Enantioselective Imine Reduction Catalyzed by Phosphenium Ions

Article abstract of DOI:10.1021/jacs.9b07293

The first use of phosphenium cations in asymmetric catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from commercially available materials, catalyzes the hydroboration or hydrosilylation of cyclic imin

Full text of DOI:10.1021/jacs.9b07293

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Communication
Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
Travis Lundrigan, Erin N. Welsh, Toren Hynes, Chieh-Hung Tien, Matt R
Adams, Kayelani R. Roy, Katherine N. Robertson, and Alexander W. H. Speed
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07293 • Publication Date (Web): 23 Aug 2019
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Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
Travis Lundrigana, Erin N. Welsha, Toren Hynesa, Chieh-Hung Tiena, Matt R. Adamsa, Kayelani R.
Roya, Katherine N. Robertsonb, Alexander W. H. Speeda*
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aDepartment of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2
bDepartment of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, Canada B3H 3C3
*Email: aspeed@dal.ca
Supporting Information Placeholder
recent development.7 We have shown that achiral
ABSTRACT: The first use of phosphenium cations in
triazaphosphenium cations with chloride counterions are
able to catalyze imine reduction.8 Kinjo and co-workers
have demonstrated a general 1,4-reduction of pyridines
using achiral diazaphosphenium triflate 2a.9
asymmetric catalysis is reported. A diazaphosphenium
triflate, prepared in two or three steps on a multi-gram
scale from commercially available materials catalyzes the
hydroboration or hydrosilation of cyclic imines with
enantiomeric ratios of up to 97:3. Catalyst loadings are as
low as 0.2 mole percent. Twenty-two aryl/heteroaryl
pyrrolidines and piperidines were prepared using this
method. Imines containing functional groups such as
thiophenes or pyridyl rings that can challenge transition
metal catalysts were reduced employing these systems.
Diazaphospholenes are hydridic reagents and catalysts
which have recently been shown to be the strongest
neutral metal-free hydride donors on the Mayr
nucleophilicity scale.1,2 Diazaphospholenes are attractive
catalysts for reductions, since they are tolerant of alkenes,
alkynes, and Lewis-basic sites, which may pose issues for
metal-based
reduction
catalysts.3
Use
of
diazaphospholenes in asymmetric catalysis is a recent
development. Precatalyst 1a, developed by our group,
exhibited enantiomer ratios (e.r.) of up to 88:12 for imine
reduction at 2 mol % catalyst loading.4 Cramer and co-
workers subsequently disclosed a strategically designed
family of polycyclic diazaphospholenes, exemplified by
1b, that are more selective than the P-methoxy variant of
1a for asymmetric conjugate reduction.5 The synthesis of
these catalysts is relatively lengthy compared with that of
1a. The use of 1b for imine reductions has not been
reported. Both 1a and 1b are alkoxy diazaphospholene
precatalysts that generate a diazaphospholene hydride
during the reaction.6 This work shows that chiral
diazaphosphenium triflates are highly active catalysts for
imine reduction, maintain the ease of synthesis of 1a, and
achieve the highest enantioselectivities yet reported in
diazaphospholene catalysis.
Figure 1. Diazaphospholene-based reduction catalysts
We contemporaneously investigated the 1,4-reduction of
pyridines using neutral precatalyst 2b, which was less
active than 2a, and only functioned when the pyridines
bore electron withdrawing groups.10 We sought to
ascertain if moving from neutral catalysts such as 1a to
phosphenium cations such as 3a for asymmetric imine
reduction would exhibit a corresponding increase in
Phosphenium cations have long been a subject of
investigation, but their use in catalysis is a relatively
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activity. Most importantly, since there is no literature
precedent for the use of phosphenium cations in
asymmetric catalysis, we also sought to determine if the
level of asymmetric induction would be perturbed by the
move from a neutral to cationic manifold.
Page 2 of 8
6a and 3a were purified by washing with dry diethyl ether
under nitrogen. Alternatively, TMS triflate can be added
to the diazaphospholene bromide formation reaction one
hour after addition of the diimine allowing a one-pot
conversion of 5a to 3a. Material prepared in this manner
has equivalent catalytic performance to that prepared in
two steps from 5a. The synthesis of 3a in either two or
three steps from commercially available amine 4a
compares favorably in cost, step-count, throughput, and
ease of syntheses relative to most chiral phosphine
ligands employed in asymmetric catalysis.14 Related
phosphenium cations 3b, where ethyl groups were used
in place of methyl groups, 3c, where naphthyl was
replaced with 3-benzothienyl, and 3d, derived from (S)-
1-aminotetralin were also prepared. X-Ray diffraction
studies on 3c and 3d (See Supporting Information)
confirmed their ionic character.
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Chiral phosphenium cations are readily accessed via a
modification of the protocol originally developed for
achiral phosphenium cations by Macdonald and co-
workers.11 Condensation of amine 4a with glyoxal
readily forms diimine 5a on a 70-gram scale (Scheme
1).12 Exposure of 5a to PBr3 with cyclohexene as a
bromine scavenger affords diazaphospholene bromide
6a. Large scale synthesis of 6a required modification of
the existing procedure since addition of PBr3 to a mixture
of 5a and cyclohexene gave poor product cleanliness and
yields upon scale-up. Premixing PBr3 and cyclohexene in
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dichloromethane, followed by addition of
a
dichloromethane solution of diimine 5a resulted in clean,
scalable cyclization to form 6a.
We initially explored reductions of cyclic imines (Table
1) since the product aryl pyrrolidines are common
structural motifs in pharmaceuticals and natural
products,3, 15 as well as components of anion-binding
organocatalysts.16 Cyclic imines are readily prepared
substrates.17 Unlike acyclic alkyl imines they are stable to
aqueous hydrolysis and chromatography, and there is no
possible Z/E isomerism.18 Because of their utility, a
variety of strategies have been developed for the
asymmetric synthesis of the product aryl pyrrolidines,19
including imine and enamine reduction.20 Stoichiometric
sparteine mediated asymmetric lithiation followed by
Negishi coupling is especially common,19a however
practical issues include challenges sourcing sparteine and
unequal supply of the enantiomers.21 Organometallic
complex-catalyzed reductions of imines are known, but
lengthy or challenging catalyst syntheses present hurdles
in these methods,3,20a,b Readily accessible catalysts for
asymmetric cyclic imine reduction would have
immediate utility.
Scheme 1. Chiral Phosphenium Triflates 3a–3d
As a baseline result, the reduction of imine 7a with
precatalyst 1a (entry 1) afforded amine 8a in 86:14 e.r.,
comparable to acyclic imine reductions with 1a.4
Absolute configuration of 8a was confirmed by
comparison of its optical rotation with literature values,20c
and was consistent with hydride delivery to the Re face of
the imine by (R,R) catalyst, as previously observed with
1a for acyclic imines.4 Use of phosphenium triflate 3a at
ambient temperature in THF resulted in the same level
and sense of induction (entry 2), verifying that
phosphenium cations are capable of asymmetric catalysis.
A solvent screen, found in the Supporting Information,
confirmed that THF provides the optimal induction for
this substrate when using 3a as the catalyst.22
No decrease in yield or purity of 6a was observed at the
largest scale tested (36 grams of 6a obtained in one
batch). We speculate that the beneficial effect of this
alteration of addition order arises from minimizing the
concentration of diimine present in the oxidative
environment of the cyclization process.13 Bromide 6a
was converted to analytically pure, light beige
phosphenium triflate 3a through treatment with
trimethylsilyl (TMS) triflate in dichloromethane on a 15
gram scale.11 A single crystal of 3a grown from a
THF/ether solution of 3a confirmed the structure and
ionization of the compound in the solid state. Compounds
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Table 1. Varying Reductant and Catalyst Structurea,b
derived imines for turnover, making use of 3a a
complementary process.25 Catalyst 3b gave equivalent
performance to 3a (entry 14). Benzothiophene-based 3c
showed slightly less selectivity than that obtained with 3a
(entry 15). Amino-tetralin derived catalyst 3d also
exhibited lower enantioselectivity than 3a (entry 16).
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We propose a mechanism for imine hydroboration
resembling pyridine reductions by phosphenium cations,
where the phosphenium cation abstracts a hydride from a
pinacolborane-substrate complex then redelivers the
hydride to the resulting imine-borenium (Scheme 2).
Given the high enantioinduction, non-enantioselective
borenium catalyzed reduction does not appear to be
competitive.26 The selectivity is consistent with
minimizing steric interactions between the aryl
substituent on the imine and catalyst naphthyl groups.9,10
While neutral silanes do not complex with imines, a
similar mechanism where hydride transfer from the silane
to a Lewis acid initiates formation of a silyliminium has
been proposed by Piers and coworkers. 27
7
8
9
entry
Reductant
Mol % cat
Conv.
e.r.
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1a
2a
3b
4b
HB(pin)
HB(pin)
HB(pin)
HB(pin)
HB(pin)
HB(pin)
HB(pin)
HB(cat)
Ph2SiH2
Ph2SiH2
PhSiH3
5 mol % 1a
5 mol % 3a
5 mol % 1a
5 mol % 3a
1 mol % 3a
>98
>98
<10
>98
>98
86:14
86:14
n.d.
95:5
5b
95:5
95:5
89:11
86:14
84:16
n.d.
6b,c
7b,c
8b
0.2 mol % 3a >98
0.1 mol % 3a >98
5 mol % 3a
5 mol % 3a
5 mol % 3a
5 mol % 3a
5 mol % 3a
1 mol % 3a
5 mol % 3b
5 mol % 3c
5 mol % 3d
>98
>98
<10
>98
>98
>98
>98
>98
>98
9a
10b
11a
12b
13b
14b
15b
16b
Scheme 2. Proposed Hydroboration Mechanism and
Induction Model
87:13
93:7
PhSiH3
PhSiH3
93:7
HB(pin)
HB(pin)
HB(pin)
5:95
91:9
20:80
a) reduction at ambient temperature b) reduction at –35 C c)
reaction conducted with 1 gram of substrate
Cooling neutral 1a to –35 C fails to give high conversion
(entry 3). Reduction of imine 7a with ionic 3a at –35 C
increased the enantiomer ratio to 95:5 with complete
conversion (entry 4), demonstrating the superior
reactivity of 3a. Decreasing the catalyst loading to 1 mol
% had no impact on conversion or enantioinduction (entry
5). A further decrease to 0.2 mol % was possible (entry
6), but when loading was decreased to 0.1 mol%, the
enantioselectivity was lower (entry 7). Catecholborane,
which reduces imines without a catalyst, showed inferior
selectivity to pinacolborane (entry 8).23 A brief screen of
other reductants revealed 3a can promote asymmetric
imine hydrosilation. Diphenylsilane was used in
diazaphospholene catalyzed carbon dioxide reduction.24
Good conversion and induction were noted with
diphenylsilane at room temperature (entry 9), however
cooling prevented full conversion (entry 10).
Phenylsilane showed similar selectivity to diphenylsilane
(entry 11), but higher reactivity at colder temperatures
increased asymmetric induction with high conversion
(entry 12). The catalyst loading could also be lowered
with phenylsilane (entry 13). Existing Lewis-basic
catalysts for imine hydrosilation use corrosive
trichlorosilane, and require electron deficient aniline-
Silyliminium cations in the Piers mechanism are reduced
by back-transfer of the hydride from the Lewis acid-
hydride adduct, and this concept could be invoked for our
observed silane reductions where 3a would take on the
role of chiral hydride abstractor and donor. Importantly,
the high enantioinduction observed with silanes shows
that 3a is not an initiator of racemic silylium ion catalysis
as recently articulated by Stephan, Oestreich, and co-
workers.28,29 Further studies to understand the interplay
of various reductants, catalyst charge, and structure in
diazaphospholene catalyzed reactions are underway in
our group. These phosphenium-catalyzed imine
reductions contrast with comparably selective metal-free
borane and bisborane-based frustrated Lewis pair imine
reduction catalysts pioneered by Klankermayer, Repo,
and Papai and co-workers,30 and recently expanded on by
Du, and Peng and Wang, and co-workers.31, 32 While
these electrophilic borane systems have been used at
loadings of 0.5–5 mol %, electron-deficient aniline
derived imines or heterocycles are required as substrates
to avoid product inhibition of the electrophilic catalysts,
in contrast to the relatively basic cyclic imines used here.
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Scheme 3. Scope of asymmetric reductiona
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a) Isolated yields and enantiomer ratios for reactions performed on 100 mg scale, using 1 mol % catalyst 3a, and 1.2 equiv of HB(pin) at –
35 C. Enantiomer ratios determined by HPLC on a chiral stationary phase, configurations assigned by analogy to 8a. b) Catalyst ent-3a
used in reduction c) previous e.r. obtained with 2 mol % 1a at 25 C in reference 4.
To study scope, substrates were reduced on a 100 mg
scale, using a 1 mol % loading of catalyst (Scheme 3).
Amine 8b formed with comparable selectivity to isomeric
To further demonstrate utility, we prepared 8t, an
8a. Benzothiophene and dibenzothiophene amines 8c–8e
intermediate in the synthesis of the tyrosine kinase
were obtained with good to excellent selectivity.
inhibitor larotrectnib 11 (Scheme 4), on gram scale.
Preparation of 8e, formerly used as a component of chiral
Amine 8t was previously prepared by a 0.4 mol %
catalysts, previously required stoichiometric sparteine,
iridium-complex catalyzed hydrosilation of 7t with a
and 5 mol% palladium catalyst.16,19a Ortho-methyl
reported e.r. ranging from 87.5:12.5 to 92.5:7.5.34 Our
substitution patterns 8f and 8g and meta-substituted 8h–
catalyst provided a comparable e.r. of 88:12 at 0.5 mol %
8j were well tolerated. Electron donating groups on the
loading without requiring iridium. An X-ray diffraction
para or ortho positions of 8k–8n did not interfere.
study on crystalline derivative 12 provided further proof
Thiophenes 8o and 8p were also well tolerated. Sulfur-
of configuration.35
containing functional groups can challenge some
transition-metal based catalysts.33 Diazaphospholenes
can catalyze the 1,4 hydroboration of certain 3-
substituted pyridines,10 however halogen or methoxy
substituents in the 6-position allowed selective reduction
of the imine to nornicotine analogues 8q–8s. Substitution
of the 6-position to avoid catalyst inhibition was needed
in pyridyl imine hydrogenation with an iridium-based
catalyst.3 Two arylpiperidines, 9a and 9b were prepared
from reduction of the six membered cyclic imines, with
slightly lower selectivity than pyrrolidine analogues 8a
and 8e.
Scheme 4. Synthesis of larotrectnib intermediate 8t
Acyclic amines 10a, 10b, and 10c were prepared by
reduction of the corresponding imines catalyzed by 1 mol
% of 3a at –35 C. These acyclic imine reductions
exhibited comparable selectivity to the previously
reported reduction with precatalyst 1a (albeit at lower
catalyst loading).4 It appears for now that cyclic imines
are the optimal substrate for reductions with 3a.
a) Recovery and e.r. after crystallization with (R)-malic acid
In conclusion, we have demonstrated the first example of
an asymmetric reaction catalyzed by a phosphenium
cation. The synthesis of the catalyst was conducted in
three steps on a multi-gram scale. Good to excellent
enantioselectivities for preparation of arylpyrrolidones
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heterocyclic phosphines: unusual structures and the unique reactivity
were obtained at catalyst loadings of 0.2–1 mol %. We
anticipate this technology will be useful for the
preparation of many cyclic secondary amines. Further
developments of cationic catalysts that are highly
selective at room temperature, and more selective in
acyclic imine reduction will be reported in due course.
Both enantiomers of catalyst 3a will soon be
commercially available from Strem Chemicals.
of 1,3,2-diazaphospholenes. Dalton Trans. 2016, 45, 5896–5907. (e)
Gudat, D. Diazaphospholene Chemistry. In Encyclopedia of Inorganic
and Bioinorganic Chemistry,Online, 2nd ed.; Scott, R. A., Ed.; John
Wiley and Sons: Hoboken, NJ, 2018
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(2) Zhang, J.; Yang, J.-D.; Cheng, J.-P. Nucleophilicity Scale for the
Reactivity of Diazaphospholenium Hydrides: Structural Insights and
Synthetic Applications. Angew. Chem., Int. Ed. 2019, 58, 5983–5987.
(3) Guo, C.; Sun, D.-W.; Yang, S.; Mao, S.-J.; Xu, X.-H.; Zhu, S.-F.;
Zhou, Q.-L. Iridium-Catalyzed Asymmetric Hydrogenation of 2-
Pyridyl Cyclic Imines: A Highly Enantioselective Approach to
Nicotine Derivatives. J. Am. Chem. Soc. 2015, 137, 90–93.
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(4) Adams, M. R.; Tien, C.-H.; McDonald, Robert; Speed, A. W. H.
Supporting Information
Asymmetric
Imine
Hydroboration
Catalyzed by
Chiral
Diazaphospholenes. Angew. Chem., Int. Ed. 2017, 56, 16660–16662.
Synthetic procedures, NMR spectra of catalysts,
substrates and products, reaction optimization tables, and
HPLC traces are available as a PDF file.
(5) Miaskiewics, S.; Reed, J. H.; Donets, P. A.; Oliveira, C. C.; Cramer,
N. Chiral 1,3,2-Diazaphospholenes as Catalytic Molecular Hydrides
for Enantioselective Conjugate Reductions. Angew. Chem., Int. Ed.
2018, 57, 4039–4042.
(6) (a) Chong, C. C.; Hirao, H.; Kinjo, R. Metal-Free Sigma-Bond
Metathesis in 1,3,2-Diazaphospholene-Catalyzed Hydroboration of
Carbonyl Compounds. Angew. Chem., Int. Ed. 2015, 54, 190–194. (b)
Adams, M. R.; Tien, C.-H.; Huchenski, B. S. N.; Ferguson, M. J.;
Speed, A.W. H. Diazaphospholene Precatalysts for Imine and
Conjugate Reductions. Angew. Chem., Int. Ed. 2017, 56, 6268–6271.
(c) Chong, C. C.; Rao, B.; Kinjo, R. Metal-Free Catalytic Reduction of
,-Unsaturated Esters by 1,3,2-Diazaphospholene and subsequent C–
C Coupling with Nitriles. ACS Catal. 2017, 9, 5812–5819.
CIF files for compounds 3a, 3c, 3d and 12.
The Supporting Information is available free of charge on
the ACS publications website.
AUTHOR INFORMATION
Corresponding Author
(7) (a) Fleming, S.; Lupton, M. K.; Jekot, K. Synthesis of a cyclic
fluorodialkylaminophosphine and its coordination with boron acids.
Formation of a unique dialkylaminophosphine cation. Inorg. Chem.
1972, 11, 2534–2540. (b) Cowley, A. H.; Kemp, R. A. Synthesis and
reaction chemistry of stable two-coordinate phosphorus cations
(phosphenium ions). Chem. Rev. 1985, 85, 367–382. (c) Carmalt, C. J.;
Lomeli, V.; McBurnett, B. G.; Cowley, A. H. Cyclic phosphenium and
arsenium cations with 6pi electrons and related systems. Chem.
Commun. 1997, 2095–2096. (d) Denk, M. K.; Gupta, S.; Lough, A. J.
Synthesis and Reactivity of Subvalent Compounds, 8 Aromatic
Phosphenium Cations. Eur. J. Inorg. Chem. 1999, 41–49.
*E-mail: aspeed@dal.ca
Funding Sources
We thank NSERC of Canada for a Discovery Grant and an
Idea to Innovation Grant. Springboard Atlantic also funded
this work with a proof-of-concept grant. Labrador’s Post-
Secondary Student Support Program is thanked for graduate
funding (E.N.W). The Faye Sobey Undergraduate Research
award (T.H.), Nova Scotia Graduate Scholarship (E.N.W.)
and the Killam Foundation (C.H.T.) are also thanked for
student support.
(8) Tien, C.-H.; Adams, M. R.; Ferguson, M. J.; Johnson, E. R.; Speed,
A. W. H. Hydroboration Catalyzed by 1,2,4,3-Triazaphospholenes.
Org. Lett. 2017, 19, 5565–5568.
Notes
(9) a) Rao, B.; Chong, C. C.; Kinjo, R. Metal-Free Regio- and
Chemoselective Hydroboration of Pyridines Catalyzed by 1,3,2-
Diazaphosphenium Triflate. J. Am. Chem. Soc. 2018, 140, 652–656.
(b) For earlier fundamental physical studies on this class of cation, see:
Ould, D. M. C.; Rigby, A. C.; Wilkins, L. C.; Adams, S. J.; Platts, J.
A.; Pope, S. J. A.; Richards, E.; Melen, R. L. Investigations into the
Photophysical and Electronic Properties of Pnictoles and Their
Pnictenium Counterparts. Organometallics 2018, 37, 712–719.
Competing financial interests: Dalhousie University has
filed patents on chiral phosphenium triflates for asymmetric
imine reduction, from which royalty payments may be
derived.
ACKNOWLEDGMENT
Dr. Michael Lumsden and Mr. Xiao Feng (Dalhousie
University) are thanked for assistance with NMR
spectroscopy and mass spectrometry, respectively.
Participants in Chemistry Twitter are thanked for advice on
HPLC separations.
(10) Hynes, T. H.; Welsh, E. N.; McDonald, R.; Ferguson, M. J.;
Speed, A. W. H. Pyridine Hydroboration with a Diazaphospholene
Precatalyst. Organometallics 2018, 37, 841–844.
(11) Dube, J. W.; Farrar, G. J.; Norton, E. L.; Szekeley, K. L. S.;
Cooper, B. F. T.; Macdonald, C. L. B. A Convenient Method for the
Preparation of N-Heterocyclic Bromophosphines: Excellent Precursors
to the Corresponding N-Heterocyclic Phosphenium Salts.
Organometallics, 2009, 28, 4377–4384.
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(14) Amine 4a is used in the preparation of the medication Cinacalcet,
and both enantiomers are commercially available for a cost of $1
USD/gram or less.
decreasing reaction efficiency. Dichloromethane and trifluorotoluene
have only slightly inferior performance, while acetonitrile gives 72:28
e.r. under the same conditions as the best result with THF.
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(34) (a) Arrigo, A. B.; Juengst, D.; Shah, K. “Crystalline form of (S)-
N-(5-(R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo-[1,5-A]-
pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
hydrogen
sulfate” US 2017/0165267 2017 (b) The ee of the product was further
upgraded to >96% by crystallization as a salt of D-malic acid. A yield
of greater than 75% was reported for this step on page 26 of the above
patent.
(22) Diethyl ether and toluene have comparable performance; however
imines are less soluble in these solvents at reduced temperature,
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(35) Compound 10 exhibits conglomerate behavior. Crystals that
89:11 ratio was obtained from multiple analyses of an amorphous
sample of 10 prepared by concentration of a dichloromethane solution
of 10.
formed in ethyl acetate/hexanes were used for X-ray analysis. HPLC
analysis of a solution made from these crystals showed they were
almost enantiopure and corresponded to the major enantiomer. The
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