Solvent effects in gold-catalysed A3-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.10.141

Gold-catalysed A³-reactions proceed efficiently when conducted in 2,2,2-trifluoroethanol as solvent. The rates of these reactions are accelerated considerably when conducted in a microwave reactor.

Full text of DOI:10.1016/j.tetlet.2013.10.141

Tetrahedron Letters 55 (2014) 151–154
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent effects in gold-catalysed A3-coupling reactions q
⇑
⇑
⇑
Gregory A. Price, Alan K. Brisdon , Kevin R. Flower , Robin G. Pritchard, Peter Quayle
School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Gold-catalysed A3-reactions proceed efficiently when conducted in 2,2,2-trifluoroethanol as solvent. The
rates of these reactions are accelerated considerably when conducted in a microwave reactor.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Article history:
Received 28 July 2013
Revised 25 October 2013
Accepted 29 October 2013
Available online 6 November 2013
Keywords:
Gold
A3-reaction
Trifluoroethanol
Microwave
Solvent effect
The development of domino, multi-component and cascade
reactions continues to be an area of intense academic interest1
NR2R3
O
[M]
even though they were first documented over a century ago.2
A
HNR2R3
R4
H
R1
R1
H
particularly useful example is the ‘A3-coupling reaction’, an
atom-economic, single step process for the preparation of synthet-
ically useful propargyl amines3,4 from aldehydes, alkynes and
amines (Scheme 1). This reaction is found to be catalysed by a
number of transition metal complexes5 in a process that does not
require the pre-generation of stoichiometric quantities of nucleo-
R4
Scheme 1. Transition metal catalysed A3 coupling reaction.
Our interest8a,b in the chemistry of organogold complexes
encouraged us to investigate the use of complexes 1À4 in A3-cou-
pling reactions and led us to question whether these complexes
could be employed as homogeneous solutions in organic solvents.
Complexes 1À4 (Fig. 1) used in this study were initially screened in
a standard A3-reaction between benzaldehyde (1 mmol) and phen-
ylacetylene (1.5 mmol) using either dibenzylamine or piperidine
(1.1 mmol) as the amine partner, in a range of solvents at temper-
atures in the range between 40 °C and 60 °C.
Initial results indicated that the Au(III) complex 1 was catalyti-
cally active and resulted in quantitative conversion to the requisite
A3-coupled product after 24 h in most of the solvents examined
(Table 1, entries 1À4). Complexes 2, 3 and 4 also promoted the
A3-reaction, albeit at a much reduced rate, when the reactions
were conducted in water (entries 6, 15 and 18; <20% conversion
at 40 °C for 24 h). Most notably, exchange of water for chloroform
as reaction medium afforded homogeneous reaction mixtures
which resulted in a significant improvement in conversion rates,
even when the less reactive catalysts 2 and 3 were employed
(entries 9 and 16). Further studies clearly indicated that this was
a solvent, rather than a temperature effect, as attempted coupling
at 100 °C in water failed to force the reaction to go to completion
(entries 7 and 8).
philic
r-alkyne organometallic reagents. The use of strong bases
(Grignard or organolithium reagents) is therefore obviated in these
reactions, a factor which contributes to their greater synthetic po-
tential, flexibility and atom economy.
Concurrent with the development of multi-component reac-
tions there has also been a resurgence of interest in the chemistry
of gold, especially as applied to A3-coupling reactions.6 In their
seminal Letter7 Wei and Li noted that the efficiency of gold-cata-
lysed A3-reactions was greatly dependent upon the reaction condi-
tions employed: reactions carried out at 100 °C in water for 12 h,
using catalyst loadings of 1%, proved to be optimal for the
substrates used in these initial investigations. The use of organic
solvents (THF, DMF and toluene), rather than water, proceeded in
lower conversions and with concomitant formation of undesired
by-products.7
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding authors. Tel.: +44 (0)1612754619; fax: +44 (0)1612754598.
E-mail address: peter.quayle@manchester.ac.uk (P. Quayle).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.141

152
G. A. Price et al. / Tetrahedron Letters 55 (2014) 151–154
Table 1
Solvent and catalyst screening experiments for A3 reactions
Entry
Catalysts
Solvent/T
Amine
Reaction time (h)
Conversiona,b, %
1
2
3
4
5
1
1
1
1
1
H2O/40 °C
HNBn2
HNBn2
HNBn2
HNBn2
HNBn2
24
24
24
24
24
97 (85)
100
90
96 (84)
51
CHCl3/60 °C
PhCF3/60 °C
CF3CH2OH/40 °C
MeOH/40 °C
6
7
8
9
10
11
12
13
14
2
2
2
2
2
2
2
2
2
H2O/40 °C
H2O/60 °C
H2O/100 °C
CHCl3/60 °C
PhCF3/60 °C
CF3CH2OH/60 °C
CF3CH2OH/60 °C
CF3CH2OH/40 °C
MeOH/40 °C
Piperidine
Piperidine
Piperidine
Piperidine
HNBn2
Piperidine
HNBn2
HNBn2
24
24
24
24
24
24
24
24
24
18
33
75
100
15
100
100
100
54
HNBn2
15
16
17
3
3
3
H2O/40 °C
CHCl3/60 °C
CF3CH2OH/60 °C
HNBn2
HNBn2
HNBn2
24
24
24
9
65
88
18
19
20
21
22
23
4
4
4
4
4
4
H2O/40 °C
HNBn2
HNBn2
HNBn2
HNBn2
HNBn2
HNBn2
72
24
72
168
24
24
10
22
31
62
96
39
CHCl3/60 °C
CHCl3/60 °C
CHCl3/60 °C
CF3CH2OH/40 °C
MeOH/40 °C
24
25
26
27
No catalyst
No catalyst
No catalyst
No catalyst
H2O/40 °C
HNBn2
HNBn2
HNBn2
HNBn2
24
24
24
24
0
0
0
0
CHCl3/60 °C
CF3CH2OH/40 °C
PhCF3/60 °C
Reaction conditions: 1 mmol benzaldehyde, 1.1 mmol amine, 1.5 mmol phenylacetylene, 1 mol % catalyst, 2 mL solvent, 24 h.
a
Conversion determined by 1H NMR analysis of the crude reaction mixtures based on benzaldehyde conversion.
Isolated yield.
b
Table 2
It is conceivable that the increased rate observed for complex 2
Screening experiments for microwave reactions
when the reactions were conducted in chloroform was simply due
to an improved solubility of the complex in this solvent. A similar
rate enhancement was also observed when the sterically encum-
bered complex 4 was employed, although the degree of conversion
plateaued at 62% even after extended reaction times (entries 19–
21). The use of methanol9 or benzotrifluroride (PhCF3; a nontoxic
alternative10 to CH2Cl2 and CHCl3) instead of chloroform proved
to be deleterious to conversion rates. The fluorinated alcohol,
2,2,2-trifluoroethanol, (TFE) exhibits a number of unique proper-
Entry
Catalysts
Solvent
Conversiona (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
2
2
2
2
2
2
H2O
CHCl3
PhCF3
Perfluorodecalin
CF3CH2OH
MeOH
PEG-400
H2O
CHCl3
PhCF3
Perfluorodecalin
MeOH
PEG-400
CF3CH2OH
89
43
33
76
86
50
61
10
10
11
30
40
27
77
ties (pKa = 12.4; ENT = 0.898;
a
= 1.51; b = 0; N = À2.78; Y = 3.82),
9
10
11
12
13
14
and proved to have a pronounced effect on conversion rates of
A3-reactions (entries 11–13, 17 and 22).
For the most active catalyst 1, substitution of water by TFE had
no appreciable effect upon the overall rate of conversion or isolated
yield of A3-products (H2O and TFE afford isolated yields of 85% and
84%; entries 1 and 4); these results which should be compared to
the relatively poor outcome obtained using methanol as solvent
(entry 5). A quite different result was encountered with the less ac-
tive catalysts 3 and 4. In the case of the least active catalyst 4, near
quantitative conversion to the desired A3-product was achieved
when using TFE as solvent after 24 h at 40 °C (entry 22). This out-
come should be compared to the poor conversions in either water
(10% after 72 h at 40 °C; entry 18) or chloroform (62% conversion
after 168 h at 60 °C; entry 21). A similar improvement in conver-
sion, when compared to water as solvent, was also observed with
3 in combination with TFE as reaction solvent (entry 17). It should
be noted that A3-coupling reactions did not proceed when con-
ducted in the absence of gold in TFE (entries 24-27).
Reaction conditions: 1 mmol benzaldehyde, 1.1 mmol dibenzylamine, 1.5 mmol
phenylacetylene, 1 mol % catalyst, 1 mL solvent, 100 °C, lW, 30 min.
Conversion determined by 1H NMR analysis of the crude reaction mixtures
a
based on benzaldehyde conversion.
Highest conversions using 1 as catalyst were obtained when either
H2O (entry 1) or TFE (entry 5) were used as solvents. The use of
either cis/trans-perfluorodecalin14 or PEG-400 (an environmentally
benign solvent15) also proceeded with good efficiencies. This
observation may facilitate the development of ‘green’, A3-coupling,
reactions where the propargylamine product can be readily sepa-
rated from the fluorous solvent and also enable recycling of a flu-
orous catalyst.16 The effectiveness of 2, which generally has a
lower catalytic activity than 1 in A3-reactions, under the conditions
of microwave activation, was also briefly investigated. Here the use
of either water, chloroform or benzotrifluoride as solvent resulted
in low conversion rates (entries 8–10) whereas reactions carried
out in cis/trans-perfluorodecalin, methanol or PEG-400 resulted in
While there are numerous examples of microwave-assisted
copper catalysed A3-reactions,12 application of this technique to
homogeneous, gold-catalysed A3-reactions is, to our knowledge,
without literature precedent.13 The effect of microwave irradiation
on gold-catalysed A3-reactions is tabulated above (Table 2).

G. A. Price et al. / Tetrahedron Letters 55 (2014) 151–154
153
a slight enhancement in conversion rates (entries 11–13). Most
startling however was the observation that, once again, the rate
of A3-reactions are substantially accelerated when conducted in
TFE as solvent (entry 14).
We have also applied our standard reaction conditions to other
A3-coupling reactions (Fig. 2). We find that either thermal or
microwave activation proves to be effective in the promotion of
these reactions in TFE and that product isolation using this solvent
system proves to be trivial.17
From this study, and in contrast to an earlier Letter,7 it is clear
that the use of solvents, other than water, are compatible with effi-
cient Au-catalysed A3-reactions. In particular we note that TFE has
a beneficial effect upon both thermal and microwave-promoted
gold-catalysed A3-reactions, such that these reactions can be
driven to completion with short reaction times and without loss
in yields. The TFE-modification does not require the use anaerobic
conditions, proceeds efficiently in reagent grade solvents, and
enables facile product isolation (TFE has a bp of 77 °C).
Conclusions
Gold complexes 1À4 were found to be effective catalysts for the
A3-coupling reaction. The use of TFE as solvent results in improved
rates, an effect which can be further augmented by the application
of microwave irradiation. We surmise that, in the case of TFE in
particular, the observed solvent effects are due to a favourable
combination of physical properties as listed in Table 3. TFE is a
highly polar, H-bonding, nonnucleophilic solvent which presum-
ably favours both initial iminium ion formation and subsequent
F
F
NMe2
capture with an acetylenic gold
r
-complex.18 Studies are now
N
N
underway for the development of recyclable, fluorous-tagged cata-
ClAuPPh3
Au Cl
Cl
lysts for use in A3-reactions.
F
F
Au
Cl
3
Acknowledgments
1
2
G.A.P. thanks the EPSRC for a research studentship. We thank
Alfa Aesar/JM for kind donation of sodium tetrachloroaurate.
N
N
Supplementary data
H3C
CH3
Au
Cl
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.141.
4
References and notes
Figure 1. Gold complexes utilised in this investigation.
1. (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012,
41, 3790–3807; (b) Brauch, S.; Van Berkela, S. S.; Westermann, B. Chem. Soc.
Rev. 2013, 42, 4948–4962; (c) Gupta, A. K.; Singh, N.; Singh, K. N. Curr. Org.
Chem. 2013, 17, 474–490; (d) Liu, Y.; Wang, H.; Wan, J. Asian. J. Org. Chem. 2013,
2, 374–386; (e) Green, N. J.; Sherburn, M. S. Aust. J. Chem. 2013, 66, 267–283; (f)
Pellissier, H. Chem. Rev. 2013, 113, 442–524; (g) Marson, C. M. Chem. Soc. Rev.
2012, 41, 7712–7722.
Ph
Ph
Ph
Bn2N
Bn2N
Bn2N
2. (a) Strecker, A. Justus Liebigs Annal. Chem. 1850, 75, 27–45; (b) Mannich, C.;
Krosche, W. Arch. Pharm. 1912, 250, 647–667; (c) Robinson, R. J. Chem. Soc.
1917, 111, 762–768.
NO2
CN
NBn2
Ph
3. Jiang, B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43, 2543–2546.
90% (thermal)
70% (thermal)
82% (thermal)
86% (µW)
NBn2
4. (a) Wright, J. L.; Gregory, T. F.; Kesten, S. R.; Boxer, P. A.; Serpa, K. A.; Meltzer, L.
T.; Wise, L. D.; Espitia, S. A.; Konkoy, C. S.; Whittemore, E. R.; Woodward, R. M. J.
Med. Chem. 2000, 43, 3408–3419; (b) Kung, K. K.-Y.; Li, G. L.; Zou, L.; Chong, H.-
C.; Leung, Y.-C.; Wong, K.-H.; Lo, V. K.-Y.; Che, C.-M.; Wong, M.-K. Org. Biomol.
Chem. 2012, 10, 925–930; (c) Uhlig, N.; Li, C. J. Org. Lett. 2012, 14, 3000–3003;
(d) Renhack, A.; Jumpertz, T.; Ness, J.; Baches, S.; Pietrzik, C. U.; Weggen, S.;
Bulic, B. Bioorg. Med. Chem. 2012, 20, 6523–6532.
5. (a) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263–4275; (b) Zhou, X.; Lu, Y.; Zhai,
L.-L.; Zhao, Y.; Liu, Q.; Sun, W.-Y. RSC Advances 2013, 3, 1732; (c) Yao, X.; Li, C.-J.
Org. Lett. 2005, 7, 4395–4398; (d) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473–
4475; (e) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268–269; (f) Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 2535–2538; (g) Bieber,
L. W.; da Silva, M. F. Tetrahedron Lett. 2004, 45, 8281–8283; (h) Wie, C.; Li, C.-J. J.
Am. Chem. Soc. 2002, 124, 5638–5639; (i) Li, P.; Zhang, Y.; Wang, L. Chem. Eur. J.
2009, 15, 2045–2049; (j) Chen, W.-W.; Nguyen, R. V.; Li, C.-J. Tetrahedron Lett.
2009, 50, 2895–2898; (k) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319–
4321; (l) Pin-Hua, L.; Lei, W. Chin. J. Chem. 2005, 1076–1080.
Ph
Ph
Ph
Bn2N
Ph
N
N
Ph
Ph
89% (thermal)
77% (thermal)
Thermal: CF3CH2OH, 40 °C, 24 h, 1 mol% 1;
µW: CF3CH2OH, 30 min, 100 °C, 1 mol% 1.
Figure 2. Representative A3-reactions conducted in TFE.
6. (a) Schmidbaur, H.; Schier, A. Arab. J. Sci. Eng. 2012, 37, 1187–1225; (b) De Haro,
T.; Nevado, C. Synlett 2011, 2530–2539; (c) Oña-Burgos, P.; Fernández, I.; Roces,
L.; Fernández, L. T.; Garícia-Granda, S.; Ortiz, F. L. Organometallics 2009, 28, 1739–
1747; (d) Kidwai, M.; Bansal, V.; Kumar, A.; Mozumdar, S. Green Chem. 2007, 9,
742–745; (e) Graf, T. A.; Anderson, T. K.;Bowden, N. B. Adv. Synth. Catal. 2011, 353,
1033–1038; (f) Elie, B. T.; Levine, C.; Ubarretxena-Belandia, I.; Varela-Ramírez,
A.; Aguilera, R. J.; Ovalle, R.; Contel, M. Eur. J. Inorg. Chem. 2009, 3421–3430; (g)
Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358–4361; (h) Lili, L.; Xin, Z.;
Jinsen, G.; Chunming, X. Green Chem. 2012, 14, 1710–1720; (i) Lo, V. K.-Y.; Liu, Y.;
Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529–1532; (j) Villaverde, G.; Corma,
A.; Iglesias, M.; Sánchez, F. ACS Catal. 2012, 2, 399–406.
Table 3
Selected properties of solvents10,11
Solvent
EN (polarity)
HBD
0
Dipole moment (D)
T
Perfluorodecalin
PhCF3
CH2Cl2
CHCl3
PEG-400
MeOH
TFE
0
—
0.241
0.309
0.259
0.575
0.762
0.898
1.0
2.9
1.57
1.2
4.3
1.7
2.03
1.87
—
0.13
0.1
0.31
0.93
1.51
1.17
7. Wie, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–9585.
8. (a) Price, G. A.; Flower, K. R.; Pritchard, R. G.; Brisdon, A. K.; Quayle, P. Dalton
Trans. 2011, 40, 11696–11697; (b) Price, G. A.; Brisdon, A. K.; Randall, S.;
Whittaker, D. M.; Pritchard, R. G.; Muryn, C. A.; Flower, K. R.; Quayle, P. Dalton
Trans. 2013 (submitted).
H2O

154
G. A. Price et al. / Tetrahedron Letters 55 (2014) 151–154
9. Chen, M.-T.; Landers, B.; Navarro, O. Org. Biomol. Chem. 2012, 10, 2206–2208.
994–995; For use of perfluoromethyldecalin in microwave-assisted reactions
see: (c) Benali, O.; Deal, M.; Forrant, E.; Tapolczay, D.; Wheeler, R. Org. Process
Res. Dev. 2008, 12, 1007–1011.
10. (a) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450–451; (b) Maul, J. J.;
Ostrowski, P. J.; Ublacker, G. A.; Linclau, B.; Curran, D. P. Top. Curr. Chem. 1999,
206, 79–105.
15. For multicomponent reactions in PEG: (a) Gu, Y. Green Chem. 2012, 14, 2091–
2128; Cu-catalysed A3-reactions in PEG: (b) Zhang, Q.; Chen, J.-X.; Gao, W.-X.;
Ding, J.-C. Appl. Organometal. Chem. 2010, 24, 809–812.
16. (a) Hong, M.; Cai, C.; Yi, W. B. Chin. Chem. Lett. 2011, 22, 322–325; (b) Vincent,
J.-M. Top. Curr. Chem. 2012, 308, 153–174.
17. Full experimental details can be found in the Supplementary data.
18. For similar solvent effects in related condensation–addition reactions of
aldehydes see: (a) Heydari, A.; Khaksar, S.; Tajbaksh, M. Tetrahedron Lett.
2009, 50, 77–80; (b) Hosseinzadeh, R.; Alinezhad, H.; Ghahari, S.; Heydari, A.
Synthesis 2011, 490–496; (c) Khaksar, S.; Alipour, M. Monatsh Chem. 2013, 144,
395–398.
11. (a) Shuklov, I.; Dubrovina, N.; Börner, A. Synthesis 2007, 2925–2943; (b)
Brégué, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18–29.
12. (a) Shi, L.; Tu, Y.; Wang, M.; Zhang, F.; Fan, C. Org. Lett. 2004, 6, 1001–1003; (b)
Ju, Y.; Li, C.-J.; Varma, R. QSAR Comb. Sci. 2004, 23, 891–894; (c) Kabalka, G.;
Wang, L.; Pagni, R. Synlett 2001, 676–678; (d) Bariwal, J. B.; Ermolat’ev, D. S.;
Van der Eycken, E. V. Chem. Eur. J. 2010, 16, 3281–3284.
13. For a MACOS A3-reaction see: Shore, G.; Yoo, W.-J.; Organ, M. G. Chem. Eur. J.
2010, 16, 126–133.
14. For the use of cis/trans-perfluorodecalin see: (a) Hong, M.; Cai, C.; Yi, W.-B. J.
Fluorine Chem. 2010, 131, 111–114; (b) Shi, M.; Cui, S.-C. Chem. Commun. 2002,