Superacid-promoted reactions of N-acyliminium ions: An effective route to substituted 3-oxo-1,2,3,4-tetrahydroisoquinolines and related products

Article abstract of DOI:10.1055/s-2006-942387

Intramolecular cyclizations involving N-acyliminium ions are shown to give products in good yields from reactions with CF₃SO₃H (triflic acid). The resulting 3-oxo-1,2,3,4-tetrahydroisoquinolines have been converted in high yields to 1,2-diaryl-1,2,3,4-tetrahydroisoquinolines, which have been recently shown to be selective estrogen receptor modulators. In a reaction using a chiral N-acyliminium ion, cyclization is found to occur in moderately high diastereoselectivity. Several examples of intermolecular triflic acid-promoted reactions are also reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942387

PAPER
1775
Superacid-Promoted Reactions of N-Acyliminium Ions: An Effective Route to
Substituted 3-Oxo-1,2,3,4-tetrahydroisoquinolines and Related Products
S
uperacid-Promote
i
dReac
l
tions
o
i
f
N
-A
c
a
yliminium
nIons g Zhang, Patrick J. Kindelin, Daniel J. DeSchepper, Chong Zheng, Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA
Fax +1(815)7534802; E-mail: dklumpp@niu.edu
Received 3 January 2006
O
–
CH3
CH3
X
Ph
Abstract: Intramolecular cyclizations involving N-acyliminium
ions are shown to give products in good yields from reactions with
CF3SO3H (triflic acid). The resulting 3-oxo-1,2,3,4-tetrahydroiso-
quinolines have been converted in high yields to 1,2-diaryl-1,2,3,4-
tetrahydroisoquinolines, which have been recently shown to be se-
lective estrogen receptor modulators. In a reaction using a chiral N-
acyliminium ion, cyclization is found to occur in moderately high
diastereoselectivity. Several examples of intermolecular triflic acid-
promoted reactions are also reported.
i
N
+
Ph
N
Ph
Cl
Ph
Ph
+
Cl
O
O
CH3
1
2
Ph
N
Ph
CH3
N
(62%)
O
3
Key words: electrophilic aromatic substitutions, N-acyliminium
ions, tetrahydroisoquinolines, superacid, superelectrophile
Scheme 1 Reagents and conditions: i) AlCl3 (1.0 equiv), 80 °C, 1 h.
in dichloromethane (Table 1). The resulting products
were then treated with excess triflic acid (40 equiv) to give
the 3-oxo-1,2,3,4-tetrahydroisoquinolines 3–13. By com-
parison, the triflic acid promoted reactions gave higher
yields than similar conversions with AlCl3. For example,
products 3 and 4 were obtained in 62% and 65% yields,
respectively, from AlCl3-promoted reactions, while the
same products were obtained in 95% and 97% yields from
triflic acid (Table 1, entries 1 and 2). The AlCl3-promoted
conversions were done at 80 °C for three hours, but the tri-
flic acid promoted reaction was found to give a complete
conversion to product 4 in just five minutes at 25 °C. The
enhanced reactivity of the triflic acid promoted conver-
sions may be the result of several effects. As the a-chloro-
amide dissociates to the N-acyliminium ion salt, the
chloride ion reacts immediately with triflic acid to pro-
duce HCl (then evolved as a gas), and consequently, the
equilibrium is shifted towards the N-acyliminium ion.
In a series of reports, Mollov and coworkers described in-
tra- and intermolecular AlCl3-catalyzed reactions of N-
acyliminium ion salts and aromatic nucleophiles.1,2 For
example, they found that substituted imines can be reacted
with arylacetyl chlorides in the presence of AlCl3 to give
3-oxo-1,2,3,4-tetrahydroisoquinolines 3 in fair yields
(36–76%) by an intramolecular reaction (Scheme 1). The
reaction was found to work best in reactions involving ac-
tivated aryl groups (i.e., nucleophilic aryl groups). A sim-
ilar procedure was also reported by Katritzky and co-
workers.3 The Brønsted superacid CF3SO3H (triflic acid)
has been shown to be an effective catalyst for several
types of reactions involving N-acyliminium ions,4 and it
has been demonstrated in a number of cases to be superior
to AlCl3 in electrophilic reactions.5 With the recent disclo-
sure by Novartis researchers regarding the ERa-selective
estrogen receptor modulator activities of aryl-substituted
tetrahydroquinolines,6 we sought to determine if these
types of compounds could be prepared in good yields us-
ing superacid-catalyzed reactions of the N-acyliminium
ions. In the following paper, we describe these results and
demonstrate that triflic acid can be used to promote the re-
actions of N-acyliminium ion salts with aromatic nucleo-
philes in good yields. Both intra- and intermolecular
reactions are shown to be promoted by triflic acid, and
modest diastereoselectivity is seen in the reaction of a
chiral N-acyliminium ion.
Moreover, the Brønsted superacid may partially protonate
the acyl oxygen, generating an electrophile with higher re-
activity. This type of protosolvation has been described as
superelectrophilic activation by Olah and others.7 The cy-
clization step is found to readily occur with the phenyl
group (entries 1–3, 7–10), the fluorophenyl group (entry
11), and the activated dimethoxyphenyl group (entries 4–
6). Efforts to extend this chemistry to more highly deacti-
vated aryl groups were not successful. For example, all ef-
forts failed to cyclize the N-acyliminium intermediates
derived from (3,4-dichlorophenyl)acetyl chloride. In con-
trast, many dicationic, superelectrophilic species have
been shown to be capable of reacting with o-dichloroben-
zene and even nitrobenzene.8 If superelectrophilic activa-
tion is occurring in the intramolecular reactions of the N-
acyliminium ions, the failure to react with the 3,4-dichlo-
rophenyl group suggests that it is only a weak superelec-
trophilic activation (Scheme 2).
Following the general procedure described by Mollov,1 a
variety of N-acyliminium ion salts (in equilibrium with
the appropriate a-chloroamides) were prepared by the re-
actions of arylacetyl chlorides and aryl-substituted imines
SYNTHESIS 2006, No. 11, pp 1775–1780
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.05.2006
DOI: 10.1055/s-2006-942387; Art ID: M00106SS
© Georg Thieme Verlag Stuttgart · New York

1776
Y. Zhang et al.
PAPER
Table 1 Products and Yields for the Triflic Acid Promoted Cyclizations of N-Acyliminium Saltsa
O
R
O
N
i
X
+
N
R
Cl
R'
R"
X
R'
R"
Entry
1
Product
Yield (%)b
95
Entry
Product
Yield (%)b
7
86
O
O
O
N
N
N
Me
Ph
Ph
9
3
2
3
4
97
69
90
8
92
O
N
Ph
Ph
Ph 4
10
F
F
F
9
91
55
O
O
N
N
CH2Ph
Ph
5
F
11
10
OMe
O
O
N
Ph
F
NH
Ph
F
F
OMe
OMe
Ph
6
F
12
5
6
37c
90
11
95
O
O
N
F
Ph
N
N
Ph
Ph
13
OMe
OMe
Ph
7
O
Me
OMe
Ph
8
a Reagents and conditions: i) CF3SO3H (40 equiv), r.t., 2 h.
b Isolated yields of purified product.
c A significant amount of product decomposes during purification.
In order to extend the scope of this synthetic chemistry, the imine was not being effectively acylated by these
efforts were made to prepare spirocyclic products like 14 types of acid chlorides. Cyclization towards a benzoyl
by the reactions of imines with 1-phenyl-1-cyclopentane- group could not be achieved with compound 15, however
carbonyl chloride followed by cyclizations with triflic ac- the cyclization towards the naphthoyl group does give the
id. Although product 14 could be isolated in low yield (< 1H-benz[de]isoquinolin-1-one 16 as a major product in
10%), the spirocyclic conversions were generally not suc- 65% yield (Scheme 3). A number of published reports de-
cessful. Analysis of the failed conversions suggested that scribe stereoselective reactions of N-acyliminium ion
salts,9 and attempts were made to prepare optically active
tetrahydroisoquinolines by the intramolecular reactions of
N-acyliminium ions. While compounds 17 and 18 failed
to cyclize in triflic acid, the optically active N-acylimini-
um ion salt 19, prepared from Moser’s acid chloride, gave
the cyclization product 20 in reasonably high diastereose-
lectivity (100% dr after recrystallization) albeit in low
yield (Scheme 4). The absolute configuration of the prod-
Ph
Ph
CH2
CH3
O
N
N
δ
HOTf
δ O
Scheme 2
Synthesis 2006, No. 11, 1775–1780 © Thieme Stuttgart · New York

PAPER
Superacid-Promoted Reactions of N-Acyliminium Ions
1777
O
uct was obtained by single crystal X-ray diffraction. With
respect to structure-activity relationships of the ERa-se-
lective estrogen receptor modulators, the recent Novartis
report showed that the optimum configuration of aryl-sub-
stituted tetrahydroisoquinolines is the R configuration at
C-1. The present result demonstrates the possibility of us-
ing diastereoselective cyclization to achieve this desired
configuration at the C-1 position.
δ
δ
O
i
Me
Ph
HOTf
Ph
N
Ph
Ph
N
Ph
N
R
Me
TfO
Ph
21 (58%)
22
O
O
O
Ph
Me
Ph
Me
Me
Me
O
Ph
N
Me
N
Me
N
Me
+
N
MeO
MeO
N
Ph
Ph
Ph
Ph
O
Ph
–
X
Me
23 (76%)
24 (53%)
25 (50%)
15
14
Scheme 5 Reagents and conditions: i) CH3COCl, C6H6, r.t., 2 h;
CF3SO3H (20 equiv), r.t., 2 h.
Ph
N
O
Ph
O
i
+
N
Ph
–
intramolecular chemistry, these results suggest that if su-
perelectrophilic activation (22) is involved in the reac-
tions of these N-acyliminium ion electrophiles, it is only a
modest activating effect.
Ph
X
16 (65%)
Scheme 3 Reagents and conditions: i) CF3SO3H (40 equiv), r.t., 2 h.
In order to prepare the aryl-substituted tetrahydroisoquin-
olines, a series of the 3-oxo-1,2,3,4-tetrahydroisoquino-
lines (4, 7, 10, 12, 13) was subjected to lithium aluminum
hydride reduction in refluxing diethyl ether (Table 2).10
The aryl-substituted tetrahydroisoquinolines 26–30 were
obtained in good yields in all cases.
Ph
Ph
N
Ph
N
Ph
Ph
NH3
2 X
O
O
X
Cl
17
18
Table 2 Products and Yields from the Reactions of 3-Oxo-1,2,3,4-
tetrahydroisoquinolines with LiAlH4
CF3
MeO
Ph
N
CF3
OMe
O
i
Ph
Entry
1
Starting material Product
Yield (%)a
77
N
Ph
Ph
O
X
27% yield
90% dr
10
Ph
F
19
20
Scheme 4 Reagents and conditions: i) CF3SO3H (40 equiv), r.t., 2 h.
N
Ph
F
Besides the intramolecular reactions of the N-acylimini-
um ion salts, it is found that triflic acid is an effective acid
catalyst for intermolecular reactions. For example, the N-
acetyliminium ion reacts with benzene in triflic acid
(TfOH) to give the aryl-substituted amide product 21 in
58% isolated yield (Scheme 5). In contrast, the AlCl3-pro-
moted reaction gives product 21 in just 37% yield. The in-
creased yield for the superacid-catalyzed conversion is
consistent with the involvement of a protosolvated, super-
electrophilic species like 22. This trend is also observed in
the triflic acid-promoted reaction leading to product 23 in
76% yield. The same reaction in AlCl3 gives product 23 in
just 65% yield. Products from p-xylene 24 and o-
dimethoxybenzene 25 were also obtained from triflic acid
promoted reactions; however, the yields are lower. This
may be due to the protonation of the aromatic nucleo-
philes, p-xylene and o-dimethoxybenzene, by the supera-
cidic media. Efforts were unsuccessful in extending the
chemistry to deactivated arenes. Even with heating and in-
creasing quantities of superacid, aromatic compounds
such as 1,4-fluorobenzene and o-dichlorobenzene did not
react with the N-acyliminium ions. As in the case of the
26
2
3
12
94
93
F
F
F
F
Ph
N
27
7
OMe
Ph
N
Ph
MeO
28
4
5
13
4
87
77
F
Ph
N
Ph
29
Ph
N
Ph
30
a Isolated yields of purified products.
Synthesis 2006, No. 11, 1775–1780 © Thieme Stuttgart · New York

1778
Y. Zhang et al.
PAPER
J = 20.9 Hz, 1 H), 5.68 (s, 1 H), 6.59 (d, J = 8.7 Hz, 1 H), 6.63 (d,
J = 8.7 Hz, 1 H), 7.14–7.25 (m, 5 H).
In summary, these results show that 1,2-diaryl-1,2,3,4-tet-
rahydroisoquinolines having a variety of substituents can
be prepared in good yields by exploiting the superacid- 13C NMR (125 MHz, CDCl3): d = 31.0, 33.3, 55.5, 55.6, 62.4, 108.8,
109.2, 121.2, 125.0, 126.9, 127.6, 128.5, 140.6, 148.7, 149.9, 169.0.
catalyzed cyclizations of N-acyliminium ion salts fol-
lowed by lithium aluminum hydride reduction. The super-
acid catalyst gives the key cyclization products in higher
yields than AlCl3, and moreover, the CF3SO3H can be
quantitatively recycled.11 It is also shown that the cycliza-
tion step can be accomplished with modest diastereoselec-
tivity by using an optically active precursor. The results
from the superacid-catalyzed reactions suggests the in-
volvement of superelectrophilic N-acyliminium ion salts;
however, compared to other superelectrophiles the magni-
tude of electrophilic activation is relatively small.
HRMS: m/z calcd for C18H19NO3: 297.1365; found: 297.1359.
2-Naphthalen-1-yl-1-phenyl-1,4-dihydro-2H-isoquinolin-3-one
(9)
White solid; mp 138–140 °C.
1H NMR (500 MHz, CDCl3): d = 4.08 (d, J = 19.8 Hz, 1 H), 4.30 (d,
J = 19.8 Hz, 1 H), 5.86 (s, 1 H), 7.09–7.74 (m, 14 H), 7.90 (d, J =
8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 38.0, 69.1, 122.2, 125.5, 126.3,
126.4, 126.9, 127.1, 127.2, 127.3, 127.9, 128.1, 128.6, 128.9, 129.5,
135.1, 135.5, 137.5, 141.1, 169.6.
HRMS: m/z calcd for C25H19NO: 349.1467; found: 349.1471.
Trifluoromethanesulfonic acid (triflic acid) was distilled under an
Ar atmosphere before use. All compounds and solvents were com-
1,2-Bis(4-fluorophenyl)-1,4-dihydro-2H-isoquinolin-3-one (11)
White solid; mp 65–71 °C.
1
mercially available and were used as received. H and 13C NMR
spectra were recorded on a Bruker 500 MHz Avance DRX-500
spectrophotometer and mass spectra were recorded on an Agilent
6890 gas chromatograph with an Agilent 5973 mass-selective de-
tector. Melting points were measured with a Mel-Temp device and
are uncorrected. High-resolution mass spectra were obtained from
the analytical services department at University of Illinois.
1H NMR (500 MHz, CDCl3): d = 3.83 (d, J = 19.6 Hz, 1 H), 3.97 (d,
J = 19.6 Hz, 1 H), 5.95 (s, 1 H), 6.94–7.02 (m, 4 H), 7.15–7.29 (m,
8 H).
13C NMR (125 MHz, CDCl3): d = 37.8, 68.6, 115.9 (d, J = 20.9 Hz),
116.0 (d, J = 19.9 Hz), 126.3, 127.2, 127.9, 128.1, 128.6 (d, J = 7.9
Hz), 128.9 (d, J = 8.3 Hz), 131.3, 135.3, 136.5, 137.8, 161.2 (d, J =
247 Hz), 162.3 (d, J = 247 Hz), 169.9.
5,8-Dimethoxy-1,1-diphenyl-1,4-dihydro-2H-isoquinolin-3-one
(6); Typical Procedure
HRMS: m/z calcd for C21H15F2NO: 335.1122; found: 335.1120.
Benzophenone imine (0.1 g, 0.55 mmol) was dissolved in CH2Cl2
(5 mL) and (2,5-dimethoxyphenyl)acetyl chloride (0.118 g, 0.55
mmol) was added to the solution. After stirring for 2 h, triflic acid
(2 mL, 0.023 mmol) was added and stirred for 2 h at r.t. (Note: HCl
gas is produced, potentially creating pressure if done on a larger
scale). The product mixture was then poured over ice, and the aque-
ous solution was extracted with CHCl3 (3 × 20 mL). The organic
phase was washed with water and then with brine, after which it was
dried with anhyd MgSO4. The product was then purified by silica
gel column chromatography (hexanes–EtOAc). After removal of
the chromatography solvent, product 6 was isolated (0.176 g, 0.49
mmol, 90%) as a light yellow solid; mp 180–183 °C.
1-Pentafluorophenyl-2-phenyl-1,4-dihydro-2H-isoquinolin-3-
one (12)
White solid; mp 177–181 °C.
1H NMR (500 MHz, CDCl3): d = 3.95 (d, J = 20.9 Hz, 1 H), 4.16 (d,
J = 20.9 Hz, 1 H), 6.56 (s, 1 H), 7.11–7.19 (m, 3 H), 7.26–7.42 (m,
6 H).
13C NMR (125 MHz, CDCl3): d = 36.1, 58.7, 115.3 (t, J = 13.7, 14.5
Hz), 126.0, 127.2, 127.3, 128.0, 128.1, 128.6, 129.7, 130.2, 131.5,
137.5 (dt, J = 13.0, 254 Hz), 140.4, 141.0 (m), 144.7 (d, J = 249 Hz),
168.0.
1H NMR (500 MHz, CDCl3): d = 3.16 (s, 3 H), 3.46 (s, 2 H), 3.81
(s, 3 H), 6.70 (s, 1 H), 6.78 (d, J = 8.9 Hz, 1 H), 6.85 (d, J = 8.9 Hz,
1 H), 7.25–7.31 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 30.3, 55.8, 55.9, 68.3, 110.3,
112.1, 122.6, 127.3, 127.8, 127.9, 129.9, 144.6, 150.0, 150.5, 170.3.
HRMS: m/z calcd for C21H12F5NO: 389.0839; found: 389.0831.
7-Fluoro-1,2-diphenyl-1,4-dihydro-2H-isoquinolin-3-one (13)
White solid; mp 135–138 °C.
1H NMR (500 MHz, CDCl3): d = 3.83 (d, J = 19.3 Hz, 1 H), 3.93 (d,
J = 19.3 Hz, 1 H), 5.95 (s, 1 H), 7.01–7.09 (m, 2 H), 7.19–7.37 (m,
11 H).
HRMS (EI): m/z calcd for C23H21NO3: 359.1521; found: 359.1519.
13C NMR (125 MHz, CDCl3): d = 37.6, 68.8, 113.2 (d, J = 22.5 Hz),
115.1 (d, J = 21.4 Hz), 126.6, 126.7, 127.1, 127.3, 128.1, 129.0,
129.2, 129.5 (d, J = 7.8 Hz), 137.7 (d, J = 6.5 Hz), 139.9, 141.9,
161.6 (d, J = 246 Hz), 169.0.
5,8-Dimethoxy-1,2-diphenyl-1,4-dihydro-2H-isoquinolin-3-one
(7)
Yellow solid; mp 204–210 °C.
1H NMR (500 MHz, CDCl3): d = 3.64 (d, J = 20.9 Hz, 1 H), 3.82 (s,
3 H), 3.84 (s, 3 H), 4.16 (d, J = 20.2 Hz, 1 H), 6.29 (s, 1 H), 6.79 (d,
J = 8.9 Hz, 1 H), 6.81 (d, J = 8.9 Hz, 1 H), 7.21–7.38 (m, 10 H).
HRMS: m/z calcd for C21H16FNO: 317.1216; found: 317.1218.
13C NMR (125 MHz, CDCl3): d = 32.4, 55.8, 55.9, 63.3, 109.0,
109.7, 122.0, 126.3, 126.7, 126.8, 127.5, 128.5, 129.0, 140.7, 142.2,
148.6, 150.2, 169.5.
1,2-Diphenyl-4,4-tetramethylene-1,4-dihydro-2H-isoquinolin-
3-one (14)
Oil.
1H NMR (500 MHz, CDCl3): d = 1.99–2.28 (m, 6 H), 2.63–2.69 (m,
1 H), 2.91–2.95 (m, 1 H), 6.05 (s, 1 H), 7.07 (d, J = 7.6 Hz, 1 H),
7.11 (d, J = 8.1 Hz, 2 H), 7.14–7.30 (m, 7 H), 7.34 (t, J = 7.7, 7.8
Hz, 2 H), 7.38 (t, J = 7.6, 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H).
HRMS: m/z calcd for C23H21NO3: 359.1521; found: 359.1527.
5,8-Dimethoxy-2-methyl-1-phenyl-1,4-dihydro-2H-isoquinolin-
3-one (8)
13C NMR (125 MHz, CDCl3): d = 28.2, 28.5, 42.1, 45.7, 51.9, 68.4,
126.2, 126.5, 126.8, 127.0, 127.8, 128.0, 128.1, 128.6, 129.0, 133.1,
142.1, 142.2, 175.7.
Yellow solid; mp 158–162 °C.
1H NMR (500 MHz, CDCl3): d = 2.95 (s, 3 H), 3.49 (d, J = 20.9 Hz,
1 H), 3.66 (d, J = 1.4 Hz, 3 H), 3.67 (d, J = 1.4 Hz, 3 H), 3.88 (d,
Synthesis 2006, No. 11, 1775–1780 © Thieme Stuttgart · New York

PAPER
Superacid-Promoted Reactions of N-Acyliminium Ions
1779
HRMS (EI): m/z [M]+ calcd for C25H23NO: 353.1779; found:
1-(4-Fluorophenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
353.1777.
(26)
Oil.
2,3-Diphenyl-2,3-dihydrobenzo[de]isoquinolin-1-one (16)
White solid; mp 187–192 °C.
1H NMR (500 MHz, CDCl3): d = 2.92–3.07 (m, 2 H), 3.54–3.61 (m,
1 H), 3.74–3.79 (m, 1 H), 5.89 (s, 1 H), 6.83–7.03 (m, 5 H), 7.23–
7.36 (m, 8 H).
13C NMR (125 MHz, CDCl3): d = 28.1, 43.8, 62.4, 114.3, 115.1 (d,
J = 21.3 Hz), 117.9, 126.3, 127.2, 127.8, 128.3, 129.0 (d, J = 7.7
Hz), 129.3, 135.8, 137.7, 138.9, 149.6, 161.9 (d, J = 245 Hz).
1H NMR (500 MHz, CDCl3): d = 6.16 (s, 1 H), 7.11–7.15 (m, 1 H),
7.24–7.37 (m, 8 H), 7.61–7.80 (m, 4 H), 7.94 (d, J = 8.2 Hz, 1 H),
7.99 (d, J = 8.3 Hz, 1 H), 9.40 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 65.3, 120.0, 122.5, 124.1, 124.7,
124.8, 126.9, 127.2, 128.29, 128.3, 128.5, 128.9, 129.1, 129.4,
133.3, 133.5, 137.2, 137.8, 146.3, 168.9.
HRMS: m/z calcd for C21H18FN: 303.1423; found: 303.1416.
HRMS: m/z calcd for C24H17NO: 335.1310; found: 335.1306.
1-Pentafluorophenyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(27)
Oil.
(1R,4S)-4-Methoxy-1,2-diphenyl-4-trifluoromethyl-1,4-di-
hydro-2H-isoquinolin-3-one (20)
1H NMR (500 MHz, CDCl3): d = 3.10–3.16 (m, 2 H), 3.68 (m, 2 H),
White solid; mp 168–174 °C.
6.32 (m, 1 H), 6.87–7.03 (m, 4 H), 7.16–7.30 (m, 5 H).
1H NMR (500 MHz, CDCl3): d = 3.55 (s, 3 H), 6.08 (s, 1 H), 6.80
(d, J = 7.9 Hz, 1 H), 6.98–7.00 (m, 4 H), 7.15–7.24 (m, 6 H), 7.35
(t, J = 7.6, 7.9 Hz, 1 H), 7.49 (t, J = 7.6, 7.9 Hz, 1 H), 7.80 (d, J =
7.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 53.3, 67.2, 79.3 (q, J = 29 Hz),
123.4 (q, J = 287 Hz), 126.8, 127.5, 128.0, 128.2, 128.3, 128.5,
128.6, 128.8, 129.5, 129.6, 137.7, 140.2, 140.3, 162.3.
13C NMR (125 MHz, CDCl3): d = 29.2, 44.9, 54.1, 117.5 (m), 117.6,
120.5, 126.4, 126.8, 127.2, 128.9, 129.3, 134.4, 135.1, 137.5 (m),
140.3 (m), 145.1 (m), 149.4.
HRMS: m/z calcd for C21H14F5N: 375.1046; found: 375.1050.
5,8-Dimethoxy-1,2-diphenyl-1,2,3,4-tetrahydroisoquinoline
(28)
HRMS: m/z calcd for C23H18F3NO2: 397.1290; found: 397.1298.
Oil.
1H NMR (500 MHz, CDCl3): d = 2.66–2.72 (m, 1 H), 3.12–3.18 (m,
1 H), 3.58–3.65 (m, 2 H), 3.83 (s, 3 H), 3.85 (s, 3 H), 6.38 (s, 1 H),
6.80–6.85 (m, 3 H), 7.02 (m, 2 H), 7.26–7.36 (m, 7 H).
13C NMR (125 MHz, CDCl3): d = 20.9, 41.9, 55.7, 55.8, 56.1, 107.9,
108.7, 114.3, 117.5, 125.9, 126.7, 127.6, 127.9, 128.0, 129.3, 142.9,
149.8, 150.0, 150.9.
N-[(2,5-Dimethylphenyl)phenylmethyl]-N-methylacetamide
(24); Typical Procedure
To a solution of benzylidene methylamine (0.113 g, 1.0 mmol) in
CH2Cl2 (5 mL) and p-xylene (1 mL), acetyl chloride (0.078 g, 1.0
mmol) was added and the solution was stirred for 2 h at 25 °C. Tri-
flic acid (2 mL, 0.023 mmol) was then added and the resulting so-
lution was stirred for 2 h at r.t. The product mixture was then poured
over ice, and the aqueous solution was then extracted with CHCl3 (3
× 20 mL). The organic phase was washed with water and then with
brine, after which it was dried with anhyd MgSO4. The product was
then purified by silica gel column chromatography (hexanes–
EtOAc). After removal of the chromatography solvent, product 24
was isloated (0.174 g, 0.53 mmol, 53%) as an oil which was found
to be a mixture of two conformational isomers.
HRMS: m/z calcd for C23H23NO2: 345.1729; found: 345.1737.
7-Fluoro-1,2-diphenyl-1,2,3,4-tetrahydroisoquinoline (29)
Oil.
1H NMR (500 MHz, CDCl3): d = 2.88–3.06 (m, 2 H), 3.55–3.61 (m,
1 H), 3.73–3.77 (m, 1 H), 5.87 (s, 1 H), 6.83–7.37 (m, 13 H).
13C NMR (125 MHz, CDCl3): d = 27.3, 43.8, 62.8, 114.0, 114.4,
114.6, 118.0, 127.1, 127.5, 128.4, 129.6 (d, J = 7.8 Hz), 131.4,
139.5, 142.5, 149.5, 161.4 (d, J = 245 Hz).
1H NMR (500 MHz, CDCl3): d = 2.11–2.28 (m, 9 H), 2.73–2.78 (m,
3 H), 6.20 (s, 1 H), 6.72–6.76 (m, 1 H), 6.97–7.40 (m, 7 H).
HRMS: m/z calcd for C21H18FN: 303.1423; found: 303.1424.
13C NMR (125 MHz, CDCl3): d = 18.9, 19.1, 21.2, 21.8, 22.2, 31.1,
33.5, 58.3, 63.3, 127.1, 127.7, 128.0, 128.1, 128.3, 128.5, 128.7,
128.8, 129.0, 129.4, 130.6, 130.7, 133.5, 134.5, 135.0, 135.7, 137.5,
137.9, 139.2, 139.6, 170.6, 171.6.
Acknowledgment
The financial support of the National Institutes of Health-NIGMS
(GM071368-01) is greatly appreciated. The Department of Chem-
istry at NIU is thanked for the undergraduate research excellence
award (P.J.K.). We also thank the National Science Foundation for
support towards the purchase of the X-ray crystallography equip-
ment.
HRMS (EI): m/z [M]+ calcd for C18H21NO: 267.1623; found:
267.1622.
N-[(3,4-Dimethoxyphenyl)phenylmethyl]-N-methylacetamide
(25)
Oil (two conformational isomers).
1H NMR (500 MHz, CDCl3): d = 2.16 (br s, 3 H), 2.69–2.77 (br s,
3 H), 3.75-3.82 (br s, 6 H), 6.14 (s, 1 H), 6.60–6.84 (m, 3 H), 7.05–
7.39 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 21.9, 22.3, 30.5, 32.7, 55.8, 55.9,
59.8, 65.3, 110.9, 111.1, 111.7, 112.4, 120.8, 121.1, 127.2, 127.8,
128.2, 128.4, 128.6, 131.3, 131.7, 139.1, 139.2, 148.4, 148.7, 148.9,
149.1, 171.0, 171.5.
References
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1993, 30, 381.
HRMS (EI): m/z [M]+ calcd for C18H21NO3: 299.1521; found:
299.1517.
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