Palladium-Catalyzed Two-Component Domino Coupling Reaction of (Z)-β-Bromostyrenes with Norbornenes: Synthesis of 1,5-Enynes

Article abstract of DOI:10.1002/adsc.201500865

Polyfunctional molecules, 1,5-enynes, have been achieved via a palladium(0)-catalyzed domino coupling reaction of (Z)-β-bromostyrenes with norbornenes in the presence of cesium carbonate and N,N-dimethylformamide. The process involves a double Heck-type procedure, two-fold C(sp²) H activation and formation of two carbon-carbon bonds. There are possibilities of diversified transformation for the domino coupling of (Z)-β-bromostyrenes with norbornenes, the procedure is successfully driven to 1,5-enynes via accurate adjustment of the reaction conditions. (Figure presented.) .

Full text of DOI:10.1002/adsc.201500865

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DOI: 10.1002/adsc.201500865
Palladium-Catalyzed Two-Component Domino Coupling Reaction
of (Z)-b-Bromostyrenes with Norbornenes: Synthesis of 1,5-
Enynes
Jiangang Mao,a,b Huifang Li,c Herui Wen,a Min Li,a Xiaolin Fan,c
and Weiliang Baob,*
a
School of Metallurgical and Chemical Engineering, Jiangxi University of Science and Technology, Ganzhou 341000,
Jiangxi, Peopleꢀs Republic of China
Department of Chemistry, Zhejiang University, Hangzhou 310028, Zhejiang, Peopleꢀs Republic of China
b
Fax: +(86)-571-8827-3814; e-mail: wlbao@zju.edu.cn
Key Laboratory of Organo-Pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, Jiangxi, Peopleꢀs
c
Republic of China
Received: September 17, 2015; Revised: April 2, 2016; Published online: June 2, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500865.
Abstract: Polyfunctional molecules, 1,5-enynes,
have been achieved via a palladium(0)-catalyzed
domino coupling reaction of (Z)-b-bromostyrenes
with norbornenes in the presence of cesium carbon-
ate and N,N-dimethylformamide. The process in-
The 1,5-enyne subunit as a basic skeleton is found
in many natural products and biologically active com-
pounds.[6] The norbornene subunit is present also in
many natural products and pharmaceuticals and ex-
hibits some biological activities;[7] it is also a useful
precursor of cycloisomerization reactions in organic
synthesis.[8]
Diversity-oriented organic synthesis is always a fas-
cinating challenge which leads to structurally complex
and diverse compounds and the opportunity for drug
discovery.[9] Selective transformation of simple sub-
strates exclusively into two or more products via regu-
lating catalytic processes is an important strategy to
realize diversity-oriented organic synthesis.[10] During
previous studies on the coupling of vinyl bromides
with norbornenes, we achieved methylenecyclopro-
pane, methylcyclopropane and bismethylenecyclobu-
tane derivatives through changing the reaction condi-
tions.[11] Recently, we obtained another set of 1,5-
enyne compounds with 20 examples and up to 96%
volves a double Heck-type procedure, two-fold
2
À
C(sp ) H activation and formation of two carbon-
carbon bonds. There are possibilities of diversified
transformation for the domino coupling of (Z)-b-
bromostyrenes with norbornenes, the procedure is
successfully driven to 1,5-enynes via accurate ad-
justment of the reaction conditions.
Keywords:
(Z)-b-bromostyrenes;
1,5-enynes;
domino reactions; norbornenes; palladium-cata-
lyzed reaction
Polyfunctional molecules, 1,n-enynes, are all signifi- yield when Cs2CO3 was used as base and DMF was
cant building blocks for diversity-oriented organic employed as solvent (Scheme 1). The domino cou-
synthesis in drug discovery,[1] and are also the key in- pling reaction is much more efficient.
termediates of cyclization and cycloisomerization pro-
To reach the best results, (Z)-1-(2-bromovinyl)-3-
cesses in many total syntheses of natural products and chlorobenzene 1d and endo-N-(p-tolyl)norbornene-
other complex molecules.[2,3] However, compared to succinimide 2a were employed as model substrates to
1,3-enynes and 1,6-enynes,[4] the studies on the synthe- perform the reaction (Table 1). The desired 1,5-enyne
sis of 1,5-enynes are still inadequate.[5] The synthesis derivative 3da was obtained selectively as the final
of 1,5-enynes is mostly by three-component coupling, product instead of compounds 4da (Table 1). Then,
multi-step reactions and two-component coupling re- the reaction conditions were screened to achieve the
actions of an alkene and an alkyne,[5] the direct and best selectivity and yield of 1,5-enyne 3da. The results
high-efficiency two-component domino reaction of al- are summarized in Table 1.
kenes to synthesize 1,5-enynes remains under devel-
oped.
Firstly, the metal catalysts and the ligands were
screened in the coupling reactions. Pd(OAc)2 was
better than PdCl2, Pd(PPh3)4 and Pd(dppf)Cl2
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(Table 1, entries 1–4, 95% yield compared with 64– (entries 15–17), while the domino coupling reaction
85%). The effect of the ligand was then investigated, afforded 1,5-enyne 3da with 82% and 95% yields, re-
and PPh3 was found to be the optimal, affording 3da
in 95% yield. Other screened ligands (dppe, dppf,
TMOPP and DCHPP) could also promote the reac-
tion with decreased yields, possibly due to either
steric or electronic effects (58–88%, entries 5–8).
Varying the type and load of the solvents (DMF, tolu-
ene, DMSO, NMP, 1,4-dioxane and DEDM) influ-
enced the reaction outcome considerably (Table 1, en-
tries 9–17). The solvent had a significant effect on re-
action selectivity and product yield. The use of
2.0 mL toluene, 1.4-dioxane and diethylene glycol di-
methyl ether (DEDM) yielded bimethylenecyclobu-
Scheme 1. Pd-catalyzed domino coupling reaction of (Z)-b-
tane 4da with 91%, 70% and 81% yields, respectively bromostyrenes with norbornenes.
Table 1. Optimization of the reaction conditions for the synthesis of 1,5-enynes.[a]
Entry
[Pd]
Ligand
Solvent (mL)
Base
3da/4da/5da/6da Yield[b] [%]
1
2
3
4
5
6
7
8
PdCl2
PPh3
PPh3
PPh3
PPh3
dppe
dppf
TMOPP
DCHPP
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3[c]
Cs2CO3
CH3ONa
K2CO3
3da (85)
3da (80)
3da (95)
3da (64)
3da (62)
3da (58)
3da (88)
3da (72)
3da (82)
3da (77)
3da (61)
4da (73)
3da (71)
3da (57)
4da (91)
4da (70)
4da (81)
3da (52)
5da (66)[d]
6da (40)[e]
Pd(PPh3)4
Pd(OAc)2
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
DMF (2.0)
toluene/DMF (0.5/1.5)
toluene/DMF (1.0/1.0)
toluene/DMF (1.5/0.5)
DMSO
10
11
12
13
14
15
16
17
18
19
20
NMP
toluene (2.0)
dioxane (2.0)
DEDM (2.0)
toluene (2.0)
DMF/CH3OH (2.0/0.2)
DMF
[a]
Reaction conditions (unless otherwise noted): 1a (1.0 mmol), 2a (0.5 mmol), catalyst (0.05 mmol), ligand (0.11 mmol), base
(1.5 mmol), solvent (3.5 mL), 1108C, 12 h in a sealed tube.
Yield of isolated product; dppe=1,2-bis(diphenylphosphino)ethane, dppf=1,1’-bis(diphenylphos phino)ferrocene,
TMOPP=tris(4-methoxylphenyl)phosphine, DCHPP=dicyclohexyl(phenyl)phosphine, TCHP=tricyclohexylphosphine,
DEDM=diethylene glycol dimethyl ether.
[b]
[c]
[d]
[e]
The reaction was performed in the presence of 1.2 equiv. (n-Bu)4NBr.
The reaction was reported in Ref.[8c]
K2CO3 (0.25 mmol), DMF (2.0 mL).
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spectively (entries 9 and 3) in the solvent mixture of wanted to know whether the effects of solvent DMF
2.0 mL DMF and 3.5 mL DMF. The mixed solvent originated mainly from its interaction with the palla-
with different ratios of toluene/DMF had also a key dium atom center, thus (n-Bu)4NBr was employed as
effect on reaction selectivity and product yield. The phase transfer catalyst to carry out the reaction in the
mixed solvents (toluene/DMF=0.5 mL/1.5 mL and toluene, the product was still 1,5-enyne 3da (entry 18,
1.0 mL/1.0 mL) produced 1,5-enyne 3da with 77% 52% yield). Obviously, the basicity variation resulting
and 61% yields, respectively (entries 10 and 11), while from the solubility of Cs2CO3 in different solvents
the mixed solvent of 1.5 mL toluene and 0.5 mL DMF controlled successfully the chemoselectivity of the
provided 4da with 73% yield (entry 12). Next, we domino coupling process, and thus yielded exclusively
Table 2. Substrate scope of the Pd-catalyzed synthesis of 1,5-enynes.[a,b]
[a]
Reaction conditions (unless otherwise noted): 1a (1.1 mmol), 2a (0.5 mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.11 mmol),
Cs2CO3 (1.5 mmol), DMF (3.5 mL), 1108C, 12 h in a sealed tube.
The yield is that of the isolated product.
1a (1.0 mmol), 2a (0.6 mmol).
[b]
[c]
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bimethylenecyclobutane 4da or 1,5-enyne 3da (en- 3gd; 78–92%). A non-rigid alkene, such as cyclohex-
tries 10–12). However, the more intrinsic detailed ene, was also tested to carry out the domino coupling
mechanism of the chemoselectivity is still quite dubi- procedure, however, the reaction did not proceed
ous at the moment.[12] For the model reaction, the smoothly. The structure of the product was further
best yield of 3da was obtained when the reaction was confirmed unambiguously by an X-ray crystallograph-
catalyzed by Pd(OAc)2/PPh3 and 3.0 equiv. Cs2CO3 ic analysis of a single crystal of 3eb (see the Support-
were employed as the base in 3.5 mL DMF (Table 1, ing Information, Figure S1).[14] The formed 1,5-enyne
entry 3, 95% yield).
moiety took the exo-face of norbomene. The stereo-
With the optimized reaction conditions in hand, the chemistry of all the compounds is the same as that of
substrate scope was examined using a variety of (Z)- 3eb based on analysis of the chemical shifts and cou-
bromostyrenes 1 and norbornene derivatives 2, as pling constants (J) of their NMR data.[11] In addition,
shown in Table 2. (Z)-Bromostyrene substrates bear- only one diastereomer was isolated in all cases.
ing an electron-withdrawing group (3-Cl, 4-Cl, 4-F)
In order to better understand the reaction mecha-
on the benzene ring led to the corresponding 1,5- nism, the reaction of (Z)-1-(2-bromovinyl)-4-chloro-
enyne derivatives 3 in excellent yields (Table 2, 3da, benzene 1 and N-(4-methylphenyl)-3-exo-(4-chloro-
3db–3fb, 3dc, 3fc, 3dd–3fd), while substrates bearing benzylidene)tricyclo[3.2.1.02,4]octane-6,7-endo-dicarb-
an electron-donating (3-Me, 4-Me, 4-MeO) group on oximide 6 was carried out under the same reaction
the benzene core also afforded the desired 1,5-enyne conditions (Scheme 2). However, we did not find the
products 3 in good to high yields (Table 2, 3ba–3ca, product of 1,5-enyne 3. This means that the formation
3bb–3cb, 3bd–3cd). The differences in yields may of the 1,5-enyne may not go through the methylenecy-
result from electronic effects of the substituents. The clopropane 6 as the intermediate.
para-substituted (Z)-bromostyrene produced 1,5-
Based on the current experimental results, our pre-
enyne products 3ba, 3bb, 3eb, 3bd and 3ed in higher vious works,[11] and related precedents,[15] a postulated
yields (87%, 83%, 96%, 82% and 92% yield) due to mechanism was proposed (Scheme 3). Due to the fact
the much smaller steric hindrance compared with the that the reaction concerns a cis-to-trans alkene iso-
corresponding meta-ones 3ca, 3cb, 3db, 3cd and 3dd merisation, we carrid out DFT calculations on the
(80%, 78%, 91%, 78% and 89% yield). ortho-Substi- pathways of cis-to-trans alkene isomerization
tuted products cannot be isolated because of the (Scheme 4). The coordination of C=C bond to Pd in
strong steric hindrance and conferring on them corre- the intermediate VI generated intermediate VII, and
spondingly low yields. (E)-Bromostyrenes were exam- the energy decreased simultaneously by 15.9 kcal
ined also under the same reaction conditions, howev- molÀ1. Subsequently, the intermediate VII was trans-
er, no desired 1,5-enyne products were obtained. formed to VIII through transition state VII-TS, the
Maybe the aromatic ring of (Z)-2-bromovinylarene (Z)-alkene was changed to the (E)-configuration ac-
stabilized the intermediate norbornenyl palladium cordingly and the Er of the intermediate VIII de-
species via favorable remote coordination of the aro- creased by 5.2 kcalmolÀ1 compared with VII. Howev-
matic p system with the palladium center.[11a,b,13] How- er, if the intermediate VI with a (Z)-alkene directly
ever, the geometry of (E)-2-bromovinylarenes makes changed to VI-P with (E)-alkene via the transition
it difficult to exert the same stabilizing function. Het- state VI-TS through the vibrations of C=C bond, the
erocyclic vinyl bromides such as (Z)-3-(2-bromovin- energy increased by 1.3 kcalmolÀ1. Therefore, the in-
yl)-pyridine were also tested for the domino coupling termediate VII is probably vital to the cis-to-trans
reaction and afforded the corresponding 1,5-enyne alkene isomerization,[16] the proposed mechanism was
product 3gd with 88% yield.
well supported by the DFT calculations.
The optimized domino coupling procedure was sub-
The overall reaction mechanism is as follows
sequently applied to a range of norbornene deriva- (Scheme 3). The oxidative addition of palladium(0)
tives. endo-N-(p-Tolyl)norbornenesuccinimide 2a and
endo-N-(isobutyl)norbornenesuccinimide 2b under-
went smoothly the domino coupling reaction with
(Z)-b-bromostyrenes to provide the corresponding
1,5-enyne products 3aa–3da and 3ab–3fb in good to
excellent yields. Dicyclopentadiene 2c also yielded
the desired 1,5-enyne products 3ac, 3dc and 3fc in
78%, 86% and 90% yields, respectively. The domino
coupling of dicyclopentadiene with (Z)-b-bromostyr-
enes occurred selectively at one of its two carbon-
carbon double bonds. Norbornene itself 2d showed
also high reactivity and gave the corresponding prod-
Scheme 2. Pd-catalyzed coupling reaction of (Z)-b-bromos-
tyrene 1 with methylenecyclopropane 6 for the reaction
ucts in moderate to excellent yields (Table 2, 3ad– mechanism.
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sertion to the double bond, and resulted in the forma-
tion of a regioselective four-membered palladacycle
2
À
IV with a selective C(sp ) H bond activation on the
carbon-carbon double bond.[17] The intermediate IV
should further undergo oxidative addition to another
equivalent of 1 again and generate the intermediate
V with octahedrally coordinated palladium(IV).[11a,18]
The selective reductive elimination of the intermedi-
ate V produced styrylpalladium(II) bromide inter-
mediate VI, which once again underwent coordina-
tion with the double bond to prompt the inversion of
the double bond and then produced intermediate
VIII.[19] Ultimately, the intermediate VIII underwent
b-H elimination and afforded the desired 1,5-enyne
compound 3,[20] and meanwhile, Pd(0) I was regener-
ated.
In conclusion, a new methodology for the synthesis
of 1,5-enynes has been developed. The Pd-catalyzed
selective domino coupling of (Z)-b-bromostyrenes
with norbornene derivatives is realized under ex-
tremely concise reaction conditions. Highly function-
alized 1,5-enyne derivatives were obtained selectively
in good to excellent yields in the presence of Cs2CO3
Scheme 3. Proposed reaction mechanism for the Pd(0)-cata-
lyzed synthesis of 1,5-enynes.
species to (Z)-b-bromostyrene 1 produced (Z)-styryl- and DMF. The two-component coupling involves in
2
À
palladium(II) bromide II. Subsequently the syn addi- a double Heck-type procedure, two-fold C(sp ) H
tion of II to norbornene 2 generated norbornenylpal- bond activation and formation of two carbon-carbon
ladium complex III at the exo-face of 2. The complex bonds. The reaction is interesting both for theoretical
III underwent successively a coordination with and in- and organic synthetic chemistry.
Scheme 4. DFT calculations on the cis-to-trans alkene isomerization via either the double bond vibration itself or its coordi-
nation to palladium.
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General Procedure for the Two-Component Domino
Coupling Reaction
ˇ ´
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a
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (No. 21072168) and the PhD research startup
foundation of Jiangxi University of Science and Technology
(No. jxxjbs15009) is greatly appreciated.
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