Planar chiral [2.2]paracyclophane-based bis(thiourea) catalyst: Application to asymmetric Henry reaction

Article abstract of DOI:10.1039/c3cc41789a

A bis(thiourea) organocatalyst with a planar chiral [2.2]paracyclophane backbone has been synthesized and applied to the Henry reaction. The obtained high reactivity and enantioselectivity from the reaction of aromatic aldehydes with nitroalkanes suggeste

Full text of DOI:10.1039/c3cc41789a

ChemComm
View Article Online
View Journal
COMMUNICATION
Planar chiral [2.2]paracyclophane-based bis(thiourea)
catalyst: application to asymmetric Henry reaction†
Cite this: DOI: 10.1039/c3cc41789a
Shinji Kitagaki,*a Takahiro Uedab and Chisato Mukaib
Received 9th March 2013,
Accepted 22nd March 2013
DOI: 10.1039/c3cc41789a
www.rsc.org/chemcomm
A bis(thiourea) organocatalyst with a planar chiral [2.2]paracyclo- ligand since [2.2]PHANEPHOS,9 the pseudo-ortho-bis(diphenyl-
phane backbone has been synthesized and applied to the Henry phosphino)[2.2]paracyclophane ligand, realized the highly
reaction. The obtained high reactivity and enantioselectivity from enantioselective hydrogenation of olefins or ketones catalyzed
the reaction of aromatic aldehydes with nitroalkanes suggested by a rhodium or ruthenium complex. On the other hand,
the significant potential of [2.2]paracyclophane to serve as the [2.2]paracyclophane-based Brønsted acid organocatalysts have
backbone of the organocatalyst.
been relatively unexplored and the results reported so far
suggest that it is not easy for the cyclophane compounds to
Optically active bis(thiourea) hydrogen-bond-donating catalysts promote any organocatalytic reaction in a highly enantio-
have proven to be effective for diverse asymmetric reactions,1–6 selective manner.10 During our ongoing studies on the planar
such as the Morita–Baylis–Hillman (MBH) reaction,2 Mannich- chiral cyclophane-based bifunctional organocatalyst, we
type reaction,3 kinetic resolution of amines,4 and Diels–Alder recently addressed this issue by combining an acid function-
reaction.5 However, the chiral backbone has been mainly ality with a nucleophilic phosphine, which efficiently catalyzed
limited to the centrally chiral trans-1,2-diaminocyclohexane the enantioselective aza-Morita–Baylis–Hillman reaction.11 We
or axially chiral 1,10-binaphthyl-2,20-diamine, thus the develop- now report that the [2.2]paracyclophane framework is suitable
ment of new scaffolds to achieve other types of transfor- as a backbone for the bis(thiourea) catalyst, which realizes the
mations with excellent enantioselectivities is highly desirable highly enantioselective Henry reaction.
(Fig. 1).7
The pseudo-ortho-substituted pattern of the [2.2]paracyclo-
[2.2]Paracyclophane have attracted considerable attention as phane was selected as the target because we believe that it
a new type of planar chiral backbone8 for a mono- or bidentate would construct a wider and more efficient chiral pocket than
the pseudo-geminal- or ortho-substituted ones.11 Pseudo-ortho-
diamino[2.2]paracyclophane 4, which was selected as the
synthetic intermediate for the target bis(thiourea) 1, has been
reported to be prepared in the racemic form by the Buchwald–
Hartwig amination of (ꢀ)-dibromocyclophane.12 However,
it was synthesized from the readily available optically pure
bromo[2.2]paracyclophanyl triflate 2.13 Thus, the palladium-
catalyzed diamination of (Rp)-2 using N-tert-butyl carbamate as
the ammonia equivalent and JohnPhos as the ligand,14 and
subsequent exposure to trifluoroacetic acid afforded the
diamine (Rp)-4 in an acceptable yield. Finally, treatment of
the amine with 3,5-bis(trifluoromethyl)phenyl isothiocyanate
Fig. 1 Bis(thiourea) derivatives.
produced the desired bis(thiourea) (Rp)-1 (Scheme 1).
a Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku,
Nagoya 468-8503, Japan. E-mail: skitagak@meijo-u.ac.jp; Fax: +81 52 834 8090;
Tel: +81 52 839 2657
b Division of Pharmaceutical Sciences, Graduate School of Medical Sciences,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
† Electronic supplementary information (ESI) available: Experimental details,
1H and 13C NMR spectra, and X-ray data. CCDC 912711. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3cc41789a
The crystal suitable for an X-ray diffraction study was obtained
for rac-1 from a THF–hexane solution. The solid structure was
found to have a s-cis, trans conformation for each thiourea moiety
and included three THF molecules, one of which was simulta-
neously bound to each thiourea hydrogen atom, indicating one of
the possible activation scenarios of the substrate or reagent in the
reaction pathway if this thiourea catalyzes any reaction (Fig. 2).15
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Enantioselective Henry reaction of 5a and 6a
Entry Acid (mol%) Amine (mol%) Time (h) Yield of 7aa (%) eeb (%)
1
2
3
(Rp)-1 (10)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (2)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-1 (5)
(Rp)-8 (5)
(Rp)-9 (5)
(Rp)-10 (5)
(Rp)-11 (5)
(Rp)-12 (5)
i-Pr2NEt (20)
i-Pr2NEt (10)
i-Pr2NEt (5)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (8)
Et3N (20)
DABCO (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
i-Pr2NEt (20)
4
4
4
4
4
1
24
2
10
1.5
1.5
3
3
3
9
89
84
80
84
86
82
77
82
72
87
84
75
81
78
66
68
94
95
91
97
96
92
91
94
91
90
63
44
24
30
0
4
5c
6d
7
8
9
Scheme 1 Preparation of bis(thiourea) (Rp)-1.
10e
11f
12
13
14
15
16
3
19
a
b
Isolated yield. Determined by HPLC analysis using Daicel Chiralcel
c
d
OD-H. Result of the thiourea’s 3rd reuse. Performed at 0 1C.
e
f
Performed in CH2Cl2. Performed in toluene.
Fig. 2 X-ray crystal structure of rac-1-THF. Hydrogen-bond distances are given in Å
(hydrogen atoms except NHs and other THF molecules were omitted for clarity).
(Rp)-1117 further reduced the enantioselectivity, the latter having a
lower reactivity and no enantiodiscrimination (entries 15 and 16).
These results suggested the importance of the second thiourea
functionality, which has a proper steric hindrance and hydrogen
bond donor activity.
The substrate scope of the (Rp)-1-catalyzed Henry reaction
was examined next. Arylaldehydes with an electron-deficient
group at the para position could be smoothly transformed into
the corresponding nitroalcohols in good yields and high enantio-
meric excesses (Table 2, entries 1 and 2). Benzaldehyde or the
With the cyclophanyl thiourea catalysts in hand, we turned
our attention to their application in the organocatalytic
Henry reaction.16 Our initial experiment was carried out using
p-nitrobenzaldehyde 5a and nitromethane 6a in THF at ꢁ25 1C
under the influence of 10 mol% of (Rp)-1 and 20 mol% of
diisopropylethylamine. We were delighted to find that the
reaction proceeded smoothly to produce the desired adduct
(R)-7a in 89% yield with 94% ee (Table 1, entry 1). The reduction
of the catalyst loading to 5/10 mol% {(Rp)-1/amine} gave similar
results (entry 2). The bis(thiourea)/amine ratio affected the
enantioselectivity of the product and the best result (97% ee)
was obtained using a ratio of 5/20 (entries 3 and 4). The thiourea
catalyst could be recovered in ca. 65% by column chromato-
graphy on silica gel from the reaction mixture, and the recovered
catalyst worked well without any loss of its reactivity and
enantioselectivity up to at least the third reuse (entry 5). Raising
the reaction temperature to 0 1C or the reduction of the catalyst
loading to 2/8 mol% {(Rp)-1/amine} led to a decrease in the
enantioselectivity, but maintained the level of >90% (entries 6
and 7). The use of triethylamine or DABCO instead of diisopro-
pylethylamine and dichloromethane or toluene instead of THF
did not improve the enantioselectivity (entries 8–11). The change
of one of the two thioureas to a tert-butyl carbamoyl group or
amino group17 decreased the enantioselectivity (entries 12 and 13).
The use of hydroxy-thiourea (Rp)-1017 gave results similar to that of
amino-thiourea (Rp)-9 (entries 13 and 14). The phenyl group-
Table 2 Enantioselective Henry reaction of 5 and 6a catalyzed by (Rp)-1
(Rp)-1
(mol%) (1C)
Temp. Time Product 7a eeb
Entry Aldehyde 5 (R)
(h)
(yield, %)
(%)
1
2
3
4
5
6
7
8
9
5a ( p-NO2C6H4)
5b ( p-ClC6H4)
5c (C6H5)
5
5
5
ꢁ25
ꢁ25
0
4
48
24
12
3
1
5
7a (84)
7b (80)
7c (57)c
7d (70)c
7e (91)
7f (91)
7g (73)
7h (80)
7i (72)
97
95
90
86
96
94
91
91
68
5d ( p-MeOC6H4) 10
0
5e (m-NO2C6H4)
5f (o-NO2C6H4)
5g (3-Pyridyl)
5h (1-Naphthyl)
5i (PhCH2CH2)
5
5
10
10
10
ꢁ25
ꢁ25
ꢁ40
0
12
24
ꢁ25
a
c
b
Isolated yield. Determined by HPLC analysis using a chiral column.
Reaction was quenched before complete conversion of the starting
inserted hydroxy-thiourea (Rp)-1213 and the methyl-protected material.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.

View Article Online
ChemComm
Communication
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.
Notes and references
1 For recent reviews on asymmetric catalysis using hydrogen-bond
donors, see: Y. Takemoto, Chem. Pharm. Bull., 2010, 58, 593; X. Yu
and W. Wang, Chem.–Asian J., 2008, 3, 516; A. G. Doyle and
E. N. Jacobsen, Chem. Rev., 2007, 107, 5713.
Scheme 2 Enantioselective Henry reaction of 5 with 6b,c catalyzed by (Rp)-1.
2 Y. Sohtome, A. Tanatani, Y. Hashimoto and K. Nagasawa, Tetra-
hedron Lett., 2004, 45, 5589; A. Berkessel, K. Roland and
¨
J. M. Neudorfl, Org. Lett., 2006, 8, 4195; M. Shi and X.-G. Liu, Org.
Lett., 2008, 10, 1043; Y. Nakayama, T. Gotanda and K. Ito, Tetra-
hedron Lett., 2011, 52, 6234.
3 Y. Zhang, Y.-K. Liu, T.-R. Kang, Z.-K. Hu and Y.-C. Chen, J. Am. Chem.
Soc., 2008, 130, 2456.
4 C. K. De, E. G. Klauber and D. Seidel, J. Am. Chem. Soc., 2009,
131, 17060.
´
5 B. Tan, G. Hernandez-Torres and C. F. Barbas, III, J. Am. Chem. Soc.,
2011, 133, 12354.
6 E. M. Fleming, T. McCabe and S. J. Connon, Tetrahedron Lett., 2006,
47, 7037; X.-G. Liu, J.-J. Jiang and M. Shi, Tetrahedron: Asymmetry,
2007, 18, 2773; C. Rampalakos and W. D. Wulff, Adv. Synth. Catal.,
2008, 350, 1785; S. Allu, S. Selvakumar and V. K. Singh, Tetrahedron
Lett., 2010, 51, 446.
7 Highly enantioselective organic transformations with guanidine/
bis(thiourea) catalysts have been reported by Nagasawa and
co-workers. See: Y. Sohtome and K. Nagasawa, Chem. Commun.,
2012, 48, 7777; Y. Sohtome and K. Nagasawa, Synlett, 2010, 1.
8 S. E. Gibson and J. D. Knight, Org. Biomol. Chem., 2003, 1, 1256;
V. Rosenberg, E. Sergeeva and H. Hopf, in Modern Cyclophane
Chemistry, ed. R. Gleiter and H. Hopf, Wiley-VCH, Weinheim,
Germany, 2004, p. 435; J. Paradies, Synthesis, 2011, 3749; Special
Issue: Cyclophanes Isr. J. Chem., 2012, 52, 1.
Fig. 3 Plausible transition state model.
electron-donating arylaldehyde required a prolonged reaction
time and higher reaction temperature, and led to a slight decrease
in the enantioselectivity due to the retro-Henry reaction (entries 3
and 4).18 The position of the aryl-substituent had a minor effect
on the enantioselectivities (entries 1, 5 and 6). The desired
products from 3-pyridyl- and 1-naphthyl-aldehyde were obtained
in good yields and high enantioselectivities through a slight
modification of the reaction conditions (entries 7 and 8). Thus,
bis(thiourea) (Rp)-1 proved to work very well for a variety of
arylaldehydes. An aliphatic aldehyde produced the corresponding
nitroalcohol smoothly, as expected, but its ee was not high
enough compared to those derived from arylaldehydes (entry 9).
Diastereoselective reactions were examined using nitro-
ethane or nitropropane under several conditions, and it was
found that both syn- and anti-products were obtained in high
enantiomeric excesses although a higher diastereomer ratio
was not achieved (Scheme 2).
Although it is too soon to propose the stereochemical path-
way at this stage, the preferential formation of (R)-7 might be
explained by the transition state model inspired by the dual
activation mode, which has been proposed by Nagasawa and
co-workers for the MBH reaction using bis(thiourea), derived
from diaminocyclohexane (Fig. 3).7 Thus, the left one in Fig. 3 is
less crowded and should lead to the adduct (R)-7.
9 P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante and
P. J. Reider, J. Am. Chem. Soc., 1997, 119, 6207.
10 D. C. Braddock, I. D. MacGilp and B. G. Perry, Adv. Synth. Catal.,
¨
2004, 346, 1117; J. F. Schneider, F. C. Falk, R. Frohlich and
J. Paradies, Eur. J. Org. Chem., 2010, 2265; J. F. Schneider,
¨
R. Frohlich and J. Paradies, Synthesis, 2010, 3486; D. Enders,
M. Ludwig and G. Raabe, Chirality, 2012, 24, 215; C. Beemelmanns,
¨
R. Husmann, D. K. Whelligan, S. Ozçubukçu and C. Bolm, Eur. J. Org.
Chem., 2012, 3373.
11 S. Kitagaki, Y. Ohta, R. Takahashi, M. Komizu and C. Mukai,
Tetrahedron Lett., 2013, 54, 384.
12 B. Qu, Y. Ma, Q. Ma, X. Liu, F. He and C. Song, J. Org. Chem., 2009,
74, 6867.
13 S. Kitagaki, Y. Ohta, S. Tomonaga, R. Takahashi and C. Mukai,
Tetrahedron: Asymmetry, 2011, 22, 986.
14 J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin and S. L. Buchwald, J. Org.
Chem., 2000, 65, 1158.
15 CCDC 912711.
16 For selected examples of enantioselective Henry reaction, see:
H. Sasai, T. Suzuki, T. Arai and M. Shibasaki, J. Am. Chem. Soc.,
1992, 114, 4418; T. Marcelli, R. N. S. van der Haas, J. H.
van Maarseveen and H. Hiemstra, Angew. Chem., Int. Ed., 2006,
45, 929; D. Xin, Y. Ma and F. He, Tetrahedron: Asymmetry, 2010,
21, 333; F. He, Y. Ma, L. Zhao, W. Duan, J. Chen and Z. Zhao,
Tetrahedron: Asymmetry, 2012, 23, 809. For recent reviews, see:
Y. Alvarez-Casao, E. Marques-Lopez and R. P. Herrera, Symmetry,
2011, 3, 220; C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem.,
2007, 2561.
In conclusion, we designed and synthesized a planar chiral
bis(thiourea) catalyst based on the pseudo-ortho-substituted
[2.2]paracyclophane backbone and found that its asymmetric
environment realized a highly enantioselective Henry reaction.
Further studies regarding the details of the reaction mecha- 17 For preparation of thiourea catalysts, see ESI†.
18 Time-course studies on the reaction of 5c with 6a in the presence of
nism as well as the application of planar chiral bis(thiourea)
derivatives in other asymmetric organocatalytic reactions are
currently in progress.
(Rp)-1 (5 mol%) and diisopropylethylamine (20 mol%) in THF at 0 1C
showed that the ee of the product gradually decreased (6 h: 94% ee,
12 h: 92% ee, 24 h: 90% ee).
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.