NHC-Catalyzed Metathesis and Phosphorylation Reactions of Disulfides: Development and Mechanistic Insights

Article abstract of DOI:10.1002/chem.201700744

The development of efficient methods for the metathesis and phosphorylation reactions of disulfide compounds is of widespread interest due to their important synthetic utility in polymer, biological, medicinal and agricultural chemistry. Herein, we demonstrate the use of N-heterocyclic carbenes (NHCs) as versatile organocatalysts to promote these challenging reactions under mild conditions. This metal- and oxidant-free protocol is operationally simple with very short reaction times. The interplay between the nucleophilicity and basicity of NHCs in these reactions were also elucidated by NMR studies and high-level ab initio calculations.

Full text of DOI:10.1002/chem.201700744

A Journal of
Accepted Article
Title: NHC-Catalyzed Metathesis and Phosphorylation Reactions of
Disulfides: Development and Mechanistic Insights
Authors: Reece Douglas Crocker, Mohanad A Hussein, Junming Ho,
and Thanh Vinh Nguyen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201700744
Link to VoR: http://dx.doi.org/10.1002/chem.201700744
Supported by

10.1002/chem.201700744
Chemistry - A European Journal
COMMUNICATION
NHC-Catalyzed Metathesis and Phosphorylation Reactions of
Disulfides: Development and Mechanistic Insights
Reece D. Crocker,[a] Mohanad A. Hussein,[a] Junming Ho*[b] and Thanh V. Nguyen*[a]
Abstract: The development of efficient methods for the metathesis
NHC
S
S
R'
S
S
R
R
R'
R3
R
R'
and phosphorylation reactions of disulfide compounds is of
widespread interests due to their important synthetic utility in
polymer, biological, medicinal and agricultural chemistry. Herein, we
demonstrate the use of N-heterocyclic carbenes (NHCs) as versatile
organocatalysts to promote these challenging reactions under mild
conditions. This metal-free oxidant-free protocol is operationally
simple with very short reaction times. The interplay between the
nucleophilicity and basicity of NHCs in these reactions were also
elucidated by NMR studies and high-level ab initio calculations.
S
R
R
S
S
S
disulfide metathesis
N
Z
Y
O
P
R2
O
P
NHC
R4
cat. NHC
R1
R1
R
H
S
P(O) - S coupling reaction
R2
Scheme 1. NHC-catalyzed reactions of disulfides.
Several methods have been recently developed to facilitate the
disulfide metathesis reactions using phosphine catalysts[15] or
mechano-[9a,16] and photochemical processes.[17] However, it is
still an ongoing challenge to address the limitations in substrate
scope, equilibration time and the precision of these methods.
Given the fact that thiolates or phosphines can heterolytically
cleave disulfide bond via nucleophilic attack,[9a,18] we envision
that the highly nucleophilic NHCs could act as effective
organocatalyst for this reaction. Indeed, our study demonstrated
that disulfide metathesis reactions proceeded smoothly in the
presence of NHC catalysts under mild conditions with excellent
efficiency.
Our first test reaction on the metathesis of Bn-S-S-Bn (1a)
and pTol-S-S- pTol (1b, Table 1) using the standard MeIMes
NHC 3A (10 mol %) catalyst was met with instant success. The
reaction was initially carried out in CD3CN where NMR and GC-
MS analyses clearly showed that the equilibrium to Bn-S-S-pTol
(2ab) was reached within 10 minutes without any side reaction.
The product 1a:2ab:1b ≈ 25:50:25 ratio is in good agreement
with the theoretical yields of this statistical equilibrium reaction.
These favorable preliminary results, with up to 10-fold reduction
in reaction time compared to known methods,[9a,15a,17]
encouraged us to fully optimize this NHC-promoted disulfide
metathesis reaction (Table 1). Among the pool of six NHC
catalysts tested, imidazolylidenes 3A-3C gave similar results
with shorter reaction times than imidazolinylidene, triazolylidene
and thiazolylidene catalysts (3D-3E), which is in good
agreement with the nucleophilicity of these catalysts.[19]
Acetonitrile proved to be the best solvent (entries 2,7,8, Table 1),
hinting at a polar transition state for these reactions. The catalyst
loading could be reduced to 5 mol% without affecting the
equilibrium outcomes (entries 2 and 9-11, Table 1). In the
absence of NHC catalysts, no disulfide 2ab was found even
after a prolonged reaction time (entry 12, Table 1). Disulfide
exchange by homolytic cleavage of the S-S bond[9b] is ruled out
as the use of BHT as a radical scavenger still led to good
conversion (entry 15, Table 1).[20]
Sulfur-transfer chemical transformations play pivotal roles in
biological processes and synthetic chemistry.[1] Despite sulfur
being an abundant element of the chalcogen group, organic
reactions involving organosulfur compounds are relatively under-
investigated compared to their oxygen counterparts.[2] The
development of efficient metathesis[3] and phosphorylation[4]
reactions of disulfides are of particular interest due to their
synthetic values in polymer, medicinal, agricultural and catalytic
chemistry.[3,5] Recently, these reactions have also become
versatile tools for dynamic combinatorial[6] and diversity-oriented
chemistry[7] as they can rapidly generate molecular libraries for
various applications.[6a,8] Traditional methods for these reactions
normally require harsh conditions or involve toxic or unstable
reagents and catalysts with limitations in scope.[9] Herein, we
report a novel and efficient N-heterocyclic carbene (NHC)-
catalyzed procedure to promote both the disulfide metathesis
reaction and the synthesis of phosphorothiolates via phosphite-
disulfide coupling reaction (Scheme 1). High-level ab intio
studies were carried out to propose plausible mechanisms for
these reactions. This work opens up new possibilities in NHC-
mediated organic synthesis,[10] as the catalytic activity of NHCs
on organosulfur and organophosphorus substrates has been
inadequately studied.[5a,11]
The disulfide bond is one of the most interesting covalent
bonds in dynamic covalent/combinatorial chemistry (DCC) for
drug discovery and chemical biology studies.[6,12] The readily
exchangeable -S-S- linkage[13] can be utilized in metathesis
reactions to rapidly access diverse libraries of heterodimeric
analogues from a small number of disulfide building blocks.[8,14]
[a]
[b]
[**]
R. D. Crocker; M. A. Hussein; Dr T. V. Nguyen
School of Chemistry, University of New South Wales
Sydney, Australia
E-mail: t.v.nguyen@unsw.edu.au
Dr J. Ho
Institute of High Performance Computing, Agency for Science
Technology and Research, Singapore
E-mail: hojm@ihpc.a-star.edu.sg
The Supporting Information is available: Experimental and
computational de-tails, analytical data, NMR spectra, and Cartesian
coordinates of M06-2X optimized geometries are provided.
The optimized conditions were then used for dynamic
metathesis reactions between a range of disulfides (Scheme 2).
Most of them underwent rapid and clean cross metathesis with
each other to give a library of unsymmetrical disulfides. There
was negligible discrepancy in reaction outcomes for primary
This article is protected by copyright. All rights reserved.

10.1002/chem.201700744
Chemistry - A European Journal
COMMUNICATION
Table 1. Optimization of disulphide metathesis reaction
with disulfides 1c and 1d (Scheme 2b). NHC 3C presumably
acted as a nucleophilic initiator to form thio-imidazolium cation 5
and thiolate 6, which then attacks a disulfide and regenerates a
sulfide anion each time. The initiation step has a significantly
higher (ca. 20 kJ mol-1) barrier, and is consistent with reaction
times correlating inversely with nucleophilicity of the NHCs
(Table 1). Control experiments (entries 13-14 in Table 1) where
the benzylthiolate or KHMDS/BnSH are introduced directly into
the reaction mixture resulted in significantly longer reaction
times (c.f. entry 3).[20] The relatively small thermodynamic driving
force (-6 kJ mol-1) and barrier (70 kJ mol-1) associated with the
initial/regeneration step indicates that a small but non-negligible
amount of free NHC (ca. 10% of the total amount of NHC-
derived species, based on calculated ΔG) is present throughout
the reaction, which is consistent with NMR observations.[20]
Presumably, this small fraction of charge-neutral NHC catalyst
diffuses more rapidly than thiolates in acetonitrile,[22] initiating the
reaction at distal sites that would explain the observed rate
enhancement. As such, the NHC also plays a minor catalytic
role in the metathesis reactions.
H2
C
S
cat. NHC
S
S
S
S
S
solvent, rt H3C
2ab
1b
1a
Ph
Mes
Dipp
Dipp
N
S
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
3A Mes
3B
3C
3D Dipp
Dipp
3E
3F
Entry[a]
Catalyst, mol%
3A, 10
Solvent
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
Time[b]
<10
5
2ab[c]
50%
50%
50%
50%
50%
1
2
3
4
5
With the establishment of this NHC-promoted disulfide
metathesis protocol, we turned our attention to the synthesis of
phosphorothiolates from disulfide-phosphite coupling reactions.
These organo-phosphorus-sulfur compounds serve as valuable
intermediates in organic chemistry and precursors for important
3B, 10
3C, 10
<10
90
3D, 10
3E, 10
240
6
3F, 10
CD3CN
240
50%
(a) Substrate scope
nPr
iPr
nBu
tBu
Bn
pTol Cy
7
3B, 10
3B, 10
CD2Cl2
C6D5CD3
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
90
720
<10
360
720
1440
120
720
120
50%
5%
Et
Et
8
nPr
iPr
9
3B, 5
50%
20%
5%
nBu
tBu
Bn
10
11
12
13
14
15
3B, 2.5
3B, 1.3
No catalyst
NaSBn, 10
-
pTol
Cy
22%
12%
35%
= 50%,
= 5-30%;
= no reaction;
= not studied.[20]
KHMDS, 10[d]
(b) Proposed mechanism and computational studies
3B, 10 and
BHT (1.0 equiv)[20]
Et
G3(MP2)-CC/SMD
free energies
in MeCN
N
N
1c
S
S
Et
[a] Reaction conditions: NHC catalyst 3 in solvent (1.0 mL) then a mixture of
disulfide 1a (0.5 mmol) and 1b (0.5 mmol) in solvent (1.0 mL). [b] Time (in
minute) to reach equilibrium. [c] Conversion by NMR or GC/LCCMS. [d] 10
mol% BnSH was also added.
ΔG = 73 kJ mol-1
3C
ΔGsoln = -6 kJ mol-1
Et
Et
N
ΔGsoln = -13 kJ mol-1
N
N
alkyl disulfides or aryl disulfides. However, bulky substrates such
as diisopropyl, dicyclohexyl or di(tert-butyl)disulfides only
reacted sluggishly to afford the products in poor to moderate
yields (Scheme 2a). To the best of the authors’ knowledge, this
is the first example of NHC-catalyzed disulfide metathesis, and it
is of interest to understand the mechanism of these reactions.
However, mechanistic studies of these reactions is challenging
due to the short reaction times, as even at – 40 °C, the equilibria
were reached within 10-30 minutes.
S
S
S
N
Et
S
δ−
δ+
S
5
6
4
Et
ΔG = 54 kJ mol-1
Bu
ΔGsoln = -4 kJ mol-1
S
Bu
Et
1d
N
N
S
Et
S
S
5
Et
Bu
S
S
Bu
2cd
2cd
Bu
S
7
1c
6
In combination with high-level ab initio calculations,[21] we
proposed possible mechanistic pathways for this type of reaction
Scheme 2. NHC-catalyzed disulfide metathesis.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700744
Chemistry - A European Journal
COMMUNICATION
Table 2. P(O)-S coupling reactions[a]
short reaction times. The solvent effect was found to be slightly
different from the disulfide metathesis reaction where toluene
gave better reaction outcomes than acetonitrile (entries 3 and
10, Table 2). Imidazolylidene catalysts 3A, 3B again gave the
best outcomes for this P(O)-S coupling reaction (entries 1-7,
Table 2). The optimization of catalyst loading stalled at 5 mol%
for catalyst 3B (entries 3 and 8 Table 2).
O
P
O
cat. NHC
R1
P
R1
S
R
R
H
R
S
S
toluene, rt, 5 - 40 min, - RSH
R2
R2
4
5
1
Ph
Mes
Dipp
Dipp
N
N
N
N
N
N
N
N
S
N
N
N
N
Ph
Ph
3A Mes
3B
3D Dipp
3C
3E
Dipp
3F
With these optimal conditions, we were able to promote the
Entry[a]
Product
5aa
5aa
5aa
5aa
5aa
5aa
5aa
5aa
5aa
5aa
Catalyst
Cat. loading
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
Yield[b]
-
coupling reactions between
a
range of disulfides and
1
2
-
3A
organophosphorus compounds to afford phosphorothiolate
products in good to excellent yields for most cases studied (5aa-
5fc, Table 2). Thiol derivatives of the disulfide substrates were
always isolated in comparable yields to the main products. This
NHC-catalyzed reaction worked well for all three different types
of P(O)-H substrates, namely phosphites (5aa-5cd),
phosphinates (5da-5ea) and phosphine oxide (5fa-5fc). The
limitation actually arose from less reactive disulfide substrates
where steric hindrance might be at play (5ab, 5cb, 5db, 5de,
5ea, also see Scheme 2a).[20] In light of its overall good
performance, this method could serve as a convenient and
efficient organocatalytic alternative[4] for the synthesis of
synthetically valuable phosphorothiolates.
74%
83%
56%
3
3B
4
3C
5-7
8
3D-F
3B
traces-20%
17%
9
3B
10 mol%[c]
10 mol%
10 mol%
10 mol%
70%
10[d]
11
12
3B
65%
NaSBn
DBU
14%
23%
Interestingly, 31P NMR studies[20] in combination with
computational modelling[20] suggest that the reaction did not
proceed through the activation of disulfide substrate like the S-S
metathesis reaction discussed earlier (see pages S32/33 –
SI).[20] In this proposed mechanism (Scheme 3), NHC 3C acts as
a Brønsted base catalyst to activate the phosphorus center of
with 10 mol% catalyst 3B
(from phosphites)
(from phosphinates)
O
O
O
P
O
nBuO
P
MeO
P
Bn
Bn
Ph
Ph
Bn
P
Bn
S
S
S
S
nBuO
MeO
MeO
BnO
5aa, 83%, 5 min
5ca, 89%, 5 min
5da, 100%, 15 min
5ea, 12%, 24 h
(from phosphine oxide)
O
O
O
O
nBuO
pTol
P
MeO
P
pTol
Ph
substrate 4c via a proton-transfer to form an ion-pair
P
pTol
S
Ph
S
P
Bn
S
nBuO
S
MeO
MeO
intermediate 8. This is also the rate-limiting step for the reaction,
as confirmed by kinetic studies (see page S34 in the SI). The
nucleophilic phosphorus center readily reacts with the disulfide
Ph
5ab, 34%, 40 min
5cb, 19%, 40 min
5db, 45%,40 min
5fa, 94%, 5 min
O
O
O
O
nBuO
P
MeO
P
Et
Et
Ph
P
Et
a
barrier height of 27 kJ mol-1) to form the
Ph
P
pTol
S
S
S
1’ (with
S
nBuO
MeO
MeO
Ph
phosphorothiolate product 5’ via a termolecular transition state
(inset in Scheme 3). The higher catalyst loading (10 mol%)
needed in these reactions is attributed to competing reaction
between the NHC and the disulfide substrate to form the
thiolates (Scheme 2b). The proposed mechanism also agrees
well with the experimental observation that species with weak
basicity (3D-F, entries 5-7, Table 2) to drive the proton transfer
could not promote the reaction efficiently.
5ac, 84%, 5 min
5cc, 68%, 5 min
5dc, 68%, 5 min
5fb, 79%, 40 min
O
O
O
O
nBu
Ph
MeO
5de, trace
Ph
MeO
P
PhO
P
Cy
P
Et
P
Bn
S
S
S
S
MeO
Ph
PhO
5cd, 76%, 5 min
5ba, ~94%, 30 min
5fc, 96%, 5 min
[a] Reaction conditions: NHC catalyst 3 in solvent (6.0 mL) then a mixture of
disulfide 1 (0.55 mmol) and phosphite 4 (0.50 mmol) in solvent (1.0 mL) at rt.
[b] Yield of isolated product. [c] 10 mol% water was added to the reaction.
[d] MeCN was used as solvent.
In support of the proposed mechanism, we note that there is
a direct correlation between basicity and reaction outcome.
Computed relative pKa values in toluene, as well as
experimental aqueous values for structurally related NHCs
indicate that catalysts A-C are the most basic amongst the
present set of NHCs (See page S50 in the SI).[25] Additionally,
replacement of NHC catalyst (pKa in DMSO ca. 24)[26] by the
weakly basic NaSBn (pKa in DMSO ca. 10.3)[27] resulted in 14%
yield (entry 11 Table 2), whilst DBU[28] (pKa in DMSO ca. 12)
provided a slight improvement (entry 12). The calculations also
indicate that 4c’-P(III) is not likely to be an active species since
4c-P(V) to 4c’-P(III) tautomerization[29] (Scheme 3) is
thermodynamically disfavored (ΔG ca. 60 kJ mol-1).[30] Notably,
medicinal agents and agrochemicals.[4,9b] Current methods to
produces these compounds normally involve toxic and moisture-
sensitive reagents or catalysts.[4,9b,23] NHC organocatalysts were
previously known to also activate phosphites for a number of
(1,ω)-hydrophosphonylation to carbonyl compounds.[11b,11i,24]
Hence, it seems likely that NHCs should also act as effective
catalysts for the P(O)-S coupling reactions between disulfides
and P(O)H substrates.
We focused our initial investigation on the reaction between
Bn-S-S-Bn and (BuO)2P(O)H (entries 1-10, Table 2). It was
encouraging to note that the reaction proceeded smoothly and
cleanly at room temperature with excellent yields within very
This article is protected by copyright. All rights reserved.

10.1002/chem.201700744
Chemistry - A European Journal
COMMUNICATION
ΔGsoln = 59 kJ mol-1
[1] (a) E. Block, Reactions of organosulfur compounds, Academic Press,
1978; (b) R. J. W. Cremlyn, An introduction to organosulfur chemistry,
Wiley, 1996; (c) C. B. Anfinsen, Science 1973, 181, 223-230.
[2] (a) L. I. Belenʹkiĭ, Chemistry of organosulfur compounds: general
problems, E. Horwood, 1990; (b) P. Page, Organosulfur Chemistry:
Synthetic Aspects, Academic Press, 1995; (c) E. Block, Advances in
Sulfur Chemistry, Vol. 1, Elsevier Science, 2013.
[3] (a) S. P. Black, J. K. M. Sanders, A. R. Stefankiewicz, Chem. Soc. Rev.
2014, 43, 1861-1872; (b) B. Mandal, B. Basu, RSC Adv. 2014, 4, 13854-
13881.
O
H
O
H
G3(MP2)-CC/SMD
free energies
in toluene
MeO
MeO
MeO
MeO
N
P
P
N
4c - P(V)
4c' - P(III)
3C
proton-transfer
ΔG = 75 kJ mol-1; ΔGsoln = 13 kJ mol-1
Me
proton-transfer
ΔG = 55 kJ mol-1
ΔGsoln = -8 kJ mol-1
S
H
N
N
13
N
H
OMe
H
P
OMe
OMe
observed
N
OMe
O
P
by 31P NMR
(see page S31 - SI)
O
8
[4] Y. Zhu, T. Chen, S. Li, S. Shimada, L.-B. Han, J. Am. Chem. Soc. 2016,
138, 5825-5828.
[5] (a) M. Dutartre, J. Bayardon, S. Juge, Chem. Soc. Rev. 2016, 45, 5771-
9
ΔGsoln
=
-7 kJ mol-1
ΔG = 29 kJ mol-1
ΔGsoln = -58 kJ mol-1
Me
S
S
Me or 11
5794; (b) P. J. Murphy, Organophosphorus Reagents:
A Practical
1'
N
N
Approach in Chemistry, Oxford University Press, 2004; (c) Y. Deng, X.-J.
Wei, H. Wang, Y. Sun, T. Noël, X. Wang, Angew. Chem. Int. Ed. 2016,
Early View article, DOI = 10.1002/anie.201607948.
H
Me
S
OMe
OMe
10
P
O
N
[6] (a) Y. Jin, C. Yu, R. J. Denman, W. Zhang, Chem. Soc. Rev. 2013, 42,
6634-6654; (b) P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor,
J. K. M. Sanders, S. Otto, Chem. Rev. 2006, 106, 3652-3711.
[7] (a) S. L. Schreiber, Science 2000, 287, 1964-1969; (b) D. S. Tan, Nat.
Chem. Biol. 2005, 1, 74-84; (c) W. R. J. D. Galloway, A. Isidro-Llobet, D.
R. Spring, Nat. Commun. 2010, 1, 80.
5'
Me
S
11
N
10
8
3C
Me
termolecular
transition state
Et
N
N
S
S
S
Me
12
8 + 1'
(see SI for details)
5'
1'
[8] S. Otto, R. L. E. Furlan, J. K. M. Sanders, J. Am. Chem. Soc. 2000, 122,
12063-12064.
[also see Scheme 2b]
[9] (a) U. F. Fritze, M. von Delius, Chem. Commun. 2016, 52, 6363-6366;
(b) M. Xia, J. Cheng, Tetrahedron Lett. 2016, 57, 4702-4704.
[10] (a) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606-
5655; (b) in N-Heterocyclic Carbenes: From Laboratory Curiosities to
Efficient Synthetic Tools (Ed.: S. Diez-Gonzalez), RSC, Cambridge, UK,
2010, pp. 1- 442; (c) S. J. Ryan, L. Candish, D. W. Lupton, Chem. Soc.
Rev. 2013, 42, 4906-4917; (d) M. N. Hopkinson, C. Richter, M. Schedler,
F. Glorius, Nature 2014, 510, 485-496; (e) D. M. Flanigan, F. Romanov-
Michailidis, N. A. White, T. Rovis, Chem. Rev. 2015, 115, 9307-9387.
[11] (a) P. Chauhan, S. Mahajan, D. Enders, Chem. Rev. 2014, 114, 8807-
8864; (b) M. Hans, L. Delaude, J. Rodriguez, Y. Coquerel, J. Org. Chem.
2014, 79, 2758-2764; (c) J. Chen, S. Meng, L. Wang, H. Tang, Y.
Huang, Chem. Sci. 2015, 6, 4184-4189; (d) Y.-Z. Li, Y. Wang, G.-F. Du,
H.-Y. Zhang, H.-L. Yang, L. He, Asian. J. Org. Chem. 2015, 4, 327-332;
(e) Y.-T. Dong, Q. Jin, L. Zhou, J. Chen, Org. Lett. 2016, 18, 5708-5711;
(f) D. Enders, A. Saint-Dizier, M.-I. Lannou, A. Lenzen, Eur. J. Org.
Chem. 2006, 2006, 29-49; (g) S. Greenberg, D. W. Stephan, Chem. Soc.
Rev. 2008, 37, 1482-1489; (h) M. Dzięgielewski, J. Pięta, E. Kamińska,
Ł. Albrecht, Eur. J. Org. Chem. 2015, 2015, 677-702; (i) P. Arde, R.
Vijaya Anand, Org. Biomol. Chem. 2016, 14, 5550-5554.
[12] P. Dopieralski, J. Ribas-Arino, P. Anjukandi, M. Krupicka, J. Kiss, D.
Marx, Nat. Chem. 2013, 5, 685-691.
[13] J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455-2463.
[14] (a) K. C. Nicolaou, R. Hughes, J. A. Pfefferkorn, S. Barluenga, A. J.
Roecker, Chem. Eur. J. 2001, 7, 4280-4295; (b) O. Ramström, J.-M.
Lehn, ChemBioChem 2000, 1, 41-48.
[15] (a) R. Caraballo, M. Rahm, P. Vongvilai, T. Brinck, O. Ramstrom, Chem.
Commun. 2008, 6603-6605; (b) R. Caraballo, M. Sakulsombat, O.
Ramstrom, Chem. Commun. 2010, 46, 8469-8471.
Scheme 3. Proposed mechanism for the P(O)-S coupling reactions
addition of a catalytic amount of water (entry 9) or using a more
polar solvent (entry 10), known to enhance the formation of P(III)
tautomer,[28] both led to lower reaction efficiency.
In conclusion, we have developed novel NHC-catalyzed
methods to efficiently promote the disulfide metathesis as well
as the phosphite-disulfide coupling reactions under very mild
conditions and short reaction times. These metal-free protocols
were operationally simple but computational studies suggest that
they might be mechanistically more complex with interesting
activation modes. The computational studies provide
mechanistic insights into how the nucleophilicity/basicity of
NHCs can be exploited to enhance the two aforementioned
synthetic procedures. These reactions could serve as versatile
tools to rapidly generate diverse molecular libraries for
applications in synthetic and medicinal chemistry. This work also
opens up new opportunities in NHC-mediated chemistry of
organosulfur and organophosphorus compounds. Studies to
expand the scope of these methodologies in stereoselective
synthesis of bioactive compounds are on-going and will be
reported in due course.
[16] (a) A. M. Belenguer, T. Friscic, G. M. Day, J. K. M. Sanders, Chem. Sci.
2011, 2, 696-700; (b) A. M. Belenguer, G. I. Lampronti, D. J. Wales, J. K.
M. Sanders, J. Am. Chem. Soc. 2014, 136, 16156-16166.
[17] H. Otsuka, S. Nagano, Y. Kobashi, T. Maeda, A. Takahara, Chem.
Commun. 2010, 46, 1150-1152.
[18] R. Singh, G. M. Whitesides, J. Am. Chem. Soc. 1990, 112, 1190-1197.
[19] A. Levens, F. An, M. Breugst, H. Mayr, D. W. Lupton, Org. Lett. 2016,
18, 3566-3569.
Acknowledgements
[20] See the Supporting Information for more details.
[21] J. Ho, M. Z. Ertem, J. Phys. Chem. B 2016, 120, 1319-1329.
[22] M06-2X/6-31+G(d) SMD solvation free energy of NHC 3C is -63 kJ mol-1
in MeCN, whereas that of ethylthiolate is -254 kJ mol-1.
The authors thank the Australian Research Council (grant
DE150100517) and the UNSW Faculty of Science for financial
support. JH acknowledges the Singapore Agency for Science,
Technology and Research for support, and the NCI for generous
allocation of computing time.
[23] Y.-C. Liu, C.-F. Lee, Green Chem. 2014, 16, 357-364.
[24] L. He, Z.-H. Cai, J.-X. Pian, G.-F. Du, Scientific World J. 2013, 2013, 6.
[25] (a) E. M. Higgins, J. A. Sherwood, A. G. Lindsay, J. Armstrong, R. S.
Massey, R. W. Alder, A. C. O’donoghue, Chem. Commun. 2011, 47,
1559-1561; (b) R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith, A.
C. O’Donoghue, J. Am. Chem. Soc. 2012, 134, 20421-20432.
[26] R. W. Alder, P. R. Allen, S. J. Williams, J. Chem. Soc., Chem. Commun.
1995, 1267-1268.
[27] F. G. Bordwell, D. L. Hughes, J. Org. Chem. 1982, 47, 3224-3232.
[28] M. Baidya, H. Mayr, Chem. Commun. 2008, 1792-1794.
[29] B. G. Janesko, H. C. Fisher, M. J. Bridle, J.-L. Montchamp, J. Org.
Chem. 2015, 80, 10025-10032.
Keywords: N-heterocyclic carbene • organocatalysis • disulfide •
phosphorylation • high-level ab initio calculations
[30] J. P. Guthrie, Can. J. Chem. 1979, 57, 236-239.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700744
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Reece D. Crocker, Mohanad A. Hussein,
Junming Ho* and Thanh V. Nguyen*
Page No. – Page No.
NHC-Catalyzed Metathesis and
Phosphorylation Reactions of
Disulfides: Development and
Mechanistic Insights
Instant reactions: N-heterocyclic carbenes (NHCs) served as versatile
organocatalysts to promote disulfide exchange and phosphite-disulfide coupling
reactions under mild conditions. This metal-free oxidant-free protocol is
operationally simple and highly efficient with very short reaction times.
This article is protected by copyright. All rights reserved.