Broad-spectrum catalysts for the ambient temperature anti-Markovnikov hydration of alkynes

Article abstract of DOI:10.1002/anie.201404320

Anti-Markovnikov alkyne hydration provides a valuable route to aldehydes. Half-sandwich ruthenium complexes ligated by 5,5′-bis(trifluoromethyl)-2, 2′-bipyridine are remarkably active for this transformation. In the presence of 2 mol % metal, a wide range of functionalized aliphatic and aromatic alkynes are hydrated in high yield at ambient temperature. Alkyne hydration: Half-sandwich ruthenium complexes derived from 5,5′-bis(trifluoromethyl)- 2,2′-bipyridine show a high activity for the anti-Markovnikov hydration of terminal alkynes (see picture). A wide array of alkynes are efficiently hydrated to aldehydes using 2 mol % metal loadings at 25 °C within 8-24 h.

Full text of DOI:10.1002/anie.201404320

Angewandte
Chemie
DOI: 10.1002/anie.201404320
Homogeneous Catalysis
Hot Paper
Broad-Spectrum Catalysts for the Ambient Temperature Anti-
Markovnikov Hydration of Alkynes**
Le Li, Mingshuo Zeng, and Seth B. Herzon*
Abstract: Anti-Markovnikov alkyne hydration provides a val-
uable route to aldehydes. Half-sandwich ruthenium complexes
ligated by 5,5’-bis(trifluoromethyl)-2,2’-bipyridine are remark-
ably active for this transformation. In the presence of 2 mol%
metal, a wide range of functionalized aliphatic and aromatic
alkynes are hydrated in high yield at ambient temperature.
with the disclosure of 4, Grotjahn reported that cationic
complexes containing P, N-ligands, such as 5[6] and 6,[7]
displayed increased activity at lower temperatures (45–
708C) and broader scope. In a series of detailed mechanistic
studies, it was established that the dramatic rate enhance-
ments observed with 5 and 6 derive from the generation of
a hydrogen-bonding network that facilitates vinylidene for-
mation and nucleophilic addition.[8] Subsequently, Hinter-
mann and co-workers showed that mixed phosphine catalysts
such as 7 also displayed high hydration activity.[9] Breit and
Chevallier reported that the catalyst 8, which contains a self-
assembled diphosphine ligand, displayed good substrate
scope, but elevated temperatures were required to obtain
high yields (1208C).[10]
T
he discovery of highly active catalysts for the anti-
Markovnikov hydration of terminal alkynes (1!2,
Figure 1), a powerful transformation that provides an atom-
The catalysts 6 and 7 efficiently hydrate unhindered
aliphatic alkynes, but arylacetylenes and hindered aliphatic
alkynes require extended heating to obtain high conversion.
In addition, hydrations of propargylic alcohols and conju-
gated enynes are complicated by competitive rearrange-
ment[11] or elimination, and the elevated reaction temper-
atures and Lewis acidity of the catalysts promote aldol
addition reactions. We recently discovered[12] that a catalyst
derived from (h5-cyclopentadienyl) tris(acetonitrile)ruthe-
nium hexafluorophosphate (9) or (h5-cyclopentadienyl) (h6-
naphthalene)ruthenium hexafluorophosphate (10) and 2, 2’-
bipyridine (bipy, 11a) mediated the sequential hydration and
hydrogenation of aliphatic and aromatic alkynes (reductive
hydration), to provide linear alcohols, at 55–808C. The
discovery that the hydration step could be promoted by this
catalyst was surprising in light of the structures of 3–8, which
all contain phosphine-based ligands, and Grotjahnꢀs compre-
hensive mechanistic model, which established the multifunc-
tional role of the (2-heteroaryl)phosphine ligands in the most
active catalysts 5–7.[8] As many air-stable bipyridine ligands
are commercially available or readily prepared, further study
of our catalyst system seemed warranted. Herein we report
that complexes formed in situ from 9 or 10 and 5,5’-bis(tri-
fluoromethyl)-2,2’-bipyridine (11n) are remarkably active for
anti-Markovnikov alkyne hydration. A broad range of
aliphatic and aromatic alkynes are hydrated within 8–24 h at
258C and at 2 mol% metal loadings. The rate of hydration of
aromatic alkynes is faster than aliphatic alkynes, which is in
contrast to the trend observed with earlier catalysts. The
catalyst can be employed at less than 1 mol% metal loadings
on preparative scales, and an air-stable, single-component
precursor (12) has been developed.
Figure 1. Prior catalysts for anti-Markovnikov alkyne hydration and the
catalyst precursors and ligand employed herein.
economical[1] and redox-neutral entry to aldehydes, is
reported.[2] These reactions proceed by the addition of
water to metal vinylidene intermediates.[3] The first catalysts
developed for this reaction, discovered by Wakatsuki and
Tokunaga, consisted of h6-arene[4] or h5-cyclopentadienyl[5]
complexes of ruthenium ligated by electron-deficient mono-
or bidentate phosphine ligands (see 3 and 4). These com-
plexes required elevated temperatures and up to 10% metal
loadings to obtain useful reaction rates. Contemporaneous
[*] Dr. L. Li, M. Zeng, Dr. S. B. Herzon
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-8107 (USA)
E-mail: seth.herzon@yale.du
[**] Financial support from the David and Lucile Packard Foundation is
gratefully acknowledged. We thank Dr. Brandon Mercado for X-ray
analysis of 12.
To assess the influence of ligand substituents on hydration
activity, we evaluated catalysts formed in situ from 9 and
a wide array of bidentate nitrogen ligands based on the bipy
structure, using (2-fluorophenyl)acetylene (1a) as substrate at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404320.
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Table 1: Evaluation of bidentate nitrogen ligands in the hydration of 1a.[a]
Information). In the presence of 2 mol% each of 9 and 11n,
the yields of product 2a were 93%, 97%, and 94% in NMP,
DMF, and DMA, respectively, after 6 h at 258C. The initial
rates were also faster (72%, 64%, and 68% yield of 2a after
3 h for NMP, DMF, and DMA, respectively). The yields of
product correlated with the solvent dielectric constant,[13] and
may reflect an increase in the rate of vinylidene formation.[14]
A wide array of alkynes undergo hydration at ambient
temperature using the combination of 9 and 11n in aqueous
NMP (Table 2). With the exception of 2n, the yields of each
product obtained by NMR spectroscopy and after purification
(number in parentheses) are reported. High yields were
obtained within 24 h using 2 mol% catalyst, and most
arylacetylene substrates proceeded to full conversion within
8 h. Ortho-, meta-, and para-substituted arylacetylenes, which
require elevated temperatures with existing catalysts, are
efficiently converted to product at ambient temperature (2a–
2j, 80–91%). In addition, the unsubstituted aliphatic alkynes
2k, 2l, and 2m also gave high yields of product (81–95%)
after 24 h. tert-Butylacetylene, which is a particularly chal-
lenging substrate for the hydration reaction,[5a] provided
a 73% yield of 3,3-dimethylbutanal (2n) after 48 h (90%
yield after 72 h). A range of functional groups are compatible
with this catalyst, including alkyl chlorides (2o), imides (2p),
alcohols (2q), amines (2r), ketones (2s), esters (2t), amides
(2u, 2z), and carboxylic acids (2v, 82–98%). Aldehydes
derived from enynes (2w–2aa), including a conjugated enyne
(2aa), could be effectively prepared using this catalyst (80–
96%). Complexes related to 5 and 6 are remarkably active
catalysts for the isomerization of terminal alkenes[15] whereas
isomerization of the terminal alkene in 2w is not observed
using the catalyst derived from 9 and 11n. In addition, the dial
2ab is formed in 87% yield from the corresponding diyne. It is
also noteworthy that b-amino or b-hydroxy aldehydes could
be prepared with this catalyst (2ac–2af, 76–96%). Unsatu-
rated aldehydes, which are major side products formed in
reactions employing 6 and 7,[16] were produced in only minor
amounts (4% for 2ae and 15% for 2af).
[a] All reactions were conducted on a 500 mmol scale. Yields in
parentheses are after 24 h at 258C. Yields were determined by 1H NMR
analysis using mesitylene as an internal standard.
508C (Table 1). These experiments revealed a broad range of
activities. Ligands with sterically demanding substituents near
the nitrogen atoms, such as 11h and 11s, were inactive (ꢀ 1%
yield). This may be due to inefficient coordination of the
substrate to the ruthenium center. Electron-rich ligands such
as 11g and 11j also displayed poor activity (33% and 23% for
11g and 11j, respectively, versus 44% for bipy, 11a).
Electron-deficient ligands displayed good to excellent activ-
ity, with the bromo-, fluoro- carboxy-, carbomethoxy-, and
trifluoromethyl-substituted ligands 11d, 11u, 11 f, 11l, 11m,
11n, and 11o all providing good to excellent yields of 2a (80–
97% yield). These latter ligands were further evaluated at
258C (yield in parentheses). This second set of experiments
revealed complexes derived from 5,5’-bis(trifluoromethyl)-
2,2’-bipyridine (11n) as the most active at 258C. Using
2 mol% of 9 and 11n, an 80% yield of (2-fluorophenyl)ace-
taldehyde (2b) was obtained after 24 h at 258C.
To increase the practical utility of this chemistry, we
developed an air-stable, single component catalyst for this
transformation [Eq. (1)].
Stirring an equimolar mixture of 10, 11n, and benzyltriethy-
lammonium chloride in acetone at 258C formed the ruthe-
nium complex 12 in 86% yield. The complex 12 was isolated
by precipitation of benzyltriethylammonium hexafluorophos-
phate, followed by concentration of the mother liquor and
washing of the solid residue obtained (hexanes) to remove
naphthalene. Notably, all of these manipulations were con-
ducted on the benchtop under air, using reagent-grade (non-
deoxygenated) solvents. As shown below, the catalyst 12 also
Additional experiments revealed a useful rate enhance-
ment when tetrahydrofuran was replaced with N,N-dimethyl-
formamide (DMF), N,N-dimethylacetamide (DMA), or N-
methyl-2-pyrolidinone (NMP, see Table S1 in the Supporting
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Table 2: Substrate scope of the hydration reaction.[a]
displays high activity in the hydration reaction and constitutes
a useful, air-stable precursor for this transformation.
The hydrations of (2-fluorophenyl)acetylene (1a) and 4-
fluoro-dec-1-yne (1ag) were monitored continuously by
19F NMR spectroscopy using the catalyst derived from 9 and
11n, 6, and 12 at 258C (Figure 2). In all cases 2 mol% of the
metal precursor and ligand were employed. Using 9 and 11n,
Product
t [h] Yield[b] Product
t [h] Yield[b]
86%
91%
24
8
(82%)
(87%)
80%
(76%)
88%[c,d]
24
8
(82%)
83%
(77%)
96%
24
8
(90%)
83%
(77%)
98%
24
8
(91%)
88%
(82%)
82%[c]
24
8
(77%)
91%
(85%)
93%
24
8
(84%)
88%
(82%)
85%[c]
24
8
Figure 2. Comparison of the hydration activity of 9+11n, 6, and 12.
Conditions: 1a or 1ag (300 mmol), 9+11n (6 mmol each), H2O-NMP
(1:4 v/v, 0.2m), 258C; 1a or 1ag (300 mmol), 6 (6 mmol), H2O–acetone
(1:4 v/v, 0.4m), 258C; 1a (300 mmol), 12 (6 mmol), H2O–NMP (1:4 v/
v, 0.2m), 258C. [a] Employing catalyst that had been aged for one week
under air at 258C.
(80%)
87%
(81%)
80%[c,e]
24
8
(75%)
87%
24
82%
24
(80%)
(76%)
the hydration of 1a proceeded in > 99% yield after 7.6 h, and
the hydration of 1a employing 12 proceeded to 82% yield
after 10 h. The activity of 12 was unchanged after storing
under air for one week at 258C. By comparison, using catalyst
6 (in 4:1 acetone–water),[17] the hydration of 1a proceeded to
only 6% yield after 13 h. In the aliphatic series, the hydration
of 1ag proceeded to 88% yield after 13 h using 9 and 11n,
while the same reaction proceeded to 40% yield after 13 h
using 6. The hydration of 1ag using 12 proceeded to only 50%
yield after 13 h, indicating a lower reactivity of this preformed
catalyst toward aliphatic alkynes.
Finally, we conducted the hydration of phenylacetylene
(1b) using 0.8 mol% of the air-stable precursor 10 and
0.8 mol% of the ligand 11n on a 10.6 mmol scale [Eq. (2)].
Employing 10 requires preheating of the ligand and the
ruthenium precursor (608C, 3 h). In this experiment, an 84%
yield of 2b was obtained after 48 h at 258C.
89%
(84%)
96%[c]
24
8
(86%)
95%
24
82%
24
(90%)
(76%)
81%
24
87%[c]
24
(77%)
(81%)
94%
24
96%[c]
24
(90%)
(87%)
48
72
73%
90%
87%[c]
24
(81%)
93%
(86%)
92%[c]
24
24
(80%)
96%
(92%)
76%[c,e,f]
(70%)
24
24
[a] 500 mmol scale, H2O–NMP (1:4 v/v). [b] NMR yield obtained using
mesitylene as an internal standard. Isolated yield after purification by
flash-column chromatography in parentheses. [c] Reactions conducted
on a 250 mmol scale with 4.5 mol% catalyst. [d] 1 equiv PTSA was used.
[e] Reactions were conducted in 0.4m aqueous NMP. [f] 11a was used
instead of 11n; 1.5 equiv acetic acid, with respect to 2af, was employed.
In summary, we have described a comprehensive evalua-
tion of the activities of catalysts derived from the (h5-
cyclopentadienyl)ruthenium fragment and bidentate nitro-
gen-based ligands for anti-Markovnikov alkyne hydration.
These studies led to the identification of the electron-
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initially, grading to 50% ethyl acetate–hexanes, two steps) to afford
phenylacetaldehyde (2b) as a yellow oil (1.07 g, 84%).
deficient bipyridine ligand 11n as most effective. A broad
array of aliphatic and aromatic alkynes are hydrated at 258C
using 2 mol% of the ruthenium precursor 9 and ligand 11n.
For many substrates, the hydration is complete within 8 h. The
rate of hydration of aromatic alkynes is faster than aliphatic
alkynes using 9 and 11n, which is opposite to the trend
observed with earlier hydration catalysts. A single-compo-
nent, air-stable catalyst precursor (12) has been developed,
although the activity of this catalyst toward aliphatic sub-
strates is lower than 9 + 11n. Finally, the reaction may be
conducted on preparative scales with low (0.8 mol%) catalyst
loadings. These catalysts display the highest efficiencies and
broadest scope of any reported to date, and the mild, practical
conditions of the transformation should promote application
of this chemistry.[18]
Received: April 14, 2014
Published online: && &&, &&&&
Keywords: alkynes · bipyridines · homogeneous catalysis ·
.
hydration · ruthenium
[1] B. M. Trost, Science 1991, 254, 1471.
[2] For reviews of metal-catalyzed addition of oxygen-based nucle-
ophiles to alkenes and alkynes, see: a) M. Beller, J. Seayad, A.
Tillack, H. Jiao, Angew. Chem. 2004, 116, 3448; Angew. Chem.
Int. Ed. 2004, 43, 3368; b) L. Hintermann, A. Labonne, Synthesis
2007, 1121; c) L. Hintermann, Top. Organomet. Chem. 2010, 31,
123.
[3] a) C. Bruneau, P. H. Dixneuf, Acc. Chem. Res. 1999, 32, 311;
b) C. Fischmeister, C. Bruneau, P. H. Dixneuf in Ruthenium in
Organic Synthesis Wiley-VCH, Weinheim, 2004, p. 189; c) B. M.
Trost, M. U. Frederiksen, M. T. Rudd, Angew. Chem. 2005, 117,
6788; Angew. Chem. Int. Ed. 2005, 44, 6630.
[4] M. Tokunaga, Y. Wakatsuki, Angew. Chem. 1998, 110, 3024;
Angew. Chem. Int. Ed. 1998, 37, 2867.
[5] a) T. Suzuki, M. Tokunaga, Y. Wakatsuki, Org. Lett. 2001, 3, 735;
b) M. Tokunaga, T. Suzuki, N. Koga, T. Fukushima, A. Horiuchi,
Y. Wakatsuki, J. Am. Chem. Soc. 2001, 123, 11917.
[6] D. B. Grotjahn, C. D. Incarvito, A. L. Rheingold, Angew. Chem.
2001, 113, 4002; Angew. Chem. Int. Ed. 2001, 40, 3884.
[7] D. B. Grotjahn, D. A. Lev, J. Am. Chem. Soc. 2004, 126, 12232.
[8] a) D. B. Grotjahn, V. Miranda-Soto, E. J. Kragulj, D. A. Lev, G.
Erdogan, X. Zeng, A. L. Cooksy, J. Am. Chem. Soc. 2008, 130,
20; b) D. B. Grotjahn, E. J. Kragulj, C. D. Zeinalipour-Yazdi,
V. n. Miranda-Soto, D. A. Lev, A. L. Cooksy, J. Am. Chem. Soc.
2008, 130, 10860; For a review, see: c) D. B. Grotjahn, Pure Appl.
Chem. 2010, 82, 635.
[9] a) A. L. Labonne, T. Kribber, L. Hintermann, Org. Lett. 2006, 8,
5853; b) L. Hintermann, T. T. Dang, A. Labonne, T. Kribber, L.
Xiao, P. Naumov, Chem. Eur. J. 2009, 15, 7167; c) F. Boeck, T.
Kribber, L. Xiao, L. Hintermann, J. Am. Chem. Soc. 2011, 133,
8138.
Experimental Section
Representative procedure for the hydration of 1a employing 9 and
11n: In a nitrogen-filled drybox, a 4 mL vial was charged sequentially
with 5,5’-bis(trifluoromethyl)-2,2’-bipyridine (11n, 2.9 mg, 10 mmol,
0.020 equiv), tris(acetonitrile) (h5-cyclopentadienyl)ruthenium hexa-
fluorophosphate (9, 4.4 mg, 10 mmol, 0.020 equiv), a mixture of water-
N-methyl-2-pyrrolidinone (1:4 v/v, 2.5 mL, deoxygenated by sparging
with nitrogen for 30 min), and (2-fluorophenyl)acetylene (1a,
60.0 mg, 500 mmol, 1 equiv). The vial was sealed with a Teflon-lined
cap and the sealed vial was removed from the drybox. The mixture
was stirred for 8 h at 258C. The product mixture was transferred to
a separatory funnel and diluted with ethyl acetate (20 mL). The
organic layer was washed with brine (3 ꢁ 20 mL). Mesitylene (40.0 mL,
288 mmol) was added to the washed organic layer, and an aliquot of
this mixture (1 mL) was removed and diluted with chloroform-d
(2.0 mL). The diluted mixture was transferred to an NMR tube and
analyzed by 1H NMR spectroscopy, which indicated an 86% yield of
2a. To obtain an isolated yield, the NMR sample was combined with
the remaining ethyl acetate layer and the combined solution was
concentrated. The residue obtained was purified by flash-column
chromatography (eluting with 1% ethyl acetate–hexanes initially,
grading to 2% ethyl acetate-hexanes, one step) to provide (2-
fluorophenyl)acetaldehyde (2a) as a clear, colorless oil (56.6 mg,
82%).
[10] F. Chevallier, B. Breit, Angew. Chem. 2006, 118, 1629; Angew.
Chem. Int. Ed. 2006, 45, 1599.
Representative procedure for the hydration of 1b employing 10
and 11n: A 100 mL round-bottomed flask fused to a Teflon-coated
valve was charged sequentially with (h5-cyclopentadienyl) (h6-naph-
thalene)ruthenium hexafluorophosphate (10, 37.3 mg, 84.8 mmol,
0.008 equiv), 5,5’-bis(trifluoromethyl)-2,2’-bipyridine (11n, 24.8 mg,
84.8 mmol, 0.008 equiv), and a Teflon-coated stirbar. The headspace in
the reaction vessel was purged with nitrogen for 15 min. N-Methyl-2-
pyrrolidone (42 mL, deoxygenated by sparging with nitrogen for
30 min) and water (11 mL, deoxygenated by sparging with nitrogen
for 30 min) were then added in sequence to the flask via syringe. The
Teflon-coated valve was sealed, and the solution was stirred and
heated for 3 h at 608C. The dark purple mixture that formed was
cooled to 258C. Phenylacetylene (1b, 1.20 mL, 10.6 mmol, 1.00 equiv)
was added via syringe, and the resulting mixture was stirred for 48 h at
258C. The product mixture was poured into a separatory funnel and
diluted with saturated aqueous sodium chloride solution (100 mL).
The diluted solution was extracted with ethyl acetate (3 ꢁ 50 mL). The
organic layers were combined and the combined organic layer was
dried over sodium sulfate. The dried solution was filtered and the
filtrate was concentrated. The residue obtained was purified by flash-
column chromatography (eluting with 30% ethyl acetate–hexanes
[11] S. Swaminathan, K. V. Narayanan, Chem. Rev. 1971, 71, 429.
[12] L. Li, S. B. Herzon, Nat. Chem. 2014, 6, 22.
[13] J. A. Kerr in CRC Handbook of Chemistry and Physics, 79edth
ed(Ed.: D. R. Lide), CRC, New York, 1998, p. 8.120.
[14] a) R. M. Bullock, J. Chem. Soc. Chem. Commun. 1989, 165;
b) M. Jimꢂnez-Tenorio, M. C. Puerta, P. Valerga, M. A. OrtuÇo,
G. Ujaque, A. Lledꢃs, Inorg. Chem. 2013, 52, 8919.
[15] D. B. Grotjahn, C. R. Larsen, J. L. Gustafson, R. Nair, A.
Sharma, J. Am. Chem. Soc. 2007, 129, 9592.
[16] L. Hintermann, T. Kribber, A. Labonne, E. Paciok, Synlett 2009,
2412.
[17] The catalyst 6 is inactive in aqueous NMP. A 4:1 ratio of
acetone:water was employed to emulate the concentrations of
water in experiments employing 9 + 11a and 12. An excess of
water has been shown to increase the rate of hydration by
catalysts related to 6, see Ref. [9c].
[18] The ligand 11n and the complex 12 will soon be commercially-
available from Aldrich (catalog numbers L512346 and 794120,
respectively).
4
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Homogeneous Catalysis
L. Li, M. Zeng,
S. B. Herzon*
&&&& — &&&&
Broad-Spectrum Catalysts for the
Ambient Temperature Anti-Markovnikov
Hydration of Alkynes
Alkyne hydration: Half-sandwich ruthe-
nium complexes derived from 5,5’-bis(-
trifluoromethyl)-2,2’-bipyridine show
a high activity for the anti-Markovnikov
hydration of terminal alkynes (see pic-
ture). A wide array of alkynes are effi-
ciently hydrated to aldehydes using
2 mol% metal loadings at 258C within 8–
24 h.
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