Pushing the Limits of Neutral Organic Electron Donors: A Tetra(iminophosphorano)-Substituted Bispyridinylidene

Article abstract of DOI:10.1002/anie.201505378

A new ground-state organic electron donor has been prepared that features four strongly π-donating iminophosphorano substituents on a bispyridinylidene skeleton. Cyclic voltammetry reveals a record redox potential of ?1.70 V vs. saturated calomel electrode (SCE) for the couple involving the neutral organic donor and its dication. This highly reducing organic compound can be isolated (44 %) or more conveniently generated in situ by a deprotonation reaction involving its readily prepared pyridinium ion precursor. This donor is able to reduce a variety of aryl halides, and, owing to its redox potential, was found to be the first organic donor to be effective in the thermally induced reductive S N bond cleavage of N,N-dialkylsulfonamides, and reductive hydrodecyanation of malonitriles.

Full text of DOI:10.1002/anie.201505378

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201505378
German Edition: DOI: 10.1002/ange.201505378
Organic Reductants
Hot Paper
Pushing the Limits of Neutral Organic Electron Donors: A
Tetra(iminophosphorano)-Substituted Bispyridinylidene
Samuel S. Hanson, Eswararao Doni, Kyle T. Traboulsee, Graeme Coulthard, John A. Murphy,*
and C. Adam Dyker*
Abstract: A new ground-state organic electron donor has been
prepared that features four strongly p-donating iminophos-
phorano substituents on a bispyridinylidene skeleton. Cyclic
voltammetry reveals a record redox potential of À1.70 V vs.
saturated calomel electrode (SCE) for the couple involving the
neutral organic donor and its dication. This highly reducing
organic compound can be isolated (44%) or more conven-
iently generated in situ by a deprotonation reaction involving
its readily prepared pyridinium ion precursor. This donor is
able to reduce a variety of aryl halides, and, owing to its redox
potential, was found to be the first organic donor to be effective
À
in the thermally induced reductive S N bond cleavage of N,N-
dialkylsulfonamides, and reductive hydrodecyanation of malo-
nitriles.
Scheme 1. Structure of organic electron donors A, B, C, D, and 1.
R
ecently, organic electron donors[1–7] such as A (E1/2
=
À1.20 V vs. SCE) and Ba (E1/2 = À1.24 V vs. SCE), have
emerged as exciting new reagents in organic synthesis (see
Scheme 1). Such ground-state, neutral organic molecules are
associated with exceptionally negative redox potentials, yet
are soluble and tunable, and should therefore complement
traditional heterogeneous metal-based reductants in that they
can offer alternate reaction conditions (including the absence
of metallic by-products) or unique selectivity.[8,9] To date,
these reagents have been effectively used in the reduction of
organic substrates such as aryl halides,[5,7,10,11] sulfones and
arenesulfonamides,[7,12] Weinreb amides,[13] acyloin deriva-
tives,[14] triflates, and triflamide.[15] Until recently, such
reductions would only have been expected from strong
inorganic reducing agents such as alkali metals or samarium-
(II) species.[16–18]
The utility and power of these organic donors has been
further increased by their photoexcitation. Indeed, photo-
activation of Ba allows for the reduction of challenging
substrates such as activated benzenes, N,N-dialkyl arenesul-
fonamides, benzylic esters and ethers, benzyl malonates and
cyanoacetates,[19–22] which could not be reduced by Ba in the
ground state (see Scheme 1). To complement these achieve-
ments with photoactivation, it is desirable to expand the
library of known organic reducing agents, particularly into the
realm of increasingly negative redox potentials so that
increasingly difficult reductions can be effected from the
ground state.
Our groups have recently described novel bis(iminophos-
phorano)-substituted bispyridinylidenes Bb, Bc, Cb, and Cc[23]
as well as tricyclic D,[24] all of which act as two electron donors.
These compounds represent the most powerful organic
reducing agents yet reported, with redox potentials reaching
À1.50 V (D) and À1.51 V (Cc) vs. SCE (see Scheme 1).[23,24]
Whereas the extrinsic effect of solvation is highly important in
governing the redox potential of the alkali metals,[25] the
strongly reducing nature of these compounds is attributed to
the formation of aromatic rings upon their oxidation to the
respective dications, as well as the intrinsic effect of the
exceptional p-donating substituents, with iminophosphorano
groups being more powerful in this regard than typical amino
substituents.[23] Here we report on the effect of incorporating
four iminophosphorano groups onto the bispyridinylidene
skeleton, as in donor 1, which provides potentials reaching
À1.70 V vs. SCE (see Scheme 1). The utility of 1 as a ground-
state electron donor is demonstrated in the reduction of
challenging sulfonamides, aryl halides, and malononitriles,
including substrates which have proven inert to previous
organic donors, except with photoactivation.
[*] S. S. Hanson,[+] K. T. Traboulsee, Prof. Dr. C. A. Dyker
Department of Chemistry, University of New Brunswick
Fredericton, New Brunswick, E3B 5A3 (Canada)
E-mail: cadyker@unb.ca
Dr. E. Doni,[+] Dr. G. Coulthard, Prof. Dr. J. A. Murphy
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral Street, Glasgow G1 1XL (UK)
E-mail: john.murphy@strath.ac.uk
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505378.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
11236
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11236 –11239

Angewandte
Chemie
Scheme 2. Synthesis of iminophosphorano-substituted bispyridinyli-
dene 4, and its oxidation to the corresponding dichloride 42+-2ClÀ.
Scheme 3. Preparation of tetrasubstituted organic electron donor 1
(only the major Z isomer is shown).
Before attempting the preparation of 1, we targeted
bispyridinylidene 4 (Scheme 2) derived from 2-iminophos-
phoranopyridine 2, in order to assess the effect of an
iminophosphorano substituent in this position. Pyridine 2 is
known,[26] and can be easily prepared in 80% yield on a 20 g
scale. Gratifyingly, the addition of 1,3-diiodopropane to two
equivalents of this pyridine cleanly afforded the bispyridi-
nium diiodide 3, which was isolated in 83% yield. Exclusive
alkylation at the pyridyl nitrogen is in line with previous
observations involving 2,[27] but contrasts the analogous
reaction with 2-(dimethylamino)pyridine, where both the
pyridyl and exocyclic nitrogen centers were alkylated.[28]
Subsequently, the reaction of 3 with two equivalents of
KN(SiMe3)2 (KHMDS) cleanly produced the desired imino-
phosphorano-substituted donor 4, though it could only be
isolated in low yield (12%) owing to its poor solubility.
Nevertheless, the isolated quantities were sufficient to allow
for its chemical oxidation with hexachloroethane to 42+-2ClÀ
and subsequent electrochemical analysis by cyclic voltamme-
try. In this way, redox potentials of À1.25 and À1.08 V vs SCE
were determined for the 4+/4 and 42+/4+ couples, respectively.
Though 4 should still be considered a relatively strong donor,
these potentials are less reducing than for Bb (E11/2 = À1.36 V,
E21/2 = À1.23 V vs. SCE),[23] showing that the bispyridinyli-
dene framework is less sensitive to substitution at the 2-,
rather than the 4-position, of the pyridyl ring.
Encouraged by the successful preparation of 4, we then
prepared tetrasubstituted donor 1 (Scheme 3, see the Sup-
porting Information for the propylene-bridged analog of 1).
Initially, the 4-iminophosphorano functionality was intro-
duced by the addition of 5 to a dichloromethane solution
containing triethylamine and in situ generated dibromotri-
phenylphosphorane. The resulting chloropyridine 6 was
isolated on a 60 g scale in 89% yield, and was subsequently
methylated at the pyridyl nitrogen to give chloropyridinium
salt 7 (26 g, 96%). A combination of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) and aminotriphenyl-phosphonium
hours, donor 1, which is virtually insoluble in toluene, was
isolated in a 44% yield after being collected by filtration and
1
extracted into benzene. 31P{1H} and H NMR spectra of the
isolated solid show that 1 occurs as a 2:1 mixture of Z (31P: 0.4
and À7.8 ppm) and E (31P: À1.3 and À5.4 ppm) isomers. The
preference for the Z isomer is supported by ROESY NMR
experiments, and is in line with previous experimental[23] and
theoretical[29] investigations on bispyridinylidenes. The low
isolated yield for 1 should not be regarded as a major
disadvantage, as the donor can be effectively used as
a reductant when generated in situ. As for 4, donor 1 was
oxidized to its more stable dichloride salt by its reaction with
hexachloroethane, and analyzed by cyclic voltammetry. This
electrochemical analysis revealed a half-wave potential of
À1.70 V for the 12+/1 couple, making 1 the strongest neutral
organic electron donor by a substantial margin (190 mV more
powerful than Cc, and over 450 mV more powerful than Ba).
Owing to the superior reducing power of 1 over A and Ba,
we were particularly keen to investigate the use of 1,
generated in situ from an equimolar mixture of 8 and
À
KHMDS, in the reductive S N bond cleavage of sulfona-
mides (Scheme 4). In arenesulfonamide deprotections, the
ease of reductive cleavage increases with the stability of the
nitrogen leaving group, and so N,N-dialkyl arenesulfonamides
had proven to be amongst the toughest of substrates to
deprotect by previous donors under thermal activation. For
example, dialkyl arenesulfonamide 9, which lacks any p-
system to stabilize N-containing leaving group, proved to be
unreactive to A in the ground state (1108C, 18 h), but was
reduced to 10 in 65% yield by Ba (6 equiv) after 72 h of
photoexcitation.[22] Gratifyingly, even with 8 equivalents of 8
(equating to at most 4 equiv of 1), amine 10 was produced in
good yield (75%) within 24 h at 1108C. Compound 11a
proved more challenging, but with eight equivalents of donor-
precursor 8 (4 equiv of 1), yields of 12 (56%) comparable to
those achieved using 6 equiv of Ba under photolysis (59%)
were achieved.[22] As expected, yields of 12 from the
reduction of mesyl-substituted 11b (6%) were much lower
than were achieved from tosyl-derived 11a, owing to the
absence of the relatively low-energy LUMO of the arene
fragment in 11b. Nevertheless, the outcomes are a testament
=
bromide was then used to generate nucleophilic Ph3P NH,
which in the presence of excess DBU, was able to substitute
the chloride of 7 to give pyridinium salt 8 (20 g, 66% after
recrystallization). The preparation of 1 was completed by the
deprotonation of 8 with KHMDS in toluene. After three
Angew. Chem. Int. Ed. 2015, 54, 11236 –11239
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11237

.
Angewandte
Communications
Scheme 5. The reduction of aryl halides by in situ generated 1.
reaction times (1108C, 24 h), but the chloride 17c remained
inert to 1 under thermal conditions. In contrast, 1-chloroan-
thracene 22, with a lower energy LUMO owing to the
extended p system, was easily reduced to anthracene 23 (RT,
24 h).
These encouraging results prompted the investigation of
the effectiveness of 1 in the hydrodecyanation of malononi-
triles (Scheme 6). Such a process is typically conducted
through the use of tributyltin hydride/a,a’-azobisisobutyroni-
trile (AIBN),[33,34] or SmI2 in hexamethylphosphoramide,[35]
but it has more recently been effected by N-heterocyclic
carbene boranes/radical initiator,[36] or by Ba under photo-
activated conditions.[37] No organic electron donor has
achieved this reduction from its ground state. With compa-
Scheme 4. The reduction of sulfonamides by in situ generated
1 (Ts=tosyl group and Ms=mesyl group).
to the strength of ground-state donor 1, which is the first
ground-state organic electron donor able to effect the
reduction of dialkylsulfonamides.
Moving to more activated sulfonamides, two equivalents
of the in situ generated donor gave high yields of deprotected
products 14 (92%) and 16 (90%) from compounds 13 and 15,
respectively. The reduction of these substrates, which is
facilitated by the formation of a resonance-stabilized nitro-
gen-containing leaving group, has been previously accom-
plished by donor A (albeit with six equivalents of donor).[12]
In the case of aryl halides (Scheme 5), donor 1 (2 equiv)
reduces iodides 17a and 19a at room temperature, to products
18 and 20/21, respectively, where the formation of 21 suggests
the involvement of aryl anion intermediates. Recent compu-
tational studies[30] suggest that the reduction potential for aryl
radicals to form aryl anions is about À1 V vs. SCE, which is
considerably more negative than the original experimental
estimate,[31] but this potential would still be easily reached by
donor 1. Importantly, under otherwise identical conditions,
17a was quantitatively recovered in the absence of 8,
demonstrating the necessity of donor 1 in effecting the
reductions.
The reduction of iodides 17a and 19a have been similarly
effected by a number of organic donors,[7,10,32] including A,
Ba, and Ca, so more challenging aryl halide substrates were
also investigated. The related bromides 17b and 19b were
reduced by donor 1 at higher temperatures and with longer
Scheme 6. The reduction of malononitriles by in situ generated 1.
11238 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11236 –11239

Angewandte
Chemie
[9] G. P. McGlacken, T. A. Khan, Angew. Chem. Int. Ed. 2008, 47,
rable yields to those achieved by Ba, compound 1 is able to
effectively hydrodecyanate malononitriles 24, 26, and 28 to
give the respective mononitriles 25 (92%), 27 (91%), and 29
(89%). The lack of cyclized product in the case of 26 is in line
with expectations; an initially formed radical intermediate 33,
formed from generalized malononitrile substrate 32 should be
easily reduced to the corresponding anion 34 under the
heavily reducing reaction conditions.[36] These anionic mono-
nitrile products would be inert to further reduction, allowing
isolation of the mononitrile products 25, 27 and 29, in
excellent yields. Neutral mononitrile 30 is also inert to
reduction under these conditions, as was demonstrated in
a separate reaction.
In conclusion, tetra(iminophosphorano)-substituted bis-
pyridinylidene 1 represents the most reducing organic neutral
compound known, with its redox potential surpassing the
previous record holder by 190 mV. It is the only organic
electron donor with the ability to reduce dialkylarenesulfo-
namides as well as malononitriles without photoexcitation.
Further reductions involving donor 1 are currently under
investigation.
1819 – 1823; Angew. Chem. 2008, 120, 1843 – 1847.
[10] J. Garnier, J. A. Murphy, S. Z. Zhou, A. T. Turner, Synlett 2008,
2127 – 2131.
[11] R. Sword, L. A. Baldwin, J. A. Murphy, Org. Biomol. Chem.
2011, 9, 3560 – 3570.
[12] F. Schoenebeck, J. A. Murphy, S. Zhou, Y. Uenoyama, Y. Miclo,
T. Tuttle, J. Am. Chem. Soc. 2007, 129, 13368 – 13369.
[13] S. P. Y. Cutulic, J. A. Murphy, H. Farwaha, S. Z. Zhou, E.
Chrystal, Synlett 2008, 2132 – 2136.
[14] S. P. Y. Cutulic, N. J. Findlay, S. Z. Zhou, E. J. T. Chrystal, J. A.
Murphy, J. Org. Chem. 2009, 74, 8713 – 8718.
[15] P. I. Jolly, N. Fleary-Roberts, S. OꢀSullivan, E. Doni, S. Zhou,
J. A. Murphy, Org. Biomol. Chem. 2012, 10, 5807 – 5810.
[16] M. Szostak, D. J. Procter, Angew. Chem. Int. Ed. 2012, 51, 9238 –
9256; Angew. Chem. 2012, 124, 9372 – 9390.
[17] M. Szostak, M. Spain, D. J. Procter, Chem. Soc. Rev. 2013, 42,
9155 – 9183.
[18] M. Szostak, N. J. Fazakerley, D. Parmar, D. J. Procter, Chem.
Rev. 2014, 114, 5959 – 6039.
[19] E. Cahard, F. Schoenebeck, J. Garnier, S. P. Y. Cutulic, S. Zhou,
J. A. Murphy, Angew. Chem. Int. Ed. 2012, 51, 3673 – 3676;
Angew. Chem. 2012, 124, 3733 – 3736.
[20] E. Doni, B. Mondal, S. OꢀSullivan, T. Tuttle, J. A. Murphy, J. Am.
Chem. Soc. 2013, 135, 10934 – 10937.
[21] E. Doni, S. OꢀSullivan, J. A. Murphy, Angew. Chem. Int. Ed.
2013, 52, 2239 – 2242; Angew. Chem. 2013, 125, 2295 – 2298.
[22] S. OꢀSullivan, E. Doni, T. Tuttle, J. A. Murphy, Angew. Chem.
Int. Ed. 2014, 53, 474 – 478; Angew. Chem. 2014, 126, 484 – 488.
[23] S. S. Hanson, N. A. Richard, C. A. Dyker, Chem. Eur. J. 2015, 21,
8052 – 8055.
[24] H. S. Farwaha, G. Bucher, J. A. Murphy, Org. Biomol. Chem.
2013, 11, 8073 – 8081.
[25] B. Eberle, O. Hubner, A. Ziesak, E. Kaifer, H.-J. Himmel, Chem.
Eur. J. 2015, 21, 8578 – 8590.
Acknowledgements
We are grateful for the support of NSERC of Canada, the
Canada Foundation for Innovation, the New Brunswick
Innovation Foundation, EPSRC (current grant number EP/
K033077/1) and the Harrison McCain Foundation. S.S.H. is
grateful to the government of Akwa Ibom State, Nigeria for
financial support.
[26] I. Yavari, M. Adib, L. Hojabri, Tetrahedron 2002, 58, 7213 – 7219.
[27] J. Boedeker, B. Richter, P. Koeckritz, Z. Chem. 1980, 20, 417 –
418.
Keywords: electron transfer · iminophosphoranes ·
[28] M. J. Corr, M. D. Roydhouse, K. F. Gibson, S. Zhou, A. R.
Kennedy, J. A. Murphy, J. Am. Chem. Soc. 2009, 131, 17980 –
17985.
organic reductants · reduction · substituent effects
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11236–11239
Angew. Chem. 2015, 127, 11388–11391
[29] D. Zhang, J. P. Telo, C. Liao, S. E. Hightower, E. L. Clennan, J.
Phys. Chem. A 2007, 111, 13567 – 13574.
´
[30] P. P. Romanczyk, G. Rotko, S. S. Kurek, Electrochem. Commun.
2014, 48, 21 – 23.
[1] S. Zhou, H. Farwaha, J. A. Murphy, Chimia 2012, 66, 418 – 424.
[2] J. A. Murphy, J. Org. Chem. 2014, 79, 3731 – 3746.
[3] E. Doni, J. A. Murphy, Chem. Commun. 2014, 50, 6073 – 6087.
[4] J. Broggi, T. Terme, P. Vanelle, Angew. Chem. Int. Ed. 2014, 53,
384 – 413; Angew. Chem. 2014, 126, 392 – 423.
[5] J. A. Murphy, S. Zhou, D. W. Thomson, F. Schoenebeck, M.
Mahesh, S. R. Park, T. Tuttle, L. E. A. Berlouis, Angew. Chem.
Int. Ed. 2007, 46, 5178 – 5183; Angew. Chem. 2007, 119, 5270 –
5275.
[6] J. A. Murphy, T. A. Khan, S. Zhou, D. W. Thomson, M. Mahesh,
Angew. Chem. Int. Ed. 2005, 44, 1356 – 1360; Angew. Chem.
2005, 117, 1380 – 1384.
[7] J. A. Murphy, J. Garnier, S. R. Park, F. Schoenebeck, S. Zhou,
A. T. Turner, Org. Lett. 2008, 10, 1227 – 1230.
[31] C. P. Andrieux, J. Pinson, J. Am. Chem. Soc. 2003, 125, 14801 –
14806.
[32] R. Sword, S. OꢀSullivan, J. A. Murphy, Aust. J. Chem. 2013, 66,
314 – 322.
[33] D. P. Curran, C. M. Seong, J. Am. Chem. Soc. 1990, 112, 9401 –
9403.
[34] D. P. Curran, C. M. Seong, Synlett 1991, 107.
[35] H. Y. Kang, S. W. Hong, S. Y. Cho, H. Y. Koh, Tetrahedron Lett.
1995, 36, 7661 – 7664.
[36] T. Kawamoto, S. J. Geib, D. P. Curran, J. Am. Chem. Soc. 2015,
2015, 137, 8617 – 8622.
[37] E. Doni, J. A. Murphy, Org. Chem. Front. 2014, 1, 1072 – 1076.
[8] M. Kuroboshi, M. Tanaka, S. Kishimoto, K. Goto, M. Mochizuki,
H. Tanaka, Tetrahedron Lett. 2000, 41, 81 – 84.
Received: June 11, 2015
Published online: July 23, 2015
Angew. Chem. Int. Ed. 2015, 54, 11236 –11239
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11239