Catalytic asymmetric Passerini-type reaction: Chiral aluminum- organophosphate-catalyzed enantioselective α-addition of isocyanides to aldehydes

Article abstract of DOI:10.1021/jo9017765

(Chemical Equation Presented) A chiral Lewis acid catalyst was prepared by mixing 2 equiv of chiral binol-derived organophosphoric acid and 1 equiv of Et₂AlCl. In the presence of a catalytic amount of [4j] ₂Al(III)Cl complex (0.05 eq

Full text of DOI:10.1021/jo9017765

pubs.acs.org/joc
organic chemistry and medicinal chemistry.2 In spite of the
Catalytic Asymmetric Passerini-Type Reaction:
Chiral Aluminum-Organophosphate-Catalyzed
Enantioselective r-Addition of Isocyanides to
Aldehydes
great efforts dedicated to this field, only limited success has
been recorded highlighting the difficulties associated with
the development of such a catalyst.3 In this context, Den-
mark developed a Lewis base-catalyzed enantioselective
two-component Passerini-like reaction.4 Domling per-
€
Tao Yue,†,‡ Mei-Xiang Wang,*,†,‡ De-Xian Wang,†,‡
formed a massive parallel screening of a large number of
metal-ligand combinations and found that a stoichiometric
amount of Ti-Taddol complex was capable of promoting the
Passerini three-component (P-3CR) reaction to afford the R-
acyloxyamides in moderate enantioselectivity.5 Schreiber
demonstrated that an indan (PyBox)-Cu(II) complex was
able to catalyze the P-3CR; however, enantio-enriched Pas-
serini adducts were obtained only when the chelating alde-
hydes were used as a reaction partner.6 We have reported
that chiral (salen)Al(III)Cl7 was able to catalyze efficiently
the reaction of nonchelating aldehydes, isocyanides, and
carboxylic acids or hydrazoic acid leading to the P-3CR
adducts in good to excellent enantioselectivities.8
§
Geraldine Masson, and Jieping Zhu*
,§
ꢀ
†Beijing National Laboratory for Molecular Sciences, CAS
Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China, ‡Key Laboratory of Bioorganic Phosphrous
Chemistry & Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China, and §Institut de Chimie des Substances
Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
mxwang@iccas.ac.cn; zhu@icsn.cnrs-gif.fr
Received August 17, 2009
The difficulty encounted in developing enantioselective
catalysts for the R-addition of isocyanides to aldehydes is
intriguing since a variety of chiral Lewis acids and Brønsted
acids are known to catalyze the enantioselective addition of
nucleophiles to the carbonyl group. We have previously
shown that (salen)Al(III)Cl is able to catalyze the reaction
of aldehydes (3) and R-isocyanoacetamides (2) to afford the
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(4) (a) Denmark, S.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825–7827. (b)
A chiral Lewis acid catalyst was prepared by mixing 2
equiv of chiral binol-derived organophosphoric acid and
1 equiv of Et2AlCl. In the presence of a catalytic amount
of [4j]2Al(III)Cl complex (0.05 equiv), reaction between
R-isocyanoacetamides (2) and aldehydes (3) afforded the
corresponding 5-aminooxazoles (1) in good yields and en-
antioselectivities. Complex [4j]2Al(III)Cl isolated as a white
solid displayed similar reactivity as that prepared in situ.
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In view of the extraordinary molecular diversity and
complexity that one can create by taking advantage of the
carbene-like reactivity of isocyanides,1 the development of
catalysts for enantioselective nucleophilic addition of diva-
lent isonitrile carbon to polarized double bonds (carbonyl
group, imine, etc.) could have significant impact in synthetic
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€
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Published on Web 09/29/2009
DOI: 10.1021/jo9017765
r
2009 American Chemical Society

Yue et al.
JOCNote
SCHEME 1. A Chiral Al-Organophosphate-Catalyzed Enan-
tioselective R-Addition of R-Isocyanoacetamides to Aldehydes
TABLE 1. Reaction of 2a and 3a in the Presence of Phosphoric Acid 4a
and Et2AlCla
entry
4 (equiv)
Et2AlCl (equiv)
T (° C)
yieldb
eec
22
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4a (0.2)
4a (0.2)
4a (0.1)
4a (0.24)
4a (0.3)
4a (0.1)
4b (0.1)
4c (0.1)
4d (0.1)
4e (0.1)
4f (0.1)
4g (0.1)
4h (0.1)
4i (0.1)
4j (0.1)
4k (0.1)
4l (0.1)
4j (0.1)
4j (0.1)d
4j (0.1)e
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-40
-40
-40
71
68
89
78
71
68
62
22
23
89
80
91
65
84
82
57
87
81
81
71
0.1
0.1
0.1
0.1
49
-16
40
39
47
12
5
enantiomerically enriched 2-(1-hydroxyalkyl)-5-aminooxa-
zoles (1).9,10 Very recently, Matsunaga, Shibasaki, and co-
workers elegantly demonstrated that a heterobimetallic Ga/
Yb-Schiff base complex was highly efficient in catalyzing the
same reaction providing 5-aminooxazoles (1) in excellent
yields and enantioselectivities.11 As a continuation of our
interests in this reaction, we report herein the development of
a chiral aluminum organophosphate catalyst and its applica-
tion in the synthesis of enantio-enriched 2-(1-hydroxyalkyl)-
5-aminooxazoles (1) by reaction of R-isocyanoacetamides (2)
and aldehydes (3, Scheme 1).
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
22
7
33
48
22
62
51
0
51
59
71
71
Chiral phosphoric acids are now well established as bifunc-
tional organocatalysts, particularly in catalyzing the addition
of nucleophiles to imines/acylimines12,13 However, examples
on the enantioselective activation of aldehydes using this
aGeneral reaction conditions: 2a/3a=1/1, in toluene c=0.1 M. bYield of
chromatographically pure material. cDetermined by chiral HPLC analysis.
dReaction performed at c=0.07 M. eReaction performed at c =0.05 M.
family of Brønsted acids were rare.14 We initially examined
the reaction of R-benzyl-R-isocyanoacetamide (2a) and 2-
methylpropanal (3a)15 in the presence of chiral phosphoric
acids. Although the reaction did proceed, the enantioselectivity
was low (entry 1, Table 1).16 Stimulated by the work of Furono
and Inanaga on the activation of carbonyl compounds by
chiral rare earth organophosphates,17 in conjunction with the
established catalytic power of Al-based chiral Lewis acid on
the above transformation,8,10 the reaction between 2a and 3a
was performed in the presence of phosphoric acid 4 and
Et2AlCl. As shown in Table 1, the ratio of 4a to Et2AlCl
influenced the reaction outcome and the best ee was obtained
when they were mixed in a 2/1 ratio (entry 2). Interestingly,
when 4a and Et2AlCl were used in a 1/1 ratio, the sense of
asymmetric induction was reversed (entry 3). This intriguing
result provided indirect evidence that the Al-organophosphate
complex was indeed an active catalytic species and that the chiral
environment varied depending on the number of phosphate
ligands associated with the metal center. Similar ee was observed
when the loading of Et2AlCl and phosphoric acid was reduced
to 5 and 10 mol %, respectively (entry 6).
(11) Mihara, H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 8384–8385.
(12) Selected examples: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566–1568. (b) Uraguchi, D.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 11804–11805. (c) Rowland, G. B.; Zhang, H.;
Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am.
Chem. Soc. 2005, 127, 15696–15697. (d) Hofmann, S.; Seayad, A. M.; List, B.
Angew. Chem., Int. Ed. 2005, 44, 7424–7427. (e) Rueping, M.; Sugiono, E.;
Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617–2619. (f ) Storer, R. I.;
Carrera, D. E.; Ni, D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
84–86. (g) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am.
Chem. Soc. 2006, 128, 14802–14803. (h) Kang, Q.; Zhao, Z.-A.; You, S.-L.
J. Am. Chem. Soc. 2007, 129, 1484–1485. (i) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.;
Zhang, C.-M.; Zhou, Q. L. Angew. Chem., Int. Ed. 2007, 46, 5565–5567. ( j)
Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487. (k) Sickert,
M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631–3634. (l) Baudequin,
C.; Zamfir, A.; Tsogoeva, S. B. Chem. Commun. 2008, 4637–4639. (m)
Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int.
Ed. 2008, 47, 5661–5665. (n) Xu, S.; Wang, Z; Zhang, X.; Zhang, X.; Ding, K.
Angew. Chem., Int. Ed. 2008, 47, 2840–2843. (o) Jiang, J.; Yu, J.; Sun, X.-X.;
Rao, Q.-Q.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 2458–2462. (p)
Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed. 2008, 47,
5079–5081. (q) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008,
47, 759. (r) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K.
Angew. Chem., Int. Ed. 2009, 48, 908–910. (s) Liu, H.; Dagousset, G.;
Masson, G.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598–4599. (t) Terada,
M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553–
2556. (u) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445–2447.
(13) (a) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758. (b) Terada, M.
Chem. Commun. 2008, 4097–4112. (c) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713–5743.
Different phosphoric acids (Figure 1) were next screened
under the following conditions: 4 (0.1 equiv), Et2AlCl (0.05
(14) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626–9627. (b) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B.
J. Angew. Chem., Int. Ed. 2007, 46, 2097–2100. (c) Rueping, M.; Nachtsheim,
B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593–596.
(d) Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47,
4122–4125. (e) Garcia-Garcia, P.; Lay, F.; Garcia-Garcia, P.; Rabalakos, C.;
List, B. Angew. Chem., Int. Ed. 2009, 48, 4363–4366.
(16) For phosphoric acids- and phosphinic acids-catalyzed Ugi-type
reactions, see: (a) Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47,
3622–3625. (b) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J.
Angew. Chem., Int. Ed. 2009, 48, 6717–6721.
(17) (a) Jin, X. L.; Sugihara, H.; Daikai, K.; Tateishi, H.; Jin, Y. Z.;
Furono, H.; Inanaga, J. Tetrahedron 2002, 58, 8321–8329. (b) Furono, H.;
Hayano, T.; Kambara, T.; Sugimoto, Y.; Hanamoto, T.; Tanaka, Y.; Jin,
Y. Z.; Kagawa, T.; Inanaga, J. Tetrahedron 2003, 59, 10509–10523. (c)
Suzuki, S.; Furono, H.; Yokoyama, Y.; Inanaga, J. Tetrahedron: Asymmetry
2006, 17, 504–507.
(15) The R-isocyanoacetamides are easily available, see: (a) Fayol, A.;
ꢀ
Housseman, C.; Sun, X.; Janvier, P.; Bienayme, H.; Zhu, J. Synthesis 2005,
161–165. (b) Housseman, C.; Zhu, J. Synlett 2006, 1777–1779. (c) Domling,
€
A.; Beck, B.; Fuchs, T.; Yazbak, A. J. Comb. Chem. 2006, 8, 872–880.
J. Org. Chem. Vol. 74, No. 21, 2009 8397

Yue et al.
JOCNote
SCHEME 2. Possible Conformations of Complex [4]2Al(III)Cl
FIGURE 1. List of phosphoric acids examined.
5-aminooxazole 1a was produced in 81% yield with 71% ee
(entry 19). Further decreasing the concentration (c = 0.05 M)
ledtoareducedyieldof1a without significant impact on the ee.
The scope of the reaction was explored by using the opti-
mized conditions (0.1 equiv of 4j,18 0.05 equiv of Et2AlCl,
toluene, -40 °C, c = 0.07 M) with representative aldehydes
and R-isocyanoacetamides (Figure 2). Aliphatic aldehydes,
including propionaldehyde, hexanal, isobutyaldehyde, and 3-
phenylpropanal, gave the corresponding oxazoles in good
yields and good enantioselectivities. The R-branched aldehyde
gave in general higher ee than the linear ones (1i, ee 87%). The
R-phenyl-, R-benzyl-, and R-methyl-substituted R-isocyanoa-
cetamides participated well in this reaction to afford the
expected adducts. The absolute configuration of these oxazoles
was determined to be (S) by comparing the optical rotation
value with that of the known compounds.10a
The phosphoric acid 4j is insoluble in toluene. However,
by adding 0.5 equiv of Et2AlCl into the suspension, a clear
solution was formed. Evaporation of solvent allowed us to
isolate a presumed catalyst (4j)2AlCl in the form of white
solid.19 Reaction of 2a and 3a in the presence of 5 mol % of
this presynthesized catalyst afforded 1a in 82% yield with
71% ee. These results indicated that the isolated catalyst has
the same catalytic properties as that generated in situ.
However, attempts to obtain a single crystal failed and
1HNMR data did not allow us to propose a structure for
this Al complex. In principle, the 2 to 1 complex formed
between phosphoric acid and Et2AlCl could exist in three
different conformers 5a, 5b, and 5c and they could have
different catalytic properties (Scheme 2).7b The moderate ee
obtained in this work may in part due to the conformational
mobility of this complex. We are currently attempting to
synthesize ligands that could potentially favor the trans-
metal complex of type 5c. We assumed that access to this
conformer would be essential for achieving the high ee of
compoud 1.8,10
FIGURE 2. Al-organophosphate-catalyzed synthesis of 2-(1-
hydroxyalkyl)-5-aminooxazoles (1). General reaction conditions:
2/3 = 1/1, toluene (c = 0.05 M), 4j/Et2AlCl (0.05 equiv), -40 °C,
48 h. y: Yield of chromatographically pure material. Determined by
chiral HPLC analysis.
equiv), toluene, c = 0.1 M, -20 °C. Increasing the size of the
Ar group reduced the ee of the oxazole 1a (entries 7-11).
Introduction of an electron-donating group at the 4-position
of the Ar group exerted also a negative effect on the reaction
(entry 13), whereas the presence of an electron-withdrawing
group (4i, 4j) in the Ar group increased the ee of 1a (entries 14
and 15), probably due to the slightly increased Lewis acidity
of the catalyst in the latter cases. Using phosphoric acid 4l, an
octahydro-analogue of 4a, afforded ee similar to that ob-
tained with 4a (entry 17). Finally, it was found that the
reaction concentration influenced the ee of the product.
Reducing the concentration from c = 0.1 to 0.07 M, the
(18) Using phosphoric acid 4i as ligand gave non-reproducible results,
presumably due to the interaction between the nitro group and aluminium.
The reaction was preferably performed at 0.05 M instead of 0.07 M for the
solubility issue.
(19) For the synthesis of (TFA)2AlMe, see: (a) Itoh, A.; Oshima, K.;
Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1980, 53, 2050–2054. (b)
Hashimoto, S.; Itoh, A.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 4192–4194.
8398 J. Org. Chem. Vol. 74, No. 21, 2009

Yue et al.
In summary, we have reported an efficient phosphoric
JOCNote
mixture was then stirred at room temperature until a clear
solution was formed. The aldehyde (0.25 mmol, in 0.5 mL of
toluene) was then introduced and the resulting mixture was
stirred at room temperature for 30 min. The reaction mixture
was cooled to -40 °C and a solution of R-isocyanoacetamide
(0.25 mmol) in toluene (2.0 mL) was added slowly via a syringe
pump (addition time 1.5 h). After being stirred at -40 °C for
48 h, the reaction mixture was purified by flash column chro-
matography (SiO2, petroleum ether then petroleum ether/EtO-
Ac = 1/1) to give the corresponding oxazole. 2-Methyl-1-(5-
morpholino-4-phenyloxazol-2-yl)propan-1-ol (1c): white solid,
mp 117-118 °C; [R]20D þ5.5 (c 0.85, CHCl3); yield 95%, ee 81%
(ADH, hexane/iPrOH = 9/1, 25 °C, 0.5 mL/min); IR (KBr) ν
3237, 2966, 2849, 1636, 1381, 1114, cm-1; 1HNMR (CDCl3, 300
MHz) δ 7.95 (d, J = 8.5 Hz, 2H), 7.42-7.37 (m, 2H), 7.29-7.24
(m, 1H), 4.49 (t, J = 5.9 Hz, 1H), 3.87-3.84 (m, 4H), 3.11-3.08
(m, 4H), 2.96 (d, J = 5.9 Hz, 1H), 2.21-2.15 (m, 1H), 1.00 (d,
J = 7.1 Hz, 3H), 0.98 (d, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 159.7, 151.1, 131.6, 128.5, 127.1, 125.9, 123.7, 73.0, 66.9,
50.4, 33.5, 18.4, 17.3 ; MS (ESI) m/z 303 (M þ H), 325 (M þ Na).
Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found:
C, 67.24; H, 7.33; N, 9.26.
acid-Al complex-catalyzed R-addition of R-isocyanoaceta-
mides to aldehydes for the synthesis of enantio-enriched
2-(1-hydroxyalkyl)-5-aminooxazoles. In view of the frequent
occurrence of oxazole in natural products and medicinally
relevant compounds, its unique reactivity for generating the
molecular complexity, and diversity,20,21 we believe that
the present protocol could be of synthetic value. We also
expected applications of these Al-phosphate complexes in
other catalytic asymmetric transformations.22
Experiment Section
General Procedure. In a flame-dried round-bottomed flask
equipped with a stir bar were added binol-derived phosphoric
acid (4j, 0.025 mmol) and dry toluene (1 mL). The mixture was
stirred at room temperature for several minutes, to which a
solution of Et2AlCl (0.0125 mmol) in toluene was added. The
(20) Selected examples: (a) Fayol, A.; Zhu, J. Angew. Chem., Int. Ed.
ꢀ
2002, 41, 3633–3635. (b) Janvier, P.; Bienayme, H.; Zhu, J. Angew. Chem.,
ꢀ
~
ꢀ
Int. Ed. 2002, 41, 4291–4294. (c) Gamez-Montano, R.; Gonzalez-Zamora,
E.; Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351–6358. (d) Fayol, A.; Zhu, J.
Org. Lett. 2005, 7, 239–242. (e) Bughin, C.; Masson, G.; Zhu, J. J. Org. Chem.
2007, 72, 1826–1829. (f ) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem., Int.
Ed. 2007, 46, 2485–2488.
Acknowledgment. We gratefully acknowledge the Na-
tional Science Foundation of China (NSFC) and CNRS
(France) for financial support.
(21) For reviews on the chemistry of oxazole see: (a) Karpeiskii, M. Y.;
Florent’ev, V. L. Russ. Chem. Rev. 1969, 38, 540–546. (b) Jacobi, P. A. Adv.
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Supporting Information Available: Experimental proce-
dures, product characterization, as well as copies of H NMR
1
(22) ForreviewsonAl-Binolcomplexcatalyzedasymmetricreactions, see: (a)
Wulff, W. D. Chiral aluminium Lewis acids in organic synthesis. In Lewis acids in
organic synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
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available free of charge via the Internet at http://pubs.acs.org.
€
pp 283-354. (b) Groger, H. Chem.;Eur. J. 2001, 7, 5247–5251.
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