Bifunctional N-acyl-aminophosphine-catalyzed asymmetric [4+2] cycloadditions of allenoates and imines

Article abstract of DOI:10.1002/chem.201100850

Try bifunctional aminophosphines! An asymmetric organocatalytic [4+2] cycloaddition between α-substituted allenoates and tosylaldimines using bifunctional N-acyl aminophosphine catalysts was described (see scheme). This operationally simple catalytic syst

Full text of DOI:10.1002/chem.201100850

DOI: 10.1002/chem.201100850
Bifunctional N-Acyl-Aminophosphine-Catalyzed Asymmetric [4+2]
Cycloadditions of Allenoates and Imines
Hua Xiao,[a] Zhuo Chai,[b] Hai-Feng Wang,[b] Xiao-Wei Wang,[b] Dong-Dong Cao,[a]
Wen Liu,[a] Ying-Peng Lu,[b] Ying-Quan Yang,[a] and Gang Zhao*[a, b]
Tetrahydropyridines are important structural motifs pres-
ent in a huge number of pharmaceutically interesting sub-
stances and bioactive natural products. For example, the
ergot alkaloid derivative lysergic acid diethylamide (LSD,
1), a strongly psychedelic agent; tadalafil (2), a drug which
has been marketed for the treatment of erectile dysfunction
and pulmonary hypertension, and the cytotoxic bisindole al-
kaloid Leucoridine B (3) all share the chiral tetrahydropyri-
dine structure.[1] Although many powerful synthetic methods
for accessing these nitrogen-containing six-membered het-
erocycles have been established,[2] the development of cata-
lytic asymmetric approaches allowing for the construction of
these structures in optically active forms remains an attrac-
tive goal in organic synthesis.[3]
these reactions has greatly expanded the reaction scope.[8]
Particularly, in 2003, Kwon pioneered the use of a-substitut-
ed allenoates in the annulation reaction with imines, leading
to a novel [4+2] cycloaddition reaction in which the alle-
noates served as novel “C4 synthons”.[8a] Such a reaction
provides an efficient and atom-economical access to multi-
functional tetrahydropyridines. Later, this kind of [4+2] cy-
cloaddition was further successfully extended to electron-de-
ficient alkenes and trifluoromethylketones to give highly
functionalized cyclohexenes[8c] and dihydropyrans.[8h]
Despite the above impressive progress achieved in phos-
phine-catalyzed cycloaddition reactions of allenoates, the
development of enantioselective variants remains rather lim-
ited and unbalanced. Up to now, most enantioselective an-
nulations in this field were achieved only with non-substitut-
ed allenoates and electron-deficient species, namely asym-
metric [3+2] cycloadditions.[9,10] To the best of our knowl-
edge, there is only one report on an asymmetric a-substitut-
ed allenoate–imine [4+2] cycloaddition catalyzed by a
chiral monodentate phosphine developed by Fu in 2005, two
years after Kwonꢀs finding of the non-enantioselective reac-
tion.[8d] Therefore, there is still a great potential for asym-
metric catalysis to be fulfilled in this field. Inspired by the
works from Miller and Jacobsen,[10a–b] our group have recent-
ly developed simple bifunctional N-acyl aminophosphines
derived from amino acids as organocatalysts for highly
regio- and enantioselective [3+2] cycloadditions between
allenoates and dual-activated olefins.[11] Besides their acces-
sibility and air stability, these bifunctional catalysts could
also obviate some demanding reaction conditions such as an
inert atmosphere and anhydrous solvents usually required
for chiral monodentate phosphine catalysts. As part of our
efforts to extend the application of these catalysts in asym-
metric synthesis, we describe herein the highly diastereose-
lective and enantioselective [4+2] cycloadditions between
allenoates and tosylaldimines catalyzed by bifunctional N-
acyl aminophosphines.
Since the seminal work of Lu and co-workers reported in
1995,[4] the phosphine-catalyzed cycloaddition reactions of
allenoates have evolved to be an efficient method for the
construction of a variety of synthetically useful carbo- and
heterocycles due to intensive research efforts.[4–8] In addition
to the initial fruitful use of unsubstituted allenoates as a “C3
synthon” in this type of reaction with various electrophiles,
the incorporation of a and/or g-substituted allenoate into
[a] H. Xiao, D.-D. Cao, W. Liu, Y.-Q. Yang, Prof. Dr. G. Zhao
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P.R. China)
Fax : (+86)21-64166128
Initially, the reaction between 2-(2-ethoxy-2-oxoethyl)-2,
3-butadienoate and N-tosylbenzaldimine in CH2Cl2 was
chosen to probe the catalytic efficiency of the bifunctional
phosphines (Table 1). Interestingly, the isoleucine-derived
catalyst 7 f, the best catalyst identified in our previous asym-
metric [3+2] cycloaddition, also proved the best one in this
[4+2] cycloaddition, giving the desired cycloadduct 6a in
85% yield and with 90% enantiomeric excess (ee) (Table 1,
E-mail: zhaog@mail.sioc.ac.cn
[b] Z. Chai, H.-F. Wang, X.-W. Wang, Y.-P. Lu, Prof. Dr. G. Zhao
Laboratory of modern synthetic chemistry
Shanghai institute of organic chemistry
354 Fenglin Road, Shanghai, 200032
Chinese Academy of Sciences (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100850.
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Chem. Eur. J. 2011, 17, 10562 – 10565

COMMUNICATION
Table 1. Screening of reaction conditions for the asymmetric [4+2] cy-
bonding acceptor atom (O or N), such as Et2O and acetone,
were not suitable for the reaction (Table 1, entries 15–16).
Polar aromatic solvents such as PhCl and PhCF3 were most
favorable in terms of the enantioselectivity and reaction
time, albeit with diminished yields (Table 1, entries 18–19).
As a compromise of both the yield and ee value, the reac-
tion could be performed in a co-solvent of CH2Cl2 and
PhCF3 (v/v=1:1) to give the product in 78% yield and with
93% ee (Table 1, entry 20). The addition of 4 ꢂ molecule
sieves, which may minimize the decomposition of the mois-
ture-sensitive Ts-imine, proved to be beneficial to the chem-
ical yield (Table 1, entries 21 and 23).
cloaddition.[a]
Subsequently, we examined the reactivity of three other
allenoates with different substituents (R) on the a carbon
atom (Scheme 1). Consistent with the observations from
Kwon and Fu, the anion-stabilizing ability of the substitu-
ents (R) plays a key role in this reaction; changing the ester
group in 5a to the aryl groups in 5b and 5c led to decreased
yield and enantioselectivity, but with improved diastereose-
lectivity, and the simple allene 5d (R=H) failed to undergo
the reaction in our case.
Entry
Catalyst
Solvent
t
Yield[b]
[%]
d.r.[c]
ee[d]
[%]
[h]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7 f
7g
7h
7i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
24
48
24
24
48
8
8
8
8
12
8
46
28
NR[g]
41
26
85
68
81
76
44
90
74
61
26
20
31
33
68
61
78
99
65
85
19:1
19:1
–
79
60
–
19:1
19:1
19:1
14:1
19:1
19:1
19:1
17:1
19:1
17:1
5:1
9:1
9:1
9:1
19:1
15:1
15:1
19:1
15:1
15:1
73
23
90
24
88
88
90
88
90
91
95
58
71
90
96
97
93
89
95
92
The scope of the asymmetric [4+2] cycloaddition with
regard to different aldimines was next investigated
(Table 2). In general, all the N-tosylaldimines derived from
9
10
11
12
13
14
15
16
17
18
19
20
21[f]
22[f]
23[f]
7j
7k
7l
8
7 f
7 f
7 f
7 f
7 f
7 f
7 f
7 f
7 f
7 f
7 f
12
12
12
12
12
6
6
12
8
CCl4
Et2O
acetone
m-xylene
PhCl
PhCF3
Scheme 1. Asymmetric [4+2] cycloaddition of N-tosylbenzaldimine 4a
and different substituted allenoates.
[e]
[e]
CH2Cl2/PhCF3
CH2Cl2
PhCF3
Table 2. Enantioselective [4+2] cycloadditions of allenoate 5a with N-
tosylaldimines 4 catalyzed by 7 f.[a]
12
12
CH2Cl2/PhCF3
[a] All reactions were carried out with 4a (0.1 mmol) and 2-(2-ethoxy-2-
oxoethyl)-2, 3-butadienoate 5a (0.2 mmol) in the presence of
7
(0.01 mmol) in solvent (1.0 mL). [b] Yields of isolated products. [c] Deter-
mined by 1H NMR spectroscopy. [d] Determined by chiral HPLC analy-
sis. [e] 1:1 (v/v) co-solvent of CH2Cl2 and PhCF3. [f] 20 mg of 4 ꢂ MS was
added. [g] NR=no reaction.
Entry
4
Ar
Product
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
4a
4b
4c
4d
4e
4 f
4g
4h
4i
Ph
6a
6b
6c
6d
6e
6 f
6g
6h
6i
85
94
88
80
15:1
15:1
4:1
6:1
16:1
7:1
92
90
96
95
entry 6). Compared with catalysts bearing the 3, 5-bistri-
fluoromethylbenzoyl group, 7b, 7d and 7g with any other
groups such as an acyl, benzoyl or tert-butoxycarbonyl (Boc)
group may be expected to give a slightly weaker acidity on
the NH functionality, and these catalysts gave inferior re-
sults, whereas the more acidic 7c was completely ineffective
in the reaction, which highlights the importance of the NH
functionality in the catalytic process (Table 1, entries 2–7).
Moreover, the structure of the chiral backbones of these cat-
alysts seemed highly influential on the catalytic activity; the
isoleucine or tert-butylleucine-derived catalysts were much
better than those derived from phenylalanine. In contrast,
the diastereoselectivity of the product 6a was much less in-
fluenced by this kind of catalyst alteration. An examination
of the solvent effect revealed that solvents with a hydrogen-
4-MeOC6H4
2-ClC6H4
2-FC6H4
4-ClC6H4
3-BrC6H4
2-naphthyl
4-MeC6H4
4-PhC6H4
3-FC6H4
2-furyl
3[e]
4[e]
5
67 (78)[f]
66 (73)[f]
66 (76)[f]
80
96 (93)[f]
96 (94)[f]
90 (87)[f]
92
6
7
8
9
10
11
12
9:1
15:1
11:1
12:1
11:1
12:1
72
81
72
98
91
95
89
82
4j
4k
4l
6j
6k
6l
2-thienyl
[a] All reactions were carried out with 4 (0.1 mmol) and 5a (0.2 mmol) in
solvent (1.0 mL) at RT for 12 h. [b] Yields of isolated products. [c] Deter-
mined by 1H NMR spectroscopy unless otherwise noted. [d] Determined
by chiral HPLC analysis. [e] Determined by the isolated product yields of
each of the two isomers. [f] Data in the parenthesis refer to reactions run
in CH2Cl2 without adding 4 ꢂ MS.
Chem. Eur. J. 2011, 17, 10562 – 10565
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10563

G. Zhao et al.
aromatic aldehydes worked well in the reaction,[12] providing
a series of chiral tetrahydropyridine derivatives in good
yields and diastereoselectivities, and with good to excellent
enantioselectivities. Substrates with electron-withdrawing
substituents on the arene rings in general gave higher ee
values than those with electron-donating ones. Similar to the
observations in Fuꢀs monodentate phosphine system,[8d] a re-
markable drop in diastereoselectivity was also observed for
orthosubstituted imines in this system (Table 2, entries 3 and
4). Pleasingly, some imines that did not work well in Fuꢀs
system gave somewhat improved results here: the electron-
rich 4-anisyl imine 4b, a sluggish coupling partner, which in
that system that gave a rather low yield (42%), worked well
in our system to give an excellent yield of 94%, albeit with
a decrease in ee value (98%!90%; Table 2, entry 2). The
result of 2-chlorobenzene aldimine 4c was also considerably
improved from 75% yield, 60% ee to 88% yield and 96%
ee (Table 2, entry 3). These complementary results from the
two catalyst systems would be valuable for the practical syn-
thetic application of this asymmetric annulation. In addition,
for substrates 4e–4g with modest yields in the co-solvent
used, performing the reaction in CH2Cl2 alone could im-
prove the yield appreciably with slightly reduced enantiose-
lectivity (Table 2, entries 5–7). Heteroaryl imines were also
tolerated in the reaction, albeit with somewhat diminished
ee values (Table 2, entries 11–12). The absolute configura-
tions of the products were assigned by comparison of the
optical rotation values with literature values[8d] (for known
compounds) and by analogy (for new compounds).
Scheme 2. A possible reaction mechanism.
To demonstrate the potential utility of the present [4+2]
cycloaddition reaction, the cycloadduct 6a was converted to
diol 8[13] in moderate diastereoselectivty by reduction with
LiBH4. Subsequent detosylation of 8 under Na/naphthalene
conditions gave a highly functionalized chiral piperidine
product 9 (Scheme 3), which may allow easy transformations
to more complex N-containing compounds with pharma-
ceutical interests.[14]
Based on Kwonꢀs mechanistic
proposal for the reaction[8a] and
previously
proposed
acting
models of bifunctional phos-
phine catalysts in related reac-
tions,[10a,b] a possible mechanism
Scheme 3. Useful conversion of the cycloadduct 6a.
was proposed for the reaction
(Scheme 2). After the initial for-
mation of the phosphadienolate structure, two possible tran-
sition states TS-I and TS-II, through either of which the cat-
alyst may function, could be proposed based on the ob-
served stereochemical results. As proposed by Marinetti,[9g]
the arrangement of the phosphorus center in the two transi-
tion states may be square-pyramidal (trigonal-bypyramidal
is also possible). Similar to the transition state drawn by
Miller for their multifunctional phosphine catalysts,[10a] TS-I
involves the formation of a zwitterion between the catalyst
and the allenoate 5a, which is possibly assisted by a hydro-
In conclusion, we have successfully extended the applica-
tions of our previously developed bifunctional N-acyl ami-
nophosphine catalysts to an efficient asymmetric organoca-
talytic [4+2] cycloaddition between a-substituted allenoates
and tosylaldimines, which provides facile accesses to optical-
ly active tetrahydropyridines. In addition to the ready cata-
lyst availability and simple manipulation, some substrates,
which gave not-so-satisfactory results with the chiral mono-
phophine catalysts, could also give improved results in this
system. Endeavors toward the application of these N-acyl
aminophosphine catalysts in other related reactions are cur-
rently underway in our laboratories.
[10k]
ꢀ
gen bonding interaction and a P O interaction;
the dien-
olate might approach the Re face of the imine to minimize
the steric repulsion between the catalyst backbone and the
Ts group of the imine. TS-II was drawn with reference to
the transition states proposed by Lu[10h] and Jacobsen;[10b]
Experimental Section
ꢀ
the hydrogen-bonding interaction and P O interaction
might adapt the flexible chiral bone of the catalyst to adopt
a conformation favoring the Re-face attack of the imine.
The firstly formed chiral center (R configuration) would
direct the formation of the second one.
Typical procedure: 4 ꢂ molecular sieves (20 mg) were added to a stirred
solution of N-tosylaldimines 4 (0.1 mmol) and catalyst 7 (0.01 mmol) in a
1:1 (v/v) co-solvent of PhCF3 and CH2Cl2 (1 mL) at room temperature.
The reaction mixture was stirred for 10 min before a-substituted 2, 3-bu-
10564
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Chem. Eur. J. 2011, 17, 10562 – 10565

Aminophosphine-Catalyzed Asymmetric [4+2] Cycloadditions
COMMUNICATION
tadienoate 5a (0.2 mmol) was added in one portion using a micro-sy-
ringe, followed by vigorously stirring at RT. After the reaction was com-
plete (monitored by TLC), the mixture was directly purified by column
chromatography on silica gel (petroleum ether/ethyl acetate 5:1, v/v) to
give the corresponding product.
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Acknowledgements
The financial support from the National Basic Research Program of
China (973 Program, 2010CB833200) the National Natural Science Foun-
dation of China (Nos. 20172064, 203900502, 20532040), Shanghai Natural
Science Council, and the Excellent Young Scholars Foundation of Na-
tional Natural Science Foundation of China (20525208) are gratefully ac-
knowledged.
Keywords: aminophosphines
·
asymmetric catalysis
·
bifunctional catalyst · cycloaddition · organocatalysis
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[12] Similar to previous reports (refs. [8a] and [8d]), N-tosylaldimines de-
rived from aliphatic aldehydes and N-Boc protected imines all
proved unreactive in this system.
[13] The structure of compound 8 was confirmed by X-ray crystallo-
graphic analysis (see the Supporting Information for details).
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Received: March 19, 2011
Published online: August 18, 2011
Chem. Eur. J. 2011, 17, 10562 – 10565
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10565