Guanidine-thiourea bifunctional organocatalyst for the asymmetric Henry (nitroaldol) reaction

Article abstract of DOI:10.1002/adsc.200505148

Novel bifunctional catalysts having guanidine and thiourea functional groups were developed for the asymmetric Henry (nitroaldol) reaction. Various structural developments of the catalyst revealed that the compound having an octadecyl-substituted guanidin

Full text of DOI:10.1002/adsc.200505148

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DOI: 10.1002/adsc.200505148
Guanidine-Thiourea Bifunctional Organocatalyst for the
Asymmetric Henry (Nitroaldol) Reaction
Yoshihiro Sohtome,b Yuichi Hashimoto,b Kazuo Nagasawaa,*
a
Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Fax: (þ81)-42-388-7295, e-mail: knaga@cc.tuat.ac.jp
b
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032,
Japan
Fax: (þ81)-3-5841-8495
Received: April 11, 2005; Accepted: July 11, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Novel bifunctional catalysts having guani- promoted the Henry reaction. This bifunctional orga-
dine and thiourea functional groups were developed nocatalyst 1e also gave high asymmetric inductions
for the asymmetric Henry (nitroaldol) reaction. Vari- with aliphatic cyclic aldehydes and branched aliphatic
ous structural developments of the catalyst revealed aldehydes (82–90% ee).
that the compound having an octadecyl-substituted
guanidine and thiourea groups linked with a chiral Keywords: bifunctional organocatalyst; guanidines;
spacer derived from phenylalanine, i.e., 1e, efficiently nitroaldol; organic catalysis; thioureas
Introduction
guanidine compounds effectively catalyzed the Henry
reaction, but afforded only low to moderate asymmetric
The Henry reaction (nitroaldol reaction) is a fundamen- inductions (20–50% ee). Recently, Ma et al. reported
tal carbon-carbon bond-forming reaction.[1] Transfor- highly diastereoselective Henry reactions with nitrome-
mations of the Henryreaction adducts, such as reduction thane and aldehydes derived from amino acids, using a
to amines or oxidation (Nef reaction) to carbonyl com- chiral aliphatic guanidine catalyst (92% de).[7c] Howev-
pounds, give a variety of useful synthetic intermedi- er, the highly enantioselective, direct Henry reaction
ates.[2] Thus, great efforts have been directed to the de- catalyzed by organocatalysts remains insufficiently de-
velopment of a catalytic asymmetric version of this reac- veloped. Herein, we report highly enantioselective Hen-
tion. Shibasaki et al. reported a series of bimetallic cat- ry reactions catalyzed by a guanidine-thiouea bifunc-
alysts that proved to be effective for the asymmetric tional organocatalyst.
Henry reaction.[3] Trost et al. reported a dinuclear Zn
catalyst that induces high enantioselectivity in the addi-
tion of nitromethane to a variety of cyclic, aliphatic and Results and Discussion
aromatic aldehydes.[4] Evans et al. developed a bis(oxa-
zoline)-Cu catalyst for highly enantioselective Henry re- Bifunctional-type organocatalysts[12] are an attractive
actions.[5] As well as these metal-containing catalysts, type of organocatalyst. Since the two functional groups
environmentally friendly organocatalysts[6] have been in the bifunctional catalysts interact with different reac-
introduced for the Henry reaction. [7–9] One class of or- tion components, various reactions are expected to be
[7,10]
ganocatalysts, guanidine compounds,
interacts promoted efficiently. In the case of the Henry reaction,
with nitro compounds through nitronate anion forma- nitroalkanes and aldehydes are involved, and they are
tion as a counter partner,[11] so chiral guanidine com- known to interact with and/or be activated by guani-
pounds are thought to be good candidates for asymmet- dines[11] and thioureas,[13] respectively. Thus, catalysts
ric Henry reaction catalysts. Najera et al. have reported which contain guanidine and thiourea functional groups
chiral aliphatic guanidine catalysts[7a] and recently Mur- linked by a chiral spacer might promote the asymmetric
phy et al. reported C2-symmetrical cyclic guanidine Henry reaction. We therefore designed linear guani-
compounds for the asymmetric Henry reaction.[7b] These dine-thiourea linked bifunctional catalysts 1a–g (Fig-
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Figure 1. Structures of guanidine-thiourea type bifunctional
compounds
ure 1). In the thiourea moiety of 1, aromatic rings having
electron-withdrawing groups were introduced for the ef-
ficient activation of carbonyl compounds. Various sub-
stituents were also introduced onto the guanidine group.
The thiourea-guanidine bifunctional compounds
1a–g were prepared as depicted in Scheme 1. The amine
6, which was derived from l-phenylalanine (5), was con-
Scheme 1. Synthesis of catalysts 1a–g.
verted into the thiourea 7 with carbon disulfide in 90% the Henry reaction, giving 11a in 91% yield and 43%
yield. Various amines, such as butylamine, dibutylamine, ee (entry 5).
pyrrolidine, octylamine and octadecylamine were react-
Next, we attempted to improve the asymmetric induc-
ed with the thiourea 7 using mercury(II) chloride. The tion. While retaining the R1 and R2 groups of 1e, the
Boc groups were removed with TFA, and subsequent starting amino acid, l-phenylalanine (5) was changed
thiourea formation with thioisocyanate 8 followed by to l-alanine, l-valine and l-tert-leucine (R3 ¼methyl,
treatment with ammonium chloride gave 1a–e in isopropyl and tert-butyl, respectively) to give 2–4 (Fig-
57%–91% yields. The aromatic group-substituted 1f ure 1). Compounds 2–4 effectively promoted the Henry
and 1g were synthesized from 6 via the dissymmetrical reaction in 55–89% yield (Table 1, entries 8–10), but
thiourea 9 in 77% and 75% yield, respectively.
With the guanidine-thiourea bifunctional catalysts 1 was the original benzyl group, i.e., 1e.
the ee value of 11a was greatest when the R3 group
in hand, the Henry reaction between nitromethane
To explore the optimal reaction conditions of 10a with
and cyclohexanecarboxaldehyde (10a) was explored. nitromethane in the presence of 1e, firstly, various inor-
The reaction was performed in the presence of ganic salts were examined as additives, since the effects
5 mol % of catalysts under biphasic conditions in tol- of the counter anion of not only ammonium salts,[14] but
uene-aqueous potassium hydroxide at 08C, and the re- also guanidinium salts[7b] have been reported to influ-
sults are summarized in Table 1. The catalysts 1a, 1b, ence both catalytic activity and asymmetric induction.
1c, 1f and 1g did not give good results (entries 1–3, 6 Table 2 summarizes the effects of the inorganic salts.
and 7). Since increasing the solubility of the catalyst in The tetrafluoroborates KBF4 and NaBF4 did not give
the organic solvent is known to be effective for promot- high ee values (entries 1 and 2).[15] With KBr and
ing the reaction, especially under phase-transfer condi- NaBr, the ee values were increased to 57% and 60%, re-
tions, octyl- and octadecyl-substituted catalysts 1d and spectively (entries 3 and 4). The softer anionic species,
1e were examined. Compound 1e efficiently promoted LiI and NaI, were effective in terms of ee value (entries
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Organocatalyst for the Asymmetric Henry (Nitroaldol) Reaction
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Table 1. Henry reaction with bifunctional catalysts 1a–g and
2–4.
Table 2. Effects of additives on Henry reaction catalyzed by
1e.
[a]
(S)-11a was obtained as the major product.
Table 3. Henry reaction with various aldehydes.
5 and 6). The best result was obtained with KI: 11a was
obtained in 88% yield and 74% ee (entry 7).[16] We
next examined the optimum ratio of the solvents. Final-
ly, a 1 to 1 ratio of toluene-H2O in the presence of nitro-
methane (10 equivs.), 1e (10 mol %), KI (50 mol %) and
KOH (5 mol %) at 08C, gave the Henry product 11a in
91% yield and up to 92% ee [Eq. (1)].[17]
ð1Þ
Using these optimized reaction conditions, the reactions
of various aldehydes were examined, and the results are
summarized in Table 3. In the case of aliphatic cyclic and
a-branched-chain aldehydes, the corresponding Henry
adducts 11b–e were generated in high yield and high
ee of 82–88% (entries 1–4). However the unbranched
aliphatic aldehyde 10f gave the adduct 11f with only a
moderate enantiomeric excess of 55% (entry 6). The re-
[a]
10 equivs. of nitromethane was used.
action rate of this Henry reaction can be controlled by in the aldehyde (R group) favors an anti conformer rath-
changing the amount of KOH. In the case of reactive al- er than a gauche position, and nitromethane and the al-
dehydes 10c–f, a lower amount of KOH (5–10 mol %) dehyde 10 react to form the new carbon-carbon bond.
probably contributed to the high asymmetric inductions Thus, (R)-11 should be generated as the major coupling
by reducing the reaction rate (entries 2–5).
product.
Since the stereochemistry of the newly generated al-
cohol in 11 is R, the transition state of this Henry reac-
tion can be considered to be as shown in Figure 2. Nitro- Conclusion
methane and the aldehyde 10 coordinate to the guanidi-
nine and thiourea groups, respectively, through hydro- In summary, we have developed the new bifunctional or-
gen-bonding interactions. In this case, the substituent ganocatalyst 1e for the asymmetric Henry reaction. This
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Typical Procedure for the Asymmetric Henry
Reaction
To a mixture of 1e (12.9 mg, 0.0112 mmol), KI (9.3 mg,
0.0558 mmol) and nitromethane (65.2 mL, 1.12 mmol) in tol-
uene (1.12 mL)/5 mM aqueous KOH (1.12 mL) was added cy-
clohexanecarboxaldehyde (10a; 13.4 mL, 0.112 mmol) at 08C.
The resulting mixture was stirred vigorously at 08C for 24 h.
Then saturated aqueous NH4Cl was added, and the organic lay-
er was extracted with ethyl acetate. The extracts were dried
over MgSO4, filtered and concentrated under vacuum, and
the residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate¼20/1 ! 5/1 ! chloroform/meth-
anol¼9/1) to give 11a (yield: 17.4 mg, 91%) and 1e (12.8 mg,
99% recovery). The enantiomeric excess of 11a (92% ee) was
determined by means of chiral HPLC analysis [Chiralcel
OD-H, 0.46 cm (f)ꢀ25 cm (L), n-hexane/2-propanol¼97/3,
1.0 mL/min, (R) major; 19.3 min, (S) minor; 21.2 min]. The ab-
solute stereochemistry of 11a was determined based on the re-
tention time reported by Trost et al.[4a,5]
Spectral data for 11a:[4a,5] 1H NMR (500 MHz, CDCl3): d¼
4.48 (dd, J¼13.1 Hz, 2.7 Hz, 1H), 4.42 (dd, J¼13.1 Hz,
8.9 Hz, 1H), 4.10 (m, 1H), 2.42 (br s, 1H), 1.82 (m, 2H), 1.68
(m, 2H), 1.47 (m, 1H), 1.30–1.06 (m, 6H).
Figure 2. Proposed transition state of the guanidine-thiourea
bifunctional compound-catalyzed Henry reaction.
Spectral data for 11b: 1H NMR (500 MHz, CDCl3): d¼4.48
(dd, J¼13.2 Hz, 2.7 Hz, 1H), 4.39 (dd, J¼13.2 Hz, 9.0 Hz, 1H),
4.14 (m, 1H), 2.56 (br s, 1H), 1.93 (m, 1H), 1.84 (m, 1H), 1.76–
1.57 (m, 5H), 1.47 (m, 1H), 1.28 (m, 1H). The enantiomeric ex-
cess of 11b was determined by the use of chiral HPLC analysis
[Chiralcel OD-H, 0.46 cm (f)ꢀ25 cm (L), n-hexane/2-prop-
anol¼98/2, 1.0 mL/min, (R) major; 22.5 min, (S) minor;
25.0 min].
catalyst utilizes guanidine and thiourea groups for the
nitromethane and aldehyde interaction and/or activa-
tion, respectively. The long alkyl chain (octadecyl
group) of the guanidine substituent of 1e was also man-
datory to promote the reaction effectively. In the pres-
ence of KI as an additive, 1e catalyzed the Henry reac-
tion in 70–91% yield and 82–92% ee with a-branched
aldehydes. Although an asymmetric induction is still in-
Spectral data for 11c:[4a,5] 1H NMR (500 MHz, CDCl3): d¼
4.53 (dd, J¼12.9 Hz, 2.0 Hz, 1H), 4.37 (dd, J¼12.9 Hz,
10.1 Hz, 1H), 4.04 (dd, J¼10.1 Hz, 2.0 Hz, 1H), 2.42 (br s,
1H), 0.99 (s, 9H). The enantiomeric excess of 11c was deter-
sufficient in the case of unbranched aldehydes, the cata- mined by the use of chiral HPLC analysis [Chiralcel OD-H,
0.46 cm (f)ꢀ25 cm (L), n-hexane/2-propanol¼97/3, 1.0 mL/
lyst could be easily modified by changing the chiral
min, (R) major; 15.1 min, (S) minor; 18.8 min].
spacer, which might improve the asymmetric induction
for a variety of substrates. Further works along this
line is in progress.
Spectral data for 11d:[4a,5] 1H NMR (500 MHz, CDCl3): d¼
4.48 (dd, J¼13.2 Hz, 3.2 Hz, 1H), 4.40 (dd, J¼13.2 Hz,
8.5 Hz, 1H), 4.11 (m, 1H), 1.81 (m, 1H), 1.01 (d, J¼4.1 Hz,
3H), 0.97 (d, J¼4.4 Hz, 3 H). The enantiomeric excess of 11d
was determined by the use of chiral HPLC analysis [Chiralcel
OD-H, 0.46 cm (f)ꢀ25 cm (L), n-hexane/2-propanol¼97/3,
1.0 mL/min, (R) major; 18.3 min, (S) minor; 21.7 min].
Spectral data for 11e:[4a] 1H NMR (500 MHz, CDCl3): d¼
4.46 (d, J¼2.2 Hz, 1H), 4.43 (s, 1H), 4.42–4.31 (m, 1H), 2.38
(d, J¼4.6 Hz, 1H), 1.56–1.21 (m, 5H), 0.94 (t, J¼7.2 Hz, 6
H). The enantiomeric excess of 11e was determined by the
use of chiral HPLC analysis [Chiralcel OD-H, 0.46 cm (f)ꢀ
25 cm (L), n-hexane/2-propanol¼98/2, 1.0 mL/min, (R) major;
21.0 min, (S) minor; 25.2 min].
Experimental Section
General Remarks
Flash chromatography was performed using silica gel 60
(spherical, particle size 0.040–0.100 mm; Kanto Co., Inc., Ja-
pan). Optical rotations were measured with a JASCO DIP po-
larimeter 370. IR spectra were measured with JASCO VAL-
Spectral data for 11f:[4a,5] 1H NMR (500 MHz, CDCl3): d¼
7.38–7.18 (m, 5H), 4.41 (s, 1H), 4.39 (d, J¼2.0 Hz, 1H),
4.35–4.26 (m, 1H), 2.92–2.20 (m, 2H), 2.64 (br s, 1H), 1.94–
1.72 (m, 2H). The enantiomeric excess of 11f was determined
by the use of chiral HPLC analysis [Chiralcel AD-H, 0.46 cm
(f)ꢀ25 cm (L), n-hexane/2-propanol¼95/5, 1.0 mL/min, (R)
major; 23.2 min, (S) minor; 29.5 min].
1
OR-III FT-IR spectrophotometer. H and 13C NMR spectra
were recorded on JEOL ALPHA500 instrument. Mass spectra
were recorded on JEOL JMA-HX110 spectrometer. Charac-
terization data for compounds 1a–g and 2–4 can be found in
the Supporting Information.
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Acknowledgements
This research was supported in part by Mitubishi Chemical Cor-
poration Fund, the Uehara Memorial Foundation, and Nagase
Science and Technology Foundation.
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Yoshihiro Sohtome et al.
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[16] The effects of iodide as a counter anion of guanidine on
the ee values are not clear at this stage.
[17] When the reaction was performed in the presence of tri-
ethylamine instead of KOH in toluene (homogeneous
conditions), the yield of 11a was decreased to 13%
(58% ee). In the case of the reaction under the base
form of 1e in toluene (homogeneous conditions), the re-
action did not proceed.
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