Hydroboration Catalyzed by 1,2,4,3-Triazaphospholenes

Article abstract of DOI:10.1021/acs.orglett.7b02695

The synthesis and study of the catalytic activity of 1,2,4,3-triazaphospholenes (TAPs) is reported. TAPs represent a more modular scaffold than previously reported diazaphospholenes. TAP halides were shown to catalyze the 1,2 hydroboration of 19 imines, and three α,β unsaturated aldehydes with pinacolborane, including examples that did not undergo hydroboration by previously reported diazaphospholene systems. DFT calculations support a mechanism where a triazaphospholene cation interacts with the substrate, a mechanism distinct from diazaphospholene catalyzed hydroborations.

Full text of DOI:10.1021/acs.orglett.7b02695

Letter
pubs.acs.org/OrgLett
Hydroboration Catalyzed by 1,2,4,3-Triazaphospholenes
Chieh-Hung Tien,† Matt R. Adams,† Michael J. Ferguson,‡ Erin R. Johnson,*,†
and Alexander W. H. Speed*,†
†Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000, Halifax, Nova Scotia, Canada B3H 4R2
‡X-ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
S
* Supporting Information
ABSTRACT: The synthesis and study of the catalytic activity of
1,2,4,3-triazaphospholenes (TAPs) is reported. TAPs represent a
more modular scaffold than previously reported diazaphospho-
lenes. TAP halides were shown to catalyze the 1,2 hydroboration
of 19 imines, and three α,β unsaturated aldehydes with
pinacolborane, including examples that did not undergo
hydroboration by previously reported diazaphospholene sys-
tems. DFT calculations support a mechanism where a
triazaphospholene cation interacts with the substrate, a
mechanism distinct from diazaphospholene catalyzed hydro-
borations.
etal-free reductions of unsaturated organic molecules
represent a burgeoning field. This is both due to
pholenes with groups other than aryl and tert-butyl has proven
challenging in our hands: low molecular weight diimines that
are potential precursors for less sterically hindered diazaphos-
pholenes are lachrymatory,13 rendering their exploration an
unattractive prospect. Additionally in our hands, diimines with
smaller substituents than tert-butyl, such as cyclohexyl, do not
give clean cyclizations.14 Triazolium carbenes represent a
privileged structure in catalysis and a modular scaffold for
modifications.15 We sought to explore phosphorus-based
analogues of triazolium carbenes, based on an extension of
the notion that diazaphospholenes are analogous to N-
heterocyclic carbenes (Figure 1).16
Only a handful of references to triazaphospholenes are
known to us, and no examples are employed in catalysis.17 We
envisioned formation of triazaphospholenes by the reaction of
an amidrazone with a phosphorus trihalide in the presence of
an acid scavenger. A variety of amidrazones are known, but
many are only reported as intermediates, and not isolated.18 In
our initial explorations, we chose to react bulky amidrazone 1,
isolable as a free base, with phosphorus tribromide in the
presence of triethylamine.19 This reaction cleanly provided
triazaphospholene bromide 2a, the structure of which was
verified by a single crystal X-ray crystallography experiment
(Scheme 1).
M
increasing environmental, economic, and toxicological concerns
associated with the use of transition metals in catalysis1 and,
perhaps more crucially, because main-group-element based
catalysts may provide differing reactivity profiles to transition
metal catalysts.2 Frustrated Lewis pairs, most frequently
containing boron Lewis acids, are preeminent catalysts for
metal-free hydrogenation of imines.3 The use of terminal
reductants other than hydrogen is often attractive for work on
smaller scales. Until the past decade, hydroboration of imines
has received little attention since seminal reports by Baker and
co-workers involving the use of coinage metal catalysts.4 Imine
hydroboration catalyzed by borenium cations was reported by
Crudden and co-workers in 2012.5 Melen, Oestreich, and co-
workers have recently reported imine hydroboration using
specially tailored neutral Lewis acids.6
Diazaphospholenes represent an emerging class of reduction
catalysts. Gudat and co-workers disclosed seminal reports of
stoichiometric reduction reactions.7 Development of conditions
for catalytic reduction was pioneered by Kinjo and co-workers,
employing various terminal reductants for diazenes, carbonyl
compounds, and carbon dioxide.8 Our group recently reported
the convenient synthesis of diazaphospholene precatalysts from
symmetrical diimines and demonstrated their utility in the
reduction of imines and conjugate acceptors.9 Radosevich and
co-workers have also reported imine reduction using the
diazaphospholene motif.10 Kinjo and co-workers recently
reported catalytic conjugate reduction of unsaturated esters.11
Despite the convenience of our reported precatalyst, we wished
to explore more elaborate structures. The synthesis of
nonsymmetrical diimines represents a significant challenge,
limiting opportunities to explore nonsymmetrical diazaphos-
pholene architecture.12 In addition, the synthesis of diazaphos-
We next explored the formation of triazaphospholene
hydrides. Bromide 2a could be transformed to alkoxide 3 by
treatment with sodium benzyloxide in toluene. While exposure
of alkoxytriazaphospholene 3 to HB(pin) in CH3CN did not
result in a reaction, exposure to the more reactive HB(cat)
resulted in the formation of a P−H bond, as evidenced by the
Received: August 30, 2017
© XXXX American Chemical Society
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Table 1. Reduction of an Imine Employing TAP Halides
entry
catalyst
solvent
conversion (%)
1
3
THF
0
44
2
2h
2h
2a
2b
2c
2d
2e
2f
THF
3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
>98
10
4
5
29
6
37
7
68
8
>98
74
Figure 1. Analogy of N-heterocyclic carbenes and diazaphospholenes
with triazolium carbenes and triazaphospholenes.
9
10
2g
64
Scheme 1. Synthesis and Reactivity of Triazaphospholene
2a
a
a
Table 2. Hydroboration of Imine Substrate Scope Using 2h
a
The thermal ellipsoids are scaled at the 30% probability level.
Hydrogen atoms are omitted for clarity. Selected interatomic distances
(Å): P1−Br1 2.4032(5), P1−N2 1.6810(14), P1−N3 1.6865(15).
a
b
Reaction performed in THF unless otherwise stated. Isolated yield
c
after column chromatography. Reaction performed in MeCN.
Figure 2. Synthesized triazaphospholene halides and alkoxide.
less hindered amidrazones.17,18,22 These were subsequently
converted to the corresponding triazaphospholene halides
(2b−2h, Figure 2) by cyclization with a phosphorus trihalide
in the presence of triethylamine. Unfortunately, attempts to
convert these compounds to benzyloxides did not give clean
product mixtures. We then explored catalytic imine reductions
in THF with HB(pin) as the terminal reductant using imine 5a
as the substrate (Table 1). Due to the paucity of alkoxytriaza-
phospholenes, we decided to investigate the ability of the
triazaphospholene halides shown in Figure 2 to serve directly as
catalysts for reduction. As might be expected from the lack of
reactivity with pinacolborane in a stoichiometric experiment,
compound 3 was not a competent catalyst for reduction in an
initial attempt (entry 1).
appearance of a diagnostic doublet (J = 154.0 Hz) at 67.4 ppm
in a proton coupled 31P NMR experiment. While compound 4
was not isolated, this diagnostic doublet is at a comparable
chemical shift range to a dimesityl diazaphospholene P−H
signal (64.6 ppm).20 HB(cat) is not an ideal reductant for
catalyst controlled imine reductions due to a significant
background reaction with imines.21 We attributed the inability
of HB(pin) to convert the alkoxytriazaphospholene to the
corresponding hydride to the high steric hindrance around the
phosphorus atom in triazaphospholene 3.
Regardless of this result, the syntheses of 2a, 3, and 4
establish spectroscopic parameters for observing more reactive
triazaphospholenes by NMR. Accordingly, we prepared several
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Scheme 2. Additional Hydroboration Substrate Scope Using
2b to 2h (Bolded Bonds Indicate Former Unsaturation
Position except for 10 and 11, Where They Indicate
Absolute Stereochemistry)
Scheme 3. Proposed Catalytic Cycle and Enthalpies
Calculated by DFT
a
a
b
Reaction performed using 2e as catalyst. Reaction performed using
c
2h as catalyst. Product could not be isolated from sm by column
chromatography; bracket indicates conversion (%).
a
Energies given in kcal/mol relative to starting materials.
We chose compound 2h to investigate the activity of
triazaphospholene halides. Gratifyingly, the combination of
imine 5a, HB(pin), and 10 mol % of 2h in THF resulted in
44% conversion of the imine to amine 6a (entry 2). We
subsequently observed quantitative conversion to 6a in
acetonitrile (entry 3). Unlike alkoxide 3, triazaphospholene
halide 2a did allow formation of some reduced product;
however, conversion was poor, presumably due to its steric bulk
(entry 4). We observed a clear trend where TAPs derived from
more electron-rich hydrazines gave the highest conversion
(entries 5−8). It should be noted that imine 5a was not
hydroborated by our previously reported diazaphospholene
precatalyst.9
We investigated the scope of imines for the reduction
reaction (Table 2). Even though 2h and 2e afforded
comparable reactivity, we chose 2h as the main catalyst for
our scope study due to the ease of isolation of the
corresponding amidrazone. Either THF or MeCN were
acceptable solvents for reductions of alkyl imines 7b−7p to
corresponding amines, while MeCN was the optimal solvent
choice for reduction of aniline derived imine 5a, and the ortho-
substituted imine 7a.
Other ortho-substituted imines such as 7i, 7o, and 7p
underwent clean reduction in THF. Alkyl amine derived imines
all gave high conversions regardless of the ketone counterpart.
Heterocycles such as pyridine and furan do not interfere with
the reduction of imines 7m and 7n. A more hindered
isobutyrophenone-derived imine 7c was also well tolerated.
Cyclopropyl and alkyne groups were not affected during the
reaction by ring-opening or hydroboration, respectively (entries
5 and 16). Two members of our substrate table are
pharmaceuticals, fendiline (8h, entry 9) and rasagiline (8o,
entry 16), showing the applicability of this reduction method
toward commercially important compounds. We additionally
screened 2e (Scheme 2) in several reduction reactions. We
found this was also an excellent catalyst for reduction of aniline
derived imines 5a−5c, and hindered benzyl imine 7a. Notably,
reduction of 5c, which did not go to completion with catalyst
2h, did go to completion with 2e. We also screened reduction
of α, β-unsaturated aldehydes and observed exclusive 1,2
reductions to allylic alcohols 9a−9c where the geometry of the
alkenes also remained intact. This contrasts with our previously
reported diazaphospholene chemistry, where conjugate accept-
ors underwent 1,4 reduction or decomposition rather than 1,2
reduction.9 We also examined reduction of chiral imine 10.
While diastereoselectivity was modest, a dependence of
selectivity on catalyst structure was observed, with bulky
mesityl containing catalyst 2d providing the highest selectivity
for meso product 11.
We next considered the mechanism of the reaction. Mixtures
of 2h, imine 7b, and HB(pin) in CD3CN showed no evidence
of formation of a P−H bond by 31P NMR spectroscopy. A 1:1
mixture of 2h and imine 7b in CD3CN showed downfield shifts
1
in the H spectrum of the imine (approximately 0.05 ppm for
the methyl and benzylic signals) indicating a possible
interaction between 2h and 7b (see Supporting Information
for spectra). Compound 2h is likely ionized in CD3CN since
the methylene signals on the backbone do not demonstrate
diastereotopic character, indicating a likely planarization of the
phosphorus center. We investigated a potential mechanism
using DFT calculations with the LC-ωPBE functional,23 and
the exchange-hole dipole moment (XDM) dispersion model
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(Scheme 3).24,25 Starting with a complex of triazaphospholene
cation with imine (I), an interaction suggested by the NMR
experiment, formation of the van der Waals prereaction
complex II, where HB(pin) interacts with the nitrogen bearing
a tert-butyl group, is feasible. Subsequent hydride transfer
through a six-membered transition state is exothermic, with an
activation barrier of 23.0 kcal/mol above complex II, leading to
complex III. We investigated interaction of HB(pin) with other
Lewis basic sites on the molecule, but found subsequent
barriers to elimination were prohibitive. Finally, regeneration of
the triazaphospholene cation, by release of the borylated amine,
is accomplished through B−N bond formation, followed by
dissociation of the borylated amine, with a modest barrier of
11.7 kcal/mol for this step. The overall process is exothermic
by −27.4 kcal/mol. This process resembles the reduction
process proposed for Itsuno/CBS type boranes,26 with the
distinction that phosphorus serves as the Lewis acid in this case.
In conclusion, we have demonstrated that triazaphospholene
halides can be employed to catalyze imine hydroborations,
including imines derived from aniline, which did not undergo
reaction with diazaphospholene catalysts. We are currently
synthesizing nonracemic triazaphospholenes for the exploration
of asymmetric catalysis and investigating nonreductive trans-
formations employing this motif.
REFERENCES
■
(1) Egorova, K. S.; Ananikov, V. P. Angew. Chem., Int. Ed. 2016, 55,
12150−12162.
(2) Wilkins, L. C.; Melen, R. L. Coord. Chem. Rev. 2016, 324, 123−
139.
(3) (a) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew.
Chem., Int. Ed. 2007, 46, 8050−8053. (b) Stephan, D. W. Science 2017,
354, 1248.
(4) Baker, R. T.; Calabrese, J. C.; Westcott, S. A. J. Organomet. Chem.
1995, 498, 109−117.
(5) Eisenberger, P.; Bailey, A. M.; Crudden, C. M. J. Am. Chem. Soc.
2012, 134, 17384−17387.
(6) Yin, Q.; Soltani, Y.; Melen, R. L.; Oestreich, M. Organometallics
2017, 36, 2381−2384.
(7) Gudat, D.; Haghverdi, A.; Nieger, M. Angew. Chem., Int. Ed. 2000,
39, 3084−3086.
(8) (a) Reduction of diazene: Chong, C. C.; Hirao, H.; Kinjo, R.
Angew. Chem., Int. Ed. 2014, 53, 3342−3346. (b) Carbonyl reduction:
Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed. 2015, 54,
190−194.
(9) Adams, M. R.; Tien, C.-H.; Huchenski, B. S. N.; Ferguson, M. J.;
Speed, A. W. H. Angew. Chem., Int. Ed. 2017, 56, 6268−6271.
(10) Lin, Y.-C.; Hatzakis, E.; McCarthy, S. M.; Reichl, K. D.; Lai, T.-
Y.; Yennawar, H. P.; Radosevich, A. T. J. Am. Chem. Soc. 2017, 139,
6008−6016.
(11) Chong, C. C.; Rao, B.; Kinjo, R. ACS Catal. 2017, 7, 5814−
5819.
(12) (a) Schmid, D.; Bubrin, D.; Forster, D.; Nieger, M.; Roeben, E.;
̈
ASSOCIATED CONTENT
■
Strobel, S.; Gudat, D. C. R. Chim. 2010, 13, 998−1005. (b) Hans, M.;
Lorkowski, J.; Demonceau, A.; Delaude, L. Beilstein J. Org. Chem. 2015,
11, 2318−2325.
(13) Kliegman, J. M.; Barnes, R. K. Tetrahedron 1970, 26, 2555−
2560.
(14) Chang, Y.-C.; Lee, Y.-C.; Chang, M.-F.; Hong, F.-E. J.
Organomet. Chem. 2016, 808, 23−33.
(15) (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J.-J.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
1021−1023. (b) Enders, D.; Breuer, K.; Kallfass, U.; Balensiefer, T.
Synthesis 2003, 1292−1295.
(16) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis,
T. Chem. Rev. 2015, 115, 9307−9387.
(17) (a) Hormuth, v. P. B.; Becke-Goehring, M. Z. Anorg. Allg. Chem.
1970, 372, 280−284. (b) Zhang, J.; Cao, Z. Synthesis 1985, 1985,
1067−1069. (c) Rodi, Y. K.; Lopez, L.; Malavaud, C.; Boisdon, M.-T.;
Fayet, J.-P. Can. J. Chem. 1993, 71, 1200−1205. (d) Smadhi, M.;
Abderrahim, R. Phosphorus, Sulfur Silicon Relat. Elem. 2010, 185,
2229−2232.
(18) (a) Neilson, D. G.; Roger, R.; Heatlie, J. W. M.; Newlands, L. R.
Chem. Rev. 1970, 70, 151−170. (b) Kerr, M. S.; Read de Alaniz, J.;
Rovis, T. J. Org. Chem. 2005, 70, 5725−5728.
(19) Amidrazone 1 has previously been used in the synthesis of
boron heterocycles by Kinjo and co-workers: Lu, W.; Hu, H.; Li, Y.;
Ganguly, R.; Kinjo, R. J. Am. Chem. Soc. 2016, 138, 6650−6661.
(20) Burck, S.; Gudat, D.; Nieger, M.; Du Mont, W.-W. J. Am. Chem.
Soc. 2006, 128, 3946−3955.
(21) Enders, D.; Rembiak, A.; Seppelt, M. Tetrahedron Lett. 2013, 54,
470−473.
(22) Liew, S. K.; Holownia, A.; Tilley, A. J.; Carrera, E. I.; Seferos, D.
S.; Yudin, A. K. J. Org. Chem. 2016, 81, 10444−10453.
(23) Vydrov, O. A.; Scuseria, G. E. J. Chem. Phys. 2006, 125, 234109.
(24) Otero-de-la Roza, A.; Johnson, E. R. J. Chem. Phys. 2013, 138,
204109.
(25) Johnson, E. R. The Exchange-Hole Dipole Moment Dispersion
Model. In Non-covalent Interactions in Quantum Chemistry and Physics;
Otero-de-la-Roza, A., DiLabio, G. A., Eds.; Elsevier: Amsterdam, 2017;
Chapter 5, pp 169−194.
(26) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551−5553.
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02695.
Crystallographic data for 2a (CIF)
General considerations, reagents, ORTEP drawing for
2a, Cartesian coordinates for DFT calculations, NMR
spectra of TAPs and products, references (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: erin.johnson@dal.ca.
*E-mail: aspeed@dal.ca.
ORCID
Michael J. Ferguson: 0000-0002-5221-4401
Erin R. Johnson: 0000-0002-5651-468X
Alexander W. H. Speed: 0000-0002-8997-3807
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Dalhousie University (start-up funding),
NSERC Discovery Grant (A.W.H.S. and E.R.J.), 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.) are gratefully acknowl-
edged. Dr. Mike Lumsden and Mr. Xiao Feng (Dalhousie
University) are thanked for assistance with NMR spectroscopy
and mass spectrometry, respectively. Prof. Jean Burnell
(Dalhousie University) is thanked for a helpful suggestion.
Compute Canada (Westgrid) is thanked for computational
resources.
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DOI: 10.1021/acs.orglett.7b02695
Org. Lett. XXXX, XXX, XXX−XXX