Comparative activity of aryl, alkyl, and cycloalkyl halides in the suzuki reaction catalyzed with acyclic diaminocarbene complex of palladium

Article abstract of DOI:10.1134/S1070363215110079

Relative activity of halogenated arenes, alkanes, and alkanes in the Suzuki reaction catalyzed with acyclic diaminocarbene complex of palladium has been investigated. Under all the investigated conditions, 4-iodoanisole has been more active than the alkyl

Full text of DOI:10.1134/S1070363215110079

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 11, pp. 2541–2546. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © S.A. Kras’ko, S.S. Zlotskii, V.P. Boyarskii, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 11, pp. 1799–1804.
Comparative Activity of Aryl, Alkyl, and Cycloalkyl Halides
in the Suzuki Reaction Catalyzed
with Acyclic Diaminocarbene Complex of Palladium
a,b
b
a
S. A. Kras’ko , S. S. Zlotskii , and V. P. Boyarskii
a
St. Petersburg State University, Universitetskaya nab. 7–9, St. Petersburg, 199034 Russia
e-mail: vadim.boyarskiy@chem.spbu.ru
b
Ufa State Petroleum Technical University, Ufa, Russia
Received September 10, 2015
Abstract—Relative activity of halogenated arenes, alkanes, and alkanes in the Suzuki reaction catalyzed with
acyclic diaminocarbene complex of palladium has been investigated. Under all the investigated conditions, 4-
iodoanisole has been more active than the alkyl halides. The reaction with 4-methyl-1-(chloromethyl)benzene
has afforded the target 4-methyl-1-(phenylmethyl)benzene along with significant amount of by-products; other
alkyl and cycloalkyl halides do not participate into the cross-coupling reaction. Ethanol has been found the
most suitable solvent for the reaction. The reaction in acetonitrile provides noticeable yield of the products only
in the presence of polyethylene glycol and water.
Keywords: the Suzuki reaction, acyclic diaminocarbene complex of palladium, organic halide
DOI: 10.1134/S1070363215110079
Over the recent decade, acyclic diaminocarbene com-
plexes of palladium (Pd-ADC) have attracted emerging
attention as catalysts [1, 2]: they have appeared a
suitable alternative to the well known heterocyclic
carbene complexes (Pd-NHC) [3] due to simplicity of
their one-step preparation from bis(isocyanide) palla-
dium complexes and N-nucleophiles [1, 4, 5]. The Pd-
ADC complexes catalyze various cross-coupling reac-
tions of aryl halides, such as the Suzuki reaction [6–8],
the Sonogashira reaction [6, 9–13], the Heck reaction
The catalyst was prepared via the method ela-
borated in [22, 23], the reaction of bis(cyclohexyliso-
cyanide)palladium(II) chloride 9 with 4-nitrophenyl-
hydrazine 10 in CH Cl at room temperature (Scheme 2).
2
2
The Suzuki cross-coupling was investigated under
the convenient conditions described in [7], the most
efficient in the cases of the reactions with aryl halides.
The reactions were carried out in refluxing ethanol in
the presence of K CO . The following compounds
2
3
were used as substrates: aryl halide 1, alkyl halide 2,
cycloalkyl halides 3–6, and benzyl halide 7 (Scheme 1).
The obtained results are given in Table 1.
[6, 14], and the Buchwald–Hartwig reaction [14].
The Suzuki reaction is among the most important
reactions of C–C cross-coupling in organic synthesis
15–19]. It is most often used for synthesis of unsym-
It was demonstrated that under the studied condi-
tions only aryl halide 1 and benzyl halide 7 formed the
cross-coupling products 11 and 12; other alkyl and
cycloalkyl halides did not participate in the Suzuki
reaction even in the presence of KI as additive,
facilitating the in situ formation of alkyl iodides from
chlorine and bromine derivatives.
[
metrical biaryls. Alkyl halides have been rarely used in
this reaction as substrates [20, 21], and the information
on this reaction involving cycloalkyl halides has been
lacking. On top of that, data on comparative activity of
aryl and alkyl halides is absent in the literature to the
very best of our knowledge. In view of that, the present
work aimed to compare the activity of various organic
halogenated derivatives 1–7 in the Suzuki reaction
catalyzed with acyclic diaminocarbene complex of
palladium(II) 8 (Scheme 1).
Compounds 3 and 6 underwent partial chlorine–
iodine exchange in the presence of KI. However, gem-
dihalocyclopropanes 4 and 5 were inert under the
applied conditions; the corresponding iodocyclo-
2
541

2
542
KRAS’KO et al.
Scheme 1.
[
Pd]
RX + PhB(OH)
RPh
2
_
1
7
I
Cl
Cl
Ph Ph
Ph Ph
Cl
Cl (4),
Br
Br (5),
Cl
Cl (6),
RX =
(1), n-C H I (2),
(3),
CH Cl (7),
5
11
2
OMe
Cl
Cl
HN C H -4-NO
6
4
2
[Pd] =
Pd
(8).
NH
C
C
N
NH
Cy
Cy
Scheme 2.
Cy
Cy
N
N
C
C
CH Cl2
Cl
Cl
2
HN C H -4-NO
6
4
2
Pd
+ 4-NO -C H NHNH
2
Pd
2
6
4
NH
Cl
Cl
C
C
N
NH
Cy
Cy
9
10
8
Scheme 3.
8
(0.05%)
1
+ PhB(OH)2
MeO
Ph
K CO
2
3
EtOH, 85°C
1
1
8
(0.05%)
7
+ PhB(OH)2
CH Ph +
CH OEt +
CH2
2
2
K CO
2
3
2
EtOH, 85°C
1
2
13
14
propanes were not found in the reaction mixture (Table 1).
Substitution of the chlorine with iodine in compound 6
has been observed earlier when performing the
reaction in DMF at 50–55°C [24].
palladium complex 15 either due to homolysis of
complex 15 followed by recombination of benzyl
radicals (direction a, Scheme 4) or via its reaction with
the second molecule of benzyl halide followed by
reductive elimination of compound 14 from dibenzyl
complex of palladium(II) 16 (direction b, Scheme 4).
In the case of aryl iodide 1, the reaction proceeded
selectively: 4-methoxybiphenyl 11 was the only product.
Halide 7 provided exclusively 4-methyl-1-(ethoxy-
methyl)benzene 13 formed as a result of ethanolysis of
the starting compound. Along with the target com-
pound 12 and the ethanolysis product 13, compound
The absence of para-xylene (the possible product
of halide 7 reduction) in the reaction mixture proved
that direction a was not operative under the investi-
gated conditions. The fact that the yield of compound
14 was significantly increased when adding KI to the
reaction mixture also confirmed its formation through
dibenzylpalladium complex 16, since that complex
should be formed much more easily in the reaction of
complex 15 with 1-(iodomethyl)-4-methylbenzene
1
4 was formed via the homo coupling of halide 7
(
Scheme 3). The reference experiment demonstrated
that in the absence of the palladium catalyst the
product 14 was not formed. That evidenced that
compound 14 could be formed only through the benzyl
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

COMPARATIVE ACTIVITY OF ARYL, ALKYL, AND CYCLOALKYL HALIDES
2543
Scheme 4.
Table 1. Reactivity of halogenated arenes, alkanes, and
cycloalkanes in the Suzuki reaction catalyzed with acyclic
a
0
diaminocarbene complex of palladium in ethanol
CH Cl + (Pd )
2
Reaction mixture composition after the
KI
RX (mol/mol
RX)
7
b
c
reaction completion (mol %)
CH (Pd)Cl
RX
33
RPh
67
ROEt R2
RI
33
2
1
2
3
3
4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1
5
a
100
100
95
–
–
100
–
I
CH + (Pd )Cl
2
–
–
0.5
–
–
–
5
CH CH
2
2
100
100
100
100
100
76
–
–
–
1
4
0
.5
–
–
–
5
6
–
–
–
–
b
II
CH (Pd )CH
2
3
7
0.5
–
–
–
–
1
6
–
–
–
formed in situ in the presence of KI than in that with
the starting halide 7.
0
.5
–
–
24
–
7
–
–
26
13
18
71
7
3
Note that ethanolysis of halide 7 proceeded
significantly slower than the cross-coupling at the
initial stage of the reaction. In detail, the conversion of
compound 7 within 10 min was of 20%, the cross-
coupling product 12 yield being of 13%. Hence, the
catalytic system was not stable under the reaction
conditions; the target product was formed within the
first 30–40 min of the reaction, and later the catalyst
became inactive.
d
–
80
–
–
0
.5
–
59
19
4
а
2
Reaction conditions: EtOH, 85°C, molar ratio 1 : RX : PhB(OH) :
b
c
d
2
K CO
3
= 0.0005 : 1 : 1 : 2, 2 h. By GLC–MS. By GLC. Reac-
tion time 10 min.
reduction of the cross-coupling products yield both for
aryl iodide 1 and chloride 7. On the other hand,
solvolysis of aryl halide 7 was impeded insignificantly.
While MeCN was used as solvent, the reaction was
even more decelerated. Addition of PEG-1500 as a
phase-transfer catalyst (the technique often used for
the reactions in the presence of K CO in organic
The reactivity of aryl iodide 1 and alkyl halide 7 in
the Suzuki reaction catalyzed with complex 8 was
compared taking advantage of the competitive reac-
tions method. Halide 1 occurred to be somewhat more
reactive than compound 7; the relative rate constant
k /k determined by measuring the yield of the cross-
2
3
1
7
solvents [25]) did not cause appreciable increase of the
cross-coupling products yield. Addition of water (only
0%) to the mixture of MeCN and PEG-1500
coupling products 11 and 12 at low conversion of the
starting halides was of 1.4.
1
Taking into account that the cross-coupling reaction
of halide 7 with phenylboronic acid in ethanol afforded
by product of the solvolysis, it seemed interesting to
investigate the use of less nucleophilic medium. To do
so, we performed the Suzuki reaction catalyzed with
complex 8 in propan-2-ol and acetonitrile. 4-Iodo-1-
significantly promoted the reaction, and the product
yields were comparable to those obtained in the
reaction performed in ethanol. However, in the case of
alkyl halide 7 it resulted in hydrolysis of significant
fraction of the starting substrate.
In summary, 4-iodoanisole was found to be more
reactive in the Suzuki reaction catalyzed with acyclic
diaminocarbene complex of palladium than alkyl
halides. The reaction with 4-methyl-1-(chloromethyl)-
benzene provided the target 4-methyl-1-(phenyl-
methyl)benzene along with noticeable amount of by-
(
methoxy)benzene 1 and 4-methyl-1-(chloromethyl)-
benzene 7 were used as the model halides. The
obtained results are given in Table 2.
The data demonstrated that the change of EtOH
with i-PrOH was not rational since it led to significant
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

2
544
KRAS’KO et al.
Table 2. Reactivity of 4-iodo-1-(methoxy)benzene 1 and 4-methyl-1-(chloromethyl)benzene 7 in the Suzuki reaction
a
catalyzed with acyclic diaminocarbene complex of palladium in propan-2-ol and acetonitrile
b
Reaction mixture composition after the reaction completion
KI
(mol/mol
RX)
c
(
mol%)
RX
Solvent
product
of solvolysis
RX
RPh
R
2
RН
RI
1
i-PrOH
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
82
97
93
34
52
92
86
–
–
18
3
–
–
–
–
5
82
97
93
34
MeCN
–
–
MeCN + 10% PEG-1500
MeCN + 30% PEG-1500 + 10% Н
i-PrOH
–
7
–
2
О
О
–
61
–
7
41 (i-ROPr )
3.5
–
0.5
3.0
MeCN
–
–
5.1
9.5
2.4
4.0
8
0.5
0.5
9
–
–
–
MeCN + 10% PEG-1500
MeCN + 30% PEG-1500 + 10% Н
2
65 (ROH)
18
а
b
c
Reaction conditions: 85°C, molar ratio 1 : RX : PhB(OH)
2
: K
2
CO
3
= 0.0005 : 1 : 1 : 2, 2 h. By GLC–MS. By GLC.
products; the other studied alkyl and cycloalkyl halides
did not participate in the cross-coupling reaction.
Ethanol was found the most suitable solvent for the
studied reaction. The reaction in acetonitrile proceeded
with appreciable yield only in the presence of PEG and
water. It was reasonable to suppose that the true
catalyst was formed from acyclic diaminocarbene
complex of palladium in its reaction with a protic
solvent in the presence of a base.
0.10 mmol) and 4-nitrophenylhydrazine (16 mg,
0.10 mmol) in 2 mL of CH Cl was incubated at room
temperature for 48 h. Then the reaction mixture was
2
2
diluted with 2 mL of n-hexane; white precipitate was
filtered off, washed with anhydrous Et O (3 mL), and
2
dried in air. Yield 43 mg (76%), white crystalline
1
compound, mp >160°С (decomp.). H NMR spectrum
(CDCl ), δ, ppm: 1.24–2.20 m (20H, 10CH ), 3.85–
3
2
4.15 m (1H, CHNC), 4.25–4.67 m (1H, CHNH), 6.90
d (2H , J 8.7 Hz), 7.05 br.s (1H, NH), 7.75 s (1H,
Ar
EXPERIMENTAL
ArNH), 8.10 d (2H , J 8.7 Hz), 9.90 br.s (1H, NH).
Ar
1
H NMR spectra were registered using a Bruker
Experimental procedure for the Suzuki reaction.
An appropriate organic halide (0.5 mmol), phenyl-
boronic acid (61 mg, 0.5 mmol), K CO (140 mg,
1.0 mmol), KI (when need, 41 mg, 0.25 mmol), PEG-
1500 (when needed, 150 mg) were placed into an
ampoule with twisted stopper equipped with magnetic
stirrer, and the appropriate solvent (2 mL) was added.
The reaction mixture was heated at stirring to start
refluxing (heating bath temperature was 85°C for all
the used solvents), and 0.1% solution of complex 1
AvanceII+ spectrometer at 400.13 MHz at room
temperature. Gas–liquid chromatography analysis was
performed using a Khromatek Kristal 5000.2 instru-
ment equipped with a flame ionization detector;
capillary column VRKh-1 (10 m × 0.53 mm × 2.65 μm).
Analysis by means of GLC–MS was performed with a
Shimadzu GCMS QP-2010 SE instrument (electron
impact ionization; an Rtx-5MS capillary column, 30 m ×
2
3
0
.32 mm × 0.25 mm).
(
0.14 mL) in the used solvent was added; the stopper
Chloromethyl-gem-dichlorocyclopropane 6 was
was closed, and heating was continued. The solution
got immediately brown-reddish, then in few minutes
the color turned to orange-yellowish; the color in the
course of the reaction gradually disappeared changing
to greyish due of the metallic palladium particles
formed at the catalysis decomposition. The reaction
mixture was heated during 2 h and cooled; the
prepared via dichlorocarbeniation of allyl chloride
according to the known procedure; its physico-
chemical parameters coincided well with the literature
26].
Synthesis of complex 1 [22, 23]. A mixture of bis-
cyclohexylisocyanide)palladium(II) chloride (40 mg,
[
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

COMPARATIVE ACTIVITY OF ARYL, ALKYL, AND CYCLOALKYL HALIDES
2545
specimen for the analysis was sampled (0.2 mL),
diluted with n-hexane (2 mL) and water (1 mL), and
shaken; the hexane layer was separated and analyzed
by GLC and GLC-MS.
4. Boyarskiy, V.P., Bokach, N.A., Luzyanin, K.V., and
Kukushkin, V.Y., Chem. Rev., 2015, vol. 115, no. 7,
p. 2698. DОI: 10.1021/cr500380d.
5. Vignolle, J., Catton, X., and Bourissou, D., Chem. Rev.,
2
009, vol. 109, no. 8, p. 3333. DOI: 10.1021/cr800549j.
. Dhudshia, B., and Thadani, A.N., Chem. Commun.,
006, no. 6, p. 668. DOI: 10.1039/B516398F.
Preparative procedure for Suzuki reaction (in
ethanol). 4-Methyl-1-(chloromethyl)benzene (703 mg,
6
7
2
5
.0 mmol), phenylboronic acid (610 mg, 5.0 mmol),
. Luzyanin, K.V., Tskhovrebov, A.G., Carias, M.C.,
Guedes da Silva, M.F.C., Pombeiro, A.J.L., and
Kukushkin, V.Y., Organometallics, 2009, vol. 28,
no. 22, p. 6559. DОI: 10.1021/om900682v.
and K CO (1.38 g, 1.0 mmol) were placed into a
2
3
5
0 mL round-bottom flask equipped with magnetic
stirrer and a condenser; ethanol (20 mL) was added to
the mixture. The reaction mixture was heated at
stirring till beginning of reflux (bath temperature 85°C),
and 0.1% solution of complex 1 in ethanol (1.35 mL,
8
9
. Kinzhalov, M.A., Luzyanin, K.V., Boyarskiy, V.P.,
Haukka, M., and Kukushkin, V.Y., Organometallics,
2013, vol. 32, no. 18, p. 5212. DОI: 10.1021/om4007592.
1
.35 mg, 2.5μmol) was added through the condenser.
. Khaibulova, T.Sh., Boyarskaya, I.A., and Boyarskii, V.P.,
The solution was refluxed during 2 h. Then the
reaction mixture was cooled, diluted with n-hexane
Russ. J. Org. Chem., 2013, vol. 49, no. 3, p. 360. DOI:
1
0.1134/S1070428013030081.
(
10 mL) and water (5 mL), and stirred during 10 min.
1
1
0. Mikhailov, V.N., Savicheva, E.A., Sorokoumov, V.N.,
and Boyarskii, V.P., Russ. J. Org. Chem., 2013, vol. 49,
p. 551. DOI: 10.1134/S107042801304009X.
The upper hexane layer was separated, and the rest of
the reaction mixture was washed with n-hexane
(
10 mL). The combined hexane fractions were washed
1. Savicheva, E.A., Kurandina, D.V., Nikiforov, V.A., and
Boyarskiy V.P., Tetrahedron Lett., 2014, vol. 55,
no. 13, p. 2101. DОI: 10.1016/j.tetlet.2014.02.044.
with 1% solution of KOH in MeOH (20 mL), then
with water (20 mL), and dried over anhydrous Na SO .
2
4
The solvent was distilled off under reduced pressure;
the residue was distilled in vacuum, discharging the
first portion of the distillate (≈ 20%).
12. Valishina, E.A., Guedes da Silva, M.F.C., Kinzhalov, M.A.,
Timofeeva, S.A., Buslaeva, T.M., Haukka, M.,
Pombeiro, A.J.L., Boyarskiy, V.P., Kukushkin, V.Y.,
and Luzyanin, K.V., J. Mol. Catal. (A), 2014, vol. 395,
p. 162. DОI: 10.1016/j.molcata. 2014.08.018.
4
-Methyl-1-(phenylmethyl)benzene [27]. Yield
1
1
60 mg (18%, purity 90% by H NMR), yellowish oily
liquid, bp 90°C (0.5 mbar). H NMR spectrum
1
1
3. Timofeeva, S.A., Kinzhalov, M.A., Valishina, E.A.,
Luzyanin, K.V., Boyarskiy, V.P., Buslaeva, T.M.,
Haukka, M., and Kukushkin, V.Y., J. Catal., 2015,
vol. 329, p. 449. DОI: 10.1016/j.jcat.2015.06.001.
(
CDCl ), δ, ppm: 2.47 s (3H, CH ), 4.66 s (2H, CH ),
3 3 2
7
.22 t (1H , J 8.7 Hz), 7.29–7.33 m (4H ), 7.36–7.41
Ar Ar
m (4HAr).
1
1
4. Kremzow, D., Seidel, G., Lehmann, C.W., Fürstner, A.,
ACKNOWLEDGMENTS
Chem. Eur. J., 2005, vol. 11, no. 6, p. 1833. DOI:
1
0.1002/chem. 200400928.
5. Alonso, F., Beletskaya, I.P., and Yus, M., Tetrahedron,
008, vol. 64, no. 14, p. 3047. DOI: 10.1016/
This work was financially supported by the Russian
Foundation for Basic Research (project no. 15-33-
0125) and carried out using the equipment of the
Resource Centre of St. Petersburg State University
Magnetic Resonance Methods” and Educational
Resource Centre “Khimiya.”
2
5
j.tet.2007.12.036.
1
1
6. Suzuki, A., Heterocycles, 2010, vol. 80, no. 1, p. 15.
“
DOI: 10.3987/COM-09-S(S)Summary.
7. Wu, X.-F., Anbarasan, P., Neumann, H., and Beller, M.,
Angew. Chem. Int. Ed., 2010, vol. 49, no. 48, p. 9047.
DOI: 10.1002/anie.201006374.
REFERENCES
. Boyarskiy, V.P., Luzyanin, K.V., and Kukushkin, V.Y.,
1
1
8. Boron Science. New Technologies and Applications,
Hosmane, N.S., Ed., Boca Raton: CRC Press, 2011,
p. 741. DOI: 10.1201/b11199-36.
1
Coord. Chem. Rev., 2012, vol. 256, nos. 17–18, p. 2029.
DОI: 10.1016/j.ccr.2012.04.022.
9. Maluenda, I., and Navarro, O., Molecules, 2015, vol. 20,
2
. Slaughter, L.M., ACS Catal., 2012, vol. 2, no. 8,
p. 1802. DОI: 10.1021/cs300300y.
no. 5, p. 7528. DOI: 10.3390/molecules20057528.
3
. Fortman, G.C., and Nolan, S.P., Chem. Soc. Rev., 2011,
20. Kambe, N., Iwasaki, T., and Terao, J., Chem. Soc. Rev.,
vol. 40, no. 10, p. 5151. DOI: 10.1039/c1cs15088j.
2011, vol. 40, no. 10, p. 4937. DOI: 10.1039/c1cs15129k.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015

2
2
546
KRAS’KO et al.
1. Colombel, V., Rombouts, F., Oehlrich, D., and
Molander, G.A., J. Org. Chem., 2012, vol. 77, no. 6,
p. 2966. DOI: 10.1021/jo202686p.
24. Raskil’dina, G.Z., Vil’danova, Z.R., Borisov, N.I.,
Kazakova, A.N., Nizaeva, E.R., and Zlotskii, S.S., Bash.
Khim. Zh., 2012, vol. 19, no. 2, p. 16.
2
2
2. Miltsov, S.A., Karavan, V.S., Boyarsky, V.P.,
Gуmezde, Pedro S., Alonso-Chamarro, J., and Puyol, M.,
Tetrahedron Lett., 2013, vol. 54, no. 10, p. 1202. DОI:
2
5. Bentley, T.W., Jones, R.V.H., Larder, A.H., and Lock, S.J.,
J. Chem. Soc. Chem. Commun., 1994, no. 19, p. 2309.
DOI: 10.1039/C39940002309.
1
0.1016/j.tetlet. 2012.12.060.
2
6. Arbuzova, T.V., Zlotskii, S.S., and Rakhmankulov, D.L.,
3. Ryabukhin, D.S., Sorokoumov, V.N., Savicheva, E.A.,
Boyarskiy, V.P., Balova, I.A., and Vasilyev, A.V.,
Tetrahedron Lett., 2013, vol. 54, no. 19, p. 2369. DОI:
Bash. Khim. Zh., 2005, vol. 12, no. 2, p. 19.
27. Gilman, H., and Diehl, J., J. Org. Chem., 1961, vol. 26,
1
0.1016/j.tetlet.2013.02.086.
no. 12, p. 4817. DOI: 10.1021/jo01070a010.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 11 2015