Amide Bond Formation: Beyond The Myth of Coupling Reagents: Eric Valeur W and Mark Bradley
Amide Bond Formation: Beyond The Myth of Coupling Reagents: Eric Valeur W and Mark Bradley
Amide Bond Formation: Beyond The Myth of Coupling Reagents: Eric Valeur W and Mark Bradley
Fig. 1 Examples of top drugs containing an amide bond. These 1.2 Use of additives
examples are just a small selection of drugs containing amide bonds
illustrating the importance of this functional group. In order to reduce the epimerisation level when using carbo-
diimides as coupling reagents, Koenig and Geiger introduced
1-hydroxy-1H-benzotriazole (HOBt) 9 as an additive,24,25
showing that, when using this additive, yields were higher
and epimerisation levels lower. For example, when coupling
Z-Gly-Phe-OH to H-Val-OMe, the epimerisation levels
dropped from 35% to 1.5%.
HOBt 9 is believed to work by initially reacting with the
O-acylurea 6 to give the OBt active ester 10, which enhances the
reactivity of the ‘‘activated ester’’ by encouraging/stabilising
the approach of the amine via hydrogen bonding (Scheme 3).
Scheme 1 Principle of the activation process for amide-bond However, HOBt can yield by-products, thus it catalyses the
formation. formation of diazetidine 11 (Scheme 4).26
In 1994, Carpino reported a related additive, 1-hydroxy-
the first time can be completely lost. The process can be made 7-azabenzotriazole (HOAt) 12 (Fig. 2), which was even more
even more complicated as epimerisation, usually through an efficient than HOBt 9 in terms of yield, kinetics and reduced
oxazoline intermediate, may take place during amide bond epimerisation levels.27 For example epimerisation during
formation. Thus, when coupling reagents are evaluated, coupling of Z-Val-OH and H-Val-OMe using DCC 5 dropped
several tests that have been developed to assess the extent of from 41.9% with HOBt 9 to 14.9% with HOAt 12, while
epimerisation (see Table 1) should be carried out. during the coupling of Z-PheVal-OH to H-Ala-OMe using
Table 1 Common epimerisation tests used for coupling reagent evaluation involving amino acids
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half-life of the activated esters of Z-Aib-OH in the presence of Fig. 5 Aminium and uronium isomers.
4-chloroaniline. HOAt-based reagents HAM2PyU 41a,
HAM2PipU 42a, HAE2PyU 43a, HAE2PipU 44a, HATeU activated esters might be hydrolysed rather than coupled to
45a reacted more quickly than the HOBt-based reagents the poorly nucleophilic 4-chloroaniline. Epimerisation was
HBM2PyU 41b, HBM2PipU 42b, HBE2PyU 43b, HBE2PipU low (Anteunis test) when the reagents were used in the
44b, HBTeU 45b. However no yields were given, which makes presence of collidine but was as high as 11.8% in the presence
the direct comparison of the reagents impossible. Indeed, the of DIPEA when using HBTeU 45b. Overall it was not evident
that any of the new reagents reported were beneficial over a 2.4 Other reagents
reagent like HATU 28a. DepOBt (originally called BDP) 62b was reported by Kim
Recently, El-Faham reported further development of such (Fig. 9).63 The reagent appeared to couple aniline to benzoic
coupling reagents.49 HDMA 46a, HDMB 46b, and 6-HDMCB acid or phenylacetic acid in high yield, and also aminoacids
47 were evaluated and little variation on epimerisation levels was (Phe, Val, Met, Ile) to other amino acids (Gly, Ser, Val) in high
noticed, but HDMA 46a proved to give higher yields for the yield although N-Methylated substrates were not tested.
synthesis of Fmoc-Val-Val-NH2 compared to HATU 28a. Other Epimerisation was evaluated via Young’s test and found to
reagents such as 6-HDMFB 48, 4-HDMA 49, HDMTA 50a and be low. The same group reported DpopOBt 63b but epimeri-
HDMTB 50b were also synthesised.50 Overall there was hardly sation was high.64
any difference between the different reagents. HDMB 46b Carpino reported DepOAt 62a, DpopOAt 53a, DmppOAt
displayed the best hydrolytic stability while having better solubility 64, DtpOAt 65a and DtpOBt 65b.65 Again, no real improve-
than HATU 28a. Morpholino derivatives HDMA 46a and ment was gained compared to HATU 33a. For the synthesis of
HDMB 46b showed better efficiency than their thio analogues ACP(65-74), HATU 33a outperformed any of these reagents.
HDMTA 50a and HDMTB 50b. An epimerisation study for the coupling of Z-Phe-Val-OH and
H-Pro-NH2 showed that DmppOAt 64 (3.6% of LDL isomer)
2.2 Phosphonium salts
and DtpOAt 65a (2.9%) gave less epimerisation than HATU
Another family of coupling reagents based on HOBt/HOAt 28a (5.0%), while DtpOBt 65b was worse (11.4%), but no
uses a phosphonium group. Phosphonium salts have the explanation was given.
advantage of not yielding guanidinium by-products via reac- HAPyTU 66, a thio-analogue of HAPyU 31, was tested by
tion of the coupling reagent with amines. The first HOBt/ Klose but proved to be unsuccessful as yields were lower and
HOAt-phosphonium salt introduced was BOP 51b,51 but its epimerisation higher than HAPyU 31.66
use has been limited due to the carcinogenicity and respiratory Another type of reagent based on sulfonates was developed
toxicity associated with HMPA generated when BOP 51b is by Itoh.67 These reagents 67–70 incorporated HOBt or HOCt
used in coupling reactions, leading to the development of the (6-chloro-HOBt) with different substituents on the sulfonate.
pyrrolidino derivative PyBOP 52b.52 Carpino prepared AOP37 The best results were obtained with HCSCP 70, the chlorine
51a and PyAOP37,53 52a and compared them to BOP 51b and group enhancing the reactivity of the reagent. However, the
PyBOP 52b, and showed that the aza-derivatives were more reagents were not compared directly to each other. Compared
reactive. to DCC 5 (without using HOBt), these reagents gave less
For the synthesis of thioamides, Hoeg-Jensen developed side-reactions and the by-products were easily removed during
phosphonium coupling reagents based on 6-nitro HOBt aqueous workup. According to the authors, epimerisation was
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lower than with DCC 5, but this was no surprise as DCC alone reacted quickly with amines to form amides. This original
give very high levels of epimerisation. method was quite harsh and not compatible with many
protecting groups. It has however been adapted by Carpino
2.5 Conclusion on 1H-benzotriazole-based reagents to synthesise peptides via a Fmoc strategy.70 Triphosgene has
1-H-benzotriazole-based reagents probably represent the also been reported to generate amino-acid acid chlorides,71
widest class of coupling reagents. Although differences in especially useful for hindered substrates.72 Similarly, acid
reactivities have been reported by their authors, there is cyanides and azides have been used to synthesise amides.73
practically very little difference, as exemplified by Hachman,68 Cyanuric fluoride 71 can be used to synthesise acid
and HBTU 28b or TBTU 30b are reagents which usually fluorides,74 which couple N-methylated amino-acids very
perform very well. Surprisingly, the potential explosive prop- efficiently. A variety of other reagents have been reported
erties of these reagents is almost always disregarded.30,31 for the formation of acid fluorides, and include Deoxo-Fluor
72 and DAST 73 (Fig. 10).75 However a side-reaction is
observed when using Deoxo-Fluor 72 especially with hindered
3. Reagents generating acid halides amines (Scheme 7), which limits the applicability of this
reagent. In addition, Deoxo-Fluor 72 and DAST 73 are
3.1 General reagents used in organic chemistry and triazine-type
expensive and hazardous reagents, and purification by
reagents
chromatography is required after reaction.
Fischer reported the first synthesis of a dipeptide (Gly-Gly) in Part of this category of reagents is based on triazines
1901 using acid chlorides for coupling.69 The general approach (cyanuric fluoride, chloride and derivatives) and has been
consisted of using reagents such as thionyl chloride or phos- reviewed in details by Kaminski.76 The mechanism of activa-
phorus pentachloride to generate the acid chloride which tion involves the generation of an acid halide moiety
Fig. 7 Phosphonium type coupling reagents. Fig. 9 Other coupling reagents based on 1-hydroxybenzotriazole and
1-hydroxy-7-azabenzotriazole.
Yield (%)
Entry Amine PyClock PyBOP
1 H-Tyr-NMeVal-Phe-Leu-NH2 11 0
2 H-Tyr-Aib-Aib-Phe-Leu-NH2 97 83
3 H-Tyr-Arg-Arg-Phe-Leu-NH2 85 75 Fig. 10 Structure of Deoxo-Fluor 72 and DAST 73.
(Scheme 8). Thus CDMT 74 and DCMT 75 (2,4-dichloro-6- 76c (79%), for the coupling of Fmoc-Val-OH to H-Ile-PEG-PS,78
methoxy-1,3,5-triazine) have been successfully applied in the but overall, BTFFH 77 gave the best conversions.79
synthesis of acid anhydrides (Fig. 11).77 El-Faham synthesised three acid fluoride generating
reagents: DMFFH 80, DEFFH 81 and TEFFH 82,48 but
these were poorly stable to hydrolysis in the presence of a
3.2 Halo-uronium and halo-phosphonium type reagents
base (most of the reagent hydrolysed within 1 h). The reactivity
(Fig. 12)
of these reagents was studied by monitoring acid fluoride
TFFH 76a,78 BTFFH 77,78,79 and DFIH78 78a have been used formation for various hindered and unhindered amino acids,
to generate acid fluorides with amino acids such as histidine and all three reagents were shown to be less reactive than
and arginine since the activated form of Fmoc-Arg-OH under- TFFH 76a or BTFFH 77.
went deactivation via lactam formation when using cyanuric Reagents aimed at generating acid chlorides or bromides
fluoride.78 PyFloP 79a did not yield any acid fluoride.78 under milder conditions than thionyl chloride have been
Interestingly, TFFH 76a (100% coupling after 10 min) gave targeted. BroP 83a was first synthesised by Coste,80 followed
better results than the analogues TCFH 76b (86%) and TBFH by PyBroP 79b and PyCloP 79c.81 These reagents were shown
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Scheme 7 Side-reaction observed during the activation process when using Deoxo-Fluor.
reagent, BMTB 95, was proposed by Wischnat (Scheme 9).90 4. Other coupling reagents
BMTB 95 performed better than HATU 28a in coupling
4.1 Reagents generating carbonic anhydrides (Fig. 15)
Boc-N(Me)-Ile to N(Me)-Ile-OBn. However BMTB 95 was
not compared to BEMT 94. EEDQ 99, was originally developed in 1967.93 EEDQ 99 offers
Li reported 2-halopyridinium salts such as BEP 96a, FEP several advantages over most coupling reagents, as the
96b, BEPH 97a and FEPH 97b (Fig. 14).91 Mukaiyama has reaction with an amine cannot yield a guanidinium salt, a
extensively used 2-chloro- and 2-bromo-pyridinium iodide 98 typical side reaction observed with uronium type coupling
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Table 4 Comparison of EEDQ and IIDQ DABCO proved to give the best yield. However a full study
was carried out on the N-methylmorpholine derivative 102,
IIDQ EEDQ
Entry Amine Acid yield yield
because of its lower production cost. The reagent proved to be
particularly efficient with high yields and low epimerisation
1 4-tert- Phenylacetic 96 94 levels. For the synthesis of the 65–74 segment of ACP, each
Butylaniline acid
2 Benzylamine Phenylacetic 91 87 coupling went faster (15 min.) than with TBTU 30b (45 min)
acid or HATU 28a (30 min) and gave better purities (84%) than
3 Morpholine Phenylacetic 38 32 TBTU 30b (69%).99 Sulfonates of N-triazinylammonium salts
acid
4 4-tert- Benzoic acid 88 85
were also synthesised, but a complete evaluation of these
Butylaniline reagents was not reported.100 The reagents were further
5 Benzylamine Benzoic acid 85 66 optimised by replacing the methoxy groups by benzyloxy
6 Morpholine Benzoic acid 50 41 groups (Fig. 16).101
Average 76 67
Remarkably, reagents such as triazine 103 proved to be
stable in DMF with only 2.5% decomposition after 48 h.
reagents. In addition, the carbonic anhydride is formed slowly Comparison between the parent methoxy compounds (e.g. 97)
but consumed rapidly, which avoids its accumulation and and the benzyloxy derivatives (e.g. 103) showed that the later
therefore minimises the possibility of side-reactions such as were more efficient for the synthesis of the 65–74 segment
epimerisation, and it can also be used with unprotected of ACP.
hydroxy residues.93 EEDQ 99 has thus been used for the
synthesis of various amide derivatives.94,95 Analogues of
EEDQ 99 have also been successfully investigated such as 4.3 Pentafluorophenol (HOPfp)-based coupling reagents
IIDQ 100, and a number of unsymmetrical reagents.96 Not (Fig. 17)
many comparison studies have been published, but IIDQ 100 These types of reagents are based on the traditional penta-
proved, over a few examples, to perform slightly better than fluorophenol leaving group and the generation of active esters.
EEDQ 99 (Table 4).97 Interestingly, when compared to other They usually require the addition of HOAt as the level of
coupling reagents without activation, IIDQ 100 outperformed epimerisation is quite high: when coupling Z-Phe-Val-OH to
HATU 28a, PyAOP 52a and BOP-Cl 86.97 H-Pro-NH2, 33.7% of the LDL isomer was observed in solution
phase when using HPyOPfp 104a, while epimerisation
4.2 Triazine-based reagents (not generating acid halides)
dropped to 1.7% when adding HOAt to the reaction mixture.
DMTMM 101 is a triazine derivative, which has the particular The use of a thiophenol-analogue, HPySPfp 104b did not
advantage of promoting amide synthesis in alcohols or aqu- change the outcome of the coupling reactions.66 Like most
eous media, without ester formation and with selectivity reagents based on HOAt/HOBt, these reagents are not ideal
comparable to DCC 5 and EDC 20.98 Recently, a series of for solution-phase chemistry as the use of an additive means
reagents based on DMTMM 101 was developed by Kaminski that this has to be removed from the reaction mixture after
(Scheme 10).99 N-Triazinylammonium salts were synthesised coupling.
using different tertiary bases and the derivative incorporating Li described a pentafluorophenyl immonium type reagent
FOMP 105,56 but this reagent was not as efficient as the other
immonium type reagents, based on HOBt/HOAt.
A reagent, PFNB 106, was reported by Pudhom, but
Boc-Gly-OH reacted slowly and incompletely and it was necessary
to add HOBt to get good conversion.102 In order to synthesise
thioamides, Hoeg-Jensen synthesised PyPOP 107, but this
reagent was not as efficient as PyNOP 53 or PyFOP 54.54
Other reagents include FDPP 108, which gave lower epimer-
isation levels than HBTU 28b, BOP 51b and DCC 5.103
Recently, HDMPfp 109 was synthesised by El-Faham but
Scheme 10 Exchange of counter anion on DMTMM 101. the reagent proved to be outperformed by HATU 28a.50
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Another coupling reagent TFMS-DEP 140 was produced by synthesis of O-alkyl hydroxamic acids (Scheme 11).130 Yields
activating diethylphosphate with trifluoromethanesulfonalide.121 were excellent for the 12 amides synthesised but comparison
Using 1.2 equiv. of coupling reagent, hindered tert-butylamine with other coupling reagents was not carried out.
was coupled in 89% yield to acetic acid. Other examples
showed goods yields, typically over 80% yield, including a
4.7 Miscellaneous reagents
secondary amine (N-methylbenzylamine) and two anilines
(N-methylaniline and aniline). Application for peptide synthesis CPMA 171, a reagent based on a chloroimmonium salt
was studied by carrying out Young’s test, which showed 2% (Fig. 22), mediated the esterification of carboxylic acids,131
epimerisation. Also, the difficult synthesis of Z-Aib-Aib-OMe and in terms of amide bond formation, the reagent performed
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proved to be successful affording the product in a satisfactory well (complete conversion) but only two examples were
70% yield. reported.
A wide range of phosphorus-based coupling reagents 2-Mercaptopyridone-1-oxide 172 was used as a starting
141–153 were investigated by Mukaiyama.122 Using Young’s material to generate a cheaper and new type of uronium
test as model reaction, it was concluded that the bis(nitrophenyl) coupling reagent TOTT 173 and HOTT 174 (Scheme 12).132
phenylphosphonates 149 and 150 gave the best results. Further Both reagents gave better results that DCIH 78b or PyBrop
studies, using this time phosphinic esters 154–158 showed 79b and were comparable to HATU 28a, and the dipeptide
that (5-nitropyridyl)diphenylphosphinate 154 was an efficient Z-MeVal-Aib-OMe was obtained in 80% yield (89% for
coupling reagent, giving 92% of the expected dipeptide in HATU 28a). The epimerisation level was evaluated via
Young’s test, with less than 2% epimerisation.123 Young’s test and the use of TOTT 173 resulted in only 3.7%
DEBP124 159 and DPOOP125 160 have been proposed as epimerisation compared to BOP 51b (20%), PyBOP 52b
coupling reagents, but for both reagents, examples were (15%), or HATU 28a (20%). TOTT 173 and HOTT 174 have
limited to a few dipeptides and were not compared to any also been successfully used to synthesise primary amides from
classical methods. T3P 161 was claimed to be more efficient carboxylic acids and ammonium chloride.133
than HAPyU 31 for head-to-tail cyclisation of hindered Najera synthesised two analogues of HOTT/TOTT, HODT
peptides.126 However, the use of T3P may be limited as yields 175 and TODT 176 (Fig. 23).134 These two reagents gave
were lower and epimerisation higher than HAPyU when higher yields in solid phase peptide synthesis, but associated
segment coupling studies were carried out. with more epimerisation.
Other reagents include FDMP 162, which gave poor results A reagent similar to the ones based on 2-mercaptopyridine
(2% yield compared to 84% yield for BEMT when coupling oxide was proposed by Knorr but TPTU 177 (Fig. 24), based
Z-Gly-Phe-OH to H-Val-OMe),57 BIODPP 163, which gave on 2-hydroxypyridine-N-oxide, gave high epimerisation level
amides in good yields but was not compared to any other when used without an additive.40
coupling reagent,127 and DEPBO 164 and DOPBO 165, which The possibility of using a 2-pyridinone based reagent,
proved to be not as efficient as DepODhbt 114.107 PyDPP 166 DPTC 178 (Fig. 25), for amide synthesis was investigated by
was reported as giving low epimerisation rates, but was not Shiina.135 Carboxylic acids were activated as 2-pyridyl esters
compared to other coupling reagents.128 using DPTC 178 and a catalytic amount of DMAP. However,
Kokare reported three new reagents 166–169 based on a long pre-activation time was required (over 25 min) to limit
phosphate derivatives of 1-hydroxy-2-phenylbenzimidazole.129 the formation of an isothiocyanate specie (and probably a
The reagents gave in most cases similar results and yields over a thiourea) upon addition of an amine. Thus the application of
wide range of substrates (e.g. 4-nitrobenzoic acid, cinnamic DPTC 178 is limited although simple amides can be obtained
acid, anisic acid, piperidine, tert-butylamine) were excellent. in good yield at room temperature. More hindered substrates
However, one can wonder at the purity of the isolated products. imply carrying out the synthesis at higher temperature.
The synthesis of the three reagents were reported (63–71% yields), An original coupling reagent based on the rearrangement of
but when used for amide bond formation, the reagents were carboxylic–sulfonic mixed anhydrides has been reported. Sub-
generated in situ through the reaction of 2-phenylbenzimidazole stituted O-hydroxybenzenesulfonyl chlorides 179 were used as
with a chlorophosphate or phosphinic chloride. The acid condensation reagents via the mechanism suggested in
and then amine were added to this mixture, and side- Scheme 13.136 Using this method various peptides were
reactions were thus likely to occur. Kokare also used the obtained in good yields. The epimerisation level was assessed
diethylphosphate derivative 170 as a coupling reagent for the through optical purity, but no comparison was made with any
common coupling reagent. Itoh investigated the possibility of
using sulfonate-based coupling reagents, and developed
2-methanesulfonyloximino-2-cyanoacetate 180 (Fig. 26),
which proved however to be outperformed by HCSCP 69.67
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2-yloxy)silane.
carbodiimides maintain the same drawbacks as their
solution-phase equivalents, in particular in terms of epimerisation
in the absence of an additive. Furthermore, one can wonder
at the interest of PS-EDC 190 (Fig. 27) in comparison to
PS-DCC 191 as EDC 20 was originally designed and synthesised
to be water soluble. Having the ‘‘extractable’’ moiety on a
polystyrene support appears to be odd, especially as the
ionic part of EDC 20 in solution-phase has proven to be
Scheme 17 Disproportionation issue with the mixed anhydride counterproductive regarding the coupling reaction rate
method. compared to DIC 13.34 A polyhexamethylene-carbodiimide
has also been reported.161
Charette ‘‘attached’’ carbodiimides to tetraarylphosphonium
5.3 Direct preparation of active esters salts as a means of ‘‘tagging’’ the reagent.162 Reaction
The direct formation of active esters has often attracted a lot was carried out in solution phase, before precipitation of the
of attention due to the stability of many of them, which allows salt with apolar solvents. Several carbodiimides derivatives
storage. Many example of active esters have therefore been 192 were synthesised (Fig. 28), and the ethyl and isopropyl
reported and include –O-succinimides,150 –OBt and derivatives,24 derivatives based on a hexafluorophosphate salt were the most
p-nitrophenol,151 –OPfP,152 –ODhbt,153 and PTOC.154 As this efficient, both in terms of yields and purities.
review focuses directly on coupling reagents, this useful
6.2 Immobilised additives and reagents based on HOBt
method of amide-bond formation will not be discussed
herein, but the reader is referred to Montalbetti’s review for Some coupling reagents in solution can in rare cases be
further details.13 extracted after reaction (e.g. EDC 20). However, the use of
an additive is often required to limit epimerisation, and this
additive has also to be separated from the reaction mixture.
5.4 Newer approaches to amide bond formation
Therefore polymer-supported HOBt has been reported in
Several alternatives to the use of coupling reagents have been different guises.163,164 PS-HOBt 193 has also been used as a
reported. These interesting new methods were reviewed by core for synthesising supported reagents for the preparation of
Bode,155 and include the so-called native chemical ligation and N-hydroxysuccinimide active esters.165
the Staudinger ligation (Scheme 18). Recently, Milstein The idea of using PS-HOBt 193 to form an immobilised
reported another approach based on the ligation of amines HOBt-based coupling reagent was first exploited by Chinchilla,
to alcohols using a ruthenium complex as catalyst.156 who synthesised polymer-supported TBTU 194.166 This idea
Molecular hydrogen was formed during the reaction and was also applied by Filip for the synthesis of polymer-
amides were obtained in high yield. supported BOP 195.167 These reagents offer however the same
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but no secondary amine was tested while the reagent was not
compared to other classical amide bond formation methods.
PS-DMC 197, a supported equivalent of DMC 89, was
reported by Ishikawa.170 Yields over five examples were
slightly lower for the polymer-supported version of the
reagent, and the examples provided did no allow a full display
of the scope and limitations of the reagent.
Chinchilla developed some reagents based on polymeric
Fig. 28 Tetraarylphosphonium-supported carbodiimides.
succinimides such as P-TSTU 198 and P-HSTU 199,171 and
200 (Fig. 27).172 The results were good for classic amino acids
drawbacks as TBTU 30b and BOP 51b in solution, while the
but the yields were moderate to low when coupling hindered
structure of the reagent means that part of it will end up in
amino acids. Globally these reagents did not really add any
solution after the coupling, clearly an undesirable occurrence
benefit to the range of coupling reagents available, and, like
for a supported reagent.
PS-TBTU 194 and PS-BOP 195, part of the reagent ended up
in solution.
6.3 Other immobilised reagents
More recently, Convers reported an immobilised Mukaiyama
Triazine-based coupling reagents have been widely used in reagent 201.173 However, Crosignani investigated this new
solution-phase. In 1999, Taddei reported polymer-supported reagent and concluded that the synthesis was poorly reprodu-
chlorotriazine 196.168 Although amides were synthesised in cible, and developed another route.174 This reagent 202
moderate to good yield using this reagent, the 1H NMR of the appeared to work very efficiently for the synthesis of esters
crude compounds revealed the presence of 5 to 10% of and amides including hindered substrates, secondary amines
by-products. Hioki used another strategy to obtain polymeric and anilines.174,175
triazine-type reagents.169 Using a norbornene-derivatised Polymer-supported IIDQ 203 is an immobilised version of
triazine, they synthesised via ROMP an immobilised mono- the solution-phase IIDQ 100 reagent.97,176 It was synthesised
methoxychlorotriazine, which was tested on anilines and in three steps from Merrifield resin and 6-hydroquinoline to
primary amines. Yields were good (nine examples, 80–98%), provide a high loading reagent (41.68 mmol/g). The main
advantages of PS-IIDQ 203 are that no base is required during 7. Conclusion on available coupling reagents
coupling, while the order of addition of amine, carboxylic acid
and reagent do not influence the outcome of the reaction Although hundreds of coupling reagents have been reported,
(Scheme 19). conclusions on their efficiency are in fact quick and simple.
This reagent was compared to other classically used and Most of these reagents are simply not efficient for a broad
commercially available coupling reagents such as Polymer- range of amide bond formation. Some reagents do perform
supported EDC 190 and DCC 191, as well as HATU 28a. well in general, but differences are typically small. Solid-phase
Interestingly, PS-IIDQ 203 performed better than any of these peptide chemists may find useful reagents which display fast
reagents on a set of three amines and three carboxylic acids, kinetics for coupling as the synthesis of long peptides has
including anilines and bulky substrates (Table 5). Furthermore, ideally to be rapid. However, for the general organic chemist,
PS-IIDQ 203 was evaluated on 9 amines and 5 carboxylic simple reagents are often the most appropriate allowing
acids and gave an average yield of 73%. Epimerisation was coupling reagents to be used on a large selection of substrates
low as Anteuni’s test did not reveal any trace of the diastereo- with varying reactivities.
isomer by NMR. PS-IIDQ 203 was stable under standard This summary can be illustrated by the comparison of
laboratory storage conditions and it was shown that the coupling reagents carried out by Hachman.68 Very few
reagent could be advantageously recycled after any coupling comparisons of reagents have been published and the work by
reaction. Thus PS-IIDQ 203 appears to be a very versatile Hachman displayed the importance of a comparison system.
coupling reagent for the parallel synthesis of amides. Hachman compared classical reagents such as phosphonium
Very recently, Kakarla duplicated these studies to make salts, uronium salts, reagents generating acid halides and
PS-EEDQ 204.177 It was obtained using identical conditions carbodiimides. During the synthesis of decapeptides, HBTU
for the transformation of PS-Quinoline into PS-EEDQ 28b was the ‘‘fastest’’ reagent after 2 min while almost none of
204, the only variation being the use of a Wang resin. However the expected amide was formed by DIC after this time.
the loading of the so-called ‘‘high-loading’’ PS-EEDQ 204 However, after 8 min, DIC 13 was comparable to HBTU
was erroneous (starting from a 1.7 mmol/g Wang resin, the 28b. In addition very few side-reactions were observed with
maximum physical loading of PS-EEDQ 204 would be DIC 13 (in particular deletion) compared to BOP 51b or
1.19 mmol/g assuming total conversion during synthesis, HATU 28a. This demonstrated that a simple reagent like
while the authors claimed 1.36 mmol/g loading), while a Wang DIC 13 (using HOBt as additive) performs well in many cases,
linker was clearly of no use. When looking at the efficiency and a compromise of speed/purity/by-products needs to be
of EEDQ 99 and IIDQ 100 (Table 4),97 the choice sought.
appears evident. An important point is the way new coupling reagents are
reported. As stated and demonstrated by Hachman: ‘‘the use
of only one model sequence for evaluation of synthetic
Table 5 Comparison of the yields and purities obtained over three reagents [. . .] can be misleading.’’ As such, unless new reagents
amines (4-tert-butylaniline, benzylamine, H-PhG-OMe) and three
are systematically tested against commonly considered ‘‘top
carboxylic acids (Boc-Aib-OH, phenylacetic acid, benzoic acid)
coupling reagents’’, such as HATU 28a, and traditional
Entry Coupling reagent Average yield (%) Average purity (%) methods such as DIC/HOBt, it is likely that most new
1 PS-IIDQ 72 100 coupling reagents will have an application limited to the
2 HATU 55 98 original publication by their authors.
3 PS-EDC 41 96 Overall, keeping in mind all possible issues (side-reactions),
4 PS-DCC 26 97
HATU 28a and HBTU 28b offer generally excellent reactivity.
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If quick coupling times are required, HATU 28a probably BEMT 2-bromo-3-ethyl-4-methylthiazolium
represents the reagent of choice, providing the substrates are tetrafluoroborate
not hindered. Otherwise, the traditional method DCC 5 (or BEP 2-bromo-1-ethylpyridinium tetrafluoroborate
DIC 13) /HOBt remains an excellent choice for many sub- BEPH 2-bromo-1-ethylpyridinium hexachloroanti-
strates. One has nevertheless to keep in mind potential hazards monate
when using reagents based on 1H-benzotriazole due to the 4,5-B(HATU) N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-c]-
potential explosive properties of HOBt.30,31 isoquinolin-3-yloxy)-N-methylmethanaminium
For difficult couplings (e.g. secondary amines), our experi- hexafluorophosphate
ence tells us that PyBrop 79b is generally reliable.178 Triazines 5,6-B(HATU) 1-[bis(dimethylamino)methylene]-1H-1,2,3-
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can be an alternative for difficult coupling, although the most triazolo[4,5-b]quinolinium hexafluorophosphate-
reactive reagents tend to give side-products. However, the 3-oxide
recent developments by Kaminski are bringing new applica- BIODPP diphenyl benzo[d]isoxazol-3-ylphosphonate
tions to this class of coupling reagents. BMC N-tert-butyl-N 0 -methylcarbodiimide
Finally, for library synthesis either the PS-Mukaiyama BMMP 1-(1-(1H-benzo[d][1,2,3]triazol-1-yloxy)ethyl-
reagent 202 or polymer-supported IIDQ 203 are clearly the idene)pyrrolidinium hexachloroantimonate
most suitable reagents,179 and their efficiency has been con- BMP-Cl N,N 0 -bismorpholinophosphonic chloride
firmed by many groups. These reagents have the advantage of BMTB 2-bromo-3-methyl-4-methylthiazolium
simplifying purification as the reagent is separated via simple bromide
filtration after reaction. BOI 2-(benzotriazol-1-yl)oxy-1,3-dimethylimid-
In conclusion, selecting suitable coupling reagents could be azolidinium hexafluorophosphate
summarised by ‘‘keep it simple’’ as most reagents appear to be BOMI benzotriazol-1-yloxy-N,N-dimethylmethan-
merely fancy and costly alternatives. Finding a universal iminium hexachloroantimonate
coupling reagent remains elusive considering the wide portfolio BOP benzotriazolyl-N-oxytrisdimethylaminophos-
of potential substrates and it is generally wise to avoid phonium hexafluorophosphate
‘‘exotic’’ reagents and not be mislead by ‘‘fast’’ coupling BOP-Cl N,N 0 -bis(2-oxo-3-oxazolidinyl)phosphinic
reagents. Efficiency is the key, with high conversions, low chloride
levels of epimerisation and limited by-products all being BPMP 1-(1H-benzotriazol-1-yloxy)phenylmethylene
essential criteria. pyrrolidinium hexachloroantimonate
BroP bromotris(dimethylamino)phosphonium
hexafluorophosphate
BTFFH bis(tetramethylene)fluoroformamidinium
List of abbreviations hexafluorophosphate
General CBDO 2-chlorobenzo[d][1,3]dioxol-1-ium hexachloro-
antimonate
ACP acyl carrier protein decapeptide 65–74 CBMIT 1,10-carbonylbis(3-methylimidazolium) triflate
DABCO bicyclo[2,2,2]-1,4-diazaoctane CDI carbonyldiimidazole
DCU dicyclohexylurea CDMS chlorodimethylsulfonium hexachloroantimonate
DMAP 4-dimethylaminopyridine CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine
DMPU dimethylpropyleneurea
CDTP 2-chloro-1,3-dimethyl-3,4,5,6-tetrahydro-
HMPA hexamethylphosphoramide
pyrimidin-1-ium perchlorate
LHRH Luteinising Hormone Releasing Hormone
CIP 2-chloro-1,3-dimethylimidazolidinium
NMM N-methylmorpholine
hexafluorophosphate
ROMP Ring Opening Metathesis Polymerisation
CloP chlorotris(dimethylamino)phosphonium
Coupling reagents and additives hexafluorophosphate
CMMM chloro(4-morpholino)methylene
ACTU (2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3- morpholinium hexafluorophosphate
tetramethylaminium) hexachloroantimonate CPMA (chlorophenylthiomethylene)dimethyl-
AOMP 5-(7-azabenzotriazol-1-yloxy)-3,4-dihydro-1- ammonium chloride
methyl-2H-pyrrolium hexachloroantimonate
CPDT 2-chloro-5-phenyl-1,3-dithiol-1-ium
AOP (7-azabenzotriazol-1-yl)oxytris(dimethyl-
hexachloroantimonate
amino)phosphonium hexafluorophosphate
Cpt-Cl 1-oxo-chlorophospholane
BBC benzotriazoloxy-bis(pyrrolidino)carbonium
hexafluorophosphate DAST diethylaminosulfur trifluoride
BDDC bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl]- DCC dicyclohexylcarbodiimide
carbodiimide DCIH 1,3-dimethyl-2-chloro-4,5-dihydro-1H-
BDMP 5-(1H-benzotriazol-1-yloxy)-3,4-dihydro-1- imidazolium hexafluorophosphate
methyl-2H-pyrrolium hexachloroantimonate DCMT 2,4-dichloro-6-methoxy-1,3,5-triazine
BDP benzotriazol-1-yl diethylphosphate DEBP diethyl-2-(3-oxo-2,3-dihydro-1,2-benziso-
BEC N-tert-butyl-N 0 -ethylcarbodiimide sulfonazolyl)phosphonate
hexafluorophosphate
phosphate HAE2PyU O-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-1,1-
DepOBt diethoxyphosphinyloxybenzotriazole diethyl-3,3-tetramethyleneuronium hexafluoro-
DepODhbt diethyl 4-oxobenzo[d][1,2,3]triazin-3(4H)-yl phosphate
phosphate HAMDU O-(7-azabenzotriazol-1-yl)-1,3-dimethyl-1,3-
DFIH 1,3-dimethyl-2-fluoro-4,5-dihydro-1H-imid- dimethyleneuronium hexafluorophosphate
azolium hexafluorophosphate HAM2PipU O-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-1,1-
DIC diisopropylcarbodiimide dimethyl-3,3-pentamethyleneuronium
DMC 2-chloro-1,3-dimethylimidazolinium chloride hexafluorophosphate
DMCH N-(chloro(morpholino)methylene)-N-methyl- HAM2PyU O-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-1,1-
methanaminium hexafluorophosphate dimethyl-3,3-tetramethyleneuronium
DMFFH 1,2-dimethyl-3,3-tetramethylenefluoroform- hexafluorophosphate
amidinium hexafluorophosphate HAMTU O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(penta-
DMFH N-(fluoro(morpholino)methylene)-N-methyl- methylene)uronium hexafluorophosphate
methanaminium hexafluorophosphate HAPipU O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(penta-
DmppOAt 1-(2,8-dimethylphenoxaphosphinyloxy)-7- methylene)uronium hexafluorophosphate
azabenzotriazole HAPyTU S-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetra-
DMTMM 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl- methylene)thiouronium hexafluorophosphate
morpholinium chloride HAPyU 1-(1-pyrrolidinyl-1H-1,2,3-triazolo[4,5-b]pyridin-
DOMP 5-(3 0 ,4 0 -dihydro-4 0 -oxo-1 0 ,2 0 ,3 0 -benzotriazin- 1-ylmethylene)pyrrolidinium hexafluorophos-
3 0 -yloxy)-3,4-dihydro-1-methyl 2H-pyrrolium phate N-oxide
hexachloroantimonate HATeU O-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-
DOPBO N-(2-oxo-1,2,3-dioxaphosphorinanyl)benz- 1,1,3,3-tetraethyluronium
oxazolone hexafluorophosphate
DOPBT 3-[O-(2-oxo-1,2,3-dioxaphosphorinanyl)oxy]- HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetra-
1,2,3-benzotriazin-4(3H)-one HBE2PipU methyluronium hexafluorophosphate
DPOOP diphenyl-2-oxo-3-oxazolinylphosphonate O-(1H-benzotriazol-1-yl)-1,1-diethyl-3,3-penta-
Dpop-Cl diphenyl phosphorochloridate methyleneuronium hexafluorophosphate
DpopOAt 1-(diphenoxyphosphoryloxy)-7-azabenzo- HBE2PyU O-(1H-benzotriazol-1-yl)-1,1-diethyl-3,3-tetra-
triazole methyleneuronium hexafluorophosphate
DpopOBt 1-(diphenoxyphosphoryloxy)benzotriazole HBMDU O-(benzotriazol-l-yl)-l,3-dimethyl-l,3-di-
DpopODhbt 3-(diphenoxyphosphinyloxy)-3,4-dihydro-4- methyleneuronium hexafluorophosphate
oxo-1,2,3-benzotriazene
HBMP 1H-benzo[d][1,2,3]triazol-1-ylmethanesulfonate
DPP diphenylphosphite
HBM2PipU O-(1H-benzotriazol-1-yl)-1,1-dimethyl-3,3-
DPPA diphenylphosphoryl azide
pentamethyleneuronium hexafluorophosphate
Dpp-Cl diphenylphosphinic chloride
HBM2PyU O-(1H-benzotriazol-1-yl)-1,1-dimethyl-3,3-
DPTC O,O 0 -di(2-pyridyl)thiocarbonate
tetramethyleneuronium hexafluorophosphate
DPTF 2,2-dichloro-5-(2-phenylethyl)-4-(trimethylsilyl)-
HBPipU O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)-
3-furanone
uronium hexafluorophosphate
DtpOAt 1-[di(O-tolyl)phosphinyloxy]-7-azabenzotriazole
HBSP 1H-benzo[d][1,2,3]triazol-1-ylbenzenesulfonate
DtpOBt 1-[di(O-tolyl)phosphinyloxy]benzotriazole
3-di(O-tolyl)phosphinyloxy]-3,4-dihydro-4- HBTeU O-(1H-benzotriazol-1-yl)-1,1,3,3-tetraethyl-
DtpODhbt
oxo-1,2,3-benzotriazine uronium hexafluorophosphate
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodi- HBTU O-(benzotriazol-1-yl)-1,1,3,3-tetramethyl-
imide uronium hexafluorophosphate
EEDQ N-ethoxycarbonyl-2-ethoxy-1,2-dihydro- HCTU (2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3-
quinoline tetramethylaminium) hexafluorophosphate
ENDPP phosphoric acid 3,5-dioxo-10-oxa-4-azatri- HCSCP 6-chloro-1H-benzo[d][1,2,3]triazol-1-yl-4-
cyclo[5.2.1.02,6]dec-8-en-4-yl ester diphenyl ester chlorobenzenesulfonate
FDMP 3,5-bis(trifluoromethyl)phenyl HCSP 6-chloro-1H-benzo[d][1,2,3]triazol-1-ylbenzene-
diphenylphosphinate sulfonate
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