One-pot Van Leusen synthesis of 4,5-disubstituted oxazoles in ionic liquids

Article abstract of DOI:10.1055/s-0028-1087547

An efficient and mild protocol for the preparation of 4,5-disubstituted oxazoles through an improved one-pot van Leusen oxazole synthesis in ionic liquids is described. The oxazole products were prepared from tosylmethyl isocyanide (TosMIC), aliphatic hal

Full text of DOI:10.1055/s-0028-1087547

500
LETTER
One-Pot Van Leusen Synthesis of 4,5-Disubstituted Oxazoles in Ionic Liquids
One-Pot
Van
L
eu
o
se
n
Synthesis of
4W
u
s
in Ionic
L
,
iquids Jun Wen, Ji Zhang, Jing Li, Yong-Zhe Xiang, Xiao-Qi Yu*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu,
Sichuan 610064, P. R. of China
Fax +86(28)85415886; E-mail: xqyu@scu.edu.cn
Received 8 October 2008
for the formation of 7 as final products in next step. There-
Abstract: An efficient and mild protocol for the preparation of 4,5-
fore, by combining Method C and the van Leusen oxazole
disubstituted oxazoles through an improved one-pot van Leusen ox-
reaction, we studied the one-pot synthesis of 7, in which
two steps were involved, from TosMIC 4, aliphatic ha-
azole synthesis in ionic liquids is described. The oxazole products
were prepared from tosylmethyl isocyanide (TosMIC), aliphatic ha-
lides and various aldehydes in high yields. The recovered ionic liq- lides 5 and aldehydes 6 in ionic liquids.
uids could be reused as solvent for six runs without significant loss
of yields.
R1CH2NC
1
Key words: ionic liquids, van Leusen oxazole synthesis, tosyl-
methyl isocyanide, halides, aldehydes
BuLi
method A
TsF
N
method B
Ts NHCHO
method C
Oxazole ring, as a fundamental construction unit, exists in
a large number of pharmacological compounds.1 There-
fore, many strategies for the synthesis of oxazoles have
been developed,2 but only a few approaches are available
for the preparation of 4,5-disubstituted oxazoles 7.3
Among these protocols, a rather convenient and attractive
way is the cyclocondensation between aldehydes 6 and
monosubstituted tosylmethyl isocyanide 2 developed by
van Leusen et al.3i,j However, the bottleneck of this proce-
dure lies with the preparation of precursors 2.
NaOH
H
C
CH
R1
H2
C
PTC
Ts
C
Ts
N C
R1X
POCl3
Et3N
R1
3
5
4
2
MeOH
K2CO3
reflux
R2CHO
van Leusen reaction
6
O
N
R2
Today, ionic liquids have shown their significant role in
controlling reactions as solvents or catalysts.4 They have
been recognized as an alternative green reaction media be-
cause of their unique chemical and physical properties, in-
cluding nonvolatility, high polarity, thermal stability,
nonflammability, controlled miscibility and recyclability.
We have recently shown that van Leusen pyrrole synthe-
sis could be efficiently carried out from tosylmethyl iso-
cyanide (TosMIC; 4) and nitroolefins in ionic liquids.5
Subsequently, we further extended our studies to explore
the novel uses of ionic liquids in van Leusen oxazole-
forming reaction.
R1
7
Scheme 1
In this study, 1-bromobutane (5a) was used to optimize
the reaction conditions for the preparation of precursors 2,
and the results are summarized in Table 1. Both the base
used and the temperature employed had considerable ef-
fects on the reaction, but the anion of ionic liquids had
nearly no influence. In the presence of a strong base such
as NaOH and KOH, the reactions in [bmim]Br were much
faster (entries 1 and 7) than those with a weaker base such
as K2CO3 (entry 8). However, the reactions with strong
bases always led to the decreased yields of 2a due to the
formation of disubstituted product 8a and the decomposi-
tion of TosMIC. On the other hand, no products were de-
tected with Na2CO3 (entry 19). The reactions in [bmim]Br
(1-butyl-3-methylimidazolium bromide), [bmim][BF4]
(1-butyl-3-methylimidazolium fluoroborate) and [bmim]-
[PF6] (1-butyl-3-methylimidazolium hexafluorophosphate)
gave almost same results (entries 8, 17 and 18). In these
reactions, the target compound 2a could be obtained in
high yields without any formation of disubstituted
byproduct. Methanol, a traditional solvent for van Leusen
oxazole synthesis, was tested, and the results indicated
that no substituted products were found (entries 3 and 10).
As shown in Scheme 1, monosubstituted TosMIC precur-
sors 2 could be prepared by three methods. The drawbacks
of method A6 are the toxicity and instability of alkyl iso-
cyanides 1. Method B7 is suitable for both aryl- and alkyl-
substituted TosMIC, but the synthesis of isocyanides pre-
cursors 3 is expensive, and the yield of 2 is moderate.
Method C,8 although it is unsuitable for the halide 5 when
R1 = Ar or t-Bu, and the total yields of 7 were moderate
(32–78%)3i,j with occasional formation of a disubstituted
side products, works well with primary alkyl halides, and
the basic reaction conditions are similar to those required
SYNLETT 2009, No. 3, pp 0500–0504
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087547; Art ID: W15808ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Van Leusen Synthesis of 4,5-Disubstituted Oxazoles in Ionic Liquids
501
Table 1 Optimization of Monosubstitution Reaction Conditionsa
n-Bu
H2
C
H
C
+
+
Ts
Ts
N C
Ts
N
C
C
N C
n-BuBr
n-Bu
n-Bu
5a
Entry
1
4
2a
8a
Base
Solvent
[bmim]Br
Temp (°C)
Time (h)b
Yield (%)c of 2a
Yield (%)c of 8a
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
4
4
50
33
0
20
15
0
2
[bmim]Br–H2Od
MeOH
3
4
4
[bmim]Br–MeOHd
THF
4
25
20
30
42
95
75
0
15
30
25
27
0
5
10
10
4
6
MeCN
7
[bmim]Br
[bmim]Br
[bmim]Br–H2Od
MeOH
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
r.t
12
10
6
9
r.t
0
10
11
12e
13e
14
15
16
17
18
19e
r.t
0
[bmim]Br–MeOHd
THF
r.t
6
35
trace
trace
95
90
75
95
94
0
10
0
r.t.
r.t.
0
24
24
12
6
MeCN
0
[bmim]Br
[bmim]Br
[bmim]Br
[bmim][BF4]
[bmim][PF6]
[bmim]Br
0
40
60
r.t
0
4
5
10
10
24
0
r.t
0
r.t
0
a Reaction conditions: 5a (1.5 mmol), base (2 mmol), TosMIC 4 (1 mmol), solvent (2.5 mL).
b Monitored by TLC (PE–EtOAc, 5:1).
c Isolated yields, product was identified by 1H NMR and 13C NMR.
d Ratio of volume (2:1).
e About 70% of TosMIC was recovered.
Absolutely anhydrous condition was not necessary for the monoalkyl products were obtained in excellent yields
reaction, but the addition of water or methanol to the reac- from TosMIC and primary aliphatic halides including al-
tion resulted in a lower yield of 2a with the formation of lyl bromide (entry 7) and benzyl halides (entries 5 and 6).
8a (entries 2, 4, 9 and 11). Other solvents, such as THF Secondary alkyl halide also gave monosubstituted
and acetonitrile were also tested. However, both 2a and 8a TosMIC in good yield (entry 8). For tertiary alkyl halides,
were obtained in the presence of NaOH (entries 5 and 6), this method failed due to the steric hindrance. Further-
but no reaction product was found with K2CO3 (entries 12 more, aryl halides could not give any desired products.
and 13). Because of the instability of TosMIC, higher
Subsequent studies were then focused on the one-pot syn-
temperatures (entries 15 and 16) were not suitable for the
thesis of 4,5-disubstituted oxazoles. After a brief optimi-
reaction. So the conditions in entry 6 were chosen for next
zation, the generality of the present synthetic method was
extended to different aliphatic halides and aldehydes. The
investigations.
In order to evaluate the scope of this reaction sequence, a results are listed in Table 3. Treatment of different alde-
series of products 2a–g, serving as cyclocondensation pre- hydes with monosubstituted TosMIC formed in situ af-
cursors for the van Leusen oxazole synthesis, was pre- forded the corresponding 4,5-disubstituted oxazoles 7 in
pared on the basis of the success of the monosubstitution high yields. Aliphatic aldehydes (entries 13, 14, 17 and
model system. From the results listed in Table 2, all 19) had only slightly lower yields than the reactions using
Synlett 2009, No. 3, 500–504 © Thieme Stuttgart · New York

502
B. Wu et al.
LETTER
Table 2 Preparation of Monosubstituted TosMIC from Aliphatic
Table 3 One-Pot Preparation of 4,5-Disubstituted Oxazoles 7 from
Halides and TosMIC in [bmim]Bra,9
Aliphatic Halides, TosMIC and Aldehydes in [bmim]Bra,b,10,11
H2
C
O
[bmIm]Br, K2CO3
H
C
R1X
H2
C
[bmIm]Br, K2CO3
+
Ts
N C
Ts
N C
N
R2
Ts
N C
1. R1X
2. R2CHO
R1
R1
7a–t
2a–g
5a–h
4
5a,c,f–h
6a–p
4
Entry R1X
Temp Timeb Product Yield
Entry R1
R2
Product Yield (%)c
7a
(°C)
r.t.
0
(h)
12
4
(%)c
95
96
96
90
90
95
94
80
1
2
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
n-Bu (5a)
Et (5c)
Ph (6a)
85
80
82
90
85
78
82
86
88
81
82
90
78
75
87
85
80
87
80
75
1
2
3
4
5
6
7
8d
BuBr (5a)
MeI (5b)
EtBr (5c)
2a
2b
2c
2d
2e
2e
2f
4-MeOC6H4 (6b) 7b
3
4-MeC6H4 (6c)
4-FC6H4 (6d)
4-BrC6H4 (6e)
2-ClC6H4 (6f)
3-ClC6H4 (6g)
4-ClC6H4 (6h)
4-O2NC6H4 (6i)
1-naphthyl (6j)
styryl (6k)
1-furyl (6l)
i-Bu (6m)
7c
7d
7e
7f
r.t.
r.t.
r.t
10
12
6
4
Me(CH2)7Br (5d)
BnBr (5e)
5
6
BnCl (5f)
r.t.
10
10
24
7
7g
7h
7i
CH2=CHCH2Br (5g) r.t.
8
i-PrBr (5h) r.t.
2g
9
a Reaction conditions: 5a–h (1.5 mmol), K2CO3 (2 mmol), TosMIC 4
(1 mmol), [bmim]Br (2.5 mL).
10
11
12
13d
14d
15
16
17d
18
19d
20e
7j
b Monitored by TLC (PE–EtOAc, 5:1).
c Isolated yields, product was identified by 1H NMR and 13C NMR.
d Amount of 5h used: 2 mmol.
7k
7l
aromatic and heterocyclic aldehydes as substrates (entries
1–12, 15, 16 and 18). Aromatic aldehydes with electron-
withdrawing group displayed higher reactivity (entries 4
and 9). On the other hand, steric effects of either ortho
substituents on aryl ring (entry 6) or secondary alkyl ha-
lide (entry 20) decreased the yields.
7m
7n
7o
7p
7q
7r
7s
7t
c-Hex (6n)
Ph (6a)
Bn (5f)
Ph (6a)
The recyclability of ionic liquid for the one-pot van
Leusen oxazole synthesis was investigated on a relatively
larger scale (15 mL; Table 4). After completion of the first
run, the reaction mixture was poured into equal volume of
water and extracted with diethyl ether. Evaporation of wa-
ter layer under reduced pressure gave the recovered ionic
liquid, which could be used in the next run. The recovered
Bn (5f)
n-Pr (6o)
allyl (5g)
allyl (5g)
i-Pr (5h)
Ph (6a)
n-Hex (6p)
Ph (6a)
a Reaction conditions: K2CO3 (3 mmol), aliphatic halides 5 (1.5
mmol), TosMIC (4; 1 mmol), [bmim]Br (2.5 mL), after 4 was con-
sumed, aldehyde 6 (1.2 mmol) was added. After about another 10 h
the reaction was complete.
Table 4 Recycling of Ionic Liquid Solvent
b Monitored by TLC (PE–EtOAc, 5:1).
Entry
Run
1b
Yield (%)a
c Isolated yields; product was identified by 1H NMR, 13C NMR and
GC–MS.
1
2
3
4
5
6
85
82
78
75
70
64
d Aliphatic aldehyde 6 (2 mmol).
2c
e Amount of 5h used: 2 mmol.
3c
ionic liquid could be reused for several times with slight
decrease of reaction yields in each run.
4c,d
5c
In conclusion, we have demonstrated that the synthesis of
4,5-disubstituted oxazoles could be achieved in one pot
from TosMIC, aliphatic halides and aldehydes. The im-
proved van Leusen oxazole synthesis offers marked im-
provements with regard to its operational simplicity, mild
conditions, general applicability, high isolated yields of
products, and recyclable green solvent. Although it was
not suitable for tertiary alkyl or aryl halides, it provides a
6c
a Isolated yields; product was identified by GC–MS.
b Reaction conditions: K2CO3 (15 mmol), 5a (7.5 mmol), TosMIC (5
mmol), [bmim]Br (15 mL), 6a (6 mmol).
c Reaction conditions: K2CO3 (7.5 mmol), 5a (7.5 mmol), TosMIC (5
mmol), recycled [bmim]Br (about 15ml), 6a (6 mmol).
d Another 2 mL of fresh [bmim]Br was added.
Synlett 2009, No. 3, 500–504 © Thieme Stuttgart · New York

LETTER
One-Pot Van Leusen Synthesis of 4,5-Disubstituted Oxazoles in Ionic Liquids
503
combined organics were washed with H2O and brine. The
organic phase was dried over Na2SO4, and concentrated in
vacuum. The crude product was purified by chromatography
on silica gel (PE–EtOAc, 4:1) to provide pure compound 2a
(95%).
practical alternative procedure better than the existing
methods.3
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(10) Representative Preparation of 4,5-Disubstituted
Oxazoles: 1-Bromobutane (5a; 0.206 g, 1.5 mmol) was
added to the mixture of TosMIC (4; 0.195 g, 1 mmol),
K2CO3 (0.414 g, 3 mmol) and [bmim]Br (2.5 mL). After
vigorous stirring 12 h at r.t., 4 was consumed, and
benzaldehyde (6a; 0.127 g, 1.2 mmol) was added. After
about 10 h of stirring, the mixture was poured into H2O (10
mL), and was extracted with Et2O (3 × 10 mL). The
combined organics were washed with H2O and brine. The
organic phase was dried over Na2SO4, and concentrated in
vacuum. The crude product was purified by chromatography
on silica gel (PE–EtOAc, 10:1) to provide pure compound
7a (85%).
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (Nos.: 20725206 and 20732004) and the
Specialized Research Fund for the Doctoral Program of Higher
Education.
References and Notes
(1) (a) Wipf, P. Chem. Rev. 1995, 95, 2115. (b) Janvier, P.;
Sun, X.; Bienayme, H.; Zhu, J. J. Am Chem. Soc. 2002, 124,
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Petrillo, D. E.; Leone, J. F.; Laquidara, J.; Marcune, B.;
Karady, S.; Armstrong, J. D.; Volante, R. P. Tetrahedron
Lett. 2005, 46, 1867.
(2) (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389.
(b) Wasserman, H. H.; McCarthy, K. E.; Prowse, K. S.
Chem. Rev. 1986, 86, 845. (c) Yeh, V. S. C. Tetrahedron
2004, 60, 11995. (d) Martin, R.; Cuenca, A.; Buchwald,
S. L. Org. Lett. 2007, 9, 5521. (e) Herrera, A.; Martinez-
Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J. J. Org. Chem.
2006, 71, 3026. (f) Davies, J. R.; Kane, P. D.; Moody, C. J.
Tetrahedron 2004, 60, 3967.
(3) (a) Brahma, S.; Ray, J. K. J. Heterocycl. Chem. 2008, 45,
311. (b) Li, B.; Buzon, R. A.; Zhang, Z. J. Org. Process Res.
Dev. 2007, 11, 951. (c) Baumann, M.; Baxendale, I. R.; Ley,
S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231.
(d) Miller, R. A.; Smith, R. M.; Marcune, B. J. Org. Chem.
2005, 70, 9074. (e) Davies, J. R.; Kane, P. D.; Moody, C. J.
Tetrahedron 2004, 60, 3967. (f) Xia, Q.; Ganem, B.
Synthesis 2002, 1969. (g) Ohba, M.; Kubo, H.; Seto, S.;
Fujii, T.; Ishibashi, H. Chem. Pharm. Bull. 1998, 46, 860.
(h) Matsumoto, K.; Suzuki, M.; Yoneda, N.; Miyoshi, M.
Synthesis 1976, 805. (i) Possel, O.; Van Leusen, A.
Heterocycles 1977, 7, 77. (j) van Leusen, A. M.;
Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972,
13, 2369.
(4) For reviews, see: (a) Welton, T. Chem. Rev. 1999, 99, 2071.
(b) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000,
39, 3772. (c) Parvulescu, V. I.; Hardacre, C. Chem. Rev.
2007, 107, 2615. (d) van Rantwijk, F.; Sheldon, R. A. Chem.
Rev. 2007, 107, 2757. (e) Martins, M. A. P.; Frizzo, C. P.;
Moreira, D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev.
2008, 108, 2015. (f) de Maria, P. D. Angew. Chem. Int. Ed.
2008, 47, 2.
(11) Spectroscopic Data for Products:
Compound 2a: 1H NMR (400 MHz, CDCl3): d = 0.91–0.95
(t, J = 14.4 Hz, 3 H), 1.33–1.49 (m, 3 H), 1.56–1.65 (m, 1 H),
1.79–1.88 (m, 1 H), 2.15–2.21 (m, 1 H), 2.48 (s, 3 H), 4.43–
4.46 (m, 1 H), 7.41–7.44 (d, J = 8.0 Hz, 2 H), 7.85–7.87 (d,
J = 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 13.7,
21.8, 21.8, 27.4, 28.2, 73.0, 130.1, 130.2, 131.2, 146.6,
164.9.
Compound 2b: 1H NMR (400 MHz, CDCl3): d = 1.74–1.75
(d, J = 6.8 Hz, 3 H), 2.50 (s, 3 H), 4.60–4.65 (m, 1 H), 7.44–
7.46 (d, J = 8.0 Hz, 2 H), 7.87–7.89 (d, J = 8.0 Hz, 2 H). 13
C
NMR (100 MHz, CDCl3): d = 15.5, 21.8, 68.3, 130.2, 130.7,
146.7, 164.6.
Compound 2c: 1H NMR (400 MHz, CDCl3): d = 1.16–1.19
(t, J = 15.2 Hz, 3 H), 1.84–1.92 (m, 1 H), 2.23–2.29 (m, 1 H),
2.49 (s, 3 H), 4.38–4.42 (m, 1 H), 7.42–7.44 (d, J = 8.0 Hz,
2 H), 7.86–7.88 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): d = 9.9, 21.8, 22.5, 74.2, 130.0, 130.2, 131.3, 146.6,
164.9.
Compound 2d: 1H NMR (400 MHz, CDCl3): d = 0.86–0.90
(t, J = 13.6 Hz, 3 H), 1.27–1.37 (m, 10 H), 1.40–1.48 (m,
1 H), 1.58–1.65 (m, 1 H), 1.78–1.88 (m, 1 H), 2.14–2.22 (m,
1 H), 2.49 (s, 3 H), 4.43–4.47 (m, 1 H), 7.42–7.44 (d, J = 8.0
Hz, 2 H), 7.86–7.88 (d, J = 8.4 Hz, 2 H). 13C NMR (100
MHz, CDCl3): d = 14.3, 22.0, 22.8, 25.6, 28.6, 28.8, 29.2,
29.3, 31.9, 73.2, 130.3, 130.3, 131.4, 146.7, 165.1.
Compound 2e: 1H NMR (400 MHz, CDCl3): d = 2.49 (s, 3
H), 2.96–3.02 (m, 1 H), 3.58–3.62 (m, 1 H), 4.58–4.61 (m, 1
H), 7.26–7.27 (m, 2 H), 7.29–7.37 (m, 3 H), 7.43–7.45 (d,
J = 8.0 Hz, 2 H), 7.90–7.92 (d, J = 8.4 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): d = 21.8, 34.8, 74.2, 128.1, 129.1, 129.3,
130.2, 130.2, 131.2, 133.3, 146.8, 166.0.
Compound 2f: 1H NMR (400 MHz, CDCl3): d = 2.49 (s,
3 H), 2.53–2.61 (m, 1 H), 2.95 (s, 1 H), 4.47–4.51 (m, 1 H),
5.28–5.33 (m, 2 H), 5.73–5.83 (m, 1 H), 7.43–7.45 (d, J = 8.0
Hz, 2 H), 7.87–7.89 (d, J = 8.4 Hz, 2 H). 13C NMR (100
MHz, CDCl3): d = 21.8, 21.8, 29.7, 33.1, 72.3, 121.3, 121.4,
129.3, 130.2, 131.1, 146.7, 165.5.
(5) Wu B., Zhang J., Zheng Z.-G., Yang M., Yu X.-Q.; Chin. J.
Chem.; 2008, in press
(6) van Leusen, A. M.; Boerma, G. J. M.; Helmholdt, R. B.;
Siderius, H.; Strating, J. Tetrahedron Lett. 1972, 2367.
(7) Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H.
Tetrahedron Lett. 1996, 37, 8113.
Compound 2g: 1H NMR (400 MHz, CDCl3): d = 1.16–1.18
(d, J = 6.8 Hz, 3 H), 1.21–1.22 (d, J = 6.4 Hz, 3 H), 2.48 (s,
3 H), 2.70–2.77 (m, 1 H), 4.33–4.34 (d, J = 3.6 Hz, 1 H),
7.41–7.43 (d, J = 8.0 Hz, 2 H), 7.86–7.88 (d, J = 8.0 Hz, 2
H). 13C NMR (100 MHz, CDCl3): d = 16.9, 20.8, 27.9, 30.9,
78.0, 129.6, 130.2, 133.0, 146.4, 165.5.
(8) van Leusen, A. M.; Bouma, R. J.; Possel, O. Tetrahedron
Lett. 1975, 3487.
(9) Representative Preparation of Monosubstituted
TosMIC: 1-Bromobutane (5a; 0.206 g, 1.5 mmol) was
added to the mixture of TosMIC (4; 0.195 g, 1 mmol),
K2CO3 (0.414 g, 3 mmol) and [bmim]Br (2.5 mL). After
vigorous stirring for 12 h at r.t., the mixture was poured into
H2O (10 mL), and was extracted with Et2O (3 × 10 mL). The
Compound 7a: 1H NMR (400 MHz, CDCl3): d = 0.93–0.97
(t, J = 14.8 Hz, 3 H), 1.38–1.48 (m, 2 H), 1.69–1.77 (m, 2 H),
2.75–2.79 (t, J = 15.6 Hz, 2 H), 7.31–7.35 (t, J = 14.8 Hz,
1 H), 7.42–7.46 (t, J = 15.2 Hz, 2 H), 7.59–7.61 (d, J = 8.8
Hz, 2 H), 7.83 (s, 1 H). 13C NMR (100 MHz, CDCl3): d =
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13.9, 22.5, 26.7, 30.8, 125.6, 127.8, 128.7, 129.0, 135.8,
145.3, 149.1. GC–MS (ES): m/z = 201 [M]+.
Hz, 1 H), 7.34–7.38 (t, J = 15.2 Hz, 2 H), 7.47–7.49 (d, J =
7.6 Hz, 2 H), 7.77 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.8, 13.9, 22.3, 31.0, 31.1, 112.5, 112.5, 126.4, 128.0,
128.0, 128.3, 128.4, 128.8, 128.8, 136.7, 136.7, 137.7,
145.1, 149.4, 149.4. GC–MS (ES): m/z = 227 [M]+.
Compound 7b: 1H NMR (400 MHz, CDCl3): d = 0.92–0.96
(m, 3 H), 1.37–1.46 (m, 2 H), 1.68–1.75 (m, 2 H), 2.71–2.75
(t, J = 15.2 Hz, 2 H), 3.84 (s, 3 H), 6.96–6.98 (m, 2 H), 7.51–
7.53 (m, 2 H), 7.80 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.9, 22.5, 26.6, 30.9, 55.3, 114.3, 121.7, 130.1, 130.1,
134.4, 145.4, 148.7, 159.3. GC–MS (ES): m/z = 231 [M]+.
Compound 7c: 1H NMR (400 MHz, CDCl3): d = 0.92–0.96
(t, J = 14.8 Hz, 3 H), 1.37–1.47 (m, 2 H), 1.68–1.76 (m, 2 H),
2.38 (s, 3 H), 2.73–2.77 (t, J = 15.2 Hz, 2 H), 7.23–7.25 (d,
J = 8.0 Hz, 2 H), 7.48–7.50 (d, J = 8.0 Hz, 2 H), 7.81 (s, 1
H). 13C NMR (100 MHz, CDCl3): d = 13.9, 21.2, 22.5, 26.7,
30.9, 125.7, 126.2, 129.5, 135.2, 137.8, 145.5, 148.9. GC–
MS (ES): m/z = 215 [M]+.
Compound 7l: 1H NMR (400 MHz, CDCl3): d = 0.90–0.94
(t, J = 14.4 Hz, 3 H), 1.33–1.43 (m, 2 H), 1.64–1.71 (m, 2 H),
2.75–2.79 (t, J = 15.2 Hz, 2 H), 6.47–6.48 (m, 1 H), 6.54–
6.54 (d, J = 3.2 Hz, 1 H), 7.47 (s, 1 H), 7.76 (s, 1 H). 13
C
NMR (100 MHz, CDCl3): d = 13.8, 22.3, 25.8, 30.8, 107.1,
111.3, 136.0, 138.6, 142.4, 149.0. GC–MS (ES): m/z = 191
[M]+.
Compound 7m: 1H NMR (400 MHz, CDCl3): d = 0.87–0.93
(m, 9 H), 1.28–1.34 (m, 2 H), 1.53–1.59 (m, 2 H), 1.88–1.95
(m, 1 H), 2.37–2.43 (m, 4 H), 7.65 (s, 1 H). 13C NMR (100
MHz, CDCl3): d = 13.9, 22.3, 22.4, 25.3, 28.1, 31.2, 33.5,
135.0, 146.5, 148.9. GC–MS (ES): m/z = 181 [M]+.
Compound 7n: 1H NMR (400 MHz, CDCl3): d = 0.89–0.92
(t, J = 14.4 Hz, 3 H), 1.26–1.35 (m, 6 H), 1.50–1.59 (m, 4 H),
1.70–1.83 (m, 4 H), 2.42–2.49 (m, 2 H), 2.60–2.66 (m, 1 H),
7.64 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.9, 22.3,
25.3, 25.8, 26.3, 31.5, 31.7, 34.8, 132.7, 148.5, 151.1. GC–
MS (ES): m/z = 207 [M]+.
Compound 7d: 1H NMR (400 MHz, CDCl3): d = 0.92–0.96
(t, J = 14.8 Hz, 3 H), 1.36–1.46 (m, 2 H), 1.67–1.75 (m, 2 H),
2.71–2.74 (t, J = 15.2 Hz, 2 H), 7.10–7.16 (m, 2 H), 7.53–
7.58 (m, 2 H), 7.81 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.9, 22.5, 26.6, 30.8, 115.8, 116.0, 125.2, 125.2, 127.5,
135.5, 135.5, 144.6, 149.1, 161.0, 163.5. GC–MS (ES):
m/z = 219 [M]+.
Compound 7e: 1H NMR (400 MHz, CDCl3): d = 0.93–0.96
(t, J = 14.8 Hz, 3 H), 1.39–1.44 (m, 2 H), 1.68–1.74 (m, 2 H),
2.72–2.76 (t, J = 5.6 Hz, 2 H), 7.45–7.47 (d, J = 8.8 Hz, 2 H),
7.56–7.58 (d, J = 8.4 Hz, 2 H), 7.84 (s, 1 H). 13C NMR (100
MHz, CDCl3): d = 13.9, 22.5, 26.7, 30.7, 121.8, 127.1,
127.9, 128.1, 132.0, 136.4, 144.4, 149.3. GC–MS (ES):
m/z = 279 [M]+.
Compound 7o: 1H NMR (400 MHz, CDCl3): d = 1.31–1.35
(t, J = 15.2 Hz, 3 H), 2.78–2.84 (m, 2 H), 7.32–7.35 (t, J =
14.8 Hz, 1 H), 7.41–7.46 (m, 2 H), 7.59–7.61 (d, J = 7.6 Hz,
2 H), 7.84 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.1,
20.3, 125.7, 127.9, 128.8, 128.9, 136.9, 145.1, 149.2. GC–
MS (ES): m/z = 173 [M]+.
Compound 7f: 1H NMR (400 MHz, CDCl3): d = 0.85–0.89
(t, J = 14.4 Hz, 3 H), 1.29–1.35 (m, 2 H), 1.61–1.67 (m, 2 H),
2.51–2.55 (t, J = 15.2 Hz, 2 H), 7.33–7.39 (m, 3 H), 7.49–
7.51 (m, 1 H), 7.91 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.8, 22.3, 25.7, 30.6, 126.7, 127.9, 130.2, 130.5, 131.8,
134.2, 137.9, 143.4, 150.2. GC–MS (ES): m/z = 235 [M]+.
Compound 7g: 1H NMR (400 MHz, CDCl3): d = 0.94–0.97
(t, J = 14.8 Hz, 3 H), 1.38–1.47 (m, 2 H), 1.69–1.77 (m, 2 H),
2.75–2.78 (t, J = 15.2 Hz, 2 H), 7.29–7.31 (m, 1 H), 7.35–
7.39 (t, J = 15.6 Hz, 1 H), 7.46–7.49 (m, 1 H), 7.59–7.60 (t,
J = 3.6 Hz, 1 H), 7.84 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.4, 22.5, 26.7, 30.7, 123.6, 125.6, 127.8, 130.0, 130.6,
134.8, 136.9, 144.1, 149.4. GC–MS (ES): m/z = 235 [M]+.
Compound 7h: 1H NMR (400 MHz, CDCl3): d = 0.93–0.96
(t, J = 14.8 Hz, 3 H), 1.39–1.45 (m, 2 H), 1.68–1.76 (m, 2 H),
2.72–2.76 (t, J = 15.2 Hz, 2 H), 7.39–7.42 (m, 2 H), 7.51–
7.53 (m, 2 H), 7.83 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 13.9, 22.5, 26.7, 30.7, 126.8, 127.4, 129.0, 129.4, 129.4,
133.7, 136.3, 144.4, 149.2. GC–MS (ES): m/z = 235 [M]+.
Compound 7i: 1H NMR (400 MHz, CDCl3): d = 0.95–0.99
(t, J = 14.8 Hz, 3 H), 1.42–1.48 (m, 2 H), 1.72–1.78 (m, 2 H),
2.82–2.86 (t, J = 15.6 Hz, 2 H), 7.77–7.79 (m, 2 H), 7.93 (s,
1 H), 8.30–8.32 (m, 2 H). 13C NMR (100 MHz, CDCl3): d =
13.9, 22.5, 27.1, 30.6, 124.3, 125.7, 128.1, 129.8, 134.9,
139.6, 143.5, 146.7, 150.3. GC–MS (ES): m/z = 246 [M]+.
Compound 7j: 1H NMR (400 MHz, CDCl3): d = 0.82–0.86
(t, J = 14.8 Hz, 3 H), 1.26–1.35 (m, 2 H), 1.63–1.71 (m, 2 H),
2.55–2.59 (t, J = 15.6 Hz, 2 H), 7.50–7.56 (m, 4 H), 7.83–
7.85 (m, 1 H), 7.89–7.95 (m, 2 H), 8.00 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 13.8, 22.4, 25.9, 31.0, 125.1, 125.5,
126.0, 126.3, 126.7, 128.4, 128.5, 129.8, 131.9, 133.8,
137.8, 145.2, 150.2. GC–MS (ES): m/z = 251 [M]+.
Compound 7k: 1H NMR (400 MHz, CDCl3): d = 0.93–0.97
(t, J = 14.8 Hz, 3 H), 1.34–1.43 (m, 2 H), 1.63–1.71 (m, 2 H),
2.60–2.63 (t, J = 4.8 Hz, 2 H), 6.85–6.89 (d, J = 16.4 Hz,
1 H), 6.99–7.03 (d, J = 16.4 Hz, 1 H), 7.26–7.29 (t, J = 12.0
Compound 7p: 1H NMR (400 MHz, CDCl3): d = 4.15 (s,
2 H), 7.19–7.28 (m, 4 H), 7.30–7.35 (m, 2 H), 7.40–7.43 (m,
2 H), 7.59–7.62 (m, 2 H), 7.87 (s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 32.9, 125.9, 126.5, 128.3, 125.5, 128.5, 128.6,
128.9, 133.9, 138.6, 146.6, 149.5. GC–MS (ES): m/z = 235
[M]+.
Compound 7q: 1H NMR (400 MHz, CDCl3): d = 0.89–0.92
(t, J = 14.8 Hz, 3 H), 1.58–1.67 (m, 2 H), 2.55–2.59 (t, J =
14.8 Hz, 2 H), 3.82 (s, 1 H), 7.11–7.22 (m, 4 H), 7.24–7.30
(m, 1 H), 7.70 (s, 2H). 13C NMR (100 MHz, CDCl3): d =
13.6, 21.6, 26.5, 32.1, 126.3, 128.5, 128.6, 133.2, 139.3,
148.0, 149.1. GC–MS (ES): m/z = 235 [M]+.
Compound 7r: 1H NMR (400 MHz, CDCl3): d = 3.53–3.54
(d, J = 6.0 Hz, 2 H), 5.12–5.14 (m, 1 H), 5.17 (s, 1 H), 6.00–
6.10 (m, 1 H), 7.30–7.34 (t, J = 14.4 Hz, 1 H), 7.40–7.44 (t,
J = 15.2 Hz, 2 H), 7.58–7.60 (d, J = 8.0 Hz, 2 H), 7.84 (s,
1 H). 13C NMR (100 MHz, CDCl3): d = 31.4, 116.6, 125.8,
128.2, 128.6, 128.8, 133.1, 134.4, 146.2, 149.4. GC–MS
(ES): m/z = 185 [M]+.
Compound 7s: 1H NMR (400 MHz, CDCl3): d = 0.85–0.88
(t, J = 13.6 Hz, 3 H), 1.27 (s, 6 H), 1.55–1.60 (m, 2 H), 2.57–
2.61 (t, J = 14.8 Hz, 2 H), 3.21–3.23 (d, J = 6.4 Hz, 2 H),
5.05–5.11 (m, 2 H), 5.87–5.96 (m, 1 H), 7.69 (s, 1 H). 13
C
NMR (100 MHz, CDCl3): d = 14.0, 22.5, 24.4, 28.1, 28.7,
30.2, 31.4, 116.0, 131.9, 135.2, 147.9, 148.9. GC–MS (ES):
m/z = 193 [M]+.
Compound 7t: 1H NMR (400 MHz, CDCl3): d = 1.32–1.34
(t, J = 6.8 Hz, 6 H), 3.23–3.30 (m, 1 H), 7.32–7.36 (t, J = 15.2
Hz, 1 H), 7.43–7.46 (t, J = 15.2 Hz, 2 H), 7.57–7.60 (t, J =
8.4 Hz, 2 H) 7.84 (s, 1 H). 13C NMR (100 MHz, CDCl3): d =
22.0, 25.7, 126.1, 128.0, 128.8, 129.0, 140.9, 144.2, 149.4.
GC–MS (ES): m/z = 187 [M]+.
Compound 8a: 1H NMR (400 MHz, CDCl3): d = 0.90–0.94
(t, J = 14.8 Hz, 6 H), 1.29–1.36 (m, 4 H), 1.38–1.46 (m, 2 H),
1.49–1.55 (m, 2 H), 1.88–2.05 (m, 4 H), 2.48 (s, 3 H), 7.40–
7.42 (d, J = 8.0 Hz, 2 H), 7.85–7.87 (d, J = 8.4 Hz, 2 H).
Synlett 2009, No. 3, 500–504 © Thieme Stuttgart · New York

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