In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium salts/[RuCl2(p-cymene)]2 system for transfer hydrogenation reactions

Article abstract of DOI:10.3906/kim-1104-4

Hydrogen-transfer reduction processes are attracting increasing interest from synthetic chemists in view of their operational simplicity. In the present study novel ruthenium carbene complexes were generated in situ and tested for their transfer hydrogena

Full text of DOI:10.3906/kim-1104-4

Turk J Chem
5 (2011) , 699 – 709.
3
¨
˙
ꢀ
c TUBITAK
doi:10.3906/kim-1104-4
In situ catalytic activities of
,3-dialkyltetrahydropyrimidinium
salts/[RuCl (p-cymene)] system for transfer
1
2
2
hydrogenation reactions
¨
¨
1
2
¨
¨
1
˙
2
Emine Ozge OZCAN , Deniz MERCAN , Nevin GURBUZ , Engin C¸ ETINKAYA
˙
2
˙
¨
˙
1,∗
Bekir C¸ ETINKAYA , Ismail OZDEMIR
In o¨ n u¨ University, Faculty of Science, Department of Chemistry,
4280 Malatya - TURKEY
1
˙
4
e-mail: iozdemir@inonu.edu.tr
2
Ege University, Faculty of Science, Department of Chemistry,
˙
3
5100 Bornova, Izmir-TURKEY
Received: 02.04.2011
Hydrogen-transfer reduction processes are attracting increasing interest from synthetic chemists in view
of their operational simplicity. In the present study novel ruthenium carbene complexes were generated
in situ and tested for their transfer hydrogenation reactions. The in situ prepared 3 component 1,3-
2 2
dialkyltetrahydropyrimidinium salts (LHX)/[RuCl (p-cymene)] and KOH catalyzed quantitatively the
transfer hydrogenation of ketones under mild reaction conditions in 2-propanol.
Key Words: Ruthenium, tetrahydropyrimidin-2-ylidene, N -heterocyclic carbene, transfer hydrogenation,
ketone
Introduction
The reduction of ketones or aldehydes is an important reaction in organic synthesis. One of the most commonly
used methods is transfer hydrogenation (Scheme 1); it is a valuable, atom-efficient reaction, and compared
with conventional hydrogenation, using molecular hydrogen, transfer hydrogenation offers a safer, more cost
∗
Corresponding author
6
99

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
effective, and simpler experimental procedure. A large number of alcohols and other reagents are available as a
1
source of hydrogen, and mild reaction conditions are used. Transfer hydrogenation of ketones by 2-propanol is
convenient in large-scale synthesis since there is no need to employ a high hydrogen pressure or to use hazardous
2
reducing agents.
Scheme 1
A large number of ruthenium complexes have been reported as catalyst precursors for transfer hydro-
3
−6
genation of ketones and have shown high activity.
Several recent examples of ruthenium complexes bearing
7
−9
10−12
13,14
15−17
phosphane,
N -heterocyclic carbene,
diamin,
diaminodiphosphane or aminodiphosphane,
1
8
19−22
23
amine-bis(phenolate), chiral phosphanes,
nitrogen containing chiral ligands, and nitrogen containing
2
4−28
heterocyclic ligands
have become the most prominent members for the reduction of ketones in high yields.
The use of N -heterocyclic carbene ligands (NHCs) for the preparation of homogeneous catalysts has
now become one of the most productive fields in organometallic chemistry. Since 1995, when Herrmann
2
9
reported the first use of a NHC ligand in the preparation of a homogeneous catalyst,
there have been
enormous developments in NHC chemistry, which has been triggered by the search for enhanced or even new
3
0−34
catalytic processes.
Probably one of the main benefits of NHCs is that their preparation is simple and
that the coordination methodologies that are now available allow the preparation of NHC complexes of almost
any transition metal in a variety of oxidation states, affording a wide set of potential catalytic applications.
3
5
The nucleophilic N -heterocyclic carbenes (NHCs),
with stronger σ -donor properties than bulky tertiary
3
6
phosphines, have emerged as a new family of ligands. In contrast to metal phosphine complexes, the metal-
NHC complexes appear to be extraordinarily stable towards heat, air, and moisture due to the high dissociation
3
7
energies of the metal-carbon bond.
Recently, research has also been devoted to the synthesis of functionalized ligands containing NHC
3
8−41
moieties, in order to modify the ligand properties and catalytic activities.
The first application of NHC
4
2
complexes for the transfer hydrogenation reaction was reported by Nolan in 2001. With regard to transfer
4
3,44
45−47
48−50
51
hydrogenations different carbene or carbene-phosphane systems containing Rh,
have been reported.
Ir,
Ru,
and Ni
Due to the economical benefit of Ru metal compared to Rh or Ir and the advantages of phosphine-free
systems, it is an important goal to search for more active ruthenium carbene catalysts. Herein, we report
the use of the in situ generated catalytic system composed of [RuCl2(p-cymene)]2 as ruthenium source, 1,3-
5
2
dialkyl-3,4,5,6- tetrahydropyrimidinium halide, 1a-k, (Scheme 2) as carbene precursors and KOH as a base
for transfer hydrogenation of aryl ketones in 2-propanol.
7
00

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
o
o
o
o
N
N
N
N
N
N
N
N
Cl-
+) Cl -
)
Cl-
Cl -
Cl -
+
N
N
o
o
o
o
a
b
c
d
e
symmetrical salts
o
o
o
o
o
o
N
N
+ ) Br
N
N
N
N
+
N
N
Br-
-
+
)
)
Br-
+ ) Br-
N
) Br-
+ ) Br-
N
+
N
N
f
g
h
j
k
i
non-symmetrical salts
Scheme 2. 1,3-Dialkyl-tetrahydropyrimidinium salts.
Experimental
All reactions for the preparation of 1 were carried out under Ar in flame-dried glassware using standard Schlenk-
5
2
type flasks. The 1,3-dialkyl-tetrahydropyrimidinium salts (1a-k) were prepared according to known methods.
The solvents used were purified by distillation over the drying agents indicated and were transferred under Ar:
1
Et2 O (Na/K alloy), C2 H5 OH (Mg). All reagents were purchased from Aldrich Chemical Co. H-NMR and
1
3
1
C-NMR spectra were recorded using a Varian AS 400 Merkur spectrometer operating at 400 MHz ( H)
1
3
and 100 MHz ( C) in CDCl3 with tetramethylsilane as an internal reference. Column chromatography was
performed using silica gel 60 (70-230 mesh). All reactions were monitored on an Agilent 6890N GC system by
GC-FID with a HP-5 column of 30 m length, 0.32 mm diameter, and 0.25 μm film thickness.
Typical procedure for catalytic transfer hydrogenation of ketones
Under an inert atmosphere [RuCl2(p-cymene)]2 (0.01 mmol), tetrahydropyrimidinium salts, 1a-1k, (0.02
mmol), KOH (4 mmol), and 10 mL of i-PrOH were added to a small Schlenk tube and the mixture was
stirred at room temperature for 0.5 h. Then ketone (1 mmol) was added to the mixture, which was heated at
◦
8
0
C for 1 h. The solvent was then removed under reduced pressure and product distribution was determined
7
01

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
1
by H-NMR spectroscopy and GC. The yield calculations were based on the relative areas of signal peaks of
chromatograms.
Results and discussion
The symmetric and non-symmetric tetrahydropyrimidinium salts 1 were prepared in a 3-step procedure start-
5
2
ing from the 2,2-dimethyl-1,3-diaminopropane according to a known procedure. The symmetrical salts were
obtained via initial formation of diimine, which were reduced to diamine salts and then ring closing using triethy-
lortoformate. The non-symmetrical salts were synthesized by monoalkylation, ring closure, and quaternization
steps. The salts are air and moisture stable both in the solid state and in solution.
Catalytic reduction is preferred to stochiometric reduction for large-scale industrial uses of ketones
5
3
54
hydrogenation.
Hydrogen gas presents considerable safety hazards especially for a large-scale reaction.
The use of solvent that can donate hydrogen overcomes these difficulties. 2-Propanol is a popular reactive
◦
solvent for the transfer hydrogenation since it is easy to handle (b.p. 82 C) and is relatively non-toxic,
environmentally benign, and inexpensive. The volatile acetone product can also be easily removed to shift an
3
unfavorable equilibrium. Owing to its efficiency in the transfer hydrogenation of acetophenone derivatives, in
situ generated ruthenium complexes were further investigated by transfer hydrogenation of various methyl aryl
ketones.
As the starting point, the performance of the catalysts in the transfer hydrogenation was screened by
using acetophenone as a model substrate. In order to ensure complete formation of the active catalyst a
2
3
-propanol solution of 1 mol% [RuCl2(p-cymene)]2 and 2 mol% 1,3-bis(2,4,5-trimethylbeznyl)-5,5-dimethyl-
,4,5,6-tetrahydropyrimidine chloride (1a) was stirred in the presence of 4 mmol of KOH at room temperature
◦
for 0.5 h. Then acetophenone (1.00 mmol) was added and solution was produced at 80 C over 1 h. The
reactions were conducted at a substrate/catalyst/base (S/C/base) molar ratio of 1:0.01:4.
It is well known that transfer hydrogenation is sensitive to the nature of the base. For the choice of base,
we surveyed K2 CO3 , KOH, NaOH, and tBuOK. Addition of bases like KOH or NaOH leads to similar final
conversion, but the highest rate was observed when KOH was employed. In the absence of a base no transfer
hydrogenation of the ketones was observed.
A variety of ketones were transformed to the corresponding secondary alcohols. Typical results are
shown in Tables 1 and 2. Under those conditions p-methoxyacetophenone, 3,4,5-trimethoxyacetophenone, and
p-floroacetophenone react very cleanly and in good yields with 2-propanol (Table 1, entries 8, 13, 28, and Table
2
, entries 9, 14, 34).
Under the reaction conditions salt 1c and 1h proved to be most effective catalyst relative to other salts.
The reduction of acetophenone with tetrahydropyrimidinium salts was completed within 1 h in high yields.
It is evident that the NHC precursors that contain electron donating methoxyethyl, substituent (1h), are the
most effective of the salts examined. Moreover, the best catalytic activity was observed with the salt bearing
3
,4,5-trimethoxybenzyl substituent at the nitrogen atom.
7
02

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
a
Table 1. Transfer hydrogenation of ketones catalyzed by symmetrical tetrahydropyrimidium salts (1a-1e).
Entry
LHX
1a
1b
1c
Substrate
Product
Yield(%)
96
1
2
3
4
5
6
7
8
9
91
98
1d
1e
98
91
1a
1b
1c
95
93
98
1d
1e
90
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
89
1a
1b
1c
96
95
97
1d
1e
98
90
1a
1b
67
64
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03

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
Table 1. Contunied.
Entry
LHX
1c
Substrate
Product
Yield(%)
72
1
1
2
2
2
2
2
2
2
2
2
2
3
8
9
0
1
2
3
4
5
6
7
8
9
0
1d
1e
68
62
1a
1b
1c
96
96
98
1d
1e
97
92
1a
1b
1c
90
93
99
1d
1e
98
90
a
Reaction conditions: [RuCl
2
(p-cymene)]
2
(0.01 mmol), tetrahydropyrimidinium halide, 1a-1e, (0.02 mmol), KOH (4
i
◦
mmol), PrOH (10 mL), substrate (1.0 mmol), 80 C, 1 h. Purity of compounds is checked by GC and yields are based
on ketones. The yield calculations were based on the relative areas of signal peaks of chromatograms.
The in situ catalytic system also catalyzed the transfer hydrogenation of benzophenone very effectively
(Table 1 entries 21-25 and Table 2 entries 25-30). The conversion of ketones with bulky substituent on the
aromatic ring was not observed or slightly decreased. For example, when 2,4,6- trimethylbenzyl-methyl ketone
was used conversion decreased (Table 1 entries 16-20 and Table 2, entries 19-24). The general trend can be
summarized as follows: 1e < 1b < 1a < 1d ∼ gc in the symmetrical salts and 1j < 1i < 1g < 1k < 1f
∼
gh in the non-symmetrical salts.
7
04

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
a
Table 2. Transfer hydrogenation of ketones catalyzed by non-symmetrical tetrahydropyrimidinium salts (1f-1k).
Entry
LHX
1f
Substrate
Product
Yield(%)
93
1
2
3
4
5
6
7
8
9
1g
1h
1i
92
94
92
1j
90
1k
1f
93
97
1g
1h
96
99
1
1
0
1
1i
1j
90
7
0
1
1
1
1
1
1
1
2
3
4
5
6
7
8
1k
1f
90
98
95
98
96
94
97
1g
1h
1i
1j
1k
7
05

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
Table 2. Contunied.
Entry
LHX
1f
Substrate
Product
Yield(%)
80
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1g
1h
1i
68
79
67
1j
62
1k
1f
69
97
1g
1h
1i
91
99
84
1j
90
1k
1f
98
98
1g
1h
1i
96
99
97
1j
94
1k
99
a
Reaction conditions: [RuCl
2
(p-cymene)]
2
(0.01 mmol), tetrahydropyrimidinium halide, 1f-1k, (0.02 mmol), KOH (4
i
◦
mmol), PrOH (10 mL), substrate (1.0 mmol), 80 C, 1 h. Purity of compounds is checked by GC and yields are based
on ketones. The yield calculations were based on the relative areas of signal peaks of chromatograms.
7
06

¨
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In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
Conclusions
We demonstrated the application of in situ prepared Ru catalysts containing carbene ligands. This concept
for making catalysts in situ opens the way for the discovery of many new catalysts via the interaction of
commercially available metal complexes and suitable electron releasing ligands. The 3,4,5,6tetrahydropyrimidin-
2
-ylidene ligand/[RuCl2(p-cymene)]2 catalyst system disclosed herein represents an easy to handle, robust, and
high yielding procedure for transfer hydrogenation reactions of ketones using 2-propanol in the presence of KOH.
Furthermore, the procedure is simple and efficient towards various aryl ketones. Research in our lab is currently
on-going to extend the coordination chemistry of functionalized NHCs to other transition metals such as Ru,
Rh, Ag, and Au, and to explore their potential applications in catalysis.
Acknowledgements
˙
We are grateful to In o¨ n u¨ University Research Fund (BAP 2011/G u¨ d u¨ ml u¨ -4) and Ege University Research Fund
2006/Fen/066) for their financial support of this work and the Scientific and Technological Research Council
(
¨
˙
of Turkey (TUBITAK) for a grant.
References
Gladali, S.; Alberico E. in: Transition Metals for Organic Synthesis, Eds.: Beller, M.; Bohm, C., Wiley-VCH,
1.
Weinheim, 2004.
2.
3.
4.
5.
6.
7.
Jiang, H.; Qiao, Q. D.; Gong, H. E. React. Kinet. Catal. L 1998, 65, 193-197.
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
B ¨a ckvall, J. -E. J. Organomet. Chem. 2002, 652, 105-111.
Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300-1308.
Wang, W.; Li, Z.; Mu, W.; Su, L.; Wang, Q. Catal. Commun 2010, 11, 480-483.
Doucet, T.; Ohkuma, K.; Murata, T.; Yokozawa, M.; Kozawa, E.; Katayama, A. F.; England, T.; Ikariya, T.;
Noyori, R. Angew. Chem. Int. Edit. 1998, 37, 1703-1707.
8
.
.
Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490-13503.
Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931-7944.
9
1
1
1
1
1
1
1
0. Poyatos, M.; Mata, J. A.; Falomir, E.; Crabtree, R. H.; Peris, E. Organometallics 2003, 22, 1110-114.
1. Danopoulos, A. A.; Winston, S.; Motherwell, W. B. Chem. Commun 2002, 1376-1378.
2. Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312-11313.
3. Noyori, R.; Okhuma, T. Angew. Chem. Int. Ed. 2001, 40, 40-73.
4. Okhuma, T.; Takeno, H.; Noyori, R. Adv. Synth. Catal 2001, 343, 369-375.
5. Dong, Z. R.; Li, Y. Y.; Chen, J. S.; Li, B. Z.; Xing, Y.; Gao, J. X. Org. Lett. 2005, 7, 1043-1045.
6. Bianchini, C.; Farnetti, E.; Glendenning, L.; Graziani, M.; Nardin, G.; Peruzzini, M.; Rocchini, E.; Zanobini, F.
Organometallics. 1995, 14, 1489-1502.
7
07

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
1
1
1
2
2
2
7. Park, S.; Lough, A. J.; Morris, R. H. Inorg. Chem. 1996, 35, 3001-3006.
8. Kannan, S.; Kumar, K. N.; Ramesh, R. Polyhedron 2008, 27, 701708.
9. Clarke, M. L.; Diaz-Valenzuela, M. B.; Slawin, A. M. Z. Organometallics 2007, 26, 16-19.
0. Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc 1972, 94, 6429-6433.
1. Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc 1977, 99, 6262-6267.
2. Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc 1980, 102,
7932-7934.
2
2
2
2
3. Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev., 2000, 100, 2159-2231.
4. Zhao, M.; Yu, Z.; Yan, S.; Li, Y. J. Organomet. Chem 2009, 694, 30683075.
5. Schlattera, A.; Woggon, W. -D. Adv. Synth. Catal 2008, 350, 995-1000.
6. Baratta, W.; Ballico, M.; Baldino, S.; Chelucci, G.; Herdtweck, E.; Siega, K.; Magnolia, S.; Rigo, P. Chem. Eur.
J. 2008, 14, 9148-9160.
27. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Schatte, G.; Stradiotto, M. Angew. Chem. Int. Ed. Engl. 2007,
4
6, 4732-4735.
28. Baratta, W.; Rigo, P. Eur. J. Inorg. Chem. 2008, 4041-4053.
29. Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus, G. R. J. Angew. Chem. Int. Ed. Engl. 1995, 34,
2371-2374.
3
3
3
3
3
3
3
3
0. Herrmann, W. A. Angew. Chem. Int. Ed. Engl. 2002, 41, 1291-1309.
1. Mata, J. A.; Poyatos, M.; Peris, E. Coord. Chem. Rev. 2007, 251, 841-859.
2. Pugh, D.; Danopoulos, A. A. Coord. Chem. Rev. 2007, 251, 610-641.
3. Peris, E.; Crabtree, R. H. Coord. Chem. Rev. 2004, 248, 2239-2246.
4. Gade, L. H.; Bellemin-Laponnaz, S. Coord. Chem. Rev. 2007, 251, 718-725.
5. Herrmann, W. A.; Weskamp, T.; B ¨o hm, V. P. W. Adv. Organomet. Chem. 2001, 48, 1-69.
6. Huang, J.; Schanz, H. J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 2370-2375.
7. Schwarz, J.; B ¨o hm, V. P. W.; Gardiner, M. G.; Grosche, M.; Herrmann, W. A.; Hieringer, W.; Raudaschl-Sieber,
G. Chem. Eur. J. 2000, 6, 1773-1780.
3
3
4
4
4
4
4
4
4
4
8. Liddle, S. T.; Edworthy, I. S.; Arnold, P. L. Chem. Soc. Rev. 2007, 36, 1732-1745.
9. K u¨ hl, O. Chem. Soc. Rev. 2007, 36, 592-608.
0. Nolan, S. P. (Eds.: Nolan, S. P.), N-Heterocyclic Carbenes in Synthesis; Wiley: Weinheim, 2006.
1. Corberan, R.; Mas-Marza, E.; Peris, E. Eur. J. Inorg. Chem. 2009, 13, 1700-1716.
2. Hillier, A. C.; Lee, H. M.; Stevens, E. D.; Nolan, S. P. Organometallics 2001, 20, 4246-4252.
3. Mas-Marza, E.; Poyatos, M.; Sanau, M.; Peris, E. Organometallics 2004, 23, 323-325.
4. T u¨ rkmen, H.; Pape, T.; Hahn, F. E.; C¸ etinkaya, B. Organometallics 2008, 27, 571-575.
5. Hahn, F. E.; Holtgrewe, C.; Pape, T.; Martin, M.; Sola, E.; Oro, L. A. Organometallics 2005, 24, 2203-2209.
6. Miecznikowski, J. R.; Crabtree, R. H. Organometallics 2004, 23, 629-631.
7. Albrecht, M.; Miecznikowski, J. R.; Samuel, A.; Faller, J. W.; Crabtree, R. H. Organometallics 2002, 21, 3596-3604.
7
08

¨
¨
In situ catalytic activities of 1,3-dialkyltetrahydropyrimidinium..., E. O. OZCAN, et al.
4
4
8. Burling, S.; Whittlesey, M. K.; Williams, J. M. J. Adv. Synth. Catal 2005, 347,591-594.
9. Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.; Edney, D.
D. Chem. Commun 2004, 90-91.
¨
˙
5
5
5
5
5
0. Ozdemir, I.; Ya ¸s ar, S.; C¸ etinkaya, B. Transition Metal Chem. 2005, 30, 831-83
1. Kuhl, S.; Schneider, R.; Fort, Y. Organometallics 2003, 22, 41844186.
2. Mercan, D.; C¸ etinkaya, E.; C¸ etinkaya, B. J. Organomet. Chem. 2011, 696, 1359-1366.
3. Genet J. P. Acc. Chem. Res. 2003, 36, 908-918.
4. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev. 1985, 85, 129-170.
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