Synthesis of Chiral Tetrahydroisoquinoline and C 2-Symmetric Bistetrahydroisoquinoline Ligands and Their Application in the Enantioselective Henry Reaction

Article abstract of DOI:10.1055/s-0035-1561634

Application of chiral tetrahydroisoquinoline and bistetrahydroisoquinoline scaffolds in asymmetric reactions is limited by the inefficient synthesis of their chiral structural variants. We have conveniently synthesized 24 such variants and applied them as

Full text of DOI:10.1055/s-0035-1561634

SYNTHESIS
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1
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
Synthesis of Chiral Tetrahydroisoquinoline and C2-Symmetric
Bistetrahydroisoquinoline Ligands and Their Application in the
Enantioselective Henry Reaction
Duc Thinh Khong
THIQ
Cu(OAc)2·H2O, EtOH
OTMS
Zaher M. A. Judeh*
O
OH
N
r.t., 48 h
+
CH3NO2
NO2
School of Chemical and Biomedical Engineering, Nanyang
Technological University, 62 Nanyang Drive, N1.2–B1-14,
Singapore 637459
R
R
H
N
zaher@ntu.edu.sg
R: Ph, substituted Ph,
cinnamyl, naphthyl, 2-furyl
(up to 96% yield
up to 80% ee)
17 examples
THIQ
Received: 16.11.2015
Accepted after revision: 08.04.2016
Published online: 01.06.2016
tion,15 alkynylations,16 alkylation,17 aluminum- and borane-
mediated reductions,18 and Henry19 reactions. For example,
chiral THIQs 1 (R1 = oxazolinyl and R3 = Ph) catalyzed the
reaction between aromatic aldehydes and nitromethane
and gave the β-nitro alcohol adducts with 40–77% ee.19
However, chiral isoquinolines catalyzed the asymmetric
Henry reaction between nitrobenzaldehyde and nitrometh-
ane and gave the β-nitro alcohol adducts with just 11%
ee.19b The enantioselectivity obtained suggested the poten-
tial of these aza-ligands in the asymmetric Henry reaction.
The reported THIQs have structural variations mostly at R1
and R2 while R3 is limited to either hydrogen or phenyl,
since the synthesis of chiral THIQs with varying R3 is very
challenging.18b,20 Further development of THIQs and its di-
mers BIQs into efficient chiral ligands is hindered by the
difficulty in synthesizing their structural variants for ligand
optimization.
DOI: 10.1055/s-0035-1561634; Art ID: ss-2015-n0661-op
Abstract Application of chiral tetrahydroisoquinoline and bistetrahy-
droisoquinoline scaffolds in asymmetric reactions is limited by the inef-
ficient synthesis of their chiral structural variants. We have conveniently
synthesized 24 such variants and applied them as ligands in the enanti-
oselective Henry reaction. The conformational rigidity of these ligands
and the size of the coordination sphere control the enantioselectivity of
the products. The conformationally rigid chiral tetrahydroisoquinoline
THIQ–Cu(OAc)2·H2O complex successfully catalyzed the enantioselec-
tive Henry reaction between various aldehydes and nitromethane and
gives the β-nitro alcohol adducts in up to 96% yield and 80% ee.
Key words tetrahydroisoquinoline, C2-symmetric ligand, bistetrahy-
droisoquinoline, Henry reaction, asymmetric catalysis
The Henry (or nitroaldol) reaction is a classical C–C
bond-forming reaction between carbonyl compounds and
nitroalkanes. It is used to construct β-nitro alcohol ad-
ducts.1 The adducts can be converted into β-amino alco-
hols,2 β-amino acids,3 nitroalkenes,3 and α-nitro ketones.4
These compounds are key intermediates in the total synthe-
ses of numerous biologically active molecules.5 Shibasaki
et al. reported the first asymmetric Henry reaction using
chiral BINOL–La(O-t-Bu)3 complexes.6 Since then, complex-
es of various ligands with metals, such as rare earth metals,
zinc, copper, cobalt, and magnesium, have been used with
varying degrees of success.7,8 Earlier work revealed that chi-
ral aza-ligand–Cu complexes, such as bisoxazoline–,7,9 di-
amine–,10 aminopyridine–,11 N,N′-dioxide–,12 and tetrahy-
dro-Salen–Cu complexes,13 are particularly efficient for this
reaction.
R1
R2
N
N
3
R2
R2
1
N
N
R2
N
1
n
1'
R3
THIQ (1)
C1-BIQ (2)
C2-BIQ (3)
R1 = H, oxazolinyl
R2 = H, alkyl
R3 = H, phenyl
R2 = H, alkyl
R2 = H, alkyl
n = 0, 1
Figure 1 Chiral THIQ, and C1- and C2-BIQ ligands
We have recently reported the simple, modular, and di-
rect synthesis of chiral THIQs 4 with varying R3 substitu-
ents at C1 (Scheme 1) and successfully extended the syn-
thesis to chiral C2-BIQs 5 (Scheme 2).21 This, in combination
with the successful application of C1-BIQs 217,22 and C2-BIQs
Our group and others have used tetrahydroisoquino-
lines14 (THIQs) 1 as well as their dimers C1-bisisoquinolines
(C1-BIQs) 2 and C2-bistetrahydroisoquinolines (C2-BIQs) 3
(Figure 1) as chiral aza-ligands for asymmetric hydrogena-
3
23 (Figure 1) as ligands for the asymmetric Henry reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
as well as other asymmetric reactions,22e,24 prompted us to
query if our new THIQs 4 (Scheme 1) and C2-BIQs 5
(Scheme 2) could be effective aza-ligands for the enantiose-
lective Henry reaction.
Herein, we report the synthesis of chiral THIQ and C2-
BIQ ligands and their application in the enantioselective
Henry reaction.
of the cycloadducts afforded C2-BIQs 5a–c (Scheme 2).21
MeI was used to N-methylate C2-BIQs 5a–c to C2-BIQs 10a–c
(Scheme 2).23b While we successfully isolated C2-BIQs 10b
and 10c in 59% and 63% yield, respectively, C2-BIQ 10a was
unstable and decomposed during purification on column
chromatography.
R
OH
R
Synthesis of Chiral THIQ and C2-BIQ Ligands
NH
R
i, ii
O
X
HN
R
The synthesis of THIQs 4a–h is depicted in Scheme 1.21
The key step involved Pictet–Spengler condensation be-
tween (S)-4-benzyloxazolidin-2-one (6) and several ali-
phatic and aromatic aldehydes to give the respective cyc-
loadducts as one diastereomer. Subsequent treatment of
the cycloadducts with NaOH cleanly afforded THIQs 4a–h in
overall 57–79% yields. Based on our previous experience,24b
N-methylated chiral BIQ ligands gave better enantio-
selectivity in the Henry reaction in comparison to the non-
methylated counterparts.24b Therefore, we also prepared
the N-methylated THIQs 7a–h (Scheme 1). Reductive meth-
ylation of THIQs 4a,b,d–h using HCHO/NaCNBH325 provided
the corresponding N-methylated THIQs 7a,b,d–h in 81–94%
yield. However, under such condition, N-methylation of
THIQ 4c, bearing a free o-amino group, afforded instead cy-
clic aminal THIQ 8 in 96% yield. Nevertheless, reaction of
THIQ 4c with MeI provided the desired N-methylated THIQ
7c in 67% yield (Scheme 1).
R
O
NH
OH
6: R = H
R
9: R = OMe
5a: R = H, X = 0 (55%)
5b: R = OMe, X = -CH2- (21%)
5c: R = H, X = 1,3-phenylene (54%)
R
OH
OH
N
N
R
R
iii
X
R
10b: R = OMe, X = -CH2- (59%)
10c: R = H, X = 1,3-phenylene (63%)
Scheme 2 Synthesis of chiral C2-BIQs 5a–c, and 10b–c. Reagents and
conditions: (i) glyoxal trimer dihydrate (5a), maldondialdehyde (5b),
isophthalaldehyde (5c), H2SO4, CHCl3, reflux, 12 h; (ii) NaOH, MeOH,
H2O, reflux, 48 h; (iii) MeI, r.t., 12 h.
Screening of the THIQ and BIQ Ligands in the Cu-
Catalyzed Enantioselective Henry Reaction
OH
OH
i, ii
iii or iv
O
NH
N
HN
R3
4a: R3 = Ph (79%)
R3
7a: R3 = Ph (91%)
O
With the enantiopure THIQs 4a–h, 7a–h, 8 and C2-BIQs
5a–c, 10b, and 10c in hand, we examined their catalytic
abilities in the enantioselective benchmark Henry reaction
between benzaldehyde (11a) and nitromethane (12) in the
presence of Cu(OAc)2·H2O (Table 1).7a The chiral ligand–cop-
per complexes were prepared in situ by mixing the respec-
tive ligand with Cu(OAc)2·H2O in 1:1 molar ratio in EtOH at
room temperature for 2 hours to ensure effective complex
formation before addition of benzaldehyde (11a). In all
cases, the Henry reaction proceeded smoothly to provide β-
nitro alcohol 13a in moderate to excellent 42–93% yields
(Table 1). THIQs with aryl substituents at C1 afforded better
enantioselectivities in comparison to the same with alkyl
substituents (Table 1, entries 1–4 vs 5–8). However, differ-
ences in the stereoelectronic effects of the C1-aryl substitu-
ents has no significant impact on the enantioselectivity
since β-nitro alcohol 13a was obtained in ~ 34% ee in all
cases (Table 1, entries 1–4). However, with C1-alkyl substit-
uents, as the steric size of the alkyl substituents increased
from n-Pr (THIQ 4e) to i-Pr (THIQ 4f) to t-Bu (THIQ 4g), the
enantioselectivity of the β-nitro alcohol 13a changed from
22% ee to 2% ee to 34% ee, respectively (Table 1, entries 5–
7). THIQ 4h, where C1 is cyclohexyl provided similar results
to THIQ 4f (Table 1, entries 6 vs 8).
6
4b: R3 = 2-MeOC6H4 (76%) 7b: R3 = 2-MeOC6H4 (92%)
4c: R3 = 2-H2NC6H4 (57%) 7c: R3 = 2-Me2NC6H4 (67%)
4d: R3 = 2-naphthyl (73%)
4e: R3 = n-Pr (78%)
4f: R3 = i-Pr (63%)
4g: R3 = t-Bu (74%)
4h: R3 = Cy (62%)
7d: R3 = 2-naphthyl (94%)
7e: R3 = n-Pr (85%)
7f: R3 = i-Pr (81%)
7g: R3 = t-Bu (88%)
7h: R3 = Cy (90%)
OH
iii
OH
NH
N
96%
NH2
N
4c
8
Scheme 1 Synthesis of chiral THIQs 4a–h, 7a–h, and 8. Reagents and
conditions: (i) R3CHO, H2SO4, CHCl3, r.t., 12 h; (ii) NaOH, MeOH, H2O,
reflux, 24 h; (iii) 37% HCHO, NaCNBH3, AcOH, THF, r.t., 4–5 h (for
4a,b,d–h to 7a,b,d–h); (iv) MeI, r.t. (for 4c to 7c).
Likewise, Pictet–Spengler condensation between oxazo-
lidinones 6 or 9 and the dialdehydes glyoxal, malondialde-
hyde, and isophthalaldehyde followed by NaOH hydrolysis
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
Table 1 Screening of Chiral THIQ and C2-BIQ Ligands in the Enantiose-
Though conformational analysis of THIQ–Cu(II) com-
plexes is beyond the scope of this work, we speculate that
the modest ees can be attributed to the low conformational
rigidity of THIQ–Cu(II) complexes. With a low energy barri-
er for N-inversion,26 Bowen et al.27 demonstrated the signif-
icant presence of two conformers of THIQs in which the N–
H was at the pseudoaxial or pseudoequatorial positions.28
We believe that restricting the N-inversion would give more
conformationally restricted THIQ ligands and this would
lead to improvement in the enantioselectivity. Therefore,
we prepared N-methylated ligands 7a–h. To examine the
axial/equatorial disposition at the nitrogen, the chemical
shifts of the C1-protons of the THIQs were compared before
and after N-methylation. After N-methylation, the chemical
shift of the C1-protons moved upfield due to the shielding
effect experienced from the axial nitrogen lone pair elec-
trons (see Table 1 in the Supporting Information). This sug-
gested that the N-methyl groups occupied the equatorial
position in all THIQs (except THIQ 7e) forcing the nitrogen
lone pair electrons into the axial position.27
Indeed, the N-methylated counterparts THIQs 7a–h
gave the β-nitro alcohol 13a in higher yields (up to 86%)
and with significantly improved enantioselectivities (up to
73% ee) (Table 1, entries 1–8 vs 9–16). THIQs 7e–h with C1-
alkyl substituents demonstrated a positive relationship be-
tween the bulkiness of the alkyl groups and the enantiose-
lectivity. The enantioselectivity increased as the steric size
of the C1-alkyl substituents increased from Pr to i-Pr (or Cy)
to t-Bu (Table 1, entries 13–16). THIQ 7g with a C1 t-Bu sub-
stituent gave 70% ee. In comparison, C2-BIQs 5a–c and N-
methylated counterparts C2-BIQs 10b–c gave lower enantio-
selectivities for the β-nitro alcohol 13a most probably as a
result of their larger and conformationally more flexible
copper coordination sphere (six- to eight-membered-ring
structure) (Table 1, entries 18–22).
lective Henry Reactiona
Cu(OAc)2·H2O
EtOH, r.t., 48 h
OH
∗
CHO
NO2
MeNO2
+
THIQ or C2-BIQ
11a
12
13a
R
OH
N
N
OH
R
R2
R2
or
X
N
R2
R
R
R3
THIQ
OH
C2-BIQ
Entry THIQ
R2
R3
Yieldb (%) eec (%)
1
2
4a
4b
4c
4d
4e
4f
H
Ph
73
78
42
74
78
70
71
67
75
83
80
78
86
67
71
70
34 (R)
36 (S)
27 (S)
34 (R)
22 (R)
2 (S)
H
2-MeOC6H4
2-H2NC6H4
2-naphthyl
n-Pr
3
H
4
H
5
H
6
H
i-Pr
7
4g
4h
7a
7b
7c
7d
7e
7f
H
t-Bu
34 (S)
5 (S)
8
H
Cy
9
Me
Me
Me
Me
Me
Me
Me
Me
Ph
39 (R)
73 (S)
28 (S)
44 (R)
43 (R)
59 (R)
70 (R)
60 (R)
10
11
12
13
14
15
16
2-MeOC6H4
2-H2NC6H4
2-naphthyl
n-Pr
i-Pr
7g
7h
t-Bu
Cy
N
17
8
74
76 (S)
We envisioned that further conformational restriction
of THIQs would be beneficial. Indeed, the highly restricted
THIQ 8 with a methylene bridging group between the two
nitrogens gave the β-nitro alcohol 13a in 74% yield with
76% ee (Table 1, entry 17). We anticipated that further ste-
ric hindrance at the hydroxyl group of THIQ 8 could influ-
ence the enantioselectivity. Therefore, we prepared the si-
lylated THIQs 14a and 14b in high yields as shown in
Scheme 3. Asymmetric Henry reaction with THIQs 14a and
14b proceeded smoothly to give the β-nitro alcohol 13a in
82% and 75% yield (Table 2). THIQ 14a with moderately
bulky trimethylsilyl group improved the ee to 80% (Table 2,
entry 1), THIQ 14b with bulkier tert-butyldimethylsilyl
group severely reduced the ee to 52% (Table 2, entry 2). The
results showed that the steric hindrance at the hydroxyl
group has little influence on the enantioselectivity of the
Henry reaction.
C2-BIQ
5a
R
R2
H
X
18
19
H
–
80
93
55 (S)
11 (R)
5b
OMe
H
-CH2-
20
21
22
5c
H
H
85
85
85
6 (S)
26 (R)
14 (R)
10b
10c
OMe
H
Me
H
-CH2-
a Reaction conditions: benzaldehyde (11a, 0.2 mmol), MeNO2 (12, 10
equiv), ligand–Cu(OAc)2·H2O (1:1, 10 mol%), EtOH (2 mL).
b Isolated yields.
c Measured by HPLC (Chiralcel OD-H column, hexane/i-PrOH 90:10, flow
rate = 0.8 mL/min, λ = 215 nm): tR = 18.1 (R), 22.2 min (S). Absolute config-
uration of 13a was assigned by comparison with the literature values (see
Supporting Information for details).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
comparable ee to the reaction from Cu(OAc)2·H2O. The ex-
act role of water in this mechanism is not clear.29 We con-
cluded that Cu(OAc)2·H2O is the optimal metal salt and it
was used for further optimization.
OH
OR
N
N
i
N
N
Table 3 Screening of Metal Salts in the Enantioselective Henry Reac-
tion Catalyzed by THIQ 14aa
8
14a: R = TMS (71%)
14b: R = TBDMS (76%)
Scheme 3 Synthesis of THIQs 14a and 14b by O-silylation of THIQ 8.
Reagents and conditions: (i) RCl, 1H-imidazole, r.t., 3 h.
14a, metal salt
EtOH, r.t., 48 h
OH
CHO
NO2
+
MeNO2
Table 2 Screening of THIQs 14a and 14b in the Enantioselective
Henry Reactiona
11a
12
13a
Entry
Metal salts
Catalyst (mol%) Yieldb (%)
eec (%)
THIQ
Cu(OAc)2·H2O
OH
CHO
NO2
+
MeNO2
1
2
Co(OAc)2
Mn(OAc)2
10
10
10
10
10
10
10
10
10
10
65
54
85
80
82
78
76
35
56
73
1
1
EtOH, r.t., 48 h
11a
12
13a
3
Zn(OAc)2·2H2O
Ni(OAc)2·4H2O
Cu(OAc)2·H2O
Cu(OAc)2
CuOAc
0
4
1
Entry
THIQ
Yieldb (%)
eec (%)
5
80
76
72
14
68
3
1
2
14a
14b
82
75
80 (S)
52 (S)
6
7
a Reaction conditions: benzaldehyde (11a, 0.2 mmol), MeNO2 (12, 10
equiv), ligand–Cu(OAc)2·H2O (1:1, 10 mol%), EtOH (2 mL).
b Isolated yields.
8
CuCl2
c Measured by HPLC (Chiralcel OD-H column, hexane/i-PrOH 90:10, flow
rate = 0.8 mL/min, λ = 215 nm): tR = 18.1 (R), 22.2 min (S). ) Absolute con-
figuration of 13a was assigned as (S) by comparison with the literature val-
ues (see Supporting Information for details).
9
CuCl
10
Cu(OTf)2
a Reaction conditions: benzaldehyde (11a, 0.2 mmol), MeNO2 (12, 10
equiv), ligand–metal (1:1, 10 mol%), EtOH (2 mL).
b Isolated yields.
c Measured by HPLC (Chiralcel OD-H column, hexane/i-PrOH 90:10, flow
rate = 0.8 mL/min, λ = 215 nm): tR = 18.1 (R), 22.2 min (S).
Optimization of the Enantioselective Henry Reaction
Using THIQ 14a
Next, the effect of THIQ 14a–Cu(OAc)2·H2O catalyst
loading using 2.5, 5, 10, 15, and 20 mol% was examined
(Figure 2). As catalyst loading increased, a gradual increase
in the yield of β-nitro alcohol 13a from 53% to 91% was ob-
served. As the catalyst loading increased from 2.5 to 5 to 10
mol%, the enantioselectivity gradually increased from 67%
to 73% to 80% ee, respectively. However, further increase in
the loading to 15 mol% and then to 20 mol%, caused no ef-
fect on the ee which remained constant at ~80% ee. There-
fore, catalyst loading of 10 mol% was deemed optimal (Fig-
ure 2).
Next, solvent effects were examined (Table 4). Polar
protic solvents such as MeOH, EtOH, and i-PrOH afforded
the highest yields of 85%, 82%, and 86%, respectively, of β-
nitro alcohol 13a (Table 4, entries 1–3). Ether-type solvents
such as THF, Et2O, and i-Pr2O caused the Henry reaction to
become very sluggish, and even after seven days, only mod-
est yields of up to 31% of the β-nitro alcohol 13a were ob-
tained with inferior ee (Table 4, entries 4–6). Other solvents
including CH2Cl2, MeCN, and MeNO2 (Table 4, entries 7–9)
gave similar results to ether-type solvents. Therefore, EtOH
remained as the optimal solvent of choice (Table 4, entry 2).
These conditions were very similar to the Evan’s conditions
under which bisoxazoline ligands worked best.7a
With THIQ 14a as the optimal ligand, we proceeded to
optimize the reaction by exploring the effects of metal
salts, catalyst loading, solvents, and external bases on the
yield and enantioselectivity. First, the effect of metal salts
was examined. All THIQ 14a–metal acetate complexes suc-
cessfully catalyzed the reaction and gave the β-nitro alcohol
13a in 54–85% yield (Table 3, entries 1–7). However, only
Cu(II) and Cu(I) complexes effectively induced enantiose-
lectivity (Table 3, entries 5–7) while other metal acetate
complexes gave racemic products (Table 3, entries 1–4).8b
THIQ 14a by itself did not yield the β-nitro alcohol 13a sug-
gesting its insufficient basicity to deprotonate nitrometh-
ane (12).29 The effect of the counterion of the copper salts
was also examined (Table 3, entries 8–13). Complexes of
Cu(acac)2, CuI, or Cu(NO3)2·2.5H2O with THIQ 14a failed to
give β-nitro alcohol 13a as they were barely soluble in EtOH
(not shown). Complexes of CuCl2, CuCl, and Cu(OTf)2 with
THIQ 14a were soluble, but gave inferior yields and enanti-
oselectivities in comparison to those obtained from THIQ
14a–Cu(OAc)2·H2O complex (Table 3, entries 8–10 vs 5). An-
hydrous Cu(OAc)2 gave slightly inferior results in compari-
son to those obtained with Cu(OAc)2·H2O (Table 3, entries 5
and 6). Addition of equimolar amount of H2O to anhydrous
Cu(OAc)2 during the complex formation step provided a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
Scope and Limitations of the Asymmetric Henry Re-
action
The scope and limitations of the asymmetric Henry re-
action under the optimized conditions (Table 4, entry 2)
were examined using various aldehydes (Table 5). Aromatic
aldehydes 11a–q with electron-donating and -withdrawing
substituents reacted smoothly with nitromethane (12) to
give the corresponding β-nitro alcohols 13a–q in high
yields (67–96%) and with moderate to high enantioselectiv-
ities (54–80% ee). An exception to this is p-nitrobenzalde-
hyde (Table 5, entry 2), which due to its strong electron-
withdrawing activating nitro group, its faster reaction rate
led to higher 91% yield and lower 54% ee. Interestingly, the
substitution pattern at the aromatic rings had no major ef-
fect on the enantioselectivity, but more pronounced effects
on the yield of the β-nitro alcohols with meta substituents
providing lower yields in comparison to ortho or para sub-
stituents (Table 5, entry 4 vs 3; entry 6 vs 5 and 7, and entry
11 vs 10). Other aromatic aldehydes such as 2-naphthalde-
Figure 2 Screening of the loading of THIQ 14a–Cu(OAc)2·H2O com-
plex in the enantioselective Henry reaction
Table 4 Screening of Solvents in the Enantioselective Henry Reaction
Catalyzed by THIQ 14a–Cu(OAc)2·H2O Complexa
14a, Cu(OAc)2·H2O
solvent, r.t., 48 h
OH
CHO
NO2
+
MeNO2
Table 5 Scope of the Enantioselective Henry Reaction Catalyzed by
THIQ 14a–Cu(OAc)2·H2Oa
11a
12
13a
Entry
Solvent
Yieldb (%)
eec (%)
THIQ 14a
Cu(OAc)2·H2O
OH
O
NO2
1
MeOH
EtOH
85
82
86
25
31
12
21
15
79
63
80
70
58
74
63
68
28
71
+
MeNO2
R
H
EtOH, r.t., 48 h
2
11a–q
12
13a–q
3
i-PrOH
THF
4d
5d
6d
7d
8d
9
Entry
R
Aldehyde
Product
Yieldb (%) eec(%)
Et2O
1
2
Ph
11a
11b
11c
11d
11e
11f
13a
13b
13c
13d
13e
13f
82
91
88
80
96
79
95
94
67
83
61
96
93
80
93
76
76
80
54
77
71
76
74
80
78
78
74
71
78
68
64
78
61
77
i-Pr2O
CH2Cl2
MeCN
MeNO2
4-O2NC6H4
4-ClC6H4
3-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-FC6H4
3
4
5
a Reaction conditions: benzaldehyde (11a, 0.2 mmol), MeNO2 (12, 10
equiv), ligand–Cu(OAc)2·H2O (1:1, 10 mol%), EtOH (2 mL).
b Isolated yields.
6
7
11g
11h
11i
13g
13h
13j
c Measured by HPLC (Chiralcel OD-H column, hexane/i-PrOH 90: 10, flow
rate = 0.8 mL/min, λ = 215 nm): tR = 18.1 (R), 22.2 min (S).
d Reactions run for 7 d.
8
9
4-FC6H4
10
11
12
13
14
15
16
17
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-PhC6H4
3-MeOC6H4
2-naphthyl
trans-PhCH=CH
2-furyl
11j
13k
13l
ortho-Iodobenzoates as counterions in copper-catalyzed
reactions increased the enantioselectivity of the Henry re-
action.7b Likewise, the use of catalytic or stoichiometric
amount of external tertiary amine bases (e.g., DIPEA, DAB-
CO, etc.) has been reported in some cases to improve the ee
and yield of the enantioselective Henry reactions.10i,30 How-
ever, under our experimental conditions, addition of DIPEA
slightly improved the yield to 93%, but significantly reduced
the enantioselectivity to 70%. In this case, most likely DIPEA
catalyzed the Henry reaction and produced racemic β-nitro
alcohol 13a.
11k
11l
13m
13n
13o
13p
13q
13r
11m
11n
11o
11p
11q
a Reaction conditions: benzaldehyde 11a–m (0.2 mmol), MeNO2 (12, 10
equiv), ligand–Cu(OAc)2·H2O (1:1, 10 mol%), EtOH (2 mL).
b Isolated yields.
c Measured by HPLC. Absolute configuration of the β-nitro alcohol products
13a–q was assigned by comparison with the literature values (see Support-
ing Information for details).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
hyde (11o), trans-cinnamaldehyde (11p), and furfural (11q)
also gave the corresponding β-nitro alcohols 13o, 13p, and
13q, respectively, in good yields and ee (Table 5, entries 15–17).
Fortunately, with this catalytic system, no side products
such as nitroalkenes and epimerization were observed and
no special precautions were taken to exclude moisture or
air from the reaction flask. The modular synthesis of these
THIQ ligands provides opportunities for flexible ligand de-
sign and optimization to further improve the enantioselec-
tivity of the enantioselective Henry reaction.
[(1R,3S)-2-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-
yl]methanol (7a)
The crude product from N-methylation of THIQ 7a was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7a as a
21
white solid; yield: 230 mg (91%); mp 137 °C; [α]D –144 (c 1.0,
MeOH).
FTIR (KBr): 709, 2917, 1459, 1050, 753, 709 cm–1
.
1H NMR: δ = 2.41 (s, 3 H), 2.61–2.80 (m, 2 H), 3.20 (quint, J = 4.8 Hz, 1
H), 3.50 (dd, J = 5.4, 10.5 Hz, 1 H), 3.60 (dd, J = 5.4, 10.5 Hz, 1 H), 4.89
(s, 1 H), 6.99 (d, J = 7.5 Hz, 1 H), 7.12–7.29 (m, 8 H).
13C NMR: δ = 25.9, 35.9, 53.6, 61.1, 67.9, 126.2, 127.0, 127.5, 128.2,
We synthesized chiral THIQ and C2-BIQ ligands and ap-
plied them successfully in enantioselective Henry reactions.
The results showed strong dependence of the enantioselec-
tivity on the conformational rigidity of the ligands and size
of the copper coordination sphere rather than the type of
aldehyde used. The configurationally rigid complex THIQ
14a–Cu(OAc)2·H2O catalyzed the enantioselective Henry re-
action of a broad range of aldehydes and gave the β-nitro
alcohol adducts in up to 93% yield and 80% ee. The pros-
pects of the newly synthesized THIQs and C2-BIQs in asym-
metric catalysis are very promising. A great variety of struc-
tures can be synthesized in a modular and direct fashion
that require no chiral resolution steps according to the pro-
tocol developed in this work. Application of these chiral li-
gands in other asymmetric reactions will be reported soon.
129.2, 129.4, 129.6, 133.4, 134.2, 142.3.
HRMS (ESI+): m/z [M + H]+ calcd for C17H19NO: 254.1545; found:
254.1536.
[(1S,3S)-1-(2-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroiso-
quinolin-3-yl]methanol (7b)
The crude product from N-methylation of THIQ 7b was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7b as a
white solid; yield: 260 mg (92%); mp 95 °C; [α]D22 –140 (c 1.0, MeOH).
FTIR (KBr): 1594, 1484, 1241, 1098, 1027, 746 cm–1
1H NMR: δ = 2.39 (s, 3 H), 2.66–2.82 (m, 2 H), 3.32 (s, 1 H), 3.51–3.65
(m, 2 H), 3.91 (s, 3 H), 5.35 (s, 1 H), 6.61 (d, J = 7.2 Hz, 1 H), 6.74–6.79
(m, 1 H), 6.92 (d, J = 7.8 Hz, 2 H), 7.10–7.26 (m, 4 H).
.
13C NMR: δ = 25.9, 35.3, 53.3, 55.8, 60.8, 61.2, 110.7, 119.9, 126.1,
126.4, 128.4, 129.0, 129.4, 130.7, 131.6, 134.3, 135.9, 157.9.
HRMS (ESI+): m/z [M + H]+ calcd for C18H21NO2: 284.1651; found:
284.1713.
Chemical reagents were purchased from Sigma-Aldrich or Alfa Aesar
and used as received without further purification. 1H NMR spectra
were recorded at 300 MHz on a Bruker Avance DPX 300. Unless stated
otherwise, data refer to solutions in CDCl3 with TMS as an internal
reference. 13C NMR spectra were recorded at 75.47 MHz on a Bruker
Advanced DPX 300. HRMS were recorded on Qstar XL MS/MS system.
FTIR spectra were recorded on Perkin Elmer FTIR system Spectrum
BX. Analytical TLC was performed using Merck 60 F254 precoated silica
gel plates (0.2-mm thickness) and visualized using UV radiation (254
nm). Flash chromatography was performed using Merck silica gel 60
(230–400 mesh). Optical rotation values were measured on JASCO P-
1020 polarimeter.
[(1R,3S)-2-Methyl-1-(naphthalen-2-yl)-1,2,3,4-tetrahydroisoquin-
olin-3-yl]methanol (7d)
The crude product from N-methylation of THIQ 7d was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7d as a
22
white solid; yield: 285 mg (94%); mp 127–129 °C; [α]D –197 (c 1.0,
MeOH).
FTIR (KBr): 2926, 1454, 1042, 747 cm–1
.
1H NMR: δ = 2.46 (s, 3 H), 2.66–2.84 (m, 2 H), 3.24 (quint, J = 2.4 Hz, 1
H), 3.49 (dd, J = 5.4, 10.5 Hz, 1 H), 3.65 (dd, J = 5.4, 10.5 Hz, 1 H), 5.02
(s, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 7.14–7.32 (m, 4 H), 7.39–7.51 (m, 3
H), 7.66–7.69 (m, 1 H), 7.76–7.81 (m, 2 H).
13C NMR: δ = 26.1, 36.0, 53.3, 61.12, 67.9, 125.8, 125.9, 126.1, 126.8,
127.3, 127.6, 128.0, 128.0, 129.4, 129.8, 132.7, 132.9, 133.9, 134.8,
141.1.
HRMS (ESI+): m/z [M + H]+ calcd for C21H21NO: 304.1701; found:
304.1701.
N-Methylation Using HCHO/NaCNBH3; General Procedure
A 37 wt% aq solution of HCHO (0.75 mL, 10 equiv) was added to a
solution of THIQ (1 mmol, 1 equiv) in THF (5 mL) and the mixture was
stirred for 15 min at r.t. NaCNBH3 (310 mg, 5 equiv) was then added
and the mixture was stirred for an additional 15 min. Glacial AcOH
(0.6 mL, 10 equiv) was then added dropwise and the mixture was
stirred for a further 3–4 h. Sat. NaHCO3 solution (10 mL) was then
added and the mixture extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic extracts were washed with brine, dried (MgSO4), fil-
tered, and evaporated under reduced pressure. The crude mixture
was purified by column chromatography. The procedure was used to
synthesize the following compounds:
[(1R,3S)-2-Methyl-1-propyl-1,2,3,4-tetrahydroisoquinolin-3-
yl]methanol (7e)
The crude product from N-methylation of THIQ 7e was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7e as a yel-
low oil; yield: 186 mg (85%); [α]D22 –27 (c 1.0, MeOH).
FTIR (KBr): 1962, 1456, 1035, 752 cm–1
.
1H NMR: δ = 0.99 (t, J = 7.5 Hz, 3 H), 1.53–1.65 (m, 3 H), 1.74–1.83 (m,
1 H), 2.22 (s, 3 H), 2.46 (dd, J = 5.1, 16.8 Hz, 1 H), 2.60 (dd, J = 5.1, 16.8
Hz, 1 H), 3.34–3.43 (m, 1 H), 3.54–3.66 (m, 3 H), 7.06–7.26 (m, 4 H).
13C NMR: δ = 14.0, 20.2, 24.5, 34.5, 37.9, 52.3, 61.8, 63.6, 126.1, 126.1,
128.1, 129.0, 133.1, 138.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C14H21NO: 220.1701; found:
13C NMR: δ = 30.6, 36.6, 56.0, 59.9, 65.1, 70.2, 111.5, 117.1, 122.4,
220.1701.
125.6, 127.4, 127.8, 128.0, 128.3, 128.4, 134.5, 137.6, 145.8.
HRMS (ESI+): m/z [M + H]+ calcd for C18H20N2O: 281.1654; found:
281.1659.
[(1R,3S)-1-Isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-
yl]methanol (7f)
The crude product from N-methylation of THIQ 7f was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7f as a yel-
low oil; yield: 177 mg (81%); [α]D22 –14 (c 1.0, MeOH).
N-Methylation of THIQ and C2-BIQ Using MeI; General Procedure
A solution of the respective THIQ or C2-BIQ (1 mmol) in MeI (4 mL)
was stirred for 12 h at r.t. The mixture was then evaporated under re-
duced pressure to give a dark gum. CH2Cl2 (5 mL) and 5 M aq NaOH
solution (5 mL) were added to the gum. The resulting biphasic mix-
ture was stirred for 1 h, and then the layers were separated. The aque-
ous phase extracted with CH2Cl2 (3 × 10 mL) and the combined organ-
ic phases were washed with brine, dried (MgSO4), filtered, and evapo-
rated under reduced pressure. The crude product obtained was
purified by column chromatography. The procedure was used to syn-
thesize the following compounds:
FTIR (KBr): 2967, 1457, 1241, 1033 cm–1
.
1H NMR: δ = 1.03 (d, J = 6.6 Hz, 3 H), 1.11 (d, J = 6.6 Hz, 3 H), 1.92–2.04
(m, 1 H), 2.15 (s, 3 H), 2.52 (d, J = 8.4 Hz, 2 H), 3.13 (d, J = 9.3 Hz, 1 H),
3.48 (quint, J = 7.5 Hz, 1 H), 3.62 (dd, J = 2.1, 9.5 Hz, 2 H), 7.09–7.20
(m, 4 H).
13C NMR: δ = 20.7, 21.3, 24.9, 32.0, 34.6, 52.7, 62.2, 70.7, 125.2, 126.2,
129.0, 129.8, 133.5, 136.5.
HRMS (ESI+): m/z [M + H]+ calcd for C14H21NO: 220.1701; found:
220.1698.
[(1S,3S)-1-{2-(Dimethylamino)phenyl]-2-methyl-1,2,3,4-tetrahy-
droisoquinolin-3-yl}methanol (7c)
[(1R,3S)-1-tert-Butyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-
yl]methanol (7g)
The crude product was purified by column chromatography (hex-
ane/EtOAc, 1:1) to give compound 7c as a white solid; yield: 200 mg
(67%); mp 155–156 °C; [α]D22 –88 (c 1.0, MeOH).
FTIR (KBr): 2939, 1488, 1454, 1102, 947, 744 cm–1
1H NMR: δ = 2.41 (s, 3 H), 2.75 (d, J = 6.9 Hz, 2 H), 2.85 (s, 6 H), 3.48–
3.70 (m, 3 H), 5.59 (s, 1 H), 6.70 (d, J = 7.2 Hz, 1 H), 6.83–6.94 (m, 2 H),
7.06–7.10 (m, 1 H), 7.11–7.23 (m, 4 H).
The crude product from N-methylation of THIQ 7g was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7g as a yel-
low solid; yield: 205 mg (88%); mp 67 °C; [α]D22 –3 (c 1.0, MeOH).
.
FTIR (KBr): 2978, 2887, 1091, 1041, 756 cm–1
.
1H NMR: δ = 1.03 (s, 9 H), 2.18 (s, 3 H), 2.51 (d, J = 7.5 Hz, 2 H), 3.39 (s,
1 H), 3.56–3.68 (m, 3 H), 7.07–7.26 (m, 4 H).
13C NMR: δ = 24.5, 29.8, 35.0, 36.6, 52.6, 62.5, 73.2, 125.3, 126.3,
13C NMR: δ = 25.5, 35.1, 45.9, 53.2, 61.3, 61.4, 120.6, 123.5, 126.3,
128.0, 128.9, 129.6, 131.2, 133.7.
129.1, 129.8, 133.8, 135.6.
HRMS (ESI+): m/z [M + H]+ calcd for C15H23NO: 234.1858; found:
HRMS (ESI+): m/z [M + H]+ calcd for C19H24N2O: 297.1967; found:
297.1973.
234.1858.
Bis[(1S,3S)-3-(hydroxymethyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolin-1-yl]methane (10b)
[(1R,3S)-1-Cyclohexyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-
yl]methanol (7h)
The crude product was purified by column chromatography
(CH2Cl2/MeOH, 95:5) to give 10b as a white foam; yield: 286 mg
(59%); mp 144 °C; [α]D22 –19 (c 1.0, MeOH).
The crude product from N-methylation of THIQ 7h was purified by
column chromatography (hexane/EtOAc, 1:3) to give THIQ 7h as a yel-
low oil; yield: 233 mg (90%); [α]D22 –49.5 (c 1.0, MeOH).
FTIR (KBr): 2936, 2857, 1759, 1453, 1037, 754 cm–1
1H NMR: δ = 1.05–1.18 (m, 6 H), 1.46–1.67 (m, 5 H), 2.05 (s, 3 H), 2.44
(d, J = 8.1 Hz, 2 H), 2.82 (br s, 1 H), 3.13 (d, J = 9 Hz, 1 H), 3.38 (quint,
J = 8.0 Hz, 1 H), 3.51 (d, J = 3.3 Hz, 1 H), 3.53 (d, J = 0.9 Hz, 1 H), 6.97–
7.11 (m, 4 H).
13C NMR: δ = 24.8, 26.44, 26.49, 26.51, 30.8, 31.5, 34.5, 41.4, 52.4,
62.3, 69.7, 125.0, 126.3, 129.1, 130.0, 133.5, 136.2.
HRMS (ESI+): m/z [M + H]+ calcd for C17H25NO: 260.2014; found:
FTIR (KBr): 2940, 1514, 1467, 1350, 1242, 1119, 1029 cm–1
.
.
1H NMR: δ = 2.12 (t, J = 7.5 Hz, 2 H), 2.32 (s, 6 H), 2.40–2.61 (m, 4 H),
3.36–3.42 (m, 2 H), 3.57–3.73 (m, 4 H), 3.89 (s, 6 H), 3.90 (s, 6 H), 3.98
(t, J = 7.8 Hz, 2 H), 6.54 (s, 2 H), 6.58 (s, 2 H).
13C NMR: δ = .23.9, 34.1, 38.8, 50.06, 50.49, 55.9, 61.9, 109.9, 111.7,
124.9, 129.3, 147.63, 147.68.
HRMS (ESI+): m/z [M + H]+ calcd for C27H38N2O6: 487.2808; found:
487.2816.
260.2018.
(1R,3R)-3-(Hydroxymethyl)-1-{3-[(1R,3R)-3-(hydroxymethyl)-2-
methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}-2-methyl-
1,2,3,4-tetrahydroisoquinoline (10c)
[(8S,13bS)-5-Methyl-6,8,9,13b-tetrahydro-5H-isoquinolino[2,1-
c]quinazolin-8-yl]methanol (8)
The crude product was purified by column chromatography
(CH2Cl2/MeOH, 95: 5) to give 10c as a white foam; yield: 270 mg
(63%); [α]D22 –140 (c 1.0, MeOH),
The crude product from N-methylation of THIQ 8 was purified by col-
umn chromatography (hexane/EtOAc, 1: 1) to give THIQ 8 as a white
solid; yield: 270 mg (96%); mp 179 °C; [α]D22 +260 (c 1.0, CH2Cl2).
FTIR (KBr): 1605, 1328, 1219, 1087, 1016, 742 cm–1
1H NMR: δ = 1.65 (br s, 1 H), 2.67–2.84 (m, 2 H), 2.88 (s, 3 H), 3.23–
3.28 (m, 1 H), 3.46 (dd, J = 6.3, 9 Hz, 1 H), 3.68 (dd, J = 6.3, 9 Hz, 1 H),
4.03 (d, J = 10.8 Hz, 1 H), 4.3 (d, J = 10.8 Hz, 1 H), 5.23 (s, 1 H), 6.61 (dt,
J = 0.9, 7.5 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 6.76 (d, J = 7.5 Hz, 1 H),
7.10–7.25 (m, 5 H).
FTIR (KBr): 2943, 1738, 1654, 1454, 1243, 1042, 748 cm–1
.
.
1H NMR: δ = 2.38 (s, 6 H), 2.41–2.73 (m, 4 H), 3.13 (quint, J = 3.8 Hz, 2
H), 3.46–3.62 (m, 4 H), 4.87 (s, 2 H), 6.87 (dd, J = 7.65, 1.5 Hz, 2 H),
7.16 (d, J = 7.2 Hz, 2 H), 7.09–7.25 (m, 8 H).
13C NMR: δ = 25.8, 35.6, 52.9, 61.7, 67.9, 126.0, 126.8, 127.6, 128.2,
129.2, 129.6, 130.1, 133.8, 134.6, 142.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
D. T. Khong, Z. M. A. Judeh
Paper
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C28H32N2O2: 429.2542; found:
429.2549.
Acknowledgment
O-Silylation of THIQ 8; General Procedure
We are grateful to the Nanyang Technological University and Mari-
time Port Authority, Singapore (MPA1034/2011) for financial support.
To a solution of THIQ 8 (280 mg, 1 mmol) in CH2Cl2 (5 mL) was added
1H-imidazole (136 mg, 2 mmol) followed by gradual addition of the
silyl chloride (3 equiv). The mixture was stirred at r.t. for 3 h, and then
the reaction was quenched with distilled H2O (10 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were washed
with brine, dried (MgSO4), filtered, and evaporated under reduced
pressure. The crude residue was purified by column chromatography
(hexane/EtOAc, 5: 1). The procedure was used to synthesize O-silylat-
ed THIQs 14a and 14b.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561634.
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References
(8S,13bS)-5-Methyl-8-[(trimethylsilyloxy)methyl]-6,8,9,13b-tetra-
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.
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122.6, 125.4, 127.2, 127.3, 127.8, 128.4, 128.7, 137.8, 145.9.
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352.1754.
(8S,13bS)-8-[(tert-Butyldimethylsilyloxy)methyl]-5-methyl-
6,8,9,13b-tetrahydro-5H-isoquinolino[2,1-c]quinazoline (14b)
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matography gave 14b as viscous oil; yield: 299 mg (76%); [α]D22 +2 (c
1.0, CH2Cl2).
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FTIR (KBr): 1605, 1505, 1258, 1099, 838, 747 cm–1
.
1H NMR: δ = 0.1 (s, 6 H), 0.86 (s, 9 H), 2.72–2.83 (m, 2 H), 2.88 (s, 3 H),
3.22–3.26 (m, 1 H), 3.43 (t, J = 8.9 Hz, 1 H), 3.56–3.61 (m, 1 H), 4.09 (d,
J = 11.1 Hz, 1 H), 4.46 (d, J = 11.1 Hz, 1 H), 5.33 (s, 1 H), 6.49 (t, J = 7.5
Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 7.5 Hz, 1 H), 7.05 (t, J = 7.8
Hz, 1 H), 7.11–7.23 (m, 4 H).
13C NMR: δ = –5.4, –5.3, 18.4, 26.0, 30.5, 36.3, 56.2, 60.5, 65.8, 70.3,
110.8, 116.6, 122.7, 125.5, 127.1, 127.3, 127.8, 128.3, 128.7, 134.6,
138.1, 146.1.
HRMS (ESI+): m/z [M + H]+ calcd for C24H34N2OSi: 395.2519; found:
395.2514.
Enantioselective Henry Reaction Using THIQ 14a under Optimal
Conditions; General Procedure
A solution of THIQ 14a (7 mg, 0.02 mmol) and Cu(OAc)2·H2O (4 mg,
0.02 mmol) in EtOH was stirred at r.t. for 2 h followed by addition of
the aldehyde (0.2 mmol) and then nitromethane (12, 125 μL, 2
mmol). The resulting mixture was stirred at r.t. for 48 h. The mixture
was then evaporated. The crude mixture was purified by column
chromatography (EtOAc/hexane, 1:5) to give the corresponding β-ni-
tro alcohol products. The configuration and ee were determined by
HPLC and compared with literature data (see Supporting Informa-
tion).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
D. T. Khong, Z. M. A. Judeh
Paper
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I