FeCl3·6H2O-promoted skeleton-rearrangement of 1-substituted-3-benzazepines: Substrate extension and product utilization

Article abstract of DOI:10.1016/j.tet.2010.12.038

FeCl₃·6H₂O-promoted skeleton-rearrangement of 1-substituted-3-benzazepines was further exploited. Both 1-aryl- and 1-alkyl- or 1-alkenyl-benzazepines underwent this reaction smoothly. The rearrangement products were used to prepare a

Full text of DOI:10.1016/j.tet.2010.12.038

Tetrahedron 67 (2011) 842e848
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FeCl3$6H2O-promoted skeleton-rearrangement of 1-substituted-3-benzazepines:
substrate extension and product utilization
,
,
,
a,
*
Jing Zhang a y, Kui Wu b y, Meining Wang a, Jianqin Jiang b , Ao Zhang
*
a Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
b Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2010
Received in revised form 4 December 2010
Accepted 14 December 2010
Available online 17 December 2010
FeCl3$6H2O-promoted skeleton-rearrangement of 1-substituted-3-benzazepines was further exploited.
Both 1-aryl- and 1-alkyl- or 1-alkenyl-benzazepines underwent this reaction smoothly. The rearrange-
ment products were used to prepare a series of novel derivatives containing both tetrahydroisoquinoline
(THIQ) and tetrahydropyrimidin-4(1H)-one scaffolds through a Mannich-type process.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1-Substituted benzazepine
Tetrahydroisoquinoline
Ring arrangement
Iron (III) chloride
Tetrahydropyrimidin-4(1H)-one
1. Introduction
Iron reagents (FeCl3, FeCl2, FeSO4, Fe(ClO4)3, Fe(acac)3) have
attracted increasing interests in organic reactions and synthesis
recently due to their low cost and readily availability.1 We recently
reported a novel skeleton-rearrangement of 1-aryl-3-benzazepines
with the assistance of 2.0 equiv of FeCl3$6H2O in PhNO2 (Scheme 1).2
The N-substituents in the benzazepine substrates played a dramatic
influence on the structural characters of the products. In the case of
N-alkylbenzazepines, 1-aryl-tetrahydroisoquinolines (THIQs) were
obtained, whereas N-acyl-benzazepines yielded a series of C1 qua-
ternary 1-aryl-1-formyl-tetrahydroisoquinolines. However, in spite
of the simplicity of the protocol and the unique feature of the
products, this method suffered from several weakness, especially in
view of the substrate limitation (mostly 1-aryl-benzazepines), high
loading of FeCl3$6H2O (2 equiv) and the use of high boiling solvent
nitrobenzene, which make the purification of the products trou-
blesome. Accordingly, in the current report we further elaborated
this FeCl3$6H2O-initiated rearrangement, with focus on broadening
the scope of the substrates to 1-alkyl- or 1-alkenyl-benzazepines, as
well as exploring the utility of the rearranged products.
H3CO
H3CO
H3CO
H3CO
3N
R
FeCl3·6H2O (2 equiv.)
PhNO2, 120oC
1
N
R
X
2
1
when R = alkyl, X = H
when R = acyl, X = CHO
Scheme 1. Our previously reported FeCl3$6H2O-promoted rearrangement.
2. Results and discussion
First, 1-alkyl-N-cyclopropanecarbonylbenzazepines 3aec were
prepared according to the literature procedures3 and subjected to
the FeCl3$6H2O-initiated rearrangement. As expected, the corre-
sponding 1-alkyl-1-formyl-tetrahydroisoquinolines (THIQs) 4aec
were obtained in 27e50% yields (Scheme 2). This result confirmed
that not only 1-aryl, but also 1-alkylbenzazepines can undergo the
FeCl3$6H2O-initiated skeleton rearrangement.
Similarly, we found that 1-alkenylbenzazepines 3def also went
through the skeleton rearrangement with activation of FeCl3$6H2O
in PhNO2 leading to the corresponding aldehydes 4a, 4b, 4f in 70%
yields (Scheme 3). It is of note that the olefinic moiety in benza-
zepines 3def was saturated in the rearranged process, and led to
* Corresponding authors. Tel./fax: þ86 21 50806035; e-mail addresses: cpuqj@
yahoo.cn (J. Jiang), aozhang@mail.shcnc.ac.cn (A. Zhang).
y
These two authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.038

J. Zhang et al. / Tetrahedron 67 (2011) 842e848
843
O
H3CO
H3CO
FeCl3(2 equiv.),
H2O18(12 equiv.)
PhNO2, 120oC
H3CO
H3CO
O
O
H3CO
H3CO
FeCl3·6H2O (2 equiv.)
PhNO2, 120oC
3N
N
1a
1
N
O
CHO
4a-c
R'
R
(60% O18
)
C=O
H
Ph
2a
3a-c
(R =
)
(a, R = CH3, 50%; b, R = CH2CH3, 45%; c, R = i-Pr, 27%)
Scheme 2. Rearrangement of 1-alkylbenzazepines.
FeCl3(2 equiv.),
H2O18(12 equiv.)
PhNO2, 120oC
O
N
H3CO
H3CO
the same products as obtained in Scheme 2. Compared with the
1-alkyl substrates 3aec, unsaturated compounds 3def reacted
much quicker and provided the products with higher yields.
3d
(66% O18
)
C=O
H
4d
Scheme 4. Rearrangement of 1a and 3d under FeCl3 and H2O18
.
O
H3CO
H3CO
FeCl3·6H2O
(2 equiv.)
PhNO2, 120oC
H3CO
H3CO
3N
O
reaction, and adding 100 equiv of water and conducting the reaction
in oxygen atmosphere significantly enhanced this reaction pro-
viding product 2a in 50% yield (entry 5). Encouraged by this result,
reactions with reduced amount of FeCl3$6H2O were investigated. It
was found that both 0.5 and 0.2 equiv of FeCl3$6H2O can start this
reaction (entries 7 and 8) yielding product 2a in 49% and 36% yield,
respectively. Addition of water can enhance the yield (entry 7 vs 6).
These results confirmed that the rearrangement reaction does not
necessarily require excessive catalyst, 0.5 or 0.2 equiv were enough
to ignite the transformation although the reaction yield was lower.
The relative lower yield may be due to the production of chloride 7
that was detected during the catalytic reaction. Compound 7 was
structurally confirmed by X-ray analysis (Fig. 1) and can be alter-
natively prepared by treating benzazepine 1a with DDQ in 57% yield.
Interestingly, conversion of compound 7 to final product 2awas very
sluggish in this reaction but was remarkedly promoted to comple-
tion in 2 h (44% yield) with addition of excessive FeCl3$6H2O.
R'
1
N
R'
R
CHO
R
4a (69%)
4b (69%)
4f (70%)
3d, R = H, R' = cyclopropyl;
3e, R = CH3, R' = cyclopropyl;
3f, R = CH3, R' = Ph
Scheme 3. Rearrangement of 1-alkenylbenzazepines.
In the mean time, we examined the rearrangement of benza-
zepines 5aed4 bearing an amide function on the azepine ring in-
stead of as a side chain (Table 1). Interestingly, these substrates did
undergo ring-contraction, but the expected aldehydes were not
obtained. In the case of 5a, 1-phenyl-1,2-dihydroisoquinolin-3(4H)-
one 6a was produced in 50% yield indicating the endocyclic amide
function was not involved in the rearrangement, likely due to the
steric effect. This was further evidenced in the case of N-allyl
substituted 5b, which also participated in the skeleton rearrange-
ment similarly yielding 1-phenyl-1,2-dihydroisoquinolin-3(4H)-
one 6b in 61% yield. In order to generate aldehyde products, imides
5c and 5d were prepared and subjected to the same rearrangement
reaction. However, the imido moiety mostly failed to survive from
the acidic reaction condition, and both reactions yielded N-deacy-
lated dihydroisoquinolin-3(4H)-ones 6a as well as recovered N-
deacylated substrate 5a.
Table 2
Optimization of reaction conditions of benzazepine 1a
O
DDQ
O
H3CO
H3CO
H3CO
H3CO
FeCl3.6H2O
(44%)
(57%)
1a
N
N
O
Ph CHO
(R =
)
Cl
Ph
2a
7
Entrya FeCl3$6H2O (equiv) Solvent H2O (equiv) Additive (equiv) Yield (2a)
Table 1
1
2
3
4
5
6
7
8
2.0
1.0
1.0
1.0
1.0
0.5
0.5
0.2
0.2
0.2
0.2
PhNO2 None
PhNO2 None
MeNO2 None
None
None
None
66%
<5%
0
Rearrangement of benzazepines 5aed
MeNO2
MeNO2 100
MeNO2
0
DDQ (2)
DDQ (2)
DDQ (2)
DDQ (2)
DDQ (2)
DDQ (2)
DDQ (2)
DDQ (2)
38%
50%
22%
49%
36%
38%
29%
0
0
MeNO2 100
MeNO2 100
MeNO2 80
MeNO2 50
MeNO2 10
9
10
11
Substrate
R
Product (yield)
5a
5b
5c
5d
H
Allyl
Acetyl
Benzoyl
6a (50%)
6b (61%)
6a (15%)
6a (20%)
a
All the yields were isolated yields after chromatography.
5a (40%)
5a (40%)
With the alternative reaction condition described above,
the synthetic application of the rearrangement products was ex-
plored. Initially, we proposed to prepare compound 10 by treating
benzylamine with rearranged product aldehyde 8 through a re-
ductive amination followed by intramolecular Michael addition
(Scheme 5). To our surprise, we were not able to obtain compound
10, instead 1,3-dibenzyl-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-tetrahydropyrimidin-4(1H)-one (11) was
obtained as the major product. It was further found that compound
11 can be obtained simply by treating aldehyde 8 with benzylamine
in the absence of NaBH3CN in 58% yield.
The structure of compound 11 was determined by all spectro-
scopic analysis, especially 2D NMR (HMBC, HMQC, 1He1H COSY),
and finally secured by X-ray analysis (Fig. 2). Several unique char-
acters can be observed from the X-ray structure. Similar to typical
1-arylbenzazepines5 where the 1-phenyl ring is located in the
Next, we decide to explore the possibility of reducing the loading
of FeCl3$6H2O. Since we have proposed in our previous work2 that
the formyl oxygen in aldehyde products 2 or 4aec was originated
from FeCl3$6H2O complex, therefore additional water would be
needed if we reduce the amount of FeCl3$6H2O. In this regard, we
firstly conducted the reaction of benzazepines 1a and 3d using in
situ prepared iron reagent from anhydrous FeCl3 and 6 equiv of O18
-
enriched water (H2O18). As expected, the expected aldehydes 2a and
4d were obtained containing 60% and 66% of O18, respectively
(Scheme 4), confirming the role of water in FeCl3$6H2O.
In our previous report,2 1 equiv of FeCl3$6H2O was found unable
to ignite the reaction (entries 2 and 3, Table 2) with either high
boiling solvent PhNO2 or lower boiling solvent MeNO2. It was found
that adding 2 equiv of DDQ as oxidative additive could start this

844
J. Zhang et al. / Tetrahedron 67 (2011) 842e848
equational orientation, the newly formed tetrahydropyrimidin-4
(1H)-one ring is also positioned in the equational orientation,
which pushes both benzyl moieties to the east side of the molecule.
Therefore, the three phenyl ring (1-phenyl, 20- and 60-N-benzyl)
formed a sandwich-like conformation, thus the chemical shifts of
benzyl methylene protons shifting to high field (2.5e3.5 ppm,
Fig. 2), whereas the
a
-H in the 20-N-benzylic methylene unit
showed a unique chemical shift of 5.5 ppm due to the spatial
neighboring interaction with the carbonyl group (Fig. 2).
To rationale the formation of compound 11, a Mannich-type
mechanism was proposed. As illustrated in Fig. 3, a Michael addi-
tion would occur upon treating aldehyde 8 with benzylamine
forming intermediate I. Compound I may subsequently undergo
a Mannich-type condensation with one additional molecule of
benzylamine to form [1,4]diazepino[2,1-a]isoquinolin-5(12bH)-one
network II in which intramolecular nucleophilic attack of the sec-
ondary amino function to the amide carbonyl moiety would then
occur to release the high ring-tension, and yield pyrimidione 11.
O
O
MeO
MeO
N
BnNH2
N
MeO
MeO
NHBn
CHO
Ph
I
CHO
Ph
Mannich
reaction
BnNH2
8
Fig. 1. Structure of compound 7.
MeO
MeO
O
O
N
N
MeO
11
NH
N
Bn
Ph
BnHN
Ph
H3CO
H3CO
Ph
N
Bn
H3CO
O
MeO
Bn
2
II
Ph
NH2
NH
1
N
ClCH2CH2Cl
reflux
58%
H3CO
1' Ph
Fig. 3. Proposed mechanism for production of compound 11.
6'
Ph
CHO
N
N
8
Ph
2'
Since both THIQ6 and pyrimidin-4(1H)-one7 are important phar-
macophoresinmanybiologicallyactivecompounds,thismethodmay
provide a practical technique to prepare compounds like 11 bearing
both pharmacophores. Therefore, generality of this method was
evaluated by employing a variety of primary amines to react with
aldehyde 8.
3' O
Ph
NH2
THF
11
NaBH3CN
H3CO
H3CO
H3CO
O
O
N
N
H3CO
From the results summarized in Table 3, all the primary amines
participated in this reaction smoothly and yielded products 11e28
Ph
Ph
Ph
HN
Ph
N
9
10
Table 3
Reaction of aldehyde 8 with primary amines
Scheme 5. Reaction of aldehyde 8 with benzylamine.
H3CO
H3CO
H3CO
O
NH
ClCH2CH2Cl
90 oC, 4h
+
R
NH2
H3CO
N
Ph
N
CHO
Ph
R
N
R
8
H3CO
H3CO
O
11-28
NH
Ph H
Entry
R
Product
Yielda
H
N
H
N
1
2
3
4
Ph
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
58%
58%
43%
47%
51%
41%
30%
30%
52%
55%
50%
56%
55%
48%
52%
41%
49%
50%
Ph
Ph
O
2-ClePh
4-ClePh
3-ClePh
4-FePh
3-FePh
4-MeOePh
2-MeOePh
4-Tolyl
3-Tolyl
2-Tolyl
3-CF3ePh
1-Naphthyl
2-Furyl
H
H
H
H
(Key HMBC correlations)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
PhCH2
3-MeOePhCH2
PhCH2CH2
CH3CH2
a
Isolated yield after chromatography.
Fig. 2. Structure determination of compound 11.

J. Zhang et al. / Tetrahedron 67 (2011) 842e848
845
in 30e58% isolated yields. The relatively lower yields were partially
due to the difficulty in isolating the products from excessive polar
substrates amines. The electronic nature, size, and location of the
substituent in arylmethyl amine substrates did not play significant
effects on the yields. Much bulky amines, 1-naphthylmethyl amine
(entry 13) and heteroarylmethyl amine, 2-furylmethylamine (entry
14) also participated in this transformation very well and delivered
corresponding products 23 and 24 in 55% and 48% yield, re-
spectively. Extension of the alkyl chain to arylethylamines (entries
15 and 16) and arylpropylamine (entry 17) all went through the
reaction smoothly and provided corresponding products 25e27 in
41e52% yield. Simple alkylamine, e.g., propylamine (entry 18) also
underwent the reaction and yielded product 28 in 50% yield. All the
results above confirmed the generality of this protocol in prepa-
ration of THIQ substituted tetrahydropyrimidin-4(1H)-ones.
(m,1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.51 (m, 1H), 3.04 (m, 2H), 2.78 (m,
1H), 1.87 (m, 1H), 1.03 (m, 5H), 0.84 (m, 5H); 13C NMR (100 MHz,
CDCl3):
d 189.2, 172.7, 148.4, 148.2, 128.6, 122.9, 111.2, 110.5, 73.0,
55.9, 55.8, 42.4, 34.9, 30.2, 19.7, 19.0, 12.0, 7.6, 7.4; EI-MS m/z: 331
(Mþ); HR-MS calcd for C19H25NO4 (Mþ) 331.1784, found: 331.1792.
4.1.4. 2-Benzoyl-1-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line-1-carbaldehyde (4f). Yellow liquid. 1H NMR (300 MHz, CDCl3):
d
9.20 (s, 1H), 7.46 (m, 5H), 6.72 (s, 1H), 6.62 (s, 1H), 4.07 (m, 1H),
3.86 (s, 3H), 3.84 (s, 3H), 3.39 (m, 1H), 2.94 (m, 1H), 2.67 (m, 2H),
2.48 (m, 1H), 0.95 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
192.6, 171.0, 148.6, 148.5, 135.4, 130.2, 128.7, 126.9, 121.6, 111.2,
110.0, 71.0, 56.0, 55.8, 44.9, 30.1, 26.0, 8.8; EI-MS m/z: 353 (Mþ); HR-
MS calcd for C21H23NO4 (Mþ) 353.1627, found: 353.1623.
4.1.5. 6,7-Dimethoxy-1-phenyl-1,2-dihydroisoquinolin-3(4H)-one
3. Conclusions
(6a). Yellow solid. 1H NMR (300 MHz, CDCl3):
d 7.30 (m, 4H), 7.07
(m, 2H), 6.52 (br s, 1H), 6.48 (s, 1H), 4.44 (dd, J¼6.3, 2.1 Hz, 1H), 3.91
In summary, FeCl3$6H2O-promoted skeleton-rearrangement of
1-substituted-3-benzazepines was further exploited. Both 1-aryl-
and 1-alkyl- or 1-alkenylbenzazepines can undergo this reaction
providing corresponding aldehydes in reasonable yields. Further,
the rearrangement products were used to prepare tetrahy-
droisoquinoline (THIQ)-substituted tetrahydropyrimidin-4(1H)-
ones through a Mannich-type process and a total 18 analogues
were prepared in moderate yields.
(m, 4H), 3.74 (s, 3H), 3.60 (m, 1H).
4.1.6. 2-Allyl-6,7-dimethoxy-1-phenyl-1,2-dihydroisoquinolin-3(4H)-
one (6b). Yellow solid. 1H NMR (300 MHz, CDCl3):
d 7.31 (m, 5H),
7.06 (m, 2H), 6.45 (s, 1H), 5.60 (m, 1H), 5.15 (d, J¼10.2 Hz, 1H), 5.04
(d, J¼17.1 Hz,1H), 4.44 (d, J¼7.2 Hz,1H), 4.31 (dd, J¼4.8,15.0 Hz,1H),
3.91 (m, 4H), 3.72 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 193.3,
166.7, 153.4, 148.4, 141.2, 137.7, 131.8, 129.0, 128.7, 127.7, 127.6, 118.9,
113.2, 111.4, 56.0, 51.0, 49.9, 48.8; EI-MS m/z: 323 (Mþ); HR-MS
calcd for C20H21NO3 (Mþ) 323.1521, found: 323.1517.
4. Experimental section
4.1. General procedure for the rearrangement of compounds
3aef, 5aed
4.2. General procedure for the rearrangement of compounds
1a and 3d under FeCl3 and H2O18
A mixture of benzazepine substrate (1.0 equiv) and FeCl3$6H2O
(2.0 equiv) in nitrobenzene (10 mL) was stirred at 120 ꢀC under O2
atmosphere for about 2e10 h until the starting material was con-
sumed. Then the dark mixture was cooled to rt, diluted with CH2Cl2
and washed with 10% HCl aqueous solution. The aqueous solution
was further extracted with CH2Cl2 twice. The combined organic
layer was washed with brine, and dried over anhydrous Na2SO4.
The crude product was concentrated and chromatographed on
silica gel column (CH2Cl2, then CH2Cl2/EtOAc) to give the corre-
sponding rearrangement product.
To a mixture of compound 1a or 3d (1.0 equiv), H2O18 (97% O18
-
enriched, 12.0 equiv) and FeCl3 (2.0 equiv) under O2 atomosphere
was added nitrobenzene (distilled over anhydrous CaCl2) via sy-
ringe, then the mixture was allowed to stir under 100 ꢀC for 1 or 4 h.
After standard work-up, a mixture of labled and unlabled product
was obtained. The relative amounts of oxygen-18 labled and
unlabled products were determined by mass spectrometry (see
copies of the MS spectra in Supplementary data).
4.3. General procedure for the catalytic version of the
rearrangement
4.1.1. 2-(Cyclopropanecarbonyl)-6,7-dimethoxy-1-methyl-1,2,3,4-
tetrahydroisoquinoline-1-carbaldehyde (4a). Colorless liquid. 1H
NMR (300 MHz, CDCl3): d 8.91 (s, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 4.43
A mixture of compound 1a, FeCl3$6H2O, H2O (as indicated in
Table 2) and DDQ in nitromethane was refluxed under O2 atmo-
sphere for 4 h. Then it was cooled down and filtered. The filtrate
was concentrated, and dissolved in CH2Cl2, which was further
washed with saturated Na2CO3 aqueous solution, brine, and dried
over anhydrous Na2SO4. After evaporation of the solvent, the resi-
due was chromatographied (pet. ether/EtOAc¼1:1) to give the de-
sired compound 2a, with compound 7 as side product.
(dd, J¼2.4, 10.8 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.38 (dt, J¼3.3,
12.6 Hz,1H), 3.09 (m,1H), 2.80 (m,1H),1.85 (m,1H),1.68 (s, 3H),1.11
(m, 1H), 0.92 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 192.5, 172.5,
148.4,148.0,127.5,123.9,111.1,110.3, 67.2, 55.9, 55.8, 40.4, 29.9, 19.6,
11.6, 7.9, 7.6; EI-MS m/z: 303 (Mþ); HR-MS calcd for C17H21NO4 (Mþ)
303.1471, found: 303.1475.
4.1.2. 2-(Cyclopropanecarbonyl)-1-ethyl-6,7-dimethoxy-1,2,3,4-tet-
4.3.1. (4-Chloro-7,8-dimethoxy-5-phenyl-1H-benzo[d]azepin-3(2H)-
rahydroisoquinoline-1-carbaldehyde (4b). Yellow liquid. 1H NMR
yl)(cyclopropyl)methanone (7). White solid. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
8.88 (s, 1H), 6.62 (s, 1H), 6.61 (s, 1H), 4.48 (m,
CDCl3):
d
7.33 (m, 5H), 6.76 (s, 1H), 6.29 (s, 1H), 4.76 (dt, J¼5.4,
1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (dt, J¼3.3, 12.6 Hz, 1H), 2.98 (m,
13.8 Hz, 1H), 3.90 (s, 3H), 3.74 (dd, J¼8.1, 13.8 Hz, 1H), 3.63 (s, 3H),
3.16 (dt, J¼6.9, 14.1 Hz, 1H), 2.69 (dd, J¼5.4, 13.8 Hz, 1H), 2.06 (m,
1H), 2.78 (dt, J¼2.7, 15.6 Hz, 1H), 2.37 (m, 2H), 1.87 (m, 1H), 1.00 (m,
2H), 0.80 (m, 5H); 13C NMR (100 MHz, CDCl3):
d
192.4, 172.5, 148.3,
1H), 0.87 (m, 4H); 13C NMR (100 MHz, CDCl3):
d 173.6, 149.0, 147.7,
148.2, 128.7, 121.9, 111.0, 110.0, 70.7, 55.8, 55.7, 42.1, 30.0, 26.1, 11.8,
8.7, 7.6, 7.5; EI-MS m/z: 317 (Mþ); HR-MS calcd for C18H23NO4 (Mþ)
317.1627, found: 317.1633.
140.6, 138.1, 131.8, 131.5, 130.0, 128.5, 128.1, 125.4, 112.5, 111.6, 56.1,
55.9, 53.5, 31.3, 13.4, 9.1, 8.2; EI-MS m/z: 383 (Mþ); HR-MS calcd for
C22H22ClNO3 (Mþ) 383.1288, found: 383.1285.
4.1.3. 2-(Cyclopropanecarbonyl)-1-isopropyl-6,7-dimethoxy-1,2,3,4-
4.3.2. 2-(Cyclopropanecarbonyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-
tetrahydroisoquinoline-1-carbaldehyde (4c). Colorless liquid. 1H
tetrahydroisoquinoline-1-carbaldehyde (2a). Yellow liquid. 1H NMR
NMR (300 MHz, CDCl3):
d
8.88 (s, 1H), 6.62 (s, 1H), 6.61 (s, 1H), 4.51
(300 MHz, CDCl3) d 9.22 (s, 1H), 7.38 (m, 2H), 7.29 (m, 3H), 6.73 (s,

846
J. Zhang et al. / Tetrahedron 67 (2011) 842e848
1H), 6.41 (s, 1H), 4.29 (m, 1H), 3.91 (s, 3H), 3.66 (s, 3H), 3.41 (dt,
J¼3.0, 12.9 Hz, 1H), 3.17 (dt, J¼5.1, 15.9 Hz, 1H), 2.88 (dt, J¼15.6,
2.7 Hz, 1H), 1.77 (m, 1H), 1.14 (m, 1H), 0.86 (m, 3H); 13C NMR
26.4; EI-MS m/z 615 (Mþ); HR-MS calcd for C35H35Cl2N3O3 (Mþ)
615.2055, found: 615.2029.
(100 MHz, CDCl3)
d
189.1, 172.1, 148.8, 147.6, 139.6, 130.2, 129.0,
4.5.4. 1,3-Bis(3-chlorobenzyl)-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-
127.8, 127.7, 121.9, 112.3, 111.0, 72.4, 55.9, 55.8, 40.1, 29.5, 11.8, 7.8,
7.6; EI-MS m/z: 365 (Mþ); HR-MS calcd for C22H23NO4 (Mþ)
365.1627, found: 365.1626.
tetrahydroisoquinolin-1-yl)tetrahydropyrimidin-4(1H)-one (14). 1H
NMR (300 MHz, CDCl3):
d 7.25 (m, 9H), 6.85 (m, 5H), 6.63 (s, 1H),
5.48 (d, J¼14.1 Hz, 1H), 4.50 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.46
(d, J¼14.4 Hz, 1H), 3.30 (d, J¼14.4 Hz, 1H), 3.00 (m, 1H), 2.81 (m,
2H), 2.52 (m, 5H), 1.87 (d, J¼18.6 Hz, 1H); 13C NMR (100 MHz,
4.4. 2-Acryloyl-6,7-dimethoxy-1-phenyl-1,2,3,4-
tetrahydroisoquinoline-1-carbaldehyde (8)
CDCl3):
d 169.3, 147.7, 146.1, 145.1, 139.2, 139.0, 134.1, 134.1, 129.0,
128.9, 128.2, 127.9, 127.6, 127.3, 127.0, 126.9, 112.7, 111.9, 81.7,
64.4, 57.0, 55.7, 55.6, 45.4, 41.5, 37.9, 30.4, 26.4; EI-MS m/z 615
(Mþ); HR-MS calcd for C35H35Cl2N3O3 (Mþ) 615.2055, found:
615.2053.
This compound was synthesized from 1-(7,8-dimethoxy-1-
phenyl-4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)prop-2-en-1-one
by following our previously reported literature procedure2 in 65%
yield or the catalytic reaction condition (DDQ and FeCl3$6H2O in
nitromethane) as described above in 56% yield. Yellow liquid, 1H
4.5.5. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
NMR (300 MHz, CDCl3):
d
9.31 (s, 1H), 7.44 (m, 2H), 7.31 (m, 3H),
1-yl)-1,3-bis(4-fluorobenzyl) tetrahydropyrimidin-4(1H)-one (15). 1H
6.72 (s, 1H), 6.58 (dd, J¼10.8, 16.8 Hz, 1H), 6.41 (s, 1H), 6.37 (dd,
J¼2.1, 16.8 Hz, 1H), 5.78 (dd, J¼1.8, 10.8 Hz, 1H), 4.06 (m, 1H), 3.91 (s,
3H), 3.66 (s, 3H), 3.38 (dt, J¼3.3, 12.6 Hz, 1H), 3.13 (m, 1H), 2.86 (m,
NMR (300 MHz, CDCl3): d 7.29 (m, 5H), 6.93 (m, 6H), 6.79 (m, 3H),
6.64 (s, 1H), 5.45 (d, J¼14.1 Hz, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.85 (s,
3H), 3.43 (d, J¼12.9 Hz, 1H), 3.27 (d, J¼12.6 Hz, 1H), 2.96 (m, 1H),
2.77 (m, 2H), 2.51 (m, 5H), 1.80 (m, 1H); 13C NMR (100 MHz, CDCl3):
1H); 13C NMR (100 MHz, CDCl3):
d 189.1, 165.4, 148.9, 147.8, 139.5,
130.3, 129.6, 128.8, 128.0, 127.9, 127.2, 121.8, 112.4, 111.0, 55.9, 55.8,
40.5, 29.5; EI-MS m/z: 351 (Mþ); HR-MS calcd for C21H21NO4 (Mþ)
351.1471, found: 351.1474.
d 169.3, 163.5, 163.2, 161.2, 160.8, 147.6, 146.5, 145.7, 133.2, 132.7,
130.8,130.7,130.6,130.5,129.8,128.9,128.1,127.8,127.3,115.3,115.2,
115.1, 115.0, 112.5, 112.0, 81.4, 64.2, 56.5, 55.8, 55.6, 45.1, 41.2, 37.8,
30.5, 26.4; ESI-MS m/z 584 (MþH); HR-MS calcd for
C35H35F2NaN3O3 (MþNa) 606.2544, found: 606.2538.
4.5. General procedure for reaction of compound 8 with
primary amines
4.5.6. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
A mixture of 8 (1.0 equiv) and an appropriately substituted
primary amine (3.0 equiv) in ClCH2CH2Cl was refluxed at 90 ꢀC for
4 h, then it was cooled down and concentrated. The obtained res-
idue was chromatographed on silica gel column to give the corre-
sponding products 11e28.
1-yl)-1,3-bis(3-fluorobenzyl) tetrahydropyrimidin-4(1H)-one (16). 1H
NMR (300 MHz, CDCl3):
d 7.29 (m, 7H), 6.92 (m, 2H), 6.71 (m, 6H),
5.48 (d, J¼15.0 Hz, 1H), 4.52 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43 (d,
J¼12.9 Hz, 1H), 3.26 (d, J¼12.6 Hz, 2.98, 1H), 2.97 (m, 1H), 2.78 (m,
2H), 2.51 (m, 5H), 1.84 (d, J¼18.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
d 169.3, 163.8, 161.4, 147.8, 146.3, 145.7, 139.7, 129.9, 129.8,
4.5.1. 1,3-Dibenzyl-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahy-
129.7, 129.6, 128.9, 128.2, 128.0, 127.4, 124.6, 124.4, 116.0, 115.8,
115.6, 114.7, 114.5, 114.3, 112.7, 112.0, 81.9, 64.4, 57.0, 55.7, 55.6, 45.5,
41.3, 37.8, 30.4, 26.4; EI-MS m/z 583 (Mþ); HR-MS calcd for
C35H35F2N3O3 (Mþ) 583.2646, found: 583.2652.
droisoquinolin-1-yl)tetrahydropyrimidin-4(1H)-one (11). 1H NMR
(300 MHz, CDCl3):
d 7.29 (m, 10H), 7.00 (m, 2H), 6.85 (m, 3H), 6.63
(s, 1H), 5.54 (d, J¼14.1 Hz, 1H), 4.59 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H),
3.46 (d, J¼12.9 Hz,1H), 3.31 (d, J¼12.9 Hz,1H), 2.96 (m,1H), 2.74 (m,
2H), 2.61 (m, 7H), 1.80 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
169.5,
4.5.7. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
147.6, 146.6, 145.8, 137.3, 129.8, 129.1, 129.0, 128.3, 128.2, 128.0,
127.5, 127.4, 127.2, 112.6, 112.2, 82.1, 64.4, 57.5, 55.8, 55.6, 46.0, 40.8,
37.9, 30.5, 26.4; EI-MS m/z: 547 (Mþ); HR-MS calcd for C35H37N3O3
(Mþ) 547.2835, found: 547.2838.
1,3-bis(4-methoxybenzyl) tetrahydropyrimidin-4(1H)-one (17). 1H
NMR (300 MHz, CDCl3):
d
7.28 (m, 5H), 6.92 (d, J¼9.0 Hz, 2H), 6.77
(m, 7H), 6.62 (s, 1H), 6.45 (d, J¼15.0 Hz, 1H), 4.60 (s, 1H), 3.87 (s, 3H),
3.84 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.37 (d, J¼14.1, 1H), 3.24 (d,
J¼12.9 Hz, 1H), 2.95 (m, 1H), 2.65 (m, 2H), 2.50 (m, 5H), 1.75 (d,
4.5.2. 1,3-Bis(2-chlorobenzyl)-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-
J¼18.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 169.4, 158.9, 158.7,
tetrahydroisoquinolin-1-yl)tetrahydropyrimidin-4(1H)-one (12). 1H
147.5, 146.5, 145.6, 130.2, 129.7, 129.4, 129.3, 128.9, 128.0, 127.2, 113.6,
113.4, 112.5, 112.2, 81.5, 64.2, 56.7, 55.7, 55.5, 55.1, 45.3, 40.6, 37.8,
30.4, 26.3; EI-MS m/z 607 (Mþ); HR-MS calcd for C37H41N3O5 (Mþ)
607.3046, found: 607.3047.
NMR (300 MHz, CDCl3):
d
7.29 (m, 12H), 6.95 (d, J¼6.9 Hz, 1H), 6.84
(s, 1H), 6.62 (s, 1H). 5.11 (d, J¼15.9 Hz, 1H), 4.83 (s, 1H), 4.01 (d,
J¼13.8 Hz,1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.79 (d, J¼13.8 Hz, 1H), 3.33
(d, J¼15.9 Hz, 1H), 2.94 (m, 1H), 2.64 (m, 7H), 1.84 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d
169.9, 147.7, 146.1, 145.9, 135.2, 134.7, 134.0,
4.5.8. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
133.4, 130.8, 130.0, 129.9, 129.8, 129.6, 128.9, 128.7, 128.4, 128.2,
128.1, 127.2, 126.6, 126.4, 112.7, 112.3, 84.4, 65.1, 55.9, 55.6, 45.9,
40.6, 38.0, 30.6, 26.8; EI-MS m/z 615 (Mþ); HR-MS calcd for
C35H35Cl2N3O3 (Mþ) 615.2055, found: 615.2060.
1-yl)-1,3-bis(2-methoxybenzyl) tetrahydropyrimidin-4(1H)-one (18).
1H NMR (300 MHz, CDCl3):
d 7.54 (s, 2H), 7.22 (m, 7H), 6.88 (m, 4H),
6.75 (d, J¼7.8 Hz,1H), 6.61 (s, 1H), 5.15 (s, 1H), 4.88 (d, J¼15.0 Hz,1H),
3.90 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.68 (m, 2H), 3.64 (s, 3H), 3.21
(d, J¼14.7 Hz, 1H), 2.91 (m, 3H), 2.48 (m, 4H), 1.62 (d, J¼16.8 Hz, 1H);
4.5.3. 1,3-Bis(4-chlorobenzyl)-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-
13C NMR (100 MHz, CDCl3):
d 169.8, 157.9, 157.4, 147.6, 145.8, 131.0,
tetrahydroisoquinolin-1-yl)tetrahydropyrimidin-4(1H)-one (13). 1H
130.5, 129.1, 128.5, 128.2, 127.8, 126.9, 126.2, 124.9, 120.3, 119.9, 112.5,
112.4, 110.6, 110.2, 109.7, 84.6, 65.2, 56.0, 55.6, 55.1, 54.6, 52.5, 43.9,
39.4, 38.0, 30.5, 26.5; EI-MS m/z 607 (Mþ); HR-MS calcd for
C37H41N3O5 (Mþ) 607.3046, found: 607.3027.
NMR (300 MHz, CDCl3):
d
7.26 (m, 9H), 6.89 (d, J¼8.4 Hz, 2H), 6.77
(d, J¼5.7 Hz, 3H), 6.64 (s, 1H), 5.45 (d, J¼14.1 Hz, 1H), 4.48 (s, 1H),
3.89 (s, 3H), 3.84 (s, 3H), 3.44 (d, J¼13.8 Hz, 1H), 3.27 (d, J¼13.8 Hz,
1H), 2.96 (m, 1H), 2.78 (m, 2H), 2.45 (m, 6H), 1.82 (d, J¼17.7 Hz, 1H);
13C NMR (100 MHz, CDCl3):
d
169.4, 147.7, 146.5, 145.8, 135.8, 135.5,
4.5.9. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-1-
133.5, 133.2, 130.4, 130.2, 129.9, 128.9, 128.8, 128.5, 128.1, 128.0,
127.4, 112.7, 112.2, 81.6, 64.4, 56.7, 55.8, 55.6, 45.3, 41.5, 37.9, 30.5,
yl)-1,3-bis(4-methylbenzyl) tetrahydropyrimidin-4(1H)-one (19). 1H
NMR (300 MHz, CDCl3):
d 7.30 (m, 5H), 7.04 (m, 4H), 6.83 (m, 5H),

J. Zhang et al. / Tetrahedron 67 (2011) 842e848
847
6.62 (s, 1H), 5.49 (d, J¼15.0 Hz, 1H), 4.61 (s, 1H), 3.88 (s, 3H), 3.85 (s,
3H), 3.41 (d, J¼13.2 Hz, 1H), 2.27 (d, J¼13.2 Hz, 1H), 2.95 (m, 1H),
2.85 (m, 2H), 2.52 (m, 5H), 2.33 (s, 3H), 2.31(s, 3H), 1.77 (dd,
(m, 1H), 2.68 (d, J¼15.6 Hz, 1H), 2.47 (m, 5H), 1.79 (m, 1H); 13C NMR
(100 MHz, CDCl3):
d 169.3, 151.0, 150.2, 147.8, 145.8, 142.6, 142.3,
129.8, 129.1, 128.1, 127.5, 112.5, 112.0, 110.2, 110.1, 109.4, 109.1, 81.7,
64.3, 55.8, 55.6, 50.3, 41.1, 39.8, 37.7, 30.1, 26.4; EI-MS m/z 527 (Mþ);
HR-MS calcd for C31H33N3O5 (Mþ) 527.2420, found: 527.2402.
J¼6.9,18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 169.5, 147.6, 146.6,
145.7, 137.1, 137.0, 134.3, 134.2, 129. 8, 129.1, 129.0, 129.0, 128.9,
128.0, 127.2, 112.5, 112.3, 82.0, 64.3, 57.2, 55.8, 55.6, 45.7, 40.6, 37.9,
30.5, 26.3, 21.1; EI-MS m/z 575 (Mþ); HR-MS calcd for C37H41N3O3
(Mþ) 575.3148, found: 575.3113.
4.5.15. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)-1,3-diphenethyl tetrahydropyrimidin-4(1H)-one (25). 1H NMR
(300 MHz, CDCl3):
d
7.54 (s, 2H), 7.22 (m, 11H), 6.92 (d, J¼7.2 Hz,
4.5.10. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
2H), 6.74 (s, 1H), 6.62 (s, 1H), 4.64 (s, 1H), 3.88 (s, 3H), 3.80 (s, 4H),
1-yl)-1,3-bis(3-methylbenzyl) tetrahydropyrimidin-4(1H)-one (20).
2.78 (m, 7H), 2.43 (m, 6H), 2.22 (m, 1H), 1.68 (m, 1H); 13C NMR
1H NMR (300 MHz, CD3OD):
d
6.99 (m, 9H), 6.59 (s, 2H), 6.47 (s, 3H),
(100 MHz, CDCl3): d 169.0, 147.7, 145.8, 139.3, 138.3, 129.6, 128.8,
6.34 (s, 1H), 5.23 (d, J¼14.1 Hz, 1H), 4.45 (s, 1H), 3.63 (s, 3H), 3.53 (s,
3H), 3.21 (m, 3H), 2.62 (m, 3H), 2.39 (m, 3H), 2.18 (m, 2H), 2.09 (s,
3H), 2.01 (s, 3H), 1.51 (d, J¼25.5 Hz, 1H); 13C NMR (100 MHz,
128.7, 128.3, 128.1, 127.4, 126.2, 112.5, 111.9, 85.5, 64.5, 55.8, 55.6,
55.5, 46.5, 40.3, 37.5, 34.8, 33.3, 30.2, 26.3; EI-MS m/z 575 (Mþ); HR-
MS calcd for C37H41N3O3 (Mþ) 575.3148, found: 575.3175.
CD3OD):
d 172.7, 150.0, 147.8, 139.8, 139.4, 139.0, 138.4, 132.1, 131.5,
131.2, 130.7, 130.2, 129.7, 129.2, 128.0, 127.5, 114.7, 114.5, 82.5, 66.4,
58.9, 56.8, 56.8, 47.6, 43.3, 39.5, 31.3, 27.8, 22.05, 22.02; EI-MS m/z
575 (Mþ); HR-MS calcd for C37H41N3O3 (Mþ) 575.3148, found:
575.3154.
4.5.16. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)-1,3-bis(3-methoxyphenethyl) tetrahydropyrimidin-4(1H)-one
(26). 1H NMR (300 MHz, CDCl3):
d 7.53 (s, 1H), 7.25 (m, 5H), 7.05 (t,
J¼8.4 Hz, 1H), 6.74 (m, 4H), 6.62 (s, 2H), 6.50 (d, J¼7.8 Hz, 1H), 6.45
(s, 1H), 4.61 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.72 (s,
3H), 2.78 (m, 8H), 2.44 (m, 7H), 2.23 (m,1H),1.68 (d, J¼12.9,1H); 13C
4.5.11. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)-1,3-bis(2-methylbenzyl) tetrahydropyrimidin-4(1H)-one (21).
NMR (100 MHz, CDCl3): d 169.1, 159.6, 159.5, 147.7, 145.8, 141.0,
1H NMR (300 MHz, CDCl3):
d
7.38 (s, 2H), 7.24 (m, 7H), 7.14 (m, 3H),
139.9, 129.8, 129.4, 129.2, 129.0, 128.1, 127.4, 121.3, 121.1, 114.7, 114.2,
112.6, 111.9, 111.4, 85.7, 64.4, 55.9, 55.6, 55.2, 55.1, 46.6, 40.5, 37.6,
35.4, 33.1, 30.3, 29.7, 26.4; EI-MS m/z 635 (Mþ); HR-MS calcd for
C39H45N3O5 (Mþ) 635.3359, found: 635.3364.
6.79 (d, J¼10.5 Hz, 2H), 6.61 (s, 1H), 5.23 (d, J¼15.9 Hz, 1H), 4.79 (s,
1H), 3.87 (s, 3H), 3.84 (d, J¼13.5 Hz, 1H), 3.81 (s, 3H), 3.67 (d,
J¼13.5 Hz, 1H), 3.20 (d, J¼16.2 Hz, 1H), 2.8 (m, 5H), 2.50 (m, 3H),
2.24 (s, 3H), 1.93 (dd, J¼5.4, 8.1 Hz, 1H), 1.77 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
169.7, 147.6, 146.4, 145.9, 137.6, 136.2, 135.4,
4.5.17. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
134.0, 130.6, 130.4, 129.5, 128.6, 128.1, 127.6, 126.9, 126.7, 125.6,
112.6, 112.0, 83.5, 64.9, 56.3, 55.8, 55.6, 44.6, 40.5, 38.0, 30.4, 26.5,
19.2,18.7; EI-MS m/z 575 (Mþ, 2%), 576 (Mþ1, 12%); HR-MS calcd for
C37H41N3O3 (Mþ) 575.3148, found: 575.3170.
1-yl)-1,3-bis(3-phenylpropyl) tetrahydropyrimidin-4(1H)-one (27).
1H NMR (300 MHz, CDCl3):
d 7.46 (s, 2H), 7.21 (m, 10H), 7.02 (d,
J¼7.5 Hz, 2H), 6.78 (s, 1H), 6.65 (s, 1H), 4.66 (s, 1H), 3.89 (s, 3H), 3.80
(s, 3H), 2.98 (dd, J¼5.1, 12.9 Hz, 1H), 2.70 (m, 5H), 2.47 (m, 9H), 2.11
(m, 1H), 1.95 (m, 2H), 1.82 (m, 1H), 1.59 (m, 2H); 13C NMR (100 MHz,
4.5.12. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
CDCl3): d 169.1, 147.7, 146.5, 145.8, 141.6, 141.4, 129.9, 128.6, 128.4,
1-yl)-1,3-bis(3-(trifluoromethyl) benzyl)tetrahydropyrimidin-4(1H)-
128.4, 128.3, 128.2, 128.0, 127.9, 127.2, 126.0, 125.8, 112.6, 112.1, 84.1,
64.2, 55.9, 55.6, 53.5, 44.5, 41.3, 37.7, 33.4, 33.1, 30.5, 30.2, 28.3,
26.5; EI-MS m/z 603 (Mþ); HR-MS calcd for C39H45N3O3 (Mþ)
603.3461, found: 603.3463.
one (22). 1H NMR (300 MHz, CDCl3):
d 7.49 (m, 2H), 7.34 (m, 8H),
7.22 (d, J¼15.6 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J¼8.4 Hz, 1H), 6.81 (s,
1H), 6.66 (s, 1H), 5.60 (d, J¼15.0 Hz, 1H), 4.45 (s, 1H), 3.89 (s, 3H),
3.84 (s, 3H), 3.57 (d, J¼13.5 Hz, 1H), 3.36 (d, J¼13.5 Hz, 1H), 2.95 (m,
1H), 2.79 (m, 2H), 2.57 (m, 5H), 1.86 (dd, J¼7.5, 18.3 Hz, 1H); 13C
4.5.18. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
NMR (100 MHz, CDCl3):
d
169.4, 147.8, 146.4, 145.9, 138.1, 138.0,
1-yl)-1,3-dipropyl tetrahydropyrimidin-4(1H)-one (28). 1H NMR
132.2, 131.9, 130.8, 130.7, 130.5, 130.4, 130.0, 128.9, 128.7, 128.3,
127.9, 127.5, 125.8, 125.3, 124.6, 124.4, 122.6, 112.8, 111.9, 81.9, 64.3,
57.0, 55.8, 55.6, 45.4, 41.6, 37.8, 30.5, 26.4; EI-MS m/z 683 (Mþ); HR-
MS calcd for C37H35F6N3O3 (Mþ) 683.2583, found: 683.2566.
(300 MHz, CDCl3):
d
7.47 (s, 2H), 7.25 (d, J¼4.8 Hz, 3H), 6.75 (s, 1H),
6.64 (s, 1H), 4.71 (s, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.70 (m, 1H), 2.99
(dd, J¼5.1, 12.6 Hz, 1H), 2.81 (t, J¼15.3 Hz, 1H), 2.55 (m, 6H), 1.65 (m,
4H), 1.30 (m, 4H), 0.98 (t, J¼7.2 Hz, 3H), 0.55 (t, J¼7.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 169.0, 147.7, 145.8, 129.7, 128.7, 128.0,
4.5.13. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)-1,3-bis(naphthalen-1-ylmethyl)tetrahydropyrimidin-4(1H)-one
127.2, 112.5, 112.1, 83.7, 64.2, 55.9, 55.8, 55.6, 45.9, 41.0, 37.7, 30.4,
26.3, 21.6, 19.7, 11.7, 11.0; EI-MS m/z 451 (Mþ); HR-MS calcd for
C27H37N3O3 451.2835, found: 451.2817.
(23). 1H NMR (300 MHz, CDCl3):
d 7.83 (m, 4H), 7.65 (m, 2H), 7.44
(m, 7H), 7.26 (m, 3H), 7.16 (t, J¼7.2 Hz, 1H), 6.99 (s, 1H), 6.89 (d,
J¼6.6 Hz, 1H), 6.61 (s, 1H), 6.47 (d, J¼6.6 Hz, 1H), 6.13 (d, J¼15.0 Hz,
1H), 4.75 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.76 (d, J¼10.8 Hz, 1H),
3.41 (t, J¼12.6 Hz, 2H), 2.71 (m, 4H), 2.46 (m, 3H), 1.92 (d, J¼12.3 Hz,
Acknowledgements
The authors are grateful to the Chinese National Science
Foundation (30772625,81072528), Shanghai Commission of Sci-
ence and Technology (10410702600, 10JC1417100, 10dz1910104),
National Science & Technology Major Project on ‘Key New Drug
Creation and Manufacturing Program’ (2009ZX09301-001,
2009ZX09103-062).
1H); 13C NMR (100 MHz, CDCl3):
d 169.9, 147.6, 146.4, 145.9, 133.8,
133.6, 132.8, 132.2, 131.9, 131.6, 129.7, 129.1, 128.6, 128.5, 128.4,
128.2, 128.1, 127.9, 127.0, 126.8, 126.2, 125.8, 125.7, 125.5, 124.8,
124.7,124.2,123.8,112.6,112.5, 82.5, 64.7, 55.8, 55.5, 44.6, 40.6, 38.0,
30.5, 26.7; EI-MS m/z 647 (Mþ); HR-MS calcd for C43H41N3O3 (Mþ)
647.3148, found: 647.3140.
Supplementary data
4.5.14. 2-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)-1,3-bis(furan-2-ylmethyl) tetrahydropyrimidin-4(1H)-one (24).
Supplementary data related to this article can be found online
version, at doi:10.1016/j.tet.2010.12.038. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
1H NMR (300 MHz, CDCl3):
d 7.37 (s, 2H), 7.28 (m, 5H), 6.85 (s, 1H),
6.63 (s, 1H), 6.27 (s, 2H), 5.99 (m, 2H), 5.34 (d, J¼15.0 Hz, 1H), 4.83 (s,
1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.53 (s, 2H), 2.99 (d, J¼13.2 Hz, 1H), 2.82

848
J. Zhang et al. / Tetrahedron 67 (2011) 842e848
4. Berney, D.; Schuh, K. Helv. Chim. Acta 1981, 64, 373.
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