Efficient One-Pot Synthesis of 2,2-Dimethyl-2 H -chromenes via Pd(II)-Catalyzed Coupling and SiO 2-Promoted Condensation of o -Halophenols with 2-Methyl-3-buten-2-ol

Article abstract of DOI:10.1080/00397911.2015.1056371

An efficient synthesis of 2,2-dimethyl-2H-chromenes was accomplished by Pd(II)-catalyzed coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-buten-2-ol (1,1-dimethylallyl alcohol) in one pot. The method is very general and can be useful for the synthesis of some natural 2,2-dimethyl-2H-chromenes.

Full text of DOI:10.1080/00397911.2015.1056371

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An Efficient One-Pot Synthesis of 2,2-Dimethyl-2H-
chromenes via Pd(II)-Catalyzed Coupling and Sio2-
Promoted Condensation ofo-Halophenols with 2-
Methyl-3-buten-2-ol
Jia Ti Teea, Marzieh Yaeghoobia, Chin Fei Cheea & Noorsaadah Abd. Rahmana
a Dept. of Chemistry, University of Malaya, Kuala Lumpur, Malaysia
Accepted author version posted online: 03 Jun 2015.
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To cite this article: Jia Ti Tee, Marzieh Yaeghoobi, Chin Fei Chee & Noorsaadah Abd. Rahman (2015): An Efficient One-Pot
Synthesis of 2,2-Dimethyl-2H-chromenes via Pd(II)-Catalyzed Coupling and Sio2-Promoted Condensation ofo-Halophenols with
2-Methyl-3-buten-2-ol, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2015.1056371
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An efficient one-pot synthesis of 2,2-dimethyl-2H-chromenes via Pd(II)-catalyzed
coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-buten-
2-ol
Jia Ti Tee1, Marzieh Yaeghoobi1, Chin Fei Chee1, Noorsaadah Abd. Rahman1
1Dept. of Chemistry, University of Malaya, Kuala Lumpur, Malaysia
Address correspondence to Chin Fei Chee, Dept. of Chemistry, University of Malaya,
50603 Kuala Lumpur, Malaysia. E-mail: cfchee@yahoo.com
Abstract
An efficient synthesis of 2,2-dimethyl-2H-chromenes was accomplished by Pd(II)-
catalysed coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-
buten-2-ol (1,1-dimethyl allyl alcohol) in one-pot condition. The method is very general
and can be useful to the synthesis of some natural 2,2-dimethyl-2H-chromenes.
KEYWORDS: 2,2-dimethyl-2H-chromene; palladium; phenol; 2-methyl-3-buten-2-ol
INTRODUCTION
2,2-Dimethyl-2H-chromenes (2,2-dimethyl-2H-1-benzopyran) are commonly found as a
parent structure in natural products.1 It is also an important intermediate for the
syntheses of numerous pharmaceutical and biologically active compounds.2 Therefore, a
1

number of methods have been reported for the construction of 2,2-dimethyl-2H-
chromenes. In particular, the condensation of phenols with α,β-unsaturated carbonyls
(aldehydes or acetals) under different reaction conditions, is the most commonly used
method.3 Other methods include condensation of phenols with 2-methyl-3-butyn-2-ol
(1,1-dimethyl propargyl alcohol) catalysed by ReCl(CO)5,4 catalysed by BF3.Et2O5 or
other Lewis acids,6 condensation of phenols with 3-chloro-3-methylbut-1-yne catalysed
by Ph3PAuNTf2,7 dehydration of chromanols,8 Pd-catalysed cyclisation of o-prenyl
phenols,9 and photocyclisation of 3-aryl-1,1-dimethylprop-2-en-1-ol.10 Although there
are many reports on the preparation of 2,2-dimethyl-2H-chromenes, developing an
efficient method which uses easily accessible starting materials is still of interest.
Here we describe an efficient route to 2,2-dimethyl-2H-chromenes by Pd(II)-catalysed
coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-buten-2-ol
(1,1-dimethyl allyl alcohol) in one-pot condition.
RESULTS AND DISCUSSION
We began investigating the condensation reaction of o-iodophenol 1a and 2-methyl-3-
buten-2-ol 2a using a variety of Pd catalysts (PdCl2, Pd(OAc)2, Pd(PPh3)4, Pd(TFA)2,
Pd(dba)2), bases (Na2CO3, K2CO3, KOAc), additive (n-Bu4NCl, molecular sieve 4Å) and
solvents (DMF, DMSO, toluene) and the results are summarised in Table 1. Mixture of
1a (1.0 mmol), 2a (10 mmol) and PdCl2 (1 to 10 mol %) in the present of K2CO3 (3
equiv.) in toluene (1 mL) was heated in a pressure tube under nitrogen atmosphere at
100 C, TLC analysis of the reaction mixture showed that 1a to be completely consumed
2

after 24 h. As expected, the Heck coupling product 3a was the major product obtained
(35 – 45% yield, entries 1-3). The desired product, 2,2-dimethyl-2H-chromene (4a), was
isolated only in low yield (5 – 10%, entries 1-3). Increasing the reaction temperature to
140 C resulted in a slightly increased yield of 4a (20%, entry 4 vs entry 3). Presumably, a
higher reaction temperature improved the formation of 4a, most likely due to increase in
the rate of condensation of 3a. Indeed, when the reaction was repeated at 150 C in DMF
(entry 5) and DMSO (entry 6), 4a was obtained in 23% and 25% yields, respectively.
Attempts to increase the yield of 4a using microwave irradiation, however, were
unsuccessful (entries, 7-8). It is noteworthy that identical results are observed under both
air and nitrogen atmosphere (entries 4 and 5).
We next examined the catalytic activity of other Pd catalysts. Notably, the yields of 3a
and 4a were slightly increased with catalytic Pd(OAc)2 (entries 9-10). Although three
other Pd catalysts, Pd(PPh3)4, Pd(TFA)2, Pd(dba)2, had activity for the reaction, they were
less effective than Pd(OAc)2 (entries 11-13). Adding n-Bu4NCl had no significant effect
on formation of 3a and 4a (entry 10 vs entry 14). The effect of base on the yield of
reaction was also evaluated (entries 15-17). The yields of 3a and 4a were reduced when
Et3N was used (entry 17). We also found that both Na2CO3 and KOAc were less efficient
for the Heck coupling reactions (entries 15-16). Amongst the bases, K2CO3 gave the best
result (entries 10 & 14).
Subsequently we investigated the condensation reaction of o-iodophenol 1a with 1,1-
dimethyl allylic acetate (2-methylbut-3-en-2-yl acetate) 2b. Li and co-workers described
3

a selective Heck reaction of 4-iodoanisole with 2b to give (E)-4-(4-methoxyphenyl)-2-
methylbut-3-en-2-ol in quantitative yield.11 Thus we anticipated that the condensation of
1a with 2b could enhance the formation of 3 and 4. However, condensation of 1a with
2b under the present optimal reaction condition (Pd(OAc)2 (10 mol%), K2CO3 (3 equiv.),
DMF (1M), 140 C) significantly decreased the yield of 3a and 4a (entry 18),
accompanied with the formation of undesired side-product.
Since present condensation reaction of 3a to 4a did not proceed well at elevated
temperature or under microwave irradiation, we investigated the condensation under
acidic condition, i.e. AcOH,12 H3PO4.13 Considering sensitivity of some functional
groups (i.e. ethoxy methoxy group, EOM) in acidic condition, we decided to use a milder
reagent such as molecular sieve or silica gel (SiO2). However, the condensation reaction
of 3a to 4a did not proceed well in present of molecular sieve (entry 8). To our delight,
the condensation reaction proceeded extremely good in present of SiO2 to afford 4a in
good yield (76 – 80%, entries 19-20). A controlled experiment was carried out to
examine the role of SiO2 as a dehydrating agent (Scheme 1). Treatment of allylic alcohol
3a in the present of SiO2 afforded chromene 4a in nearly quantitative yield under the
standard conditions.
Consequently, the scope of o-halophenols was explored for condensation reaction under
the optimised conditions (Table 2). In the presence of Pd(OAc)2 and K2CO3, a variety of
o-halophenols 1b-j were examined by reacting with 2-methyl-3-buten-2-ol 2a (entries 1-
9). The results indicated that both electron-rich and electron-deficient aryl iodides to be
4

suitable for the reaction. Aryl bromide 1b had similar activity as iodide 1a (entry 1).
However, aryl bromides bearing aldehyde and naphthol moieties gave lower product
yield (entries 4 & 8). Aryl chloride had no activity (entry 5). The ethoxy methoxy
protecting group (EOM) was cleaved under the optimised conditions (entry 2).
With regards to the synthesis of natural products, isoencecalin 4d and 2-
demethoxymillepachine 4j, it is noteworthy that the present protocol allows the
installation of 2,2-dimethylchromene ring at the late-stage of synthesis. In contrast, the
conventional synthesis of millepachine for example, required preparation of 2,2-
dimethylchromene ring at earlier stage of the synthesis.14 The late-stage installation of
2,2-dimethylchromene ring could provide an alternative method for diversity-oriented
synthesis of small molecules.
In conclusion, a Pd(II)-catalysed Heck coupling and SiO2-promoted condensation of o-
halophenols with 2-methyl-3-buten-2-ol has been described for preparing 2,2-dimethyl-
2H-chromenes in moderate to good yields in one-pot condition. This procedure is simple
and efficient. Importantly, this protocol provides a facile synthesis of naturally occurring
2,2-dimethyl-2H-chromenes.
EXPERIMENTAL
All chemicals were obtained from commercial suppliers and used without further
purification. Anhydrous toluene was distilled from calcium hydride under positive
pressure of nitrogen. Anhydrous DMSO and DMF were purchased from Aldrich. All
5

reactions were carried out under nitrogen atmosphere unless specified. Pressure tube was
purchased from Ace Glassware (USA). NMR spectra were obtained using a Jeol ECA
400 (400 MHz) NMR spectrometer with TMS as the internal standard. All chemical
shifts are reported in ppm. Mass spectra were recorded on a Agilent G6530A Accurate-
Mass Q-TOF LC/MS spectrometer. Analytical thin layer chromatography (TLC) was
carried out on Merck pre-coated aluminum silica gel sheets (Kieselgel 60 F-254).
Column chromatography was done with silica gel 60 (230-400 mesh) from Merck. All
target compounds were characterized by 1H, 13C-NMR and HRMS analysis. Compound
4a (CAS registration number 2513-25-9),8b 4c (CAS registration number 60986-49-4),15
4d (CAS registration number 30414-95-0),16 4e (CAS registration number 162335-02-
6),17 4i (CAS registration number 157495-19-7)4 were known.
General Procedure For The Synthesis Of 2,2-Dimethyl-2h-Chromenes.
A mixture of o-halophenol (1 equiv.), Pd(OAc)2 (10 mol%), K2CO3 (3 equiv.), and 2-
methyl-3-buten-2-ol (10 equiv.) in DMF (1 mL per mmol) in a pressure tube was heated
to 140°C for 6 ~ 8 h. The reaction was monitored by TLC until the starting material was
completely consumed. Then, silica gel (20 equiv.) was added to the reaction mixture,
followed by heating at 140°C for another 4 ~ 16 h to give the desired 2,2-dimethyl-2H-
chromenes.
8-Chloro-2,2-Dimethyl-2H-Chromene-6-Carbaldehyde (4f)
6

1H-NMR (400MHz, CDCl3): δ 9.79 (1H, s, CHO), 7.81 (1H, s, phenyl-H), 7.62 (1H, s,
phenyl-H), 6.57 (1H, d, J = 9.8 Hz, -CH=), 5.95 (1H, d, J = 10.1 Hz, -CH=), 1.46 (6H, s,
2 x Me); 13C-NMR (100MHz, CDCl3): δ 190.5, 153.1, 132.5, 131.3, 130.1, 125.8, 122.5,
120.7, 120.6, 79.5, 28.1; HRMS calcd for C12H12ClO2 [M+H]+ = 223.0518. Found:
223.0512
SUPPLEMENTAL MATERIAL
Full experimental detail and 1H and 13C NMR, and HRMS spectra for this article can be
accessed on the publisher’s website.
ACKNOWLEDGMENT
This work was supported by FRGS grant (2012-R085) from the Ministry of Education,
Malaysia.
REFERENCES
1)
Ellis, G. P. Chromenes, chromanones and chromones. Wiley-Interscience, New
York, 1977.
2) (a) Mannhold, R.; Cruciani, G.; Weber, H.; Lemoine, H.; Derix, A.; Weichel, C.;
Clementi, M. J. Med. Chem. 1999, 42, 981–991 (b) Sant Anna, S. S.; Evangelista, E. A.;
Alves, R. B.; Raslan, D. S. Chem. Nat. Compd. 2005, 41, 385–387 (c) Page, P. C. B.;
7

Buckley, B. R.; Heaney, H.; Blacker, A. J. Org. Lett. 2005, 7, 375–377 (d) Szczepanik,
M.; Obara, R.; Szumny, A.; Gabrys, B.; Halarewicz-Pacan, A.; Nawrot, J.; Wawrzenczyk,
C. J. Agric. Food Chem. 2005, 53, 5905–5910.
3) (a) Sartori, G.; Casiraghi, G.; Bolzoni, L.; Casnati, G. J. Org. Chem. 1979, 44, 803-
805 ; (b) Prado, S.; Janin, Y. L.; Bost, P. E. J. Heterocycl. Chem. 2006, 43, 1605-1608.
(c) Bröhmer, M. C.; Volz, N.; Bräse, S. Synlett. 2009, 1383-1386 (d) Maiti, A.; Maiti, D.
Green Chem. 2012, 14, 2314-2320 (e) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.;
Real, S. D.; Chen, H. Y. J. Org. Chem. 1995, 60, 3397-3400 (f) Chauder, B. A.; Lopes,
C. C.; Lopes, R. S. C.; da Silva, A. J. M.; Snieckus, V. Synthesis 1998, 279–282 (g) Lee,
Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46, 7539-7543 (h) Subburaj, K.;
Trivedi, G. K. Bull. Chem. Soc. Jpn. 1999, 72, 259-263 (i) Adler, M. J.; Baldwin, S. W.
Tetrahedron Lett. 2009, 50, 5075-5079 (j) Lamcharfi, E.; Menguy, L.; Zamarlik, H.
Synth. Commun. 1993, 23, 3019-3028.
4) Zeng, H.; Ju J.; Hua, R. Tetrahedron Lett. 2011, 52, 3926-3928.
5) Madabhushi, S.; Jillella, R.; Godala, K. R.; Mallu, K. K. R.; Beeram, C. R.; Chinthala,
N. Tetrahedron Lett. 2012, 53, 5275-5279.
6) (a) Zhao, W.; Carreira, E. M. Org. Lett. 2003, 5, 4153–4154 (b) Gabbutt, C. D.; Heron,
B. M.; Instone, A. C.; Thomas, D. A.; Partington, S. M.; Hursthouse, M. B.; Gelbrich, T.
Eur. J. Org. Chem. 2003, 1220–1230 (c) Dong, Y. W.; Wang, G. W.; Wang, L.
Tetrahedron 2008, 64, 10148–10154 (d) McCubbin, J. A.; Nassar, C.; Krokhin, O. V.
Synthesis 2011, 3152–3160 (e) Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Sartori, G.
J. Org. Chem. 1997, 62, 7024–7027
8

7) Lykakis, I. N.; Efe, C.; Gryparis, C; Stratakis, M. Eur. J. Org. Chem. 2011, 2334-
2338.
8) (a) Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492–504 (b) Kureshy, R. I.;
Ahmad, I.; Pathak, K.; Khan, N. H.; Abdi, S. H. R.; Jasra, R. V. Catal. Commun. 2009,
10, 572–575.
9) (a) Iyer, M.; Trivedi, G. K. Synth. Commun. 1990, 20, 1347-1351 (b) Larock, R. C.;
Wei, L.; Hightower, T. R. Synlett. 1998, 522-524.
10) Pandey, G.; Krishna, A. J. Org. Chem. 1988, 53, 2364-2365.
11) Liu, Y.; Yao, B.; Deng, C. L.; Tang, R-Y.; Zhang, X. G.; Li, J. H. Org. Lett. 2011,
13, 1126-1129.
12) Cotterill, W. D.; Iqbal, M.; Livingstone, R. J. Chem. Res. (S) 1998, 2-3.
13) (a) Yus, M.; Foubelo, F.; Ferrández, José V. Eur. J. Org. Chem. 2001, 2809-2813 (b)
Goujon, J. Y.; Zammattio, F.; Kirschleger, B. Tetrahedron: Asymm. 2000, 11, 2409-2420.
14) Wang, G.; Wu, W.; Peng, F.; Cao, D.; Yang, Z.; Ma, L.; Qiu, N.; Ye, H.; Han, X.;
Chen, J.; Qiu, J.; Sang, Y.; Liang, X.; Ran, Y.; Peng, A.; Wei, Y.; Chen, L. Eur. J. Med.
Chem. 2012, 54, 793-803.
15) Manners, G. D.; Jurd, L. J. Chem. Soc. Chem. Commun. 1976, 448.
16) Lee, Y. R. Synthesis 2006, 603-608.
17) Yamaguchi, S.; Ishibashi, M.; Akasaka, K.; Yokoyama, H.; Miyazawa, M.; Hirai, Y.
Tetrahedron Lett. 2001, 42, 1091-1093.
9

Table 1. Pd(II)-catalysed coupling of o-iodophenol 1a and 2-methyl-3-buten-2-ol 2a.
Entry Catalysta
(mol %)
Base
Additive
Solvent Temp Time Yield
2
(°C)
toluene 100
toluene 100
toluene 100
(h)
24
24
24
24
24
24
0.5
(%)d
(3:4)
35:5
(equiv.)
K2CO3
(1.5)
(equiv.)
n-Bu4NCl
(1.5)
1
PdCl2 (1)
PdCl2 (5)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
2a
2a
2a
2a
2a
2a
2a
2
K2CO3 (2) n-Bu4NCl
40:10
45:10
40:20
43:23
45:25
65:15
(1.5)
K2CO3 (3) n-Bu4NCl
(1.5)
3
4
K2CO3 (3) n-Bu4NCl
(1.5)
DMF
DMF
140
150
5b
6
K2CO3 (3) n-Bu4NCl
(1.5)
K2CO3 (3) n-Bu4NCl
(1.5)
DMSO 150
7c
K2CO3 (3) n-Bu4NCl
(1.5)
DMF
140
10

8c
PdCl2 (10)
K2CO3 (3) MS 4Å
(10)e
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
140
140
140
140
140
140
140
140
140
140
140
140
0.5
24
24
24
24
24
24
24
24
24
24
24
70:10
52:15
55:20
40:12
35:5
38:5
55:15
40:8
35:5
25:3
10: -
-
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
9
Pd(OAc)2
(5)
K2CO3 (3) n-Bu4NCl
(1.5)
10
11
12
13
14
15
16
17
18f
19
Pd(OAc)2
(10)
K2CO3 (3) n-Bu4NCl
(1.5)
Pd(TFA)2
(10)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
KOAc (3)
-
-
-
-
-
-
-
-
Pd(PPh3)4
(10)
Pd(dba)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Na2CO3
(3)
Pd(OAc)2
(10)
Et3N (3)
Pd(OAc)2
(10)
K2CO3 (3)
Pd(OAc)2
K2CO3 (3) SiO2 (10)g
11

(10)
:76
-:80
20
Pd(OAc)2
(10)
K2CO3 (3) SiO2 (20)g
DMF
140
24
2a
aReaction conditions: 1a (1.0 equiv.), 2a (10 equiv.), solvent 1 ml/mmol; bUnder air
condition; cMicrowave irradiation; dIsolated yield after chromatography; eIn present of
molecular sieve 4Å (10 equiv.); f Using 2b (10 equiv.); gSilica gel (SiO2, MW=60, size
230-400 mesh) was added to the reaction mixture after heating for 16 h.
12

Table 2. Pd(II)-catalysed coupling and SiO2-promoted condensation of o-halophenols 1
and 2-methyl-3-buten-2-ol 2a.a
Entr Halide 1
y
Tim
e
Product
Yiel
d
(h)
15
(%)
75
1
4a
4c
1b
2
15
12
80
60
1c
3
4d
1d
4
5
20
20
25
70
4e
1e
1f
4f
6
7
20
18
15
85
4g
1g
1h
4h
4i
8
9
30
24
17
65
1i
13

1j
4j
aReaction conditions:1 (1.0 mmol), 2a (10 mmol), Pd(OAc)2(10 mol %), K2CO3 (3.0
equiv), and DMF (1 mL) at 140 C under air for 8 ~ 14 h. The reaction was monitored by
TLC until 1 was completely consumed. Silica gel (20 equiv.) then was added to the
reaction mixture, followed by heating at 140°C for another 4 ~ 16h to yield desired
product. bIsolated yield.
14

Scheme 1. Controlled experiment
15