New reduction reaction of benzylic alcohols with acid and proof of the intermolecular hydride shift mechanism

Article abstract of DOI:10.3987/COM-99-8786

The new reduction reaction of the hydroxy groups of 4-hydroxy-4-phenyl- 1,2,3,4-tetrahydroisoquinolines (1) to the corresponding alkanes (2) with mineral and Lewis acids is reported. A stereoselective intermolecular hydride shift mechanism of the reduction was proved by reaction of the deuterated derivatives (14 and 15) of 1a with 10N HCl-C₂H₅OH and BBr3 in CH₃CN.

Full text of DOI:10.3987/COM-99-8786

HETEROCYCLES, Vol. 53, No. 2, 2000, pp. 359 - 372, Received, 20th October, 1999
NEW REDUCTION REACTION OF BENZYLIC
ALCOHOLS WITH ACID AND PROOF OF THE
INTERMOLECULAR HYDRIDE SHIFT MECHANISM
Masaru Kihara,* Jun-ichi Andoh, and Chiaki Yoshida
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-
machi, Tokushima 770-8505, Japan
Abstract - The new reduction reaction of the hydroxy groups of 4-hydroxy-4-
phenyl-1,2,3,4-tetrahydroisoquinolines (1) to the corresponding alkanes (2) with
mineral and Lewis acids is reported. A stereoselective intermolecular hydride shift
mechanism of the reduction was proved by reaction of the deuterated derivateives
(14 and 15) of 1a with 10N HCl-C H OH and BBr in CH CN.
2 5
3
3
The general method for the preparation of alkanes from benzyl alcohols includes a reduction process and
1
2
catalytic reduction of the hydroxy groups of benzyl alcohols and the double bond of olefins obtained
from benzyl alcohols with acid was used. Recently, the convenient reductions of the hydroxy groups of
2
3
4
benzyl alcohols with NaBH and triethylsilane in TFA were reported. In the course of our study on the
4
synthesis of 1,2-dihydro-3,4-diphenylisoquinolines as anti-breast cancer agents, we found a novel
5
reduction of a tetrahydroisoquinoline derivative (1a) having a benzylic hydroxy group with boiling 10N
HCl-EtOH to an alkane (2a) with a dehydrated compound (3a) and an amide (4a) (Scheme 1). This
reaction and the mechanism are very interesting since the reduction proceeded without using a reducing
6
reagent. In the previous paper, we reported the reduction of 1a to 2a proceed via 3a with a stereo-
selective intermolecular hydride shift mechanism. In this paper, we report the reaction of some derivatives
and the related compounds of 1a with mineral and Lewis acids. In addition, the mechanism is discussed in
detail by the results of the reaction of deuterated compounds of 1a with 10N HCl-EtOH and BBr .
3
Scheme 1
10N HCl-C H OH
2
5
OH
N
H
N
+
+
reflux
N
N
CH
CH
CH
CH
3
3
3
3
1a
2a
3a
4a
O
4
In our previous paper, we reported that the treatment of 3,4-diphenyl-4-hdyroxy-1,2,3,4-tetrahydro-
isoquinoline (5) with boiling HBr-AcOH gave a reduced product (6a) even in low yield (14%) with 3,4-
diphenyl-1,2-dihydroisoquinoline (7a) (35%) as a tamoxifen analogue. In order to examine the appropriate

Scheme 2
OCH
OR
3
OR
HBr-CH COOH(1:1)
H
OH
3
+
or BF •O(C H )
2 5 2
3
N
CH
5
N
N
7a, b
CH
CH
3
3
3
6a, b
a: R=H b:R=CH
3
acid such as 10N HCl-C H OH, 2% CF SO H-C H , 85% H SO and reaction conditions (reaction
2 5 6 6
3
3
2
4
temperature and time) for the new reduction, the prototype compound (1a) was selected as a substrate for
the reaction. The treatment of 1a with 10N HCl-C H OH under reflux for 10 h gave the best result and the
2 5
reduction product (2a), the dehydrated compound (3a), and the oxygenated compound (4a) of 3a were
5
obtained in 48%, 7%, and 17% yields, respectively (Table 1). The treatment of some derivatives (1b-e)
(Scheme 3) of 1a in the similar reaction conditions gave the reduced compounds (2b-e) in 37-48% yields
(Table 1). It is interesting to note that treatment of the 4-cyclohexyl derivative (8) replaced the phenyl
group of 1a under the similar conditions gave a reduced compound (9) (40 %) with an olefin (10) and an
amide (11) (Scheme 4). These facts show that the hydroxy groups of 4-alkylated 4-hydroxy-1,2,3,4-
tetrahydroisoquinolines could be reduced by this method.
Scheme 3
2
2
2
2
R
R
R
R
Acid
H
OH
+
+
N
N
N
N
3
3
3
N
3
R
1
1
1
1
R
R
R
R
R
R
R
O
1b-k
2b-k
3b-k
4b-k
12
1
2
3
1
2
3
R
R
R
R
R
R
g: CH C H
b: CH C H
H
H
H
OCH
H
H
H
H
H
H
H
H
H
H
H
Cl
OCH
CF
H
2
6
5
2
6
5
h: C H
c: CH
2
5
3
3
i: CH(CH )
d: CH
e: CH
3 2
3
3
j: CHO
k: H
3
3
f: CH
Cl
3
Scheme 4
OH
H
N
+
HCl-C H OH
+
2
5
reflux, 10 h
CH
N
N
N
CH
CH
CH
3
3
3
3
8
O
9
11
10

7
During the synthetic study on anti-breast cancer agents, we also observed the reduction reaction of the 4-
hydroxyisoquinoline (5) with boron trifluoride etherate to an isoquinoline (6b) with a dehydrated product
(7b), indicating the possibility of reduction reaction with Lewis acid. Thus, we examined the appropriate
boron trihalide and the reaction conditions for the reduction using 1a as a substrate (Table 2). As a best result,
the reduced compound (2a) was obtained in 57% yield by using BBr under reflux in CH CN with 3a and
3
3
4a (Entry 8), whereas the reaction at room temperature gave a poor yield of 2a (Entry 7). The use of other
Lewis acids such as AlCl , FeCl , TiCl , SnCl , ZnI , and CuCl for the reduction gave no good results.
3
3
4
4
2
2
In the similar conditions to that of 1a as above, a variety of 4-hydroxy-4-phenyl-1,2,3,4-tetrahydroiso-
5
quinolines (1b, d-k) were treated with BBr in CH CN (Table 3). The reaction of N-alkylated derivatives
3
3
(1b,d,f-i) afforded the reduced products (2b,d,f-i) in moderate yields, respectively. The methoxy-
isoquinoline (1e) gave the low yield of 7-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (13),
8
which was accompanied by the cleavage of the methoxy group of 2e. On the other hand, the reaction of N-
formyl compound (1j) did not give a reduced compound (2j) but afforded the dehydrated compound (3j) in
good yield with 4-phenylisoquinoline (12), suggestting the importance of the basicity of the nitrogen atom
for the reduction reaction. The reaction of the secondary amine (1k) gave 4-phenylisoquinoline (12) in 53 %
yield with the reduced compound (2k).
Table 1. Reaction of 4-Hydroxy-4-phenyl-1,2,3,4-tetrahydro-
isoquinolines (1a-e) with 10N HCl-EtOH under Reflux.
a)
Starting
material
1
Product (%)
Reaction
time (h)
2
3
4
a(HCl salt)
b(HCl salt)
c
d
e
10
10
7
10
8
48
48
45
37
46
7
4
---
3
17
7
12
8
---
10
a)Isolated yield.
Table 2. Reaction of 1a with Lewis Acids.
a)
Product(%)
Reaction condition
Entry
2a
Lewis acid
Solvent
Temp. Time (h)
3a
4a
13
15
16
21
29
46
10
57
49
54
1
2
3
4
5
6
7
8
9
BF •Et O
CH Cl
rt
72
7
7
3
7
7
7
7
7
7
----
3
32
----
11
4
4
19
2
6
6
13
13
12
9
13
16
15
12
3
2
2
2
BF •Et O
CH Cl
reflux
reflux
reflux
reflux
reflux
rt
reflux
reflux
reflux
3
2
2
2
BF •Et O
CH CN
3
2
3
BCl
CH Cl
3
2 2
BCl
CH CN
3
3
BBr
BBr
BBr
BBr
BBr
CH Cl
3
3
3
3
3
2 2
CH CN
3
CH CN
3
toluene
10
CH CN-
8
3
xylene(1:1)
a) Isolated yield.

Table 3. Reaction of 4-Hydroxy-4-phenyl-1,2,3,4-tetrahydro-
isoquinolines (1b, d-k) with BBr in CH CN under Reflux.
3
3
Starting
material
1
Product (%)a)
Reaction
time
2
3
4
12
10
7
35
28
25
45
48
54
50
----
20
6
4
---
4
3
6
---
77
---
7
---
---
---
---
---
---
---
15
53
12
---
10
11
6
3
---
---
b)
10
10
10
10
10
7
10
a) Isolated yield. b) Yield of 7-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetra-
hydroisoquinoline (13).
The new reduction reaction of the benzylic hydroxy groups of 4-hydroxy-1,2,3,4-tetrahydroisoquinolines
(1) to the corresponding alkanes (2) was found to proceed by use of both of mineral and Lewis acids
described above. On the basis of these results and the following facts, the reaction of 1 to 2 was suggested
to proceed through the olefins (3) as an intermediates. In general, benzyl alcohols are easily dehaydrated
4
with acid to the corresponding olefins. In fact, TLC behavior of the reaction mixture of 1a with 10N HCl-
C H OH at room temperature for 30 min showed a presence of the olefin (3a) as a sole product. This
2 5
mixture was successively refluxed for 3 h to give 2a in 33% yield, indicating the intermediate from 1a to
2a to be 3a. On the other hand, the amide (4a) was thought to be formed by the oxidation of 2-methyl-4-
phenylisoquinolinium chloride derived from the intermediate (3a) since N-substituted isoquinolinium salt
9
are known to be oxidized to the corresponding amides.
Furthermore, the reaction of 1k with BBr in CH CN (Table 3) also suggests the olefin (3k) to be
3
3
intermediate from 1k to 2k as follows. The secondary amine (1k) gave 4-phenylisoquinoline (12) in 53%
yield without an amide (4k). The compound (12) should be formed by oxidation of the 1,2-
10
dihydroisoquinoline (3k) since N-unsubstituted 1,2,3,4-tetrahydroisoquinolines are known to be
oxidized easily to 3,4-dihydroisoquinolines. The reaction of 1k also afforded the reduced product (2k)
(20%). On the other hand, the reaction of N-formyl compound (1j) with BBr gave a good yield of the
3
dehydrated product (3j), which may be unable to give reduced compound (2j) because of the high stability
of 3j due to its amide structure.
Since the reduction process from the intermediates (3) to 2 described above can be regarded as a formal
hydrogen addition to the double bond at C-3 and C-4, it is important to clarify the hydrogen source for this
reaction. We expected that the hydrogens at C-1 or C-3 of the substrate (1) may be a possible hydrogen
source. In order to confirm this possibility, we undertook the synthesis of 1- and 3-deuterated compounds
(14 and 15) to examine the reaction with 10N HCl-C H OH and BBr in CH CN.
2 5
3
3
Compound (14) was prepared from the deuterated 2-iodobenzyl alcohol (19) as a key intermediate shown
in Scheme 5. PCC oxidation of 17 (48% D) obtained by reduction of 2-iodobenzaldehyde (16) with
NaBD gave a deuterated benzaldehyde (18) (84% D). This high deuterated ratio should be due to the
4

11
isotope effect of the deuterium of 17 for the oxidation with PCC. The successive NaBD reduction, PCC
4
oxidation, and NaBD reduction of 18 resulted in 98% D of 2-iodobenzyl alcohol (19). Mesylation of 19,
4
followed by amination of the product with methylamine gave a benzylamine (20). Intramolecular Barbier
5b
reaction of the phenacylamine (21) obtained from 20 gave the deuterated compound (14). The structure
1
of 14 was determined by its MS spectrum and the similarity of H-NMR spectrum of 14 to that of 1a
except for the absence of the methylene protons at C-1. The 3-deuterated compound (15) (78% D) was
prepared by intramolecular Barbier reaction of phenacylamine (23) (80% D), which was obtained by
5b
12
treatment of phenacylamine (22) with Et N and D O in CH OD.
The deuterated ratio and the
3
2
3
1
structure of 15 were determined by its H-NMR and MS spectra.
Scheme 5
CHO
CHDOH
I
CDO
I
CD OH
2
NaBD
1) NaBD
4
PCC
4
2) PCC
3) NaBD
I
I
17
18
4
16
19
98%D
90%(48%D)
83%(84%D)
CH
3
CD NHCH
2
3
COCH NCD
2
2
n-C H Li
1) MsCl
4 9
OH
N
C H COCH Br
6
5
2
2) CH NH
I
3
2
I
21
20
60%
CH
3
D
D
65%
14 60%(98%D)
CH
3
CH
3
COCH NCH
2
2
(C H ) N, D O
COCD NCH
2 2
n-C H Li
2
5 3
2
4
9
OH
D
in CH OD
3
I
I
D
N
22
23 quant.(80%D)
CH
3
15 56%(78%D)
The reaction of compound (15) thus obtained with boiling 10N HCl-C H OH gave the reduced product
2 5
9
(25) in 40% yield with oxygenated compound (26) having a deuterium (80% D) (Scheme 6). The
+
molecular ion peak [m/z 224.1432(M ); C H DN] of 25 showed that the reduced compound had one
16 16
1
deuterium. The deuterium was found to be located at C-3α by comparison of the H-NMR spectrum with
that of non-deuterated compound (2a) (Table 4). These facts indicate that the reaction did not proceed by
direct reduction of the hydroxy group but proceeded through a dehydrated compound as an intermediate in a
stereoselective manner. On the other hand, the reaction of 1,1-dideuterated compound (14) with boiling
10N HCl-C H OH gave reduced product (24) bearing three deuteriums [FAB-MS m/z 227.1631(M+1);
2 5
1
C H D N] with non-deuterated amide (4a) in 48% and 4% yields, respectively. The H-NMR spectral
16 15 3
data (Table 4) of 24 reveal that the deuteriums are at C-1 and C-3β. The deuterated ratio at C-3β was
found to be 81%, while the presence of deuterium was not observed at C-3α. Furthermore, the
deuteriums (90% D) at C-1 of 24 were retained on the reaction of 14 (98% D). These findings indicate
that the deuterium at C-3β of reduced compound (24) is not generated from C-1 of the same molecule but

Scheme 6
H
OH
H
OH
D HCl-
H
D
H
D
H
HCl-
+
+
N-CH
D
D
N C H OH
N
D
3
C H OH
N-CH
2
5
3
N
N
2
5
3
CH
CH
3
CH
D
CH
D
D
3
3
O
O
14
15
24 48%
4a 4%
25 40%
26 22%
Scheme 7
D
D
OH
D
OH
BBr
D
BBr
3
H
D
H
H
3
+
H
H
+
D CH CN
3
N
N-CH
CD CN
N
N-CH
3
N
3
N
3
CH
CH
CH
CH
3
3
3
3
O
O
15
45%
1
1a
53%
28
27
26 4%
4a 9%
Table 4. H-NMR Spectral Data of 2a, 24, 25, 27, and 28.
C
1
C
3
C
4
H
3.04
H
3.77
Hα
3.61
Hα
2.56
β
β
4.29
2a
(dd,J=8.5,
5.6 Hz)
(ddd,J=11.5
5.6, 1.2 Hz)
--------
(d,J=14.7 Hz) (d,J=14.7 Hz)
(dd,J=11.5,
8.5 Hz)
2.54
-------- --------
24
25
4.27
(d,J=8.5 Hz)
(d,J=8.5 Hz)
3.76
3.62
3.00
(d,J=5.6 Hz)
4.27
(d,J=5.6 Hz)
--------
--------
2.56
(d,J=14.9 Hz) (d,J=14.9 Hz)
27
28
3.75
3.62
3.00(s)
--------
--------
(d,J=14.9 Hz) (d,J=14.9 Hz)
3.76
3.61
3.02
(d,J=14.9 Hz) (d,J=14.9 Hz)
(d,J=12.0 Hz) (d,J=12.0 Hz)
from that of another molecule. Namely, this reduction includes a stereoselective and intermolecular shift of
a deuterium from C-1 of one molecule to C-3 of another molecule.
Next, we carried out the reaction of 3,3-dideuterated compound (15) with boiling BBr in CH CN. The
3
3
1
reduced compound (27) was obtained in 45 % yield with the amide (26) (Scheme 7). The H-NMR
spectrum (Table 4) of 27 showed the presence of deuteriums at C4 (26% D) and C3α (82% D), indicating
the deuterium source at C4 to be from C3. The deuterated ratio (26%) at C4 of 27 suggests that the
hydrogen source at C4 may be one from CH CN as a solvent. In order to confirm this suggestion,
3
compound (1a) was treated with BBr in deuterated acetonitorile (CD CN). The reduced product (28) was
3
3
found to possess a deuterium (76% D) at C4 (Table 4) according to our expectation, whereas the reaction of
1a with BBr in deuterated benzene (C D ) gave no deuterated product. From these findings, the reduction
3
6 6
reaction of 4-hydroxy-tetrahydroisoquinolines (1) with BBr in CH CN should proceed in stereoselective
3
3

manner as well as with 10N HCl-C H OH and the hydrogen sources at C4 are those from C3 of 1 and
2 5
solvent (CH CN).
3
On the basis of these results, in the reaction of 1,1-deuterated compound (14) with 10N HCl-C H OH, the
2 5
-
reduction was concluded to proceed by a novel intermolecular deuteride(D ) shift mechanism as shown in
Scheme 8. The benzylic alcohol (14) is dehydrated to give the olefin (29), to which adds acid(HCl) to form
a quaternary iminium salt (30). The deuteride leaved from C-1 of another molecule of 29 attacks to C-3 of
30 from the opposite side of the 4-phenyl group because of a steric hindrance and thus produces the
reduced compound (24) having cis configuration between H-4 and D-3. On the other hand, the
9
isoquinolinium salt (31) formed by leaving the deuteride from C-1 of 29 is oxidized to the amide (4a).
The reason for this stereoselective reaction is not clear but may be explained in term of intermolecular
13
stacking between 29 and 30 in the deuteride shift process. Knabe
14
15
and Dyke et al. reported the
rearrangement of 1-benzyl-1,2-dihydroisoquinolines with mineral acid into 3-benzyl-3,4-dihydroiso-
15
quinolines. Their proposed bimolecular exchange mechanism for the rearrangement also supports the
intermolecular hydride shift mechanism of the reaction of 14 to 24 found in this study. In the reaction of
3,3-dideuterated compound (15) with 10N HCl-C H OH, the cis configuration between H-3 and H-4 of
2 5
the product (25) and the yield of the amide (26) having a deuterium at C3 support the mechanism similar to
that shown in Scheme 8.
In the case of reaction of 3,3-dideuterated compound (15) with BBr in CH CN, the stereoselective and
3
3
intermolecular hydride shift mechanism as shown in Scheme 9 is also supported by the formation of the
reduced compound (27) having deuteriums at C3α and C4 and the amide (26). The deuterium bromide
(DBr) formed by the reaction of 15 with BBr should be deuterium source at C4 in the dehydrated
3
Scheme 8
+
H
H
+
H
H
+
O
HCl-C H OH
2
5
H
H
H
H
H
+
N
D
N-CH
N_
N-CH
D
3
-
CH3
3
CH
D
3
Cl
D
D
D
D
D
14
29
29
30
[O]
H
H
H
+
D
H
N-CH
N-CH
N
3
3
-
CH
3
Cl
D
D
D
O
24
4a
31

Scheme 9
+ -
H
+
Br
D
BBr
2
D
+
BBr
O
3
Br
D
D
D
D
D
in CH CN
+
3
N
H
N-CH
N_
N-CH
H
3
-
CH3
3
CH
H
3
Br
H
H
H
H
H
15
32
32
33
[O]
D
N
D
D
+
H
D
N-CH
N-CH
3
3
-
CH
3
Br
H
H
O
27
26
34
compound (32), giving 4-deuterated compound (27). In the same way, the reaction of compounds (1) and
the related compound (8) with 10N HCl-EtOH and BBr in CH CN should also proceed by the
3
3
intermolecular hydride shift mechanism depicted in Schemes 8 and 9.
In conclusion, we have found a new reduction reaction of benzylic hydroxy groups of 4-hydroxy-4-phenyl-
1,2,3,4-tetrahydroisoquinolines without using a reducing agent under acidic conditions. The reduction
mechanism presented in this study is a novel example of intermolecular hydride shift under acidic
conditions, although the reaction proceeded by intermolecular hydride shift machanism with strong base is
16
well known as Cannizzaro reaction.
EXPERIMENTAL
High-resolution mass spectra (HRMS) were recorded on JELO SX-102A and JEOL JMS-D 300
1
spectrometers. H-NMR spectra were recorded on a JEOL JNM-FX 200 spectrometer in CDCl with
3
tetramethylsilane as a standard and are given in δ values.
General Procedure for the Reaction of 4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-
isoquinolines (1) with 10N HCl-C H OH This is examplified by the reaction of 1a with 10N
2 5
HCl-C H OH. The hydrochloride (73.5 mg, 0.267 mmol) of 1a was refluxed with 10N HCl-C H OH
2 5 2 5
(3.0 mL) for 10 h. The reaction mixture was evaporated in vacuo. Water (20 mL) was added to the residue.
The mixture was basified with 28% NH OH and extracted with CH Cl (50 mL x 5). The extract was
4
2 2
washed with water, dried over MgSO , and evaporated in vacuo to give an oily product. This was
4
subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of Rf 0.22-0.41 gave 2a
2 3
1
2 2
as a yellow oil (28.0 mg, 48%). H-NMR (CDCl ) δ: 7.20 (1H, dd, J=8.0, 2.2 Hz), 7.03 (1H, dd,
3
J=7.4, 2.4 Hz), 6.85 (1H, d, J=7.1 Hz), 4.29 (1H, dd, J=8.5, 5.6 Hz), 3.77 (1H, d, J=14.7 Hz), 3.61
(1H, d, J=14.7 Hz), 3.04 (1H, ddd, J=11.5, 5.6, 1.2 Hz), 2.56 (1H,dd, J=11.5, 8.5 Hz), 2.43 (3H, s).

+
HRMS (m/z) M : Calcd for C H N: 223.1360. Found: 223.1341. The fraction of Rf 0.04-0.11 gave
16 17
1
4a as a powder (10.3 mg, 17%) (mp 178-181.5°C). H-NMR (CDCl ) δ: 8.53 (1H, dd, J=7.3, 1.7 Hz),
3
+
7.36-7.64 (8H, m), 7.04 (1H, s), 3.65 (3H, s). HRMS (m/z) M : Calcd for C
H
NO: 235.0997.
16 13
Found: 235.0998. Anal. Calcd for C
H
NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.54; H, 5.57;
1
16 13
N, 5.91. The fraction of Rf 0.69-0.78 gave 3a as an oil (4.0 mg, 7%). H-NMR (CDCl ) δ: 7.30-7.38
3
+
(5H m), 7.00-7.10 (4H, m), 6.22 (1H, s), 4.19 (2H, s), 2.82 (3H, s). HRMS (m/z) M : Calcd for
C H N: 221.1206. Found: 221.1200.
16 15
The reaction of other tetrahydroisoquinolines (1b-e) with 10N HCl-C H OH was carried out in the same
2 5
way as 1a (Table 1).
Reaction of 4-Cyclohexyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (8) with
10N HCl-C H OH Compound (8) (61.9 mg, 0.253 mmol) was refluxed with 10N HCl-C H OH
2 5 2 5
(7.0 mL). The reaction mixture was treated in the same way as 1a to give a pale brown oil. This crude
product was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of Rf 0.21-
2 3 2 2
1
0.40 gave 9 as an oil (23.0 mg, 40%). H-NMR (CDCl ) δ: 7.07-7.25 (3H, m), 7.01 (1H, d, J=6.4 Hz),
3
3.57 (1H, d, J=14.8 Hz), 3.44 (1H, d, J=14.8 Hz), 2.80 (1H, m), 2.66 (2H, m), 2.41 (3H, s). HRMS
+
(m/z) M : Calcd for C H N: 229.1831. Found: 229.1834. The fraction of Rf 0.04-0.06 gave 11 as an
16 23
1
oil (3.3 mg, 5 %). H-NMR (CDCl ) δ: 8.50 (1H, d, J=8.3 Hz), 7.55-7.75 (2H, m), 7.38-7.52 (1H, m),
3
+
6.85 (1H, s), 3.61 (3H, s). HRMS (m/z) M : Calcd for C H NO: 241.1467. Found: 241.1473. The
16 19
1
fraction of Rf 0.78-0.86 gave 10 as an oil (2.8 mg, 5%). H-NMR (CDCl ) δ: 7.00-7.20 (4H, m), 5.89
3
(1H, s), 3.96 (2H, s), 2.72 (3H, s).
General Procedure for the Reaction of 4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-
isoquinolines (1) with BBr in CH CN This is examplified by the reaction of 1a with BBr in
3
3
3
CH CN. BBr (1.0 M sol. in CH Cl , 0.025 mL, 1.47 mmol) was added to a solution of 1a (76 mg,
2 2
3
3
0.32 mmol) in CH Cl (2.5 mL) at 0°C under N . The mixture was stirred for 20 min at rt and then
2 2
2
refluxed for 7 h. Water (20 mL) was added and the mixture was basified with 28% NH OH, extarcted with
4
CH Cl (50 mL x 3). The extact was washed with water, dried over MgSO , and evaporated in vacuo to
2 2
4
give an oil. The crude product was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2).
2 3 2 2
The fractions of Rf 0.20-0.37, Rf 0.66-0.76, and Rf 0.04-0.10 gave 2a (oil, 40.7 mg, 57%), 3a (oil, 13.2
mg, 19 %), and 4a (white powder, 11.8 mg, 16%), respectively. The structures of 2a, 3a, and 4a
1
obtained with BBr were confirmed by comparisons of their H-NMR spectra with those of 2a, 3a, and
3
4a obtained with 10N HCl-C H OH.
2 5
The reaction of 1a with other Lewis acids was carried out in the same way as with BBr (Table 2) and the
3
reaction of other tetrahydroisoquinolines (1b, d-i) with BBr was performed in the same way as 1a (Table
3
3).
Reaction of 2-Formyl-4-hydroxy-4-phenyl-1,2,3,4-tetrahydroisoquinolines (1j) with
BBr in CH CN BBr (1.0 M sol. in CH Cl , 0.033 mL, 1.96 mmol) was added to a solution of 1j
2 2
3
3
3
(80 mg, 0.316 mmol) in CH Cl (2.75 mL) at 0°C under N . The mixture was stirred for 20 min at rt and
2 2
2
then refluxed for 7 h. The reaction mixture was treated in the same way as 1a to give an oil. The crude
product was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fractions of Rf 0.22-
2 3 2 2

1
0.38 gave 3j as an oil (58.0 mg, 77%). H-NMR (CDCl ) δ: 8.37 and 8.23 (1H, each s), 7.01-7.52 (9H
3
+
m), 6.62 (1H, s), 4.49 and 4.78 (2H, each s). HRMS (m/z) M : Calcd for C H NO: 235.0997. Found:
16 13
1
235.0999. The fraction of Rf 0.16-0.22 gave 12 as an oil (9.8 mg, 15%). H-NMR (CDCl ) δ: 9.26
3
+
(1H, s), 8.49 (1H, s), 7.89-8.06 (2H, m), 7.68-7.26 (7H m). HRMS (m/z) M : Calcd for C
H
15 11
N:
205.0891. Found: 205.0892.
Reaction of 4-Hydroxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline (1k) with BBr in
3
CH CN BBr (1.0 M sol. in CH Cl , 0.020 mL, 1.18 mmol) was added to a solution of the
3
3
2
2
hydrochloride (77 mg, 0.30 mmol) of 1k in CH Cl (5 mL) at 0°C under N . The mixture was stirred for
2 2
2
2 min at rt and then refluxed for 10 h. The reaction mixture was treated in the same way as 1a to give an oil.
The crude product was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of
2 3 2 2
1
Rf 0.03-0.08 gave 2k as an oil (12.5 mg, 20%). H-NMR (CDCl ) δ: 7.07-7.41 (8H, m), 6.90 (1H, d,
3
+
J=7.8 Hz), 3.92-4.20 (3H, m), 3.40 (1H, m), 3.09 (1H, m). HRMS (m/z) M : Calcd for C
H
N:
15 15
209.1205. Found: 209.1195. The fraction of Rf 0.13-0.33 gave 12 as an oil (32 mg, 53%).The structure
1
of this product was confirmed by comparison of its H-NMR spectrum with that of 12 obtained from 1j.
1
H-NMR and MS Spectral Data of Tetrahydroisoquinolines (2b-i), 1,2-Dihydroisoquino-
1
lines (3b,d, f-h), Amides (4b-i), and Phenolic Tetrahydroisoquinoline (13) 2b: H-NMR
(CDCl ) δ: 7.23 (2H, d, J=6.6 Hz), 7.11 (2H, d, J=6.6 Hz), 6.86 (1H, d, J=7.6 Hz), 4.17 (1H, m), 3.72
3
+
(2H, s), 3.65(2H, s), 3.00 (1H, dd, J=11.5, 5.1 Hz), 2.66 (1H, dd, J=11.5, 6.8 Hz). HRMS (m/z) M :
1
Calcd for C H NCl: 333.1284. Found: 333.1274. 3b: H-NMR (CDCl ) δ: 7.26-7.35 (14H, s), 6.38
22 20
3
1
(1H, s), 4.22 (4H, s). 4b: H-NMR (CDCl ) δ: 8.56 (1H, dd, J=7.6, 2.0 Hz), 7.42 and 7.30 (each 2H,
3
+
d, J=8.3 Hz), 7.04 (1H, s), 5.27 (2H, s). HRMS (m/z) M : Calcd for C H NOCl: 345.0921. Found:
22 16
1
345.0915. 2c: H-NMR (CDCl ) δ: 7.11 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 4.23 (1H, m),
3
3.72-3.78 (3H, m), 3.59 (1H, d, J=14.9 Hz), 3.01 (1H, dd, J=11.3, 5.5 Hz), 2.53 (1H, dd,J=11.3, 8.8
+
1
Hz), 2.42 (3H, s). HRMS (m/z) M : Calcd for C H NO: 253.1467. Found: 253.1464. 4c: H-NMR
17 19
(CDCl ) δ: 8.52 (1H, dd, J=7.3, 1.2 Hz), 7.33 (2H, d, J=8.7 Hz), 7.00 (2H, d, J=8.7 Hz), 3.88 (3H, s),
3
+
1
3.65 (3H, s). HRMS (m/z) M : Calcd for C
H
17 15
NO : 265.1102. Found: 265.1098. 2d: H-NMR
2
(CDCl ) δ: 7.54 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=8.1 Hz), 7.09-7.17 (3H, m), 6.83 (1H, d, J=7.3Hz),
3
+
4.32 (1H, m), 3.69 (2H, s), 2.99 (1H, dd, J=11.5, 5.4 Hz), 2.42 (3H, s). HRMS (m/z) M : Calcd for
1
C
H
NF : 291.1235. Found: 291.1238. 3d: H-NMR (CDCl ) δ: 6.29 (1H, s), 4.25 (2H, s), 2.87
17 16
3
3
1
(3H, s). 4d: H-NMR (CDCl ) δ: 8.55 (1H, dd, J=7.6, 1.5 Hz), 7.74 (2H, d, J=8.1 Hz), 7.56 (2H, d,
3
+
J=8.1 Hz), 7.07 (1H, s), 3.68 (3H, s). HRMS (m/z) M : Calcd for C
H
NOF : 303.0871. Found:
17 12 3
1
303.0888. 2e: H-NMR (CDCl ) δ: 6.70 (1H, dd, J=6.6, 2.6 Hz), 6.61 (1H, d, J=2.6 Hz), 4.20 (1H,
3
dd, J=6.2, 5.7 Hz), 3.76 (3H, s), 3.65 (2H, m), 3.00 (1H, ddd, J=11.4, 5.7, 0.9 Hz), 2.58 (1H, dd,
+
J=11.4, 6.2 Hz), 2.41 (3H, s). HRMS (m/z) M : Calcd for C H NO: 253.1468. Found: 253.1467.
17 19
1
4e: H-NMR (CDCl ) δ: 7.93 (1H, d, J=3.0 Hz), 6.94 (1H, s), 3.94 (3H, s), 3.77 (3H, s). HRMS (m/z)
3
+
1
M : Calcd for C H NO : 265.1103. Found: 265.1099. 2f: H-NMR (CDCl ) δ: 7.24 (2H, d, J=8.5
17 15
2
3
Hz), 7.12 (2H, d, J=8.5 Hz), 6.83 (1H, d, J=7.1 Hz), 4.23 (1H, m), 3.70 (1H, d, J=15.1 Hz), 3.62 (1H,
d, J=15.1 Hz), 2.97 (1H, dd, J=11.5, 5.6 Hz), 2.55 (1H, dd, J=11.5, 5.8 Hz), 2.41 (3H, s). HRMS
+
1
(m/z) M : Calcd for C H NCl: 257.0971. Found: 257.0989. 3f: H-NMR (CDCl ) δ: 6.21 (1H, s),
17 16
3

1
4.21 (2H, s), 2.84 (3H, s). 4f: H-NMR (CDCl ) δ: 8.53 (1H, m), 7.50 (2H, d, J=8.3 Hz), 7.34 (2H, d,
3
+
J=8.3 Hz), 7.03 (1H, s), 3.66 (3H, s). HRMS (m/z) M : Calcd for C
H
16 12
NOCl: 269.0608. Found:
1
269.0608. 2g: H-NMR (CDCl ) δ: 7.04 (1H, dd, J=7.9, 2.9 Hz), 6.88 (1H, d, J=7.6 Hz), 4.25 (1H,
3
dd, J=7.8, 5.4 Hz), 3.74 (2H, s), 3.07 (1H, dd, J=11.5, 5.4 Hz), 2.67 (1H, dd, J=11.5, 7.8 Hz). HRMS
+
1
(m/z) M : Calcd for C H N: 299.1675. Found: 299.1672. 3g: H-NMR (CDCl ) δ: 7.14-7.29 (11H,
22 21
3
+
m), 6.87-7.00 (3H, m), 6.32 (1H, s), 4.12 (4H, s). HRMS (m/z) M : Calcd for C
1
H
22 19
N: 297.1519.
Found: 297.1497. 4g: H-NMR (CDCl ) δ: 8.56 (1H, d, J=7.8 Hz), 7.07 (1H, s), 5.27 (2H, s). HRMS
3
+
1
(m/z) M : Calcd for C H NO: 311.1310. Found: 311.1314. 2h: H-NMR (CDCl ) δ: 7.00-7.34 (8H,
22 17
3
m), 6.84 (1H, d, J=8.1 Hz), 4.27 (1H, dd, J=8.6, 5.8 Hz), 3.88 (1H, d, J=14.8 Hz), 3.61 (1H, d,
J=14.8 Hz), 3.14 (1H, ddd, J=11.5, 5.8, 1.5 Hz), 2.50-2.63 (3H, m), 1.16 (3H, t, J=7.2 Hz). HRMS
+
1
(m/z) M : Calcd for C
H
17 19
N: 237.1517. Found: 237.1513. 3h: H-NMR (CDCl ) δ: 6.32 (1H, s),
3
1
4.26 (2H, s), 3.15 (2H, m), 1.42 (3H, t, J=7.2 Hz). 4h: H-NMR (CDCl ) δ: 8.54 (1H, d, J=7.6 Hz),
3
+
7.40-7.60 (8H, m), 7.05 (1H, s), 4.12 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz). HRMS (m/z) M :
1
Calcd for C H NO: 249.1153. Found: 249.1163. 2i: H-NMR (CDCl ) δ: 7.19-7.34 (5H, m), 7.02-
17 15
3
7.13 (3H, m), 6.84 (1H, d, J=7.3 Hz), 4.23 (1H, m), 3.84 (2H, s), 3.12 (1H, dd, J=11.5, 5.6, Hz),
+
2.90 (1H, m), 2.62 (1H, dd, J=11.5, 9.0 Hz), 1.09 (6H, m). HRMS (m/z) M : Calcd for C
H
N:
18 21
251.1674. Found: 251.1664. 4i: 8.55 (1H, d, J=6.8 Hz), 7.09 (1H, s), 5.47 (1H, m), 1.42 (6H, d, J=6.8
+
1
Hz). HRMS (m/z) M : Calcd for C
H
NO: 263.1310. Found: 262.1316. 13: H-NMR (CDCl ) δ:
18 17 3
7.14-7.29 (5H, m), 6.67 (1H, d, J=8.5 Hz), 6.55 (1H, dd, J=8.5, 2.4 Hz), 6.12 (1H, d, J=2.4 Hz), 4.25
(1H, m), 3.49 (1H, d, J=14.9 Hz), 3.33 (1H, d, J=14.9 Hz), 3.11 (1H, dd, J=11.8, 6.0 Hz), 2.46 (1H,
+
m), 2.42 (3H, s). HRMS (m/z) M : Calcd for C H NO: 239.1311. Found: 239.1321.
16 17
α
-Deutero-2-iodobenzyl Alcohol (17) A solution of NaBD (98% atom D, 0.568 g, 14.0 mmol) in
4
CH OD (10 mL) was added to a solution of 2-iodobenzaldehyde (16) (2.50 g, 10.8 mmol) in CH OD (15
3
3
mL) and the mixture was stirred for 30 min at 0°C under N . The reaction mixture was evaporated in vacuo.
2
Water (50 mL) was added to the residue and the mixture was extracted with CH Cl . The extract was
2 2
washed with water, dried over MgSO , and evaporated to give 17 as a colorless powder (2.289 g, 90%).
4
1
H-NMR (CDCl ) δ: 7.82 (1H, d, J=7.8 Hz), 7.20-7.50 (2H, m), 7.03 (1H, ddd, J=7.8, 7.6, 1.7 Hz),
3
4.63 (0.96H, s), 2.17 (1H, s). This product was used for PPC oxidation without further purification.
α
-Deutero-2-iodobenzaldehyde (18) PCC (3.15 g, 14.6 mmol) was added to a solution of 17
(2.289 g, 9.74 mmol) in CH Cl (30 mL) and the mixture was stirred for 30 min at rt. The reaction mixture
2 2
was subjected to flash chromatography on Florisil (5.0 g) with ether. The eluent was evaporated in vacuo.
The residue was purified by flash chromatography on SiO with hexane-benzene (1:5) to give 18 as an oil
2
1
(1.88 g, 83%). H-NMR (CDCl ) δ: 10.03 (0.16H, s), 7.15-7.95 (4H, m). FAB-HRMS (m/z) M+1:
3
Calcd for C H DIO: 233.9526. Found: 233.9525.
7 5
α,α
-Dideutero-2-iodobenzyl Alcohol (19) Compound (18) (1.88 g, 8.10 mmol) was treated with
NaBD (440 mg, 10.7 mmol) in CH OD (15 mL) in the same way as 17 to give α,α-dideutero-2-
4
3
iodobenzyl alcohol (1.91 g, 99% yield, 91% D). This product (1.89 g, 8.00 mmol) was oxidized with PCC
(3.00 g, 14 mmol) in the same way as 18 to give α-deutero-2-iodobenzaldehyde (1.67 g, 90%). Usual
treatment of this product (1.67 g, 7.16 mmol) with NaBD (390 mg, 9.31 mmol) in CH OD (15 mL) gave
4
3

1
19 as colorless needles (1.60 g, 95%). H-NMR (CDCl ) δ: 7.80 (1H, d, J=8.1 Hz), 7.20-7.50 (2H, m),
3
+
6.98 (1H, ddd, J=8.1, 7.8, 1.7 Hz), 2.49 (1H, br s). HRMS (m/z) M : Calcd for C H D OI: 235.9667.
7 5 2
Found: 235.9672.
α,α
-Dideutero-2-iodo-N-methylbenzylamine (20) CH SO Cl (1.70 ml, 22.0 mmol) and
3
2
triethylamine (3.07 mL, 22.0 mmol) were added to a solution of 19 (2.60 g, 11.0 mmol) in CH Cl (30
2 2
mL) at 0°C under N . The mixture was stirred for 30 min at 0°C and 5% HCl (15 ml) was added. The
2
mixture was extracted with CH Cl (50 ml x 5). The extract was washed with water, dried over MgSO ,
2 2
4
1
and evaporated in vacuo to give the mesylate of 19 as an oil (3.44 g, 99%). H-NMR (CDCl ) δ: 7.89
3
(1H, d, J=7.8 Hz), 7.36-7.50 (2H, m), 7.09 (1H, d, J=7.4 Hz), 3.03 (3H, m). FAB-HRMS (m/z)
M+NaI: Calcd for C H D O INaS: 336.9340. Found: 336.9367.
8 7 2 3
A solution of methylamine in CH OH (40%, 23.68 mL, 240 mmol) was added to a solution of the mesylate
3
(3.40 g, 10.8 mmol) of 19 obtained above in dry ether (22 mL) at 0°C under N . The mixture was stirred
2
for 45 min at 0°C and evaporated in vacuo. 5% HCl (12 mL) and water (20 mL) were added and the residue
was washed with ether (80 mL x 3). The aqueous layer was basified with 28% NH OH and extracted with
4
CH Cl (100 mL x 3). The extract was washed with water, dried over MgSO , and evaporated in vacuo to
2 2
4
give an oil. This crude product was converted to the hydrochloride of 20 as colorless needles (1.85 g,
1
69%). FAB-HRMS (m/z) M-Cl: Calcd for C H D NI: 250.0062. Found: 250.0055. H-NMR (free base,
8 9 2
CDCl ) δ: 7.82 (1H, d J=7.8 Hz), 7.35 (2H, m), 6.95 (1H, m), 2.81 (1H, br s), 2.45 (3H, s).
3
α,α
-Dideutero-N-benzoylmethyl-N-methylbenzylamine (21) A solution of phenacyl bromide
(2.05 g, 10.5 mmol) and propyrene oxide (7.78 mL, 134.0 mmol) in dioxane (10 mL) was added to a
solution of 20 (free base, 2.57 g, 10.3 mmol) in dioxane (20 mL). The mixture was stirred for 12 h at rt
and filtered. The filtrate was evaporated in vacuo. The residue was subjected to flash chromatography on
1
SiO with hexane-benzene-ethyl acetate (25:10:1) to give 21 as an oil (2.47 g, 65%). H-NMR (CDCl )
2
3
δ: 7.96 (2H, dd, J=7.1, 1.5 Hz), 7.84 (1H, d, J=7.8 Hz), 7.26-7.56 (5H, m), 6.96 (1H, ddd, J=7.8, 7.7,
1.7 Hz), 3.90 (2H, s), 2.43 (3H, s). FAB-HRMS (m/z) M+1: Calcd for C
H
D NOI: 368.0481.
16 15 2
Found: 368.0464.
1,1-Dideutero-4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (14)
n-C H Li (1.6 M sol. in hexane, 7.7 mL, 12.3 mmol) was added to a solution of 21 (2.26 g, 6.15 mmol)
4 9
in dry THF (25 mL) at -78°C under N and the mixture was stirred for 30 min at -78°C. Water (20 mL) was
2
added and the mixture was extracted with ether (100 mL x 3). The extract was washed with water, dried
over MgSO , and evaporated in vacuo to give an oil. This was subjected to flash chromatography on SiO
4
2
1
with hexane-ethyl acetate (3:2) to give 14 as colorless prisms (830 mg, 60%). H-NMR (CDCl ) δ: 6.94-
3
7.46 (9H, m), 4.49 (1H, br s), 2.94 (1H, d, J=11.7 Hz), 2.63 (1H, d, J=11.7 Hz), 2.38 (1H, d, J=11.7
Hz). FAB-HRMS (m/z) M+1: Calcd for C H D NO: 242.1514. Found: 242.1528.
16 16 2
α,α
-Dideutero-N-(2-iodobenzyl)-N-methylphenacylamine (23) Triethylamine (230 µL, 1.65
5
mmol) and D O (45 µL, 2.49 mmol) were added to a solution of compound (22) (298 mg, 0.82 mmol) in
2
CH OD (5 mL) at 0°C uner N . The mixture was stirred for 2 h at 50°C and evaporated in vacuo to give 23
3
2
1
as an oil (299 mg, 99%). H-NMR (CDCl ) δ: 7.96 (2H, dd, J=7.9, 1.7 Hz), 7.84 (1H, d, J=8.1 Hz),
3
+
7.26-7.58 (5H, m), 6.96 (1H, ddd, J=8.1, 7.6, 1.7 Hz), 3.75 (2H, s), 2.42 (3H, s). HRMS (m/z) M :

Calcd for C H D NOI: 367.0403. Found: 367.0410. This product was used for the cyclization with n-
16 14 2
C H Li without further purification.
4 9
3,3-Dideutero-4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (15)
Reaction of 23 (295 mg, 0.81 mmol) in dry THF (5 mL) with n-C H Li (1.6 M sol. in hexane, 760 mL,
4 9
1.22 mmol) at -78°C was carried out in the same way as 21 to give crude product. This was subjected to
flash chromatography on SiO with CHCl -acetone (6:1) to give 15 as colorless prisms (109 mg, 56%).
2
3
1
H-NMR (CDCl ) δ: 7.07-7.47 (8H, m), 6.94 (1H, d, J=7.5 Hz), 3.80 (1H, d, J=14.9 Hz), 3.44 (1H, d,
3
+
J= 14.9 Hz), 2.45 (3H, s). HRMS (m/z) M : Calcd for C H D NO: 241.1436. Found: 241.1433.
16 15 2
Reaction of 14 with 10N HCl-C H OH Compound (14) (76.1 mg, 0.318 mmol) was refluxed
2 5
with 10N HCl-C H OH (5.0 mL). The reaction mixture was evaporated in vacuo. Water (20 mL) was
2 5
added to the residue. The mixture was basified with 28% NH OH and extracted with CH Cl (60 mL x 3).
2 2
4
The extract was washed with water, dried over MgSO , and evaporated in vacuo to give an oily product.
4
This was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of Rf 0.23-0.42
2 3 2 2
1
gave 24 as a yellow oil (32.9 mg, 48%). H-NMR (CDCl ) δ: 7.02-7.29 (8H, m), 6.86 (1H, d, J=7.3
3
Hz), 4.27 (1H, d, J=8.5 Hz), 2.54 (1H, d, J=8.5 Hz), 2.43 (3H, s). FAB-HRMS (m/z) M+1: Calcd for
C
H
D N: 227.1628. Found: 227.1631. The fraction of Rf 0.05-0.10 gave 4a as a powder (2.3 mg,
16 15 3
1
4%). The structure of this product was confirmed by comparison of its H-NMR spectrum with that of 4a
obtained from 1a.
Reaction of 15 with 10N HCl-C H OH Compound (15) (76.7 mg, 0.317 mmol) was refluxed
2 5
with 10N HCl-C H (7.0 mL). The reaction mixture was treated in the same way as 14 to give crude
2 5
product. This was subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of Rf
2 3 2 2
1
0.20-0.40 gave 25 as an oil (28.6 mg, 40%). H-NMR (CDCl ) δ: 6.78 (1H, d, J=7.3 Hz), 4.27 (1H, d,
3
J=5.6 Hz), 3.76 (1H, d, J=14.9 Hz), 3.62 (1H, d, J=14.9 Hz), 3.00 (1H, d, J=5.6 Hz), 2.43 (3H, s).
+
HRMS (m/z) M : Calcd for C H DN: 224.1423. Found: 224.1432. The fraction of Rf 0.05-0.10 gave
16 16
1
26 as a powder (16.2 mg, 22%). H-NMR (CDCl ) δ: 8.53 (1H, d, J=7.8 Hz), 7.41-7.62 (8H, m), 3.49
3
+
(3H, s). HRMS (m/z) M : Calcd for C H DNO: 236.1060. Found: 236.1053.
16 12
Reaction of 15 with BBr in CH CN BBr (1.0 M sol. in CH Cl , 250 µL, 1.46 mmol) was
3
3
3
2
2
added to a solution of 15 (76.1 mg, 0.32 mmol) in CH CN (2.5 mL) at 0°C under N . The mixture was
3
2
stirred for 20 min at rt and then refluxed for 17 h. Water (20 mL) was added and the mixture was basified
with 28% NH OH, extracted with CH Cl (50 mL x 3). The extract was washed with water, dried over
4
2 2
MgSO , and evaporated in vacuo to give an oil. This crude product was subjected to preparative TLC on
4
1
Al O with hexane-CH Cl (3 : 2). The fraction of Rf 0.20-0.40 gave 27 as an oil (32 mg, 45%). H-
2 3 2 2
NMR (CDCl ) δ: 6.78 (1H, d, J=7.3 Hz), 4.26 (0.74H, d, J=5.4 Hz), 3.75 (1H, d, J=14.9 Hz), 3.62
3
+
(1H, d, J=14.9 Hz), 3.00 (1H, d, J=5.4 Hz), 2.42 (3H, s). HRMS (m/z) M : Calcd for C H D NO:
16 15 2
241.1436. Found: 241.1430. The fraction of Rf 0.05-0.10 gave 26 as a powder (2.5 mg, 4%). The
1
structure of this product was confirmed by comparison of its H-NMR spectrum with that of 26 obtained
from 15 with 10N HCl-C H OH.
2 5
Reaction of 1a with BBr in CD CN BBr (1.0 M sol. in CH Cl , 249 µL, 1.46 mmol) was
3
3
3
2
2
added to a solution of 1a (76 mg, 0.32 mmol) in CD CN (3 mL) and the mixture was refluxed for 7 h.
3

The reaction mixture was treated in the same way as 15 in CH CN to give crude product. This was
3
subjected to preparative TLC on Al O with hexane-CH Cl (3 : 2). The fraction of Rf 0.21-0.43 gave 28
2 3 2 2
1
as an oil (37.3 mg, 53%). H-NMR (CDCl ) δ: 7.09-7.30 (8H, m), 6.86 (1H, d, J=7.1 Hz), 4.27
3
(0.24H, m), 3.76 (1H, d, J=14.9 Hz), 3.61 (1H, d, J=14.9 Hz), 3.02 (1H, d, J=12 Hz), 2.56 (1H, m),
+
2.43 (3H, s). HRMS (m/z) M : Calcd for C H DN: 224.1423. Found: 224.1415. The fraction of Rf
16 16
0.05-0.10 gave 4a as a powder (6.4 mg, 9%). The structure of this product was confirmed by comparison
1
of its H-NMR spectrum with that of 4a obtained from 1a.
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