Synergistic effect of a bis(proazaphosphatrane) in mild palladium-catalyzed direct α-arylations of nitriles with aryl chlorides

Article abstract of DOI:10.1002/ejoc.201402466

The effect of a bis(proazaphosphatrane) ligand on the palladium-catalyzed direct α-arylation of nitriles with various aryl chlorides under mild conditions is reported. Comparisons of the catalytic properties of this ligand with those of three related mono(proazaphosphatrane)s under the same reaction conditions revealed that bis(proazaphosphatrane) displayed a synergistically enhanced activity. In the presence of the bis(proazaphosphatrane) ligand, ethyl cyanoacetate and primary as well as secondary nitriles were efficiently coupled with a wide variety of aryl chlorides that contained electron-rich, electron-poor, and electron-neutral groups.

Full text of DOI:10.1002/ejoc.201402466

FULL PAPER
DOI: 10.1002/ejoc.201402466
Synergistic Effect of a Bis(proazaphosphatrane) in Mild Palladium-Catalyzed
Direct α-Arylations of Nitriles with Aryl Chlorides
So Han Kim,[a] Wonseok Jang,[a] Min Kim,*[a] John G. Verkade,*[b] and Youngjo Kim*[a]
Keywords: Synthetic methods / Arylation / Cross-coupling / Palladium / P ligands
The effect of a bis(proazaphosphatrane) ligand on the palla-
dium-catalyzed direct α-arylation of nitriles with various aryl
chlorides under mild conditions is reported. Comparisons of
the catalytic properties of this ligand with those of three re-
lated mono(proazaphosphatrane)s under the same reaction
conditions revealed that bis(proazaphosphatrane) displayed
a synergistically enhanced activity. In the presence of the
bis(proazaphosphatrane) ligand, ethyl cyanoacetate and pri-
mary as well as secondary nitriles were efficiently coupled
with a wide variety of aryl chlorides that contained electron-
rich, electron-poor, and electron-neutral groups.
nitriles that employs aryl chlorides under mild conditions
(80 °C for 4 h) and a lower Pd loading (1 mol-%).
Introduction
α-Aryl-substituted nitriles[1] and α-amino-substituted
nitriles[2] are proving to be versatile intermediates for the
syntheses of diamines,[2b] amino acids,[2c] carbonyl com-
pounds,[2d] and heterocycles.[2e] Traditional synthetic meth-
ods to obtain α-aryl-substituted nitriles include the cyan-
ation of benzylic alcohols[3] and halides.[4] Although the di-
rect α-arylation of nitriles is known to be difficult, some
examples of the conversion by employing aryl fluorides,[5]
bromides,[6] or iodides[7] have been reported in the literature.
Although aryl chlorides are less expensive and more abun-
dant than other aryl halides, they are much less reactive.
Thus, examples of the direct α-arylation of nitriles by using
aryl chlorides are quite rare.[6a,6b,8] The first example of this
approach was reported in 2001 by Hartwig et al.[6a,6b] They
reported that the reaction reached completion after more
than 12 h at 100 °C when carried out in the presence of
1.0 mol-% [(allyl)PdCl]2 or 2 mol-% Pd(dba)2 (dba = di-
benzylidenacetone) with either Na3PO4 or K3PO4, respec-
tively. Verkade and You were able to reduce the temperature
to 90 °C and decrease the time to 5 h when the reaction was
carried out in the presence of 2–4 mol-% [Pd2(dba)3] and a
proazaphosphatrane ligand.[8] Herein, we describe a new
and improved catalytic system for the direct α-arylation of
Over the past 20 years, bicyclic proazaphosphatranes
have proven to be useful, nonionic, strong bases as well as
potent catalysts for a variety of valuable transformations.[9]
The introduction of the appropriate substituents[9] at each
of the three nitrogens of the P–N bonds in the proazaphos-
phatrane framework makes it possible to create fine-tuned
proazaphosphatranes that have different electronic and
steric properties. Until now, much of the research of new
proazaphosphatranes has been directed toward analogues
with various alkyl or aryl substituents.[9] However, there
have not yet been reports about bis(proazaphosphatrane)s.
On the basis of dramatic improvements in catalytic trans-
formations that employ multinuclear metal complexes,
which benefit from synergistic and cooperative effects be-
tween the metal centers linked by bridging ligands,[10] we
speculate that similar effects might operate between the
speculated phosphorus centers of bis(proazaphosphatrane)s.
Because tris(2-isobutylamino)proazaphosphatrane func-
tioned in a previous study as the best catalytic system for
the direct α-arylation of nitriles with aryl chlorides,[8] we
synthesized a bis(analogue) by combining two diisobutyl-
substituted proazaphosphatranes and a p-benzylic linker.
Herein, we report the first synthesis of a bis(proazaphos-
phatrane) (1) and then utilize it in the direct α-arylation of
nitriles with a broad range of aryl chlorides under mild re-
action conditions.
[a] Department of Chemistry and BK21+ Program Research
Team, Chungbuk National University,
Cheongju, Chungbuk, 361-763, Republic of Korea
E-mail: minkim@chungbuk.ac.kr
ykim@chungbuk.ac.kr
https://sites.google.com/site/minkimchem/
http://omlab2005.chungbuk.ac.kr/
Results and Discussion
[b] Department of Chemistry, Iowa State University,
Ames, Iowa 50011, United States
The synthesis of bis(proazaphosphatrane) 1 was ac-
complished by using a three-step sequence that started from
a reaction between a diisobutyl-substituted tren [tren =
tris(2-aminoethyl)amine[11]] and terephthaldicarbaldehyde
E-mail: jverkade@iastate.edu
http://www.chem.iastate.edu/faculty/John_Verkade
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402466.
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S. Han Kim, W. Jang, M. Kim, J. G. Verkade, Y. Kim
FULL PAPER
(see Scheme 1). To determine whether 1 could compete with analogues, we synthesized the three mono(proazaphos-
the catalytic abilities of related mono(proazaphosphatrane) phatrane)s 2–4. The four proazaphosphatranes 1–4 were
Scheme 1. Synthetic route for bis(proazaphosphatrane) 1 (THF = tetrahydrofuran).
Table 1. Comparison of the Pd2(dba)3/1–4 catalytic systems in the direct α-arylation of ethyl cyanoacetate with chlorobenzene.[a]
Entry
Ligand
Temperature [°C]
Time [h]
% Yield[b]
1
2
3
4
5
6
7
8
9
10
1
50
50
50
50
80
80
80
80
80
80
12
12
12
12
4
4
4
4
4
4
87
54
43
31
93
69
56
45
0
2
3
4
1
2
3
4
P(tBu)3
BINAP
0
[a] Reagents and conditions: aryl chloride (1.0 mmol), ethyl cyanoacetate (1.1 mmol), Pd2(dba)3 (0.01 mmol, 1 mol-%), 1 (0.02 mmol,
2 mol-%) or 2–4 (0.04 mmol, 4 mol-%), KOtBu (2.0 mmol) in toluene (2.0 mL) under nitrogen. [b] Isolated yields based on aryl chloride
after silica gel column chromatography (average of two runs).
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Mild Pd-Catalyzed α-Arylations of Nitriles
then employed in the direct α-arylation of ethyl cyanoacet- tris(2-isobutylamino)proazaphosphatrane[8] or Pd2(dba)3.[9]
ate with chlorobenzene under the same reaction conditions. In contrast, P(tBu)3 (tri-tert-butylphosphine) and BINAP
For each proazaphosphatrane, a loading of 4 mol-% of total [2,2Ј-bis(diphenylphosphanyl)-1,1Ј-binaphthyl] showed no
phosphorus atoms was used (see Table 1). When the reac- catalytic activity for the α-arylation of ethyl cyanoacetate
tion was conducted at 50 and 80 °C without ligands 1–4 in with chlorobenzene under the optimized reaction condi-
the presence of Pd2(dba)3, the product yield was only 10 tions of 4 mol-% of P(tBu)3 or 2 mol-% of BINAP at 80 °C
and 17%, respectively. However, no reaction was observed over 4 h (see Table 1, Entries 9 and 10).
when the reaction was conducted at both temperatures but
We then carried out the α-arylation of a variety of nitriles
in the absence of Pd2(dba)3. Bis(proazaphosphatrane) 1 with a range of aryl chlorides at a reaction temperature of
showed the highest activity after 12 h of reaction time at a 80 °C (see Tables 2 and 3). First, we investigated the cou-
temperature of 50 °C to give a product yield of 87% (see pling of various aryl chlorides with ethyl cyanoacetate in
Table 1, Entry 1). By performing the reaction at 80 °C, 1 toluene by using KOtBu as the base in the presence of a
required only 4 h to achieve a 93% product yield (see catalytic system that was generated in situ from 1 mol-%
Table 1, Entry 5). At both temperatures, the catalytic activi- Pd2(dba)3 and 2 mol-% 1 (see Table 2). Under these condi-
ties decrease in the order of 1 ϾϾ 2 Ͼ 3 Ͼ 4, which indi- tions, a broad range of aryl chlorides such as electron-neu-
cated the presence of a synergistic effect for 1. An ad- tral (see Table 2, Entry 1), electron-rich (see Table 2, En-
ditional observation is that our palladium loading of 1 mol- tries 2–9), electron-poor (see Table 2, Entries 10–12), steri-
% (see Table 1 is one-half of that previously reported for cally hindered (see Table 2, Entries 2 and 5–7), and fused-
Table 3. Direct α-arylation of various nitriles with chlorobenzene
by using the Pd2(dba)3/1 catalytic system.[a]
Table 2. Direct α-arylation of ethyl cyanoacetate with various aryl
chlorides by using the Pd2(dba)3/1 catalytic system.[a]
[a] Reagents and conditions: aryl chloride (1.0 mmol), ethyl cyano-
[a] Reagents and conditions: aryl chloride (1.0 mmol), nitrile
acetate (1.1 mmol), Pd2(dba)3 (0.01 mmol, 1 mol-%), 1 (0.02 mmol, (1.1 mmol), Pd2(dba)3 (0.01 mmol, 1 mol-%), 1 (0.02 mmol, 2 mol-
2 mol-%), KOtBu (2.0 mmol) in toluene (2.0 mL) at 80 °C for 4 h
under nitrogen. [b] Isolated yields based on aryl chloride after silica
gel column chromatography (average of two runs).
%), KOtBu (2.0 mmol) in toluene (2.0 mL) at 80 °C for 4 h under
nitrogen. [b] Isolated yields based on aryl chloride after silica gel
column chromatography (average of two runs).
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S. Han Kim, W. Jang, M. Kim, J. G. Verkade, Y. Kim
FULL PAPER
= 0.00 ppm for 85% phosphoric acid]. HRMS data were recorded
with a Shimadzu LCMS 2010 instrument. Column chromatography
was performed with 300–400 mesh silica gel by using flash column
techniques. Compounds 2 and 4 were synthesized according to pre-
viously reported procedures.[9c]
Synthesis of 1: Diisobutyl-substituted tren[11] (12.9 g, 50.0 mmol)
and terephthaldicarbaldehyde (3.35 g, 25.0 mmol) in methanol
(150 mL) were heated at reflux for 24 h. The reaction mixture was
cooled to room temperature, and then NaBH4 (2.84 g, 75.1 mmol)
was added slowly. Purification afforded 1Octamine (14.4 g, 93.0%)
as a yellow oil. 1H NMR (400.13 MHz, CDCl3): δ = 7.19 (m, 4 H),
3.70 (s, 4 H), 2.56 (m, 8 H), 2.47 (m, 8 H), 2.31 (m, 8 H), 1.59 (m,
4 H), 1.62 (br. signal, 2 H), 0.81 (d, J = 6.6 Hz, 24 H) ppm. 13C
NMR (100.63 MHz, CDCl3): δ = 138.8, 127.9, 57.97, 54.30, 54.20,
ring aryl chlorides (see Table 2, Entries 13 and 14) as well
as a heteroaryl chloride (see Table 2, Entry 15) were easily
coupled to produce the expected products in excellent iso-
lated yields (90–93%). An attempt to use thenoyl chloride
as a coupling partner resulted in only a trace amount of the
product. Pyridyl chlorides were the only heteroaryl chlor-
ides that gave good product yields. The arylation of ethyl
cyanoacetate with p-dichlorobenzene afforded exclusively
the para-substituted dicoupled aromatic product in excel-
lent yield (see Table 2, Entry 16), and no monocoupled aro-
matic product was observed.
As expected, a wide range of nitriles were successfully
employed as the reaction partner for the α-arylation with
Pd2(dba)3/1 as the catalytic system (see Table 3). The reac- 53.60, 47.68, 47.00, 28.14, 20.51 ppm. HRMS (ESI): calcd. for
C36H75N8 [M + H]+ 619.6115; found 619.6104. To a solution of
tions between primary (see Table 3, Entries 1–6) and sec-
[9c]
PCl(NMe2)2
[generated in situ from PCl3 (0.2 mL, 2.29 mmol)
ondary nitriles (see Table 3, Entries 7 and 8) and chloroben-
zene gave the expected products in excellent isolated yields
(83–92%) within 4 h under the stated reaction conditions.
Interestingly, an alkyl nitrile that contained both O and N
atoms (i.e., 4-morpholineacetonitrile, see Table 3, Entry 6)
produced the corresponding product in a slightly lower
yield (83%) than the other nitriles. It is also noteworthy
that, in contrast to results that were obtained with some
and P(NMe2)3 (0.83 mL, 4.58 mmol)] in CH2Cl2 (30 mL) was
added dropwise a solution of 1Octamine (2.12 g, 3.43 mmol) in
CH2Cl2 (30 mL) at 0 °C. The reaction mixture was maintained at
room temperature overnight, and then all volatiles were removed
under reduced pressure. The residue was washed with Et2O (3ϫ)
and then dried under reduced pressure to give the desired product
1·2HCl (2.52 g, 98.2%) as a yellow power. 1H NMR (400.13 MHz,
CDCl3): δ = 7.11 (s, 4 H), 5.83 (s, 1 H), 4.84 (s, 1 H), 4.06 (d, J =
palladium-ligand systems,[6c,8] no diarylated products were 12.9 Hz, 4 H), 3.55 (br. s, 12 H), 3.11 (m, 8 H), 2.96 (m, 4 H), 2.68
(m, 8 H), 1.79 (m, 4 H), 0.86 (d, J = 2.1 Hz, 12 H), 0.85 (d, J =
2.0 Hz, 12 H) ppm. 13C NMR (100.63 MHz, CDCl3): δ = 136.3 (d),
127.1, 55.11 (d), 50.52 (d), 46.77 (d), 39.06 (d), 38.41, 34.04, 26.34,
19.41 ppm. 31P NMR (161.79 MHz, CDCl3): δ = –7.36 ppm.
HRMS (ESI): calcd. for C36H70N8P2 [M – 2Cl–] 676.5199; found
676.5174. A solution of 1·2HCl (1.22 g, 1.63 mmol) and KOtBu
(1.1 g, 9.78 mmol) in THF (30 mL) was stirred at room temperature
for 1 h, and then the volatile compounds were removed under re-
duced pressure. Compound 1 was extracted with n-hexane, and
then all volatiles were removed under reduced pressure to give the
desired dimeric 1 (0.84 g, 76.3%) as a yellow gel. 1H NMR
(400.13 MHz, C6D6): δ = 7.43 (s, 4 H), 4.14 (d, J = 8.8 Hz, 4 H),
2.37 (m, 32 H), 1.8 (m, 4 H), 0.96 (d, J = 3.3 Hz, 24 H) ppm. 13C
NMR (100.63 MHz, C6D6): δ = 140.5 (d), 129.1, 58.65 (d), 53.79
(d), 51.63 (d), 51.42 (d), 46.87 (d), 45.54 (d), 28.83 (d), 20.87
(dd) ppm. 31P NMR (161.79 MHz, C6D6): δ = 129.93 ppm. HRMS
(ESI): calcd. for C36H69N8P2 [M + H]+ 675.5120; found 675.5115.
formed by using our Pd2(dba)3/1 catalyzed reaction condi-
tions for this direct α-arylation reaction.
Conclusions
In summary, we have prepared the first example of a bis-
(proazaphosphatrane) ligand to assist in the catalysis of an
organic transformation. The bis(proazaphosphatrane) li-
gand demonstrated better catalytic activity than the mono-
(proazaphosphatrane) ligands in this carbon-carbon bond-
forming reaction. By using the Pd2(dba)3/1 catalytic system,
ethyl cyanoacetate and primary as well as secondary nitriles
were efficiently coupled with a wide variety of aryl chlorides
that contained electron-rich, electron-poor, and electron-
neutral groups.
Synthesis of 3: Diisobutyl-substituted tren[11] (6.46 g, 32.0 mmol)
and 4-(dimethylamino)benzylaldehyde (5.22 g, 35.0 mmol) in meth-
anol (100 mL) were stirred at room temperature overnight. To the
stirring reaction mixture was slowly added NaBH4 (1.82 g,
48.0 mmol), and the stirring was continued for 2 h. After purifica-
tion, the product 3Pentamine [10.5 g, 83.7%, (iBuNHCH2CH2)2-
NCH2CH2NHCH2C6H4-p-NMe2] was obtained as a colorless oil.
1H NMR (400.13 MHz, CDCl3): δ = 7.14 (d, J = 11 Hz, 2 H), 6.66
(d, J = 11 Hz, 2 H), 3.67 (s, 2 H), 2.90 (s, 6 H), 2.53 (m, 12 H),
2.35 (d, J = 8.9 Hz, 4 H), 1.64 (m, 2 H), 1.40 (br. s, 3 H), 0.85 (d,
J = 8.8 Hz, 12 H) ppm. 13C NMR (100.63 MHz, CDCl3): δ = 149.7,
129.0, 128.5, 112.7, 58.20, 54.61, 54.47, 53.56, 47.93, 47.10, 40.75,
28.38, 20.70 ppm. HRMS (ESI): calcd. for C23H46N5 [M + H]+
Experimental Section
General Methods: All reactions of air- and moisture-sensitive mate-
rials were carried out under nitrogen by using standard Schlenk-
type glassware with a dual manifold Schlenk line in a glove box.
The nitrogen was deoxygenated by using an activated Cu catalyst
and was dried with Drierite. All reagents were purchased from Ald-
rich and used as supplied, unless otherwise indicated. All solvents
were dried by distillation from sodium diphenylketyl under nitro-
gen and stored over activated molecular sieves (3 Å). NMR sol-
vents such as CDCl3 and C6D6 were dried with activated molecular
sieves (4 Å) and used after vacuum transfer to a Schlenk tube that
was equipped with a Young valve. The 1H, 13C, and 31P NMR
spectroscopic data were recorded with a 400 MHz NMR spectrom-
eter by using CDCl3 or C6D6 as the solvent [for 1H NMR, internal
standard at δ = 7.24 ppm (residual CHCl3) and 7.15 ppm (residual
C6D5H); for 13C NMR, internal standard at δ = 77.0 ppm (CDCl3)
and 128.0 ppm (C6D6); and for 31P NMR, external standard at δ
[9c]
392.3753; found 392.3751. To a solution of PCl(NMe2)2 [gener-
ated in situ from PCl3 (0.24 mL, 2.75 mmol) and P(NMe2)3
(1.00 mL, 5.50 mmol)] in CH2Cl2 (30 mL) was added dropwise a
solution of 3Pentamine (3.23 g, 8.25 mmol) in CH2Cl2 (30 mL) at
0 °C. The reaction mixture was maintained at room temperature
overnight, and then all volatiles were removed under reduced pres-
sure. The residue was washed with Et2O (3ϫ) and then dried under
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Mild Pd-Catalyzed α-Arylations of Nitriles
reduced pressure to give the desired product 3·HCl (3.25 g, 86.4%)
as a yellow power. H NMR (400.13 MHz, CDCl3): δ = 6.96 (d, J 2013R1A1A1061399 to M. K.).
= 9.9 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 6.15 (s, 0.5 H), 4.49 (s,
NRF-2013R1A1A2006317
to Y. K.
and
grant
NRF-
1
0.5 H), 3.94 (d, J = 22 Hz, 2 H), 3.44 (m, 6 H), 3.06 (m, 4 H), 2.58
(m, 12 H), 1.80 (m, 2 H), 0.84 (d, J = 3.0 Hz, 6 H), 0.82 (d, J =
2.7 Hz, 6 H) ppm. 13C NMR (100.63 MHz, CDCl3): δ = 149.8,
128.0, 127.9, 124.0, 123.9, 112.3, 55.40, 55.23, 50.68, 50.48, 46.75,
46.65, 40.16, 39.34, 39.26, 38.43, 38.35, 26.63, 26.57, 19.67 ppm.
31P NMR (161.79 MHz, CDCl3): δ = –7.87 ppm. HRMS (ESI):
calcd. for C23H43N5P [M – H+ – Cl–] 420.3256; found 420.3260. A
solution of 3·HCl (1.21 g, 2.65 mmol) and KOtBu (0.89 g,
7.95 mmol) in THF (30 mL) was stirred at room temperature for
1 h, and then the volatile compounds were removed under reduced
pressure. Compound 3 was extracted with n-hexane, and then all
volatiles were removed under vacuum to give the desired mono-
meric 3 (0.83 g, 74.5%) as a yellow gel. 1H NMR (400.13 MHz,
C6D6): δ = 7.35 (d, J = 11 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 4.16
(d, J = 12 Hz, 2 H), 2.72 (m, 16 H), 2.53 (s, 6 H), 1.80 (m, 2 H),
0.99 (d, J = 2.9 Hz, 6 H), 0.96 (d, J = 3.0 Hz, 6 H) ppm. 13C NMR
(100.63 MHz, C6D6): δ = 150.1, 129.9, 129.8, 129.3, 129.3, 113.1,
58.12, 58.61, 53.13, 51.70, 51.64, 51.53, 51.60, 46.74, 46.83, 45.21,
45.29, 40.49, 28.77, 28.84, 20.86, 20.87, 20.91, 20.92 ppm. 31P
NMR (161.79 MHz, C6D6): δ = 129.7 ppm. HRMS (ESI): calcd.
for C23H43N5P [M + H]+ 420.3256; found 420.3254.
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Representative Procedure for Direct α-Arylation of Nitriles with Aryl
Chlorides by Using the Pd2(dba)3/1 Catalytic System: A dried
Schlenk flask, which was equipped with a magnetic stirring bar,
was charged with Pd2(dba)3 (9.2 mg, 0.01 mmol) and KOtBu
(0.24 g, 2.0 mmol) in a nitrogen-filled glove box. After the flask
was capped with a rubber septum and then removed from the glove
box, toluene (2 mL), 1 (13 mg, 0.02 mmol), and the aryl halide
(1.0 mmol) were successively added. After stirring at room tem-
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Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, and 31P NMR spectra and HRMS spectra of all prod-
ucts as well as references for known compounds.
Acknowledgments
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Received: April 22, 2014
The authors gratefully acknowledge financial support by the Ko-
rean Government (MOE), National Research Foundation (grant
Published Online: August 6, 2014
Eur. J. Org. Chem. 2014, 6025–6029
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