Evaluation of alternative solvents in common amide coupling reactions: Replacement of dichloromethane and N,N-dimethylformamide

Article abstract of DOI:10.1039/c2gc36900a

A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamide.

Full text of DOI:10.1039/c2gc36900a

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Evaluation of Alternative Solvents in Common Amide Coupling
Reactions: Replacement of Dichloromethane and N,N-
Dimethylformamide†
Donna S. MacMillan,a Jane Murray,b Helen F. Sneddon,c Craig Jamieson,a and Allan J. B. Watson*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A range of alternative solvents have been evaluated within
amidation reactions employing common coupling reagents
with
a view to identifying suitable replacements for
10 dichloromethane and N,N-dimethylformamide.
The amide bond is one of the most fundamental functional group
linkages and underpins the connectivity of basic biomolecules
(e.g., proteins) as well as being commonly found in many widely
used materials (e.g., nylons) and key pharmaceuticals (e.g.,
15 penicillin, lipitor).1,2 In this latter context, amide bond formation
is the single most common synthetic transformation used within
medicinal chemistry. Indeed, several studies have demonstrated
the prevalence of this particular transformation within the
pharmaceutical sector: MacDonald’s analysis of the
20 GlaxoSmithKline (GSK) Respiratory Centre of Excellence for
Drug Discovery revealed that 17% of all reaction types conducted
in array (focussed library) format were to prepare amide or
sulfonamide moieties.3 Similarly, Roughley’s analysis of the
most common reactions used within synthetic medicinal
25 chemistry research across three of the largest pharmaceutical
companies (GSK, AstraZeneca, and Pfizer) indicated that N-
acylation to prepare amides ranked 1st for frequency of use,
accounting for 16% of all reactions performed and with the amide
linkage present in 54% of the compound set analysed.4
50 Figure 1 Coupling agents, solvents, and representative reactions for the
amidation survey.†
reactions using SciFinder revealed that 83% of approximately
680,000 amidation reactions employed either CH2Cl2 (36%) or
DMF (47%) as the reaction media.9 By contrast, the emerging
55 green solvent 2-methyltetrahydrofuran accounted for only 0.04%
of this reaction set.9 Despite their utility, CH2Cl2 and DMF are
clearly not compatible with the current drive towards more
sustainable and environmentally cognisant medicinal chemistry
processes.10
30
While carboxamide formation is formally a condensation
between a suitable carboxylic acid and amine combination that
can be achieved simply by heating the requisite components
together,5 this is typically not an efficient or particularly useful
method due to the formation of an unreactive carboxylate–
35 ammonium salt which commonly leads to poor yields, lengthy
reaction times, or substrate compatibility issues.6 As such,
carboxamide formation is often more conveniently achieved
through application of a suitable coupling agent.7 Over the years,
amide bond coupling reagents have been the subject of some
40 considerable development to the stage that a bank of these
reagents are available for deployment and guides have been
devised to assist the practitioner in selecting the most effective
reagent for a desired amidation.8
60
As part of a programme focussed on enabling sustainable
medicinal chemistry practices, we have been interested in
addressing solvent selection within both reaction and purification
scenarios.11 Herein, we describe our evaluation of a selection of
alternative solvents for use within amidation reactions using
65 common amide coupling agents with a view to identifying
suitable replacements for CH2Cl2 and DMF.
Throughout this area, however, the most widespread solvents
45 employed are those with major regulatory issues such as
chlorinated (dichloromethane, 1,2-dichloroethane) or N,N-
dimethylformamide (DMF). For example, a survey of amidation
Results and Discussion
Methods
For our study, we elected to use five of the most common amide
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Table 3 Assessment of promising solvents in a range of amidations using
COMU as the preferred coupling agent.a†
Entry
Product
Completion Time b
CH2Cl2 DMF DMC EtOAc 2-MeTHF
1
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
2
3
Figure 2 Representative example of conversion data: Amidation Reaction
3 using HATU with the range of solvents.†
4
24 h 24 h
4 h
4 h
4 h
5
6
4 h 5 minc 24 h
4 h
4 h
48 h
4 h
24 h 24 h
4 h
7
8
9
5 minc 4 h
24 h 24 h
4 h
4 h
5 minc 5 minc
5 Figure 3 Representative example of conversion data: Amidation Reaction
3 with the range of coupling agents in 2-MeTHF.†
4 h
4 h
4 h
4 h
coupling reagents or reagent combinations: (1-cyano-2-ethoxy-2-
oxoethylidenaminooxy)dimethylamino-morpholino-carbenium
hexafluorophosphate
(COMU),12
N,N’-
4 h 5 minc 4 h
10 diisopropylcarbodiimide/hydroxybenzotriazole (DIC/HOBt),13 N-
[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-
ylmethylene]-N-methylmethanaminium hexafluorophosphate N-
10
4 h
4 h
4 h
24 h
4 h
oxide
yloxy)tripyrrolidinophosphonium
(HATU),14
(benzotriazol-1-
hexafluorophosphate
15 (PyBOP),15 and n-propylphosphonic anhydride (T3P®)16 (Figure 35 Reaction conditions: acid (1 equiv, 0.2 mmol), amine (1.2 equiv, 0.24
a
mmol), i-Pr2NEt (2 equiv, 0.4 mmol), COMU (1.5 equiv, 0.3 mmol),
solvent (1 mL, 0.2 M), RT. Determined by HPLC analysis. See
Supporting Information. Taken at 0 h time point, represents first data
1). In addition, we aimed to evaluate these reagents within the
amidation reactions of representative examples of both aryl and
b
c
alkyl acids and amines in order to probe alkyl-alkyl, aryl-aryl,
and alkyl-aryl couplings (Figure 1). In terms of solvent selection,
20 to compare directly with CH2Cl2 and DMF, we selected emerging
or existing solvents including tert-butyl methyl ether (TBME),
cyclopentylmethyl ether (CPME), dimethylcarbonate (DMC),
ethyl acetate (EtOAc), iso-propyl alcohol (IPA), and 2-
methyltetrahydrofuran (2-MeTHF) (Figure 1).17 Other potential
25 alternative solvents such as MeOH, EtOH, and acetone were
discounted based on unfavourable potential side reactions
(esterification and condensation pathways). Overall, we elected to
evaluate 160 different sets of reaction conditions in this initial
stage of our survey.
point sampled.
40 conversion curve, which could be directly compared across the
solvent selection. Reactions and aliquots were repeated and
analysed up to a maximum of four times to ensure reliability.†
Analysis
An illustrative example chart of conversion vs. time for Reaction
45 3 using COMU is shown in Figure 2. The data indicated that this
amidation proceeded effectively in most solvents and was
generally complete after 4 h with the exception of TBME (8 h)
and CPME (24 h - data point not shown). An alternative view of a
section of the generated data is obtained from analysis of
50 coupling agents for a particular reaction in a given solvent. For
example, Figure 3 displays the conversion vs. time data for
Reaction 3 in 2-MeTHF using the five coupling agents.†
30
To ascertain the reaction performance of the alternative
solvents, we analysed each reaction by HPLC at a range of time
points (0 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, and 24 h) to give a
2
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Table 2 Illustrative representation of the amidation dataset.a
Solvent
Amide Coupling Type
Aryl Acid – Alkyl Amine Alkyl Acid – Aryl Amine
Aryl Acid – Aryl Amine
Alkyl Acid – Alkyl Amine
DIC
HOBt
DIC
HOBt
DIC
HOBt
DIC
HATU COMU
PyBOP T3P HATU COMU
PyBOP T3P HATU COMU
PyBOP T3P HATU COMU
PyBOP T3P
HOBt
**
**
**
*
**
**
**
*
TBME
CPME
CH2Cl2
DMC
DMF
EtOAc
IPA
*
*
*
*
**
**
*
**
*
*
*
*
*
**
**
**
**
**
*
**
**
*
**
**
*
**
**
**
*
**
*
*
*
**
*
*
*
*
*
*
**
*
**
**
*
*
**
**
**
*
*
*
**
*
**
*
**
*
**
*
*
*
**
*
**
**
*
*
*
*
**
**
**
**
**
**
*
**
*
**
**
**
**
*
**
**
**
**
*
*
*
*
*
*
**
**
*
**
**
*
*
*
2-MeTHF
*
*
*
*
**
*
*
**
a Key: Red = <50% conv., orange = 50-70% conv., green = >70% conv.; * Indicates 100% conv. within 4 h. ** Indicates 100% conv. within 1 h.
From consideration of the overall data set (see Supporting
Information), a series of general observations could be made.
Firstly, unsurprisingly, aryl-aryl couplings (Reaction 1) tended to
screening process that reactions using COMU in DMC, EtOAc,
and 2-MeTHF were generally complete within 4 h, the reactions
in Table 2 were analysed at 0 h (effectively within 5 min), 4 h,
5
be the slowest processes in general while alkyl-alkyl couplings 45 and 24 h. In addition to increased functionality, the acids and
(Reaction 4) were faster overall. Most reactions (81% of the
dataset) proceeded to 100% conversion, 74% were complete
within 4 h, and 36% were complete within 1 h. In terms of
amines were selected on the basis that they would deliver amide
products that had a physicochemical profile that was consistent
with being lead-like (H-Bond Acceptors, 2-7;
Donors, 0-2; Rotatable Bonds, 3-10; Polar Surface Area, 20-93
generally good for aryl-aryl (Reaction 1) and alkyl-alkyl 50 Å2; Molecular Weight, 231-332; XLogP, 0-2.4).18
H-Bond
10 general trends observed for the array of solvents: (i) TBME was
(Reaction 4) couplings and poor for aryl-alkyl (Reaction 2) and
alkyl-aryl (Reaction 3) couplings; (ii) CPME was generally poor
across the spectrum of reaction conditions examined with the
15 exception of the more reactive alkyl-alkyl coupling (Reaction 4),
As can be seen from Table 3, the amidation reactions were
generally complete within the first four hours and comparable to
CH2Cl2 and DMF in the majority of reactions. Indeed, there were
very few cases where CH2Cl2 or DMF were shown to outperform
Reaction 1 using HATU, PyBOP, and T3P, and Reaction 2 using 55 the alternative solvents over the substrate range evaluated under
T3P. (iii) As expected, CH2Cl2 and DMF were generally very
good for all reactions. (iv) Pleasingly, DMC, EtOAc, and 2-
MeTHF were found to be generally very good for all reactions.
20 (v) Somewhat surprisingly, IPA performed very well with only a
these reaction conditions. Overall, these results suggest that
DMC, EtOAc, and 2-MeTHF would be effective replacements for
CH2Cl2 and DMF for similar amidation processes. In addition,
and with specific regard to DMF, an additional practical value of
few exceptions (particularly for Reaction 3). An additional 60 employing DMC, EtOAc, or 2-MeTHF as alternatives is that they
observation relating to TBME and CPME is that reactions tended
to become heterogeneous as time progressed. This may help to
explain why these reactions were generally less successful than
25 the equivalent reactions in the other solvents. Lastly, all coupling
would simplify the work up procedure involved prior to any
purification as both the boiling points and the water miscibility of
these solvents are considerably lower than that of DMF,17 leading
to more effective aqueous work up and concentration processes,
agents were effective in each class of reaction (depending on 65 where appropriate.
solvent as discussed above) with the exception of T3P for alkyl
acid-aryl amine couplings (Reaction 3) which were generally
very poor. A summary of the overall analysis is provided in Table
30 2.
Conclusions
In summary, we have evaluated several alternative solvents as
potential replacements for CH2Cl2 and DMF as the medium for
four benchmark amide bond forming reactions using common
70 amide coupling reagents or reagent combinations. These studies
revealed that CH2Cl2 and DMF could potentially be readily
replaced with more environmentally acceptable and sustainable
alternatives. We subsequently applied three of these solvents in a
range of amidation reactions using a variety of carboxylic acids
75 and amines with functionality frequently encountered within
Medicinal Chemistry programmes, employing COMU as the
preferred coupling agent. This assessment demonstrated that the
general rates of reaction using DMC, EtOAc, and 2-MeTHF were
Based on all of this, it was evident that DMC, EtOAc, and 2-
MeTHF were the alternative solvents which offered the greatest
potential as replacements for CH2Cl2/DMF. Additionally, COMU
has emerged as an effective and greener amide coupling agent
35 which operated efficiently within the benchmark reaction survey
and, indeed, in several cases more effectively than the ‘gold
standard’2n reagent HATU. As such, we decided to further
evaluate DMC, EtOAc, and 2-MeTHF as the reaction solvent
alongside CH2Cl2 and DMF for comparison utilising COMU as
40 the coupling agent over a broader range of substrates possessing
increased functionality (Table 3). Based on observations from the
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65 7 It should be noted that catalytic amide bond formation techniques
broadly comparable to those observed using CH2Cl2 or DMF and
have also been extensively developed. For general examples, see ref
2. For examples of boronic acid-catalysed processes, see: (a) H.
Charville, D. Jackson, G. Hodges, and A. Whiting, Chem. Commun.,
2010, 46, 1813; (b) T. Maki, K. Ishihara and H. Yamamoto,
Tetrahedron, 2007, 63, 8645; (c) K. Ishihara, S. Ohara and H.
Yamamoto, J. Org. Chem., 1996, 61, 4196; (d) P. Tang, Org. Synth.,
2005, 81, 262; (e) K. Arnold, B. Davies, R. L. Giles, C. Grosjean, G.
E. Smith and A. Whiting, Adv. Synth. Catal., 2006, 348, 813; (f) K.
Arnold, A. S. Batsanov, B. Davies and A. Whiting, Green Chem.,
2008, 10, 124; (g) R. M. Al-Zoubi, O. Marion and D. G. Hall, Angew.
Chem., Int. Ed., 2008, 47, 2876; (h) K. Ishihara, Tetrahedron, 2009,
65, 1085; (i) T. Marcelli, Angew. Chem., Int. Ed., 2010, 49, 6840. For
boronic ester-based processes, see: (j) P. Starkov and T. D. Sheppard,
Org. Biomol. Chem., 2011, 9, 1320. Catalytic amidation of alcohols
and amines is also highly effective, see: (k) C. Gunanathan, Y. Ben-
David, D. Milstein, Science, 2007, 317, 790; (l) L. U. Nordstrøm, H.
Vogt and R. Madsen, J. Am. Chem. Soc., 2008, 130, 17672; (m) A. J.
A. Watson, A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009,
11, 2667; (n) S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Xu and S. H.
Hong, Adv. Synth. Catal., 2009, 351, 2643.
delivered equally high levels of conversion to product. Overall,
we believe that DMC, EtOAc, and 2-MeTHF would be practical
alternatives to conventionally-used media for routine amide
coupling processes and would be highly beneficial for more
environmentally benign synthesis programmes in both academia
and industry.
5
70
75
80
85
90
95
Acknowledgements
We are grateful to GlaxoSmithKline and Sigma Aldrich for the
10 kind donation of consumables. DSM wishes to thank the
University of Strathclyde Knowledge Transfer Account for
postdoctoral funding. Graham Inglis and Dr Simon MacDonald
(GSK) are thanked for helpful discussions.
Notes and references
15 aDepartment of Pure and Applied Chemistry, WestCHEM, University of
Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow,
G1 1XL, UK. Fax: +44 (0)141 548 4822; Tel: +44 (0)141 548 2439; E-
mail: allan.watson.100@strath.ac.uk.
8
9
For example, see ref 2j and 2k.
SciFinder, American Chemical Society, 2012. Search conducted
November 19th 2012.
bSigma-Aldrich, The Old Brickyard, New Road, Gillingham, Dorset, SP8
20 4XT, UK.
10 (a) R. K. Henderson, C. Jiménez-González, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and A. D.
Curzons, Green Chem., 2011, 13, 854; (b) D. J. C. Constable, C.
Jiménez-González and R. K. Henderson, Org. Process Res. Dev.,
2007, 11, 133; (c) K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S.
Jennings, T. A. Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D. A.
Perry and M. Stefaniak, Green Chem., 2008, 10, 31; (d) B. W. Cue
and J. Zhang, Green Chem. Lett. Rev., 2009, 2, 193.
cGreen Chemistry Performance Unit, GlaxoSmithKline, Medicines
Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1
2NY, UK.
† Electronic Supplementary Information (ESI) available: Experimental
25 procedures, analytical data, charts of conversion vs. time for all substrates
in all solvents and for all coupling agents. See DOI: 10.1039/b000000x/
1
(a) A. Greenberg, C. M. Breneman and J. F. Liebman, The Amide
Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and
Material Science. Wiley: New York, 2000. (b) N. Sewald and H.-D.
Jakubke, Peptides: Chemistry and Biology.Wiley-VCH Verlag 100
GmbH: Weinheim, 2002; (c) M. A. Fischbach and C. T. Walsh,
Chem. Rev., 2006, 106, 3468; (d) M. Funabashi, Z. Yang, K. Nonaka,
M. Hosobuchi, Y. Fujita, T. Shibata, X. Chi and S. G. Van Lanen,
Nat. Chem. Biol., 2010, 6, 581; (b) M. Simonovic and T. A. Steitz,
11 D. S. MacMillan, J. Murray, H. F. Sneddon, C. Jamieson, and A. J.
B. Watson, Green Chem., 2012, 14, 3016.
12 (a) A. El-Faham, R. Subirós-Funosas, R. Prohens, and F. Albericio,
Chem. Eur. J., 2009, 15, 9404. See also: (b) A. El-Faham, and F.
Albericio, J. Org. Chem., 2008, 73, 27; (c) R. Subirós-Funosas, R.
Prohens, R. Barbas, A. El-Faham, and F. Albericio, Chem. Eur. J.,
30
35
40
45
50
55
2009,
15,
9394;
(d)
http://www.sigmaaldrich.com/
chemistry/chemical-synthesis/technology-spotlights/comu.html; (e)
M. Junkers, Aldrich Chemfiles, 2010, 10, No. 1.
Biochim. Biophys. Acta, 2009, 1789, 612.
105
2
For reviews of amide coupling processes, see: (a) P. D. Bailey, I. D.
Collier and K. M. Morgan, In Comprehensive Organic Functional
Group Transformations; A. R. Katritzky, O. Meth-Cohn and C. W.
Rees, eds.; Pergamon: Cambridge, 1995; Vol. 5; Chapter 6. (b) L. A.
13 (a) N. L. Benoiton and F. M. F. Chen, J. Chem. Soc., Chem.
Commun., 1981, 543; (b) M. Junkers, Aldrich ChemFiles 2007, 7.2,
5.
14 (a) I. Abdelmoty, F. Albericio, L. A. Carpino, B. M. Forman, S. A.
Kates, Lett. Pept. Sci., 1994, 1, 57; (b) M. Junkers, Aldrich
ChemFiles 2007, 7.2, 9.
15 (a) J. Coste, D. Le Nguyen, and B. Castro, Tetrahedron Lett., 1990,
31, 205; (b) M. Junkers, Aldrich ChemFiles 2007, 7.2, 8.
16 (a) H. Wissmann and H.-J. Kleiner, Angew. Chem., Int. Ed. Engl.,
1980, 19, 133; (b) R. Escher and P. Bünning, Angew. Chem., Int. Ed.,
Carpino, M. Beyermann, H. Wenschuh and M. Bienert, Acc. Chem. 110
Res., 1996, 29, 268; (c) J. M. Humphrey and A. R. Chemberlin,
Chem. Rev., 1997, 97, 2243; (d) Y. S. Klausner and M. Bodansky,
Synthesis, 1972, 9, 453; (e) F. Albericio, R. Chinchilla, D. J.
Dodsworth and C. Nájera, Org. Perp. Proc. Int., 2001, 33, 203; (f) P.
Li and J. C. Xu, J. Pept. Res., 2001, 58, 129; (g) D. T. Elmore, Amino 115
Acids, Pept., Proteins, 2002, 33, 83; (h) F. Albericio, Curr. Opin.
Chem. Biol., 2004, 8, 211; (i) S.-Y. Han and Y.-A. Kim,
Tetrahedron, 2004, 60, 2447; (j) C. A. G. N. Montalbetti and V.
Falque, Tetrahedron, 2005, 61, 10827; (k) P. D. Bailey, T. J. Mills,
Engl.
1986,
25,
277;
(c)
(d)
http://www.archimica.com/pdf/archimica_t3p_brochure.pdf;
http://www.archimica.com/pdf/archimica_t3p_datasheet.pdf; (e) M.
Junkers, Aldrich ChemFiles, 2007, 7.2, 11.
R. Pettercrew and R. A. Price, In Comprehensive Organic Functional 120 17 For selected further information relating to the solvents used in this
Group Transformations II; A. R. Katritzky and R. J. K. Taylor, eds.;
Elsevier: Oxford, 2005; Vol. 5; Chapter 7; (l) J. W. Bode, Curr.
Opin. Drug. Disc. Dev., 2006, 9, 765; (m) E. Valeur and M. Bradley,
Chem. Soc. Rev., 2009, 38, 606; (n) A. El-Faham and F. Albericio,
Chem. Rev., 2011, 111, 6557; (o) V. R. Pattabiraman and J. W. Bode, 125
Nature, 2011, 480, 471.
T. W. J. Cooper, I. B. Campbell, and S. J. F. MacDonald, Angew.
Chem. Int. Ed., 2010, 49, 8082.
S. D. Roughley and A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
study, see: (a) www.sigmaaldrich.com; (b) K. Watanabe, N.
Yamagiwa and Y. Torisawa, Org. Process Res. Dev., 2007, 11, 251;
(c) http://www.zeon.co.jp; (d) R. Aul and B. Comanita,
Manufacturing Chemist, May 2007, 33; (e) J. Bian, M. Xiao, S.
Wang, Y. Lu and Y. Meng, Catal. Commun., 2009, 10, 1142; (f) M.
Winterberg, E. Schulte-Korne, U. Peters and F. Nierlich, Methyl tert-
Butyl Ether in Ullmann’s Encyclopedia of Industrial Chemistry,
Wiley-VCH, 2010; (g) V. Antonucci, J. Coleman, J. B. Ferry, N.
Johnson, M. Mathe, J. P. Scott and Jing Xu, Org. Process Res. Dev.,
2011, 15, 939; (h) M. Nielsen, H. Junge, A. Kammer and M. Beller,
Angew. Chem. Int. Ed., 2012, 51, 5711.
3
4
60 5 For example, see: (a) J. A. Mitchell and E. E. Reid, J. Am. Chem. 130
Soc., 1931, 53, 1879 and references therein; (b) B. S. Jursie and Z.
Zdravkovski, Synth.Commun.,1993, 23, 2761.
18 The KNIME program (www.knime.org) was used to determine the
relvant physicochemical parameters. For further information, see the
Supporting Information.
6
For example, see: L. Perreux, A. Loupy and F. Volatron,
Tetrahedron, 2002, 58, 2155.
135
4
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