Diazaphospholene Precatalysts for Imine and Conjugate Reductions

Article abstract of DOI:10.1002/anie.201611570

The first examples of 1,3,2-diazaphospholene-catalyzed imine reduction and conjugate reduction reactions are reported. This approach employs readily synthesized alkoxydiazaphospholene precatalysts that can be handled in open air. Reduction of substrates containing Lewis basic functionality, isolated unsaturation, and protic functional groups was accomplished. The synthetic utility of this approach is demonstrated by the synthesis of the important antiparkinson medicine rasagiline and the natural product zingerone.

Full text of DOI:10.1002/anie.201611570

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611570
German Edition: DOI: 10.1002/ange.201611570
Homogeneous Catalysis
Diazaphospholene Precatalysts for Imine and Conjugate Reductions
Matt R. Adams, Chieh-Hung Tien, Blake S. N. Huchenski, Michael J. Ferguson, and
Alexander W. H. Speed*
Abstract: The first examples of 1,3,2-diazaphospholene-cata-
lyzed imine reduction and conjugate reduction reactions are
reported. This approach employs readily synthesized alkox-
ydiazaphospholene precatalysts that can be handled in open
air. Reduction of substrates containing Lewis basic function-
ality, isolated unsaturation, and protic functional groups was
accomplished. The synthetic utility of this approach is demon-
strated by the synthesis of the important antiparkinson
medicine rasagiline and the natural product zingerone.
suited for imine hydroboration. Two examples are a borenium
cation catalyzed imine hydroboration reported by Crudden
and co-workers,[7] and a magnesium diketiminato catalyzed
imine hydroboration reported by Hill and co-workers.[8]
Phosphorus-based reductive catalysts have potential for
providing alternative types of selectivity to the aforemen-
tioned acidic catalysts, because of the low Lewis acidity of
neutral phosphorus(III) centers and consequent reduced
sensitivity to Lewis basic reaction components and impurities.
The development of phosphorus-based catalysts has under-
gone a surge of interest in recent years. Kawashima and co-
workers demonstrated stoichiometric hydridic character at an
anionic PV center through the reduction of benzaldehydes (1,
Scheme 1),[9] while Gudat and co-workers demonstrated the
Amine functional groups are ubiquitous in natural products
and drug molecules. The reduction of imines represents one of
the most important methods for accessing amines, owing to
the ease of preparation of imines from readily available
ketones and aldehydes. Use of catalysis for the reduction of
imines affords opportunities to control selectivity, especially
in the reduction of substrates containing multiple reactive
functional groups. Platinum-group metal-complex catalyzed
hydrogenations of imines are well-established methods,[1]
however the expense and scarcity of precious metals provides
impetus for the development of alternative methods. Metal-
free catalytic reduction is an emerging field.[2] Imine reduc-
tion using frustrated Lewis pairs and dihydrogen is a burgeon-
ing area of investigation in main-group catalysis.[3] In small-
scale exploratory work such as drug discovery or total
synthesis, where scope and reliability are of prime concern,
imine reduction by hydroboration has several attractive
aspects. Common hydroboration reagents such as pinacolbor-
ane, [HB(pin)] are readily handled liquids that do not require
the use of high-pressure equipment. The resultant amines are
also transiently protected as boron adducts, thus minimizing
catalyst inhibition by the amine products. Despite the
importance of imine reduction, examples of catalyzed imine
hydroboration are scarce. Seminal reports of imine hydro-
boration involved coinage-group metals,[4] and there are very
recent reports with nickel and ruthenium.[5] A chiral phos-
phoric acid catalyzed imine reduction employing catechol-
borane has also been reported.[6] In the main-group area, both
s- and p-block catalysts have recently emerged as being well-
Scheme 1. Comparison of existing technologies for reductions cata-
lyzed by phosphorus complexes.
hydridic character of the P H bond of PIII diazaphospholene
À
2a in stoichiometric reactions, including reductions of ben-
zaldehyde and cinnamaldehyde.[10] In the catalytic manifold,
Radosevich and co-workers have shown the ability of
phosphorus pincer complexes such as 3 to mediate diazene
reduction by ammonia borane.[11] Catalytic hydride delivery
from phosphorus(V) species in electrophilic fluorophospho-
nium-based Lewis pairs has recently been reported for olefin
hydrogenation by Stephan and co-workers.[12] With the PIII
system, Kinjo and co-workers have shown that 2a can be
employed in catalytic carbonyl hydroboration reactions, using
[*] M. R. Adams, C.-H. Tien, B. S. N. Huchenski,
Prof. Dr. A. W. H. Speed
Department of Chemistry, Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: aspeed@dal.ca
Dr. M. J. Ferguson
X-ray Crystallography Laboratory, Department of Chemistry
University of Alberta, Edmonton, Alberta T6G 2G2 (Canada)
À
À
HB(pin) to regenerate the P H bond from the P O bond
formed during carbonyl reduction.[13] Both diazaphospho-
lenes and tertiary phosphines have also been used in the
hydroboration of carbon dioxide.[14]
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611570.
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Despite this progress, no examples of imine hydrobora-
tion by phosphorus(III)-based catalysts have been reported.
Herein, we disclose imine reduction and conjugate reduction
reactions enabled by the readily handled precatalyst 4a.
Our initial studies toward imine reduction by diazaphos-
pholenes began with the development of a simple way to
generate and handle 2a, which is a highly air- and moisture-
sensitive liquid, thus making routine use in exploratory
organic synthesis challenging.[10a] We surmised on the basis
of the work of the Kinjo group that an alkoxydiazaphospho-
lene would be an appropriate entry point for catalysis.[13b]
According to a reported procedure, diimine 5 was
converted into bromodiazaphospholene 6,[15,16] (Scheme 2).
Treatment of 6 with benzyl alcohol and triethylamine
afforded known benzyloxydiazaphospholene 4b, which is
a solid with a low melting point. An analogous reaction with
neopentyl alcohol gave 4a, a readily handled, pentane-
soluble, sublimable white solid. Exposure of a 30 mg sample
of solid 4a to ambient atmosphere for 30 minutes resulted in
only 10% decomposition, as ascertained by 1H and 31P NMR,
meaning that 4a can be handled in open air. The mesityl
variant 4c was prepared from the corresponding bromodia-
zaphospholene by an analogous route.[17] To explore the role
of unsaturation in the backbone, saturated compound 7 was
also prepared in two steps from the corresponding diamine
(see the Supporting Information for details).[18] We chose not
to pursue 4b in further studies because its melting point
around ambient temperature made it less convenient to
transfer in small quantities than solids 4a and 4c.
formation of 2a and 2b. Diazaphospholane 7 did not undergo
this transformation, thus indicating that unsaturation in the
backbone is necessary for reactivity. Exposure of 4a to excess
HB(pin) in acetonitrile resulted in initial formation of 2a,
followed by the appearance of a triplet in the 31P NMR
spectrum at À42.9 ppm (JPH = 195.9 Hz), thus indicating the
À
formation of a compound with two P H bonds through
endocyclic cleavage. This was followed by formation of
phosphine (PH3), as evidenced by a quartet at À243.6 ppm.
Compound 4c underwent an analogous decomposition.[19]
The two-step preparation of 4a and 4c from the correspond-
ing diimines can be conducted on a multigram scale, and they
represent convenient precatalysts for 2a and 2b.
With precatalysts 4a and 4c in hand, we turned our
attention to the development of imine reduction with 8a as
a test substrate (Table 1). Hydroboration of 8a with HB(pin)
was complete in 5 hours when using 10 mol% 4a at ambient
temperature (entry 1). Work-up with acid and then base
provided amine 9a. In the absence of catalyst 4a, or when
using saturated diazaphospholane 7 in the place of 4a,
negligible conversion of 8a was observed (entries 2 and 3).
Far less reduction was observed with aged solutions of
HB(pin) and 4a, which contain PH3 as the predominant
phosphorus containing species (entry 4).
Table 1: Development and optimization of the imine reduction.
Exposure of diazaphospholenes 4a and 4c to one
À
À
equivalent of HB(pin) in dry acetonitrile caused P O to P
H bond conversion as evidenced by 31P NMR, resulting in the
Entry Deviation from standard conditions
Conv. [%][a] Yield[b]
1
2
3
4
5
6
7
8
9
none
no catalyst
7 instead of 4a
4a+HB(pin) aged 24 h before additing 8a
4c instead of 4a
HB(cat) instead of HB(pin)
2 mol% loading of 4a (12 h)
1 mol% loading of 4a (12 h)
>98
<2
<2
36
25
67
95
na
na
nd
nd
nd
95
nd
97
>98
66
2 mol% loading (12 h, gram scale for 8a) >98
[a] Conversion based on NMR analysis of starting material and product.
[b] Yields of isolated product arere after acidic work-up and then
basification and basic alumina chromatography.
Mesityl diazaphospholene 4c provided inferior conver-
sion in the reduction (entry 5). The use of catecholborane,
[HB(cat)] with 4a resulted in lower conversion (entry 6).
NMR studies suggest that exocyclic cleavage to PH3 is
especially rapid with this reagent. The catalyst loading could
be reduced to 2 mol% (entry 7); however a drop in con-
version was observed at 1 mol% loading (entry 8). The
reaction could be conducted on a gram scale with no loss of
efficiency (entry 9). A final important feature of this reaction
is that the presence of the corresponding ketone as an
impurity in the imine is not detrimental to the imine
reduction.
Scheme 2. Precatalyst synthesis, crystal structure of 4a,[a] and activa-
tion and decomposition pathways for 4a and 4c. [a] Non-hydrogen
thermal ellipsoids are shown at 30% probability. Hydrogen atoms are
shown with arbitrarily small thermal parameters. Selected interatomic
distances for 4a: [ꢀ] P–O 1.6470(11), P–N1 1.7072(13), P–N2 1.7060-
(13), C1–C2 1.323(2).
Preliminary insight into a mechanism was provided by
stoichiometric reactions (Scheme 3). A purified sample of 2a
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12d resulted from the reduction of the corresponding diimine
in the presence of 2 equivalents of HB(pin). An attempted
monoreduction was not successful. Imines derived from cyclic
aliphatic ketones were reduced, leading to amines 13a and
13b. Imines derived from acyclic aliphatic ketones were also
reduced, yielding imines 13c and 13d.
Finally, racemic chiral imine 14 was reduced to 15 with
high diastereoselectiviy.[23] A tert-butyl sulfenylimine of
acetophenone,[24] the benzyl imine of trifluoroacetophenone,
and the phenyl imine of acetophenone were not successful
substrates. We hypothesize that these electron-withdrawing
Scheme 3. Observation of intermediates in the proposed catalytic
cycle.
À
À
groups inhibit the regeneration of the P H bond from the P
N intermediate. Computational studies have suggested that
electron-poor diazaphospholenes possess less polarized exo-
cyclic bonds.[25]
À
was exposed to imine 10. Formation of the P N compound 11
was observed on the basis of 1H and 31P NMR data. A sample
of 11, independently generated through reaction of 6 with
lithiated dibenzylamine, possessed identical spectral proper-
ties.[20] Exposure of 11 to HB(pin) in acetonitrile resulted in
the reformation of 2a. These results show that 2a can reduce
imines and can be regenerated through cleavage of the
We wished to investigate the potential of our precatalyst
in other reduction reactions. Gudat reported that stoichio-
metric 2a reduced cinnamaldehyde in a 1,4 fashion, prompt-
ing our exploration of catalyzed conjugate reductions (Fig-
ure 2).[10b] Conjugate reduction reactions are commonly
performed using reagents such as copper-based Strykerꢀs
reagent[26] or L-Selectride.[27] Catalytic copper-based reduc-
tion using various terminal reductants, especially silanes, is an
active area of study.[28] A notable catalytic hydroboration
method involves rhodium-catalyzed hydroboration with HB-
(cat).[29]
À
resulting P N bond, thus suggesting the cycle shown in
Scheme 3, which is analogous to the catalytic cycle proposed
by Kinjo for carbonyl reduction, is possible.[13b]
We further explored the scope of the imine reduction
(Figure 1). In an extension from imine 8a, reduction of a more
hindered indanone-derived imine yielded amine 9b. Amine
9c, the monoamine oxidase inhibitor rasagiline, was cleanly
produced from the corresponding imine, with no observed
alkyne hydroboration, thus showing that imines other than
benzyl imines, and alkynes are both tolerated.[21] A p-
methoxybenzyl protecting group is tolerated in product 9d.
A Lewis basic pyridyl group did not have a detrimental effect
on the reaction, as evidenced by the clean formation of 9e,
and additionally, no reduction of the pyridyl ring was
observed.[22] Aldimines exhibiting different steric demand
were reduced, producing amines 12a, 12b, and 12c. Diamine
Figure 2. Substrate scope of the conjugate reduction. Bonds shown in
bold indicate former alkene positions. Yields refer to isolated products
after B(pin) cleavage. [a] 10 mol% 4a used; [b] reaction conducted at
248C; [c] reaction conducted at 508C.
Combination of precatalyst 4a (10 mol%), cinnamalde-
hyde, and HB(pin) in acetonitrile resulted in the formation of
a complex mixture. Since cinamaldehyde is a potent bifunc-
tional electrophile, we surmised that side products arise from
the reaction of enolate intermediates with highly reactive
starting material. Accordingly, we switched to less electro-
philic methyl cinnamate and observed clean reduction to
methyl hydrocinnamate 16a with 10 mol% catalyst upon
modest heating in acetonitrile (408C). No reduction was
observed in acetonitrile in the absence of catalyst. A
trisubstituted olefin (> 95% E) was also a viable partner,
giving product 16b. Ketones proved to be excellent conjugate
Figure 1. Amines successfully formed through imine reduction. Bonds
shown in bold indicate former imine position except for 15, where they
denote relative stereochemistry. [a] 10 mol% 4a employed. Yields refer
to isolated products after work-up.
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Acknowledgements
Financial support from Dalhousie University (start-up fund-
ing), NSERC (USRA for M.R.A., CGS-M for B.S.N.H.), the
Nova Scotia Innovation and Research Scholarship and Killam
Foundation (C.-H.T.), and the Nova Scotia Black and First
Nations Entrance Scholarship (M.R.A.) is gratefully acknowl-
edged. Dr. Mike Lumsden and Mr. Xiao Feng are thanked for
assistance with NMR spectroscopy and mass spectrometry,
respectively. Prof. Jean Burnell and Prof. Mark Stradiotto are
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Conflict of interest
The authors declare no conflict of interest.
Keywords: homogeneous catalysis · diazaphospholenes ·
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Manuscript received: November 27, 2016
Final Article published: && &&, &&&&
4
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Angewandte
Communications
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Communications
Homogeneous Catalysis
1,3,2-diazaphospholene-catalyzed imine
reduction and conjugate reduction reac-
tions are reported. This approach
employs readily synthesized alkoxydiaza-
phospholene precatalysts that can be
handled in air. Substrates containing
Lewis basic functionality, isolated unsa-
turation, and protic functional groups are
well tolerated.
M. R. Adams, C.-H. Tien,
B. S. N. Huchenski, M. J. Ferguson,
A. W. H. Speed*
&&&& — &&&&
Diazaphospholene Precatalysts for Imine
and Conjugate Reductions
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!