ee (en-
try 3). Thus, both enantiomers of 11a are equally available using
both enantiomers of 3b obtained via the optical resolution process
of 6.17,18 The unsatisfactory results using the phenol-protected
phosphine (Sp)-3f suggested that the hydroxy functionality would
play a crucial role in both the rate acceleration and the asymmetric
induction (entry 4). On the other hand, phosphine-amide 3c, -thio-
urea 3d, or -carboxylic acid 3e was found not to have a sufficient
Scheme 1. Reagents and conditions: (i) Ph2P(O)H, Pd(OAc)2 (10 mol %), dppf
(18 mol %), i-Pr2NEt, DMSO, 100 °C; (ii) boronic acid, PdCl2(dppf) (5 mol %), K3PO4,
toluene, 80–100 °C; (iii) boronic acid, Pd(PPh3)4 (5 mol %), K3PO4, dioxane, 85 °C;
(iv) boronic acid, Ph2P(O)H, PdCl2(PPh3)2 (5 mol %), Na2CO3, DMSO/H2O (10:1),
85 °C; (v) TBAF, THF; (vi) HSiCl3, i-Pr2NEt, xylene, 140 °C; (vii) BBr3, CH2Cl2,
0 °C ? rt; (viii) AcCl, py; (ix) ArNCS, THF, 0 °C ? rt; (x) KOH, MeOH, reflux; (xi) aq
NaOH, dioxane/MeOH. Ar = 3,5–(CF3)2C6H3.

386
S. Kitagaki et al. / Tetrahedron Letters 54 (2013) 384–386
Table 2
a significant decrease in the reactivity and enantioselectivity (entry
6).
Aza-MBH reaction of aldimine 9 catalyzed by (Sp)-8c in toluene
In conclusion, we synthesized phosphine-Brønsted acid cata-
lysts based on the pseudo-ortho-substituted [2.2]paracyclophane
backbone and evaluated their reactivity and chiral discrimination
ability based on the aza-MBH reaction using the tosylaldimine 9
and MVK 10. Our efforts led to the development of the phos-
phine-phenol 8c, which showed an exceptionally high reactivity
and good enantioselectivity in the aza-MBH reaction by virtue of
a spacer aryl group. To the best of our knowledge, this is the first
successful example of a planar chiral acid-base bifunctional organ-
ocatalyst based on the [2.2]paracyclophane, which might provide a
new direction to the design of the chiral catalyst backbone. Efforts
toward the improvement of the enantioselectivity including fur-
ther modification of the catalyst structure and further studies of
the application of 8c in the asymmetric reaction are currently in
progress.
Entry
Substrate 9 (R)
Time (min)
Product 11
Yield (%)
eea,b (%)
1
2
3
4
5
6
9a (p-Cl)
10
10
10
25
10
40
11a
11b
11c
11d
11e
11f
99
57c
71
96
97
85
75
69
79
9b (p-NO2)
9c (p-Me)
9d (p-OMe)
9e (m-OMe)
9f (o-Me)
85
76d
40e
a
b
c
Determined by HPLC analysis using chiral stationary phase column.
Preferred configuration was determined by the sign of the specific rotation.
Cascade adduct of aza-MBH/MBH reaction 12 was obtained in 27% yield.
Preferred configuration was determined by comparison of elution order of HPLC
using the reported value.
d
e
Acknowledgments
Preferred configuration was not determined.
This work was supported in part by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan, for which we are thankful.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.021.
reactivity to complete the aza-MBH reaction; therefore, the asym-
metric induction using the optically active 3c–e was not tested
(entries 5–7). The phosphine-phenol (Sp)-8a bearing an aryl group
as a spacer not connected to a hydroxyl group but to a phosphino
group showed a higher reactivity and lower enantioselectivity
compared to (Sp)-3a (entry 1 vs entry 9). Although the phos-
phine-phenol (Rp)-5, both of whose functionalities were directly
connected to the cyclophane backbone, generated the aza-MBH ad-
duct 11a in quantitative yield after stirring for 2 days, the ee was
poor, demonstrating that our design concept, in which an aryl
group as a spacer is a characteristic of the catalyst, was reasonable
for both the rate acceleration and the asymmetric induction (entry
8).
References and notes
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The relatively higher reactivity of (Sp)-8a prompted us to try the
use of solvents other than THF. Surprisingly, the reaction in toluene
was completed within 10 min and the desired product was ob-
tained in quantitative yield with 48% ee (entry 10). The change in
the two phenyl groups on the phosphorous atom of (Sp)-8a signif-
icantly influenced the enantioselectivity of the product. In fact,
(Sp)-8bà bearing two p-tolyl groups instead of phenyl groups and
(Sp)-8cà equipped with m-xylyl groups improved the product ee for
the reaction in toluene to 66% and 75%, respectively, without any
loss of reactivity (entries 11 and 12).21,22 Lowering the reaction tem-
perature to 0 °C did not improve the product ee (entry 13). The use of
(Sp)-3g,§ bearing two m-xylyl groups instead of phenyl groups on the
phosphorous atom of 3b, in THF did not improve the product ee (en-
try 14).
A preliminary assessment of the scope of the imine substrates
was made using 5 mol % of (Sp)-8c in toluene at room temperature.
The electron-rich arylaldimines were found to be susceptible to
undergo the aza-MBH reaction with a higher enantioselectivity
(Table 2). The highest ee was obtained with p-methoxybenzaldi-
mine 9d, in which the reaction afforded the product in 96% yield
with 85% ee (entry 4). The substituent at the ortho position led to
7. Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2007, 18, 1990.
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20. For selected examples of catalytic asymmetric aza-MBH reaction, see: (a)
Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1; (b) Ma, G.-N.;
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21. The reaction in toluene with (Sp)-8c was completed even after 2 min
(confirmed by TLC) and the desired product was obtained in 93% yield with
75% ee. For fast catalytic asymmetric aza-MBH reaction, see: Lei, Z.-Y.; Ma, G.-
N.; Shi, M. Eur. J. Org. Chem. 2008, 3817. See also Ref. 22.
à
According to the procedure shown in Scheme 2, (Sp)-8b and 8c were prepared
22. Anstiss, C.; Garnier, J.-M.; Liu, F. Org. Biomol. Chem. 2010, 8, 4400.
using the corresponding m-(diarylphosphinyl)phenylboronic acid ester.
§
According to the procedure shown in Scheme 1, (Sp)-3g was prepared using the
corresponding diarylphosphine oxide.