Phosphine-mediated domino benzannulation strategy for the construction of highly functionalized multiaryl skeletons

Article abstract of DOI:10.1002/chem.201200305

A skeleton crew: A phosphine-mediated domino benzannulation strategy was developed for the synthesis of multiaryl skeletons (see scheme). A wide range of aromatic compounds and functional groups can be assembled into a multiaryl molecule through a core domino process. Copyright

Full text of DOI:10.1002/chem.201200305

COMMUNICATION
DOI: 10.1002/chem.201200305
Phosphine-Mediated Domino Benzannulation Strategy for the Construction
of Highly Functionalized Multiaryl Skeletons
Peizhong Xie, You Huang,* and Ruyu Chen[a]
Multiaryl compounds, especially biaryl compounds, repre-
sent privileged structural motifs in natural products, phar-
maceuticals, polymers, sensors,[1] and functional organic ma-
terials.[2] Consequently, efficient methods for the construc-
tion of multiaryl compounds are of utmost importance and
have been greatly investigated. Traditional strategies have
process.[5e] As a consequence, the construction of multiaryl
À
À
compounds containing C X bonds through aryl aryl bond
formation strategies is extremely challenging. Moreover,
harsh reaction conditions and difficulties associated with the
control of chemo- and regionselectivity are often problemat-
ic in the cross-coupling reactions.[6] All of these offer unique
opportunities to discover novel strategies for the formation
of multiaryl compounds, especially halide-containing and
unsymmetrical multiaryl compounds, which could serve as
a basic skeleton for further structural modification. Herein,
we report a new domino benzannulation strategy (Fig-
ure 1b) for the construction of multiaryl skeletons. Diverse
aromatic compounds and functional groups will be assem-
bled in a multiaryl molecule through a core domino process.
Although many benzannulation reactions[7] have gradually
been used in the construction of aromatic compounds, the
asymmetry and complexity of acyclic substrates, as well as
the poor regiochemistry of these reactions are always prob-
lematic.[7d] In addition, significant domino approaches have
recently been developed in the intramolecular benzannula-
tion reaction, some of which have been primarily used in
the construction of multiaryl skeletons.[7i–m] However, inter-
molecular versions[7d,f] of these reactions remain a challenge.
On the other hand, phosphine-mediated domino reactions
have become powerful tools in the generation of carbo- and
heterocycles.[8] In particular, phosphine-catalyzed domino re-
actions with allenoates or allylic carbonates have emerged
as a key platform for the generation of molecular complexi-
ty.[9] So far, to the best of our knowledge, no aromatic com-
pound has been directly constructed by this strategy.[10]
Based upon these studies, as well as our work concerning
phosphine-mediated domino reactions,[11] we now report the
first phosphine-mediated benzannulation reaction between
b,g-unsaturated a-ketoester 1 and allyic carbonate 2. In this
reaction, carbonate 2 served as a new kind of C3 synthon,[12]
which is different from its traditional 1,3-zwitterionic inter-
mediate or C1 manner of reacting.[13]
À
focused on the aryl aryl bond-formation reaction (Fig-
ure 1a) through “the change of partner” methodology, for
Figure 1. Strategies for the construction of multiaryl compounds: a) the
À
traditional aryl aryl bond-formation strategy and b) the domino benzan-
nulation strategy investigated in this work.
which various catalytic methods and substrates have been
developed.[3–6] Transition-metal-assisted cross-coupling reac-
tions[3] and homolytic aromatic substitution (HAS) with aryl
radicals[4] have become the predominant strategies for the
À
aryl aryl bond-formation reaction. Recently, elegant ap-
À
proaches, such as organocatalyzed direct C H arylation re-
actions,[5] have also been developed. Although great strides
À
have been made in the aforementioned aryl aryl bond for-
mation strategies, with most of those devised to date relying
À
heavily on the activation of aryl halides (Ar X, X=I, Br, or
Cl) through a two-electron or single-electron reduction
We initiated our investigation by subjecting carbonate 2a
to b,g-unsaturated a-ketoester 1a in the presence of PPh3 at
room temperature. To our delight, triaryl compound 3a was
obtained in 38% yield (Table 1, entry 1). The use of THF,
CH3CN, or toluene as the solvent led to triaryl compound
3a as the major compound in moderate or lower yield
(Table 1, entries 2–4). DMF as the solvent gave a relatively
better result for 3a with respect to the reaction time and
yield (Table 1, entry 5). The yield, to some extent, was sensi-
[a] P. Xie, Prof. Dr. Y. Huang, Prof. Dr. R. Chen
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University
Tianjin 300071 (P.R. China)
Fax : (+86)22-23503627
E-mail: hyou@nankai.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200305.
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Table 1. Optimization of the phosphine-mediated domino benzannula-
tion reaction.[a]
Table 2. Phosphine-mediated domino reaction for the construction of tri-
aryl compounds.[a]
Entry
PR3
T
[8C]
Solvent
t
Yield
[%][b]
Entry
R1
R2
t
Yield
[%][b]
[h]
[h]
1
2
3
4
5
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh2Et
PPhEt2
RT
RT
RT
RT
RT
80
DCE
THF
CH3CN
toluene
DMF
DMF
DMF
DMF
DMF
24
24
12
24
12
38
16
44
48
55
72
66
73
80
83
84
80
85
72
64
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[c]
16[d]
4-Br
4-Br
4-Br
3-Br
3-Br
2-Cl
2-Cl
2,4-Cl
2,4-Cl
H
4-Me
4-Me
4-OMe
4-NO2
2-naphthyl
furan-2-yl
4-Br
H
1.5
2.0
2.5
1.5
1.5
2.0
2.0
0.5
5.0
2.0
2.5
2.0
2.5
0.5
3.0
3.0
84 (3a)
74 (3b)
65 (3c)
80 (3d)
77 (3e)
85 (3 f)
80 (3g)
62 (3h)
66 (3i)
76 (3j)
70 (3k)
81 (3l)
68 (3m)
49 (3n)
62 (3o)
69 (3p)
4-Me
3-Br
4-Br
4-Br
3-Br
4-Br
2,4-Cl
4-Br
H
4-Br
4-Br
4-NO2
H
6
1.5
2
1
1.5
1.5
1.5
1.5
1.5
1
7[c]
8[d]
9
80
80
120
150
120
120
120
120
120
10
11
12[e]
13
14
15
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
P
N
4
[a] Reaction conditions: 1a (1.0 equiv, 0.25 mmol), 2a (1.5 equiv), PPh3
(1.1 equiv) in a solvent (5.0 mL) at the indicated temperature (DCE=di-
chloroethene). [b] Isolated yields. [c] 2a (1.2 equiv) was used. [d] 2a
(2.0 equiv) was used. [e] PPh3 (2.0 equiv) was used.
4-Br
[a] Reaction conditions: 1 (1.0 equiv, 0.25 mmol), 2 (1.5 equiv), PPh3
(1.1 equiv), DMSO (5.0 mL), 1208C. [b] Isolated yields. [c] R1C6H4 =2-
naphthyl. [d] R1C6H4 =furan-2-yl.
tive to the temperature and thus the reaction benefitted
from higher temperatures (Table 1, entries 5 and 6). Further-
more, DMSO was proven to be the best solvent (Table 1,
entries 9 and 11). Altering the ratio of 1a to 2a or increas-
ing the amount of PPh3 had little effect on the yield
(Table 1, entries 6–8). Next, the effect of the nucleophilicity
of the phosphine on this reaction was studied. PPh3 and
PPh2Et gave similar results (Table 1, entries 11 and 13), sug-
gesting that adjusting the nucleophilicity could not result in
a higher yield (Table 1, entries 14 and 15).
Under the optimized reaction conditions, we evaluated
the generality of this domino reaction. The results showed
that these processes serve as a general and efficient method
to prepare a variety of triaryl compounds (3) in modest to
high yields. Furthermore, the electronic properties and posi-
tion of substitution on 1 and 2 were found to have a limited
effect on these processes (Table 2). For the b,g-unsaturated
a-ketoester 1 and substrate 2 bearing a strong electron-with-
drawing group on the aromatic ring, such as a nitro group
(Table 2, entry 14), the desired product could also be ob-
tained in moderate yield. However, increased steric hin-
drance on substrates 2 was found to negatively influence the
reaction time (Table 2, entry 9). More importantly, halide-
substituted mixed triaryl compounds could be constructed
by this method (Table 2, entries 1–13 and 16). The presence
substituted b,g-unsaturated a-ketoesters 1 were also success-
fully employed in this reaction (Table 2, entries 15 and 16).
Inspired by these results, we envisaged that Heck-like
products might be obtained by this strategy. Indeed, this hy-
pothesis was proven by further investigation [Eq. (1)]. For
example, the reaction of 1k with 2 was sluggish, but gave
the desired product 3q in 30% yield with 16% recovered
1k. Pleasingly, 1l gave the corresponding Heck-like product
3r in 49% yield, indicating that to some extent the yield
and reaction time was sensitive to the reactivity of b,g,d,e-
unsaturated a-ketoester 1. To our knowledge, this was the
first time the construction of Heck-like products had been
achieved in a metal-free manner.
Subsequently, the reaction of unsubstituted carbonate 2
was examined under the optimal conditions to obtain biaryls
4. This reaction also showed good tolerance of electronic
properties and the position of the aryl-substitution on 1,
À
of C X bonds in multiaryl skeletons increases the possibility
for structural modification and thereby enhances the syn-
thetic utility of this reaction. Furan-2-yl- and 2-naphthyl-
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Phosphine-Mediated Domino Benzannulation
COMMUNICATION
Table 3. Phosphine-mediated domino reaction for the construction of
biaryl compounds.[a]
Entry
R1
R2
R3
t
Yield
[%][b]
[h]
1
2[c]
3[c]
4[c]
5
4-Me
4-Br
4-Cl
4-Br
3-Me
H
2-naphthyl
4-Me
4-Me
4-Me
furan-2-yl
2-Cl
Me
Me
Me
iPr
Me
Me
Me
Me
Me
Me
Me
Me
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
CN
COOBu
COOMe
COOEt
COOEt
1.5
1.0
1.0
1.5
1.5
1.5
1.5
2.0
1.5
1.5
2.0
1.0
71 (4a)
52 (58; 4b)
51 (57; 4c)
46 (56; 4d)
61 (4e)
66 (4 f)
57 (4g)
50 (4h)
61 (4i)
70 (4j)
49 (4k)
6
7[d]
8
9
10
11[e]
12[c]
58 (63; 4l)
[a] Reaction conditions:
1 (1.0 equiv, 0.5 mmol), 2 (1.5 equiv), PPh3
(1.1 equiv), DMSO (5.0 mL), 1208C. [b] Isolated yields. [c] The yields in
parentheses are for the reactions carried out at 808C. [d] R1C6H4 =2-
naphthyl. [e] R1C6H4 =furan-2-yl.
Scheme 1. The application of the synthesized multiaryl compounds
(DME=dimethoxyethane).
giving compounds 4 in modest to good yields. However, the
reaction was sensitive to the size of the ester substituent R3
(Table 3, entries 1, 9, and 10). Moreover, tert-butyl(2-cya-
noallyl) carbonate was also able to accomplish the forma-
tion of 4, albeit with a slightly lower yield (Table 3, entry 8).
The structures of 3 and 4 were characterized by a combina-
tion of NMR and HRMS spectra and single-crystal X-ray
analysis (4b).[14] In addition, unsubstituted carbonate 2 was
much more active than the Ar-substituted analogue. Howev-
er, some side reactions resulted in the formation of the de-
sired product in relatively lower yields when it reacted with
more active b,g-unsaturated a-ketoesters 1 (Table 3, en-
tries 2–4). For instance, in Table 3, entries 2 and 3, a trace
amount of dihydrofurans 5 (5a and 5b) was isolated or
could be detected by NMR spectroscopy (Table 3, entry 4)
as by-products.[15] It should be noted that at a lower temper-
ature (808C) more active b,g-unsaturated a-ketoesters 1 per-
formed better than at 1208C (Table 3, entries 2–4 and 12).
This phosphine-mediated domino reaction strategy is
complementary to the traditional cross-coupling methods.
The combination of these two methods could provide a pow-
erful platform for generating complex multiaryl compounds,
which is especially powerful for the construction of asym-
metric multiaryl skeletons, such as 6a and 6b (Scheme 1).
These skeletons are often exploited in the design of organic
electroluminescent (OEL) devices and liquid crystalline ma-
terials.[16] Moreover, after transformation from 3 or 4 in
a few steps, the biologically active molecular arcaine ana-
logues, which act as inhibitors of [3H]MK-801 binding, can
be obtained.[17]
The detailed mechanisms of these selective domino reac-
tions have not yet been clarified. However, according to our
experimental results[13b,15] and some related studies,[18] the
formation of the dihydrofuran byproducts was through
a [4+1] annulation reaction, in which allyic carbonate 2
served as a C1 synthon. The aforementioned reaction was in-
itiated by the formation of the allylic phosphorus ylide A
through the commonly accepted addition–elimination and
deprotonation processes (Scheme 2). Subsequently, ylide A
underwent the sterically favored g-carbanion addition to
b,g-unsaturated a-ketoester 1a, yielding intermediate B. In-
termediate B interconverts with C through proton transfer
(path a, between the g- and a-carbon atoms). Then, intra-
molecular annulation involving oxygen-anion addition to the
olefinic double bond delivers the 2,3-dihydrofurans.[15]
However, this reaction was highly chemoselective in favor
of the formation of the multiaryl compounds. Presumably,
the intermolecular Wittig reaction first occurs between allyl-
ic phosphorus ylide A and 1 to produce intermediate D.
Then, intermediate D accomplishes an electrocyclization re-
action, generating intermediate E. Intermediate E subse-
quently undergoes an oxidative aromatization processes to
give product 3 or 4 (path b). In this mechanism, the aryl
rings are attached to the carbon centers directly involved in
the 6p-electrocyclization step. Thus, it allows for a logical
explanation for the observed effects relating to the electron-
ic properties of the aryl substituents. In addition, in another
possible reaction pathway (path c), which could not be com-
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Y. Huang et al.
might be the driving force in losing hydrogen by air oxida-
tion to form the aromatic compound easily.[7i]
In conclusion, we have developed a novel domino benzan-
nulation reaction strategy for the construction of multiaryl
compounds in moderate to high yields. In these reactions,
À
diverse aromatic compounds and functional groups (C X)
can be assembled in a multiaryl molecule through a core
domino process, which increases the possibilities for struc-
tural modification. This approach has also been applied to
the synthesis of Heck-like products. Furthermore, the allyic
carbonate 2 serves as a new kind of C3 synthon, which is dif-
ferent from its traditional 1,3-zwitterionic intermediate reac-
tion mode. Further effort towards the application of this
strategy in organic synthesis and the detailed mechanism
will be investigated by our group.
Experimental Section
Experimental details: PPh3 (1.1 equiv) was added to a mixture of b,g-un-
saturated a-keto ester 1 (1.00 equiv, 0.25 mmol) and allylic carbonate 2
(1.50 equiv) in DMSO (5.0 mL). The resulting suspension was kept at
1208C until completion of the reaction (the reaction was monitored by
TLC). Dichloromethane (20 mL) was then added to the reaction mixture
and it was washed with water (3ꢁ10 mL). The organic layer was separat-
ed and dried over sodium sulfate. After filtration and concentration on
a rotary evaporator, the residue was purified by column chromatography
on silica gel (gradient eluent: petroleum ether/ethyl acetate 30:1–20:1) to
afford the multiaryl compound.
Acknowledgements
We thank the National Natural Science Foundation of China (20972076,
21172115) and the Natural Science Foundation of Tianjin
(10JCYBJC04000) for financial support.
Keywords: benzannulation reactions · domino reactions ·
multiaryls · organocatalysts · phosphine
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Received: January 28, 2012
Revised: March 24, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Y. Huang et al.
Domino Reactions
P. Xie, Y. Huang,* R. Chen &&&& — &&&&
Phosphine-Mediated Domino Benzan-
nulation Strategy for the Construction
of Highly Functionalized Multiaryl
Skeletons
A skeleton crew: A phosphine-medi-
ated domino benzannulation strategy
was developed for the synthesis of
wide range of aromatic compounds
and functional groups can be assem-
bled into a multiaryl molecule through
a core domino process.
multiaryl skeletons (see scheme). ACTHUNGTRENNNUG
&
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!