Tetrahydroisoquinoline-based N-oxides as chiral organocatalysts for the asymmetric allylation of aldehydes

Article abstract of DOI:10.1002/ejoc.201100923

The short synthesis of a series of novel chiral N-oxideorganocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane is reported. These readily modifiable organocatalysts are

Full text of DOI:10.1002/ejoc.201100923

FULL PAPER
DOI: 10.1002/ejoc.201100923
Tetrahydroisoquinoline-Based N-Oxides as Chiral Organocatalysts for the
Asymmetric Allylation of Aldehydes
Tricia Naicker,[a] Per I. Arvidsson,[a,b,c] Hendrik G. Kruger,[d] Glenn E. M. Maguire,[d] and
Thavendran Govender*[a]
Keywords: Organocatalysis / Allylation / Heterocycles / Aldehydes / Lewis bases / Tetrahydroisoquinoline
The short synthesis of a series of novel chiral N-oxide
organocatalysts and their evaluation in the asymmetric al-
lylation reaction of aromatic and α-β-unsaturated aldehydes
with allyltrichlorosilane is reported. These readily modifiable
organocatalysts are the first of their kind based on the tetra-
hydroisoquinoline framework. The chiral homoallyl products
were obtained with good chemical efficiency (up to 93%
yield) and high enantioselectivity (up to 91%ee) under mild
reaction conditions (23 °C).
jima and co-workers reported the first chiral heterocyclic
N-oxide-type organocatalysts capable of acting as Lewis
bases for enantioselective allylation reactions through the
activation of allyltrichlorosilane and its derivatives.[8] This
was based on the inherent nucleophilicity of N-oxides
towards organosilicon reagents or substrates. The principle
behind this mode of activation was based on the coordina-
tion of the N-oxide catalyst (which acts as a Lewis base) to
a tetracoordinated silicon atom. This increases the Lewis
acidity of the now hypervalent silicon center, which be-
comes a highly reactive carbon nucleophile. Since Nakaji-
ma’s report, various N-oxide-based organocatalysts have
been developed.[9] These can be largely classified into three
types (Figure 1): the first being N,N-dioxides with two pyr-
idine moieties bearing a stereogenic axis (I),[8] the second
having N-oxides incorporated into a pyridine ring within a
chiral framework (II),[10] and the third type in which the N-
oxide is part of a pyrrolidine (III)[11] or piperidine ring.[12]
Introduction
Organocatalysis has rapidly expanded in the last decade
to encompass a wide variety of small organic molecules that
are capable of either activating substrates or transforming
them into more reactive forms.[1] Various fundamental
asymmetric reactions that once required metal–ligand cata-
lysts can now be conducted with comparable efficiencies by
using organocatalysts that are more stable, cheaper, and less
toxic than their metal complex counterparts.[2] A classic ex-
ample is the promotion of the enantioselective allylation of
aldehydes that was previously catalyzed by Lewis acids
(metal complexes) to give chiral homoallylic alcohols. This
can now be carried out in the presence of a range of organic
Lewis bases in the form of chiral phosphoramides, for-
mamides, imines, phosphane oxides, sulfoxides, or N-ox-
ides.[2b,2c,3] Homoallylic alcohol products are important
building blocks for more complex molecules. One example
in which a homoallylic alcohol (i.e., cinnamaldehyde as the
substrate) is an important precursor, is in the synthesis of
the natural product goniothalamin, which exhibits anti-fun-
gal,[4] immunosuppressive, and anti-inflammatory activity[5]
as well as cytotoxic[6] and anti-tumor properties.[7] Naka-
[a] School of Pharmacy and Pharmacology,
University of KwaZulu-Natal,
Durban Private Bag 4000, South Africa
Fax: +27-72603091
E-mail: govenderthav@ukzn.ac.za
[b] Organic Pharmaceutical Chemistry,
Department of Medicinal Chemistry,
Uppsala Biomedical Centre,
Figure 1. Examples of N-oxide-based organocatalysts.
Uppsala University, Box 574, 751 23 Uppsala, Sweden
[c] Innovative Medicines, CNSP iMed,
AstraZeneca R&D Sodertalje,
Amongst these, the catalysts possess either monodentate
or bidentate N-oxide moieties. There are only a few exam-
ples of the third type of N-oxide catalysts, and derivative
III is currently the only example of a monodentate N-oxide
bonded to an sp3 nitrogen atom. With this in mind, we
wanted to investigate catalysts 1–8 (Figure 2) derived from
151 85 Sodertalje, Sweden
[d] School of Chemistry, University of KwaZulu-Natal,
Westville, Durban, South Africa
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100923.
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T. Govender et al.
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Figure 2. Catalysts evaluated for the allylation reaction.
the tetrahydroisoquinoline (TIQ) backbone. This would
constitute the second example of an organocatalyst with a
monodentate N-oxide bonded to an sp3 nitrogen atom.
In addition to the allylation of aldehydes, N-oxide
organocatalysts have been shown to promote several other
important asymmetric transformations.[9a] However, prepa-
ration of these catalysts follows multistep synthetic pro-
cedures and requires extensive optimization, such as low
temperatures to ensure a high level of chiral induction. In
this study, we have introduced a new class of easily access-
ible (four steps or less) TIQ-based N-oxide organocatalysts
that function under mild reaction conditions (23 °C). The
TIQ molecule and its derivatives have been widely investi-
gated due to their biological and pharmaceutical proper-
ties.[13] We have recently had much success with TIQ-based
ligands for catalytic asymmetric reactions, including trans-
fer hydrogenation of prochiral ketones,[14] the Henry reac-
tion,[15] the hydrogenation of olefins,[16] and we also ex-
panded the potential of these TIQ derivatives as organocat-
alysts in the Diels–Alder cycloaddition between α,β-unsatu-
rated aldehydes and cyclopentadiene.[17] Herein we report a
logical approach to the synthesis of novel Lewis base N-
oxide organocatalysts 1–8 possessing TIQ as a readily tun-
able backbone for the asymmetric reaction of allyltri-
chlorosilane with aryl and α,β-unsaturated aldehydes.
Scheme 1. Synthetic route to catalysts 1, 2, and 4–6. Reagents and
conditions: (i) HBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrameth-
yluronium hexafluorophosphate], DMF, respective amine, 4 h at
r.t.; (ii) m-CPBA, K2CO3, DCM, –78 °C, 3 h.
1
by H NMR spectroscopy after both the coupling of the
amide and the oxidation steps.
A similar procedure to that used for the synthesis of cata-
lysts 1–6 was followed for catalyst 3 (Scheme 2) except com-
mercially available N-methyl tetrahydroisoquinoline amino
acid 11 was used instead of 9.
Scheme 2. Synthetic route to catalyst 3. Reagents and conditions:
(i) HBTU, DMF, benzylamine, 4 h at r.t.; (ii) m-CPBA, K2CO3,
DCM, –78 °C, 3 h.
Results and Discussion
Catalyst Synthesis
Catalysts 1, 2, and 4–6 (Scheme 1) were synthesized from
We have previously reported the synthesis of compound
commercially available N-benzyl tetrahydroisoquinoline 13,[14] which upon protection of the secondary amine with
amino acid 9. Amide bond formation of 9 with the respec- bromocyclohexane afforded derivative 14. This underwent
tive amines yielded 10a–e. Thereafter, oxidation of the terti- oxidation with m-CPBA to produce catalyst 7. Analysis by
ary amines with m-CPBA afforded the novel catalysts.
Once the N-oxide is formed, the nitrogen atom becomes stereomer for compounds 14 and 7 (Scheme 3).
chiral and can form both diastereomers. It has been shown Catalyst 8 was derived from commercially available
1H NMR spectroscopy revealed the presence of a single dia-
in the literature with other pipecolic[18] and proline[19] deriv- amine 15. Reductive amination of 15 with benzaldehyde fol-
atives that the N-oxide orientates syn (on the same side) to lowed by cyclization of the imine yielded 16. Diastereomers
the hydrogen-bond donor substituent and is stabilized by were obtained in a 90:10 ratio of the cis/trans isomers of 16,
an intramolecular hydrogen bond. Our catalysts displayed which were easily separated by using silica gel chromatog-
the same orientation, as exemplified by the X-ray crystal raphy. Thereafter, the secondary amine underwent benz-
structures of 4 and 5. For catalysts 5 and 6 that contain an ylation, which was followed by microwave-assisted acid hy-
additional chiral center, a single diastereomer was observed drolysis of the ester. The acid was treated with diphenyl-
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Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes
Table 1. Allylation of benzaldehyde (19) and allyltrichlorosilane
(20) facilitated by catalysts 1–8 at room temperature in DCM.
Entry
Catalyst[a]
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
81
85
80
85
90
91
83
86
Ͻ10
Ͻ10
Ͻ10
15 (R)
12 (R)
20 (R)
Ͻ10
Scheme 3. Synthetic route to catalyst 7. Reagents and conditions:
(i) bromocyclohexane, K2CO3, DMSO, 70 °C, 48 h; (ii) m-CPBA,
K2CO3, DCM, –78 °C, 3 h.
44 (R)
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst; all reactions were performed in duplicate. [b] Isolated yield
after column chromatography. [c] Determined by chiral HPLC; the
values are an average of two measurements. [d] The configuration
of the chiral product was established by comparison of the HPLC
retention times with those reported in the literature.
methanamine to furnish amide 18 (only the cis isomer was
observed by H NMR spectroscopy), which was oxidized
1
with m-CPBA to produce catalyst 8 (Scheme 4).
Notably, compounds 15–18 and 8 have a second chiral
center and could not be synthesized from phenylalanine, as
it was essential to employ activated aromatic group 15 to
facilitate the cyclization.
The X-ray crystal structures of catalyst 4 and 5[20a] re-
vealed further information on how the catalysts could be
modified to enhance the enantiomeric excess values (Fig-
ures 3 and 4).
Catalyst Evaluation
The benchmark reaction for the evaluation of N-oxide-
type organocatalysts has been the asymmetric reaction be-
tween benzaldehyde (19) and allyltrichlorosilane (20).
Our study was initiated by examining the modification
of the C- and N-termini of the catalysts starting from sim-
ple TIQ derivatives 1–3 (Table 1, Entries 1–3). Although
low selectivities were observed, there was substantial con-
version to allylation product 21. Encouraged by these re-
sults we set out to introduce a more bulky group at the C-
terminus in the hope of increasing the enantiomeric excess
with catalyst 4 (Table 1, Entry 4). This moderately increased
the ee, and we anticipated that another chiral center at the
amide position could enhance the selectivity (Table 1, En-
tries 5 and 6). However, the 20%ee remained the highest
enantioselectivity obtained. Because the use of a chiral
amide resulted in a slightly higher ee, it was then decided
to synthesize proline-derived catalyst III, that is, a catalyst
with a cyclohexyl group on the nitrogen atom in hope that
this may affect the selectivity. Catalyst 7 displayed only a
Figure 3. OLEX2[20b] generated drawing of the X-ray structure of
catalyst 4.
It is evident from the crystal structures that the N-con-
marginal difference in the enantioselectivity of the reaction taining six-membered ring assumes a half-chair conforma-
product. tion with the N-oxide protruding up in order to hydrogen
Scheme 4. Synthetic route to catalyst 3. Reagents and conditions: (i) PhCHO, DCM/MeOH, molecular sieves, 1.5 h, TFA, reflux, 3 h;
(ii) BnBr, K2CO3, overnight at r.t.; (iii) microwave-assisted acid hydrolysis, HBTU, DMF, diphenylmethanamine, 4 h at r.t.; (iv) m-CPBA,
K2CO3, DCM, –78 °C, 3 h.
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Having optimized the conditions for the system, the use
of TIQ-based organocatalyst 8 was extended by applying it
to various aromatic aldehydes and allyltrichlorosilane
(Table 3, Entries 1–7) at room temperature (23 °C) in THF.
Table 3. Allylation of aldehydes and allyltrichlorosilane (20) cata-
lyzed by derivative 8 in THF (24 h) at room temperature.
Entry
R
Yield [%][a,b]
ee [%][c,d]
1
2
3
4
5
6
7
8
Ph
80
87
90
89
93
87
50
85
65 (R)
60 (R)
52 (R)
55 (R)
65 (R)
51 (S)
62 (S)
91 (S)
4-MeOC6H5
4-NO2C6H5
4-ClC6H5
4-FC6H5
Figure 4. OLEX2[20b] generated drawing of the X-ray structure of
catalyst 5.
2-naphthyl
3,5-(OMe)2C6H3
PhCH=CH
bond with the amide hydrogen. This observation explains
why the ee value was not influenced by changing groups
on the secondary amine. Catalysts 5 and 6 differ by their
configurations at the chiral center in the coupled amine and
produced 12 and 20%ee, respectively. Their crystal struc-
tures also explain why the best asymmetric induction was
obtained when a bulky diphenyl moiety is present at C11
(Figure 3), thereby creating a chiral pocket around the N-
oxide functionality. Based on these findings we postulated
that a diphenyl group on the amide and more steric bulk
closer to the oxide moiety was required. It was synthetically
possible to introduce a phenyl ring at C1 in either the cis
or trans position. The cis position seemed more viable for
chiral induction, as it was closer to the oxide atom. Catalyst
8 was thus synthesized and it significantly increased the se-
lectively to 44%ee (Table 1, Entry 8).
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst; all reactions were performed in duplicate. [b] Isolated yield
after column chromatography. [c] Determined by chiral HPLC; the
values are an average of two measurements. [d] The configuration
of the chiral products was established by the comparison of the
HPLC retention times with those reported in the literature.
All of the reactions proceeded with high conversions and
reasonable selectivities. From Table 3 it may be concluded
that the catalyst is highly sensitive to steric bulk, whereas
electronic changes seems to have less influence on the chiral
induction (cf. Table 3, Entries 1–5 vs. 6 and 7). The configu-
ration of the products changed from R to S upon increased
steric bulk (Table 3, Entries 6 and 7), suggesting such alde-
hydes orient themselves differently in the catalyst pocket be-
fore attack of the silyl substituent.
It has been shown that the appropriate choice of solvent
is crucial for asymmetric induction, rate, and yield of the
allylation reaction.[21] Therefore, catalyst 8 was tested in the
most common solvents used for this type of asymmetric
reaction (Table 2). The change in solvent had a noteworthy
effect on the enantiomeric excess of the reaction product
(Table 2, Entry 4).
In order to evaluate if catalyst 8 was not limited to aro-
matic aldehydes, it was tested with an α,β-unsaturated alde-
hyde (i.e., cinnamaldehyde). The product from this reaction
emerged with a high enantioselectivity of 91%ee (Table 3,
Entry 8), again with opposite absolute configuration than
the product originating from simple benzaldehyde sub-
strates (i.e., Table 3, Entries 1–5). This prompted us to re-
examine the solvent choice for this substrate (Table 4).
Table 2. Allylation of benzaldehyde (19) and allyltrichlorosilane
(20) catalyzed by derivative 8 in different solvents (24 h) at room
temperature.
Table 4. Allylation of cinnamaldehyde and allyltrichlorosilane (20)
catalyzed by derivative 8 in different solvents (24 h) at room tem-
perature.
Entry
Solvent[a]
Yield [%][b]
ee [%][c,d]
1
2
3
4
DCM[e]
85
80
65
85
44
53
Ͻ10
65
Entry
Solvent[a]
Yield [%][b]
ee[%][c,d]
DCE[f]
CH3CN[g]
THF[h]
1
2
3
4
DCM
DCE
CH3CN
THF
80
75
72
85
75
87
79
91
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst; all reactions were performed in duplicate. [b] Isolated yield
after column chromatography. [c] Determined by chiral HPLC; the
values are an average of two measurements. [d] The configuration
of the chiral product was established by the comparison of the
HPLC retention times with those reported in the literature. [e]
Dichloromethane. [f] 1,2-Dichloroethane. [g] Acetonitrile. [h] Tetra-
hydrofuran.
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst; all reactions were performed in duplicate. [b] Isolated yield
after column chromatography. [c] Determined by chiral HPLC; the
values are an average of two measurements. [d] The configuration
of the chiral product was established by comparison of the HPLC
retention times with those reported in the literature.
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Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes
Similar to the result for benzaldehyde, THF appeared to product goniothalamin. To the best of our knowledge, the
be the solvent of choice again, as can be seen from Table 4. highest ee reported to date for cinnamaldehyde is 79% at
Based on this result and the fact that allylations of α,β- room temperature when catalyst III was employed.[11]
unsaturated aldehydes have been rather neglected,[22] it was
decided to further expand the scope of this type of substrate
with catalyst 8 (Table 5).
Conclusions
In summary, we have identified a novel class of N-oxide
TIQ organocatalysts that promotes the enantioselective al-
lylation of both aromatic and α,β-unsaturated aldehydes.
The catalysts are easily prepared from commercially avail-
able substrates, readily modifiable (displayed by the efforts
to optimize the enantioselectivity of the reaction), and the
asymmetric allylation reaction can be done under mild reac-
tion conditions (23 °C). The products were obtained in up
to 91%ee (cinnamaldehyde). Studies into this class of or-
ganocatalysts are ongoing in our laboratory.
Table 5. Allylation of α,β-unsaturated aldehydes and allyltri-
chlorosilane (20) catalyzed by derivative 8 in THF (24 h) at room
temperature..
Entry
R1
R2
R3
Yield
ee [%][c,d]
[%][a,b]
1
2
3
4
5
6
7
8
9
Ph
4-MeOC6H5
2-MeOC6H5
4-NO2C6H5
2-NO2C6H5
4-BrC6H5
2-furyl
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
85
85
86
90
90
82
87
65
0
91 (S)
50 (S)
42 (S)[e]
30 (S)
51 (S)[e]
40 (S)
43 (S)[e]
Ͻ10 (S)
–
Experimental Section
General Methods: Reagents and solvents were purchased from Ald-
rich, Merck, and Fluka. All NMR spectra were recorded with a
Bruker Avance III 400 MHz instrument. Chemical shifts are ex-
pressed in ppm relative to CDCl3. NMR spectra were obtained at
room temperature. Thin-layer chromatography (TLC) was per-
formed by using Merck Kieselgel 60 F254. Crude compounds were
purified by column chromatography by using Silica gel 60 mesh.
All solvents were dried by using standard procedures. IR spectra
were recorded with a Perkin–Elmer spectrum 100 instrument with
a universal ATR attachment. Optical rotations were recorded with
a Perkin–Elmer Polarimeter. Microwave-assisted reactions were
carried out with a CEM Discover SP system. High-resolution mass
spectrometric data were obtained by using a Bruker microTOF-Q
II instrument operating at ambient temperatures by using a sample
concentration of approximately 1.0 ppm. The enantiomeric excess
values of the chiral allylation products were determined by either
gas chromatography by using an Agilent 6820 capillary gas chro-
matograph with a CP-Chirasil-β-Dex column (25 mϫ0.25 mm), ni-
trogen as the carrier gas, and a flame ionization detector or on
an Agilent 1100 HPLC with either a Chiralpak IA, IB, or AS-H
column.
Me
nPr
Me
Ph
10
11
55
75
17 (S)
54 (R)
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst; all reactions were performed in duplicate. [b] Isolated yield
after column chromatography. [c] Determined by chiral HPLC; the
values are an average of two measurements. [d] The configuration
of the chiral products was established by the comparison of the
HPLC or GC retention times with those reported in the literature.
[e] The absolute configuration was arbitrarily assigned based on the
sign of the optical rotation for known 1-phenyl-hexa-1,5-dien-3-ol
(Entry 1).
A range of aromatic α,β-unsaturated aldehydes including
substrates with electron-withdrawing and electron-donating
groups on the cinnamaldehyde aryl ring were employed
with allyltrichlorosilane (Table 5, Entries 1–7). All sub-
strates displayed appreciable conversions, but moderate
enantioselectivities. The large drop in stereoselectivity ob-
served upon modest changes in the substrate structure (cf.
Table 5, Entries 1, 6, 7) is surprising and difficult to ratio-
nalize, but it again advocates that this catalyst system is
highly sensitive to steric variations in the substrate.
In addition, aliphatic α,β-unsaturated aldehydes proved
to have little or no activity (Table 5, Entries 8–10). Lastly a
hydrogen atom in the α position of cinnamaldehyde was
replaced with a methyl group to determine if this increased
bulk would have a considerable effect on the ee of the chiral
product, but a decreased yield and poor selectivity were ob-
served (Table 5, Entry 11). In addition, the configuration of
this product changed, suggesting that the orientation of the
aldehyde with respect to the catalyst also changed. The best
result observed from all of the substrates screened with al-
lyltrichlorosilane remained with cinnamaldehyde (85%
yield, 91%ee) at room temperature. As mentioned earlier,
the chiral homoallylic product derived from cinnamal-
Representative Procedure for the Synthesis of TIQ-Based Amides:
(S)-2-Benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (9)
or (S)-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(11, 4.8 mmol) was dissolved in DMF (15 mL) and THF (5 mL)
followed by addition of HBTU (5.8 mmol), N,N-diisopropylethyl-
amine (DIPEA, 9.6 mmol), and the appropriate amine (5.3 mmol).
The reaction mixture was then stirred at room temperature until
no more starting material could be detected by TLC analysis (ap-
proximately 4 h). The reaction mixture was poured into 30 volumes
of chilled water; the mixture was then extracted thrice with ethyl
acetate (20 mL). The extracts were dried with anhydrous Na2SO4
and then concentrated to dryness to afford the crude product,
which was purified by column chromatography.
(S)-N,2-Dibenzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(10a): The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.50) to afford the product (1.20 g,
92%) as a yellow oil. [α]2D0 = –25.00 (c = 0.16, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 7.40–7.24 (m, 6 H), 7.23–7.11 (m, 3 H),
dehyde is a key precursor in the synthesis of the natural 7.00 (d, J = 7.2 Hz, 1 H), 3.80 (d, J = 15.2 Hz, 1 H), 3.65 (dt, J =
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T. Govender et al.
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13.3, 10.6 Hz, 3 H), 3.52 (t, J = 6.8 Hz, 1 H), 3.21–3.05 (m, 2 H),
chromatography (100% EtOAc, Rf = 0.50) to afford the product
2.78 (d, J = 5.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = (1.00 g, 77%) as a brown solid. M.p. 91–95 °C. [α]2D0 = –7.93 (c =
173.68, 138.21, 134.62, 134.36, 128.86, 128.82, 128.60, 128.56, 0.21, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.14 (m, 7
128.23, 127.50, 127.00, 126.45, 126.27, 62.18, 58.55, 51.12, 28.01,
H), 7.04 (dd, J = 32.3, 6.5 Hz, 3 H), 4.56–4.45 (m, 1 H), 4.30 (dd,
J = 15.0, 5.2 Hz, 1 H), 3.90–3.74 (m, 2 H), 3.64 (d, J = 14.2 Hz, 1
25.94 ppm. IR (neat): ν = 3322, 2937, 1654, 1524, 731, 698 cm–1.
˜
HRMS: calcd. for C18H21N2O [M + H]+ 281.1648; found 281.1664. H), 3.11 (d, J = 6.4 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 173.29, 138.33, 135.35, 133.96, 128.79,
128.57, 128.03, 127.82, 127.48, 127.25, 127.18, 127.05, 126.32,
(S)-N,2-Dibenzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(10b): The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.45) to afford the product (1.50 g,
126.12, 63.87, 55.09, 42.92, 42.89, 42.16, 29.43, 23.50 ppm. IR
(neat): ν = 3302, 2924, 1651, 1651, 1494, 743, 698 cm–1. HRMS:
˜
88%) as a yellow oil. [α]2D0 = 10.00 (c = 0.10, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.45–7.11 (m, 11 H), 7.11–6.90 (m, 3 H),
4.52–4.41 (dd, J = 15.0, 6.4 Hz, 1 H), 4.37 (dd, J = 15.0, 5.5 Hz, 1
H), 3.85–3.55 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
173.11, 138.30, 137.98, 134.99, 134.52, 129.07, 128.95, 128.63,
128.59, 128.39, 128.19, 127.51, 127.35, 127.26, 127.13, 126.48,
calcd. for C18H21N2O [M + H]+ 281.1648; found 281.1668.
(S)-2-Cyclohexyl-N-[(S)-1-phenylethyl]-1,2,3,4-tetrahydroisoquin-
oline-3-carboxamide (14): To a stirred solution of (S)-N-[(S)-1-
phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (13;
1.0 g, 3.6 mmol) in dry DMSO (50 mL) was added potassium hy-
drogencarbonate (1.5 equiv.) followed by bromocyclohexanone
(2.5 equiv.). The reaction mixture was allowed to stir for 48 h at
70 °C. Thereafter, water (50 mL) was added to the reaction. The
aqueous layer was extracted with ethyl acetate (3ϫ20 mL). The
organic extracts were combined and dried with anhydrous Na2SO4,
and the solvent was removed in vacuo to yield the unpurified
amide, which was carried to the oxidation step.
126.40, 62.17, 59.00, 51.42, 43.05, 28.59 ppm. IR (neat): ν = 3301,
˜
2929, 1654, 1264, 731, 696 cm–1. HRMS: calcd. for C24H25N2O [M
+ H]+ 357.1961; found 357.1971.
(S)-N-Benzhydryl-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-
carboxamide (10c): The crude product was purified by column
chromatography (EtOAc/hexane, 50:50; Rf = 0.45) to afford the
product (1.88 g, 91%) as a colorless oil. [α]2D0 = 5.263 (c = 0.19,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.6 Hz, 1
(1S,3S)-Methyl 6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquino-
line-3-carboxylate (16): To a stirred solution of methanol/dichloro-
methane (1:1, 6.0 mL) containing 4 Å molecular sieves was added
(S)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate (15; 1.0 g,
4.2 mmol) and benzaldehyde (1.1 equiv.) under an inert atmo-
sphere. The reaction mixture was allowed to stir for 1.5 h. There-
after, the reaction mixture was filtered, and the solvents were re-
moved in vacuo to yield the intermediate imine, which was left on
a high-vacuum pump to remove any residual water for 2 h. The
residue was then dissolved in trifluoroacetic acid (20 mL) and
heated at reflux for 3 h. The reaction mixture was then neutralized
with a saturated sodium hydrogencarbonate solution and extracted
with ethyl acetate (4ϫ20 mL). The organic extracts were combined
and dried with anhydrous Na2SO4, and the solvent was removed in
vacuo. The crude product (diastereomers) was purified by column
chromatography (EtOAc/hexane, 50:50; Rf = 0.5) to afford the
product (1.20 g, 88%) as a white solid. M.p. 97–99 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.11 (m, 5 H), 6.57 (s, 1 H), 6.10 (s,
1 H), 5.02 (s, 1 H), 3.79 (s, 4 H), 3.70 (s, 3 H), 3.52 (s, 3 H), 3.01
(s, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.96, 147.76,
147.41, 143.87, 130.22, 129.04, 128.59, 127.84, 126.07, 111.31,
110.56, 62.85, 56.54, 55.89, 55.84, 52.18, 32.22 ppm.
H), 7.36–6.68 (m, 20 H), 6.11 (d, J = 8.7 Hz, 1 H), 3.84–3.53 (m,
5 H), 3.21 (dd, J = 15.7, 5.2 Hz, 1 H), 3.11 (dd, J = 15.7, 6.8 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.39, 141.99, 141.35,
137.90, 135.50, 134.80, 129.00, 128.96, 128.74, 128.59, 128.45,
128.20, 128.16, 127.78, 127.52, 127.47, 127.35, 127.01, 126.82,
126.52, 126.44, 126.08, 62.30, 60.41, 59.66, 56.49, 51.65, 29.76,
29.36, 21.05, 14.25 ppm. IR (neat): ν = 3319, 2919, 1663, 1493, 745,
˜
697 cm–1. HRMS: calcd. for C30H29N2O [M + H]+ 433.2274; found
433.2297.
(S)-2-Benzyl-N-[(R)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline-
3-carboxamide (10d): The crude product was purified by column
chromatography (EtOAc/hexane, 30:70; Rf = 0.30) to afford the
product (1.88 g, 91%) as a brown solid. M.p. 96–99 °C. [α]2D0
=
11.36 (c = 0.22, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.61 (d,
J = 8.7 Hz, 1 H), 7.37–7.12 (m, 11 H), 7.05 (d, J = 6.5 Hz, 1 H),
6.88 (dd, J = 6.7, 2.6 Hz, 2 H), 5.08–4.94 (m, 1 H), 3.90–3.54 (m,
5 H), 3.12 (dd, J = 6.3, 2.2 Hz, 2 H), 1.39 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 172.10, 143.16, 138.16, 134.73,
134.49, 128.99, 128.79, 128.72, 128.66, 128.58, 128.38, 128.22,
127.44, 127.32, 127.05, 126.45, 126.34, 126.19, 77.39, 62.15, 58.45,
51.45, 48.36, 28.38, 21.76 ppm. IR (neat): ν = 3302, 2924, 1651,
˜
1651, 1494, 743, 698 cm–1. HRMS: calcd. for C25H27N2O
[M + H]+ 371.2118; found 371.2134.
(1S,3S)-Methyl 2-Benzyl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinoline-3-carboxylate (17): To a stirred solution of 16
(1.5 g, 4.5 mmol) in acetonitrile (30 mL) was added potassium car-
bonate (1.5 equiv.) and benzyl bromide (1.1 equiv.). The reaction
mixture was allowed to stir overnight at room temperature. There-
after, water (30 mL) and ethyl acetate (30 mL) were added to the
reaction. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3ϫ20 mL). The organic extracts
were combined and dried with anhydrous Na2SO4, and the solvent
was removed in vacuo. The crude product was purified by column
chromatography (EtOAc/hexane, 20:80; Rf = 0.50) to afford the
(S)-2-Benzyl-N-[(S)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline-
3-carboxamide (10e): The crude product was purified by column
chromatography (EtOAc/hexane, 30:70; Rf = 0.30) to afford the
product (1.88 g, 91%) as a brown solid. M.p. 96–99 °C. [α]2D0
=
1
–12.20 (c = 0.41, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.58
(d, J = 8.4 Hz, 1 H), 7.42–7.10 (m, 13 H), 7.02 (d, J = 7.2 Hz, 1
H), 5.12–4.90 (m, 1 H), 3.89–3.53 (m, 4 H), 3.53 (t, J = 6.7 Hz, 1
H), 3.14 (d, J = 6.7 Hz, 2 H), 1.54 (d, J = 12.2 Hz, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 172.26, 143.24, 138.08, 135.21,
134.65, 129.14, 128.95, 128.79, 128.64, 128.58, 128.49, 128.37,
128.23, 128.16, 127.54, 127.20, 126.90, 126.40, 125.67, 125.04,
product (1.80 g. 95%) as a white solid. M.p. 146–148 °C. [α]2D0
=
3.030 (c = 0.10, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.35 (d,
J = 7.7 Hz, 4 H), 7.22 (ddt, J = 14.3, 12.9, 7.1 Hz, 6 H), 6.65 (s, 1
H), 6.30 (s, 1 H), 4.75 (s, 1 H), 3.92 (d, J = 14.2 Hz, 1 H), 3.86–
3.78 (m, 4 H), 3.68–3.55 (m, 4 H), 3.37 (s, 3 H), 3.08 (dd, J = 15.3,
7.4 Hz, 1 H), 2.88 (dd, J = 15.3, 5.0 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 174.02, 147.81, 147.39, 143.22, 138.71,
62.25, 59.13, 51.86, 47.93, 29.72, 28.95, 22.07 ppm. IR (neat): ν =
˜
3302, 2924, 1651, 1651, 1494, 743, 698 cm–1. HRMS: calcd. for
C25H27N2O [M + H]+ 371.2118; found 371.2134.
(S)-N-Benzyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-
carboxamide (12): The crude product was purified by column
6928
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6923–6932

Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes
129.63, 129.14, 129.12, 128.14, 127.98, 127.09, 126.98, 125.94, H), 4.68 (d, J = 12.9 Hz, 1 H), 4.61–4.38 (m, 4 H), 4.21 (d, J =
111.44, 110.71, 64.79, 60.69, 59.07, 55.93, 55.90, 51.53, 30.55 ppm.
15.0 Hz, 1 H), 4.01 (dd, J = 9.9, 4.9 Hz, 1 H), 3.92–3.76 (m, 1 H),
3.24 (dd, J = 17.0, 4.9 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.28, 132.58, 130.19, 129.99, 129.42, 128.95, 128.71,
128.10, 127.80, 127.36, 126.91, 126.74, 73.64, 69.96, 65.28, 43.10,
IR (neat): ν = 2944, 1729, 1511, 1152, 753, 699 cm–1. HRMS: calcd.
˜
for C26H28NO4 [M + H]+ 418.2018; found 418.2012.
(1S,3S)-N-Benzhydryl-2-benzyl-6,7-dimethoxy-1-phenyl-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (18): Derivative 17 (0.30 g)
was dissolved in 10% aqueous HCl (5 mL) and irradiated in the
microwave for 2 h at 120 °C. The reaction mixture was then concen-
trated in vacuo, coevaporated with toluene to ensure all water had
been removed, and used for the next coupling reaction. The acid
(1.9 g, 4.7 mmol) was dissolved in DMF (15 mL) and THF (5 mL)
followed by the addition of HBTU (5.2 mmol), DIPEA (9.6 mmol),
and diphenylmethanamine (5.2 mmol). The reaction mixture was
then stirred at room temperature until no more starting material
could be detected by TLC analysis (approximately 4 h). The reac-
tion mixture was poured into 30 volumes of chilled water; the mix-
ture was then extracted thrice with ethyl acetate (20 mL). The ex-
tracts were dried with anhydrous Na2SO4 and then concentrated to
dryness to afford the crude product. This crude product was puri-
fied by column chromatography (EtOAc/hexane, 50:50; Rf = 0.6)
to afford the product (2.50 g, 92%) as a brown oil. [α]2D0 = –1.389
(c = 0.24, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.62 (d, 1 H),
7.37–7.13 (m, 15 H), 6.99–7.12 (m, 6 H), 6.78 (s, 1 H), 6.41 (s, 1
H), 6.23 (s, 1 H), 4.84 (s, 1 H), 3.92 (s, 3 H), 3.80 (m, 1 H), 3.72
(m, 4 H), 3.50 (d, J = 13.4 Hz, 1 H), 3.12 (dd, J = 17.3, 11.8 Hz,
1 H), 3.02 (dd, J = 17.4, 5.5 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 175.59, 148.23, 147.75, 143.54, 138.48, 129.05, 128.93,
128.68, 128.14, 127.56, 127.39, 127.26, 126.58, 126.32, 124.74,
116.87, 112.00, 111.80, 62.73, 55.91, 55.90, 55.37, 52.20, 23.43 ppm.
30.18 ppm. IR (neat): ν = 3031, 1671, 1542, 734, 700 cm–1. HRMS:
˜
calcd. for C24H25N2O2 [M + H]+ 373.1911; found 373.1919.
(3S)-3-(Benzylcarbamoyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline 2-
Oxide (3): The crude product was purified by column chromatog-
raphy (MeOH/DCM, 5:95; Rf = 0.25) to afford the product (0.45 g,
86%) as a white solid. M.p. 108–110 °C. [α]2D0 = –5.556 (c = 0.18,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 10.59 (s, 1 H), 7.43–
7.13 (m, 9 H), 7.02 (d, J = 7.1 Hz, 1 H), 4.70–4.36 (m, 4 H), 4.02
(dd, J = 10.1, 4.4 Hz, 1 H), 3.78 (dd, J = 17.0, 10.3 Hz, 1 H), 3.39
(s, 3 H), 3.26–3.11 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 167.61, 137.99, 130.15, 128.82, 128.76, 128.70, 128.61, 128.30,
128.02, 127.87, 127.70, 127.66, 127.38, 127.09, 126.53, 126.23,
72.91, 69.92, 58.18, 43.60, 43.03, 30.14 ppm. IR (neat): ν = 3029,
˜
1670, 1544, 736, 699 cm–1. HRMS: calcd. for C18H21N2O2 [M +
H]+ 297.1634; found 297.1598.
(3S)-3-(Benzhydrylcarbamoyl)-2-benzyl-1,2,3,4-tetrahydroiso-
quinoline 2-Oxide(4): The crude product was purified by column
chromatography (MeOH/DCM, 2:98; Rf = 0.25) to afford the prod-
uct (0.48 g, 94%) as a white solid. M.p. 157–158 °C. [α]2D0 = –5.263
(c = 0.19, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 11.74 (s, 1
H), 7.05–7.40 (m, 18 H) 6.86 (d, J = 7.4 Hz, 1 H), 6.30 (d, J =
8.8 Hz, 1 H), 4.59–4.31 (m, 3 H), 4.15 (d, J = 14.7 Hz, 1 H), 3.77
(dd, J = 16.9, 10.0 Hz, 1 H), 3.19 (dd, J = 17.1, 4.8 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 167.35, 141.75, 141.50, 132.64,
130.05, 129.98, 128.91, 128.85, 128.67, 128.12, 127.90, 127.56,
127.50, 127.26, 127.07, 126.99, 126.74, 73.43, 65.39, 69.81, 56.83,
IR (neat): ν = 3026, 1681, 1493, 1241, 751, 698 cm–1. HRMS: calcd.
˜
for C38H37N2O3 [M + H]+ 569.2820; found 569.2799.
Representative Procedure for the Synthesis of TIQ-Based N-Oxides:
The TIQ amide (0.50 g) was dissolved in dry dichloromethane
(20 mL). Potassium carbonate (2.0 equiv.) was added, and the reac-
tion mixture was cooled to –78 °C. m-CPBA (1.2 equiv.) was then
added, and the reaction was allowed to stir at –78 °C for 3 h. At
this time, the reaction was warmed to room temperature. After stir-
ring for 2 h at room temperature, dichloromethane (20 mL) was
added to dilute the reaction and Celite (200 mg) was added to aid
filtration. The reaction was filtered and concentrated to dryness to
afford the crude product, which was purified by column
chromatography.
30.17 ppm. IR (neat): ν = 2918, 1677, 1545, 749, 699 cm–1. HRMS:
˜
calcd. for C30H29N2O2 [M + H]+ 449.2224; found 449.2250.
(3S)-2-Benzyl-3-[(R)-1-phenylethylcarbamoyl]-1,2,3,4-tetrahydro-
isoquinoline 2-Oxide (5): The crude product was purified by column
chromatography (MeOH/DCM, 2:98; Rf = 0.25) to afford the prod-
uct (0.49 g, 94%) as a white solid. M.p. 163–165 °C. [α]2D0 = 66.67
(c = 0.12, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 11.29 (d, J =
8.0 Hz, 1 H), 7.61 (dd, J = 6.5, 3.0 Hz, 2 H), 7.52–7.29 (m, 7 H),
7.29–7.03 (m, 4 H), 6.94 (d, J = 7.2 Hz, 1 H), 5.29–5.14 (m, 1 H),
4.80 (d, J = 13.0 Hz, 1 H), 4.64 (d, J = 13.0 Hz, 1 H), 4.46 (d, J =
14.9 Hz, 1 H), 4.18 (d, J = 15.0 Hz, 1 H), 4.02–3.92 (m, 1 H), 3.86–
3.68 (m, 1 H), 3.17 (dd, J = 17.0, 4.8 Hz, 1 H), 1.58 (dd, J =
18.6, 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.37,
143.31, 132.62, 130.22, 130.03, 129.52, 129.03, 128.70, 128.10,
127.72, 127.18, 126.87, 126.72, 126.05, 73.78, 69.76, 65.35, 48.83,
(3S)-2-Benzyl-3-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-
Oxide (1): The crude product was purified by column chromatog-
raphy (MeOH/DCM, 10:90; Rf = 0.25) to afford the product
(0.44 g, 85%) as a white solid. M.p. 146–148 °C. [α]2D0 = 8.642 (c =
0.27, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 10.42 (s, 1 H),
7.49–7.10 (m, 8 H), 6.96 (d, J = 7.4 Hz, 1 H), 4.71 (d, J = 12.9 Hz,
1 H), 4.59 (d, J = 12.9 Hz, 1 H), 4.43 (d, J = 15.1 Hz, 1 H), 4.34–
4.20 (m, 2 H), 4.03 (dd, J = 9.5, 5.1 Hz, 1 H), 3.83 (dd, J = 17.1,
9.6 Hz, 1 H), 3.23 (dd, J = 17.1, 5.0 Hz, 1 H), 2.94 (d, J = 4.8 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.79, 132.59, 130.91,
130.19, 130.05, 129.35, 128.97, 128.83, 128.11, 127.83, 126.92,
30.12, 22.92 ppm. IR (neat): ν = 2924, 1671, 1540, 736, 699 cm–1.
˜
HRMS: calcd. for C25H27N2O2 [M + H]+ 387.2084; found
387.2067.
(3S)-2-Benzyl-3-[(S)-1-phenylethylcarbamoyl]-1,2,3,4-tetrahydro-
isoquinoline 2-Oxide (6): The crude product was purified by column
chromatography (MeOH/DCM, 2:98; Rf = 0.25) to afford the prod-
uct (0.50 g, 96%) as a white solid. M.p. 163–165 °C. [α]2D0 = 66.67
(c = 0.12, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 11.23 (d, J =
7.8 Hz, 1 H), 7.52–7.25 (m, 10 H), 7.29–7.11 (m, 5 H), 6.95 (d, J
= 7.3 Hz, 1 H), 5.29–5.13 (m, 1 H), 4.57–4.36 (m, 3 H), 4.17 (d, J
= 14.9 Hz, 1 H), 3.87 (dd, J = 26.3, 9.9 Hz, 2 H), 3.26 (dd, J =
16.4, 4.1 Hz, 1 H) 1.58 (dd, J = 18.6, 7.0 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 167.41, 143.37, 132.55, 130.27, 129.88,
129.38, 128.86, 128.75, 128.11, 128.07, 127.77, 127.31, 126.87,
126.77, 126.32, 73.35, 69.82, 65.32, 48.95, 30.32, 22.55 ppm. IR
126.76, 73.56, 70.08, 65.03, 30.15, 25.75 ppm. IR (neat): ν = 2928,
˜
1670, 1271, 736, 703 cm–1. HRMS: calcd. for C18H21N2O2 [M +
H]+ 297.1598; found 297.1592.
(3S)-2-Benzyl-3-(benzylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-
Oxide (2): The crude product was purified by column chromatog-
raphy (MeOH/DCM, 2:98; Rf = 0.20) to afford the product (0.50 g,
96%) as a white solid. M.p. 155–157 °C. [α]2D0 = 10.00 (c = 0.10,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 11.11 (s, 1 H), 7.52 (dd,
J = 7.1, 2.3 Hz, 2 H), 7.47–7.11 (m, 12 H), 6.94 (d, J = 7.3 Hz, 1
Eur. J. Org. Chem. 2011, 6923–6932
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6929

T. Govender et al.
FULL PAPER
(neat): ν = 2924, 1671, 1540, 736, 699 cm–1. HRMS: calcd. for
(R)-1-(4-Nitrophenyl)but-3-en-1-ol:[23] (Table 3, Entry 3) 1H NMR
(400 MHz, CDCl3): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.54 (d, J =
8.6 Hz, 2 H), 5.79 (d, J = 7.8 Hz, 1 H), 5.20 (ddd, J = 11.1, 6.3,
1.0 Hz, 2 H), 4.94–4.75 (m, 1 H), 2.51 (ddd, J = 22.0, 10.1, 5.6 Hz,
2 H), 2.13 (d, J = 71.3 Hz, 1 H) ppm. Optical purity was established
by chiral HPLC analysis (Chiralpak IA, hexane/2-propanol = 97:3,
0.7 mL/min, λ = 220 nm): tR = 35.0 (R), 39.0 (S) min.
˜
C25H27N2O2 [M + H]+ 387.2084; found 387.2067.
(3S)-2-Cyclohexyl-3-[(S)-1-phenylethylcarbamoyl]-1,2,3,4-tetra-
hydroisoquinoline 2-Oxide (7): The crude product was purified by
column chromatography (MeOH/DCM, 3:97; Rf = 0.25) to afford
the product (0.47 g, 90%) as a yellow oil. [α]2D0 = –69.05 (c = 0.14,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 10.57 (d, J = 8.5 Hz, 1
H), 7.47–7.40 (m, 2 H), 7.35 (dd, J = 10.3, 4.8 Hz, 2 H), 7.28–7.13
(m, 5 H), 7.00 (d, J = 6.5 Hz, 1 H), 5.14 (dd, J = 8.8, 7.1 Hz, 1 H),
(R)-1-(4-Chlorophenyl)but-3-en-1-ol:[11] (Table 3, Entry 4): 1H
NMR (400 MHz, CDCl3): δ = 7.39–7.06 (m, 4 H), 5.93–5.62 (m, 1
4.38 (d, J = 15.0 Hz, 1 H), 4.21 (d, J = 15.1 Hz, 1 H), 3.99 (d, J = H), 5.28–4.91 (m, 2 H), 4.75–4.52 (m, 1 H), 2.46 (dt, J = 14.0,
3.8 Hz, 1 H), 3.93–3.79 (m, 1 H), 3.22–3.08 (m, 1 H), 2.72 (d, J = 6.5 Hz, 2 H), 2.13 (s, 1 H) ppm. Optical purity was established by
11.7 Hz, 1 H), 1.59–1.14 (m, 10 H) ppm. 13C NMR (101 MHz,
chiral HPLC analysis (Chiralpak AS-H, hexane/2-propanol = 99:1,
CDCl3): δ = 167.36, 143.47, 131.01, 128.67, 128.30, 127.96, 127.46, 0.7 mL/min, λ = 220 nm): tR = 38.0 (R), 41.0 (S) min.
127.22, 126.87, 126.80, 126.64, 76.70, 69.35, 60.60, 48.58, 30.54,
(R)-1-(4-fluorophenyl)but-3-en-1-ol:[24] (Table 3, Entry 5) 1H NMR
29.70, 28.04, 26.09, 25.52, 25.41, 25.26, 21.72 ppm. IR (neat): ν =
˜
(400 MHz, CDCl3): δ = 7.21 (t, J = 8.4 Hz, 4 H), 5.77 (qt, J =
52.1, 26.0 Hz, 1 H), 4.92 (ddd, J = 97.4, 16.5, 8.8 Hz, 2 H), 4.11
(d, J = 7.1 Hz, 1 H), 2.58 (t, J = 32.0 Hz, 2 H), 2.38–2.13 (m, 1
H) ppm. Optical purity was established by chiral HPLC analysis
(Chiralpak AS-H, hexane/2-propanol = 99:1, 0.8 mL/min, λ =
220 nm): tR = 28.0 (R), 32.0 (S) min.
(S)-1-(Naphthalen-1-yl)but-3-en-1-ol:[11] (Table 3, Entry 6) 1H
NMR (400 MHz, CDCl3): δ = 8.01–7.75 (m, 4 H), 7.59 (dt, J =
14.9, 7.1 Hz, 3 H), 7.51–7.37 (m, 1 H), 5.93–5.63 (m, 1 H), 5.22–
4.79 (m, 3 H), 4.10 (q, J = 7.1 Hz, 1 H), 2.25 (ddd, J = 42.5, 19.9,
16.0 Hz, 2 H) ppm. Optical purity was established by chiral HPLC
analysis (Chiralpak AS-H, hexane/2-propanol = 99:1, 0.8 mL/min,
λ = 220 nm): tR = 30.0 (R), 44.0 (S) min.
(S)-1-(3,5-dimethoxyphenyl)but-3-en-1-ol: (Table 3, Entry 7) 1H
NMR (400 MHz, CDCl3): δ = 7.01 (d, J = 2.3 Hz, 2 H), 6.70 (dd,
J = 8.1, 5.9 Hz, 1 H), 5.91–5.71 (m, 1 H), 5.25–5.02 (m, 2 H), 4.74–
4.58 (m, 1 H), 3.82 (d, J = 21.6 Hz, 6 H), 2.49 (dd, J = 13.7, 6.7 Hz,
2 H) ppm. Optical purity was established by chiral HPLC analysis
(Chiralpak AS-H, hexane/2-propanol = 97:3, 0.7 mL/min, λ =
220 nm): tR = 22.0 (R), 24.0 (S) min.
2923, 1670, 1532, 1454, 739 cm–1. HRMS: calcd. for C24H25N2O2
[M + H]+ 379.2367; found 379.2401.
(1S,3S)-3-(Benzhydrylcarbamoyl)-2-benzyl-6,7-dimethoxy-1-phen-
yl-1,2,3,4-tetrahydroisoquinoline 2-Oxide (8): The crude product
was purified by column chromatography (MeOH/DCM, 3:97; Rf =
0.25) to afford the product (0.25 g, 50%) as a white solid. M.p.
180–182 °C. [α]2D0
= –100.00 (c =
0.11, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 12.38 (d, J = 8.7 Hz, 1 H), 7.43 (dd, J =
13.4, 7.3 Hz, 3 H), 7.38–7.14 (m, 16 H), 7.11–7.01 (m, 2 H), 6.87
(s, 1 H), 6.34 (d, J = 8.8 Hz, 1 H), 6.16 (s, 1 H), 4.90 (s, 1 H), 4.32
(ddd, J = 29.1, 16.5, 9.7 Hz, 3 H), 3.95 (s, 3 H), 3.85–3.66 (m, 4
H), 3.58–3.45 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
166.65, 149.48, 148.53, 142.42, 141.56, 135.21, 133.08, 132.90,
129.64, 129.49, 128.89, 128.65, 128.43, 128.07, 127.69, 127.45,
127.20, 127.07, 124.73, 123.62, 110.57, 109.89, 76.62, 66.04, 64.47,
57.28, 56.02, 56.00, 29.05 ppm. IR (neat): ν = 2924, 1667, 1531,
˜
1228, 696 cm–1. HRMS: calcd. for C38H37N2O4 [M + H]+ 585.2856;
found 585.2748.
General Procedure for Allylation Reactions: To an oven-dried
Schlenk tube was added the catalyst (0.03 mmol) followed by dry
THF (1.0 mL) and the aldehyde (0.3 mmol) while purging with Ar.
Thereafter, DIPEA (156 μL, 3.0 equiv.) was added followed by al-
lyltrichlorosilane (3.6 mmol). The reaction was sealed with a sep-
tum and kept under an Ar atmosphere while stirring for 24 h at
room temperature (23 °C). To quench, saturated aqueous NaHCO3
(1.0 mL) was added, and the reaction was vigorously stirred for
1 h. The reaction was then extracted with ethyl acetate (2ϫ5 mL).
The organic layer was dried with anhydrous Na2SO4 and concen-
trated in vacuo. The resulting residue was purified by silica gel
chromatography and analyzed as described below. Chromatographs
and retention times for all chiral products were comparable to the
racemic samples. NMR spectroscopic data for all racemic samples
synthesized were in agreement with previously reported data.
(R)-1-Phenyl-3-buten-3-ol:[11] (Table 3, Entry 1) 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 5.82 (ddt, J = 17.2,
10.0, 7.2 Hz, 1 H), 5.17 (dd, J = 17.2, 1.2 Hz, 1 H), 5.15 (dd, J =
10.4, 1.2 Hz, 1 H), 4.74 (dt, J = 6.4, 2.4 Hz, 1 H), 2.58–2.6 (m, 2
H), 2.06 (d, J = 2.8 Hz, 1 H) ppm. Optical purity was established
by chiral HPLC analysis (Chiralpak IB, hexane/2-propanol = 99:1,
0.8 mL/min, λ = 220 nm): tR = 24.0 (R), 36.0 (S) min.
1
(1E,3S)-1-Phenylhexa-1,5-dien-3-ol:[11] (Table 3, Entry 8) H NMR
(400 MHz, CDCl3): δ = 7.28 (dddd, J = 13.7, 9.4, 5.2, 3.2 Hz, 5
H), 6.59 (d, J = 15.9 Hz, 1 H), 6.23 (dd, J = 15.9, 6.3 Hz, 1 H),
5.96–5.76 (m, 1 H), 5.24–5.07 (m, 2 H), 4.34 (d, J = 6.3 Hz, 1 H),
4.10 (q, J = 7.1 Hz, 1 H), 2.41 (ddd, J = 14.5, 6.3, 4.3 Hz, 2
H) ppm. Optical purity was established by chiral HPLC analysis
(Chiralpak IB, hexane/2-propanol = 90:10, 0.8 mL/min, λ =
220 nm): tR = 8.0 (R), 9.0 (S) min.
(1E,3S)-1-(4-methoxyphenyl)hexa-1,5-dien-3-ol:[22a] (Table 5, En-
1
try 2) H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.6 Hz, 2 H),
6.83 (d, J = 8.6 Hz, 2 H), 6.51 (d, J = 15.9 Hz, 1 H), 6.08 (dd, J =
15.9, 6.6 Hz, 1 H), 5.94–5.73 (m, 1 H), 5.14 (dd, J = 12.1, 11.3 Hz,
1 H), 4.29 (d, J = 5.5 Hz, 1 H), 4.10 (d, J = 7.1 Hz, 1 H), 3.77 (s,
3 H), 2.47–2.16 (m, 2 H) ppm. Optical purity was established by
chiral HPLC analysis (Chiralpak AS-H, hexane/2-propanol =
90:10, 0.8 mL/min, λ = 220 nm): tR = 24.0 (R), 16.0 (S) min.
(1E,3R)-1-(2-Methoxyphenyl)hexa-1,5-dien-3-ol: (Table 5, Entry 3)
[α]2D0 = –3.889 (c = 1.2, MeOH). 1H NMR (400 MHz, CDCl3): δ =
7.43 (d, J = 7.5 Hz, 1 H), 7.23 (dd, J = 14.3, 6.3 Hz, 1 H), 6.98–
6.79 (m, 3 H), 6.26 (dd, J = 16.1, 6.6 Hz, 1 H), 5.97–5.75 (m, 1 H),
5.25–5.07 (m, 2 H), 4.45–4.29 (m, 1 H), 4.12 (q, J = 7.1 Hz, 1 H),
3.83 (d, J = 10.3 Hz, 3 H) ppm. HRMS: calcd. for C13H16O2 [M –
H2O + H]+ 187.1117; found 187.1172. Optical purity was estab-
lished by chiral HPLC analysis (Chiralpak IB, hexane/2-propanol
= 97:3, 0.7 mL/min, λ = 220 nm): tR = 26.0 (R), 32.0 (S) min.
(R)-1-(4-Methoxyphenyl)but-3-en-1-ol:[11] (Table 3, Entry 2) 1H
NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.84 (t, J
= 5.7 Hz, 2 H), 5.87–5.65 (m, 1 H), 5.18–4.94 (m, 2 H), 4.62 (t, J
= 6.6 Hz, 1 H), 3.76 (s, 3 H), 2.39 (ddd, J = 70.6, 14.1, 9.3 Hz, 2
H) ppm. Optical purity was established by chiral HPLC analysis
(Chiralpak IB, hexane/2-propanol
=
99:1, 0.8 mL/min,
λ
=
(1E,3S)-1-(4-nitrophenyl)hexa-1,5-dien-3-ol:[22a] (Table 5, Entry 4)
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 8.6 Hz, 1 H), 8.18
220 nm): tR = 45.0 (R), 50.0 (S) min.
6930
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6923–6932

Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes
(d, J = 8.6 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 1 H), 7.52 (dd, J = 12.1,
10.0 Hz, 1 H), 6.81 (dd, J = 16.1, 7.4 Hz, 1 H), 6.71 (d, J = 16.0 Hz,
1 H), 6.44 (dd, J = 15.9, 5.6 Hz, 1 H), 5.98–5.72 (m, 1 H), 5.30–
5.11 (m, 2 H), 4.43 (d, J = 5.8 Hz, 1 H), 2.57–2.07 (m, 2 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 134.33, 132.27, 128.74, 126.91,
126.04, 125.30, 120.65, 118.19, 110.87, 72.29, 55.43, 42.04 ppm. IR
Supporting Information (see footnote on the first page of this arti-
cle): NMR and high-resolution mass spectra of novel compounds
and chromatograph of chiral cinnamaldehyde product.
Acknowledgments
(neat): ν = 3418, 2931, 1489, 1243, 781 cm–1. Optical purity was
˜
established by chiral HPLC analysis (Chiralpak AS-H, hexane/2-
propanol = 90:10, 0.65 mL/min, λ = 230 nm): tR = 42.0 (R), 36.0
(S) min.
The authors wish to thank the National Research Foundation, the
SA/Swedish Research Links Programme grant and Aspen Pharma-
care, South Africa.
(1E,3S)-1-(2-Nitrophenyl)hexa-1,5-dien-3-ol: (Table 5, Entry 5)
[α]2D0 = –5.556 (c = 1.2, MeOH). 1H NMR (400 MHz, CDCl3): δ =
8.08–7.93 (d, J = 8.2 Hz, 5 H), 7.40 (t, J = 7.5 Hz, 1 H), 6.22 (dd,
J = 15.8, 6.0 Hz, 1 H), 5.87 (dd, J = 17.0, 10.2 Hz, 1 H), 5.31–5.13
(m, 2 H), 4.95 (s, 1 H), 4.42 (d, J = 6.3 Hz, 1 H), 2.43 (dt, J =
13.9, 6.7 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 147.30,
133.82, 132.66, 131.14, 129.08, 128.15, 125.23, 118.87, 41.77,
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36.86 ppm. IR (neat): ν = 3329, 2843, 1681, 1312, 737 cm–1.
˜
HRMS: calcd. for C12H13NO3 [M – C3H5 + H]+ 180.0655; found
180.1315. Optical purity was established by chiral HPLC analysis
(Chiralpak AS-H, hexane/2-propanol = 90:10, 0.65 mL/min, λ =
230 nm): tR = 18.0 (R), 16.0 (S) min.
(1E,3S)-1-(4-bromophenyl)hexa-1,5-dien-3-ol:[22a] (Table 5, Entry 6)
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.4 Hz, 1 H), 7.43–
7.29 (m, 2 H), 7.24 (t, J = 7.0 Hz, 3 H), 6.55 (d, J = 15.9 Hz, 1 H),
6.23 (dd, J = 15.9, 6.1 Hz, 1 H), 5.84 (ddd, J = 14.3, 10.1, 7.2 Hz,
1 H), 5.29–5.03 (m, 2 H), 4.35 (dd, J = 12.2, 6.1 Hz, 1 H), 2.51–
2.13 (m, 2 H) ppm. Optical purity was established by chiral HPLC
analysis (Chiralpak AS-H, hexane/2-propanol = 97:3, 0.60 mL/
min, λ = 220 nm): tR = 24.0 (R), 23.0 (S) min.
(1E,3S)-1-(Furan-2-yl)hexa-1,5-dien-3-ol: (Table 5, Entry 7) [α]2D0
=
1
–0.909 (c = 1.1, MeOH). H NMR (400 MHz, CDCl3): δ = 6.38–
6.23 (m, 3 H), 6.17–6.00 (m, 2 H), 5.84–5.60 (m, 1 H), 5.06 (dd, J
= 14.2, 5.6 Hz, 2 H), 4.21 (d, J = 5.3 Hz, 1 H), 2.27 (qd, J =
14.3, 7.5 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 152.36,
141.97, 133.96, 130.18, 118.60, 118.56, 111.29, 108.09, 71.23,
41.97 ppm. IR (neat): ν = 3378, 2908, 1640, 1012, 733 cm–1.
˜
HRMS: calcd. for C10H12O2 [M + Na]1+ 187.0729; found 187.1168.
Optical purity was established by chiral HPLC analysis (Chiralpak
AS-H, hexane/2-propanol = 90:10, 0.80 mL/min, λ = 220 nm): tR
= 11.0 (R), 9.0 (S) min.
(S,E)-Hepta-1,5-dien-4-ol:[22a] (Table 5, Entry 8) 1H NMR
(400 MHz, CDCl3): δ = 5.76 (dddd, J = 34.5, 21.6, 11.6, 6.7 Hz, 2
H), 5.51 (dd, J = 15.3, 6.8 Hz, 1 H), 5.23–4.99 (m, 2 H), 4.10 (dd,
J = 12.5, 6.3 Hz, 1 H), 2.44–2.11 (m, 5 H) ppm. Optical purity was
established by chiral GC analysis (80 °C for 1 min, then 1 °C/min
to 160 °C, 5 min at that temperature): tR = 54.12 (R), 55.73 (S) min.
(1E,3S)-6-Methylhepta-1,5-dien-4-ol:[22a] (Table 5, Entry 10) 1H
NMR (400 MHz, CDCl3): δ = 7.05 (s, 1 H), 5.92–5.67 (m, 1 H),
5.28–4.93 (m, 3 H), 4.38 (d, J = 8.1 Hz, 1 H), 2.37–2.12 (m, 2 H),
1.86–1.48 (m, 6) ppm. Optical purity was established by chiral GC
analysis (80 °C for 1 min, then 1 °C/min to 160 °C, 5 min at that
temperature): tR = 15.13 (R), 14.47 (S) min.
(1E,3R)-2-methyl-1-phenylhexa-1,5-dien-3-ol:[22a] (Table 5, En-
try 11) 1H NMR (400 MHz, CDCl3): δ = 7.27 (ddd, J = 19.9, 14.3,
7.6 Hz, 5 H), 6.52 (s, 1 H), 5.84 (d, J = 7.0 Hz, 1 H), 5.16 (t, J =
14.0 Hz, 2 H), 4.22 (s, 1 H), 2.52–2.33 (m, 2 H) ppm. Optical purity
was established by chiral HPLC analysis (Chiralpak AS-H, hexane/
2-propanol = 90:10, 0.8 mL/min, λ = 220 nm): tR = 27.0 (R), 31.0
(S) min.
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Eur. J. Org. Chem. 2011, 6923–6932
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6931

T. Govender et al.
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Published Online: September 26, 2011
6932
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Eur. J. Org. Chem. 2011, 6923–6932