Efficient Iridium-thioether-dithiolate catalyst for β-alkylation of alcohols and selective imine formation via N-alkylation reactions

Article abstract of DOI:10.1021/om200883e

An Ir-thioether-dithiolate complex, [Cp*Ir(η³-tpdt)] (Cp* = η⁵-C₅Me₅, tpdt = S(CH ₂CH₂S^-)₂), is evaluated for its catalytic potential in the β-alkylation of secondary alcohols and the N-alkylation of amines with alcohols. The β-alkylation reaction proceeded efficiently under low catalyst loading and in the absence of any sacrificial hydrogen additive with only water being formed as the coproduct. The same complex also proved to be efficient in the synthesis of imines via the N-alkylation reaction. The predominant formation of imines, rather than amines, in this reaction is a deviation from the product selectivity usually observed in similar N-alkylation reactions involving organometallic catalysts.

Full text of DOI:10.1021/om200883e

Note
pubs.acs.org/Organometallics
Efficient Iridium-Thioether-Dithiolate Catalyst for β-Alkylation of
Alcohols and Selective Imine Formation via N-Alkylation Reactions
†
‡
,†
Chang Xu, Lai Yoong Goh, and Sumod A. Pullarkat*
†Division of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616
‡
ICP, UTAR Global Research Network, Universiti Tunku Abdul Rahman, 46200 Petaling Jaya, Selangor, Malaysia
3
ABSTRACT: An Ir-thioether-dithiolate complex, [Cp*Ir(η -
5
−
tpdt)] (Cp* = η -C Me , tpdt = S(CH CH S ) ), is evaluated
5
5
2
2
2
for its catalytic potential in the β-alkylation of secondary
alcohols and the N-alkylation of amines with alcohols. The
β-alkylation reaction proceeded efficiently under low catalyst
loading and in the absence of any sacrificial hydrogen additive
with only water being formed as the coproduct. The same
complex also proved to be efficient in the synthesis of imines via the N-alkylation reaction. The predominant formation of imines,
rather than amines, in this reaction is a deviation from the product selectivity usually observed in similar N-alkylation reactions
involving organometallic catalysts.
INTRODUCTION
hydrogenation of the resulting enone to yield the coupled
alcohol (Scheme 2).
■
6
Transition metal complexes incorporating thiolato ligands have
attracted continuing interest by virtue of their potential
applications as models for biological systems and as catalysts
Scheme 2
1
in various processes. In particular, [Cp*IrCl2]2 and its
derivatives have attracted much attention in their role as
effective catalysts for a variety of transformations, such as
hydrogenation, C−C bond formation, allylic substitution,
2
cycloaddition, and other reactions. In ongoing investigations
3
3
on the reactions of μ-dichloro complexes [(η :η -C H )-
1
0
16
3
4
RuCl2]2 and [Cp*RuCl2]2 with thioether-thiolato ligands
XC(S)S] (X = NR , OR (R = alkyl)), we had isolated the
complex [Cp*Ir(η -tpdt)] (1), in 81% yield (Scheme 1).
[
2
2
3
5
Several transition metal complexes have been reported to
catalyze this reaction. These range from the readily available
Scheme 1
6
7
[
Cp*IrCl2]2 and [RuCl (DMSO) ] to the extremely active
2 4
Ru and Ir complexes containing N-heterocyclic carbenes
8
9
(
NHCs), phosphines (e.g., RuCl (PPh ) ), and terpyridine
2 3 3
10
10a
10a
ligands (e.g., [(terpy)Ru(PPh )Cl ], [(terpy)IrCl3] ). Of
3
2
particular interest to us is a comparison of the catalytic activity
of 1 with its precursor complex [Cp*IrCl ] in β-alkylation of
2
2
secondary alcohols with primary alcohols, bearing in mind that
the tpdt ligand is a S-bearing moiety.
In this paper, we report the effective role of 1 as a catalyst in
the β-alkylation reaction of secondary alcohols with primary
alcohols and in the N-alkylation reaction of amines with various
alcohols.
Initially, 1 mol % of catalyst was evaluated for the β-alkylation
reaction between 1-phenylethanol and phenylmethanol in the
t
presence of 1 equiv of NaO Bu (Table 1, entry 1), and 1,3-
diphenylpropan-1-ol (3a) was found to be the major product,
in admixture with 1,3-diphenylpropan-1-one (4a). The results
obtained under optimization conditions are summarized in
RESULTS AND DISCUSSION
■
a. β-Alkylation Reaction of Secondary Alcohols with
Primary Alcohols. Alkylation of secondary alcohols with
primary alcohols is an important tandem multistep reaction that
typically involves dehydrogenation of the alcohols to aldehyde
or ketone, aldol coupling, loss of water, and subsequent
Table 1. Entry 8 gives the result of Fujita’s reaction using
6
[Cp*IrCl ] as catalyst.
2 2
Received: September 21, 2011
Published: November 15, 2011
©
2011 American Chemical Society
6499
dx.doi.org/10.1021/om200883e|Organometallics 2011, 30, 6499−6502

Organometallics
Note
a
Table 1. β-Alkylation of R -Phenylethanol (1a) with Phenylmethanol (2a) under Various Conditions
1
product (%)
b
c
entry
catalyst (mol %)
R
base (mol %)
conversion
yield
3a
4a
t
1
2
3
4
5
6
1 (1.0)
H
H
H
H
NaO Bu (100)
97
96
93
87
88
98
99
92
90
68
80
82
85
88
75
95
93
94
75
81
95
77
5
7
t
1 (0.1)
NaO Bu (100)
t
1 (0.1)
NaO Bu (50)
6
1 (0.1)
NaOH (100)
25
19
5
t
1 (0.1)
4-OMe
4-Cl
H
NaO Bu (100)
t
1 (0.1)
NaO Bu (100)
d
t
7
e
1 (0.1)
NaO Bu (100)
23
t
8
[Cp*IrCl ] (1.0)
H
NaO Bu (100)
2
2
a
The reaction was carried out with secondary alcohol (1 mmol), primary alcohol (1 mmol), catalyst 1, and base in toluene (0.3 mL) at 110 °C for 17 h.
b
c
Conversions (based on the secondary alcohol) are determined by the consumption of alcohol. Yields of 3a (based on the secondary alcohol, 1a)
1
d
were determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. The reaction was allowed to proceed for 48 h.
e
6
Reported value.
The complex [Cp*IrCl2]2 as catalyst under the same
Table 2. β-Alkylation of Aliphatic Secondary Alcohol with
conditions gave 1-phenylhexan-1-ol (3a) in 75% yield, a yield
surpassed by the use of 1 (92%) (Table 1, entry 1). More
significantly, we observed that the desired product 3a could be
achieved in comparably good yield under the same reaction
conditions but with a significantly reduced catalyst loading
Primary Alcohols and Arylalkyl Secondary Alcohol with
Aliphatic Primary Alcohols
a
(
0.1 mol % vs 1.0 mol %) (entry 2). As far as we are aware, this
catalyst loading is lower than any reported for the β-alkylation
of 1a with 2a in the literature. It was also noted that
when the amount of base was decreased to 50%, the yields
were substantially reduced but the selectivity observed for the
coupling products (3a vs 4a) did not show any noticeable
change for 1 (entry 2 vs entry 3). Replacement of the base
t
NaO Bu with NaOH did not affect the catalytic potential (entry
2
vs entry 4), while Na CO gave no product yields when
2 3
employed as an alternative base. The presence of substituents
on the secondary alcohol (entry 5 and entry 6) did not produce
any drastic reduction in either yield or selectivity. As observed
8a,b
in previous reports, a longer reaction time did not improve
yields since it led to the dehydrogenation of the coupled
alcohol product to form the corresponding ketone (entry 2 vs
entry 7).
We also used complex 1 to catalyze the β-alkylation of
aliphatic secondary alcohols with primary alcohols or arylalkyl
secondary alcohols with aliphatic primary alcohols (Table 2).
It is seen that β-alkylation of isopropyl alcohol with n-pentyl
alcohol and n-hexyl alcohol gave coupled products in yields of
a
The reaction was carried out with secondary alcohol (1 mmol),
t
primary alcohol (1 mmol), catalyst 1 (0.1 mol %), and NaO Bu (100
mol %) in toluene (0.3 mL) at 110 °C for 17 h. Yields (based on the
secondary alcohol) were determined by H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal standard.
4
1% and 50%, respectively (entries 1 and 2). These yields,
b
albeit moderate, are encouraging when compared to reported
yields of the reactions of aliphatic secondary alcohols with
1
9
aliphatic primary alcohols. β-Alkylation of isopropyl alcohol
6
with benzyl alcohol gave coupled product in 67% yield (entry 3).
Entries 4 and 5 give the results of β-alkylation of 1-phenylethanol
with n-pentyl and n-hexyl alcohol, giving products in high to
moderate yields. However, isopropyl alcohol with 1-phenyl-1-
propanol does not undergo alkylation.
bonds, yielding the final product. We investigated these
individual steps in our protocol using the same methodology
adopted by Fujita et al. The analysis of the results obtained
after performing the catalytic oxidation of 1-phenylethanol to
acetophenone using acetone as hydrogen acceptor (<5% yield),
alkylation of acetophenone with phenylmethanol (55% yield),
and transfer hydrogenation of benzylideneacetophenone using
2-propanol as hydrogen donor (50% yield) prompted us to
investigate the low yield for the oxidation of secondary alcohol.
It was noted that upon completion of the oxidation, if 1 equiv
The mechanism proposed for [Cp*IrCl ] as catalyst in
2
2
β-alkylation involves a multiple-step tandem process involving
oxidation of alcohols to aldehyde and ketone, generation of a
hydrido iridium species, base-mediated cross aldol condensa-
tion, and successive transfer hydrogenation of CC and CO
6
500
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Organometallics
Note
a
Table 3. N-Alkylation of Amines with Alcohols
product (%)
b
entry
R
R′
base
reaction time (h)
yield
% imine
% amine
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
KOH
KOH
KOH
KOH
45
17
45
17
45
45
45
45
45
45
45
45
63
46
61
41
50
26
68
40
36
85
4
9
1
91
99
0
PhCH2
PhCH2
PhCH2
PhCH2
4-ClPhCH2
4-OMePhCH2
PhCH2
PhCH2
iPr
100
100
50
0
K CO
50
54
6
2
3
t
KO Bu
KOH
KOH
KOH
KOH
KOH
KOH
46
94
86
14
0
4-OMePh
nPr
100
96
10
11
12
4
Ph
100
100
0
4-OMePh
iPr
1
0
a
The reaction was carried out with amine (1 mmol), primary alcohol (1 mmol), catalyst 1 (1 mol %), and KOH (100 mol %) in toluene (0.3 mL) at
10 °C for 45 h. Yields of major product (based on the primary alcohol) were determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
b
1
1
as an internal standard.
of benzyl alcohol was added in and the reaction allowed to
proceed, the same yield of coupled alcohol products as from
our one-pot, single-step protocol was obtained.
On the basis of the aforementioned experiments we believe
that the low yield for the Oppenauer-type oxidation of
indicate any clear trend that can be attributed to the presence of
electron-withdrawing and electron-donating substituents. Ali-
phatic 1-pentanol when treated with phenylamine also gave
good yield (entry 10), while use of aliphatic 2-propanamine led
to very low yield (entries 11, 12). We also tested the reactions
of secondary benzyl alcohol with benzyl amine and benzyl
alcohol with secondary benzyl amine, and in both instances the
desired imine products were not obtained. In these reactions, a
variation of several parameters, e.g., temperature, concentration,
and catalyst loading, yielded no significant improvement.
These preliminary studies show that the presence of the
thiolate moiety disrupts the second stage of the returning
“borrowing hydrogen” procedure reported for other systems,
leading to selective formation of imines. It needs to be noted
that, in N-alkylation, imines are often intermediates that are
detected but usually not isolated due to their subsequent
reduction during the return of the borrowed hydrogen from the
metal catalyst as part of the hydrogen autotransfer process. As
1-phenylethanol may be because the acetophenone formed after
the initial hydrogen transfer to the acetone/iridium reverts back
to the secondary alcohol. Studies have shown that with hemilabile
ligands on iridium this transfer may occur predominantly through
a direct hydrogen transfer between the coordinated ketone and
1
1
alcohol. However when conducted as a single-step, one-pot
protocol, the presence of the primary alcohol allows the
β-alkylation reaction to proceed, thus precluding the possibility
of the ketone generated from the secondary alcohol reverting
back to the parent alcohol.
b. N-Alkylation of Amines with Alcohols. N-Alkylation
of amines with alcohols provides an efficient route to new
1
2
amines and can therefore be a crucial step in the atom-
economical synthesis of pharmaceutically significant molecule-
far as we know, there are only a few other catalysts known for
8
a−c
8a,14
s.
Williams et al. have recently reported an efficient
selective imine synthesis.
From our studies, complex 1
methodology for the direct alkylation of amines with alcohols
seems to perform better than previously reported cata-
14b,d,e
at 115 °C for 10 h using 1 mol % [Cp*IrI ] (SCRAM) in
lysts,
though it is much less efficient than the PNP-type
2
2
water with no added base, giving amine products in high
Ru pincer complex from the recent work by Milstein et al.,
which gave impressive yields under neutral reaction con-
1
3
yields. Complex 1 was similarly investigated in our laboratory,
but in the presence of base, and the results are presented in
Table 3. Our initial reaction was that of aniline and its
derivatives with benzyl alcohol under conditions similar to
those employed by Williams for [Cp*IrI ] (entries 1 and 2).
14c
ditions.
Our results are important in the context that it
provides an additional valuable pathway to imines, which are
much sought after as versatile synthetic intermediates for the
manufacture of dyes, pharmaceuticals, and other commercially
2
2
15
The products were amines, as expected from literature
precedents involving organometallic catalysts, obtained in
selectivities above 90%. While attempting to broaden the scope
of reactants, we found that the reaction of phenylamine with
benzyl alcohol under similar conditions gave the imine as the
sole product (entries 3 and 4) in moderate yields (61% and
important compounds. Traditionally, oxidation procedures
that use stoichiometric amounts of oxidants are used for the
14a,d
synthesis of imines.
3
In conclusion, the use of [Cp*Ir(η -tpdt)] as catalyst in the
β-alkylation of alcohols has been explored. The complex is very
efficient at low catalyst loading, especially when compared to its
parent complex [Cp*IrCl ] . Furthermore, the complex also
4
1%), which compares favorably with yields from other direct
2
2
8a,14
imine synthesis methods.
The product selectivity and yield
caused an interesting reversal in product selectivity during the
N-alkylation reaction, with imines being formed as the major
product. This catalyst thus has the potential to be active in
other synthetic scenarios especially in scenarios involving
vary considerably with base (entries 5 and 6). The conversion
to the desired imine could also be achieved using substituted
phenylamines or phenylmethanol (entry 7, 8, 9) and did not
6
501
dx.doi.org/10.1021/om200883e|Organometallics 2011, 30, 6499−6502

Organometallics
Note
transfer hydrogenation. Further studies are currently underway
to study the mechanism of the present system and its
applicability to other reactions.
(d) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349−3366. (e) Crabtree,
R. Acc. Chem. Res. 1979, 12, 331−337.
(3) Xu, C.; Pullarkat, S. A.; Goh, L. Y. Aust. J. Chem. 2009, 62, 1537−
1
543.
4) (a) Tay, E. P. L.; Kuan, S. L.; Leong, W. K.; Goh, L. Y. Inorg.
(
EXPERIMENTAL SECTION
General Procedures. All reactions and manipulations were
carried out under dry, oxygen-free argon using the standard Schlenk
technique. NMR spectra were recorded on a Bruker AV 300
■
Chem. 2007, 46, 1440−1450. (b) Kuan, S. L.; Tay, E. P. L.; Leong, W.
K.; Goh, L. Y. Organometallics 2006, 25, 6134−6141.
(5) Xu, C.; Li, Y.; Goh, L. Y.; Pullarkat, S. A. J. Organomet. Chem.
2
011, in press.
6) Fujita, K.-i.; Asai, C.; Yamaguchi, T.; Hanasaka, F.; Yamaguchi, R.
Org. Lett. 2005, 7, 4017−4019.
1
13
spectrometer ( H at 300 MHz, C at 75 MHz), a Bruker AV 400
(
1
13
1
(
H at 400 MHz, C at 100 MHz), or a Bruker AV 500 ( H at 500
13
1
MHz, C at 125 MHz). For H NMR spectra, chemical shifts are
referenced to residual solvent peak in the respective deutero-solvents.
Toluene was purified using the M. Braun MB SPS-800 solvent
purification system. 1,3,5-Trimethoxybenzene was used as supplied by
Aldrich, and Celite (Fluka AG) was dried at 140 °C overnight before
use.
́
(
7) Martinez, R.; Ramo
982−8987.
8) (a) Gnanamgari, D.; Sauer, E. L. O.; Schley, N. D.; Butler, C.;
Incarvito, C. D.; Crabtree, R. H. Organometallics 2009, 28, 321−325.
b) Pontes da Costa, A.; Viciano, M.; Sanau, M.; Merino, S.; Tejeda, J.;
Peris, E.; Royo, B. Organometallics 2008, 27, 1305−1309. (c) Pontes
da Costa, A.; Sanau
́n , D. J.; Yus, M. Tetrahedron 2006, 62,
8
(
(
́
β-Alkylation of Secondary Alcohols with Primary Alcohols:
Typical Procedure. The reaction was carried out with secondary
alcohol (1.00 mmol), primary alcohol (1.00 mmol), catalyst 1 (1.00
́
6
́
2
008, 27, 4254−4259.
9) Cho, C. S.; Kim, B. T.; Kim, H.-S.; Kim, T.-J.; Shim, S. C.
Organometallics 2003, 22, 3608−3610.
10) (a) Gnanamgari, D.; Leung, C. H.; Schley, N. D.; Hilton, S. T.;
t
μmol), and Na OBu (1.00 mmol) in toluene (0.3 mL) at 110 °C for 17
(
h. The reaction mixture was then cooled, diluted with 1 mL of CH Cl ,
2
2
and filtered through a plug of Celite. The filtrate was evacuated to
dryness, and the resulting residue was dissolved in deuterated solvents
(
Crabtree, R. H. Org. Biomol. Chem. 2008, 6, 4442−4445. (b) Cheung,
H. W.; Lee, T. Y.; Lui, H. Y.; Yeung, C. H. Adv. Synth. Catal. 2008,
350, 2975−2983.
1
and analyzed by H NMR spectroscopy with 1,3,5-trimethoxybenzene
added as an internal standard. The confirmation of the nature of the
7,8
products was performed by comparison with literature data.
(
11) (a) Handgraaf, J.-W.; Reek, J. N. H.; Meijer, E. J.
Organometallics 2003, 22, 3150−3157. (b) Samec, J. S. M.; Backvall,
J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237−248.
12) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth.
Catal. 2007, 349, 1555−1575.
13) Saidi, O.; Blacker, A. J.; Farah, M. M.; Marsden, S. P.; Williams,
J. M. J. Chem. Commun. 2010, 46, 1541−1543.
14) (a) Sun, H.; Su, F.-Z.; Ni, J.; Cao, Y.; He, H.-Y.; Fan, K.-N.
N-Alkylation of Amines with Alcohols: Typical Procedure.
The reaction was carried out with amine (1 mmol), primary alcohol
̈
(
1.00 mmol), catalyst 1 (0.01 mmol), and KOH (1.00 mmol) in toluene
(
(0.3 mL) at 110 °C for 45 h. The reaction mixture was then cooled, diluted
with 1 mL of toluene, and filtered through a plug of Celite. The filtrate
was evacuated to dryness, and the resulting residue was dissolved in
(
1
deuterated solvents and analyzed by H NMR spectroscopy with 1,3,5-
(
trimethoxybenzene added as an internal standard. The confirmation
of the nature of the products was performed by comparison with
Angew. Chem., Int. Ed. 2009, 48, 4390−4393. (b) Shimizu, K.-i.;
8a,14
Ohshima, K.; Satsuma, A. Chem.−Eur. J. 2009, 15, 9977−9980.
literature data.
(c) Gnanaprakasam, B.; Zhang, J.; Milstein, D. Angew. Chem., Int. Ed.
2
010, 49, 1468−1471. (d) Kegnæs, S.; Mielby, J.; Mentzel, U. V.;
Christensen, C. H.; Riisager, A. Green Chem. 2010, 12, 1437−1441.
(e) Esteruelas, M. A.; Honczek, N.; Olivan, M.; Onate, E.; Valencia, M.
Organometallics 2011, 30, 2468−2471.
15) Fujita, K.-i.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64,
943−1954.
AUTHOR INFORMATION
■
Corresponding Author
́
̃
*
E-mail: sumod@ntu.edu.sg.
(
1
ACKNOWLEDGMENTS
■
The authors acknowledge with thanks support from the
Nanyang Technological University and a research scholarship
to C.X.
REFERENCES
■
(
1) See, for instance, the following and the references therein:
(
a) DuBois, M. R. Chem. Rev. 1989, 89, 1−9. (b) Holm, R. H.; Ciurli,
S.; Weigel, J. A. Prog. Inorg. Chem. 1990, 38, 1−74. (c) Shibahara, T.
Coord. Chem. Rev. 1993, 123, 73−147. (d) San
́
chez-Delgado, R. A.
J. Mol. Catal. 1994, 86, 287−307. (e) Howard, J. B.; Rees, D. C. Chem.
Rev. 1996, 96, 2965−2982. (f) Burgess, B. K.; Lowe, D. J. Chem. Rev.
1
1
1
4
1
2
996, 96, 2983−3011. (g) Sellmann, D.; Sutter, J. Acc. Chem. Res.
997, 30, 460−469. (h) Curtis, M. D.; Druker, S. H. J. Am. Chem. Soc.
997, 119, 1027−1036. (i) Mathur, P. Adv. Organomet. Chem. 1997,
1, 243−314. (j) Bianchini, C.; Meli, A. Acc. Chem. Res. 1998, 31,
09−116. (k) Ogino, H.; Inomata, S.; Tobita, H. Chem. Rev. 1998, 98,
093−2121. (l) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. Angew.
Chem., Int. Ed. 2009, 48, 2534−2537. (m) Yamauchi, Y.; Miyake, Y.;
Nishibayashi, Y. Organometallics 2009, 28, 48−50. (n) Matsuzawa, H.;
Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2007, 46, 6488−
6
491.
(
2) (a) Oro, L. A.; Claver, C. Iridium Complexes in Organic Synthesis;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2009; Chapters
−5, 10, 11. (b) Suzuki, T. Chem. Rev. 2011, 111, 1825−1845. (c) Liu,
J.; Wu, X.; Iggo, J. A.; Xiao. J. Coord. Chem. Rev. 2008, 252, 782−809.
3
6
502
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