Highly active in situ catalysts for anti-Markovnikov hydration of terminal alkynes

Article abstract of DOI:10.1021/ol062455k

(Diagram presented) The anti-Markovnikov hydration of terminal alkynes to give aldehydes is catalyzed by complexes derived in situ from air-stable [CpRu(η⁶-naphthalene)]PF₆ (C) and 6-aryl-2- diphenylphosphinopyridines (L). Ligands L are readily available from a modular synthesis. Increasing the size of the ligand C-6 aryl group in the order R = Ph < mesityl < 2,4,6-triisopropylphenyl < (2,4,6-triphenyl)phenyl gave hydration catalysts of highest known activity.

Full text of DOI:10.1021/ol062455k

ORGANIC
LETTERS
2
006
Vol. 8, No. 25
853-5856
Highly Active in Situ Catalysts for
Anti-Markovnikov Hydration of Terminal
Alkynes
5
Aur e´ lie Labonne, Thomas Kribber, and Lukas Hintermann*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1, D-52074
Aachen, Germany
lukas.hintermann@oc.rwth-aachen.de
Received October 5, 2006
ABSTRACT
The anti-Markovnikov hydration of terminal alkynes to give aldehydes is catalyzed by complexes derived in situ from air-stable [CpRu(η6
naphthalene)]PF (C) and 6-aryl-2-diphenylphosphinopyridines (L). Ligands L are readily available from a modular synthesis. Increasing the
-
6
size of the ligand C-6 aryl group in the order R
highest known activity.
)
Ph < mesityl < 2,4,6-triisopropylphenyl < (2,4,6-triphenyl)phenyl gave hydration catalysts of
6
Alkynes have long been known to undergo synthetically
useful metal-catalyzed hydrations to give carbonyl com-
pounds, but only in 1998 did Tokunaga and Wakatsuki find
heterofunctionalization reactions are promising tools for
sustainable synthesis because they generate heterofunction-
7
ality with atom-economy. We have been eager to incorporate
a ruthenium catalyst that selectively produced aldehydes from
the title reaction into synthetic sequences, but progress was
initially hampered by the low activity of the first generation
catalysts 1, and later by availability of sufficient quantities
1
terminal alkynes. Complexes [CpRu(PR
3
)
2
]X (1) (R ) aryl,
5
alkyl, bridging alkyl; Cp ) η -cyclopentadienyl; X ) Cl,
PF ) have since emerged as catalysts for anti-Markovnikov
hydration with almost perfect regioselectivity. A crucial
ligand modification (PR ) L1 ) 6-tert-butyl-2-diphe-
nylphosphanylpyridine) by Grotjahn and Lev gave the
complex [CpRu(L1) (MeCN)]PF (2), which is 3 orders of
8
of complex 2.
6
2-4
These hurdles in the way of a broader synthetic application
9
of anti-Markovnikov hydration of terminal alkynes have
3
5
motivated us to search for more available and easy to handle
catalysts. We can now present in situ catalysts for the title
reaction that combine the advantages of ready availability
and air-stability, and we also report on a surprising ligand
effect that has allowed us to tune the catalyst to highest levels
of activity.
2
6
magnitude more active than 1 and thus paved the way for
synthetic applications under mild conditions.4 Catalytic
(
(
1) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867.
2) (a) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001, 3, 735.
(
b) Tokunaga, M.; Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.;
Wakatsuki, Y. J. Am. Chem. Soc. 2001, 123, 11917.
3) (a) Grotjahn, D. B.; Incarvito, C. D.; Rheingold, A. L. Angew. Chem.,
(6) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104,
3079. (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int.
Ed. 2004, 43, 3368. (c) Catalytic Heterofunctionalization; Togni, A.,
Gr u¨ tzmacher, H., Eds.; Wiley-VCH: Weinheim, Germany, 2001.
(7) Trost, B. M. Science 1991, 254, 1471.
(
Int. Ed. 2001, 40, 3884. (b) Chevallier, F.; Breit, B. Angew. Chem., Int.
Ed. 2006, 45, 1599.
(
4) (a) Grotjahn, D. B.; Lev, D. A. J. Am. Chem. Soc. 2004, 126, 12232.
b) Grotjahn, D. B. Chem. Eur. J. 2005, 11, 7146.
5) Baur, J.; Jacobsen, H.; Burger, P.; Artus, G.; Berke, H.; Dahlenburg,
L. Eur. J. Inorg. Chem. 2000, 1411.
(8) Availability of 2 is limited by the synthesis of L1 (6 steps, low overall
yield) and the use of an expensive precursor [CpRu(MeCN)3]PF6. Note,
however, that 2 is now sold in research quantities by Strem Chemicals.
(9) We are not aware of applications of this methodology in synthesis.
(
(
1
0.1021/ol062455k CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/16/2006

We initially discovered that the complex [CpRu(η6-
naphthalene)]PF (C), when combined with L1, gave a highly
active in situ catalyst for the anti-Markovnikov hydration of
was complete within an hour in acetonitrile at 50 °C and
6
catalytic hydrations were then carried out efficiently in
4
a
aqueous acetone (Table 1, entries 1 and 10-12). The
components of the in situ catalyst could be handled in air,
and the active catalyst was generated on demand. Unfortu-
nately, this practical protocol still relied on the unique ligand
terminal alkynes (Figure 1). Complex C is an air-stable
4
L1, which is necessary for high rate acceleration, but is not
5
readily available. According to Grotjahn, the peculiarity of
L1 is ascribed to steric shielding of the pyridine nitrogen by
2
the bulky tert-butyl group; this prevents both η -P-N-
chelation (Figure 2) and irreversible additions to alkyne
4
b
substrates. In the hope to find ligands with sterically
demanding R groups that would give rise to highly active
catalysts we planned to synthesize 6-aryl-substituted py-
ridylphosphanes by a straightforward sequence involving
1
2,13
selective cross-coupling reactions.
A range of new 6-aryl-2-diphenylphosphinopyridines L
was obtained in two steps from 2,6-dibromopyridine (3)
Figure 1. New in situ catalysts for anti-Markovnikov hydration
of terminal alkynes (Z ) CH or N; R ) aryl, R′ ) H or aryl).
(
Table 2). Kumada couplings with bulky aryl Grignard
1
2a,14
reagents and PCy
3
as ligand for nickel
selectively gave
1
0
material that is made in one step from ruthenocene. Its use
the monoarylated bromopyridines P. Nucleophilic phosphi-
nation of P resulted in ligands L2-L8 as crystalline solids
which could be handled in air. Complex C underwent
complete ligand exchange with L1 in MeCN to give [CpRu-
+
as a donor of the electrophilic CpRu -fragment is very
practical since it replaces the complex [CpRu(MeCN)
which is expensive and air-sensitive. The ligand exchange
3
]PF
6
,
11
Table 1. Use of the New in Situ Catalysts in the Anti-Markovnikov Hydration of Selected Terminal Alkynes To Give Aldehydesa
a
Conditions: The catalyst was generated from 2 equiv of L and 1 equiv of C in MeCN at 50-60 °C over 1 to 6 h, followed by evaporation. Hydration
of the substrates (1 to 10 mmol, 0.5 m) was carried out in acetone with 5 equiv of water under argon. See the Supporting Information for a general procedure.
See Table 2 and text for ligand structures. Time to 95% conversion was determined by GC, using an internal standard; [octyne]0 ) 0.25 m. Piv )
pivaloyl.
b
c
5854
Org. Lett., Vol. 8, No. 25, 2006

2
porating a η -P-N chelate were not detected. The more
1
9
hindered ligands L6 and L7 (cf. Figure 3) required 6 h at
Figure 2. (a) Catalyst deactivation by PN-chelation with small R
groups (H, Me). (b) Large substituents R prevent chelation. The
substrate/solvent (S) at the free coordination site may interact with
the pyridine nitrogen.4b
CN. (a) 31
P
Figure 3. In situ complexation of C and L7 in CD
3
NMR spectrum after 2.5 h of ligand exchange at 60 °C: signals
+
for L7 (s, -3.1 ppm), [CpRu(L7)(MeCN)
2
]
(s, 51.1 ppm), and
+
(MeCN)]+ 15 within 1 h at 50 °C. The monophosphine
2
[CpRu(L7)
CpRu(L7)
fragments to m/z 734 ([CpRu(L7)] ). A trace of the solvate [CpRu-
2
(MeCN)] (s, 43.3 ppm). (b) ESI-MS of in situ formed
(L1)
+
[
2 6 2
(MeCN)]PF in MeCN: m/z 1301 ([CpRu(L7) ] ),
1
+
2
complex cation [CpRu(η -L1)(MeCN) ] was detected as an
+
+
(
L7)(MeCN)] (m/z 775) is also visible.
Table 2. Two-Step Synthesis of 6-Aryl-2-pyridylphosphanesa
60 °C for complete ligand exchange. These experiments show
that a phenyl group at the C-6-position of a 2-pyridylphos-
phane ligand L is already sufficient to prevent catalyst
deactivation by P-N chelation (see Figure 2). Indeed, all of
the in situ complexes prepared from L2-L8 were catalysts
for the anti-Markovnikov hydration, but their activities
varied. Reaction progress curves for the hydration of 1-octyne
2
0
were recorded (Figure 4) and fitted to the rate law dP/dt
Arl substitutionb
entry
(Rn)
P
yield (%) ligand yield (%)
1
2
3
4
5
6
H
c
L2
L3
L4
L5
L6
L7
86
79
74
71
75
78
2,4,6-Me3
2,6-(i-PrO)2
2,6-i-Pr2
2,4,6-i-Pr3
2,4,6-Ph3
P3
P4
P5
P6
P7
70
83
67
83
57
a
b
See the Supporting Information for reaction conditions. Arl ) aryl
c
at C-6. L2 was synthesized by a different route, and compound 4 served
as starting material for L8, see the Supporting Information.
16
intermediate. Likewise, the phenyl-substituted pyridylphos-
phane L2 reacted with C (MeCN, 2.5 h, 65 °C) to give
+
17
[
[
CpRu(L2)
CpRu(L2)(MeCN)
2
(MeCN)] , with a fleeting appearance of
+
18
2
]
after 1 h. Complex species incor-
Figure 4. Hydration of 1-octyne to octanal at 60 °C (GC data
points/idealized progress curves; cf. Table 3).
(
10) K u¨ ndig, E. P.; Monnier, F. R. AdV. Synth. Catal. 2004, 346, 901.
(11) We believe that this replacement use is more general; e.g., reaction
4
of C with 1,5-cyclooctadiene in MeCN yields [CpRu(η -COD)(MeCN)]-
PF6; Hintermann, L., unpublished result.
0 2
) kLn[Ru] [H O][octyne]. The values thus obtained for kLn
were compared to the activity of the in situ catalyst from
L1 at 45 °C (Table 3). Since reaction progress did not
(12) Selective monoarylation of dihalopyridines: (a) Scott, N. M.;
Schareina, T.; Tok, O.; Kempe, R. Eur. J. Inorg. Chem. 2004, 3297. (b)
Loren, J. C.; Siegel, J. S. Angew. Chem., Int. Ed. 2001, 40, 754. (c) Alami,
M.; Peyrat, J.; Belachmi, L.; Brion, J. Eur. J. Org. Chem. 2001, 4207. (d)
Zhang, H.; Tse, M. K.; Chan, K. S. Synth. Commun. 2001, 31, 1129.
31
(
13) Conversely, reactions of bulky alkyl metals with dihalopyridines
are usually not selective, cf.: Cui, X.; Brown, R. S. J. Org. Chem. 2000,
5, 5653.
14) Modifications: [NiCl2(PCy3)2] as catalyst, THF as solvent.
(15) δ( P) in CD3CN ) 42.7 ppm (s). ESI-MS (MeCN): m/z 805.4
+
+
([CpRu(L1)2] ), 486.4 ([CpRu(L1)] ).
31
6
(16) δ( P) in CD3CN ) 49.8 ppm (s). ESI-MS (CHCl3/MeCN): m/z )
+
+
(
526.7 ([CpRu(L1)(MeCN)] ), 486.3 ([CpRu(L1)] ).
Org. Lett., Vol. 8, No. 25, 2006
5855

Some applications of the new in situ catalysts are presented
in Table 1. The bulky arylpyridylphosphanes L5-L7 per-
formed very well and gave catalysts that were also more
robust toward oxygen and substrate impurities than catalysts
based on L1. This made them the preferred ligands for
reactions at lower catalyst loadings (entries 1 and 2). In
addition to the established functional group tolerance of Ru-
Table 3. Relative Catalytic Activities of in Situ Complexes (C
+
2L) in the Hydration of 1-Octynea
RCAb
45 °C
RCA
60 °C
2-4
catalyzed anti-Markovnikov-hydration we find that â-ke-
toesters are tolerated even though they are potential ligands
entry
ligand
R
(
entries 12 and 13). Regioisomeric ketone side products were
1
2
3
4
5
6
7
8
9
L7
L6
L5
L1 (2)c
L1
L3
L2
L8
L4
2,4,6-Ph3C6H2
2,4,6-i-Pr3C6H2
2,6-i-Pr2C6H3
t-Bu
t-Bu
Mes
2.9
1.6
1.2
1.3
1
1.0
0.4
n.d.
n.d.
16.6
7.1
5.0
3.9
3.5
2.3
1.6
0.6
0.16
not observed in any of the above reactions.
In conclusion, we have introduced a family of highly active
in situ catalysts for the anti-Markovnikov hydration of
terminal alkynes that is based on a combination of the metal
6
precursor [CpRu(naphthalene)]PF (C) and 6-aryl-2-diphe-
Ph
4,6-Ph2C4N2H
2,6-(i-PrO)2C6H3
nylphosphinopyridine ligands L. The reaction of C and L
has been investigated in solution and the generation of active
catalysts similar to Grotjahns complex 2 has been observed.
The components of our in situ catalyst are readily available
and easy to handle. The straightforward, modular two-step
ligand synthesis renders the catalyst system tunable; this has
by now led to a catalyst that is four times more active than
the best previous one for anti-Markovnikov hydration. We
are currently applying this fascinating reaction in multistep
synthetic sequences, following a philosophy of sequential
catalytic synthesis with high atom-economy. Progress along
these lines will be reported in due course.
a
Conditions: [octyne]0 ) 0.25 m, [Ru] ) 5 mol %, [H2O]0 ) 1.25 m,
see the Supporting Information. Relative catalytic activities, normalized:
RCA (Ln) ) kLn/kL1@45°C. Pure complex 2 was used as catalyst.
b
c
uniformly follow the above rate law over the full range of
conversion, the results are approximate, but some conclusions
can be drawn. The activity of the catalysts increases in the
order R ) Ph < Mes < t-Bu < i-Pr
2
C
6
H
3
< i-Pr
3 6 2
C H <
Ph and thus roughly correlates with the steric size of
3
6 2
C H
the ligand, which surprised us because it was not predicted
by mechanistic models of this reaction.2 The in situ catalysts
from L5, L6, and L7 surpassed the activity of either that
from L1 or that of the pure complex 2 and therefore are the
most active catalysts for anti-Markovnikov hydration to date.
On the other hand, introduction of heteroatoms into either
the aza-arene nucleus (L8) or onto the aryl group R (L4) of
the ligands gave less active catalysts. Catalyst activity at
,4
Acknowledgment. We thank DFG for support within an
3
Emmy Noether-Programm and Umicore for a gift of RuCl .
We thank Dr. Christian M o¨ ssner (Institute of Organic
Chemistry, RWTH Aachen) for hints and Prof. Carsten Bolm
(
Institute of Organic Chemistry, RWTH Aachen) for con-
tinued support.
6
0 °C was 2 to 5 times higher than that at 45 °C. The purified
Grotjahn complex 2 was slightly more active than in situ
catalysts from L1.
Supporting Information Available: General experimen-
tal procedures, analytical data, and selected spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3
1
(
17) δ( P) in CD3CN ) 43.2 ppm (s). ESI-MS (MeCN): m/z 845.1
+
+
(
[CpRu(L2)2] ), 506.4 (-L2); 547 ([CpRu(L2)(MeCN) ], weak).
3
1
(
(
18) δ( P) in CD3CN ) 51.1 ppm (s).
+ 31
19) [CpRu(L6)(MeCN)2] : δ( P) in CD3CN ) 50.1 ppm. [CpRu(L6)2-
+
31
(
MeCN)] : δ( P) ) 43.2 ppm.
20) DYNAFIT program; Kuzmic, P. Anal. Biochem. 1996, 237, 260.
(
OL062455K
5856
Org. Lett., Vol. 8, No. 25, 2006