An efficient synthesis of 2-(guaiazulen-1-yl)furan derivatives via intramolecular Wittig reactions

Article abstract of DOI:10.1016/j.cclet.2013.04.030

An efficient and mild synthesis of 2-(guaiazulen-1-yl)furans, starting from easily accessible 1-(3-aryl-2-cyanopropenoyl)guaiazulenes, tributylphosphine and acyl chlorides, is described. The strategy employs the intramolecular Wittig protocol as a key step to append the crucial furan ring, leading to the highly functional furans in good yields.

Full text of DOI:10.1016/j.cclet.2013.04.030

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CCLET-2571; No. of Pages 3
Chinese Chemical Letters xxx (2013) xxx–xxx
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Original article
An efficient synthesis of 2-(guaiazulen-1-yl)furan derivatives via intramolecular
Wittig reactions
a
b,
a
Dao-Lin Wang a, , Zhe Dong , Jiao Xu , Di Li
*
*
a College of Chemistry and Chemical Engineering, Liaoning Key Laboratory of Synthesis and Application of Functional Compound, Bohai University, Jinzhou 121003, China
b Cosmetology Department, Jiamusi Institute, Heilongjiang University of Chinese Medicine, Jiamusi 154007, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and mild synthesis of 2-(guaiazulen-1-yl)furans, starting from easily accessible 1-(3-aryl-2-
cyanopropenoyl)guaiazulenes, tributylphosphine and acyl chlorides, is described. The strategy employs
the intramolecular Wittig protocol as a key step to append the crucial furan ring, leading to the highly
functional furans in good yields.
Received 24 January 2013
Received in revised form 3 April 2013
Accepted 9 April 2013
Available online xxx
ß 2013 Dao-Lin Wang and Jiao Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
Keywords:
Guaiazulene
Furan
Intramolecular Wittig reaction
1. Introduction
report on a novel preparation of a number of azulene substituted
furans 4 starting from 1-(3-aryl-2-cyanopropenoyl)guaiazulenes
Furans occupy an important place in the heterocyclic family of
compounds because of their prevalence as a key structural
component in a myriad of natural and pharmaceutical products
[1]. Polyfunctionalized furans are of great importance because
numerous interesting compounds bearing this heterocyclic ring
exhibit a wide array of activities and are also building blocks in
organic synthesis [2]. Although the Wittig reaction is frequently
used in the synthesis of a wide range of heterocycles [3], the
interest in intramolecular Wittig methodology in multisubstituted
furan synthesis has been growing [4].
Guaiazulene (7-isopropyl-1,4-dimethylazulene) is a known
active component of the essential oil of Guaiacum officinalis L.,
and the subject of a number of reports describing its anti-allergenic
and anti-inflammatory activities [5]. Azulene derivatives have
attracted interest in medicine as antiulcer drugs [6], anticancer
agents [7], and as antioxidant therapeutics for neurodegenerative
2, acid chlorides 3 and tributylphosphine (Bu3P), in the presence of
Et3N under mild reaction conditions (Scheme 1).
2. Experimental
A mixture of acid chloride 3 (1.1 equiv) and Bu3P (1.1 equiv)
was dissolved in dry THF (20 mL). A solution of 2 (0.5 mmol) in dry
THF (5.0 mL) was added, which was followed by the addition of
Et3N (1.2 equiv). The reaction mixture was stirred for the indicated
time at room temperature. The progress of the reaction was
monitored by TLC. Upon completion, the reaction was quenched
with aqueous saturated NaHCO3 solution, and the mixture was
extracted with EtOAc (3ꢀ 10 mL). Thereafter, the solvent was
removed by evaporation in vacuo. The residue was purified by
column chromatography on silica gel (160–200 mesh) using n-
hexane/EtOAc (4:1) as eluent to afford 2-(guaiazulen-1-yl)furans
(4a–l).
conditions [8]. To date
a variety of heterocyclic-fused and
substituted azulenes have been synthesized by several methods
and reported on from the viewpoint of chemical properties and
physiological activities [9].
3. Results and discussion
As part of our current studies on the development of new routes
to heterocyclic-substituted azulenes systems [10], we herein
First, to optimize the conditions, 1-(3-phenyl-2-cyanoprope-
noyl)guaiazulene 2a (preparation by Knoevenagel condensation of
the 1-cyanoacetylguaiazulene with aldehydes [10c]) and p-anisoyl
chloride 3a were selected as testing substrates to react with Bu3P
under different reaction conditions (Table 1). We found that
amines, such as pyrrolidine and Et3N, are beneficial for the
* Corresponding authors.
E-mail addresses: wangdaolin@sina.com (D.-L. Wang), xujiao2007@sina.com
(J. Xu).
1001-8417/$ – see front matter ß 2013 Dao-Lin Wang and Jiao Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.030
Please cite this article in press as: D.-L. Wang, et al., An efficient synthesis of 2-(guaiazulen-1-yl)furan derivatives via intramolecular
Wittig reactions, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.04.030

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CCLET-2571; No. of Pages 3
2
D.-L. Wang et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
CN
Bu3P / Et3N
RCOCl (3)
O
R
ArCHO
Ar
CN
O
O
NC
Ar
2
1
4
Scheme 1. Syntheses of 2-(guaiazulen-1-yl)furans.
Table 1
Optimization of reaction conditions on the 1-(3-phenyl-2-cyanopropenoyl)-guaiazulene 2a and p-anisoyl chloride 3a.a
Entry
Solvent
Amine
Amount of amine (equiv)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH2Cl2
CH2Cl2
Toluene
THF
Pyrrolidine
Et3N
1.2
1.2
1.2
1.2
1.2
1.0
1.2
1.5
3
3
4
3
4
3
2
2
56
62
64
75
63
83
91
86
Pyrrolidine
Et3N
Et3N
Et3N
THF
Et3N
THF
Et3N
a
Reactions were performed with 2a (0.5 mmol), 3a (1.1 equiv), and Bu3P (1.2 equiv) in dry solvent (20 mL) under nitrogen, at r.t.
b
Yield of isolated products.
Table 2
Synthesis of 2-(guaiazulen-1-yl)furans 4.
Entry
Ar (2)
R (3)
Time (h)
Producta
Yield (%)b
1
2
Ph (2a)
Ph (3a)
2
2
2
2
1
4
8
7
3
6
6
8
4a
4b
4c
4d
4e
4f
91
89
94
90
95
83
65
70
84
76
84
80
Ph (2a)
4-CH3C6H4 (3b)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-NO2C6H4 (3d)
4-NO2C6H4 (3d)
2-Furyl (3e)
3
Ph (2a)
4
4-CH3C6H4 (2b)
4-CH3OC6H4 (2c)
4-ClC6H4 (2d)
4-CH3C6H4 (2b)
4-CH3OC6H4 (2c)
4-CH3OC6H4 (2c)
Ph (2a)
5
6
7
4g
4h
4i
8
9
10
11
12
CH3 (3f)
4j
4-CH3C6H4 (2b)
4-CH3OC6H4 (2c)
CH3 (3f)
4k
4l
C2H5 (3g)
a
All products were characterized by 1H NMR and IR spectral data [11].
Yield of isolated products.
b
formation of 4a (entries 1–8). The best result was achieved when
Et3N was present in our designed reaction (entry7).
The reaction was optimized by screening solvents, such as
CH2Cl2, CH3CN, toluene and THF. As a result, we determined that
the reaction best proceeded in THF.
Next, we investigated the utility of the reaction and our
protocol with different acyl chlorides 3 (Table 2). It was observed
that aryl-substituted acid chlorides 3a–e (R = Ph, 4-CH3C6H4, 4-
CH3OC6H4, 4-NO2C6H4, and 2-furyl) with electron donating
substituents (3a–c) or a heterocyclic substituent (3e) (entries 1–
6, 9) were converted to the corresponding adducts (4a–f) in higher
yields and shorter reaction times than those with an electron-
withdrawing substitutent (3d) (entries 7, 8). It should be noted
that under the same reaction conditions, the alkyl-substituted acid
chlorides (3f, 3g) (R = CH3, C2H5), gave the corresponding furan 4j–
l in yields of 76%ꢁ84% within 6ꢁ8 h (entries 10–12).
CN
CN
CN
Bu3P
Ar
RCOCl (3)
Ar
Ar
O
O
PBu3+ Cl-
-O
O
+
PBu3
R
6
2
5
Et3N
CN
Et3N+H Cl-
O
R
_
Ar
- P(O) Bu3
O
+
PBu3
R
NC
Ar
4
7
O
Scheme 2. A proposed mechanism for the formation of 4.
Please cite this article in press as: D.-L. Wang, et al., An efficient synthesis of 2-(guaiazulen-1-yl)furan derivatives via intramolecular
Wittig reactions, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.04.030

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D.-L. Wang et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
enamines of 3-oxotetrahydrothiophenes, Chem. Lett. 12 (1983) 1721–1724;
3
On the basis of the experimental results, a plausible reaction
mechanism was proposed (Scheme 2). First, the regioselective Michael
addition of Bu3P toward 2 took place, providing the corresponding
zwitterion 5. The intermediate 5 was in situ acylated with an acid
chloride 3, leading to the formation of 6. Then deprotonation of 6 by
Et3N occurred, and the resulting ylide 7 underwent an intramolecular
Wittig reaction, affording the corresponding furan 4.
(c) K. Fujimori, H. Fukazawa, Y. Nezu, et al., Synthesis of azuleno[1,2-b]pyrrole
and azuleno[1,2-b]furan, Chem. Lett. 15 (1986) 1021–1024.
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(2011) 789–792;
(b) D.L. Wang, J.Y. Yu, W. Li, et al., Synthesis of naphthylazuleno[2, 1-d]pyrimi-
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4. Conclusion
[11] Physical and spectral data 4a: Mp: 154–156 8C; IR (KBr): n 2208 cmꢁ1 (CN);
1H NMR (400 MHz, CDCl3): d 1.40 (d, 6H, J = 6.9 Hz, CH(CH3)2), 2.66 (s, 3H, CH3),
2.76 (s, 3H, CH3), 3.11–3.16 (m, 1H, CH(CH3)2), 7.18 (d, 1H, J = 10.5 Hz), 7.40–7.48
(m, 8H), 7.53–7.56 (m, 3H), 7.90 (s, 1H), 8.29 (s, 1H). Anal. Calcd. for C32H27NO: C
87.04, H 6.16, N 3.17; found: C 87.15, H 6.23, N 3.26. 4b: Mp: 165–167 8C; IR
(KBr): n 2213 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3): d 1.40 (d, 6H, J = 6.9 Hz,
CH(CH3)2), 2.40 (s, 3H, CH3), 2.66 (s, 3H, CH3), 2.75 (s, 3H, CH3), 3.10–3.15 (m, 1H,
CH(CH3)2), 7.21 (d, 1H, J = 10.5 Hz), 7.35–7.48 (m, 7H), 7.50–7.58 (m, 3H), 7.90 (s,
1H), 8.25 (s, 1H). Anal. Calcd. for C33H29NO: C 87.00, H 6.42, N 3.07; found: C
87.16, H 6.51, N 3.14. 4c: Mp: 189–191 8C; IR (KBr): n 2208 cmꢁ1 (CN); 1H NMR
(400 MHz, CDCl3): d 1.41 (d, 6H, J = 6.9 Hz, CH(CH3)2), 2.67 (s, 3H, CH3), 2.75 (s, 3H,
CH3), 3.11–3.17 (m, 1H, CH(CH3)2), 3.80 (s, 3H, OCH3), 6.81 (d, 2H, J = 8.9 Hz), 7.18
(d, 1H, J = 10.5 Hz), 7.40–7.48 (m, 5H), 7.51–7.57 (m, 3H), 7.93 (s, 1H), 8.27 (s, 1H).
Anal. Calcd. for C33H29NO2: C 84.05, H 6.20, N 2.97; found: C 84.23, H 6.31, N 3.15.
4d: Mp: 171–173 8C; IR (KBr): n 2213 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3): d
1.40 (d, 6H, J = 6.9 Hz, CH(CH3)2), 2.42 (s, 3H, CH3), 2.66 (s, 3H, CH3), 2.74 (s, 3H,
CH3), 3.10–3.15 (m, 1H, CH(CH3)2), 3.79 (s, 3H, OCH3), 6.80 (d, 2H, J = 8.7 Hz), 7.18
(d, 1H, J = 10.5 Hz), 7.24–7.27 (m, 4H), 7.42–7.47 (m, 4H), 7.52 (d, 1H, J = 10.5 Hz),
7.92 (s, 1H), 8.26 (s, 1H). Anal. Calcd. for C34H31NO2: C 84.09, H 6.43, N 2.88;
found: C 84.17, H 6.59, N 3.04. 4e: Mp: 161–163 8C; IR (KBr): n 2216 cmꢁ1 (CN);
1H NMR (400 MHz, CDCl3): d 1.39 (d, 6H, J = 6.9 Hz, CH(CH3)2), 2.66 (s, 3H, CH3),
2.74 (s, 3H, CH3), 3.08–3.17 (m, 1H, CH(CH3)2), 3.79 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 6.81 (d, 2H, J = 8.7 Hz), 6.98 (d, 2H, J = 8.7 Hz), 7.17 (d, 1H, J = 10.8 Hz),
7.44–7.53 (5H, m), 7.92 (s, 1H), 8.27 (s, 1H). Anal. Calcd. for C34H31NO3: C 81.41,
H 6.23, N 2.79; found: C 81.58, H 6.41, N 2.96. 4f: Mp: 153–155 8C; IR (KBr):
n 2219 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3): d 1.38 (d, 6H, J = 6.9 Hz, CH(CH3)2),
2.67 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.11–3.18 (m, 1H, CH(CH3)2), 3.81 (s, 3H,
OCH3), 6.82 (d, 2H, J = 9.0 Hz), 7.19 (d, 1H, J = 10.8 Hz), 7.41–7.44 (m, 5H), 7.50
(d, 2H, J = 8.7 Hz), 7.92 (s, 1H), 8.28 (s, 1H). Anal. Calcd. for C33H28ClNO2: C 78.33,
H 5.58, N 2.77; found: C 78.47, H 5.73, N 2.89. 4g: Mp: 121–123 8C; IR (KBr):
n 2215 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3): d 1.37 (d, 6H, J = 6.8 Hz, CH(CH3)2),
2.48 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.85 (s, 3H, CH3), 3.12–3.17 (m, 1H, CH(CH3)2),
6.89 (d, 2H, J = 8.0 Hz), 7.29–7.31 (m, 4H), 7.35 (d, 1H, J = 10.8 Hz), 7.64 (d, 1H,
J = 10.8 Hz), 7.88 (s, 1H), 7.95 (d, 2H, J = 8.4 Hz), 8.31 (s, 1H). Anal. Calcd. for
In conclusion, we have successfully developed a facile and
efficient method to prepare a series of 2-(guaiazulen-1-yl)furans
with good yields via intramolecular Wittig reactions from readily
available 1-(3-aryl-2-cyanopropenoyl)guaiazulene, tributylpho-
sphine and acyl chlorides in the presence of Et3N.
Acknowledgments
The authors thank the Science and Technology Department of
Liaoning Province (No. 2011220022), and the Innovation Talent
Program of Heilongjiang University of Chinese Medicine for
financial support.
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C
33H28N2O3: C 79.18, H 5.64, N 5.60; Found: C 79.34, H 5.79, N 5.81. 4h: Mp: 115–
117 8C; IR (KBr): n 2219 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3): d 1.37 (d, 6H,
J = 6.8 Hz, CH(CH3)2), 2.62 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.11–3.15 (m, 1H,
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8.03 (d, 2H, J = 8.8 Hz), 8.30 (s, 1H). Anal. Calcd. for C33H28N2O4: C 76.73, H 5.46,
N 5.42; found: C 76.86, H 5.63, N 5.57. 4i: Mp: 139–140 8C; IR (KBr): n 2225 cmꢁ1
(CN); 1H NMR (400 MHz, CDCl3): d 1.38 (d, 6H, J = 6.3 Hz, CH(CH3)2), 2.67 (s, 3H,
CH3), 2.71 (s, 3H, CH3), 3.12–3.16 (m, 1H, CH(CH3)2), 3.84 (s, 3H, OCH3), 6.53–6.55
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(s, 1H). Anal. Calcd. for C31H27NO3: C 80.67, H 5.90, N 3.03; found: C 80.75, H 6.11,
N 3.09. 4j: Mp: 154–156 8C; IR (KBr): n 2218 cmꢁ1 (CN); 1H NMR (400 MHz,
CDCl3): d 1.35 (d, 6H, J = 6.8 Hz, CH(CH3)2), 1.53 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.86
(s, 3H, CH3), 3.13–3.16 (m, 1H, CH(CH3)2), 7.37–7.40 (m, 2H), 7.63–7.65 (m, 5H),
7.89 (s, 1H), 8.32 (s, 1H). Anal. Calcd. for C27H25NO: C 85.45, H 6.64, N 3.69; found:
C 85.57, H 6.80, N 3.73. 4k: Mp: 169–171 8C; IR (KBr): n 2215 cmꢁ1 (CN); 1H NMR
(400 MHz, CDCl3): d 1.37 (d, 6H, J = 6.8 Hz, CH(CH3)2), 1.54 (s, 3H, CH3), 2.48 (s, 3H,
CH3), 2.62 (s, 3H, CH3), 2.86 (s, 3H, CH3), 3.12–3.17 (m, 1H, CH(CH3)2), 7.19 (d, 1H,
J = 10.8 Hz), 7.20–7.25 (m, 4H), 7.53 (d, 1H, J = 10.8 Hz), 7.85 (s, 1H), 8.24 (s, 1H).
Anal. Calcd. for C28H27NO: C 85.46, H 6.92, N 3.56; found: C 85.63, H 7.11, N 3.74.
4l: Mp: 135–137 8C; IR (KBr): n 2212 cmꢁ1 (CN); 1H NMR (400 MHz, CDCl3):
d 1.05 (t, 3H, J = 7.6 Hz, CH2CH3), 1.38 (d, 6H, J = 6.8 Hz, CH(CH3)2), 1.41 (q, 2H,
J = 7.6 Hz, CH2CH3), 2.62 (3H, s, CH3), 2.85 (3H, s, CH3), 3.12–3.18 (m, 1H,
CH(CH3)2), 3.82 (s, 3H, OCH3), 7.19 (d, 1H, J = 9.2 Hz), 7.19–7.22 (m, 4H), 7.52
(d, 1H, J = 9.2 Hz), 7.85 (s, 1H), 8.24 (s, 1H). Anal. Calcd. for C29H29NO2: C 82.24, H
6.90, N 3.31; found: C 82.38, H 7.03, N 3.47.
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Please cite this article in press as: D.-L. Wang, et al., An efficient synthesis of 2-(guaiazulen-1-yl)furan derivatives via intramolecular
Wittig reactions, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.04.030