Catalytic asymmetric intramolecular hydroarylations of ω-aryloxy- and arylamino-tethered α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.200802722

The first enantioselective organocatalytic intramolecular hydroarylations of phenol and aniline-derived enals were investigated. The proposed method provided an atom economic and straightforward approach to optically active chromans and tetrahydroquinolines in high enantioselectivities and in good yields. The study demonstrated the efficiency of organocatalysis to achieve the first asymmetric intramolecular arylation of ω aryloxy- arylamino-tethered α, and β-unsaturated aldehydes using a chiral secondary amine catalyst. Proposed transformation method resulted in the production of functionalized chromans and tetrahydroquinoline in high enantiopurity. The study also examined the scope of substrates in this organocatalytic reaction using a catalyst 4/p-TsOH.H₂O in diethyl ether. The catalyst screening observed a higher yield up to 83% and comparable enantiometric excess up to 88% that can be obtained in a chiral secondary amine employed as the reaction catalyst.

Full text of DOI:10.1002/chem.200802722

DOI: 10.1002/chem.200802722
Catalytic Asymmetric Intramolecular Hydroarylations of w-Aryloxy- and
Arylamino-Tethered a,b-Unsaturated Aldehydes
Hai-Hua Lu, Hui Liu, Wei Wu, Xu-Fan Wang, Liang-Qiu Lu, and Wen-Jing Xiao*[a]
Phenols, anilines, and their derivatives are chemicals man-
ufactured in large quantities by modern chemical industries
and serve as important feedstocks in the synthesis of phar-
maceuticals, agro-, and fine chemicals.[1] The development of
direct and catalytic synthetic transformations of these
simple substrates to valuable compounds has therefore re-
mained a focal point for extensive research effort in both in-
dustrial and academic settings. Historically, these transfor-
mations are carried out by Friedel–Crafts reactions with acyl
or alkyl halides in the presence of Lewis acids.[2] Over the
past 20 years, there has been a considerable effort to achieve
catalyzed by a chiral rhodium complex, for which 22–
90% ee was observed.[6a,b] This methodology has been limit-
ed to specific substrate classes, and the olefin isomerization
in the substrate would be problematic in the presence of
metal complexes.[6d] Thus, efficient catalytic systems for
asymmetric intramolecular hydroarylation are highly desira-
ble.
Complementing organometallic catalysis, enantioselective
organocatalysis has recently emerged as the preeminent
strategy for asymmetric synthesis.[7] While organocatalyzed
enantioselective intermolecular hydroarylations of electron-
rich arenes have been extensively investigated,[8] it is surpris-
ing that no example is available for the intramolecular ver-
sion of this reaction type that employs readily available phe-
nols and anilines as starting materials. Herein, we demon-
strate that organocatalysis has been exploited to achieve the
first asymmetric intramolecular arylation of w-aryloxy- and
arylamino-tethered a, b-unsaturated aldehydes by using a
chiral secondary amine catalyst. Notably, this new transfor-
mation allows the production of functionalized chromans[9]
and tetrahydroquinolines[10] in high enantiopurity [Eq. (1)].
Starting from phenols or anilines, the substrates 1 for this
study were successfully synthesized by using cross metathe-
sis reactions of the corresponding phenyl homoallyl ethers
or amines with crotonaldehyde as the key step in the pres-
ence of Hoveyda–Grubbsꢀ second-generation catalyst 5.[5f]
The seminal work of MacMillan and co-workers[11] has es-
tablished the concept of iminium catalysis that enables the
LUMO-lowering activation of a, b-unsaturated aldehydes.
With this activation model in mind, we hypothesized that an
iminium catalysis protocol might be susceptible to the asym-
metric intramolecular hydroarylation. Mechanistically, unsa-
turated aldehyde 1 should be activated by chiral secondary
amine 4 via the reversible formation of iminium ion 6,[12] in
which the Si face is shielded by the bulky group of the cata-
lyst. As a result, we expected that the electron-rich benzene
framework would attack from the Re face of the activated
alkene, thereby generating the bicyclic system 7. Subsequent
hydrolysis of the enamine moiety would afford the requisite
À
direct C H functionalization of these electron-rich arenes
À
by C H activation mediated by transition-metal com-
plexes.[3] Among them, direct intramolecular hydroarylation
represents one of the most powerful transformations for the
rapid construction of fused aromatic heterocycles,
a
common synthon found in natural products and medicinal
agents.[4] Despite advances, increasing the diversity of possi-
ble substrates and the stereoselectivity of the reaction
remain challenges. While a variety of protocols have been
described for the intramolecular hydroarylation of the more
electron-rich indoles and pyrroles,[5] to our knowledge, only
a handful of examples are known for the analogous phenol-
and aniline-derived reactants.[6] In particular, there are only
a couple of examples known to date on the enantioselective
intramolecular hydroarylation of benzene derivatives with
reasonable enantioselectivity.[6a,b] For instance, Bergman,
Ellman, and co-workers developed an intramolecular ortho-
alkylation of meta-isobutenyl-substituted aromatic imines
[a] H.-H. Lu, Dr. H. Liu, W. Wu, X.-F. Wang, L.-Q. Lu,
Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education
College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax : (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802722.
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Chem. Eur. J. 2009, 15, 2742 – 2746

COMMUNICATION
11, Table 1). An enantioselec-
tivity/temperature profile dis-
closes that the enantioselectivi-
ty of the reaction can be further
improved to 96% ee by lower-
ing the temperature to À258C
(entry 8, Table 1). To determine
the absolute configuration of
the product, the bicyclic prod-
uct 2a with excellent enantio-
meric excess was then convert-
benzene-fused heterocycle 2 and regenerate the amine cata-
lyst 4 (Scheme 1).
Table 1. Organocatalytic intramolecular hydroarylation of w-aryloxyl
a,b-unsaturated aldehydes 1a–d in the presence of catalyst 3 or 4.[a]
Entry
Substrate (R)
Catalyst
t [h]
24
Yield [%][b]
ee [%][c]
90
1
2
1a
1b
NMe2
3
3
77
59
16
88
3
4
1c
1d
3
3
12
24
69
60
87
90
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
4
4
4
4
4
4
4
0.5
2.5
6
60
80
60
80
83
68
82
79
76
78
78
88
91[d]
92[d,e]
96[d,f]
96[d,f,g]
96[d,f,g,h]
96[d,f,g,i]
10
11
[a] Unless noted, reactions were carried out with 1 (0.25 mmol), amine (3
or 4, 0.05 mmol), and DNBA (0.05 mmol) in Et2O (2.5 mL, 0.1m of 1) at
room temperature. [b] Yield of isolated product. [c] Determined by chiral
HPLC after NaBH4/EtOH reduction. [d] 20 mol% of p-TsOH·H2O was
used instead of DNBA. [e] Conducted at 08C. [f] Conducted at À258C.
[g] 10 mol% of 4 and p-TsOH·H2O were employed. [h] Et2O (1.25 mL,
0.2m of 1) was used. [i] MTBE (1.25 mL, 0.2m of 1). DNBA=3, 5-dinitro-
benzoic acid. p-TsOH·H2O=toluenesulfonic acid monohydrate. MTBE=
methyl tert-butyl ether.
Scheme 1. Organocatalytic enantioselective intramolecular hydroaryla-
tion.
To our delight, exposure of (E)-5-[3-(dimethylamino)phe-
noxy]pent-2-enal (1a) to 20 mol% of imidazolidinone cata-
lyst 3 in the presence of 20 mol% of 3,5-dinitrobenzoic acid
in diethyl ether at room temperature did indeed provide the
desired chroman derivative 2a with enantioinduction and
good levels of reaction efficiency (Table 1, entry 1, 77%
yield, 90% ee). As revealed in Table 1, the reaction appears
quite general with respect to the nature of the nitrogen sub-
stituents (R=NMe2, pyrrolidino, piperidino, morpholino,
entries 1–4) in the benzene ring without substantial loss in
yield or enantiocontrol (59–77% yield, 87–90% ee). The
catalyst screening indicated that a higher yield (83%) and
comparable enantiomeric excess (88% ee) could be ob-
tained in a shorter reaction time when chiral secondary
amine 4 was employed as the reaction catalyst (entry 1
versus entry 5, Table 1).[12,13] Further optimization revealed
that the combination of amine 4 and p-TsOH·H2O exhibited
optimal conversion and enantiocontrol in solvents such as
diethyl ether or methyl tert-butyl ether (MTBE) (entries 6–
ed into its (1S)-(+)-10-camphorsulfonate derivative 8 in two
steps (Scheme 2). The absolute configuration was unambigu-
ously determined to be R by X-ray crystallographic analysis
(Figure 1).[14] This result supports our proposed stereochemi-
Scheme 2. Conversion of 2a to (1S)-(+)-10-camphorsulfonate derivative
8. Reagents and conditions: a) NaBH4, MeOH, RT; b) (1S)-(+)-10-cam-
phorsulfonyl chloride, Et3N,·THF, 08C to RT (37% yield, 2 steps).
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W.-J. Xiao et al.
Table 2, significant structural
variation in the benzene archi-
tecture can be realized. Intro-
duction of a methyl substituent
at the ortho- or para-position to
the oxygen atom is well tolerat-
ed, and excellent enantioselec-
tivities can be achieved in both
cases (entries 2 and 3, Table 2,
96 and 89% ee, respectively).
The N,N-dimethyl group can be
easily removed by direct deami-
nation[8e] or readily converted
to other functional groups by
Figure 1. X-ray crystal structure of (1S)-(+)-10-camphorsulfonate derivative 8.
Ni-catalyzed Suzuki cross-cou-
plings,[15] and in doing so di-
cal outcome, and the stereochemistry of other products
could be tentatively assigned by assuming an analogous
enantioinduction (Scheme 1).
Having established the optimal conditions for the intra-
molecular hydroarylation, we next examined the scope of
substrates in this organocatalytic reaction with the use of
catalyst 4/p-TsOH·H2O in diethyl ether. As highlighted in
verse and structurally complex chromans can be generated.
Moreover, the aryl framework can be successfully extended
to aniline systems (entries 4–12, Table 2). Variation in the
N-protecting group (X=NBoc, NCbz, NTs, NMe, NBn, en-
tries 4–9, Table 2) is possible with N-electron-withdrawing
groups having better enantiocontrol. Incorporation of a pi-
peridino group instead of the N,N-dimethyl group at the
Table 2. Organocatalyzed intramolecular hydroarylation of phenol- and aniline-derived enals.[a]
Entry Substrate
Product
Yield [%][b] ee [%][c] Entry Substrate
Product
Yield [%][b] ee [%][c]
1
78
72
50
70
68
96
96
89
87
87
8
61
70[d]
76[d]
74[d]
2
3
4
5
9
65
10
11
80
98 (71: 29)
92ACHTUNGTRENNUNG
(2n)[e]
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Intramolecular Hydroarylations of Aldehydes
Table 2. (Continued)
COMMUNICATION
Entry Substrate
Product
Yield [%][b] ee [%][c] Entry Substrate
Product
Yield [%][b] ee [%][c]
6
64
65
90
90
12
13
14
99
80
71
86[e]
7
79
71
[a] Reactions were carried out with 1 (0.25 mmol), amine catalyst (10–20 mol%), and pTsOH·H2O (10–20 mol%) in Et2O (0.2–0.25m of 1) at À25-08C
for 18–144 h. [b] Yield of isolated product. [c] Determined by chiral HPLC after NaBH4/EtOH reduction. [d] CH3CN as solvent, and hydrochloride as
the additive (4.0m HCl in dioxane). [e] CH2Cl2 as solvent, and hydrochloride as the additive (4.0m HCl in dioxane).
C(3) position of the substrate gave almost identical results
(entry 6 versus 7, Table 2), which implies that the modifica-
tion of the N-substituents in the benzene ring can be accom-
plished. Other alkyl, dialkyl, and alkyloxyl groups can also
be successfully introduced to the aryl framework (en-
tries 10–12, Table 2); however, the reaction affords two re-
gioisomers (2n/2n’=71:29) in 98% total yield and 92% ee
(major isomer 2n) in the case of 3,4-dimethyl phenylamino-
tethered enal 1n (entry 11, Table 2). Perhaps more impor-
tantly, benzylamino-tethered enals proved to be viable reac-
tion substrates. Thus, N-protected 4-[3-(dimethylamino)ben-
zylamino]but-2-enals 1p and 1q were employed in the reac-
tion and efficiently provided the corresponding tetrahydroi-
soquinolines[16] 2p and 2q in good yields and enantioselec-
tivities (entries 13 and 14, Table 2), respectively.
cohol for the determination of enantiomeric excess. Chiralpak AS
column, hexane/2-propanol=90:10, 1 mLminÀ1, 254 nm, tmajor =11.37 min,
tminor =15.05 min).
Acknowledgements
We are grateful to the National Science Foundation of China (20672040
and 20872043), the Program for Academic Leaders in Wuhan Municipali-
ty (200851430486), and the Program for New Century Excellent Talents
in University (NCET-05-0672) for support of this research. We thank Ma-
teria, Inc., Pasadena, CA for the generous gift of ruthenium catalysts.
Keywords: asymmetric catalysis · chroman · intramolecular
hydroarylation · organocatalysis · tetrahydroquinolines
In summary, we have developed the first enantioselective
organocatalytic intramolecular hydroarylations of phenol-
and aniline-derived enals. This methodology provides an
atom economic and straightforward approach to optically
active chromans and tetrahydroquinolines in good yields
and high enantioselectivities (up to 96% ee). Application of
this reaction to other substrates and to the preparation of
biologically relevant compounds is currently underway.
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Typical procedure: A reaction vial equipped with a magnetic stirring bar
was sequentially charged with catalyst
4 (15.0 mg, 10 mol%), Et2O
(1.25 mL), and p-TsOH·H2O (4.8 mg, 10 mol%). The mixture was stirred
at room temperature for 15 min and then cooled to À258C. Enal 1a
(54.8 mg, 0.25 mmol, recrystallized from Et2O at À408C prior to use) was
then added. After 60 h, the crude reaction mixture was directly loaded
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Received: December 24, 2008
Published online: February 9, 2009
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