β-aryl nitrile construction via palladium-catalyzed decarboxylative benzylation of α-cyano aliphatic carboxylate salts

Article abstract of DOI:10.1002/adsc.201200383

The palladium-catalyzed decarboxylative benzylation of α-cyano aliphatic carboxylate salts with benzyl electrophiles was discovered. This reaction exhibits good functional group compatibility and proceeds under relatively mild conditions. A diverse range of quaternary, tertiary and secondary β-aryl nitriles can be conveniently prepared by this method. Copyright

Full text of DOI:10.1002/adsc.201200383

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DOI: 10.1002/adsc.201200383
b-Aryl Nitrile Construction via Palladium-Catalyzed Decarboxy-
lative Benzylation of a-Cyano Aliphatic Carboxylate Salts
Rui Shang,a,b Zheng Huang,a Xiao Xiao,a Xi Lu,a Yao Fu,a,* and Lei Liua,b
a
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of
China, Hefei 230026, Peopleꢀs Republic of China
E-mail: fuyao@ustc.edu.cn
Department of Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
b
Received: May 2, 2012; Revised: June 12, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200383.
Abstract: The palladium-catalyzed decarboxylative range of quaternary, tertiary and secondary b-aryl ni-
benzylation of a-cyano aliphatic carboxylate salts triles can be conveniently prepared by this method.
with benzyl electrophiles was discovered. This reac-
tion exhibits good functional group compatibility and Keywords: benzyl chlorides; carboxylates; decarbox-
proceeds under relatively mild conditions. A diverse ylative benzylation; nitriles; palladium
Introduction
use of strong bases largely limits the substrate scope
and ruins base-sensitive functional groups. In addi-
Transition metal-catalyzed decarboxylative cross-cou- tion, for acetonitrile and primary nitriles, monobenzy-
pling represents a useful strategy for carbon-carbon lation is often complicated due to the formation of
bond construction in modern synthetic organic multiply benzylated by-products. An alterative proce-
chemistry.[1] Inspired by the seminal work of Myers[2] dure is benzylation of cyanoacetate followed by hy-
and Gooßen,[3] catalytic decarboxylative coupling re- drolysis and decarboxylation.[12] This procedure can
actions of aromatic[4], alkenyl[5] and alkynyl[6] carbox- be used for the synthesis of some secondary and terti-
ylic acids have been intensively studied. More recent- ary b-aryl nitriles efficiently, but is unable to give the
ly we developed a palladium-catalyzed decarboxyla- quaternary ones. Due to the importance of functional-
tive arylation of some aliphatic carboxylate salts with ized nitriles in both synthetic and medicinal chemis-
aryl halides. Related studies were also reported by try,[13] we now report an intermolecular Pd-catalyzed
Studer and Kwong et al.[7] Tunge et al. reported excel- decarboxylative benzylation reaction of a-cyano ali-
lent studies on intramolecular decarboxylative allyla- phatic carboxylate salts with benzyl electrophiles [Cl,
tions of some activated carboxylate allylic esters.[8] OTFA, OPO
ACTHNUTRGNEU(GN OEt)2]. This reaction provides an effi-
Recently, Tunge et al. reported an intramolecular de- cient approach to construct a diverse range of func-
carboxylative benzylation of b-keto esters, but the tionalized quaternary, tertiary and secondary b-aryl
benzyl groups participating in this chemistry were lim- nitriles. The reaction also represents the first example
ited to benzyls with extend conjugations.[9] To the best of intermolecular decarboxylative benzylation of ali-
of our knowledge, intermolecular decarboxylative phatic carboxylates, and expands the synthetic utility
benzylation of aliphatic carboxylates has not been ex- of the decarboxylative coupling methodology.
plored. Because catalytic reactions involving p-
benzyl-Pd intermediates are important and have
drawn broad attention,[10] we were interested in the Results and Disscussion
intermolecular decarboxylative benzylation of a-
cyano aliphatic carboxylates. Note that palladium-cat- We initially chose benzyl chloride and potassium 2-
alyzed intramolecular decarboxylative benzylations of cyano-2-methylpropanoate as the model substrates
a,a-disubstituted benzyl cyanoacetic esters have been for screening the decarboxylative benzylation condi-
recently reported by Tunge et al.[14b]
tions (Table 1). First, we tested the catalyst consisting
Traditionally, the b-aryl nitrile structures were con- of [Pd(allyl)Cl]2 and Xant-Phos which have been
AHCTUNGTRENNUNG
structed by strong base-mediated nucleophilic substi- shown to be the best choice for our previously report-
[11]
tution of nitrileꢀs a-C H with benzyl halides. The ed decarboxylative arylation process,[7b] but the for-
À
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Table 1. Decarboxylative benzylation under various condi-
Table 2. Survey of the benzyl electrophiles.
tions.
Entry
X
Yield (GC) Entry
X
Yield (GC)
86%
ACHTUNGRTEN(NUNG OEt)2 93%
12%
ACHTUNGTRNE(NUNG OEt) 3%
Entry M
T
Ligand
Solvent
Yield [%][a]
1
2
3
4
Cl
Br
95%
73%
5
6
7
8
OTFA
1
2
OPO
OBoc
OCO
OAc 0%
OTs 64%
1
2
3
4
5
6
7
8
K
K
K
K
K
K
K
K
K
K
K
K
1408C Xant-Phos
1408C BINAP
1408C DPPF
1408C DPE-Phos
1408C DPPPent
1408C CataCXium A mesitylene 18
1408C Ph-Dave-Phos mesitylene 78
1408C t-BuX-Phos
1408C Ru-Phos
1408C X-Phos
1408C S-Phos
mesitylene 8
mesitylene 54
mesitylene 80
mesitylene 56
mesitylene 71
53
9
trace
trace
–
–
–
–
–
–
–
–
–
boxylative benzylation of benzyl 2-cyano-2-methyl-
propanoate under the optimized conditions but failed
to obtain the benzylated product (see Supporting In-
formation).[14]
After finding the optimal conditions, we tested the
scope of the leaving groups on the benzyl electro-
philes. Data of the screening experiments are sum-
marized in Table 2. Benzyl bromide, chloride, tosylate,
trifluoroacetate and diethyl phosphate could serve as
suitable electrophiles in this reaction. Benzyl carbo-
mesitylene 32
mesitylene 95
mesitylene 94
mesitylene 98
mesitylene 74
mesitylene 94
mesitylene trace –
DMA
diglyme
NMP
DMSO
9
10
11
12
13
14[b]
15
16
17
18
19
20
21
1408C IPr·HCl
Na 1408C S-Phos
Li 1408C S-Phos
K
K
K
K
K
K
K
1408C S-Phos
1408C S-Phos
1408C S-Phos
1408C S-Phos
1108C S-Phos
1008C S-Phos
1108C S-Phos
51
95
57
20
–
–
–
6
–
–
–
nates such as OBoc and OCOACHTNUGRTENUNG(OEt)2 gave low yields,
while benzyl acetate could not be activated under the
optimized conditions with total recovery of the start-
ing material.
Table 3 illustrates the scope of the substituted
benzyl electrophiles. From a convenience perspective,
the inexpensive, stable benzyl chlorides can be easily
prepared from the corresponding benzyl alcohol. For
this reason, we decided to evaluate the scope of sub-
stituted benzyls mainly with this class of electrophiles.
To our delight, a variety of functionalized benzyl
mesitylene 95
mesitylene 95
toluene
95
[a]
GC yields using biphenyl as internal standard (average
of two runs).
Recovery of benzyl chloride in 90% yield.
[b]
mation of benzyl ester (2) was observed (entry 1). electrophiles could be well used for the benzylation
Further experiments showed that the ratio of the de- of potassium 2-cyano-2-methylpropanoate under the
carboxylative benzylation product and benzyl ester optimized conditions with good to excellent yields.
was largely affected by the choice of the ligand. The electrophiles carrying substituents on ortho (3a,
When dppf was used as the ligand, the decarboxyla- 3e), meta (3b, 3d), and para (3c) positions of the
tive benzylation product was obtained in 80% yield, benzyl ring are all amenable substrates. The para-
accompanied with only a trace amount of the benzyl methyl substitution on the benzyl ring results in a rela-
ester by-product (entry 3). Extensive screening of the tively low yield (3c).[15] Benzyl electrophiles carrying
ligands showed that Buchwald phosphines, such as S- either electron-withdrawing or electron-donating
Phos, X-Phos, Ru-Phos, were the best choice (en- functional groups including alkyl (3a–3d), aryl (3e,
tries 9, 10, and 11). When the combination of 3j), alkoxy (3r, 3s, 3t), aryloxy (3g), fluoro (3h),
[PdACHTUNGTRENNUNG(allyl)Cl]2 and S-Phos was employed, the desired chloro (3i), trifluoromethyl (3n), ester (3m), C=C
transformation took place efficiently (98% yield) with double bond (3o, 3p), amine (3q), and nitro (3f) can
no detection of the benzyl ester. We found that all react with good yields of 52–95%. 3-Chlorome-
sodium salts can also serve as good substrates thylthiophene can react and the product (3l) was ob-
(entry 13), but the lithium salts failed to give any de- tained in 87% yield. Pyridine-3-methanol-derived
sired product (entry 14). Screening of the solvents re- phosphate can also react, albeit in relatively low yield
vealed that non-polar arene solvents were good (3k, 30%). It is important to note that alkyl pinacol
choices, whereas polar solvents were less effective boronate and alkyl chloride functionality can be well
(entries 15, 17, and 18). To our delight, the reaction tolerated in the present transformation. In this way,
can take place under relatively mild conditions products bearing useful b-aryl nitrile structures can be
(entry 20) and can proceed well in refluxing toluene further transformed via other alkyl cross-coupling re-
(entry 21). Finally, we tested the intramolecular decar- actions.[16]
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b-Aryl Nitrile Construction via Palladium-Catalyzed Decarboxylative Benzylation
Table 3. Decarboxylative benzylation of 2-cyano-2-methylpropanoate salts.[a]
[a]
Reactions were carried out on a 0.5 mmol scale. Yields are isolated yields based on
the quantity of benzyl electrophiles. For more details see the Supporting Information.
À
The presence of base sensitive, enolizable acidic C
ACHTUNGTRENoNGNU ate (4c, 4d), potassium 2-cyano-4-phenylbutanoate
H bond on the benzyl electrophiles can be well toler- (4e), potassium 2-cyanohexanoate (4f, 4g), and potas-
ated (3t) and the yield is 95%. The product can be sium 2-cyanooctanoate (4i, 4j) were all amenable to
À
further modified via reactions on enolizable C H the decarboxylative benzylation reaction. The tertiary
bond.[17] Note that this product (3t) is difficult to syn- b-aryl nitrile products were obtained in moderate to
thesize via strong base-mediated deprotonation/nucle- good yields ranging from 43–78%. Potassium 2-cyano-
ophilic substitution pathways due to the presence of 3-methylbutanoate gave a low yield (4h, 28%). This is
À
the acidic C H moiety. Benzyl electrophiles with ex- possibly due to the steric hindrance of the adjacent
tended conjugations can also react, such as 1-chloro- methyl group. Next, we examined the quaternary salt
methyl naphthalene (3u) and 2-naphthyl methanol de- substrates particularly. Sodium 2-cyano-2-methylhex-
rived phosphate (3v). Unfortunately, a-substituted
benzyl electrophiles failed to react under the present to afford the corresponding product (4l) in 73% yield.
catalytic conditions (3w, 3x). Quaternary a-cyano aliphatic carboxylate salts carry-
ACHTUNGTRENaNGNU noate can react well with 3-methoxybenzyl chlorides
We next explored the scope of the a-cyano aliphat- ing aryl substitution on the aliphatic chain also serve
ic carboxylate salts (Table 4). Potassium cyanoacetate as suitable substrates (4q, 4r, 4s). The aryl substituents
can react well with benzyl electrophiles to form 3-ar- on aliphatic chain expand the scope of salt substrates.
ylpropanenitriles cleanly without forming any diben- Some other substituents on the aliphatic chain of the
zylated by-product (4a, 4b).[18] Tertiary a-cyano ali- a-cyano aliphatic carboxylates were also investigated.
phatic carboxylate such as potassium 2-cyanopropan- The results show that a pinacol boronate functionality
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Table 4. Decarboxylative benzylation of various a-cyano aliphatic carboxylate salts.[a]
[a]
Reactions were carried out on a 0.5 mmol scale. Isolated yields based on the quantity
of benzyl electrophiles.
Using X-Phos as the ligand.
[b]
[c]
Sodium salt was used because the corresponding potassium salt is difficult to crystal-
lize.
on the aliphatic chain can be well tolerated. This ex- ry carbon center without any benzylation on enoliza-
À
ample illustrates that the alkyl decarboxylative benzy- ble C H bond. These examples highlight the synthetic
lation shows selectivity toward traditional alkyl utility of the Pd-catalyzed decarboxylative benzyla-
Suzuki coupling thus giving the further possibility of tion processes.
modification via alkyl boronate transformations.[16] a-
During our optimization study for the coupling of
Cyclic and oxygen containing cyclic carboxylate salts benzyl chloride with potassium 2-cyano-2-methylpro-
also serve as good substrates (4m, 4n, 4t). Finally, it is panoate, we observed a by-product which showed
important to note that cyano and keto substitution on equal molecular weight with the desired product
the aliphatic chain were well tolerated (4o, 4p, 4u). through GC-MS analysis. NMR analysis indicated
The decarboxylative benzylation took place regiospe- that the by-product is 2-methyl-2-(p-tolyl)propaneni-
cifically on the carboxylate moiety to form a quaterna- trile. Further investigation showed the ratio of the by-
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b-Aryl Nitrile Construction via Palladium-Catalyzed Decarboxylative Benzylation
Scheme 1. Solvent effect on reaction selectivity.
the observations above and our previous studies,[20]
we consider that the outlined mechanism may contain
the following steps (Figure 1). (i) The oxidative addi-
tion of benzyl electrophiles forms a phosphine ligated
benzyl-Pd complex II. (ii) The carboxylate replaces
the halide through anion exchange to form III, and in-
termediate III transforms to IV in which the palladi-
um coordinates with the cyano nitrogen. (iii) The car-
boxylate decarboxylates on IV to form a nitrile nitro-
gen coordinated intermediate V. (iv) V isomerizes to
Scheme 2. Tentative decarboxylative alkylation.
product is largely affected by the choice of the solvent C-coordinated style VI followed by reductive elimina-
(Scheme 1). Although the detailed mechanism and tion to give the desired product. Notably, in inter-
the solvent induced selectivity for the formation of mediate V, the a-carbon of the nitrile could attack
the arylated product are not clear, the by-product for- the para site of the benzyl group to produce a dearom-
mation process may involve a dearomatization of the atized product VIII which is followed by rearomatiza-
Pd-benzyl intermediate.[19]
.
tion to form the observed by-product.[21] The forma-
Next, we tried the decarboxylative alkylation of a- tion of the arylation by-product may give evidence
cyano carboxylate salts. Under the optimal conditions that Pd interacts with the nitrile nitrogen in the cata-
for benzylation, the attempted coupling of (2-bromo- lytic process.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Interestingly, when the above reaction was carried out Conclusions
in the absence of Pd catalyst, no alkyl ester was
formed. This observation indicates that the alkyl ester In conclusion, an efficient and practical palladium-
formation is not a simple SN2 type reaction, but is cat- catalyzed decarboxylative benzylation of a-cyano ali-
alyzed by Pd under these conditions. We also tried phatic carboxylate salts with benzyl electrophiles has
the decarboxylative benzylation of benzyl chloride been established. This is the first example of intermo-
with potassium 3-ethoxy-2,2-dimethyl-3-oxopropan- lecular decarboxylative benzylation of activated ali-
ACHTUNGTRENNUNGoate, but obtained the benzyl ester without decarbox- phatic carboxylate salts. This reaction proceeds under
ylation in high yield (Scheme 3). The benzyl ester for- relatively mild conditions, avoids the use of sensitive
mation from the a-ester salt is possibly due to the dif- reagents, and possesses good functional group com-
ferent decarboxylative nature under Pd catalysis com- patibility. A diverse range of quaternary, tertiary and
pared with the a-cyano substrate and merits further secondary b-aryl nitriles can be conveniently prepared
consideration.
via this methodology. Many of these nitriles are diffi-
Although the detailed mechanism of the decarbox- cult to synthesize via traditional base-mediated nucle-
ylative benzylation is not clear at present, based on ophilic substitution reactions. Further efforts to eluci-
Scheme 3. Tentative decarboxylative benzylation of tertiary malonate ester salt.
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Figure 1. Proposed mechanism.
date the detailed mechanism and achieve an asym-
metric decarboxylative benzylation of quaternary sub-
strates will be the next goal of our research.
General Procedure for the Decarboxylative
Benzylation
A typical procedure for the decarboxylative benzylation of
potassium 2-cyano-2-methylpropanoate (3j in Table 3) is as
follows: A 10-mL oven-dried Schlenk tube was charged with
[PdClACTHUNTRGNE(UNG allyl)]2 (2 mol%), S-Phos (6 mol%), potassium 2-
Experimental Section
cyano-2-methylpropanoate (0.6 mmol) and 3-(chlorometh-
yl)-1,1’-biphenyl (0.5 mmol). The tube was evacuated and
filled with argon for three times. Then toluene (1.0 mL) was
added via a syringe under a counter flow of argon. The tube
was sealed with a screw cap, stirred at room temperature for
1 min, and stirred at 1108C (oil bath) for 12 h. Upon com-
pletion, the mixture was cooled to room temperature. Purifi-
cation of the residue by column chromatography (silica gel)
afforded 3j; yield: 93%.
3-([1,1’-Biphenyl]-3-yl)-2,2-dimethylpropanenitrile(3j):
This compound is new. 1H NMR (400 MHz, CDCl3): d=
7.61–7.57 (m, 2H), 7.54–7.48 (m, 2H), 7.46–7.38 (m, 3H),
7.37–7.31 (m, 1H), 7.24 (s, 1H), 2.87 (s, 2H), 1.38 (s, 6H);
13C NMR (101 MHz, CDCl3): d=141.37, 140.91, 136.17,
129.07, 128.79, 127.39, 127.21, 126.20, 124.72, 46.76, 33.57,
26.56; HR-MS: m/z=235.1350, calcd. for C17H17N (M+):
235.1356.
General Information
All the reactions were carried out in oven-dried Schlenk
tubes under argon atmosphere (purity ꢀ 99.999%). The tol-
uene and mesitylene solvents were bought from TCI and
used without further purification. Benzyl electrophiles were
bought from Alfa Aesar and TCI or synthesized according
to literature procedures. Allyl palladium chloride dimer was
purchased from Sigma Aldrich and Sinocompound. All
phosphine ligands were bought from Sinocompound, Sigma–
Aldrich, Strem or Alfa Aesar and used as such. All the
other reagents and solvents mentioned in this text were
bought from Sinopharm Chemical Reagent Co. Ltd or Alfa
Aesar and purified when necessary. 1H NMR, 13C NMR
spectra were recorded on a Bruker Avance 400 spectrome-
ter at ambient temperature in CDCl3 unless otherwise
1
noted. Data for H NMR are reported as follows: chemical
Supporting Information
shift (d ppm), multiplicity, integration, and coupling constant
(Hz). Data for 13C NMR are reported in terms of chemical
shift (d ppm), multiplicity, and coupling constant (Hz). Gas
chromatographic (GC) analysis was acquired on a Shimadzu
GC-2014 Series GC System equipped with a flame-ioniza-
tion detector. GC-MS analysis was performed on Thermo
Scientific AS 3000 Series GC-MS System. HR-MS analysis
was performed on Finnigan LCQ advantage Max Series MS
System. Organic solutions were concentrated under reduced
pressure on a Bꢂchi rotary evaporator. Flash column chro-
matographic purification of products was accomplished
using forced-flow chromatography on silica gel (200–300
mesh).
General experimental methods, spectroscopic characteriza-
tion and copies of 1H NMR and 13C NMR spectra for all
compounds are available in the Supporting Information.
Acknowledgements
We thank the National Basic Research Program of China
(2012CB215306), the National Natural Science Foundation of
China (21172209) and Chinese Academy of Science (KJCX2-
EW-J02) for the financial support.
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b-Aryl Nitrile Construction via Palladium-Catalyzed Decarboxylative Benzylation
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[20] Our recent mechanistic study on our previously report-
ed decarboxylative arylation of cyanoacetate salts (R.
Shang, D.-S. Ji, L. Chu, Y. Fu, L. Liu, Angew. Chem.
2011, 123, 4562; Angew. Chem. Int. Ed. 2011, 50, 4470)
showed that the most favored decarboxylation mecha-
nism corresponds to a transition state in which Pd in-
teracts with the cyano nitrogen. See: Y.-Y. Jiang, Y. Fu,
L. Liu, Sci. China Chem. 2012, 55, accepted. Please
note that there is another possible mechanism which in-
volves: (i) the Pd(II)-catalyzed decarboxylation of the
carboxylate substrate, forming a-cyanoalkyl palladiu-
m(II) intermediate, (ii) the a-cyanoalkyl palladium(II)
intermediate reacts with benzyl chloride to give the
benzylated product and regenerates the Pd(II) catalyst.
We thank a reviewer for suggesting this possible mech-
anism.
[15] Interestingly, when 4-phenylbenzyl chloride was used
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[18] Control experiments showed that without the palladi-
um catalyst, no decarboxylative benzylated product
was observed.
[19] For reported dearomatization of benzyl electrophiles in
Pd catalysis, see: a) M. Bao, H. Nakamura, Y. Yama-
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[21] Tunge et al. recently observed decarboxylative aryla-
tion on the furanyl ring in Pd-catalyzed decarboxylative
benzylation of a,a-disubstituted furan-2-ylmethyl cya-
noacetic esters. See ref.[14b]
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b-Aryl Nitrile Construction via Palladium-Catalyzed
Decarboxylative Benzylation of a-Cyano Aliphatic
Carboxylate Salts
9
Adv. Synth. Catal. 2012, 354, 1 – 9
Rui Shang, Zheng Huang, Xiao Xiao, Xi Lu, Yao Fu,*
Lei Liu
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