A direct C-C cross-coupling of alcohols at the β-position with aldehydes under co-promotion of tris(triphenylphosphine)-rhodium chloride/boron trifuoride etherate

Article abstract of DOI:10.1002/adsc.200800416

The novel tris(triphenylphosphine)rhodium chloride/boron trifuoride etherate [RhCl-(PPh₃)₃/BF₃·OEt ₂] co-promoted the C-C cross-coupling of tertiary alcohols at the β-position with aldehydes. This reaction provides an efficient synthesis of either structurally diverse 1,3-diols or polysubstituted tetrahydropyrans by controlling the substrate structures, and it could be developed to a practical syntheticmet hod for numerous natural products and medicinally important compounds.

Full text of DOI:10.1002/adsc.200800416

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DOI: 10.1002/adsc.200800416
À
A Direct C C Cross-Coupling of Alcohols at the b-Position with
Aldehydes under Co-Promotion of Tris(triphenylphosphine)-
rhodium Chloride/Boron Trifuoride Etherate
Shu-Yu Zhang,a Yong-Qiang Tu,a,* Chun-An Fan,a Yi-Jun Jiang,a Lei Shi,a
and Ke Caoa
a
State Key Laboratory of Applied OrganicChemistry and Department of Chemistry, Lanzhou University, Lanzhou
730000, Peopleꢀs Republicof China
Fax : (+86)-931-891-5557; e-mail: tuyq@lzu.edu.cn
Received: July 6, 2008; Published online: October 7, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800416.
Abstract: The novel tris(triphenylphosphine)rhodi-
um chloride/boron trifuoride etherate [RhCl-
benign nature.[2] In connection with our groupꢀs inter-
est in this subject, our previous efforts had led to a
discovery that the combination of transition metal
catalyst/Lewis acid system could accomplish the direct
À
A
pling of tertiary alcohols at the b-position with alde-
hydes. This reaction provides an efficient synthesis
of either structurally diverse 1,3-diols or polysubsti-
tuted tetrahydropyrans by controlling the substrate
structures, and it could be developed to a practical
syntheticmethod for numerous natural produtcs
and medicinally important compounds.
À
C C cross-coupling of the C=C bond of olefins with
3
À
primary alcohols at the a-position via sp C H activa-
tion.[3] This achievement encouraged us to make a
more extensive study, and recently we found that a
novel C C cross-coupling of alcohols at the b-position
À
with the C=O bond of aldehydes also could be realiz-
ed through the co-promotion of the RhCl(PPh3)3/
A
À
À
Keywords: C C coupling; C H functionalization;
1,3-diols; rhodium(I) catalyst; tetrahydropyrans
BF3·OEt2 system (Scheme 1). It was noteworthy that
this reaction could selectively achieve, by tuning the
substrate structure, either the structurally diverse 1,3-
diols (Path A) or polysubstituted tetrahydropyrans
(THP)
kind of Rh-catalyzed/Lewis acid mediated C C cross-
C C bond formation via C H bond functionalization coupling reaction between alcohols and aldehydes has
A
À
À
À
is important and fundamental to organicchemistry, in
not been reported before.
[1]
À
which the direct C C cross-coupling of alcohols has
recently become one of the most attractive reactions thons, and several conventional methods are available
since it not only constructs new C C bonds and di- to access them, such as aldol/reduction, conjugate ad-
1,3-Diols have long been used as important syn-
À
rectly introduces hydroxy functional groups, but also dition/reduction, tandem semipinacol rearrangement/
displays atom economy and an environmentally MPV reaction,[4] as well as the recently reported HLF
Scheme 1. Cross-coupling of tertiary alcohols with aldehydes.
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Shu-Yu Zhang et al.
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reaction.[5] These methods generally involve multi-
step syntheticmanipulations or sometimes give by-
products. The coupling protocol described here pro-
vides a new direct and simple way to the synthesis of
a series of 1,3-diols. Also markedly, the polysubstitut-
ed THP skeleton is the key structural elements in
many biologically active natural products, such as bre-
vetoxin B, scytophycin C and (À)-apicularen A.[6] It
alternatively provides a direct and concise approach
towards polyfunctional THP units . In this paper, we
present our preliminary experimental results.
Table 1. The coupling reaction via Path A for synthesizing
the 1,3-diol.[a]
Entry
1
Substrate
Product
Yield [%][b]
65
Our initial investigation was focused on a wide
search for the coupling conditions of 1a and 2a as the
model substrates. Among the conditions tested, the
combination of RhCl(PPh3)3 (2 mmol%), additive
A
2
3
76
47
Cs2CO3 (2 mmol%) and Lewis acid BF3·OEt2
(1.5 mmol) in toluene was found to be the best. With
these optimized conditions in hand, the substrate
scope was examined. As list in Table 1, the coupling
of the simple t-BuOH 1a with both aromaticalde-
hydes bearing the electron-drawing groups (entries 1–
5) or aliphaticaldehydes (entries 6 and 7) mainly
tended to take the Path A, in which one molecule of
1a only coupled with one molecule of the aldehyde to
afford the 1,3-diol 3a.
Remarkable is that the 1,3-diol products 3a–3e are
the important building blocks in the medicinal chemi-
cal synthesis. For example, as illustrated in Scheme 2,
3a could be further effectively converted into a chro-
manol-type molecule 3a-1 bearing the key 2,2-dimeth-
yl-benzopyran core structure via palladium-catalyzed
carbon-heteroatom coupling,[7] after which the known
synthetic routes with the conventional conversions
could be employed to accomplish the synthesis of
some important medicaments or natural products,
such as (À)-cromakalim, (À)-perrottetinene, (+)-ma-
chaeriol, and THC.[8]
Our further investigation was expanded by using
some aromaticaldehydes or other typiacl aliphatic
tertiary alcohols 1b–1d. The results obtained in
Table 2 indicated that when 2h or the electron-rich ar-
omaticaldehyde 2i was subjected to the coupling with
1a under the same conditions as above, the coupling
reaction tended to take Path B, which afforded the
double coupling products, the tetrasubstituted THP
4a and 4b (entries 1 and 2). While employing
branched tertiary alcohols 1b–1d instead of 1a, the
coupling with 2h and electron-deficient aromatic alde-
hydes 2a and 2j still took Path B to give the double
coupling products, the polysubstituted THP 4c–4e.
4
74
5
6
55 (91[c])
42
63
7
[a]
General conditions: 2 (1.0 mmol), 1 (2.5 mmol.), RhCl-
(PPh3)3 (2 mmol%), CsCO3 (2 mmol%), and BF3·OEt2
AHCTREUNG
(1.5 mmol) in toluene for 3-12 h.
Isolated yield based on the aldehyde 2 used.
Yield based on recovered starting material.
[b]
[c]
mote this coupling reaction in parallel experiments.
Although a detailed reaction mechanism remains Based on this fact, the Lewis acid-promoted/Rh-cata-
unclear at this stage, one could be proposed formally lyzed electrophilic addition of aldehyde to olefin 5
on the basis of previous reports.[9] As shown in the se- was proposed to give 6, which was further hydrolyzed
quences in Scheme 3, the tertiary hydroxy group in to give 3, or underwent elimination to give the homo-
substrate 1 may undergo an elimination preferentially allylicalcohol 7, depending on the substrateꢀs proper-
to furnish 5. It should be noted that either RhCl- ties. The latter could provide 4 via a Prins-type cycli-
(PPh3)3 or BF3·OEt2 alone could not effectively pro- zation.
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A Direct C C Cross-Coupling of Alcohols at the b-Position with Aldehydes
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Scheme 2. Application model of 3a in the synthesis of medicines and important molecules.
Scheme 3. Proposed pathways for the cross-coupling of tertiary alcohols with aldehydes.
The observed reactivity could be understood Experimental Section
through two reaction pathways (Path A and Path B)
of intermediates 6 in Scheme 3, which could preferen- Typical Procedure
tially form the olefin intermediates 7 if the substitutes
To a flame-dried, 25-mL flask were sequentially added tolu-
R3 in 6 was an alkyl group, not hydrogen. In particu-
lar, reactions using the sterically hindered triethylme-
thanol 1d gave only a low yield (37%) of the THP
product (entry 6 in Table 2). Further studies on the
mechanism, as well as the scope and application of
this coupling reaction, are currently under investiga-
tion in our laboratory.
ene (4 mL), alcohol (2.5 mmol), and RhCl(PPh3)3 (20 mg,
A
0.02 mmol). The reaction system was stirred at 308C for
20 min. The aldehyde (1 mmol) and the additive Cs2CO3
(0.02 mmol) were added and stirred at 308C for 20 min
under an argon atmosphere, and then the freshly distilled
BF3·OEt2 (0.18 mL, 1.5 mmol) was introduced into the
above reaction mixture. The reaction mixture was heated
Adv. Synth. Catal. 2008, 350, 2189 – 2193
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Shu-Yu Zhang et al.
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Table 2. The coupling reaction via Path B for synthesizing the polysubstituted THP.[a]
Entry
1
Substrates
Product[b]
Yield [%][c]
1a
1a
72
2
3
54
65
4
2a
2a
63
37
5
[a]
General conditions: 2 (1.0 mmol), 1 (2.5 mmol.), RhCl(PPh3)3 (2 mmol%), CsCO3 (2 mmol%), and BF3·OEt2 (1.5 mmol)
A
in toluene for 3–12 h.
The dr of 4a is 3:2, and for 4b–4e only one diastereomericform was isolated.
Isolated yield based on the aldehyde 2 used.
[b]
[c]
using an oil bath to 508C, and further stirred at 508C for 3– Acknowledgements
12 h. After that, it was cooled to room temperature, and di-
luted with ethyl acetate (2 mL) followed by addition of satu-
rated aqueous NaHCO3 solution (3 mL). The organiclayer
was separated, and the aqueous phase was re-extracted with
ethyl acetate (3”2 mL). The combined organic extracts
were washed with brine (20 mL), and dried over anhydrous
Na2SO4. After removal of the solvent, the residue was puri-
fied by the flash chromatography to afford the desired sepa-
rable products.
We thank the NSFC (Nos. 20621091, 20672048 and
20732002) and the Chang Jiang Scholars Program for finan-
cial support.
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