Self-assembled bidentate ligands for ru-catalyzed anti-Markovnikov hydration of terminal alkynes

Article abstract of DOI:10.1002/anie.200503826

(Figure Presented) In pairs: Bidentate ligands are generated by the self-assembly of monodentate ligands through complementary hydrogen bonding. A ruthenium complex bearing such self-assembled heterodimeric ligands is used as the catalyst in the regioselective hydration of terminal alkynes. FG = functional group, Piv = pivaloyl.

Full text of DOI:10.1002/anie.200503826

Angewandte
Chemie
Homogeneous Catalysis
DOI: 10.1002/anie.200503826
Self-Assembled Bidentate Ligands for Ru-
Catalyzed anti-Markovnikov Hydration of
Terminal Alkynes**
Floris Chevallier and Bernhard Breit*
The regioselective functionalization of terminal alkynes is a
fundamental process in organic synthesis since it allows the
installation of a variety of important functional groups into an
existing carbon skeleton.[1] Among these reactions, the
addition of water across a triple bond generally follows the
Markovnikov rule.[2] On the other hand, an anti-Markovnikov
hydration of terminal alkynes could be a convenient way to
the preparation of aldehydes, but so far only a few ruthenium
complexes have been identified which allowed the catalysis of
this unusual hydration mode.[3] The presence of bidentate
phosphine ligands,[3b] the coordination of a water molecule
stabilized by hydrogen bonding,[3e] and the use of phosphino-
pyridine ligands[3f] seem to be of major importance in these
processes.
In the course of our investigation on the formation of
bidentate ligands through hydrogen bonding,[4] we recently
reported the construction of homodimeric[5] and heterodi-
meric[6] bidentate ligands by employing self-assembly.[7] In the
latter case, an adenine/thymine base-pair analogous system
was used: the aminopyridine/isoquinolone platform
(Scheme 1).
Scheme 1. Self-assembly through hydrogen bonding of the adenine/
thymine andaminopyridine/isoquinolone systems.
The first bidentate-phosphine ligand library for homoge-
neous metal-complex catalysis based on self-assembly
through hydrogen bonding was realized, and these ligands
furnished an active rhodium catalyst for the regioselective
[*] Dr. F. Chevallier, Prof. Dr. B. Breit
Institut für Organische Chemie undBiochemie
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8715
E-mail: bernhard.breit@orgmail.chemie.uni-freiburg.de
[**] The authors would like to thank the DFG (GRK 1038), the Fonds der
Chemischen Industrie, the Alfried-Krupp Award for young university
teachers (B.B.) for financial support, andDr. M. Keller for solving
the X-ray crystal structure analyses of 5.
Angew. Chem. Int. Ed. 2006, 45, 1599 –1602
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1599

Communications
hydroformylation of terminal alkenes. Interestingly, these
drawing substituents furnished a 3 ” 3 library of self-assem-
bling ligands (Table 2). As no superior catalyst could be
identified, we decided to focus on 5.
self-assembly systems incorporate a pyridinyl-functionalized
phosphine ligand, emulate chelation, and contain a hydrogen-
bonding network that may be suited to activating a molecule
of water through further hydrogen bonding. Hence, the self-
assembly ligand systems incorporate all the features that seem
essential to allow a ruthenium-catalyzed anti-Markovnikov
addition of water to a terminal alkyne.
In a first set of experiments, we studied the catalytic
activity of a variety of half-sandwich ruthenium complexes
bearing monodentate and bidentate phosphine ligands in the
course of hydrating 1-nonyne as the test substrate. The
ruthenium complexes used in this study were obtained in
good yields (73–92%) by mixing one equivalent of each
ligand in the presence of one equivalent of [CpRu-
(CH3CN)3]PF6 (Cp = cyclopentadiene)[8] and subsequent pre-
cipitation with diethyl ether.
Table 2: Ligand matrix (3”3) of aminopyridine/isoquinolone-derived
self-assembled bidentate ligands in the Ru-catalyzed hydration of 1-
nonyne.
Aminopyridine[b]
6-D(p-MeO)PPAP
Isoquinolone[b]
6-DPPAP
6-D(p-F)PPAP
3-DPICon
3-d(p-MeO)PICon
3-d(p-F)PICon
94:0[a]
60:0
78:1.0
77:0
60:1.2
71:2.2
84:1.8
66:1.8
70:4.9
[a] Yield of aldehyde/ketone products (%) determined by GC after 26 h.
[b] 6-d(p-MeO)PPAP: 6-bis-(4-methoxyphenyl)-phosphino-2-(pivaloyl-
amino)-pyridine, 6-d(p-F)PPAP: 6-bis(4-fluorophenyl)phosphino-2-(piv-
aloylamino)-pyridine, 3-d(p-MeO)PICon: 3-bis(4-methoxyphenyl)phos-
phinoisoquinolone, 3-d(p-F)PICon: 3-bis(4-fluorophenyl)phosphinoiso-
quinolone.
The results of the catalytic hydration are depicted in
Table 1. Thus, triphenylphosphine, 2-diphenylphosphinopyr-
To get more structural information on the optimal catalyst
5, the heterodimer-ligand formation based on self-assembly
through hydrogen bonding was studied in solution by
31P NMR spectroscopic analysis. Thus, a clean AB system
with a 2J(P-P) coupling constant of 35.9 Hz confirms the
presence of two nonequivalent phosphine ligands coordinated
at the same metal center (Figure 1).[9] Additionally, 1H NM R
Table 1: Ruthenium complex-catalyzedhydration of 1-nonyne.
Entry
Cat.
L1[a]
L2[a]
t [h]
a [%][b]
k [%][b]
1
2
3
4
5
6
7
1
PPh3
dppy
dppe
6-DPPon
6-DPPAP
6-DPPAP
3-DPICon
PPh3
dppy
–
6-DPPon
3-DPICon
6-DPPAP
3-DPICon
140
168
168
168
26
1.2
4.0
2.1
2.1
94
18
2.4
20
25
0
2[c]
3
4[c]
5
6[c]
7
72
48
39
1.9
3.8
0
[a] dppy: 2-diphenylphosphinopyridine, dppe: 1,2-bis(diphenylphosphi-
no)ethane, 6-DPPon: 6-diphenylphosphino-2-pyridone, 6-DPPAP: 6-
diphenylphosphino-N-pivaloyl-2-aminopyridine, 3-DPICon: 3-diphenyl-
phosphinoisoquinolone. [b] Yieldcalculatedfrom GC response factors
relative to hexadecane internal standard. a=aldehyde, k=ketone. [c] h1-
P,h2-P,N coordination of the phosphinopyridine with replacement of the
acetonitrile ligand.
Figure 1. 31P NMR spectrum of [CpRu(CH3CN)(6-DPPAP)(3-DPI-
Con)]PF6 (5) in solution with CDCl3.
idine and bis(diphenylphosphino)ethane (dppe) gave ruthe-
nium complexes that performed with very low catalytic
activity and selectivity. Using the 6-DPPon ligand, which
should allow for self-dimerization based on hydrogen bonding
between the pyridone form and its hydroxypyridine tauto-
mer,[5] a similarly disappointing result was obtained. Con-
versely, on employing the self-assembled heterodimeric
aminopyridine/isoquinolone bidentate ligands (entry 5; see
also Scheme 1),[6] a catalyst was obtained that operated with
outstanding activity and perfect regioselectivity. It is obvious
from entries 6 and 7 that the self-assembled heterodimer is
responsible for this interesting result. Thus, neither 6-DPPAP
nor 3-DPICon ligands alone provided an active catalyst.
Moreover, modifications of the aminopyridine and iso-
quinolone ligands with electron-donating and electron-with-
experiments in CDCl3 and [D6]acetone show a substantial
shift of the 6-DPPAP and 3-DPICon NH signals to low field
after addition of [CpRu(CH3CN)3]PF6, which is in agreement
with hydrogen bonding. Furthermore NOE interactions
observed in a solution of [D6]acetone containing residual
water confirm the existence of the hydrogen-bonding network
under these conditions.
Single crystals suitable for X-ray diffraction were
obtained from slow diffusion of cyclohexane into a concen-
trated solution of 5 in dichloromethane.[10,11] As proposed, the
aminopyridine and isoquinolone ligands form the expected
hydrogen-bonding network reminiscent of the Watson–Crick
base pairing of A and T in DNA (Figure 2).[12]
1600 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1599 –1602

Angewandte
Chemie
presence of a nitrile group, which may act as a competing
ligand for the ruthenium center (entries 1–3).[3b] 1,9-Deca-
diyne was converted into the corresponding dialdehyde in
78% yield, with only traces of the monoaldehyde (entry 4).
The regioselectivity is excellent for a range of different
functionalized substrates (entries 1–7, 9, and 10), with only
one exception: a homopropargylic system bearing a benzoate
function (entry 8). In this case, the regioselectivity is slightly
diminished, which may be because of a chelation effect.
Finally, a steroid ring system substituted by a propargylic
alcohol reacted with water and gave the g-hydroxy aldehyde
selectively in 61% yield (entry 10). It should be noted that in
this example the reaction was carried out at 708C to avoid
degradation of the product into an a,b-unsaturated alde-
hyde.[13]
In summary, the present study highlights the utility of
bidentate ligands generated by the self-assembly of mono-
dentate ligands through complementary hydrogen bonding
for homogeneous catalysis. Thus, a new ruthenium catalyst
was identified, which allows highly regioselective anti-Mar-
kovnikov hydration of terminal alkynes compatible with a
wide range of functional groups. Although at this stage, the
origin of the catalytic activity remains unknown, the hydro-
gen-bonding network may play an important role besides
emulation of bidentate ligand binding.[14]
Figure 2. PLATON plot of 5 (H atoms boundto the carbon atoms and
the PF6À counterion are omittedfor clarity). Selectedinteratomic
distances [Š] and angles [8]: Ru1-P1 2.3366(7), Ru1-P2 2.3193(8),
H2···N3 2.811(3), O1···H4 2.846(3); P1-Ru1-P2 98.20(3), N2-H2···N3
135.35(3), O1···H4-N4 147.50(3).
The scope of the anti-Markovnikov hydration of various 1- Experimental Section
Representative procedure: Freshly prepared 5 (21 mg, 2 mol%) was
alkynes was examined with 5 as the catalyst (Table 3).
Reactions using 2–10 mol% of 5 gave the desired aldehydes
in good yields. Linear terminal alkynes furnished the corre-
sponding carbonyl products with complete regioselectivity,
even if the catalyst seems to be partially inhibited by the
added to a solution of 1-nonyne (124 mg, 1.0 mmol) and water (90 mg,
5.0 mmol) in deoxygenated acetone (1.6 mL). The mixture was
heated under Ar for 26 h at 1208C in a sealed tube and the reaction
progress was monitored by GC. After cooling to room temperature,
the solvent was removed in vacuo and the residue was extracted with
diethyl ether. The solution was dried
(MgSO4), filtered through a plug of
Table 3: Regioselective hydration of functionalized terminal alkynes with 5 as the catalyst.
silica, and concentrated under reduced
pressure to furnish nonanal (126 mg,
89%) as a colorless oil.
Entry
Substrate
5[%]
t [h]
a/k [%][a]
Yield[%] [b]
1
2
3
4
2
2
10
10
26
26
96
78
>99:1
>99:1
>99:1
99:1[c]
89
73
78
82
Received: October 28, 2005
Published online: January 31, 2006
Keywords: alkynes · homogeneous
catalysis · hydrogen bonding ·
ruthenium · self-assembly
.
5
5
70
>99:1
87
6
5
72
99:1
65
[1] M. Beller, J. Seayad, A. Tillack, H.
Jiao, Angew. Chem. 2004, 116,
3448 – 3479; Angew. Chem. Int.
Ed. 2004, 43, 3368 – 3398.
7
8
5
5
48
50
99:1
83
74
87:13
[2] a) Y. Fukuda, K. Utimoto, J. Org.
Chem. 1991, 56, 3729 – 3731; b) J.
Blum, H. Huminer, H. Alper, J.
Mol. Catal. 1992, 75, 153 – 160;
c) J. W. Hartman, W. C. Hiscox,
P. W. Jennings, J. Org. Chem.
1993, 58, 7613 – 7614; d) W. Bai-
dossi, M. Lahav, J. Blum, J. Org.
Chem. 1997, 62, 669 – 672; e) T.
Tsuchimoto, T. Joya, E. Shira-
9
5
28
96:4
91
10[d]
10
124
>99:1
61
[a] Determinedby GC analysis and 1H NMR spectroscopy. a=aldehyde, k=ketone. [b] Yieldof isolated
product. [c] Ratio of decane-1,10-dial/9-oxodecanal. [d] Reaction performed at 708C.
Angew. Chem. Int. Ed. 2006, 45, 1599 –1602
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1601

Communications
kawa, Y. Kawakami, Synlett 2000, 1777 – 1778; f) E. Mizushima,
M. Bonetti, L. Tonucci, A. Morvillo, M. Bressan, Eur. J. Inorg.
Chem. 2004, 810 – 817.
K. Sato, T. Hayashi, M. Tanaka, Angew. Chem. 2002, 114, 4745 –
4747; Angew. Chem. Int. Ed. 2002, 41, 4563 – 4565; g) R. Casado,
M. Contel, M. Laguna, P. Romero, S. Sanz, J. Am. Chem. Soc.
2003, 125, 11925 – 11935; h) A. Vasudevan, M. K. Verzal, Synlett
2004, 631 – 634.
[14] A first confirmation for this assumption was obtained from the
reaction of 6-DPPAP (1 equiv), 3-DPICon (1 equiv), and cis-
[PtCl2(cod)] (1 equiv; cod = cyclooctadiene) in toluene in the
presence of water to give cis-[PtCl2(6-DPPAP)(3-DPICon)-
(H2O)] quantitatively.
[3] a) M. Tokunaga, Y. Wakatsuki, Angew. Chem. 1998, 110, 3024 –
3027; Angew. Chem. Int. Ed. 1998, 37, 2867 – 2869; b) T. Suzuki,
M. Tokunaga, Y. Wakatsuki, Org. Lett. 2001, 3, 735 – 737; c) P.
Alvarez, M. Bassetti, J. Gimeno, G. Mancini, Tetrahedron Lett.
2001, 42, 8467 – 8470; d) M. Tokunaga, T. Suzuki, N. Koga, T.
Fukushima, A. Horiuchi, Y. Wakatsuki, J. Am. Chem. Soc. 2001,
123, 11917 – 11924; e) D. B. Grotjahn, C. D. Incarvito, A. L.
Rheingold, Angew. Chem. 2001, 113, 4002 – 4005; Angew. Chem.
Int. Ed. 2001, 40, 3884 – 3887; f) D. B. Grotjahn, D. A. Lev, J. Am.
Chem. Soc. 2004, 126, 12232 – 12233.
[4] B. Breit, Angew. Chem. 2005, 117, 6976 – 6986; Angew. Chem.
Int. Ed. 2005, 44, 6816 – 6825.
[5] B. Breit, W. Seiche, J. Am. Chem. Soc. 2003, 125, 6608 – 6609.
[6] B. Breit, W. Seiche, Angew. Chem. 2005, 117, 1666 – 1669;
Angew. Chem. Int. Ed. 2005, 44, 1640 – 1643.
[7] For alternative approaches to bidentate ligands through self-
assembly, see ref. [4] and: J. M. Takacs, D. S. Reddy, S. A.
Moteki, D. Wu, H. Palencia, J. Am. Chem. Soc. 2004, 126, 4494 –
4495; M. J. Wilkinson, P. W. N. M. van Leeuwen, J. N. H. Reek,
Org. Biomol. Chem. 2005, 3, 2371 – 2383; V. F. Slagt, M. Röder,
P. C. J. Kamer, P. W. N. M. van Leeuwen, J. N. H. Reek, J. Am.
Chem. Soc. 2004, 126, 4056 – 4057; V. F. Slagt, P. W. N. M.
van Leeuwen, J. N. H. Reek, Angew. Chem. 2003, 115, 5777 –
5781; Angew. Chem. Int. Ed. 2003, 42, 5619 – 5623; V. F. Slagt,
P. W. N. M. van Leeuwen, J. N. H. Reek, Chem. Commun. 2003,
2474 – 2475.
[8] For reviews of the general use of cationic CpRu complexes, see:
a) C. Slugovc, E. Ruba, R. Schmid, K. Kirchner, K. Mereiter,
Monatsh. Chem. 2000, 131, 1241 – 1251; b) B. M. Trost, F. D.
Toste, A. B. Pinkerton, Chem. Rev. 2001, 101, 2067 – 2096; an
efficient synthesis of [CpRu(CH3CN)3]PF6, see: B. M. Trost,
C. M. Older, Organometallics 2002, 21, 2544 – 2546.
[9] 31P NMR spectra of complex 5 was measured in CDCl3 and
[D6]acetone; in both cases, the AB-spin system, depicted in
Figure 1, was observed with identical chemical shifts and
coupling constants (the septet at d = À141.6 ppm (1J(P-F) =
707.7 Hz) belongs to the PF6 counterion).
[10] CCDC 289523 (5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[11] Crystal data for 5: C50H47F6N4O2P3Ru; Mr = 1043.90; T=
¯
100(2) K; l = 0.71073 Š; triclinic; space group P1, a =
11.1195(4), b = 13.0414(4), c = 18.2113(8) Š, a = 92.169(2), b =
106.9106(17), g = 97.314(2)8; V= 2498.32(16) Š3; Z = 2; Dc =
1.388 MgmÀ3
; ; F(000) = 1068; crystal size =
m = 0.474 mmÀ1
0.08 ” 0.08 ” 0.06 mm; q range for data collection: 1.58–27.528,
limiting indices: À14 ꢀ h ꢀ 14, À16 ꢀ k ꢀ 16, À23 ꢀ l ꢀ 23; 30814
reflections collected; 11483 reflections unique (Rint = 0.0509);
completeness to q = 25.008: 100.0%; absorption correction:
semiempirical from equivalents; max. and min. transmission:
0.975 and 0.937; refinement method: full-matrix least-squares on
F2; data/restraints/parameters: 11483/0/599; GOF on F2: 0.987;
final R indices: (I > 2s(I)): R1 = 0.0438, wR2 = 0.0964; R indices
(all data): R1 = 0.0718, wR2 = 0.1047; largest diff. peak and hole:
À3
0.533 and À0.585 eŠ
.
[12] a) J. D. Watson, F. H. C. Crick, Nature 1953, 171, 964 – 967;
b) M. D. Topal, J. R. Fresco, Nature 1976, 263, 285 – 289.
[13] a) B. M. Trost, R. C. Livingston, J. Am. Chem. Soc. 1995, 117,
9586 – 9587; b) T. Suzuki, M. Tokunaga, Y. Wakatsuki, Tetrahe-
dron Lett. 2002, 43, 7531 – 7533; c) N. dꢀAlessandro, M. Di Deo,
1602 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1599 –1602