Generation of Tetrahydro-3H-indeno[2,1-d]pyrimidines by the Tandem Reaction of 2-(2-Alkynylphenyl)aziridines with 2-Isocyanoacetates

Article abstract of DOI:10.1002/ejoc.201301426

A base-promoted tandem reaction of 2-(2-alkynylphenyl)aziridines with 2-isocyanoacetates in the presence of copper(II) triflate gives tetrahydro-3H-indeno[2,1-d]pyrimidines in good yields, with the formation of two new rings and three bonds.

Full text of DOI:10.1002/ejoc.201301426

FULL PAPER
DOI: 10.1002/ejoc.201301426
Generation of Tetrahydro-3H-indeno[2,1-d]pyrimidines by the Tandem Reaction
of 2-(2-Alkynylphenyl)aziridines with 2-Isocyanoacetates
Danqing Zheng[a] and Jie Wu*[a,b]
Keywords: Homogeneous catalysis / Copper / Tandem reactions / Nitrogen heterocycles / Cyclization
A base-promoted tandem reaction of 2-(2-alkynylphenyl)-
aziridines with 2-isocyanoacetates in the presence of cop-
per(II) triflate gives tetrahydro-3H-indeno[2,1-d]pyrimidines
in good yields, with the formation of two new rings and three
bonds.
Introduction
Tandem reactions[1,2] have been widely used for the diver-
Recently, important progress has been made in 2-isocy-
sity-oriented synthesis of N-heterocycles for chemical bio- anoacetate chemistry.[4–7] We were attracted by the potential
logy research and drug discovery.[3] Usually, this strategy is use of 2-isocyanoacetates for the construction of natural-
used to construct structurally diverse complex molecules product-like compounds.[4] For instance, tetrahydroindeno-
from simple substrates. The high efficiency and other ad- [2,1-b]pyrroles have been produced by the base-promoted
vantages of tandem reactions have resulted in a continual cascade reaction of (E)-2-alkynylphenylchalcone with a 2-
effort being devoted to the development of such methods isocyanoacetate (Scheme 1).[4a] Following on from this re-
for the construction of such small molecules. For example, sult, we envisaged that 2-(2-alkynylphenyl)aziridine[8] (1)
Xiao and co-workers have developed several tandem reac- might undergo a similar transformation, due to its struc-
tions for the efficient generation of diverse carbocycles and tural
similarity
with
(E)-2-alkynylphenylchalcone
heterocycles.[2a] Palladium-catalysed cascade reactions can (Scheme 1). We conceived that under suitable conditions,
also be used for the formation of polycyclic compounds.[2i] the 2-isocyanoacetate would attack the aziridine ring and
Scheme 1. A proposed synthetic route to tetrahydro-3H-indeno[2,1-d]pyrimidines by the reaction of 2-(2-alkynylphenyl)aziridines with 2-
isocyanoacetates.
the alkynyl group simultaneously to form a 1-methylene-
[a] Department of Chemistry, Fudan University,
220 Handan Road, Shanghai 200433, P. R. China
E-mail: jie_wu@fudan.edu.cn
indene ring. Subsequently, the in-situ-generated nitrogen
anion would react with the isocyanide moiety to give the
tetrahydro-3H-indeno[2,1-d]pyrimidine compounds. The
advantages of this approach are clear, since two new
rings and three new bonds would be formed during the re-
action.
http://www.chemistry.fudan.edu.cn/teacher.asp?tno=wujie
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301426.
Eur. J. Org. Chem. 2014, 767–771
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
767

D. Zheng, J. Wu
FULL PAPER
Table 1. Initial studies for the reaction of 2-[2-(phenylethynyl)-
phenyl]-1-tosylaziridine (1a) with ethyl 2-isocyanoacetate (2a).
Results and Discussion
We started to explore the feasibility of this proposed re-
action (Scheme 1). A model reaction of 2-[2-(phenylethyn-
yl)phenyl]-1-tosylaziridine (1a) and ethyl 2-isocyanoacetate
(2a) was selected for the development of the method. In our
previous report,[4a] the initial attack of the 2-isocyanoacet-
ate worked efficiently in the presence of DBU (1,8-diazabi-
cycloundec-7-ene) in acetonitrile. Therefore, the reaction
was initially tested under DBU-promoted conditions. How-
ever, when DBU (1.0 equiv.) was used as the base in MeCN
at 80 °C, only a trace amount of the product was observed
(Table 1, entry 1). Similar results were obtained when the
base was changed to iPr2NEt, NaOH, or NaOCH3 (Table 1,
entries 2–4). To our delight, the desired product (i.e., 3a)
was obtained and isolated in 35% yield when K3PO4 was
used as the base (Table 1, entry 5). The structure of tetra-
hydro-3H-indeno[2,1-d]pyrimidine 3a was proved by X-ray
diffraction analysis (Figure 1). Further investigation re-
vealed that caesium carbonate was the best choice of base,
and with this base, the expected product (i.e., 3a) was
formed in 47% yield (Table 1, entry 7). The reaction failed
when the solvent was changed to 1,4-dioxane, toluene, DCE
(1,2-dichloroethane), or THF (Table 1, entries 8–11). The
reaction did proceed in DMF or DMSO, but the yield of
the product was lower (Table 1, entries 12 and 13). A better
yield was obtained when the amount of caesium carbonate
was increased (Table 1, entries 14–17). The product (i.e., 3a)
was formed in 57% yield when 3.0 equiv. of caesium car-
bonate was used (Table 1, entry 16). Since the alkynyl group
could be activated in the presence of a Lewis acid to in-
crease its electrophilic reactivity, different metal salts were
screened as additives (Table 1, entries 18–25). We found that
compound 3a was produced in 72% yield when copper(II)
triflate (10 mol-%) was used in the reaction (Table 1, en-
try 18). The reaction temperature was crucial for the suc-
cessful conversion. The reaction failed at 50 °C (Table 1, en-
try 26). The yield could not be improved at higher tempera-
ture (Table 1, entry 27).
Entry Lewis acid
Base
Solvent
Yield [%][a]
1
2
–
–
DBU
iPr2NEt
NaOH
NaOCH3
K3PO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
toluene
DCE
trace
n.r.
trace
trace
35
40
47
trace
trace
trace
trace
37
36
33
52
57
52
72
60
61
45
41
3
4
–
–
5
6
–
–
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
8
–
–
9
10
–
–
11
12
–
–
THF
DMSO
DMF
13
–
–
–
–
14[b]
15[c]
16[d]
17[e]
18[d]
19[d]
20[d]
21[d]
22[d]
23[d]
24[d]
25[d]
26[d,f]
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
Cu(OTf)2
Cu(OAc)2
CuCl2
FeCl3
Bi(OTf)3
Yb(OTf)3
Sc(OTf)3
AgOTf
Cu(OTf)2
47
50
48
trace
63
27[d, g] Cu(OTf)2
[a] Isolated yield based on 2-[2-(phenylethynyl)phenyl]-1-tosylazir-
idine (1a). [b] 0.5 equiv. of Cs2CO3 was used. [c] 2.0 equiv. of
Cs2CO3 was used. [d] 3.0 equiv. of Cs2CO3 was used. [e] 4.0 equiv.
of Cs2CO3 was used. [f] The reaction was carried out at 50 °C. [g]
The reaction was carried out at 110 °C in a sealed tube.
The scope of the reaction of 2-(2-alkynylphenyl)-1-tosyl-
aziridines 1 with 2-isocyanoacetates 2 was then explored
under the optimized reaction conditions [i.e., Cu(OTf)2
(10 mol-%), Cs2CO3, MeCN, 80 °C]. The results are given
in Table 2. Various 2-(2-alkynylphenyl)-1-tosylaziridines
were evaluated first. In most cases, the reactions proceeded
smoothly to produce the desired products in moderate to
good yields. Different substituents, including electron-with-
drawing and electron-donating groups, on the aromatic ring
of 2-(2-alkynylphenyl)-1-tosylaziridines were compatible
under the standard conditions. However, the groups at-
tached to the triple bond seemed to have a crucial effect
on the transformation. The reactions worked well for 2-(2-
alkynylphenyl)-1-tosylaziridines with aryl groups attached
to the alkynyl moiety (R2). Only a trace amount of product
3e was observed when a 2-(2-alkynylphenyl)-1-tosylazirid-
Figure 1. X-ray ORTEP illustration of tetrahydro-3H-indeno[2,1-d]-
pyrimidine 3a (30% probability ellipsoids).
ine with a tert-butyl group attached to the triple bond was deno[2,1-d]pyrimidine 3k was generated in 67% yield when
used. Disubstituted cis-aziridines could be used in the cis-2-methyl-3-[2-(phenylethynyl)phenyl]-1-tosylaziridine
transformation as well. For instance, tetrahydro-3H-in- was used as the substrate. However, no reaction occurred
768
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 767–771

Generation of Tetrahydro-3H-indeno[2,1-d]pyrimidines
Table 2. Investigation of the scope of the tandem reaction of 2-(2-alkynylphenyl)-1-tosylaziridines 1 with 2-isocyanoacetates 2 to give
tetrahydro-3H-indeno[2,1-d]pyrimidines.[a]
[a] Isolated yield based on 2-[2-alkynylphenyl]-1-tosylaziridines 1.
ylaziridines
1
with 2-Isocyanoacetates 2: Copper(II) triflate
(0.24 mmol,
when
trans-2-methyl-3-[2-(phenylethynyl)phenyl]-1-tosyl-
(0.02 mmol, 10 mol-%), 2-isocyanoacetate
2
aziridine or trans-2-propyl-3-[2-(phenylethynyl)phenyl]-1-
tosylaziridine were used. As well as ethyl 2-isocyanoacetate,
tert-butyl 2-isocyanoacetate could also act as the coupling
partner in the reaction.
1.2 equiv.), and Cs2CO3 (0.6 mmol, 3.0 equiv.) were added to a
solution of 2-(2-alkynylphenyl)-1-tosylaziridine 1 (0.20 mmol) in
CH3CN (1.0 mL). The mixture was stirred at 80 °C for 2–3 h. After
TLC indicated that the reaction was complete, the mixture was
directly purified by flash column chromatography (EtOAc/n-hex-
ane, 1:4) to give the desired product (i.e., 3). [The 2-(2-alk-
ynylphenyl)-1-tosylaziridines were prepared according to pre-
Conclusions
In conclusion, we have described an efficient route to
tetrahydro-3H-indeno[2,1-d]pyrimidines by the base-pro-
moted tandem reaction of 2-(2-alkynylphenyl)-1-tosylazir-
idines with 2-isocyanoacetates in the presence of copper(II)
triflate. During the reaction process, two new rings and
three new bonds are formed. The use of 2-isocyanoacetates
for the construction of other N-heterocycles is currently on-
going in our laboratory.
viously reported methods.[9]
]
Ethyl (Z)-9-Benzylidene-3-tosyl-4,4a,9,9a-tetrahydro-3H-indeno-
[2,1-d]pyrimidine-9a-carboxylate (3a): 1H NMR (400 MHz,
CDCl3): δ = 8.08 (s, 1 H), 7.75 (d, J = 7.2 Hz, 2 H), 7.63 (d, J =
8.0 Hz, 2 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 2 H),
7.18–7.28 (m, 4 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.84 (d, J = 7.6 Hz,
1 H), 4.17 (d, J = 12.8 Hz, 1 H), 3.53–3.74 (m, 3 H), 3.41 (dd, J =
4.0, 12.8 Hz, 1 H), 2.44 (s, 3 H), 7.39 (t, J = 7.2 Hz, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 171.7, 144.8, 141.6, 141.2, 140.9,
138.8, 136.7, 134.4, 130.0, 129.0, 128.5, 128.2, 128.1, 127.4, 127.2,
124.2, 122.6, 121.1, 69.5, 61.5, 46.6, 38.5, 21.5, 13.3 ppm. HRMS
(ESI): calcd. for C28H26N2O4S [M + H]+ 487.1686; found 487.1673.
Experimental Section
General Procedure for the Synthesis of Tetrahydro-3H-indeno[2,1-
d]pyrimidines by the Tandem Reaction of 2-(2-Alkynylphenyl)-1-tos-
Eur. J. Org. Chem. 2014, 767–771
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
769

D. Zheng, J. Wu
FULL PAPER
CCDC-943641 contains the crystallographic data for compound 3a
has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. . These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
HRMS (ESI): calcd. for C30H30N2O6S [M + H]+ 547.1897; found
547.1895.
tert-Butyl (Z)-9-Benzylidene-6,7-dimethoxy-3-tosyl-4,4a,9,9a-tetra-
hydro-3H-indeno[2,1-d]pyrimidine-9a-carboxylate (3h): 1H NMR
(400 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.81 (d, J = 7.6 Hz, 2 H),
7.63 (d, J = 8.4 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.20–7.28 (m,
3 H), 7.02 (s, 1 H), 6.95 (s, 1 H), 6.46 (s, 1 H), 4.14 (d, J = 12.4 Hz,
1 H), 3.93 (s, 3 H), 3.78 (s, 3 H), 3.65 (s, 1 H), 3.39 (dd, J = 4.0,
12.8 Hz, 1 H), 0.96 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 171.3, 144.7, 142.3, 140.9, 140.7, 136.3, 135.4, 130.8, 130.1, 128.8,
128.4, 127.6, 127.3, 127.1, 124.4, 120.7, 71.5, 62.0, 50.7, 49.6, 21.6,
15.1, 13.8 ppm. HRMS (ESI): calcd. for C32H34N2O6S [M + H]+
575.2210; found 575.2235.
Ethyl (Z)-9-Benzylidene-6-fluoro-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3b): 1H NMR (400 MHz,
CDCl3): δ = 8.13 (s, 1 H), 7.73 (d, J = 7.2 Hz, 2 H), 7.61 (d, J =
8.4 Hz, 2 H), 7.46 (dd, J = 5.2, 8.8 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 2
H), 7.21–7.28 (m, 3 H), 7.08 (s, 1 H), 6.91 (dt, J = 1.6, 8.4 Hz, 1
H), 6.25 (dd, J = 1.6, 8.4 Hz, 1 H), 4.02 (d, J = 9.2 Hz, 1 H), 3.56–
3.71 (m, 3 H), 3.50 (dd, J = 4.0, 13.2 Hz, 1 H), 2.44 (s, 3 H), 0.76
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3,
162.9 (d, 1JC,F = 247.1 Hz), 145.3, 141.1, 140.9 (d, 3JC,F = 7.9 Hz),
140.4, 136.9, 136.5, 134.0, 130.0, 128.9, 128.2, 127.5, 127.2, 123.9,
122.5 (d, 3JC,F = 8.8 Hz), 115.6 (d, 2JC,F = 23.0 Hz), 109.7 (d, 2JC,F
= 22.1 Hz), 69.7, 61.6, 46.3, 38.3, 21.5, 13.3 ppm. HRMS (ESI):
calcd. for C28H26FN2O4S [M + H]+ 505.1592; found 505.1589.
tert-Butyl (Z)-9-Benzylidene-3-tosyl-4,4a,9,9a-tetrahydro-3H-ind-
eno[2,1-d]pyrimidine-9a-carboxylate (3i): 1H NMR (400 MHz,
CDCl3): δ = 8.07 (s, 1 H), 7.81 (d, J = 7.6 Hz, 2 H), 7.63 (d, J =
8.4 Hz, 2 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 2 H),
7.20–7.28 (m, 4 H), 7.15 (s, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.84
(d, J = 7.6 Hz, 1 H), 4.18 (d, J = 12.8 Hz, 1 H), 3.68 (s, 1 H), 3.44
(dd, J = 4.0, 12.8 Hz, 1 H), 2.45 (s, 3 H), 0.95 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.5, 144.7, 141.2, 140.9, 138.8,
137.1, 134.5, 130.0, 129.2, 128.4, 128.0, 127.3, 127.2, 124.1, 122.6,
121.0, 81.6, 70.0, 46.7, 38.5, 27.0, 21.5 ppm. HRMS (ESI): calcd.
for C30H30N2O4S [M + H]+ 515.1999; found 515.2012.
Ethyl (Z)-9-Benzylidene-7-fluoro-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3c): 1H NMR (400 MHz,
CDCl3): δ = 8.09 (s, 1 H), 7.75 (d, J = 7.6 Hz, 2 H), 7.62 (d, J =
8.4 Hz, 2 H), 7.17–7.36 (m, 6 H), 7.12 (s, 1 H), 6.68–6.78 (m, 2 H),
4.12 (d, J = 14.4 Hz, 1 H), 3.54–3.70 (m, 3 H), 3.40 (dd, J = 4.0,
12.8 Hz, 1 H), 2.45 (s, 3 H), 0.73 (t, J = 7.2 Hz, 3 H) ppm. 13C
1
NMR (100 MHz, CDCl3): δ = 171.4, 1163.2 (d, JC,F = 244.4 Hz),
tert-Butyl (Z)-9-Benzylidene-7-fluoro-3-tosyl-4,4a,9,9a-tetrahydro-
3
145.0, 143.2 (d, JC,F = 8.6 Hz), 141.3, 140.7, 136.3, 134.4, 134.3,
3H-indeno[2,1-d]pyrimidine-9a-carboxylate
(3j):
1H
NMR
3
130.1, 129.1, 128.3, 127.8, 127.2, 125.6, 124.1 (d, JC,F = 9.0 Hz),
(400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.81 (d, J = 7.6 Hz, 2 H),
7.63 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.16–7.29 (m,
4 H), 7.09 (s, 1 H), 6.69–6.79 (m, 2 H), 4.14 (d, J = 12.0 Hz, 1 H),
3.63 (s, 1 H), 3.42 (dd, J = 3.6, 12.8 Hz, 1 H), 2.46 (s, 3 H), 0.95
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 163.1 (d,
2
2
115.7 (d, JC,F = 23.5 Hz), 107.9 (d, JC,F = 23.1 Hz), 69.9, 61.6,
46.1, 38.7, 21.6, 13.3 ppm. HRMS (ESI): calcd. for C28H26FN2O4S
[M + H]+ 505.1592; found 505.1582.
Ethyl (Z)-9-Benzylidene-6-chloro-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3d): 1H NMR (400 MHz,
CDCl3): δ = 8.14 (s, 1 H), 7.74 (d, J = 7.2 Hz, 2 H), 7.61 (d, J =
8.4 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 2 H),
7.16–7.29 (m, 4 H), 7.14 (s, 1 H), 4.03 (d, J = 13.2 Hz, 1 H), 3.67–
3.71 (m, 3 H), 3.52 (dd, J = 4.0, 13.2 Hz, 1 H), 2.45 (s, 3 H), 0.76
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3,
145.3, 141.2, 140.5, 139.6, 136.4, 134.1, 134.0, 130.1, 129.1, 128.6,
128.3, 128.1, 127.8, 127.2, 125.0, 122.9, 122.2, 69.5, 61.7, 46.3, 38.4,
21.8, 13.4 ppm. HRMS (ESI): calcd. for C28H26ClN2O4S
[M + H]+ 521.1296; found 521.1306.
3
1JC,F = 244.3 Hz), 144.9, 143.5 (d, JC,F = 8.8 Hz), 141.0, 140.4,
136.7, 134.5, 134.3, 130.0, 129.3, 128.4, 127.7, 127.1, 125.4, 123.9
3
2
2
(d, JC,F = 8.9 Hz), 115.4 (d, JC,F = 23.5 Hz), 107.8 (d, JC,F
=
22.1 Hz), 81.8, 77.3, 70.3, 46.2, 38.6, 27.0, 21.5 ppm. HRMS (ESI):
calcd. for C30H29FN2O4S [M + H]+ 533.1905; found 533.1938.
Ethyl (Z)-9-Benzylidene-4-methyl-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3k): 1H NMR (400 MHz,
CDCl3): δ = 8.00 (s, 1 H), 7.55–7.22 (m, 4 H), 7.60 (d, J = 7.6 Hz,
1 H), 7.22–7.37 (m, 7 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.11 (s, 1 H),
4.41–4.25 (m,1 H), 4.01–4.13 (m, 2 H), 3.59 (d, J = 6.0 Hz, 1 H),
2.44 (m, 3 H), 1.08 (t, J = 6.8 Hz, 3 H), 0.66 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3, 144.7, 142.3, 140.9,
136.3, 135.4, 130.8, 130.1, 128.8, 128.4, 127.6, 127.3, 127.1, 124.4,
120.7, 71.5, 62.0, 50.7, 49.6, 21.6, 15.1, 13.8 ppm. HRMS (ESI):
calcd. for C29H28N2O4S [M + H]+ 501.1843; found 501.1863.
Ethyl (Z)-9-Benzylidene-6-methyl-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3f): 1H NMR (400 MHz,
CDCl3): δ = 8.09 (s, 1 H), 7.74 (d, J = 7.6 Hz, 2 H), 7.63 (d, J =
8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.19–7.34 (m, 5 H), 7.11
(s, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.62 (s, 1 H), 4.13 (dd, J = 1.2,
12.8 Hz, 1 H), 3.54–3.70 (m, 3 H), 3.42 (dd, J = 4.0, 12.8 Hz, 1 H),
2.43 (s, 3 H), 2.21 (s, 3 H), 0.73 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 171.8, 144.8, 141.6, 141.1, 139.0,
138.7, 138.4, 136.9, 134.5, 130.0, 129.3, 129.0, 128.2, 127.3, 123.3,
123.2, 121.0, 69.5, 61.5, 46.5, 38.6, 21.6, 21.5, 13.4 ppm. HRMS
(ESI): calcd. for C29H28N2O4S [M + H]+ 501.1843; found 501.1831.
Ethyl (Z)-9-Benzylidene-4-propyl-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3l): 1H NMR (400 MHz,
CDCl3): δ = 7.99 (s, 1 H), 7.81 (d, J = 8.4 Hz, 2 H), 7.73 (d, J =
7.6 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.23–7.37 (m, 7 H), 7.11
(t, J = 3.6 Hz, 2 H), 4.10–4.15 (m, 1 H), 3.91–4.00 (m, 2 H), 3.34
(d, J = 6.0 Hz, 1 H), 1.07–1.26 (m, 3 H), 1.00 (t, J = 7.2 Hz, 3 H),
0.76–0.79 (m, 1 H), 0.64 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.1, 144.5, 142.4, 141.4, 140.8, 140.5,
136.9, 135.5, 130.8, 130.0, 128.7, 128.3, 127.6, 127.3, 127.0, 124.4,
124.3, 120.7, 61.9, 55.2, 50.8, 30.1, 21.6, 19.6, 13.7, 13.6 ppm.
HRMS (ESI): calcd. for C31H32N2O4S [M + H]+ 529.2156; found
529.2186.
Ethyl
(Z)-9-Benzylidene-6,7-dimethoxy-3-tosyl-4,4a,9,9a-tetra-
hydro-3H-indeno[2,1-d]pyrimidine-9a-carboxylate (3g): 1H NMR
(400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.75 (d, J = 7.6 Hz, 2 H),
7.62 (d, J = 8.4 Hz, 2 H), 7.20–7.34 (m, 5 H), 7.02 (s, 1 H), 6.98
(s, 1 H), 6.45 (s, 1 H), 4.13 (dd, J = 1.6, 12.4 Hz, 1 H), 3.92 (s, 3
H), 3.77 (s, 3 H), 3.55–3.72 (m, 3 H), 3.37 (dd, J = 3.6, 12.8 Hz, 1
H), 2.42 (s, 3 H), 0.73 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.8, 150.5, 150.0, 145.0, 141.8, 141.2, Ethyl (Z)-9-(4-Methylbenzylidene)-3-tosyl-4,4a,9,9a-tetrahydro-3H-
137.0, 134.6, 133.4, 131.6, 130.1, 128.9, 128.5, 128.2, 127.1, 121.9,
105.2, 103.5, 69.7, 61.5, 56.1, 55.9, 46.8, 38.9, 21.5, 13.8 ppm.
indeno[2,1-d]pyrimidine-9a-carboxylate (3m): 1H NMR (400 MHz,
CDCl3): δ = 8.09 (s, 1 H), 7.61–7.64 (m, 4 H), 7.52 (d, J = 8.0 Hz,
770
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 767–771

Generation of Tetrahydro-3H-indeno[2,1-d]pyrimidines
[2]
[3]
a) L. Lu, J. Chen, W. Xiao, Acc. Chem. Res. 2012, 45, 1278; b)
U. Wille, Chem. Rev. 2013, 113, 813; c) H. Pellissier, Chem.
Rev. 2013, 113, 442; d) V. A. Peshkov, O. P. Pereshivko, E. V.
Van der Eycken, Chem. Soc. Rev. 2012, 41, 3790; e) J. Poulin,
C. M. Grisé-Bard, L. Barriault, Chem. Soc. Rev. 2009, 38, 3092;
f) P. Lu, Y. Wang, Synlett 2010, 165; g) E. J. Yoo, S. Chang,
Curr. Org. Chem. 2009, 13, 1766; h) S. H. Kim, S. H. Park, J. H.
Choi, S. Chang, Chem. Asian J. 2011, 6, 2618; i) H. Ohno,
Asian J. Org. Chem. 2013, 2, 18.
a) D. P. Walsh, Y. Chang, Chem. Rev. 2006, 106, 2476; b) P.
Arya, D. T. H. Chou, M. G. Baek, Angew. Chem. 2001, 113,
351; Angew. Chem. Int. Ed. 2001, 40, 339; c) S. L. Schreiber,
Science 2000, 287, 1964; d) M. D. Burke, S. L. Schreiber, An-
gew. Chem. 2004, 116, 48; Angew. Chem. Int. Ed. 2004, 43, 46;
e) S. L. Schreiber, Nature 2009, 457, 153; f) D. S. Tan, Nat.
Chem. Biol. 2005, 1, 74; g) C. Cordier, D. Morton, S. Murrison,
A. Nelson, C. O’Leary-Steele, Nat. Prod. Rep. 2008, 25, 719;
h) W. R. J. D. Galloway, A. I. Llobet, D. R. Spring, Nat. Com-
mun. 2010, 1, 80; i) S. Oh, S. B. Park, Chem. Commun. 2011,
47, 12754.
a) D. Zheng, S. Li, Y. Luo, J. Wu, Org. Lett. 2011, 13, 6402; b)
G. Qiu, J. Wu, Chem. Commun. 2012, 48, 6046; c) D. Zheng,
S. Li, J. Wu, Chem. Commun. 2012, 48, 8568; d) D. Zheng, S.
Li, J. Wu, Org. Lett. 2012, 14, 2655; e) S. Li, J. Wu, Chem.
Commun. 2012, 48, 8973.
For reviews, see: a) M. Suginome, Y. Ito, in: Science of Synthe-
sis vol. 19 (Ed.: S.-I. Murahashi), Thieme, Stuttgart, Germany,
2004, p. 445; b) A. Dömling, Chem. Rev. 2006, 106, 17; c) A.
Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew. Chem.
Int. Ed. 2000, 39, 3168; d) A. V. Lygin, A. D. Meijere, Angew.
Chem. 2010, 122, 9280; Angew. Chem. Int. Ed. 2010, 49, 9094;
e) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru, V. G.
Nenajdenko, Chem. Rev. 2010, 110, 5235.
1 H), 7.21–7.27 (m, 3 H), 7.14 (d, J = 8.0 Hz, 3 H), 7.02 (t, J =
6.8 Hz, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 4.16 (dd, J = 0.8, 12.8 Hz,
1 H), 3.58–3.74 (m, 3 H), 3.42 (dd, J = 4.0, 12.8 Hz, 1 H), 2.44 (s,
3 H), 2.32 (s, 3 H), 0.76 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.9, 144.8, 141.2, 141.1, 140.8, 138.7,
137.3, 134.5, 133.9, 130.0, 129.0, 128.9, 128.4, 128.1, 127.3, 124.4,
122.6, 121.0, 69.6, 61.5, 46.7, 38.6, 21.6, 21.3, 13.4 ppm. HRMS
(ESI): calcd. for C29H28N2O4S [M + H]+ 501.1843; found 501.1850.
Ethyl (Z)-9-(4-Chlorobenzylidene)-3-tosyl-4,4a,9,9a-tetrahydro-3H-
indeno[2,1-d]pyrimidine-9a-carboxylate (3n): 1H NMR (400 MHz,
CDCl3): δ = 8.06 (s, 1 H), 7.71 (d, J = 8.8 Hz, 2 H), 7.62 (d, J =
8.4 Hz, 2 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.22–7.31 (m, 5 H), 7.10
(s, 1 H), 7.05 (t, J = 7.2 Hz, 1 H), 6.84 (d, J = 7.2 Hz, 1 H), 4.16
(d, J = 12.8 Hz, 1 H), 3.63–3.75 (m, 3 H), 3.41 (dd, J = 4.0, 12.8 Hz,
1 H), 2.44 (s, 3 H), 0.79 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.7, 144.9, 142.3, 141.3, 140.6, 139.0,
135.3, 134.4, 133.3, 130.5, 130.1, 128.8, 128.4, 128.2, 127.3, 122.9,
122.8, 121.2, 69.5, 61.6, 46.7, 38.6, 21.6, 13.5 ppm. HRMS (ESI):
calcd. for C28H26ClN2O4S [M + H]+ 521.1296; found 521.1309.
[4]
[5]
Ethyl (Z)-9-(4-Methoxybenzylidene)-3-tosyl-4,4a,9,9a-tetrahydro-
3H-indeno[2,1-d]pyrimidine-9a-carboxylate
(3o):
1H
NMR
(400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.70 (d, J = 8.4 Hz, 2 H),
7.62 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.21–7.27 (m,
3 H), 7.12 (s, 1 H), 7.01 (t, J = 7.6 Hz, 1 H), 6.88 (dd, J = 1.6,
6.8 Hz, 2 H), 6.81 (d, J = 7.6 Hz, 1 H), 4.16 (d, J = 12.8 Hz, 1 H),
3.80 (s, 3 H), 3.66–3.76 (m, 3 H), 3.42 (dd, J = 3.6, 12.4 Hz, 1 H),
2.44 (s, 3 H), 0.79 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.0, 159.1, 144.8, 141.1, 139.9, 138.5, 134.5, 130.6,
130.0, 129.6, 128.2, 128.1, 127.3, 124.0, 122.6, 120.9, 113.6, 69.6,
61.8, 55.2, 46.8, 38.7, 21.6, 13.5 ppm. HRMS (ESI): calcd. for
C29H28N2O5S [M + H]+ 517.1792; found 517.1771.
[6] For selected examples, see: a) Y. Li, X. Xu, J. Tan, C. Xia, D.
Zhang, Q. Liu, J. Am. Chem. Soc. 2011, 133, 1775; b) H. Zhou,
W. Zhang, B. Yan, J. Comb. Chem. 2010, 12, 206; c) D. Monge,
K. L. Jensen, I. Marín, K. A. Jørgensen, Org. Lett. 2011, 13,
328; d) U. Schöllkopf, Angew. Chem. 1977, 89, 351; Angew.
Chem. Int. Ed. Engl. 1977, 16, 339; e) A. V. Lygin, O. V. La-
rionov, V. S. Korotkov, A. de Meijere, Chem. Eur. J. 2009, 15,
227; f) C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem.
Soc. 2006, 128, 10662; g) O. V. Larionov, A. de Meijere, Angew.
Chem. 2005, 117, 5809; Angew. Chem. Int. Ed. 2005, 44, 5664;
h) S. Kamijo, C. Kanazawa, Y. Yamamoto, J. Am. Chem. Soc.
2005, 127, 9260; i) H. Takaya, S. Kojima, S. Murahashi, Org.
Lett. 2001, 3, 421; j) M.-A. Bonin, D. Giguere, R. Roy, Tetrahe-
dron 2007, 63, 4912; k) D. Benito-Garagorri, V. Bocokiae, K.
Kirchner, Tetrahedron Lett. 2006, 47, 8641; l) Q. Cai, Z. Tao,
T. Xu, L. Fu, K. Ding, Org. Lett. 2011, 13, 340.
[7] For selected examples, see: a) A. Fayol, J. Zhu, Org. Lett. 2004,
6, 115; b) A. Fayol, J. Zhu, Org. Lett. 2007, 9, 239; c) R. Mos-
setti, T. Pirali, G. C. Tron, J. Zhu, Org. Lett. 2010, 12, 820; d)
S. Wang, M. Wang, D. Wang, J. Zhu, Org. Lett. 2007, 9, 3615;
e) T. Yue, M. Wang, D. Wang, G. Masson, J. Zhu, Angew.
Chem. 2009, 121, 6845; Angew. Chem. Int. Ed. 2009, 48, 6717;
f) D. Bonne, M. Dekhane, J. Zhu, Angew. Chem. Int. Ed. 2006,
45, 2485; g) A. Fayol, J. Zhu, Angew. Chem. 2002, 114, 3785;
Angew. Chem. Int. Ed. 2002, 41, 3633; h) C. Lalli, M. J. Bouma,
D. Bonne, G. Masson, J. Zhu, Chem. Eur. J. 2011, 17, 880.
[8] X. Du, S. Yang, J. Yang, Y. Liu, Chem. Eur. J. 2011, 17, 4981.
[9] Z. Zhang, M. Shi, Chem. Eur. J. 2010, 16, 7725, and references
cited therein.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H and
13C NMR spectra of compounds 3.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (NSFC) (grant numbers 21032007 and 21172038) is grate-
fully acknowledged.
[1] For reviews, see: a) J. Montgomery, Angew. Chem. 2004, 116,
3980; Angew. Chem. Int. Ed. 2004, 43, 3890; b) E. Negishi, C.
Coperet, S. Ma, S. Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365;
c) L. F. Tietze, Chem. Rev. 1996, 96, 115; d) R. Grigg, V. Srid-
haran, J. Organomet. Chem. 1999, 576, 65; e) T. Miura, M.
Murakami, Chem. Commun. 2007, 43, 217; f) M. Malacria,
Chem. Rev. 1996, 96, 289; g) K. C. Nicolaou, T. Montagnon,
S. A. Snyder, Chem. Commun. 2003, 39, 551; h) K. C. Nico-
laou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
7292; Angew. Chem. Int. Ed. 2006, 45, 7134; i) D. Enders, C.
Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119, 1590; An-
gew. Chem. Int. Ed. 2007, 46, 1570; j) L. F. Tietze, G. Brasche,
K. Gericke, Domino Reactions in Organic Synthesis Wiley-
VCH, Weinheim, Germany, 2006; k) L. F. Tietze, M. A. Düfert,
T. Hungerland, K. Oum, T. Lenzer, Chem. Eur. J. 2011, 17,
8452; l) J. Panteleev, L. Zhang, M. Lautens, Angew. Chem.
2011, 123, 9255; Angew. Chem. Int. Ed. 2011, 50, 9089.
Received: September 18, 2013
Published Online: November 26, 2013
Eur. J. Org. Chem. 2014, 767–771
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
771