Development of an Open-Air and Robust Method for Large-Scale Palladium-Catalyzed Cyanation of Aryl Halides:The U of i-PrOH to Prevent Catalyst Poisoning by Oxygen
Yunlai Ren,Zhifei Liu,Shebin He,Shuang Zhao,Jianji Wang,*Ruiqi Niu,and Weiping Yin
School of Chemical Engineering and Pharmaceutics,Henan Uni V ersity of Science and Technology,
Luoyang,Henan471003,P.R.China
Abstract:
Palladium-catalyzed cyanation of aryl halides is an often capricious
reaction and lacks robustness due to catalyst poisoning by oxygen.
In this report,an open-air and robust method for large-scale
cyanation was developed and the u of commercially available
i-propanol as an additive was critical for achieving the open-air, robust and scaleable process.Under the protection by i-propanol, the catalyst life was significantly prolonged.
Introduction
Aryl nitriles play an important role in organic synthesis since they not only constitute key components of a range of pharmaceuticals,agrochemicals,dyes,etc.1but can also easily be transformed into various class of compounds such as nitrogen-containing heterocycles,aldehydes,acids,and acid derivatives.2One of the most convenient methods for the synthesis of aryl nitriles is the transition metal-catalyzed cyanation of aryl halides such as the palladium-,3-10nickel-,11 and copper-catalyzed methods.12-14Of the methods,Pd-catalyzed aryl cyanation has recently attracted the most con-siderable attention owing to its versatility.Unluckily,the palladium catalysts have often been poisoned by trace amounts of oxygen in the solvent.15In order to avoid or suppress the deactivation of the catalysts,it has often been required that the solvent is rigorously degasd and the reaction is run in stringent inert conditions,15which restricts the applications of the Pd-catalyzed aryl cyanation.
多吃葡萄During the cour of applying Weissman’s ligand-free procedure to large-scale synthesis of the compound shown in Figure1,16we suffered from unexpected reaction failures,which resulted possibly from the prence of low-level amounts of oxygen either from the solvent or introduced during tup and monitoring.Thus,some inexpensive additives were screened to protect the reaction from being destroyed by oxygen.
Previous studies of palladium-catalyzed cyanation reactions revealed that zinc dust and polymethylhydrosiloxane(PMHS) are able to protect the palladium-catalysts from being poisoned by oxygen.17Considering that the u of zinc dust would lead to heavy metal waste,PMHS was chon to prevent catalyst poisoning.Unluckily,the addition of PMHS into the reaction mixture resulted in the formation of an unacceptable amount of undesired products.To our knowledge,another air-innsitive procedure is Gelman’s procedure in which1,8-bis(diisopropy-lphosphino)triptycene/Pd(OAc)2was ud as the catalyst,18but the u of an expensive ligand compelled us to abandon the application of Gelman’s procedure.
Subquently,we decided to develop a more economical and air-innsitive procedure for large-scale Pd-catalyzed aryl cyanation by improving Weissman’s ligand-free procedure.19 We report our results here.
Results and Discussion
In our initial study,cyanation of iodobenzene was chon as a model reaction,and PMHS was ud as an additive to prevent the Pd-catalyst from being deactivated.26Unluckily,the addition of PMHS led to the formation of a considerable amount
*Author to whom correspondence may be nt.Fax:86-379-64210415. E-mail:Jwang@henannu.edu.
军事成语
(1)Larock,R.C.Comprehensi V e Organic Transformations;VCH:New
York,1989,pp819-995.
(2)Rappoport,Z.Chemistry of the Cyano Group,1st ed.;John Wiley&
网络接口怎么接线Sons:London,1970.
选择素
(3)Ellis,G.P.;Romney-Alexander,T.M.Chem.Re V.1987,87,779–
794.
(4)Anderson,B.A.;Bell,E.C.;Ginah,F.O.;Harn,N.K.;Pagh,L.M.;
Wepsiec,J.P.J.Org.Chem.1998,63,8224–8228.
(5)Sundermeier,M.;Mutyala,S.;Zapf,A.;Beller,M.J.Organomet.
Chem.2003,684,50–55.
(6)Schareina,T.;Zapf,A.;Beller,M.Chem.Commun.2004,1388–1489.
(7)Schareina,T.;Zapf, A.;Ma¨gerlein,W.;Mu¨ller,N.;Beller,M.
Tetrahedron Lett.2007,48,1087–1090.
(8)Velmathi,S.;Leadbeater,N.E.Tetrahedron Lett.2008,49,4693–
4694.
(9)Ryberg,P.Org.Process Res.De V.2008,12,540–543.
(10)Erhardt,S.;Grushin,V.V.;Kilpatrick,A.H.;Macgregor,S.A.;
Marshall,W.J.;Roe,D.C.J.Am.Chem.Soc.2008,130,4828–4845.
(11)Arvela,R.K.;Leadbeater,N.E.J.Org.Chem.2003,68,9122–9125.
(12)Schareina,T.;Zapf,A.;Beller,M.Tetrahedron Lett.2005,46,2585–
2588.
(13)Schareina,T.;Zapf,A.;Ma¨gerlein,W.;Mu¨ller,N.;Beller,M.Chem.-
Eur.J.2007,13,6249–6254.
(14)Ren,Y.L.;Liu,Z.F.;Zhao,S.;Tian,X.Z.;Wang,J.J.;Yin,W.P.;
He,S.B.Catal.Commun.2009,10,768–771.(15)All the reactions of palladium-catalyzed aryl cyanation in refs12-14
were performed in inert ambiance.
(16)Kleemann,A.;Engel,J.;Kutscher,B.;Reichert,D.Pharmaceutical
鲶鱼吃什么食物substances:synthes,patents,applications,4th ed.;Georg Thieme Verlag:Stuttgart,NY,2001,pp825-826.
(17)Martin,M.T.;Liu,B.;Cooley,B.E.;Eaddy,J.J.F.Tetrahedron
Lett.2007,48,2555–2557.
(18)Grossman,O.;Gelman,D.Org.Lett.2006,8,1189–1191.
(19)Weissman,S.A.;Zewge,D.;Chen,C.J.Org.Chem.2005,70,1508–
1510
.
Figure1.Application of Weissman’s ligand-free procedure for Pd-catalyzed cyanation.
Organic Process Rearch&Development2009,13,764–768
764•Vol.13,No.4,2009/Organic Process Rearch&Development10.1021/op9000725CCC:$40.75 2009American Chemical Society Published on Web05/14/2009
of undesired products,which prompted us to u other additives. According to the previous report,20some alcohols can be ud as the reductants for Pd-catalyzed homocoupling of aryl halides, which implies that oxygen may be eliminated by alcohols in
the prence of Pd catalyst.Thus,a variety of alcohols such as MeOH,EtOH,i-PrOH,n-BuOH,t-BuOH,and t-AmOH were screened as the additives to eliminate oxygen,and it was found that i-propanol had a notable ability to protect the Pd-catalyzed cyanation from being destroyed by oxygen.As shown in Table 1,when cyanation of iodobenzene was performed completely open to the air without degassing of the solvent,the addition of i-propanol incread the yield from44%to93%(Table1, entries1,4).However,when the reaction was performed under inert conditions the beneficial effect of i-propanol was uncon-spicuous(Table1,entries2,3),which implied that the solvent effect of i-propanol was insignificant for the reaction.In conclusion,only under the condition of exposure to air,was the reaction significantly affected by i-propanol.This result revealed that i-propanol was able to protect the Pd-catalyzed cyanation from being destroyed by oxygen,which was also supported by the fact that the oxidation product of i-propanol was detected in our open air reaction.The results were possibly rationalized by assuming that active Pd(0)catalytic species were oxidated to inactive Pd(II)by oxygen,and then i-propanol reduced Pd(II)to active Pd(0).
Then our attention was turned to the optimization of the concentration of i-propanol.As shown in Table1(entries 5-10),all the reactions were performed completely open to the air without stringent degassing of the solvent.The cyanation reaction in the abnce of i-propanol gave benzonitrile in onl
y 42%yield(Table1,entry5).The yield incread from74%to 91%with the concentration of i-propanol increasing from0.3 vol%to1.2vol%,and then remained almost constant with further increa of the concentration of i-propanol(Table1, entries6-10).The results revealed that more than1.2vol% i-propanol was preferred for facilitating the open air Pd-catalyzed cyanation.Subquently,5.2vol%H2O was added into the reaction system to further improve our procedure.As en from Table1(entries11,12),the addition of H2O did accelerate the cyanation reaction,which was possibly attributed to that H2O played a role of cosolvent to help solubilize K4[Fe(CN)6].21,22Then our attentions turned to the optimization of concentration of H2O,and it was found that4-6vol%H2O was preferred for facilitating the Pd-catalyzed cyanation. Cyanation reaction with H2O as the solvent was also investi-gated,but the obtained yield was very low,resulting possibly from a poor solubility of iodobenzene in H2O.
Optimization experiments for the cyanation of bromobenzene included the effect of i-propanol,H2O,reaction time,and temperature.As en from Figures2and3,about2-6vol% i-propanol and4-6vol%H2O were optimal for facilitating the reaction.We then tried reducing the reaction time but found that this was not possible without sacrificing product yield.The same was true when we tried to reduce the catalyst loading. We tried eliminating the Na2CO3from the reaction,but such modification resulted in no conversion to product.
In order to demonstrate further the effectiveness of i-propanol in this process,Gas chromatography was ud to monitor the cyanation of iodobenzene.As en from Figure4,the open air reaction in the prence of i-propanol proceeded at esntially the same rate as the reaction performed in inert ambiance,while the same open air reaction in the abnce of i-propanol stalled after only25min(up to47%yield was obtained).The results revealed that the effectiveness of i-propanol was significant to protect Pd-catalyzed cyanation from being destroyed by oxygen. When the aforementioned reactions proceeded for60min,
(20)Hassan,J.;Se´vignon,M.;Gozzi,C.;Schulz,E.;Lemaire,M.Chem.
Re V.2002,102,1359–1470.(21)Stazi,F.;Palmisano,G.;Turconib,M.;Santagostino,M.Tetrahedron
Lett.2005,46,1815–1518.
(22)Buono,F.G.;Chidambaram,R.;Mueller,R.H.;Waltermire,R.E.
Org.Lett.2008,10,5325–5328.
Table1.Cyanation of iodobenzene catalyzed by Pd(OAc)2
a
entry ambiance i-PrOH
(vol%)b time(min)conv.(%)c yield(%)c
1air-404544
2N2-408681
3N2 4.640>9988
4air 4.840>9993
5air-404442
6air0.3408574
7air 1.240>9991
8air 2.440>9989
9air 3.340>9988小螃蟹儿歌
10air 6.940>9987
11air 4.7208169
12d air 4.8209991
a Reaction conditions are shown in the Experimental Section of this paper(1 mmol iodobenzene was ud).
b Equal to[V i-PrOH/(V i-PrOH+V NMP)]×100%.
c Determine
d by GC with n-tetradecan
e as an internal standard.d5.2vol%H2O was
ud.Figure2.Effect of concentration of H2O on the cyanation of bromobenzene(under the reaction c
onditions as shown in entry 8,Table
2).
Figure3.Effect of concentration of i-propanol on the cyanation of bromobenzene(under the reaction conditions as shown in entry8,Table2).
Vol.13,No.4,2009/Organic Process Rearch&Development•765
iodobenzene and K 4[Fe(CN)6]were again added into the reaction system to reu the catalyst without paration of the product.As shown in Figure 4,in the ca of reusing the catalyst,the rate of the open air reaction in the prence of i -propanol far exceeded the rate of the reaction performed in inert ambiance,which also implied that i -propanol was of ability to protect the catalyst from inactivation and thus prolong the catalyst life.This conclusion was supported by the following
experimental results (Figure 5):without paration of the product,the mixture containing the catalyst could be reud five times with no significant loss of activity in the ca of both the prence of i -propanol and exposing the reaction to air,while the catalyst showed a complete deactivation after being reud only one time in the ca of both the abnce of i -propanol and protecting the reaction with argon.
To clarify further the roles of i -propanol in this process,Pd(OAc)2-catalyzed cyanation of iodobenzene was purpofully
Table 2.Cyanation of various aryl halides catalyzed by Pd(OAc)2
a
a
Reaction conditions are shown in the Experimental Section of this paper (1mmol aryl halide was ud).b Characterized by comparison of 1H NMR and 13
C NMR data
with that in the literature.c Determined by GC with n -tetradecane as an internal standard.d Isolated
yield.
Figure 4.Palladium-catalyzed cyanation of iodobenzene (under the reaction conditions as shown in entry 4,Table
1).
Figure 5.Reu of the mixture containing the catalyst for cyanation of iodobenzene without paration of the product.Besides the reaction time (60min),other reaction conditions are shown in entry 4,Table 1.
766
•
Vol.13,No.4,2009/Organic Process Rearch &Development
stalled by exposure to air prior to the addition of i -propanol,and the result showed that the addition of i -propanol failed to restart the stalled reaction,revealing that i -propanol could not reactivate the catalyst that has been deactivated.
A ries of aryl iodides were then screened to determine the scope and limitation of the suggested large-scale protocol.As shown in Table 2,the cyanation reactions were able to tolerate a wide range of functional groups such as ketone,carbonyl,ester,and methoxy groups.The primary amino group was even well tolerated and did not suffer from N -arylation (Table 2,entry 5),which possibly resulted
from the high affinity of the cyanide nucleophile toward the palladium catalyst.23The electronic effect of the substrate emed to be unpredictable under our conditions.Both electron-poor and electron-rich aryl iodides gave moderate to high yields under similar conditions (Table 2,entries 2-7).4-Iodotoluene gave a yield of 98%in 0.4h,while 2-iodotoluene gave a lower yield of 69%in a longer reaction time (Table 2,entries 6,7).The results indicated that the substituent in ortho-position lowered the reaction rate.Considering that aryl bromides are less expensive than corre-sponding aryl iodides,we applied the prent open-air protocol to the cyanation of aryl bromides.Although the cyanation of aryl bromides was slower,moderate to high yields of the aromatic nitriles could still be obtained in a longer reaction time (Table 2,entries 8-14).
Subquently,the suggested protocol was applied to the large-scale cyanation of bromobenzene,and a yield of 56%was obtained (Table 3,entry 1).In an attempt to optimize the conditions for the large-scale reaction,veral experiments were conducted where different orders of addition of the reagents were evaluated.As en from Table 3,the addition of K 4[Fe(CN)6]·3H 2O to a preheated mixture of other reactants was critical for achieving a robust and scaleable process (Table 3,entry 2).The addition of i -PrOH prior to the heating operation had also positive effect on the scaleable reaction.
The isolation of the products was difficult in the ca of using NMP as the solvent,prompting us to u DMF having a lower boiling point than the solvent.Luckily,the reaction also proceeded smoothly in DMF.After the reaction proceeded to completeness,the fractionation of the mixture afforded the desired product in high purity (>95%).Whereafter,we focud on the safety issues of the scaleable reaction.Considering that volatilization of the solvent was dangerous to the environment
in the ca of exposing the reaction to air,we performed the scaleable reaction in a clod vesl without the protection of inert gas.Several aryl bromides were tested to determine the scope and limitation of this protocol for the large-scale reaction.As shown in Table 4,all the tested aryl halides proceeded efficiently with 0.4mol %catalyst on a 2.5mol scale.Conclusions眼角黑
In conclusion,an open-air and robust method for the large-scale palladium-catalyzed cyanation of aryl halides was devel-oped,and the u of i -propanol as an additive was critical for achieving the open-air,robust and scaleable process.Under the protection by i -propanol,the catalyst life was significantly prolonged.The suggested protocol allowed the cyanation of aryl halides to be smoothly completed within 0.5-7h on a 2.5mol scale.
Experimental Section
General Details.All chemicals were of reagent grade quality,obtained from commercial sources,and ud without further purification.1H NMR and 13C NMR spectra were recorded on a Bruker 400MHz spectrometer in CDCl 3.GC analysis was performed on Varian CP-3800gas chromatograph with a capillary column (CP-WAX 57CB 25mm ×0.32mm).General Experimental Procedure for Small-Scale Cya-nation of Aryl Halides.i -PrOH (4.8vol %),Na 2CO 3(159mg,1.5mmol)and Pd(OAc)2(1.4mg,0.006mmol)were ordinally added into a 10mL tube equipped with 2mL of N -methyl-2-pyrrolidone (NMP).In order to give a homogeneous solution as soon as possible,the mixture was stirred at room temperature for about 5min.Then aryl halides (1.5mmol)and NMP (2mL)were added.After the tube was aled with a 50mL balloon that was fully filled with air,the reaction mixture was heated to 140°C.K 4[Fe(CN)6](221mg,0.6mmol)was then added.The final mixture was stirred for corresponding reaction times given in Tables 1and 2at 140°C.Filtration was followed by the GC analysis of the corresponding products.The desired products were purified by column chromatography and char-acterized by comparison of 1H NMR and 13C NMR data with tho in the literature.
Typical Experimental Procedure for Large-Scale Cya-nation of Aryl Halides.i -PrOH (4.8vol %),Na 2CO 3(265g,2.5mol),Pd(OAc)2(2.3g,0.01mol),and aryl halides (2.5mol)were mixed with DMF (2.5L).
After the reaction mixture was heated to 140°C,K 4[Fe(CN)6]·3H 2O (317g,0.75mol)was added.Then the vesl was aled,and the final mixture was stirred for corresponding reaction times given in Tables 3and 4at 140°C.After the product was analyzed by GC with n -tetradecane as an internal standard,the reaction mixture was filtered,and the filter cake was washed with DMF (0.1L).Fractionation of the filtrate afforded the desired product in high purity (>95%),and the product was characterized by comparison of 1H NMR and 13C NMR data with tho in the literature.All compounds are known,and their characterization data are as follows.Benzonitrile:1H NMR (400MHz,CDCl 3):δ(ppm))7.57-7.61(m,2H),7.55-7.56(m,1H),7.39-7.45(m,2H);13C NMR (400MHz,CDCl 3)δ(ppm))132.8,132.1,129.1,118.8,112.3.4-Acetylbenzonitrile:1H NMR (400MHz,
梦见打狗(23)Zanon,J.;Klapars,A.;Buchwald,S.L.J.Am.Chem.Soc.2003,125,
2890–2891.
Table 3.Large-scale cyanation of bromobenzene a entry order of addition of the reagents
yield b 1i -PrOH,Na 2CO 3,Pd(OAc)2,K 4[Fe(CN)6]·3H 2O,and bromobenzene were mixed with NMP,whereafter the mixture was heated to 140°C 562i -PrOH,Na 2CO 3,Pd(OAc)2,and bromobenzene were heated to 140°C in NMP,whereafter K 4[Fe(CN)6]·3H 2O were added.
903
Na 2CO 3,Pd(OAc)2and bromobenzene were heated to 140°C in NMP,whereafter
K 4[Fe(CN)6]·3H 2O and i -PrOH were added.
35
a
Reaction time is 5h,other reaction conditions are shown in the Experimental Section of this paper.b Isolated yield.
Vol.13,No.4,2009/Organic Process Rearch &Development
•
767
CDCl 3)δ(ppm))8.04-8.07(m,2H),7.78-7.80(m,2H),2.66(s,3H);13C NMR (400MHz,CDCl 3)δ(ppm))196.5,139.9,132.5,128.7,117.9,116.4,26.8.Methyl-4-cyanoben-zoate:1H NMR (400MHz,C
DCl 3)δ(ppm))8.12-8.14(m,2H),7.73-7.75(m,2H),3.95(s,3H);13C NMR (400MHz,CDCl 3)δ(ppm))165.4,133.9,132.2,130.1,117.9,116.4,52.7.4-Methoxybenzonitrile:1H NMR (400MHz,CDCl 3)δ(ppm))7.57-7.61(m,2H),6.94-6.97(m,2H),3.86(s,3H);13
C NMR (400MHz,CDCl 3)δ(ppm))162.8,134.0,119.2,114.7,103.9,55.5.4-Aminobenzonitrile:1H NMR (400MHz,CDCl 3)δ(ppm))7.40-7.43(m,2H),6.64-6.67(m,2H),4.23(s,1H);13C NMR (400MHz,CDCl 3)δ(ppm))150.5,133.8,120.2,114.4,99.9.4-Methylbenzonitrile:1H NMR (400MHz,CDCl 3)δ(ppm))7.52-7.55(m,2H),7.25-7.27(m,2H),2.42(s,3H);13C NMR (400MHz,CDCl 3)δ(ppm))143.7,132.0,129.8,119.2,109.3,21.8.2-Methylbenzonitrile:1
H NMR (400MHz,CDCl 3)δ(ppm))7.39-7.44(m,1H),7.35-7.37(m,1H),7.14-7.20(m,2H),2.39(s,3H);13C NMR
(400MHz,CDCl 3)δ(ppm))141.6,132.6,132.3,130.1,126.2,117.9,112.5,20.2.
Acknowledgment
We are grateful for financial supports from the National High Technology Rearch and Development Program of China (863Program,Grant No.2007AA05Z454)and the Innovation Sci-entists and Technicians Troop Construction Projects of Henan Province (Grant No.084200510015).
Supporting Information Available
Typical experimental procedure,characterization data,and copies of 1H and 13C NMR spectra for all cyanation products.This material is available free of charge via the Internet at pubs.acs.
Received for review March 26,2009.
OP9000725
Table 4.Large-scale cyanation of various aryl halides
a
a
Reaction conditions were shown in the Experimental Section of this paper (2.5mol aryl halide was ud).
768•Vol.13,No.4,2009/Organic Process Rearch &Development
