Catalytic Generation and Chemoselective Transfer of Nucleophilic Hydrides from Dihydrogen

Article abstract of DOI:10.1002/chem.201805530

Copper(I)–N-heterocyclic-carbene (NHC) complexes enabled the catalytic generation of nucleophilic hydrides from dihydrogen (H₂) and their subsequent transfer to allylic chlorides. The highly chemoselective catalyst displayed no concomitant hydrogenation reactivity; in fact, the terminal double bond formed in the hydride transfer remained intact. Switching to deuterium gas (D₂) allowed for regioselective monodeuteration with excellent isotope incorporation.

Full text of DOI:10.1002/chem.201805530

A Journal of
Accepted Article
Title: Catalytic Generation and Chemoselective Transfer of
Nucleophilic Hydrides from Dihydrogen
Authors: Felix Pape, Lea Brechmann, and Johannes F. Teichert
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Catalytic Generation and Chemoselective Transfer of
Nucleophilic Hydrides from Dihydrogen
Felix Pape, Lea T. Brechmann, and Johannes F. Teichert*
Abstract: Copper(I)/N-heterocyclic carbene (NHC) complexes
enable the catalytic generation of nucleophilic hydrides from
dihydrogen (H2) and their subsequent transfer to allylic chlorides.
The highly chemoselective catalyst displays no concomitant
hydrogenation reactivity, as the terminal double bond formed in the
hydride transfer remains intact. Switching to deuterium gas (D2)
allows for regioselective monodeuteration with excellent isotope
incorporation.
The catalytic generation of nucleophilic hydrides from
dihydrogen (H2) would offer an atom economic[1] replacement of
commonly used complex hydrides such as aluminum- and
borohydrides or hydrosilanes, which are all producing
a
stoichiometric amount of undesired waste.[2] In order to offer a
fully catalytic alternative based on dihydrogen, both the H2
activation as well as an (ideally) chemoselective downstream
hydride transfer must be rendered feasible by the catalyst.
Scheme 1. Activation of H2, alkene hydrogenation vs. hydride transfer (TM =
transition metal, Hal = halogen leaving group).
Many transition metal complexes are excellent catalysts for H2
activation, but their tendency for catalytic hydrogenation (for
example of alkenes) prevails (Scheme 1a).[3] Nucleophilic
displacement of leaving groups such as alkyl halides by hydrides
generated from H2 is mostly an unwanted side-reaction that can
be suppressed in some cases.[4] On the other hand,
heterogeneous catalysts (with Pd/C being the prime example)
generate nucleophilic hydrides from H2, (as witnessed in
hydrodehalogenations[5] or cleavage of benzyl ethers[6]).
However, also with these catalysts, hydrogenation of alkenes is
the prime reaction pathway, hampering a potential hydride
transfer in the presence of alkenes (Scheme 1b). In order to
cinnamyl chloride (2) as optimal substrates (Scheme 2).[13,14] We
found that copper(I) halide complexes based upon electron-rich
NHC ligands such as 1[15] gave the best results in terms of SN2’
vs. SN2 regioselectivity (3/4), in combination with sodium tert-
butoxide to generate the key Cu–O-bond for H2 activation.[8]
Employment of strongly donating ligands also suppressed
undesired dechlorinated dimers (5).[16,17] To this end, Z-cinnamyl
chloride (Z-2) was fully converted with high preference for the
SN2’ product 3. Notably, no hydrogenation to propylbenzene was
observed, underscoring the chemoselectivity of the copper(I)
catalyst. We found that the configuration of the allylic double
bond has a profound influence on the regioselectivity, as E-
configured allylic chloride E-2 delivered a nearly 1:1 mixture of
the regioisomers 3 and 4. Our current hypothesis is that the
different double bond configurations lead to a switch in the
mechanism.[13,18]
effect
a chemoselective hydride generation from H2 and
subsequent transfer to an electrophile, a catalyst allowing for H2
activation that does not display hydrogenative reactivity towards
alkenes, which are common functional groups in synthetic
building blocks, is required. To the best of our knowledge, in
homogeneous catalysis, no such catalyst has been disclosed.[7]
We herein report a copper(I)/NHC complex which realizes a
catalytic hydride transfer from H2 to allylic chlorides without
effecting a catalytic alkene hydrogenation, leaving the terminal
double bond thus generated intact (Scheme 1, bottom). Our
strategy relies on heterolytic cleavage of the H–H bond by an in
situ generated Cu–O bond.[8] The use of NHC ligands is key to
suppress reactivity towards alkenes.[9–11] We chose allylic
halides as highly reactive and therefore challenging model
substrates to probe the chemoselectivity of the catalyst.[7,12]
Initial optimization of the hydride generation and subsequent
hydride transfer employing H2 identified allylic chlorides such as
Scheme 2. Hydride/deuteride transfer to cinnamyl chloride (2). Conversion
and /α ratios determined by GC analysis.
[*]
[+]
Dr. F. Pape,+ L. T. Brechmann,+ Jun.-Prof. Dr. J. F. Teichert
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: johannes.teichert@chem.tu-berlin.de
Homepage: http://www.susorg.tu-berlin.de
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
While these results showed the feasibility of using H2 as a
hydride source in a catalytic hydride transfer reaction, one
additional advantage of the current approach is that upon
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switching to deuterium gas (D2), selective monodeuteration in
the allylic position could be achieved, which leads to valuable
with hydride formation through a heterolytic H–H bond cleavage
by the intermediately formed Cu–O-bond[8,13] followed by copper-
catalyzed hydride transfer is assumed.
deuterated products. Selective isotope labeling is
a key
technology for drug discovery[19] as well as the elucidation of
reaction mechanisms[20] or biosynthetic pathways.[21] In this vein,
Generally, alkyl substituted allylic chlorides 9a-l gave excellent
results in terms of regioselectivity with slightly elevated reaction
temperature (40 °C, Scheme 4). A benzyl as well as a silyl ether
(10b, 10c) and a tosylate (10d, as potential additional leaving
group) remained intact. The former is of particular note with
respect to chemoselectivity, as many transition metal catalysts
are known to cleave benzyl ethers under hydrogenative
conditions.[6] Similarly good results were obtained with aryl
chloride 10e and aryl bromide 10f, for which no or little
deuterodehalogenation (7% for 10f) were observed. In the
context of more complex molecular architectures, estrone and
pregnenolone derivatives 9i and 9j could be monodeuterated.
Whereas the methoxy-substituent of 9i seems to interfere with
the regioselectivity of the catalyst (/α = 46:54) most probably
through coordination, 10j could be obtained with excellent
regioselectivity and good yield (76%, /α >95:5). The deuteride
transfer from D2 can also be applied to the corresponding higher
substituted allylic chlorides 9k and 9l, indicating little steric
interference with the catalyst. Finally, catalytic monodeuteration
of farnesyl chloride (9l)[26] giving the corresponding terminal
alkene 10l displays the potential applicability of the present
process for the selective labelling of biologically relevant
terpenoid molecules.
we could show that
a catalytic method for regio- and
chemoselective monodeuteration employing D2 is viable
(Scheme 2). When cinnamyl chloride (Z-2) was subjected to the
allylic reduction conditions with D2, we found that the conversion
dropped to 68% (indicating a kinetic isotope effect) with
improved regioselectivity (3-d1/4-d1 = 95:4), and excellent isotope
incorporation (>95% D of 3-d1).[22]
For the ensuing investigation of the substrate scope with D2 at
90 bar pressure,[17] the reaction time was set at 48 h to ensure
full conversion of the starting materials. Notably, in all cases, the
deuterium incorporation in the  position of the terminal alkenes
was excellent (≥96% D) and no alkene hydrogenation was
observed, highlighting the chemoselectivity of the catalyst
employed. Aryl substituted allylic chlorides 6a-f generally
showed high reactivity, and consequently,
a
reaction
temperature of 10 °C was maintained for this substrate class
(Scheme 3). Biphenyl and napththyl substituted monodeuterated
terminal alkenes 7a and 7c were obtained in good yields (72%
and 69%, respectively) and with very good regioselectivity of
91:9, favoring the  products 7.[23] This method was also
amenable to higher substituted allylic chlorides 6d-6f.[24] Of
particular note is the catalytic deuteride transfer to diaryl allylic
chloride 6e. As electrophiles with two aryl groups are rarely
viable substrates for transition metal-catalyzed allylic
substitutions,[25] the isolation of diphenylpropene 7e with a
respectable regioselectivity of 75:25 favoring the  substitution
product marks a strong point of the catalyst.
Scheme 3. Chemoselective deuteride transfer to aryl allylic chlorides. /α
ratios determined by 1H NMR or GC analysis. D incorporation determined by
quant. 1H NMR or by mass spectrometry. [a] 9% D incorporation in the α
position. [b] 8 mol% 1 were used. [c] Reaction was run with 10 mol% 1 and 2.4
equiv NaOtBu. [d] 5% D incorporation in the α position. [e] Reaction was run at
40 °C. [f] Product is volatile.
The formation of cyclopropane derivative 7f with a good 90:10
regioselectivity (/α) delivers an important indication that the
catalytic hydride transfer does not involve a carbon based
radical intermediate. Therefore, at this stage, a polar mechanism
Scheme 4. Chemoselective deuteride transfer to alkyl allylic chlorides. /α
ratios determined by 1H NMR or GC analysis. D incorporation determined by
quant. 1H NMR or by mass spectrometry. [a] 7% Deuterodehalogenation
detected. [b] The product was obtained as a mixture of tert-butyl and methyl
ester (5:1). [c] 10 mol% 1 were used.
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To further demonstrate mechanistic dichotomy of selective
single hydride (deuteride) transfer from H2 (or D2) and “classic”
hydrogenations, in which two hydrogen atoms are transferred
from H2, a combination of both processes each relying on
copper(I)/NHC complexes was carried out (Scheme 5). First, a
reductive functionalizations with copper hydride intermediates
resting on hydrosilanes,[30] this is an important improvement for
reduced waste generation.
copper(I)-catalyzed
alkyne
semihydrogenation
with
imidazolinium salt 15 as ligand precursor was carried
out,[10a,10c,27] yielding a dideuterated Z-allyl silyl ether (not shown)
from propargylic silyl ether 12. After subsequent transformation
to allylic chloride Z-13-d2, the catalytic hydride (deuteride)
transfer process gave dideuterated 14-d2 (from the allylic
substitution of Z-13-d2 with H2) as well as trideuterated 14-d3
(both catalytic processes using D2) with excellent isotope
incorporations. Therefore, a combination of hydrogenation and
hydride/deuteride transfer process each relying on H2/D2 can be
used to selectively generate H/D labeling patterns.
Scheme 6. D2-mediated reductive C–C bond formation.
In summary, we have developed a chemo- and regioselective
hydride transfer to allylic chlorides using H2 as seldomly used
and atom economic source of nucleophilic hydrides. This
approach allows for the possible replacement of commonly used
waste-generating hydride donors based on Al,
B or Si
compounds. Even though a transition metal is employed for the
activation of H2, the choice of catalyst resting on NHC ligands
completely suppresses alkene hydrogenation, leading to a
chemoselective overall hydride transfer. The fact that H2 can
easily be switched to D2 allows for a selective catalytic
monodeuteration protocol which delivers useful labelled
compounds with potential application in drug analytics and
elucidation of (bio)-synthetic reaction mechanisms.
Acknowledgements
Scheme 5. Selective preparation of labelling patterns by combination of
alkyne semihydrogenation and allylic hydride/deuteride transfer. Conditions: a)
10 mol% CuCl, 16 mol% 15, 31 mol% nBuLi, 90 bar D2, THF, 60 °C, 48 h. b) 2
equiv TBAF, THF, rt, 4 h, 68% over two steps. c) 2 equiv LiCl, 2 equiv MsCl, 2
equiv 2,6-lutidine, DMF, 0 °C to rt, 14 h, 75%. d) 5 mol% 1, 1.2 equiv NaOtBu,
90 bar H2 or D2, 1,4-dioxane/C6H6 (1:1), 40 °C, 16 h (with H2) or 48 h (for D2).
This work was supported by the German Research Council
(DFG, Emmy Noether Fellowship for J. F. T., TE1101/2-1), by
the Fonds der Chemischen Industrie (Liebig-Stipendium for J. F.
T.) and by the Daimler and Benz Foundation (postdoctoral
fellowship for J. F. T.). F. P. was supported by a predoctoral
scholarship of the Berlin International Graduate School of
Natural Sciences and Engineering (BIG-NSE). Dr. Sebastian
Kemper is acknowledged for support with the NMR analysis. Dr.
Elisabeth Irran is thanked for elucidation of the crystal structure.
Prof. Dr. Martin Oestreich (TU Berlin) is kindly thanked for
generous support.
We found that under optimized conditions, internal alkynes are
not tolerated due to competing catalytic semihydrogenation.[10]
However, when a competition experiment between an internal
alkyne (tolane, 16) and allylic chloride 9c (1:1 ratio) was carried
out, we observed the formation of skipped diene 17 (after
subsequent deprotection of the silyl ether) as result of a
reductive coupling reaction (Scheme 6). This result
demonstrates that the hydrocupration of the internal alkyne
occurs with faster rate than the transfer of the hydride to the
allylic chloride, and that a putative vinylcopper intermediate[9]
acts as a nucleophile for a subsequent allylic substitution in an
SN2’ fashion. Again, no overreduction/hydrogenation of skipped
diene 17 and/or isomerization was observed, underscoring the
chemoselectivity of the present catalyst and its suppressed
reactivity towards alkenes.[28] H2-mediated reductive coupling
reactions are attractive due to their atom economy;[29] and as can
be seen from this result, the present catalytic generation of
hydrides from H2 can not only serve as means of selective
hydride transfer, but additionally offers a possible replacement of
waste-generating hydride sources in C–C bond forming
processes. Especially in relation to the much-researched
Keywords: copper • catalysis • hydrogen • hydride • deuterium
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[16] The dimerized Wurtz-type products 5 were also formed in the absence
of H2, (with and without added TEMPO). We speculate that a polar
copper-catalyzed process not involving H2 is responsible for the
formation of these products, as in the absence of a copper catalyst,
neither of the products 3–5 were detected.
[17] Unfunctionalized allylic chlorides such as 9b could be fully converted at
H2 pressure as low as 25 bar. At even lower pressures, the conversion
and regioselectivity deteriorated and unwanted side-reactions (such as
the nucleophilic displacement of the allylic chloride by the tert-butoxide
anion) were observed. For the substrate scope, high D2 or H2 pressure
(90 bar) was applied to ensure full conversion of all substrates after
48 h. See the Supporting Information for details.
[5]
[6]
[7]
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[18] The double bond configuration has been found to be crucial in other
copper(I)-catalyzed allylic substitutions, see: a) A. Harada, Y. Makida, T.
Sato, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2014, 136, 13932–
13939; b) Y. Yasuda, H. Ohmiya, M. Sawamura, Angew. Chem. Int. Ed.
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Amsterdam, 2009, pp. 515–534.
[8]
The activation of H2 along Cu–O-bonds has been put forward in the
literature: a) J. Halpern, J. Phys. Chem. 1959, 63, 398–403; b) A. J.
Chalk, J. Halpern, J. Am. Chem. Soc. 1959, 81, 5852–5854; c) G. V.
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towards alkenes is well documented. For a review, see: a) J. Mohr, M.
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[21] J. S. Dickschat, Eur. J. Org. Chem. 2017, 4872–4882.
[22] Further evidence for a kinetic isotope effect was obtained by employing
H2/D2 mixtures, see the Supporting Information for details.
[23] Compounds 7a and 7c were isolated with minor D incorporation at the
α carbon (9% and 5% D, respectively), presumably arising from a
directing effect of the aryl groups. However, even though this data
supports the notion that at least a partial reaction between the terminal
alkene and a putative copper(I) hydride intermediate takes place, no
alkene hydrogenation product was observed.
[24] The corresponding
E isomer of 6d gave 7d with the inverse
regioselectivity of /α = 36:64 in 45% yield. This results demonstrates
that also for the higher substitued allylic chlorides, the double bond
geometry has
a profound impact on the regioselectivity of the
monodeuteration.
[25] For selected examples, see: a) J. J. van Veldhuizen, J. E. Campbell, R.
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[12] It should be noted that the allylic displacement with hydride
nucleophiles not generated from H2 and therefore not addressing
competitive catalytic hydrogenation of alkenes has been studied. a) For
an example employing aluminum hydrides, see: K. D. Reichl, N. L.
Dunn, N. J. Fastuca, A. T. Radosevic, J. Am. Chem. Soc. 2015, 137,
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see: A. G. Myers, B. Zheng, Tetrahedron Lett. 1996, 37, 4841–4844.
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[28] After the allylic reduction step, the products of both alkyne
semihydrogenation (Z-dideuterostilbene) and the allylic reduction (10c)
were observed in ~10% conversion (GC analysis).
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58, 45–51; b) H.-Y. Jang, M. J. Krische, Acc. Chem. Res. 2004, 37,
653–661.
[30] For the related copper hydride mediated hydroallylations of vinylarenes
and alkynes, see: a) Y.-M. Wang, S. L. Buchwald, J. Am. Chem. Soc.
2016, 138, 5024–5027; b) G. Xu, H. Zhao, B. Fu, A. Cang, G. Zhang, Q.
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[13] See the Supporting Information for details.
[14] The corresponding allylic acetates, phosphates and carbonates gave
only poor conversion or decomposition, see the Supporting Information
for details.
[15] Crystal structure analysis data of 1: CCDC 1811528.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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CuHl replacement. Dihydrogen (H2)
can be used as source for hydride
nucleophiles in a chemo- and
regioselective allylic substitution.
Switching to D2 allows for selective
monodeuteration.
F. Pape, L. T. Brechmann, J. F.
Teichert*
Page No. – Page No.
Catalytic Generation and
Chemoselective Transfer of
Nucleophilic Hydrides from
Dihydrogen
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