Novel quinidine-derived organocatalysts for the asymmetric substitutions of O-Boc-protected Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1002/ejoc.201100501

A series of novel quinidine-derived organocatalysts was synthesized and utilized for the asymmetric substitution of O-Boc-protected Morita-Baylis- Hillman adducts with various carbamates and tosylcarbamates, affording the corresponding products in good to high yields (up to 91% yield) with moderate to high ee values (up to 96%ee) under mild conditions. A series of novel quinidine-derived organocatalysts was synthesized and utilized for the asymmetric substitution of O-Boc-protected Morita-Baylis-Hillman adducts with various carbamates and tosylcarbamates, affording the corresponding products in good to high yields (up to 91% yield) with moderate to high ee values (up to 96%ee) under mild conditions.

Full text of DOI:10.1002/ejoc.201100501

FULL PAPER
DOI: 10.1002/ejoc.201100501
Novel Quinidine-Derived Organocatalysts for the Asymmetric Substitutions of
O-Boc-Protected Morita–Baylis–Hillman Adducts
Cheng-Kui Pei,[a] Xiu-Chun Zhang,[a] and Min Shi*[a,b]
Keywords: Organocatalysis / Asymmetric catalysis / Nucleophilic substitution / Carbamates
A series of novel quinidine-derived organocatalysts was syn-
thesized and utilized for the asymmetric substitution of O-
Boc-protected Morita–Baylis–Hillman adducts with various
carbamates and tosylcarbamates, affording the correspond-
ing products in good to high yields (up to 91% yield) with
moderate to high ee values (up to 96%ee) under mild condi-
tions.
carbamates and tosylcarbamates, affording the correspond-
ing products in good yields (up to 91% yield) with high ee
values (up to 96%ee) under mild conditions.
Introduction
Recently, asymmetric substitutions of Morita–Baylis–
Hillman (MBH) acetates or carbonates using cinchona al-
kaloid derived organocatalysts have attracted much atten-
tion because this asymmetric synthetic protocol can over-
come the shortcomings in direct catalytic asymmetric MBH
reactions in terms of substrate scope and catalytic efficiency
as well as chiral induction.[1–4] In this aspect, Lu[5a] and
Hiemstra[5b] first independently reported 4-(3-ethyl-4-oxa-
1-azatricyclo[4,4,0,03,8]dec-5-yl)quinolin-6-ol (also called as
β-isocupreidine, β-ICD) catalyzed asymmetric substitution
of MBH carbonates with various nucleophiles, affording
the corresponding amination products in excellent yields
along with modest ee values. Moreover, Chen and co-
workers recently used hydroquindine(anthraquinone-1,4-
diyl) diether [(DHQD)2AQN], hydroquindine-1,4-phthal-
azinediyl diether [(DHQD)2PHAL], hydroquinidine-2,5-di-
phenyl-4,6-pyrimidinediyl diether [(DHQD)2PYR], and β-
isocupreidine (β-ICD) in asymmetric substitutions of MBH
carbonates to achieve C–C bond,[6a–6d] C–N bond,[6e,6f] and
C–O bond[6g,6h] formation in good yields along with high
enantioselectivities under mild conditions. More recently,
Wang’s group also reported the use of cinchona alkaloids
as catalysts to construct chiral allylic phosphane oxides
through substitution of MBH carbonates in excellent yields
along with high enantioselectivities.[7] In this paper, we wish
to report the synthesis of a series of novel quinidine-derived
organocatalysts and their applications in the asymmetric
substitution of O-Boc-protected MBH adducts with various
Results and Discussion
Initially, we utilized methyl benzoylcarbamate (1a,
1.2 equiv.) and tert-butyl 2-methylene-1-(4-nitrophenyl)-3-
oxobutyl carbonate (2a, 1.0 equiv.) as the substrates and
the multifunctional cinchona alkaloid β-isocupreidine (β-
ICD)[1k,8] (Figure 1) (10 mol-%) as the catalyst in tetra-
hydrofuran (THF) to examine the reaction outcome, and
the results are shown in Table 1. It was found that the corre-
sponding substitution product 3aa was obtained in 80%
yield along with 22%ee at room temperature (25 °C;
Table 1, Entry 1). We next screened other multifunctional
cinchona alkaloid derived organocatalysts cat-I–cat-III
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237 China
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032 China
Fax: +86-21-64166128
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100501.
Figure 1. Multifunctional cinchona alkaloid derivatives.
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4479
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Table 1. Optimization of the reaction conditions.[a]
[a] All reactions were carried out using 1a (0.12 mmol) and 2a (0.10 mmol) in solvent (1.00 mL) for 10 h. [b] Isolated yield. [c] Determined
by chiral HPLC analysis. [d] The reaction was carried out at –78 °C for 36 h. [e] The reaction was carried out with cat-VIII (20 mol-%).
(Figure 1) in this reaction and found that desired product
3aa was formed in 84–89% yields along with 17–31%ee
values (Table 1, Entries 2–4).
Because these cinchona alkaloids derived catalysts are
not effective in this particular asymmetric substitution reac-
tion, we attempted to develop other multifunctional cin-
chona alkaloid derived organocatalysts in this reaction. As
shown in Scheme 1, using β-ICD as the starting material,
we prepared several novel cinchon alkaloid organocatalysts
cat-IV–cat-XIV through straightforward synthetic methods
in moderate to good yields (Scheme 1, see Supporting In-
formation for detailed experimental procedures; Figure 1).
Moreover, the structure of β-ICD-derived organocatalyst
cat-VIII was unambiguously determined by X-ray diffrac-
tion.[9] Its ORTEP drawing is shown in Figure 2. Employing
these new cinchona alkaloid derived organocatalysts, we
then investigated the reaction of 1a and 2a in the presence
of cat-IV, cat-V, cat-VIII, cat-X, and cat-XII in THF at
25 °C and found that cat-VIII was the best
organocatalyst for this reaction (Table 1, Entries 5–9). In
the presence of cat-VIII (RЈ = C6H5 and RЈ = H), 3aa was
formed in 86% yield and 43%ee (Table 1, Entry 7). The
Scheme 1. The synthetic route for the preparation of novel quin-
examination of solvent effects revealed that THF was the idine-derived organocatalysts.
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Quinidine-Derived Organocatalysts for Asymmetric Substitutions
best solvent for this reaction (Table 1, Entries 10–12). Low- Table 2. Screening of the asymmetric substitution of MBH adducts
2 with 1 catalyzed by cat-VIII.[a]
ering the reaction temperature to 0 °C or –25 °C afforded
3aa in 60 and 75%ee, respectively, along with good yields
in the presence of organocatalyst cat-VIII (Table 1, En-
tries 13 and 14). Further reducing the reaction temperature
did not improve the ee value of 3aa (Table 1, Entries 15–
18). Moreover, we also attempted to add some additives
such as diisopropylethylamine (DIEA), 4-nitrophenol, eth-
anol, tert-amyl alcohol, and benzoic acid to improve the
enantiomeric excess of 3aa in THF at –25 °C. However, no
improvement was observed under the standard conditions
(Table 1, Entries 19–23). Increasing the employed amount
of cat-VIII to 20 mol-% did not improve the reaction out-
come either (Table 1, Entry 24). Overall, this asymmetric
substitution reaction should be carried out at –25 °C in
THF using organocatalyst cat-VIII as the promoter.
[a] All reactions were carried out using 1 (0.12 mmol) and 2
(0.10 mmol) in THF (1.00 mL) for 10 h. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis.
We next attempted to use methyl tosylcarbamate (4a) to
replace carbamate 1 in this interesting asymmetric substitu-
tion reaction. Although organocatalysts β-ICD and
hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl
diether
[(DHQD)2PYR] and hydroquinine-1,4-phthalazinediyl di-
ether [(DHQ)2PHAL] did not catalyze this reaction under
the standard conditions, we were pleased to find that our
new organocatalysts cat-IV–cat-VIII (10 mol-%) could pro-
duce corresponding product 5da in moderate to good yields
along with 86–92%ee (Table 3, Entries 1–8). The substitu-
Figure 2. ORTEP drawing of organocatalyst cat-VIII.
Under these optimal conditions, we next examined the ent on the aromatic RЈ group can significantly affect the
generality of this reaction with methyl carbamates 1 and O- reaction outcome. Introducing strongly electron-donating
Boc-protected MBH adducts 2, and the results are summa- methoxy groups at the 2-position or at the 3- and 5-posi-
rized in Table 2. As for aromatic carbamates 1b–d, the sub- tions of the benzene ring (organocatalysts cat-IX and cat-
stitution reaction with 2a proceeded smoothly to give the X) afforded the corresponding product 5da in lower yield
corresponding products 3ba, 3ca, and 3da in 80–87% yields and with lower ee values (Table 3, Entries 9 and 10). Using
and 62–64%ee whether they have electron-withdrawing or organocatalyst cat-XI in which the aromatic RЈ group has
electron-donating groups on their benzene rings (Table 2, a bromine atom at the 4-position furnished 5da in 24%
Entries2–4). Changing the ester moiety from OMe to OiBu yield with 84%ee (Table 3, Entry 11). Furthermore, the re-
or C6H5 was not detrimental to the outcome of the reac- action produced 5da in 27% yield and 67%ee in the pres-
tion, as desired product 3ea or 3fa was obtained in 82 or ence of organocatalyst cat-XII in which RЈ is a phenyl
75% yield, respectively, with 65 or 52%ee, respectively group and RЈ is a methyl group, suggesting that the NH
(Table 2, Entries 5 and 6). Furthermore, in the substitution functional group is required in this reaction to give 5da in
reaction of 1a with other O-Boc-protected MBH adducts higher yield and with a higher ee value (Table 3, Entry 12).
2b, 2c, and 2d, corresponding products 3ab, 3ac, and 3ad Organocatalysts cat-XIII and cat-XIV, in which RЈ is a
were also obtained in good yields with 55–77%ee, suggest- benzyl group or a substituted benzyl group and RЈ is a hy-
ing that the electronic properties on the aromatic ring of drogen atom, are also effective catalysts in this asymmetric
the MBH adduct did not have an influence on the outcome substitution reaction, affording 5da in 65% yield with
of the reactions (Table 2, Entries 7–9). Using carbamate 1g 86%ee and 68% yield with 89%ee, respectively (Table 3,
(R1 = C6H5 and R2 = Me) as the substrate afforded desired Entries 13 and 14). Using organocatalyst cat-VIII (15 mol-
product 3gd in 48% yield and 43%ee, presumably due to %) as the catalyst produced 5da in 85% yield with 92%ee
its lability under the standard reaction conditions (Table 2, (Table 3, Entry 15). Therefore, the optimal organocatalyst
entry 10).
has been identified as cat-VIII and a catalyst loading of
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15 mol-% is required in this particular asymmetric substitu- Table 4. Optimization of the reaction conditions.[a]
tion reaction to give the corresponding product in good
yield along with high ee values.
Table 3. Cinchona alkaloid catalyzed asymmetric substitution of
MBH adduct 2d with 4a.[a]
[a] All reactions were carried out using 2d (0.10 mmol) and 4a
(0.12 mmol) in solvent (1.00 mL) for 72 h. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] The reaction was carried out
for 24 h.
[a] All reactions were carried out using 2d (0.10 mmol) and 4a
(0.12 mmol) in THF (1.00 mL) for 72 h. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] The reaction was carried out
for 80 h. [e] The reaction was carried out with cat-VIII (15 mol-%).
Further examination of solvent effects disclosed that tected MBH adduct 2i bearing a nitro group at the ortho-
THF was the solvent of choice in comparison with those position of the benzene ring, electron-neutral O-Boc-pro-
reactions carried out in halogenated organic solvents such tected MBH adduct 2b, and O-Boc-protected MBH adduct
as dichloromethane (DCM), 1,2-dichloroethane (DCE), or 2c having a methyl group at the para-position of the ben-
chloroform and in toluene (Table 4, Entries 1–6). In N,N- zene ring, the corresponding products 5ia, 5ba, and 5ca
dimethylformamide (DMF) and dimethyl sulfoxide were formed in moderate yields of 55–80% with 86–91%ee,
(DMSO), reactant 2d decomposed during the reaction perhaps due to electronic properties or steric effects
without the formation of 5da (Table 4, Entries 7 and 8). In (Table 5, Entries 7, 9, and 10). However, their yields could
ether or acetonitrile, no reaction occurred because organo- be improved when these reactions were carried out at 30 °C,
catalyst cat-VIII was insoluble in these solvents (Table 4, affording the corresponding products in 80, 85, and 83%
Entries 10 and 12). In 1,4-dioxane and acetone, 5da was yield, respectively, along with similar ee values (Table 5, En-
formed in 45% yield along with 79%ee and in 33% yield tries 13–15). As for heterocyclic group containing O-Boc-
along with 90%ee, respectively (Table 4, Entries 9 and 11). protected MBH adduct 2k, the reaction also proceeded
Raising the reaction temperature to 25 °C–50 °C did not smoothly to afford corresponding product 5ka in 69% yield
improve the outcome of the reaction (Table 4, Entries 13– with 83%ee under the standard conditions (Table 5, En-
15). When the reaction was carried out at 10 °C or at try 11), but no reaction occurred with O-Boc-protected 2-
–20 °C, either a trace amount of 5da was formed or no reac- furan-containing MBH adduct 2l (Table 5, Entry 12). Other
tion occurred (Table 4, entries 16 and 17).
tosylcarbamates such as 4b and 4c were also suitable sub-
The generality of this asymmetric substitution reaction strates in this reaction, and corresponding products 5db,
was examined using a variety of O-Boc-protected MBH ad- 5cb, 5jb, and 5dc were obtained in 76–89% yield with 84–
ducts (MBH carbonate) 2 and tosylcarbamates 4 at 20 °C 92%ee (Table 5, Entries 16–19); other related results as well
under the optimal conditions, and the results of these ex- as more examples are summarized in the Supporting Infor-
periments are summarized in Table 5. When O-Boc-pro- mation (Table S1), suggesting the wide substrate scope in
tected MBH adducts
groups at the ortho-, meta-, or para-position of the benzene
2
bearing electron-withdrawing this asymmetric substitution reaction.
The absolute configuration of products 5 was unequivo-
ring were employed as the substrates, the reactions pro- cally assigned the (S) configuration by X-ray diffraction of
ceeded smoothly to give desired products 5 in 60–91% yield 5fa bearing a bromine atom on the benzene ring.[10] Its
with 76–96%ee (Table 5, Entries 1–8). As for O-Boc-pro- ORTEP drawing is shown in Figure 3.
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Quinidine-Derived Organocatalysts for Asymmetric Substitutions
Table 5. Substrate scope of the cat-VIII-catalyzed asymmetric sub- corresponding products in good to high yields (up to 91%
stitution of MBH adducts 2 with 4.[a]
yield) with moderate to high ee value (up to 96%ee) under
mild conditions, which is applicable to a wide range of sub-
strates from MBH adducts. The obtained multiply function-
alized aza-MBH adducts are useful building blocks in a
variety of organic syntheses.[3j] Current efforts are in pro-
gress to use these novel multifunctional quinidine-derived
organocatalysts for other asymmetric catalytic reactions.
Experimental Section
Representative Procedure: A solution of compound 2d (0.10 mmol,
31.0 mg) and compound 4a (0.12 mmol, 27.5 mg) in THF
(1.00 mL) was stirred at 25 °C for 72 h in the presence of organoca-
talyst cat-VIII (15 mol-%, 6.0 mg) under an argon atmosphere. The
solvent was removed under reduced pressure, and the residue was
purified by chromatography on silica gel (petroleum ether/EtOAc,
4:1 to 2:1) to provide product 5da as a colorless solid (37.5 mg,
85% yield).
(S)-Methyl 1-(4-Chlorophenyl)-2-methylene-3-oxobutyl(tosyl)carb-
amate (5da): Colorless solid (37.5 mg, 85% yield); m.p. 126–129 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 2.41 (s, 3 H), 2.45 (s, 3
H), 3.57 (s, 3 H), 5.96 (d, J = 1.2 Hz, 1 H), 6.42 (d, J = 1.2 Hz, 1
H), 6.67 (s, 1 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.26–7.33 (m, 4 H),
7.80 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.6, 26.2, 53.5, 60.0, 128.4, 128.8, 129.0, 129.2, 129.7, 133.5, 136.2,
136.2, 144.8, 146.2, 152.6, 197.8 ppm. IR (neat): ν = 2957, 2925,
˜
1738, 1681, 1493, 1439, 1361, 1265, 1170, 1090, 1015, 814 cm–1.
MS (ESI): m/z = 444 [M + Na]. HRMS (ESI): calcd. for
C20H20NClNaO5S [M + Na] 444.0643; found 444.0645. [α]2D0
+39.0 (c = 0.3, CHCl3) (92%ee). HPLC (Chiralcel AD-H, hexane/
iPrOH = 80:20, 0.7 mL/min, 254 nm): tR = 19.02 (major), 24.94
(minor) min.
=
[a] All reactions were carried out using 2 (0.10 mmol) and 4
(0.12 mmol) in THF (1.00 mL) for 72 h. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] The reaction was carried out
at 30 °C.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data and chiral HPLC traces of the compounds
shown in Tables 1–5, X-ray crystal data of cat-VIII and product
5fa, and detailed experimental procedures.
Acknowledgments
Financial support from the Shanghai Municipal Committee of Sci-
ence and Technology (08dj1400100-2), the National Basic Research
Program of China [(973)-2010CB833302], the Fundamental Re-
search Funds for the Central Universities, and the National Natu-
ral Science Foundation of China (21072206, 20472096, 20902019,
20872162, 20672127, 20821002, 20732008, and 20702059) is grate-
fully acknowledged; Professor Jie Sun is thanked for performing
the X-ray diffraction studies.
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Conclusions
In summary, we have synthesized a series of novel quin-
idine-derived organocatalysts for the asymmetric substitu-
tions of O-Boc-protected Morita–Baylis–Hillman adducts
with various carbamates and tosylcarbamates, affording the
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[9] Crystal data for organocatalyst cat-VIII: Empirical formula:
C26H29N3O3; formula weight: 413.52; crystal color, habit:
colorless,
prismatic;
crystal
dimensions:
0.356ϫ0.311ϫ0.270 mm; crystal system: orthorhombic; lat-
tice type: primitive; lattice parameters: a = 9.5509(13) Å, b =
12.7565(17) Å, c = 18.691(3) Å, α = 90°, β = 90°, γ = 90°, V =
2277.2(5) Å3; space group: P212121; Z = 4; Dcalcd. = 1.259 g/
cm3; F(000) = 920; diffractometer: Rigaku AFC7R; residuals:
R, Rw: 0.0545, 0.1392. CCDC-770089 contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] Crystal data for 5fa: Empirical formula: C20H20BrNO5S; for-
mula weight: 466.34; crystal color, habit: colorless; crystal di-
mensions: 0.359ϫ0.321ϫ0.258 mm; crystal system: ortho-
rhombic; lattice type: primitive; lattice parameters:
a =
9.5008(10) Å, b = 14.2871(15) Å, c = 15.2971(16) Å, α = 90°, β
= 90°, γ = 90°, V = 2075.7(4) Å3; space group: P212121; z =
4; Dcalcd. = 1.492 g/cm3; F(000) = 952; diffractometer: Rigaku
AFC7R; residuals: R, Rw: 0.0383, 0.0741. CCDC-796340 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[4] For selected reports on SN2Ј–SN2Ј substitution of Morita–
Baylis–Hillman acetates or carbonates, see: a) B. M. Trost,
M. R. Machacek, H. C. Tsui, J. Am. Chem. Soc. 2005, 127,
7014–7024; b) C.-W. Cho, J.-R. Kong, M. J. Krische, Org. Lett.
2004, 6, 1337–1339; c) C.-W. Cho, M. J. Krische, Angew. Chem.
Received: April 8, 2011
Published Online: June 10, 2011
4484
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4479–4484