Copper-free arylation of 3,3-disubstituted allylic halides with triazene-softened aryl Grignard reagents

Article abstract of DOI:10.1039/c5ob00594a

A copper-free allylic arylation reaction between 3,3-disubstituted allylic halides and triazene-softened aryl Grignard reagents has been developed. This protocol presents a direct and efficient way to construct both α- or γ-isomers with high regioselectivity under environmentally benign conditions. Various functional groups can be tolerated in the reaction and the products are of high value for multiple synthetic applications. The α- and γ-isomers can be converted to the corresponding 3H-indole and indole derivatives in multigram scale respectively.

Full text of DOI:10.1039/c5ob00594a

Organic &
Biomolecular Chemistry
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Copper-free arylation of 3,3-disubstituted allylic
halides with triazene-softened aryl Grignard
reagents†
Cite this: Org. Biomol. Chem., 2015,
13, 6333
Lijun Xu, Zhubo Liu, Weipeng Dong, Jinyu Song, Maozhong Miao, Jianfeng Xu and
Hongjun Ren*
A copper-free allylic arylation reaction between 3,3-disubstituted allylic halides and triazene-softened aryl
Grignard reagents has been developed. This protocol presents a direct and efficient way to construct
both α- or γ-isomers with high regioselectivity under environmentally benign conditions. Various func-
tional groups can be tolerated in the reaction and the products are of high value for multiple synthetic
applications. The α- and γ-isomers can be converted to the corresponding 3H-indole and indole deriva-
tives in multigram scale respectively.
Received 25th March 2015,
Accepted 29th April 2015
DOI: 10.1039/c5ob00594a
www.rsc.org/obc
Introduction
Prenylated and reverse prenylated arenes are found in many
biologically and pharmacologically active compounds, such as
prenylated flavanone malheuran B1 and indole alkaloid echi-
nulin2 (Scheme 1). Thus, the development of efficient methods
to construct both normal prenylated and reverse prenylated
arenes under simple conditions is very appealing. Recently,
Organ et al. have developed a well-tailored NHC-based catalyst
for the linear-selective (normal prenylated) Suzuki–Miyaura
cross-coupling of 3,3-disubstituted allylboronates with aryl
halides.3 Buchwald et al. also reported a palladium-catalyzed
Negishi cross-coupling of allylzinc halides with aryl and vinyl
electrophiles for completely linear-selective prenylation.4 The
γ-selective coupling of 3,3-disubstituted allylboronates to
provide a sterically hindered quaternary center remains a for-
midable challenge. To address this challenge, Buchwald et al.
reported an orthogonal set of ligand-controlled palladium-
catalyzed Suzuki–Miyaura cross-coupling of allylboronates and
aryl halides for the highly selective preparation of either α- or
γ-isomers (Scheme 1).5
Scheme 1 Prenylated natural products (malheuran B and echinulin)
and our proposed regioselective prenylation of prenyl halides with “sof-
tened” Grignard reagents.
in the reaction of unsymmetrically substituted allylic sub-
strates. Copper-catalyzed allylic substitution reaction between
a Grignard reagent and an allylic substrate has been investi-
gated by Breit, Sawamura, Kobayashi et al.7 who demonstrated
that the method is efficient for the preparation of allylic pro-
ducts with good regioselectivity and even better enantio-
selectivity.8 However, the reported allylic substitutions with
Grignard reagents are still limited: (1) the nucleophiles are
limited in alkyl Grignard reagents, only a few cases have
succeeded so far in cinnamyl-type substrates when using aryl
Grignard reagents;9 (2) the electrophiles are limited in the
3-monosubstituted allylic system. 3,3-Disubstituted allylic
Compared with transition-metal catalyzed cross-coupling
reaction between aryl halides and allylic metal reagents, the
direct substitution of nucleophiles such as Grignard reagents
with allylic substrates represents
a powerful alternative
method for C–C bond formation.6 An important issue of this
type of allylic substitution is the control of the regioselectivity
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018,
P. R. China. E-mail: renhj@zstu.edu.cn
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization for new compounds. See DOI: 10.1039/c5ob00594a
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systems are scarce, and there are only a few examples of that tuted phenyl magnesium reagent was used, the γ-selective
1
have succeeded when using 3,3-disubstituted allylic systems as product was identified by H NMR (the ratio of γ : α = 4 : 96).
electrophiles in the formation of a quaternary carbon center;10 When the ortho-Py substituted magnesium reagent was used,
(3) the reaction with good selectivity needs to be catalyzed by the ratio of γ : α increased to 76 : 24 (Fig. 1). Gratifyingly, the
transition metals predominantly catalyzed by Cu(I) salts.
ratio of γ : α increased to 91 : 9 when an ortho-triazenyl phenyl
magnesium reagent13 was used. In order to improve the
selectivity, the temperature effect was screened and the reac-
tion of the ortho-triazenyl phenyl magnesium reagent with
prenyl bromide gave the best result at −40 °C. A copper catalyst
was also tested, but similar results were obtained as without a
catalyst (see the ESI†). Finally, the weaker leaving groups
such as OCOPh, OCOBu-t were also used in the reaction
with triazenyl aryl Grignard reagents; however, no reaction
occurred.
With the optimal conditions in hand, we further explored
the reaction between other functionalized triazenyl-aryl
Grignard reagents and 3,3-disubstituted allylic bromides to
examine the scope and limitation of the current prenylation
reaction. A variety of triazenyl-aryl iodides, bearing electron-
donating or -withdrawing substituents (4a–q, Scheme 3), were
efficiently converted to their corresponding branched products
Results and discussion
In the pursuit of a more environmentally benign reaction,
uncatalyzed allylic substitution with the aryl Grignard
reagent11 is very important since the method for the prepa-
ration of functionalized aromatic Grignard reagents is well
established.12 The controlled reaction of aromatic Grignard
reagents with 3,3-disubstituted allylic systems is the most
direct and powerful method for introducing prenyl and prenyl-
related side chains into aromatic systems. Normally, the
addition reaction of hard nucleophiles such as aryl Grignard
reagents with prenyl bromide would provide entirely α-selective
products (selective attack at the primary carbon will be much
faster than allylic attack at the tertiary carbon atom). This was
demonstrated by the reaction of phenyl Grignard reagent or
functionalized Grignard reagent of para-(ethoxycarbonyl)-
phenyl magnesium with prenyl bromide to afford α-selective
products completely (Scheme 2). In order to establish a
method for the formation of γ-selective products, we imagined
that if we could soften the “hardness” of the aryl Grignard
reagents, there might be a dramatic reversal in selectivity
(Scheme 2).
We commenced our study by looking for a “mask” for mag-
nesium in aryl Grignard reagents which could soften their
“hardness”. Since the phenyl and para-(ethoxycarbonyl)phenyl
magnesium reagents are naked, we tried the reaction between
ortho-substituted phenyl magnesium reagents and prenyl
bromide. Unfortunately, both the ortho-Br and the ortho-OCH3
substituted phenyl magnesium reagents provided completely
α-selective products. To our delight, when the ortho-Ph substi-
Scheme 3 Substrate scope of triazenyl-aryl Grignard reagents and 3,3-
disubstituted allylic bromides. Reaction conditions: triazenyl-aryl iodide
(1.0 mmol), iPrMgCl·LiCl (1.3 mmol), 3,3-disubstituted allylic bromide
(3.0 mmol), −40 °C, 24 h. Yields are of isolated products, see the ESI†
for details. The ratio of γ : α was determined by 1H NMR spectroscopy of
the crude reaction mixture after removing the excess 3,3-disubstituted
allylic bromide reagents using a short silica column.
Scheme 2 Regioselectivity of arylation between mask softened aryl
Grignard reagents and prenyl bromides. X = Br·LiCl or I·LiCl.
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(γ-products) with high regioselectivity (the ratio of γ : α up to
91 : 9). Both the electronic and steric effects are important
issues for the regioselectivity. Electron-donating substituents
give higher γ selectivity than the withdrawing ones (4i–k).
Steric bulk of the ortho-substituents (compared to the triazenyl
group) on aryl triazene produced a negative effect on the γ
selectivity (4a, 4l and 4m; 4n–p). The substituents on electro-
philes of 3,3-disubstituted allylic bromides also affect the
regioselectivity significantly (4r–u). The lower γ selectivity was
observed when the steric hindrance of 3-substituted group on
3,3-disubstituted allylic bromides increased. For example,
when geranyl bromide was used as an electrophile, the ratio of
γ : α was 86 : 14 (4t). The ratio of γ : α decreased to 74 : 26 when
a slightly bulkier substrate (E)-1-chloro-3,4-dimethylpent-2-ene
was tested (4s), while (E)-1-chloro-3,4,4-trimethylpent-2-ene,
bearing the bulkiest t-Bu group, gave a γ product and an α
product in 50 : 50 ratio (4r).
Since we have studied the allylic arylation of 3,3-disubsti-
tuted allylic bromide with triazene “softened” aryl Grignard
reagents, we found that transition-metal-free procedures lead
to good γ selectivity (the ratio of γ : α up to 91 : 9). We then
turned our attention to the α-selectivity of the allylic arylation
of the triazenyl Grignard reagents. Significant issues in the
control of regiochemistry are the leaving group and the catalyst
in the 3,3-disubstituted allylic substrate. Using chloride as a
leaving group, Fürstner8d and Bäckvall7a developed an allylic
arylation reaction between geranyl chloride and PhMgBr
affording high α selectivity, catalyzed by iron and Cu(I) in-
dependently. Interestingly, when we treated the triazenyl aryl
Grignard reagent with geranyl chloride at −30 °C, product 5t
with high α selectivity (α : γ up to 85 : 15) was obtained. A range
of triazenyl aryl Grignard reagents were used in the reaction
with 3,3-disubstituted allylic chlorides, which produced their
corresponding products in high α selectivities (the ratio of α : γ
up to 99 : 1) (5a–u, Scheme 4). Functional groups, such as ester
(5g, 5r–u), iodide (5p), ketone (5q) and cyanide (5h), are
tolerated well in this reaction.
Scheme 4 Substrate scope of triazenyl-aryl Grignard reagents and 3,3-
disubstituted allylic chlorides. Reaction conditions: triazenyl-aryl iodide
(1.0 mmol), iPrMgCl·LiCl (1.3 mmol), 3,3-disubstituted allylic chlorides
(3.0 mmol), −30 °C, 24 h. Yields are of isolated products, see the ESI†
for details. The ratio of α : γ was determined by 1H NMR spectroscopy of
the crude reaction mixture after removing the excess 3,3-disubstituted
allylic chloride reagents using a short silica column.
zene-softened aryl Grignard reagents probably proceeds via a
radical pathway. However, the reaction between 3,3-disubsti-
tuted allylic bromides and triazene-softened aryl Grignard
reagents favors an organometallic pathway.
In order to explore the reaction mechanism for the regio-
specific preparation of triazene-related prenylated and reverse
prenylated arenes, control experiments were carried out in the
presence of different radical scavengers. When classical radical
scavengers such as (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl
(TEMPO), di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (DPPH)
To explore the possibility by using prenylated and reverse
prenylated aryl triazenes as building blocks for the synthesis
of heterocyclic compounds, we treated branch prenylated
product 4g with NaN3 in the presence of a Lewis acid BF3·OEt2.
Instead of the formation of anticipated azide compound 7a,
unexpectedly 2,3,3-trimethyl-3H-indole 8a, a useful precursor
for the synthesis of a cyanine dye, was isolated. The present
protocol is exceptionally practical, as shown in Scheme 6, and
the reaction can be efficiently processed on a multigram scale
and the desired product can be obtained in 71% yield after
simple recrystallization. Interestingly, when a linear prenylated
product 5g was treated with NaN3 in the presence of the Lewis
acid BF3·OEt2, the desired azide 7b was obtained in 91% yield.
After heating azide 7b on a multigram scale using a catalyst of
Rh2(OAc)4 (5 mol%) according to the procedure from Driver,14
the desired indole derivative 8b was obtained in 57% yield.
and
2,6-di-tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-
1-ylidene)-p-tolyloxy (galvinoxyl free radical), were added to the
reaction system of the ortho-triazenyl phenyl magnesium
reagent and prenyl bromide, respectively, the yield of the reac-
tion was lowered to 55–65% but the ratio of γ : α was not
affected (Scheme 5). When these radical scavengers were
added to the reaction system of the ortho-triazenyl phenyl mag-
nesium reagent and prenyl chloride, the reaction was totally
inhibited and no desired prenylated or reverse prenylated
arenes were obtained. When 100% of radical initiators such as
AIBN or (PhCOO)2 were used, no reaction was observed. These
results strongly suggest that the copper-free allylic arylation
reaction between 3,3-disubstituted allylic chlorides and tria-
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method represents great functional group tolerance with
environmentally benign advantage. Also, the obtained pro-
ducts are of great value for multiple synthetic applications.
The branched and linear products can be transformed to the
corresponding 3H-indole and indole derivatives on a multi-
gram scale respectively. Further studies of the mechanism and
utility of these processes are in progress in our laboratory.
Acknowledgements
We thank the financial support from the National Nature
Science Foundation of China (21272003) as well as the
Zhejiang Provincial Top Key Academic Discipline of Chemical
Engineering and Technology of Zhejiang Sci-Tech University.
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Scheme 5 Control experiments of triazenyl-aryl Grignard reagents and
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Conclusions
In summary, we have developed a controllable copper-free
allylic arylation reaction of 3,3-disubstituted allylic halides
with triazene-softened aryl Grignard reagents to provide an
efficient route to prenylated and reverse prenylated arenes with
high regioselectivity by just switching the leaving group. This
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