Synthesis of dihydrobenzoimidazo[2,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2012.05.132

A one-pot protocol toward several substituted 5,6-dihydrobenzo[4,5] imidazo[2,1-a]isoquinolines 1 starting with 2-allylbenzaldehydes 2 was described. The process was carried out the one-pot condensation/hydroamination reaction of substituted 2-allylbenzaldehydes 2 with 1,2-diaminobenzenes 3 in refluxing toluene in good yields. Skeleton 2 was prepared via one-pot ortho-metalative PhBCl₂-mediated double alkylation of hydroxybenzaldehyde 4 with LDA in moderate yields.

Full text of DOI:10.1016/j.tetlet.2012.05.132

Tetrahedron Letters 53 (2012) 4156–4160
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of dihydrobenzoimidazo[2,1-a]isoquinolines
⇑
Meng-Yang Chang , Ming-Hao Wu, Yeh-Long Chen
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot protocol toward several substituted 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines 1 start-
ing with 2-allylbenzaldehydes 2 was described. The process was carried out the one-pot condensation/
hydroamination reaction of substituted 2-allylbenzaldehydes 2 with 1,2-diaminobenzenes 3 in refluxing
toluene in good yields. Skeleton 2 was prepared via one-pot ortho-metalative PhBCl2-mediated double
alkylation of hydroxybenzaldehyde 4 with LDA in moderate yields.
Received 19 April 2012
Revised 23 May 2012
Accepted 29 May 2012
Available online 1 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrobenzo[4,5]imidazo[2,1-
a]isoquinolines
Metalation
Hydroamination
One-pot tandem reaction
Introduction
3 via tandem condensation, followed by an intramolecular
metal-free hydroamination of the corresponding benzimidazole.
Metal-mediated hydroamination of alkenes with amines which
had been developed, was done well.7,8 However, there have been
few investigations of the metal-free hydroamination approach.
In comparison with two excellent one-pot methods (Ohno and
Yanada),5a,6d two major differences for preparing skeleton 1 are
starting the benzaldehydes with the ortho-alkynyl group and
the metal-promoted reaction condition. In previous studies, we
have explored one efficient synthetic application of 2-allylbenzal-
dehyde to generate the tricyclic structure of 1-indanonyl oxepanes
and benzodioxpanes via one-pot and facile PhBCl2-mediated dou-
ble alkylation of hydroxybenzaldehyde analogues with LDA in
moderate yields (see Scheme 1).9 Furthermore, we utilized the
one-pot and convenient protocol to prepare the tetracyclic skele-
ton of 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines 1.
Dihydroimidazoisoquinoline and its derivatives are very impor-
tant compounds due to their pharmacological and biological activ-
ities.1 For example, skeleton A is a potent phosphodiesterase
(PDE10A) inhibitor with excellent selectivity compared to other
enzymes,2,3 and skeleton B has been identified as a platelet-acti-
vating factor (PAF) antagonist (Fig. 1). Functionalized benzimi-
dazo[2,1-a]isoquinolines C are prevalent scaffolds that serve as
crucial building blocks for numerous syntheses.4–6 There are a
number of processes available to generate skeleton C, but gener-
ally, they are described as in Figure 2: (1) Pd(OAc)2-catalysed inter-
molecular tandem cyclization of 2-bromoarylaldehydes with
terminal alkynes and 1,2-diaminobenzene under the microwave-
accelerated irradiation condition,5a (2) CuI-catalysed the intramo-
lecular cyclocondensation reaction of 2-bromoarylamidines with
1,2-diaminobenzene in refluxing MeCN,5b (3) the nucleophilic sub-
stitution of 3-fluoro-4-nitrophenol with tetrahydroisoquinoline
followed by the intramolecular cyclodehydration of the resulting
N-oxides with PCl3.5c
While a great number of benzimidazo[2,1-a]isoquinolines and
their derivatives with this specific substitution pattern have been
developed, new methods for their preparation are needed.6
Because the procedures are almost transition metal-mediated
cyclization or microwave enhanced irradiation condition, we want
to explore a one-pot method for preparing tetracyclic skeleton 1 by
the treatment of 2-allylbenzaldehyde 2 with 1,2-diaminobenzene
N
MeO
MeO
R
N
N
N
2HCl
N
N
N
N
B
A
C
⇑
Corresponding author. Tel.: +886 7 3121101x2220.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
Figure 1. Structures of dihydroimidazoisoquinolines.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.132

M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 4156–4160
4157
Table 1
R
R
Br
microwave-accelerated
Reaction of compound 2c with 3a
Pd(OAc) -catalysed
2
NH
Br
tandem process
(ref. 5a)
CHO NH
2
MeO
N
H N
2
MeO
MeO
MeO
MeO
MeO
Me
H
CHO
refluxing
solvent
copper-catalysed
cyclocondensation
(ref. 5b)
2c
3a
N
N
+
R
+
H N
2
N
N
N
5a
1c
H N
2
N
nucleophilic
Entry
Solvent (mL), temp, time (h)
5a/1c, yielda,b (%)
C or 1
substitution followed by
cyclodehydration
(ref. 5c)
1
2
3
4
5
6
7
8
Toluene (5), reflux, 2
Toluene (1), reflux, 2
Toluene (1), reflux, 3
Toluene (1), reflux, 4
DMF (1), reflux, 4
Declain (1), reflux, 4
DME (1), reflux, 4
CH2Cl2 (10), reflux, 6
67/22
40/46
ꢀ8/75
—/88
NH
F
NH
CHO
H N
one-pot
2
Trace/80
Trace/76
Trace/70
89/—
condensation and
hydroamination
(our work)
2
O N
2
a
The reactions were run on a 0.5 mmol scale with 2c.
The products were >95% pure as determined by 1H NMR analysis.
Figure 2. Synthetic strategies toward skeleton 1.
b
the metalation condition. After the ordinal addition of allyl bro-
mide and alkyl halide (R1X), 2a–2f were yielded with 49–70%
yields.
O
MeO
To initiate the synthetic work of skeleton 1, one-pot condensa-
tion/hydroamination reaction of 2c (R1 = Me, Y = OMe) with 1,2-
diaminobenzene 3a in different solvent was examined. After
screening four kinds of boiling solvents (toluene, DMF, decalin or
DME), we found that 1c was isolated with the similar yields
(88%, 80%, 76% or 70%) by the reaction of 2c (0.5 mmol) with 3a
(0.55 mmol) for 4 h. Some experimental conditions and results
were shown in Table 1. Therefore, this reaction must be controlled
in nearly solvent-free condition (1 mL of toluene); otherwise, benz-
imidazole 5a was isolated as the major component among the
product mixture (entry 1).10 Toluene was chosen as the reaction
solvent due to it possessing the appropriate boiling point and bet-
ter operation convenience for the nearly solvent-free condition
among these solvents. When CH2Cl2 was chosen as the solvent un-
der this reaction condition, only 5a was isolated (entry 8). Based on
the above mentioned phenomenon, we envisioned that the nearly
solvent-free condition should be the key factor affecting the distri-
bution of hydroamination product. Compounds 1a–1r were ob-
tained by the domino condensation/hydroamination reaction of
six substituted 2-allylbenzaldehydes 2 with three 1,2-diamino-
benzenes 3 in refluxing toluene for 4 h; they are summarized in
Table 2.11
According to the facile one-pot procedure, skeleton 1 with dif-
ferent functionalized group was also synthesized with 70–88%
yields. In comparison with the isolated yields of products with dif-
ferent substituents, it was found that the skeleton 1 with hydroxyl
group (entries 2, 8 and 14) or isopropyl group (entries 4, 10 and 16)
was slightly poorer than the other analogues. Attempts to extend
this one-pot reaction to 2-aminophenol or 2-aminobenzenethiol
were unsuccessful. Only benzooxazole or benzothiazole skeleton
was isolated. The formation of eighteen cycloadducts was con-
firmed through spectral analysis. For example, the 1H NMR spec-
trum of 1c exhibited a doublet of doublet d 3.38 (J = 1.6, and
16.0 Hz) and 3.21 (J = 6.4 and 16.0 Hz) for the CH2 protons. The
methyl proton exhibited a singlet at d 1.28 (J = 6.4 Hz) and the
CH proton appeared a multiplet at the range of d 4.89 and 4.82.12
Finally, 1c was confirmed by high resolution mass spectrometry,
which showed a peak at m/z 295.1439 [M++1]. Further, five com-
pounds 1c, 1i, 1m, 1n and 1o were determined by the single-crys-
tal X-ray crystallography. Structure 1c was shown in Figure 3.13
ref. 9a
OH
O
LDA, PhBCl
2
O
MeO
MeO
then, allylBr
CHO
O
CHO
MeO
ref. 9b
O
Scheme 1. PhBCl2-mediated syntheses of 1-indanonyl oxepane and
benzodioxpanes.
OH
R O
1
LDA, PhBCl , allylBr (1.0 eq.)
2
Y
Y
then R X
1
CHO
CHO
4a, Y = H
4b, Y = OMe
R X =
1
Y = H
for a and c, MeI
2a, R = Me (62%)
1
for b, H O
Y = OMe
2
for d, i-PrBr
for e, n-BuBr
for d, BnBr
2b, R = H (60%)
1
2c, R = Me (58%)
1
2d, R = i-Pr (49%)
1
2e, R = n-Bu (66%)
1
2f, R = Bn (70%)
1
Scheme 2. Synthesis of 2-allylbenzaldehyde 2.
Results and discussion
As the starting materials, substituted 2-allylbenzaldehydes 2a–
2f were prepared from commercially available 3-hydroxybenzal-
dehyde (4a) and isovanillin (4b) in one step, according to the
known procedure with the sequence of C-allylation followed by
the O-alkylation.9b As shown in Scheme 2, the treatment of 4a or
4b with PhBCl2 and LDA afforded the dianion intermediate under

4158
M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 4156–4160
Table 2
Synthesis of substituted 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines 1a,b
R O
1
R O
1
H N
2
R
R
Y
toluene
reflux
Y
Me
2
2
+
N
H N
2
CHO
R
2
N
2a~2f
3a, R = H
1a~1r
2
3b, R = Cl
2
3c, R =Me
R
2
2
Entry Reactants
2/3
Product 1/yield (%)
Entry Reactants
2/3
Product 1/yield (%)
Entry Reactants
2/3
Product 1/yield (%)
MeO
Me
MeO
Me
MeO
Me
N
N
N
N
N
N
1
2
3
2a/3a
2b/3a
2c/3a
7
8
9
2a/3b
2b/3b
2c/3b
13
14
15
2a/3c
2b/3c
2c/3c
Cl
Me
Me
Cl
1a / 84
1g / 80
1m / 83
HO
HO
HO
MeO
Me
Me
MeO
Me
MeO
Me
N
N
N
Cl
Cl
Me
Me
N
N
N
1b / 73
1h / 70
1n / 74
MeO
MeO
MeO
MeO
MeO
Me
MeO
Me
N
N
N
N
N
Cl
Cl
Me
Me
N
1c / 88
1i / 86
1o / 82
O
O
O
O
O
MeO
MeO
Me
Me
MeO
MeO
Me
Me
MeO
MeO
Me
Me
N
N
N
N
N
N
4
2d/3a
10
2d/3b
16
2d/3c
Cl
Cl
Me
Me
N
1d / 73
1j / 72
1p / 71
O
N
N
N
N
5
2e/3a
11
2e/3b
17
2e/3c
Cl
Cl
Me
Me
N
1e / 85
1k / 82
1q / 80
O
O
O
MeO
Me
MeO
Me
MeO
Me
N
N
N
N
N
6
2f/3a
12
2f/3b
18
2f/3c
Cl
Cl
Me
Me
N
1f / 80
1l / 82
1r / 79
a
For the best one-pot reaction conditions: skeleton 2 (0.5 mmol), skeleton 3 (0.55 mmol), toluene (1 mL), reflux, 4 h.
b
The isolated products were >95% pure as determined by 1H NMR analysis.

M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 4156–4160
4159
Conclusion
A synthetic methodology for producing substituted 5,6-dihy-
drobenzo[4,5]imidazo[2,1-a]isoquinolines 1 has been successfully
presented from the one-pot facile tandem condensation/hydroam-
ination reaction of substituted 2-allylbenzaldehydes 2 with 1,2-
diaminobenzenes 3 in refluxing toluene in good yields under the
nearly solvent-free condition. The starting skeleton 2 was prepared
via one-pot ortho-metalative PhBCl2-mediated double alkylation of
3-hydroxybenzaldehyde 4 with LDA in moderate yields. Further
investigation is required regarding the structure-activity relation-
ship of the tetracyclic benzimidazo[2,1-a]isoquinoline analogues.
Figure 3. X-ray structure of 1c.
Acknowledgments
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3).
H2N
H2N
H2N
H2N
MeO
MeO
N
N
Me
N
Me
3f
(75%)
3e
Supplementary data
2a
N
N
(68%)
N
N
Supplementary data (experimental procedure and scanned pho-
tocopies of 1H and 13C NMR (CDCl3) spectral data) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.132.
1u
1t
N
H2N
H2N
(72%)
MeO
Me
3d
N
References and notes
N
1s
1. (a) Burke, P. J.; Wong, L. C.; Jenkins, T. C.; Knox, R. J.; Stanforth, S. P. Bioorg. Med.
Chem. Lett. 2011, 21, 7447; (b) Deady, L. W.; Rodemann, T.; Finlay, G. J.; Baguley,
B. C.; Denny, W. A. Anti-Cancer Drug Des. 2000, 15, 339; (c) Houlihan, W. J.;
Cheon, S. H.; Parrino, V. A.; Handley, D. A.; Larson, D. A. J. Med. Chem. 1993, 36,
3098.
Scheme 3. Reactions of 2a with 3d, 3e and 3f.
2. (a) Brunton, V. G.; Workman, P. Br. J. Cancer 1993, 67, 989; (b) Cheob, S. H.; Park,
J. S.; Jeong, S. H.; Chung, B. H.; Choi, B.-G.; Cho, W.-J.; Kang, B.-H.; Lee, C.-O.
Arch. Pharm. Res. 1997, 20, 138.
3. (a) Ho, G. D.; Seganish, W. M.; Bercovici, A.; Tulshian, D.; Greenlee, W. J.; Rijn, R.
D. V.; Hruza, A.; Xiao, L.; Rindgen, D.; Mullins, D.; Guzzi, M.; Zhang, X.;
Bleickardt, C.; Hodgson, R. Bioorg. Med. Chem. Lett. 2012, 22, 2585; (b) Seganish,
W. M.; Bercovici, A.; Ho, G. D.; Loozen, H. J. J.; Timmers, C. M.; Tulshian, D.
Tetrahedron Lett. 2012, 53, 903; (c) Ho, G. D.; Seganish, W. M.; Tulshian, D.;
Timmers, C. M.; Rijn, R. D. V. Loozen, H. J. J. PCT patent, WO 2011/008597 A1.
4. For recent reviews on the benzimidazo[2,1-a]isoquinolines, see: (a) Dawood, K.
M.; Abdel-Wahab, B. F. Arkivoc 2010, i, 333; (b) Gil, C.; Bräse, S. J. Comb. Chem.
2009, 11, 175.
5. For syntheses of benzimidazo[2,1-a]isoquinolines, see: (a) Okamoto, N.;
Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R. Tetrahedron Lett. 2009, 50,
4167; (b) Liubchak, K.; Nazarenko, K.; Tolmachev, A. Tetrahedron 2012, 68,
2993; (c) Donaghy, M. J.; Stanforth, S. P. Tetrahedron 1999, 55, 1441; (d) Jiang,
M.; Li, J.; Wang, F.; Zhao, Y.; Zhao, F.; Dong, X.; Zhao, W. Org. Lett. 2012, 14,
1420.
6. For Bu3SnH-mediated cyclization, see: (a) Moriarty, E.; Aldabbagh, F.
Tetrahedron Lett. 2009, 50, 5251; For microwave synthesis, see: (b) Perin, N.;
Hranjec, M.; Pavlovic´, G.; Karminski-Zamol, G. Dyes Pigments 2011, 91, 79; For
CuX-mediated cyclization, see: (c) Tokimizu, Y.; Ohta, Y.; Chiba, H.; Oishi, S.;
Fujii, N.; Ohno, H. Tetrahedron 2011, 67, 5168; (d) Ohta, Y.; Kubota, Y.; Watabe,
T.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 6299; For
fluoride-mediated cyclization, see: (e) Molina, P.; Aller, E.; Lorenzo, A.; Foces-
Foces, C.; Saiz, A. L. L. Tetrahedron 1996, 52, 13671; For Pd(dba)2-mediated
cyclization, see: (f) Hubbard, J. W.; Piegols, A. M.; Soderberg, B. C. G.
Tetrahedron 2007, 63, 7077.
7. For recent reviews on the hydroamination of olefins, see: (a) Hartwig, J. F. Pure
Appl. Chem. 2004, 76, 507; (b) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673.
8. For Zn-mediated hydroamination, see: (a) Dochnahl, M.; Pissarek, J.-W.;
Blechert, S.; Löhnwitz, K.; Roesky, P. W. Chem. Commun. 2006, 3405; For Pd-
mediated hydroamination, see: (b) Michael, F. E.; Cochran, B. M. J. Am. Chem.
Soc. 2006, 128, 4246; For Au-mediated hydroamination, see: (c) Bender, C. F.;
Widenhoefer, R. A. Chem. Commun. 2006, 4143.
Figure 4. X-ray structure of 1u.
To increase the synthetic application, diamine 3d was also
examined by the facile one-pot methodology (Scheme 3). Com-
pound 1s was provided via a reaction of 2a with 3d in 72% yield.
Compound 1s with a pentacyclic skeleton was constructed. When
the one-pot reaction of 2a was treated with 3,4-diaminopyridine
3e or 2,3-diaminopyridine 3f, only one isomer 1t or 1u was iso-
lated in 75% or 68% yield. The plausible reason should be the elec-
tronic repulsion effect between the nitrogen lone pair of pyridine
ring and terminal olefin. Following the previous literatures, two
proton NMR spectral data of 1t and 1u were similar to those re-
ported by the Maes group.14,15 The structural skeleton of 1u was
determined by single-crystal X-ray crystallography (Fig. 4).13 This
present methodology is the metal-free, simplest and perhaps
quickest synthesis of triaza-benzo[a]fluorene derivatives for the
whole synthetic procedure.
9. (a) Chang, M.-Y.; Lee, N.-C. Synlett 2012, 867; (b) Chang, M.-Y.; Wu, M.-H.; Lee,
T.-W. Tetrahedron 2012, 68, 6224–6230.
10. Mukhopadhyay, C.; Tapaswi, P. K. Tetrahedron Lett. 2008, 49, 6237.
11. A representative procedure of skeleton 1 is as follows: A solution of skeleton 3
(0.55 mmol) was added to a solution of skeleton 2 (0.5 mmol) in toluene
(1 mL). The reaction mixture was stirred at reflux. The reaction mixture was
cooled to rt and the solvent was concentrated. The residue was diluted with
water (10 mL) and the mixture was extracted with EtOAc (3 Â 20 mL). The
combined organic layers were washed with brine, dried, filtered and

4160
M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 4156–4160
evaporated to yield crude compound. Purification on silica gel (hexanes/
compound 1o: Yield = 82% (132 mg); Brown solid; mp = 187–188 oC
EtOAc = 4/1–1/1) afforded skeleton 1. For compound 1c: Yield 88% (130 mg);
Brown solid; mp = 126–127 °C (recrystallized from hexanes and EtOAc); HRMS
(ESI, M++1) Calcd for C18H19N2O2 295.1447. Found 295.1439; 1H NMR
(400 MHz, CDCl3): d 8.04 (d, J = 8.8 Hz, 1H), 7.80–7.76 (m, 1H), 7.36–7.32 (m,
1H), 7.28–7.22 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.89–4.82 (m, 1H), 3.92 (s, 3H),
3.84 (s, 3H), 3.38 (dd, J = 1.6, 16.0 Hz, 1H), 3.21 (d, J = 6.4, 16.0 Hz, 1H), 1.28 (d,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 154.35, 148.10, 146.69, 144.00,
133.63, 126.93, 122.18, 122.16, 122.90, 119.39, 119.30, 110.97, 108.80, 60.60,
55.69, 46.88, 28.12, 19.47; Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N,
9.52. Found: C, 73.69; H, 6.32; N, 9.80. Single-crystal X-Ray diagram: crystal of
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) Calcd for
C
20H23N2O2 323.1760. Found 323.1765; 1H NMR (400 MHz, CDCl3): d 8.01 (d,
J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.11 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.83-4.76 (m,
1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.36 (dd, J = 1.6, 16.0 Hz, 1H), 3.19 (dd, J = 6.4,
16.0 Hz, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 1.26 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 154.06, 147.31, 146.65, 142.49, 132.11, 131.29, 130.98,
126.71, 121.65, 119.68, 119.40, 110.91, 109.15, 60.59, 55.68, 46.82. 28.16,
20.50, 20.28, 19.46; Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.69; H, 7.03; N, 8.87. Single-crystal X-Ray diagram: crystal of
compound 1o was grown by slow diffusion of EtOAc into
compound 1o in CH2Cl2 to yield a prism. The compound crystallizes in the
monoclinic crystal system, space group 21/c 1, a = 6.8421(2) Å,
a solution of
compound 1c was grown by slow diffusion of EtOAc into
compound 1c in CH2Cl2 to yield a prism. The compound crystallizes in the
monoclinic crystal system, space group 21 1, a = 6.7204(9) Å,
b = 8.6319(11) Å, c = 13.1308(17) Å, V = 761.71(17) Å3, Z = 2, dCalcd = 1.283 g/
cm3, F(000) = 312, 2h range 1.55–26.40o,
indices (all data) R1 = 0.0470,
a solution of
P
1
P
1
b = 8.7801(3) Å, c = 28.6827(9) Å, V = 1720.56(9) Å3, Z = 2, dCalcd = 1.245 g/cm3,
F(000) = 688, 2h range 2.43–26.41o,
R indices (all data) R1 = 0.0851,
R
wR2 = 0.1315.
wR2 = 0.0958. For compound 1i: Yield = 86% (156 mg); Brown solid;
M.p. = 232–233 °C (recrystallized from hexanes and EtOAc); HRMS (ESI,
M++1) Calcd for C18H17Cl2N2O2 363.0667, found 363.0670; 1H NMR
(400 MHz, CDCl3): d 7.99 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.44 (s, 1H), 6.96 (d,
J = 8.4 Hz, 1H), 4.81–4.77 (m, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.41 (dd, J = 1.6,
16.0 Hz, 1H), 3.22 (dd, J = 6.4, 16.0 Hz, 1H), 1.28 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 155.02, 149.98, 146.76, 143.08, 132.89, 126.95, 126.23,
126.08, 122.39, 120.22, 118.33, 111.17, 110.22, 60.68, 55.78, 47.44, 28.02,
19.47; Anal. Calcd for C18H16Cl2N2O2: C, 59.52; H, 4.44; N, 7.71. Found: C,
59.69; H, 4.58; N, 7.53. Single-crystal X-Ray diagram: crystal of compound 1i
was grown by slow diffusion of EtOAc into a solution of compound 1i in CH2Cl2
to yield colorless prism. The compound crystallizes in the monoclinic crystal
12. The representative procedure and spectral analysis of skeleton
1 were
described in supplementary material. The series of skeleton should be
1
formed as a mixture of two diastereomers. However, the related resolutions of
diastereomers had been not observed from the NMR spectrum.
13. CCDC 870780 (1c), 870782 (1i), 875929 (1m), 875928 (1n), 875930 (1o), 876964
(1u), and 870781 (5a) contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
14. (a) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J. Org. Chem. 2006,
71, 260; (b) Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A. Tetrahedron 2007,
63, 8954.
system, space group
c = 28.6531(7) Å, V = 1698.03(8) Å3, Z = 4, dCalcd = 1.421 g/cm3, F(000) = 752,
2h range 1.42–26.38o,
indices (all data) R1 = 0.0769, wR2 = 0.1538. For
P
1
21/c 1, a = 6.7316(2) Å, b = 8.8114(2) Å,
15. (a) Zhao, D.; Hu, J.; Wu, N.; Huang, X.; Qin, X.; Lan, J.; You, J. Org. Lett. 2011, 13,
6516; (b) Livadiotou, D.; Fadel, A. M.; Tsoleridis, C. A.; Stephanidou-
Stephanatou, J. Tetrahedron 2012, 68, 4202.
R