Synthesis of 2-substituted chromenes via ring-closing metathesis and stable 1-benzopyrylium ions

Article abstract of DOI:10.1016/S0040-4039(00)00955-2

2-Substituted chromenes were obtained via combination of ring-closing metathesis of allylic acetals to the corresponding cyclic acetals, followed by Lewis acid-mediated functionalization of the resulting stable 1- benzopyrylium ion with suitable nucleophiles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00955-2

Tetrahedron Letters 41 (2000) 5979±5983
Synthesis of 2-substituted chromenes via ring-closing
metathesis and stable 1-benzopyrylium ions
Robin Doodeman,a Floris P. J. T. Rutjesb,* and Henk Hiemstraa,*
aLaboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
bDepartment of Organic Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 19 May 2000; accepted 7 June 2000
Abstract
2-Substituted chromenes were obtained via combination of ring-closing metathesis of allylic acetals to
the corresponding cyclic acetals, followed by Lewis acid-mediated functionalization of the resulting stable
1-benzopyrylium ion with suitable nucleophiles. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: benzyloxy-1,2-propadiene; ring-closing metathesis; 1-benzopyrylium ions; chromenes.
Chromenes (2H-1-benzopyran derivatives, viz. 1) are important intermediates in the synthesis
of many natural products and medicinal agents.1 Their basic structural framework for example is
a common feature of many tannins and polyphenols2 found in teas, fruits, vegetables and red
wines and these compounds have become increasingly important as a result of their health-
promoting e€ects. As a result of these interesting properties, a number of methods for their
preparation have been developed, such as the Claisen rearrangement of propargyl phenol ethers,3
Pd-catalyzed ring closure of 2-isoprenyl phenols,4 Ru-catalyzed ring closing metathesis of 2-styrenyl
allyl ethers5 and O-alkylation of reduced coumarin.6 In all of these methods, the substituent at
the 2-position is introduced in the early stages of the synthesis. Herein, we report a new and
¯exible route for the synthesis of di€erent 2-substituted-2H-chromenes 1 via selective
functionalization of the 1-benzopyrylium ions 2, where the 2-substituent is introduced in the ®nal
stages (Eq. (1)).
ꢀ1†
* Corresponding author. Fax: +31 20 525 5670.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00955-2

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This sequence, which involves the formation of the allylic acetals 3 from the corresponding
phenols 4, follows a pathway that combines oxypalladation of benzyloxy-1,2-propadiene and
Ru-catalyzed ring-closing metathesis, which was previously developed in our group for the
synthesis of six- and seven-membered ring ethers.7 9
Thus, the chromene skeleton was constructed starting with the readily available vinyl-substituted
phenols 4,10 which were reacted with benzyloxy-1,2-propadiene11 using a Pd2+-catalyst in the
presence of triethylamine and 1,3-bis(diphenylphosphino)propane (dppp) at room temperature
(Table 1). This led to the corresponding allylic acetals 3 in a remarkably selective and fast reac-
1
tion, with reaction times in the order of minutes.12,13 Although in all cases the H NMR spectra
of the crude reaction mixtures indicated that the reactions proceeded without side reactions, the
isolated yields were relatively moderate. This was probably due to partial hydrolysis of the acetals
on the silica gel during column chromatography, despite the fact that a small amount of Et3N
was added to the eluent.
Table 1
The linear acetals 3 appeared as suitable precursors for ring-closing metathesis (RCM) using
the Grubbs' Ru-catalysts 614 and 715 (Table 1). Initially, the reactions were conducted using the
well-established catalyst 6 in CH2Cl2 at room temperature under argon. As an example, reaction
of 3a in the presence of catalyst 6 yielded chromene 5a after 4 h in 77% yield. It was necessary to
add the catalyst (10 mol%) portionwise over this period to drive the reaction to completion (entry
1). Unfortunately, this problem of catalyst decomposition could not be overcome by running the
reaction at higher temperatures. Recently however, Grubbs and co-workers15 reported the more
active and stable Ru-catalyst 7, which also seemed to be the catalyst of choice for this system.
Indeed, reaction of diole®n 3a with catalyst 7 (4%) in toluene at 80ꢁC yielded chromene 5a in 1 h
in 78% yield (entry 1). Next, acetals 3b±d were subjected to similar metathesis conditions in order
to arrive at the desired products. Application to 3bÐhaving an electron-donating group in the
aromatic ring (entry 2)Ðshowed virtually no di€erence in reactivity towards both catalysts. In
both cases, the catalyst had to be added portionwise to complete the reaction. On the other hand,
substrate 3c, containing an electron-withdrawing group in the aromatic ring (entry 3) showed
similar behavior to the parent compound. Both reactions gave the same yield of 5c, but the

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process was more eciently carried out with catalyst 7. The same applied to the disubstituted
ole®n (3d, entry 4) a€ording the trisubstituted ole®n 5d in good yield with both catalysts.
Table 2
The chromene acetals 5a±d were then evaluated as precursors for functionalization at the
2-position via 1-benzopyrylium ion chemistry. To this end, the acetals 5 were treated with a mild
Lewis acid to generate the corresponding strongly colored 1-benzopyrylium ions 2.16 Trapping of
these intermediates with di€erent p-nucleophiles provided a variety of 2-substituted chromenes
.
(Table 2). Reaction of 5a in the presence of the Lewis acid BF3 OEt2 (2 equiv.) gave the dark red
colored 1-benzopyrylium ion 2, which reacted with allyltrimethylsilane (9, 2 equiv.) to yield 1a
(R2=allyl) in quantitative yield (entry 1). Other nucleophiles were also successfully used in this
reaction, such as trimethylsilyl cyanide (10), allenyl tributyltin (11) and the silyl enol ether derived
from acetophenone (12) giving the targeted products in moderate to good yields (entries 2±4).
Similarly, acetals 5b±d were subjected to identical conditions and nucleophiles providing the
expected products without surprises. In all cases, incorporation of the nucleophile took place
selectively at the more electrophilic 2-position.
Interestingly, the 1-benzopyrylium ions 2 appeared suciently stable to be characterized by
1
NMR spectroscopy so that H and 13C NMR of these cations were recorded.17 The aromatic
character was clearly observed in the proton spectra, where all the aromatic signals shifted
down®eld to values between 8 and 10 ppm. A typical example is shown in Scheme 1.
Treatment of 5a with TMSOTf in CD2Cl2 led to the formation of the tri¯ate salt of the
1-benzopyrylium ion 13 with concomitant formation of trimethylsilyl-protected benzyl alcohol.18
1
In the H spectrum of 13, the a-proton shifted from 6.4 to 9.87 ppm, while the proton at
the 4-position shifted from 5.6 to 9.72 ppm. Recording the same spectrum after storage of the
reaction mixture for 1 week led to an identical and clean spectrum, thus proving the stability of
the 1-benzopyrylium ion species.
In conclusion, we have developed a general and ¯exible transition metal-mediated route for the
synthesis of 2-substituted chromenes. This sequence provides ample possibilities for the introduction
of functional groups at di€erent positions of the skeleton without a€ecting the eciency of the
procedure. In this way, a versatile heterocyclic sca€old has been created which could be useful in
combinatorial chemistry approaches during the search for biologically active chromene derivatives.

5982
Scheme 1. Spectrum of the benzopyrylium salt 13
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5983
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1
18. Characterization of compound 5a: H NMR (400 MHz, C6D6): ꢀ=7.16±7.21 (m, 2H), 7.05±7.11 (m, 3H), 6.98±
7.03 (m, 2H), 6.85 (br.d, J=7.2 Hz, 1H), 6.74±6.78 (m, 1H), 6.36 (d, J=9.2 Hz, 1H, H4), 5.52±5.57 (m, 2H, H2,3),
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(400 MHz, CD2Cl2): ꢀ=9.87 (dd, J=1.8, 4.1 Hz, 1H, H2), 9.72 (dt, J=0.7, 8.3 Hz, 1H, H4), 8.44±8.51 (m, 2H),
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