DBN hexafluorophosphate salts as convenient sulfonylating and phosphonylating agents

Article abstract of DOI:10.1039/c6ob01854h

Air-stable N-sulfonyl and N-phosphonyl DBN hexafluorophosphate salts have been synthesised under mild conditions as sulfonylating and phosphonylating agents. These salts are highly efficient in the sulfonylation and phosphonylation of a range of N- and O-nucleophiles to generate sulfonamides, sulfonate esters, phosphoramidates and phosphonate esters in good yields.

Full text of DOI:10.1039/c6ob01854h

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DBN hexafluorophosphate salts as convenient
sulfonylating and phosphonylating agents†
Cite this: DOI: 10.1039/c6ob01854h
Caroline S. Jones,*a Steven D. Bullb and Jonathan M. J. Williamsb
Received 26th July 2016,
Accepted 25th August 2016
DOI: 10.1039/c6ob01854h
www.rsc.org/obc
Air-stable N-sulfonyl and N-phosphonyl DBN hexafluorophosphate associated with cost and toxicity have been highlighted.
salts have been synthesised under mild conditions as sulfonylating N-Hydroxybenzotriazole (HOBt) sulfonates have since been
and phosphonylating agents. These salts are highly efficient in the reported as cheaper alternatives.8 PFP-, TCP- and HOBt-
sulfonylation and phosphonylation of
a range of N- and sulfonate esters have been shown to sulfonylate a range of
O-nucleophiles to generate sulfonamides, sulfonate esters, nucleophiles without the production of free acid in the
phosphoramidates and phosphonate esters in good yields.
reaction. However, in most cases these reactions with alcohols
or amines require high temperatures or the addition of a base
such as NEt3, DIPEA or LHMDS to avoid very long reaction
times. The use of sodium sulfinates,9 sulfamoyl salts,10
sulfonyl azides11 and sulfonyl hydrazides12 have also been
reported more recently as sulfonylating reagents, though the
methodologies tend to suffer from the use of toxic or explosive
reagents. The use of phosphonylating reagents has been
explored less in the literature, although similar benzotriazole-
based phosphonylating reagents have been reported recently
as stable alternatives to halophosphates.13 Whilst these
reagents were shown to phosphonylate a range of N-, O- and
S-nucleophiles the addition of different bases was again
required for most substrates.
Previous work in our group has detailed the efficient syn-
thesis of N-acyl 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)·BPh4
salts and their subsequent use as acylating agents.14 These
crystalline solids have been shown to acylate a wide range of
nucleophiles including primary amines, secondary amines,
sulfonamides and alcohols under relatively mild conditions
(Scheme 1).
Organosulfur and organophosphorus compounds are highly
important in organic synthesis and have found a wide range of
industrial applications. Sulfonamides, for example, have been
shown to exhibit antibacterial, anti-cancer and antiviral acti-
vities and the moiety is prevalent in currently researched and
marketed drugs.1 Phosphoramidates have also shown activity
as anti-inflammatory and anti-HIV prodrugs, whilst the
functional group is also present in many pesticides.2
In many recent sulfonylation and phosphonylation
methodologies sulfonyl chlorides3 and chlorophosphates4
remain widely used as building blocks though they suffer from
drawbacks; they are highly reactive species which are readily
hydrolysed in air, making them practically difficult to work
with.5 Additionally, when employed in sulfonylations and
phosphonylations these reactions proceed with the production
of one equivalent of HCl, rendering the transformation
inefficient where acid-sensitive substrates are present.
As a result, research has looked to develop alternative
sulfonylating and phosphonylating agents to offer mild and
convenient methodologies for the sulfonylation and phos-
phonylation of nucleophiles. Whilst examples of phosphony-
lating agents have attracted less attention in the literature,
sulfonylating agents for the formation of sulfonamides and
sulfonate esters have been more widely reported.
Pentafluorophenol (PFP)5b,6 and 2,4,6-trichloro-phenol (TCP)7
based sulfonate esters have proved efficient, though drawbacks
DBN salts offer an attractive alternative to acyl halides and
acid anhydrides in synthesis as they are not susceptible to
aCentre for Sustainable Chemical Technologies, University of Bath, Claverton Down,
Bath, BA2 7AY, UK. E-mail: C.Jones@bath.ac.uk
bDepartment of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, compound characterisation and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/c6ob01854h
Scheme 1 N-Acyl DBN·BPh4 salts for the acylation of amines and
alcohols.
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decomposition in air, do not produce free HCl in acylation addition–elimination at the sulfonyl centre. All subsequent
reactions and can be used under forcing thermal conditions reactions of sulfonyl DBN salts with other primary amines,
without the appearance of any side products.15 Due to the syn- including anilines, showed conversion into the corresponding
thetic importance of sulfonyl and phosphonyl groups it was adducts with minimal, if any, sulfonamide product observed
therefore decided to investigate whether this methodology (see ESI† for further examples).
could be extended towards N-sulfonyl and N-phosphonyl DBN
salts as sulfonylating and phosphonylating agents.
Whilst investigating other amines however, it was seen that
if reactions were carried out at lower concentrations and with a
Initially various N-sulfonyl and N-phosphonyl DBN·PF6 small excess of the nucleophile some of the desired sulfon-
salts were synthesised in one step using the methodology amides could be generated as the major product.
reported previously by our group for N-acyl DBN·BPh4 salts.14
After simple purification by silica gel plug a range of
Five salts were successfully synthesised from sulfonyl chlorides sulfonylated products was isolated. Scheme 4 details the
and chlorophosphates on a gram scale to generate bench substrate scope of the reaction with respect to secondary
stable solids in good yields (Scheme 2). By exchanging the amines (4a–4j) and phenolic alcohols (4k–4n). A variety of
chloride counter ion for hexafluorophosphate the salts cyclic secondary amines was well tolerated, however yields of
obtained were stable towards moisture in the air and no loss the corresponding sulfonamide products dropped off when
in reactivity was observed over the course of this project; more sterically demanding acyclic secondary amines were
offering a practical advantage over the direct use of sulfonyl employed (4h and 4i). Functionalised phenols gave sulfonate
chlorides and chlorophosphates in synthesis.
ester products in very good yields, although 20 mol% DBN was
Focusing our attention on sulfonylation protocols first, the required as an additive to obtain the observed conversions.
reaction of N-tosyl DBN·PF6 with 4-methylbenzylamine in Primary and secondary alcohols remained unreactive under
acetonitrile was carried out. Analysis of the crude 1H NMR the given conditions, presumably due to their lower nucleo-
spectrum showed that whilst all starting DBN salt had been philicity. Though limiting the scope of the reaction, this offers
consumed, the desired sulfonamide was not present. After an advantage in the reaction selectivity that can be obtained;
aqueous work-up and characterisation of the product however,
it was determined that adduct 3a had been formed
(Scheme 3). Adduct 3a would be formed by reaction of the
nucleophilic amine with the DBN amidine center, followed by
a ring opening step, rather than the expected nucleophilic
Scheme 2 Synthesis of sulfonyl and phosphonyl DBN·PF6 salts.
Scheme 3 Reaction
4-methylbenzylamine.
of
N-tosyl
DBN·PF6
salt
with
Scheme 4 Sulfonylation of nucleophiles. Reactions carried out with
1.05 equiv. nucleophile; a 18 h; b 20 mol% DBN additive.
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Table 1 Reactivities of DBN and DABCO sulfonyl salts
Entry
1
Product
Sulfonyl salt
Yield (%)
4a
DBN
DABCO
86
82
Scheme 5 Comparative reaction of 3-hyrdoxylbenzyl alcohol with
DBN salt 1a and tosyl chloride.
2
3
6a
6b
DBN
DABCO
0
74
it has been shown that amine and phenol functionalities can
be tosylated preferentially in the presence of primary alcohol
groups (4j and 4o).
DBN
DABCO
0
89
For a direct comparison with more traditional sulfonylation
methodologies, the sulfonylation of 3-hydroxybenzyl alcohol
was carried out using tosyl chloride and pyridine (Scheme 5).
The reaction was stirred at room temperature for 18 h and
the crude reaction mixture analysed. 1H NMR spectroscopy
4
5
6
6c
4l
DBN
DABCO
0
79
DBN
DABCO
0
75
showed that
a complex mixture of products had been
produced, whilst analysis by GC-MS revealed that the major
components of this mixture were the starting material,
3-hydroxybenzyl alcohol, and the unwanted side product
3-hydroxybenzyl chloride (Scheme 5). 3-Hydroxybenzyl chloride
would be formed by sulfonylation of the benzylic alcohol,
followed by displacement of the newly installed tosyl group by
the chloride anion – a common side reaction observed when
using tosyl chloride. Products containing tosylated phenol or
benzylic alcohol groups were not observed in any appreciable
quantities. This result highlights the advantages of using DBN
salts to achieve selective sulfonylation reactions of more
complex substrates. Not only is a switch in selectivity for the
phenol over the benzylic alcohol observed, but the absence of
any free acid in our method also prevents these types of side
reactions occurring.
In an attempt to overcome issues related to DBN salt
reactivity and product distribution, especially with respect to
primary amines, a second generation N-tosyl salt was investi-
gated. The base 1,4-diazabicyclo[2.2.2]octane (DABCO) was
chosen to replace DBN in our salts due to its low cost, ready
availability and lack of a reactive amidine centre. Synthesis of
the N-tosyl DABCO·PF6 salt (5a) was carried out under the
same conditions as our DBN salts and generated our product
as a colourless solid in an 86% yield (Scheme 6).
6d
DBN
DABCO
0
82
Reactions carried out with 1.05 equiv. nucleophile (DBN salt) or 1.2
equiv. sulfonyl salt (DABCO salt).
86% and 82% yields respectively (Table 1, entry 1). However,
whilst primary amines were seen to form adducts with DBN
salts (Scheme 3), 4-methylbenzylamine reacted smoothly with
our DABCO salt to give the desired sulfonamide 6a in a 74%
yield. Pleasingly anilines and alcohols which had proved
entirely unreactive with the N-tosyl DBN·PF6 salt generated the
corresponding products in high yields when the N-tosyl
DABCO·PF6 salt was employed instead (Table 1, entries 3–6).
Products obtained from DABCO salts could also be purified by
a simple aqueous work-up due to the absence of any side
products.
Whilst this study highlighted the impressive reactivity of
the N-tosyl DABCO·PF6 salt some issues arose during its use.
The DABCO salts were seen to be unstable to moisture in the
air and proved susceptible towards decomposition (see ESI†
for results of stability studies). As a result, current work looks
to improve upon the stability of these types of salts, otherwise
they must be used soon after synthesis for best results.
With our DBN (1a) and DABCO (5a) salts in hand a study
was then undertaken to compare their relative reactivities.
With secondary amine piperidine, DBN and DABCO salts were
seen to give comparable results; generating sulfonamide 4a in
At this stage attention was then turned towards the
reactivity of our N-phosphonyl DBN·PF6 salts (2a and 2b).
Reactions with a range of secondary amines and phenolic alco-
hols in acetonitrile generated the corresponding phosphor-
amidates and phosphates in good yields (Scheme 7);
phosphonylated products proved unstable towards an aqueous
work-up so were purified by silica gel chromatography.
Phosphoramidates 7a and 7b could also be obtained in
good yields (83% and 80% respectively) by reacting piperidine
with the corresponding DBN salt at room temperature for
Scheme 6 Synthesis of N-tosyl DABCO·PF6 salt.
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Table 2 Phosphonylation of primary amines
Entry
1
Product
Yield (%)
71
8a
8b
2
3
78
66
8c
4
5
8d
8e
63
0a
Scheme 7 Phosphonylation of nucleophiles. Reactions carried out with
1.3 equiv. DBN salt; a 24 h; b 20 mol% DBN additive, 4 h.
a Conversion as determined by analysis of the crude 1H NMR
spectrum.
18 h, showing that the methodology can be employed where
temperature sensitive substrates are involved. Yields were seen
to drop off when more sterically hindered acyclic secondary
amines were employed (7g and 7h). However, the reaction
tolerated a range of functionalities and the addition of 20 mol%
DBN could bring about the phosphonylation of phenolic
substrates (7i–7k). Disappointingly none of the desired
phosphates were isolated from reaction of N-phosphonyl
DBN·PF6 salt 2b with either primary or secondary alcohols.
When looking at the phosphonylation of primary amines it
was found that the production of DBN adducts (Scheme 3)
could be minimised by altering reaction conditions. If equi-
molar amounts of the DBN salt and amine were employed,
along with high reaction concentrations, the production of the
corresponding adduct was favoured. However, a low reaction
concentration and an excess of the N-phosphonyl DBN·PF6 salt
allowed for the successful synthesis of phosphoramidates
8a–8d from primary amines in moderate to good yields
(Table 2). The phosphonylation of p-anisidine was not
observed in any quantity (8e).
In conclusion, a variety of bench-stable N-sulfonyl and
N-phosphonyl DBN·PF6 salts have been successfully syn-
thesised for use as sulfonyl and phosphonyl donors. DBN salts
offer an attractive alternative to sulfonyl chlorides and chloro-
phosphates in these types of reactions as they are practically
easy to handle and they avoid the production of free acid in
the reaction.
Our DBN salts have been shown to be highly efficient in the
sulfonylation and phosphonylation of secondary amines and
phenolic alcohols. Unexpected ring-opened side products were
observed when primary amines were employed, however under
certain reaction conditions the production of these can be
successfully minimised. Second generation N-tosyl DABCO·PF6
salts have also been investigated and proved highly reactive in
the sulfonylation of a wide range of nucleophiles. Their poor
stability towards moisture currently limits their practical
application in this field and as a result, efforts to overcome
this are ongoing.
We thank the EPSRC Doctoral Training Centre in
Sustainable Chemical Technologies (Grant EP/G03768X) for
studentship (C. S. J.).
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