Ruthenium Catalyzed Selective α- And α,β-Deuteration of Alcohols Using D2O

Article abstract of DOI:10.1021/acs.orglett.5b02254

Highly selective ruthenium catalyzed α-deuteration of primary alcohols and α,β-deuteration of secondary alcohols are achieved using deuterium oxide (D₂O) as a source of deuterium and reaction solvent. Minimal loading of catalyst (Ru-macho), base (KO^tBu), and low temperature heating provided efficient selective deuteration of alcohols making the process practically attractive and environmentally benign. Mechanistic studies indicate the D-O(D/R) bond activations by metal-ligand cooperation and intermediacy of carbonyl compounds resulting from dehydrogenation of alcohols.

Full text of DOI:10.1021/acs.orglett.5b02254

Letter
pubs.acs.org/OrgLett
Ruthenium Catalyzed Selective α- and α,β-Deuteration of Alcohols
Using D2O
Basujit Chatterjee and Chidambaram Gunanathan*
School of Chemical Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar-751 005, India
S
* Supporting Information
ABSTRACT: Highly selective ruthenium catalyzed α-deuteration of primary alcohols
and α,β-deuteration of secondary alcohols are achieved using deuterium oxide (D2O) as a
source of deuterium and reaction solvent. Minimal loading of catalyst (Ru-macho), base
(KOtBu), and low temperature heating provided efficient selective deuteration of
alcohols making the process practically attractive and environmentally benign.
Mechanistic studies indicate the D−O(D/R) bond activations by metal−ligand
cooperation and intermediacy of carbonyl compounds resulting from dehydrogenation
of alcohols.
ynthesis of deuterium labeled alcohols with a high
percentage of deuteration and selectivity is an important
pincer complex,3a which exhibited remarkable reactivity as a
result of metal−ligand cooperation.6 However, in general
ruthenium catalyzed deuteration of alcohols required high
temperature−refluxing deuterium oxide conditions (120−150
°C) and a higher loading of base (15 to 20 mol % relative to
substrate). Except for the Milstein system, all other ruthenium
catalyzed H/D exchange reactions also require a higher loading
of catalyst (1−20 mol %).5 The Ru-macho catalyst, which
exhibits amine−amide metal−ligand cooperation, is reported to
catalyze a wide range of organic transformations including
dehydrogenation of methanol under aqueous basic conditions.7
Inspired by these reports, we explored the H/D exchange of
alcohols using the Ru-macho catalyst. Herein, we report the facile
and highly efficient selective α-deuteration of primary alcohols,
and the selective α,β-deuteration of secondary alcohols catalyzed
by Ru-macho using deuterium oxide.
At the outset, deuteration of aryl methyl alcohols was tested.
When benzyl alcohol (0.5 mmol) was reacted with the Ru-
Macho catalyst (0.2 mol %) with KOtBu (0.5 mol %) in
deuterium oxide, a facile and highly selective α-deuteration is
observed at 60 °C. While 96% deuteration occurred at the α-
position to provide benzyl alcohol-d3 in only 3 h, no detectable
H/D exchange is observed with aryl protons.8 Under similar
experimental conditions catalyst 1 selectively deuterated the α-
CH2 protons of other benzyl alcohols such as 4-methylbenzyl
alcohol and piperonyl alcohol (Scheme 1). Other aryl methanols
and heteroaryl methanols required heating the reaction mixture
at 80 °C for a prolonged period. The percentage of deuterium
also largely depends on the substrate; the reaction conditions
may be further optimized for the individual alcohols to obtain
higher deuteration. Upon completion of the reaction, the α-
deuterated alcohols were easily separated from the reaction
mixture by extraction with dichloromethane.
S
transformation in organic synthesis, as deuterated pharmaceut-
icals and bioactive organic molecules play a vital role in the
metabolism of alcohols and enzymes, in addition to the regular
use as NMR solvents and also as reliable chemical probes.1 All the
deuterium atoms present in the commercially available or
synthesized chemicals are either directly or indirectly derived
from deuterium oxide. Selectively deuterated alcohols are
currently synthesized from elongated multistep procedures
using reductive reagents such as NaBD4, LiAlD4, and
SiDMe2Ph/F− from aldehyde or carbonyl derivatives of alcohols,
which result in enormous hazardous waste, and the cost of the
deuterated alcohols becomes prohibitively high.2 Thus, direct
synthesis of selectively deuterated alcohols from H/D exchange
reactions with cheap deuterium oxide is highly attractive.
Selective efficient deuteration and activation of CH bonds
under mild reaction conditions is a tantalizing task.3−5 Iridium3
and molybdenum4 based catalytic systems were reported, and
they required a higher loading of catalyst (5 mol %). While Ir-
catalyzed deuteration of alcohols required expensive benzene-d6
as a deuterium source (reaction solvent), a Mo-based catalyst is
effective for only benzylic protons of alcohols.4
Both homogeneous and heterogeneous ruthenium catalysts
received great attention for the H/D exchange reaction of
alcohols.5 Ru on carbon support is reported to catalyze selective
deuteration of the protons at the α-position of alcohols with the
catalyst loading of 20% of Ru (relative to the substrate) and
under the atmosphere of hydrogen.5d Ru and Os pincer
complexes catalyzed the selective deuteration of alcohols using
2-propanol-d8 as the deuterium source.5b Under microwave
irradiation, a Ru-based soluble catalyst provided selective
deuteration of alcohols with a 5% catalyst load.5e Exclusive
deuteration at the β-positions also occurred with 3 mol % of an in
situ generated Ru catalyst ligated by aminoalcohol.5f
Very recently, Milstein reported an interesting selective
deuteration of alcohols catalyzed by a bipyridine derived PNN
(6-di-tert-butylphosphinomethyl-2,2′-bipyridine) ruthenium
Received: August 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
deuteration of 1-butanol catalyzed by 1 in D2O is monitored
Scheme 1. Selective α-Deuteration of Aryl Methanols
Catalyzed by Ru-macho 1
a
using 1H NMR spectroscopy (Figure 1a). However, when
Figure 1. (a) 1H NMR monitoring of % D incorporation in α-position of
1-butanol (0.5 mmol) in D2O (0.4 mL). Integration of α-position is
done taking integration of δ-CH3-protons of 1-butanol as a standard. (b)
1H NMR monitoring of rate of proton loss of 2-propanol at 80 °C.
ethanol was subjected to the reaction, deuteration occurred
nonselectively; 87% and 86% deuteration were observed at the α-
and β-positions of ethanol, respectively (Table 1, entry 1).
Linear alcohols appended with aryl and heteroaryl ring systems
provided selectivity for α-deuteration in the range of 90−95%
(Table 1, entries 6−7), while 10−20% β-deuteration occurred as
observed similarly in other linear alcohols. Selective α-
deuteration alone was also observed for functionalized and
sterically hindered alcohols (Table 1, entries 8−10).
Further to expand the substrate scope, diols were tested in the
selective deuteration reaction catalyzed by Ru-macho catalyst 1.
Benzene-1,4-dimethanol and pyridine-2,6-dimethanol were
reacted with 1 (0.2 mol %) and KOtBu (0.5 mol %) and D2O,
which delivered the corresponding (both α-positions)-deuter-
ated diols. No detectable deuterium incorporation among aryl
protons was observed (Figure 2). Surprisingly, when acyclic diols
a
Conditions: Alcohol (0.5 mmol), catalyst 1 (0.001 mmol), KOtBu
(0.0025 mmol), and D2O (0.4 mL, 20 mmol) were charged in a screw
cap NMR tube under a nitrogen atmosphere, and the reaction mixture
was heated at the indicated temperature. The percentage of deuterium
incorporation was monitored by integration of residual signals of H
NMR spectroscopy. Maximum possible % deuteration for these aryl
methanols is 96.4%.
1
Deuteration of linear aliphatic alcohols catalyzed by 1 is
investigated and the results are summarized in Table 1. In
a
Table 1. Selective α-Deuteration of Linear Alcohols
Figure 2. Selective α-deuteration of diols.
such as 1,4-butanediol and 1,6-hexanediol were subjected to
deuteration under standard conditions, deuteration occurred
selectively only at both α-positions to the hydroxyl functionality
(81%). No deuteration was observed at the β-positions of these
substrates (Figure 2).
Upon reaction with Ru-macho 1 under standard reaction
conditions, secondary alcohols underwent efficient deuteration
at both α- and β-positions, contrary to the α-selective deuteration
observed in primary alcohols. Perhaps the intermediate ketones
were more long-lived than aldehydes, resulting in the effective β-
deuteration by H/D exchange via keto−enol tautomerism and
the subsequent hydrogenation providing α,β-deuterated secon-
dary alcohols. 2-Propanol underwent 88% and 87% α,β
deuteration, respectively (maximum possible deuteration is
90.9%, Table 2, entry 1). The incorporation of deuterium in
the α,β-positions of 2-propanol was unambiguously demon-
strated by monitoring the progress of the H/D-exchange
a
b
Conditions: as indicated in the footnote of Scheme 1. 1,4-Dioxane
(0.05 mmol) is used as an internal standard.
general, aliphatic alcohols, Ru-macho 1 (0.2 mol %), and KOtBu
(0.5 mol %) in deuterium oxide are heated at 80 °C over the
period indicated. Linear alcohols such as 1-butanol, 1-hexanol, 1-
heptanol, and 1-octanol underwent facile deuteration predom-
inantly at the α-position (92 to 94%); however, among these
alcohols deuteration at the β-position of alcohols is also observed
in the range of 9−12% (Table 1, entries 2−5). Progress of the α-
B
DOI: 10.1021/acs.orglett.5b02254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2, entry 1). These observations indicate the comparable
reactivity of Ru−OH complex 4 compared to that of Ru-macho
catalyst 1 and its potential involvement in the reaction. In
principle, complex 4 does not require a base to catalyze the H/D
exchange reaction between alcohols and D2O. Thus, deuteration
of 2-propanol was carried out using 4 under neutral conditions.
As anticipated, the reaction proceeded in the absence of a base;
however only after 18 h similar % deuteration as that of basic
conditions was obtained (Scheme 4d). This observation
indicates that a base may promote the H/D exchange reactions
with a solvent and catalytic system in one or more steps.
Table 2. Selective α,β-Deuteration of Secondary Alcohols
Attempts were made to observe the intermediates, if any, from
alcohol dehydrogenation during the catalysis.12 When 2-
norbornanemethanol was reacted with H2O using catalyst 1
(0.2 mol %) and base (0.5 mol %) under open conditions,
formation of the corresponding aldehyde was observed in the
reaction mixture (Scheme 3).13 Since the reaction is performed
Scheme 3. Dehydrogenation of 2-Norbornanemethanol by 1
a
b
Conditions: as indicated in the footnote of Scheme 1. 1,4-Dioxane
(0.5 mmol) is used as an internal standard. Maximum possible %
deuteration of substrates is given in the parentheses.
reaction (Figure 1b). 1-Phenylethanol exhibited both α,β
deuteration at 94% (entry 2). While 2-hexanol showed
predominantly selective α-deuteration like linear alcohols,
diphenylmethanol provided 97% α-deuteration. Under the
standard experimental conditions, cyclic secondary alcohols
also afforded effective α,β-deuteration with excellent selectivity
and efficiency (Table 2, entries 5−7).
Stoichiometric reactions were performed to obtain mecha-
nistic insight. Upon reaction of complex 1 with water and base, a
Ru(II) complex 4 (31P NMR δ = 57.3 ppm) with a hydroxyl-
ligand is obtained (Scheme 2a).9 A similar reaction of 1 with
with a minimal amount of base using water as a solvent, potential
competing pathways such as subsequent dehydrogenation of
aldehyde to carboxylic acid14 or coupling with alcohol to provide
the corresponding self-coupled esters7d are minimized and the
formation of intermediate aldehyde in the reaction mixture was
observed (Scheme 3).
Although more evidence is required based on the above
observations, a possible catalytic cycle for the selective
deuteration of alcohols is postulated in Scheme 4. The reaction
Scheme 4. Proposed Catalytic Cycle
Scheme 2. Synthesis and Reactivities of Intermediates
benzyl alcohol provided benzyloxy-ligated complex 5; interest-
ingly, the presence of a benzaldehyde coordinated ruthenium
complex (9%) is also found in the reaction mixture.10 These
reactions involve a base promoted, in situ formed unobserved
amide-ligated unsaturated intermediate (6, Scheme 4), which
reacted with H2O and BnOH to provide 4 and 5, respectively, as
a result of O−H activation by metal−ligand cooperation.6,11
When isolated complex 4 (0.2 mol %) is used as a catalyst in
the presence of base using D2O, selective 96% α-deuteration of 1-
hexanol (Scheme 2b, along with 8% D at the β-position; see
Table 1, entry 3) and 87% and 86% α,β-deuteration of 2-
propanol occurred in 12 h and 9 h, respectively (Scheme 2c; see
of complex 1 with a base provided the unsaturated Ru(II)
intermediate 6, which reacts with D2O by “amine−amide”
metal−ligand cooperation6,10 and results in complex 4-d2 as
observed in the reaction of complex 1 with H2O (Scheme 2).
Under experimental conditions, 6 is in equilibrium with 4-d2 and
6-d by O−D activation or Ru−H/D exchange with D2O,
C
DOI: 10.1021/acs.orglett.5b02254
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Wang, Q.; Sheng, X.; Horner, J. H.; Newcomb, M. J. Am. Chem.
Soc. 2009, 131, 10629−10636. (b) Klomp, D.; Maschmeyer, T.;
Hanefeld, U.; Peters, J. A. Chem. - Eur. J. 2004, 10, 2088−2093. (c) Xu,
L.; Price, N. P. Carbohydr. Res. 2004, 339, 1173−1178. (d) Miyazaki, D.;
Nomura, K.; Ichihara, H.; Ohtsuka, Y.; Ikeno, T.; Yamada, T. New J.
Chem. 2003, 27, 1164−1166. (e) Jensen, D. R.; Schultz, M. J.; Mueller, J.
A.; Sigman, M. S. Angew. Chem., Int. Ed. 2003, 42, 3810−3813.
(f) Rasmussen, T.; Jensen, J. F.; Østergaard, N.; Tanner, D.; Ziegler, T.;
Norrby, P. Chem. - Eur. J. 2002, 8, 177−184. (g) Andersson, P. G. J. Org.
Chem. 1996, 61, 4154−4156. (h) Liguori, A.; Mascaro, P.; Sindona, G.;
Uccella, N. J. Labelled Compd. Radiopharm. 1990, 28, 1277−1283.
(i) Polavarapu, P. L.; Fontana, L. P.; Smith, H. E. J. Am. Chem. Soc. 1986,
108, 94−99.
(3) (a) Yung, C. M.; Skaddan, M. B.; Bergman, R. G. J. Am. Chem. Soc.
2004, 126, 13033−13043. (b) Nishioka, T.; Shibata, T.; Kinoshita, I.
Organometallics 2007, 26, 1126−1128. (c) Klei, S. R.; Golden, J. T.;
Tilley, T. D.; Bergman, R. G. J. Am. Chem. Soc. 2002, 124, 2092−2093.
(4) (a) Balzarek, C.; Weakley, T. J. R.; Tyler, D. R. J. Am. Chem. Soc.
2000, 122, 9427−9434. (b) Breno, K. L.; Tyler, D. R. Organometallics
2001, 20, 3864−3868.
respectively. Perhaps, base assisted H/D exchange or involve-
ment of a Ru(0) intermediate cannot be ruled out, which may
also play a crucial role in the deuterium scrambling. Complex 6-d
further reacts with alcohols (RCH2OD) to provide saturated
intermediate I (as observed in stoichiometric reaction, Scheme
2a). Further, β-hydride elimination of alkoxide ligand can result
in Ru-dihydride II. Base assisted Ru−H/D exchange of II with
solvent (D2O) provides II-d. Either by direct aldehyde insertion
into a Ru−D bond of II-d or by D2 liberation followed by
aldehyde coordination (III)/decoordination pathways, mono-
deuterated alkoxy-ligated intermediate I-d was generated.
Reductive elimination of alcohols from intermediate I-d can
provide alcohols with monodeuteration at the α-position,
regenerating 6-d to complete one cycle. Alternatively, I-d may
also undergo β-hydride elimination to result in II and the
subsequent transformations would result in I-d2 that can
reductively eliminate alcohols with complete deuteration at the
α-position of alcohols (RCD2OD).
In conclusion, Ru-macho catalyzed highly efficient selective
deuterations of assorted primary and secondary alcohols are
developed using deuterium oxide, the cheapest source of
deuterium. While primary alcohols underwent deuteration
predominantly at the α-position, the secondary alcohols were
deuterated at both α- and β-positions. The reaction proceeded by
O−D activation of deuterium oxide and alcohols by the Ru-
macho catalyst, and subsequently the alkoxide ligands were
dehydrogenated to the carbonyl compounds via amine−amide
metal−ligand cooperation. While the catalytic hydrogenation of
the carbonyl motif resulted in α-deuteration, β-deuteration
perhaps occurred via keto−enol tautomerization, which was
varied based on substrate and steric hindrance. High percentage
selective deuteration, mild experimental conditions, and the low
loading and commercial availability of the catalyst make the
process highly attractive for both laboratory and large-scale
preparation of useful deuterated alcohols.
(5) For Ru catalyzed reactions: (a) Khaskin, E.; Milstein, D. ACS Catal.
2013, 3, 448−452. (b) Bossi, G.; Putignano, E.; Rigo, P.; Baratta, W.
Dalton Trans. 2011, 40, 8986−8995 (D2O used as a deuterium source in
one entry). (c) Fujiwara, Y.; Iwata, H.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Chem. Commun. 2010, 46, 4977−4979. (d) Maegawa, T.; Fujiwara,
Y.; Inagaki, Y.; Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2008, 350,
2215−2218. (e) Takahashi, M.; Oshima, K.; Matsubara, S. Chem. Lett.
2005, 34, 192−193. (f) Tse, S. K. S.; Xue, P.; Lau, C. W. S.; Sung, H. H.
Y.; Williams, I. D.; Jia, G. Chem. - Eur. J. 2011, 17, 13918−13925.
(6) For reviews, see: (a) Gunanathan, C.; Milstein, D. Acc. Chem. Res.
2011, 44, 588−602. (b) Gunanathan, C.; Milstein, D. Top. Organomet.
Chem. 2011, 37, 55−84. (c) Gunanathan, C.; Milstein, D. Chem. Rev.
2014, 114, 12024−12087.
(7) (a) Kuriyama, W.; Matsumoto, T.; Ogata, O.; Ino, Y.; Aoki, K.;
Tanaka, S.; Ishida, K.; Kobayashi, T.; Sayo, N.; Saito, T. Org. Process Res.
Dev. 2012, 16, 166−171. (b) Nielsen, M.; Alberico, E.; Baumann, W.;
Drexler, H.-J.; Junge, H.; Gladiali, S.; Beller, M. Nature 2013, 495, 85−
89. (c) Otsuka, T.; Ishii, A.; Dub, P. A.; Ikariya, T. J. Am. Chem. Soc.
2013, 135, 9600−9603. (d) Oldenhuis, N. J.; Dong, V. M.; Guan, Z.
Tetrahedron 2014, 70, 4213−4218. (e) Oldenhuis, N. J.; Dong, V. M.;
Guan, Z. J. Am. Chem. Soc. 2014, 136, 12548−12551. (f) Monney, A.;
Barsch, E.; Sponholz, P.; Junge, H.; Ludwig, R.; Beller, M. Chem.
Commun. 2014, 50, 707−709.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02254.
(8) For ruthenium catalyzed H/D exchange with aromatic hydro-
carbons, see: (a) Prechtl, M. H. G.; Hoelscher, M.; Ben-David, Y.;
Theyssen, N.; Milstein, D.; Leitner, W. Eur. J. Inorg. Chem. 2008, 2008,
3493−3500. (b) Prechtl, M. H. G.; Hoelscher, M.; Ben-David, Y.;
Theyssen, N.; Loschen, R.; Milstein, D.; Leitner, W. Angew. Chem., Int.
Ed. 2007, 46, 2269−2272.
1
2
Experimental Procedures, H, H, 13C, and 31P NMR
spectra and characterization data of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(9) For other Ru(II) hydroxyl-ligated complexes, see: (a) Reference
5a. (b) Kohl, S. W.; Weiner, L.; Schwartsburd, L.; Konstantinovski, L.;
Shimon, L. J. W.; Ben-David, Y.; Iron, M. A.; Milstein, D. Science 2009,
324, 74−77.
■
*E-mail: gunanathan@niser.ac.in.
Notes
(10) See Supporting Information.
(11) Schneider, S.; Meiners, J.; Askevold, B. Eur. J. Inorg. Chem. 2012,
The authors declare no competing financial interest.
2012, 412−429.
(12) In situ monitoring of benzyl alcohol and 2-propanol deuteration
reactions catalyzed by complex 1 failed to predict involvement of any
carbonyl compounds.
ACKNOWLEDGMENTS
■
We thank SERB New Delhi (SR/S1/OC-16/2012 and SR/S2/
RJN-64/2010) and NISER for financial support. We are grateful
to Prof. Arindam Ghosh, NISER for his kind support. B.C. thanks
UGC for a research fellowship. C.G. is a Ramanujan Fellow.
(13) 1H and 13C NMR analyses of the reaction mixture indicated the
presence of unreacted 2-norbornanemethanol and the corresponding
ester in addition to the aldehyde.
(14) Balaraman, E.; Khaskin, E.; Leitus, G.; Milstein, D. Nat. Chem.
2013, 5, 122−125.
REFERENCES
■
(1) (a) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem.,
Int. Ed. 2007, 46, 7744−7765. (b) Synthesis and Application of
Isotopically Labeled Compounds; Pleiss, U., Voges, R., Eds.; Wiley: New
York, 2001; Vol. 7. (c) Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26,
401−406.
D
DOI: 10.1021/acs.orglett.5b02254
Org. Lett. XXXX, XXX, XXX−XXX