A3-Coupling Reaction and [Ag(IPr)2]PF6: A Successful Couple

Article abstract of DOI:10.1002/ejoc.201700985

The recently described homoleptic cationic [Ag(IPr)₂]PF₆ [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolylidene] complex proved to be a versatile and highly efficient catalyst for the production of propargylamines by using the A³-coupling reaction. The reaction conditions were equally applicable to aliphatic and aromatic aldehydes and alkynes, including highly hindered aromatic aldehydes. Progargylamines were prepared in short reaction times with low catalyst loadings by using MeOH as a low-toxicity solvent. In addition, the catalyst was stable enough to support continuous-flow conditions, which showed that the reaction conditions are scalable.

Full text of DOI:10.1002/ejoc.201700985

DOI: 10.1002/ejoc.201700985
Communication
Silver Catalysis
A3-Coupling Reaction and [Ag(IPr)2]PF6: A Successful Couple
Audrey Beillard,[a] Thomas-Xavier Métro,*[a] Xavier Bantreil,*[a] Jean Martinez,[a] and
Frédéric Lamaty*[a]
Abstract: The recently described homoleptic cationic highly hindered aromatic aldehydes. Progargylamines were pre-
[Ag(IPr)2]PF6 [IPr
= 1,3-bis(2,6-diisopropylphenyl)imidazolyl- pared in short reaction times with low catalyst loadings by us-
idene] complex proved to be a versatile and highly efficient ing MeOH as a low-toxicity solvent. In addition, the catalyst was
catalyst for the production of propargylamines by using the A3- stable enough to support continuous-flow conditions, which
coupling reaction. The reaction conditions were equally applica- showed that the reaction conditions are scalable.
ble to aliphatic and aromatic aldehydes and alkynes, including
Introduction
amines, aliphatic and aromatic aldehydes, as well as alkynes
presenting varied electronic and steric properties.
We recently described a general, rapid, user-friendly, and sol-
vent-free synthesis of NHC–AgI complexes by using a ball
mill.[24] In particular, homoleptic and cationic silver(I) complexes
bearing noncoordinating tetrafluoroborate or hexafluorophos-
phate counteranions could be isolated in high yields (Fig-
ure 1).[24b]
Propargylamines are highly versatile building blocks that have
been widely used for the construction of nitrogen-containing
heterocycles, and they have found various applications ranging
from ligands for catalysis to pharmaceuticals and agrochemi-
cals.[1] The discovery that metals could catalyze the reaction
between an aldehyde, an amine, and an acetylene to form
propargylamines, also known as the A3-coupling reaction, has
led research groups to develop various strategies aimed at pro-
ducing propargylamines and related heterocycles under effi-
cient, direct, and mild experimental conditions.[2] Many catalytic
systems have been described, including copper,[3] gold,[4]
silver,[5] magnesium,[6] indium,[7] rhodium,[8] iridium,[9] iron,[10]
cobalt,[11] and zinc.[12] Whereas gold and copper appear to be
the most frequently used catalysts for such transformations,
silver presents some interesting advantages such as being
greener and cheaper than gold, as well as generally requiring
lower catalyst loadings and shorter reaction times than cop-
per.[2b,13] Since the group of Li reported AgI as an efficient cata-
lyst for the A3-coupling reaction in water,[5a] several studies de-
scribed the catalytic activity of silver used in various forms, in-
cluding salts,[14] nanoparticles,[15] nanocomposites,[16] metal–
organic frameworks,[17] and polymeric[18] as well as discrete or-
ganometallic complexes. Lately, ligands such as imidazoles,[19]
acridines,[20] pyridines,[5b,21] biarylylphosphanes,[22] and
N-heterocyclic carbenes (NHCs)[23] have been studied, but to
the best of our knowledge none of them were efficient for a
wide range of substrates, including cyclic and linear secondary
[a] Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS,
Université de Montpellier, ENSCM, Campus Triolet,
Place Eugène Bataillon, 34095 Montpellier cedex 5, France
E-mail: thomas-xavier.metro@umontpellier.fr
Figure 1. NHC–silver(I) complexes synthesized by ball milling and screened
as catalysts in the A3-coupling reaction.
xavier.bantreil@umontpellier.fr
frederic.lamaty@umontpellier.fr
http://www.greenchem.univ-montp2.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700985.
Such complexes were rarely described because of their diffi-
cult synthesis, and to date, solely three examples of their use
as catalysts were reported, including only one with N,N-diaryl-
NHCs.[25]
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Hypothesizing that the high electrophilic nature of these cat- at the end of the reaction (Table 1, Entries 5 and 6). In contrast,
ionic NHC–AgI complexes would favor efficient coordination of AgI complexes bearing N,N-diarylimidazolylidene ligands fur-
the alkyne on the catalyst and subsequent formation of the nished more satisfying results. [Ag(IMes)2]BF4 and [Ag(IMes)2]-
silver alkynide, we envisioned studying the efficiency of these PF6 enabled the production of compound 1 in yields of 66 and
cationic NHC–AgI complexes in catalyzing the A3-coupling reac- 53 %, respectively (Table 1, Entries 7 and 8). The use of sterically
tion. Both the BF4 and PF6 salts of cationic silver complexes more hindered IMesMe ligands gave results similar to those ob-
bearing the widely used IMes and IPr ligands [IMes = 1,3- tained with the use of IMes ligands (Table 1, Entries 9 and 10).
bis(2,4,6-trimethylphenyl)imidazolylidene; IPr = 1,3-bis(2,6-diiso- The best result was obtained with [Ag(IPr)2]PF6, which led to
propylphenyl)imidazolylidene], their sterically more hindered the formation of 1 in 81 % yield (Table 1, Entry 12). Gratifyingly,
homologues IMesMe and IPrMe having methyl groups on the the amounts of both piperidine and phenylacetylene could be
imidazole backbone {IMesMe = [1,3-bis(2,4,6-trimethylphenyl)- reduced to 1.1 equiv. without dramatically affecting the yield
4,5-dimethyl]imidazolylidene; IPrMe = [1,3-bis(2,4,6-trimethyl- (77 %), provided that 4 mol-% of [Ag(IPr)2]PF6 was engaged in
phenyl)-4,5-dimethyl]imidazolylidene}, as well as MeBnIm (1- the reaction. Unlike for IMes, the use of IPrMe instead of IPr was
benzyl-3-methylimidazolylidene), Bn2Im2 (1,3-dibenzylimidazol- highly detrimental to the reaction, most probably because of
ylidene) and TPT (1,3,4-triphenyl-1,2,4-triazolylidene) were eval- the low solubility of [Ag(IPrMe)2] salts in MeOH (Table 1, En-
uated.
tries 13 and 14). Despite the presence of the two highly hin-
dered IPr ligands, the efficiency of [Ag(IPr)2]PF6 could be ex-
plained by the strong Lewis acid character of the cationic silver
atom, which favors coordination of the alkyne and subsequent
formation of the silver alkynide intermediate.
Results and Discussion
Thus, benzaldehyde (1.0 equiv.), piperidine (1.2 equiv.), and
phenylacetylene (1.5 equiv.) were treated in the presence of
3 mol-% of each of these complexes in MeOH at 110 °C under
microwave irradiation for 1 h. Although enabling good conver-
sion of the substrates, complexes with N,N-dialkylimidazolyl-
idene ligands furnished propargylamine 1 in low to moderate
yields (Table 1, Entries 1–4). AgI complexes with the triazolyl-
idene ligand did not lead to better results, supposedly as a
result of an apparent low stability of the complex, as revealed
by a relatively thick silver mirror observed on the reactor wall
In view of these encouraging results, the efficacy of
[Ag(IPr)2]PF6 was evaluated for the synthesis of a wide range
of propargylamines. Given that aromatic aldehydes are less
reactive than aliphatic ones in the silver-catalyzed A3-coupling
reaction, benzaldehyde was kept to screen the amine and alk-
yne partners. Other cyclic amines such as pyrrolidine and
morpholine as well as linear dialkylamines led to the corre-
sponding propargylamines in excellent yields (Table 2; com-
pounds 2–5). Gratifyingly, dialkylated piperazine 6 was isolated
in 86 % yield within 4 h upon using 0.55 equiv. of piperazine
as the substrate (Table 2; compound 6), whereas a 24 h reaction
was necessary if a gold catalyst was used.[4b]
Table 1. Catalyst screening for the A3-coupling reaction.[a]
These reaction conditions proved to be also highly tolerant
to the terminal alkyne. Propargylamines were obtained in good
to excellent yields whether the alkyne was substituted by
phenyl groups bearing various substituents (Table 2; com-
pounds 7–11) or alkyl groups (Table 2; compounds 12–13).
These reaction conditions were also applicable with equal effi-
ciency toward a set of benzaldehydes substituted by iodo or
methoxy groups in the para and meta positions to furnish the
corresponding propargylamines 14–17 in good to excellent
yields. Even more hindered ortho-substituted benzaldehydes
reacted efficiently under the silver/microwave conditions to fur-
nish amines 18 and 19 in good yields.
Entry
Catalyst
Yield [%][b]
1
2
3
4
5
[Ag(MeBnIm)2]BF4
[Ag(MeBnIm)2]PF6
[Ag(Bn2Im)2]BF4
[Ag(Bn2Im)2]PF6
[Ag(TPT)2]BF4
51
36
11
30
8
Pleasingly, [Ag(IPr)2]PF6 was able to convert highly encum-
bered 2,4,6-trimethoxybenzaldehyde into propargylamine 20
(90 % yield). Similarly, propargylamine 21 could be isolated in
a rather good yield of 69 % upon starting from highly electron-
deficient 4-(trifluoromethyl)benzaldehyde. Of note, 21 could
also be isolated in 87 % yield after 10 h at room temperature.
A distinctive feature of this [Ag(IPr)2]PF6/microwave approach,
if compared to most silver-catalyzed A3-coupling condi-
tions,[5b,19,20,22,23] is its efficiency towards both variously substi-
tuted aromatic and aliphatic aldehydes. Indeed, cyclohexane-
carbaldehyde and heptanal could be easily transformed into
propargylamines 22–25 (86–92 % yield). Interestingly, prop-
argylamines 22 and 23 could be isolated either at 110 °C under
6
7
8
9
10
11
12
13
14
[Ag(TPT)2]PF6
12
66
53
52
55
24
[Ag(IMes)2]BF4
[Ag(IMes)2]PF6
[Ag(IMesMe)2]BF4
[Ag(IMesMe)2]PF6
[Ag(IPr)2]BF4
[Ag(IPr)2]PF6
81[c] (77)[d]
[Ag(IPrMe)2]BF4
[Ag(IPrMe)2]PF6
14
7
[a] Reaction conditions: benzaldehyde (1.0 mmol), piperidine (1.2 equiv.),
phenylacetylene (1.5 equiv.), catalyst (3 mol-%), MeOH, microwave irradiation,
110 °C, 1 h. [b] Determined by HPLC analysis by using mesitylene as an
internal standard. [c] Yield of isolated product. [d] Yield of isolated product
upon using 1.1 equiv. of both piperidine and phenylacetylene along with
4 mol-% of [Ag(IPr)2]PF6.
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Table 2. Scope of [Ag(IPr)2]PF6 as a catalyst for the A3-coupling reaction.[a]
[a] Reaction conditions: aldehyde (1.0 mmol), amine (1.1 equiv.), acetylene (1.1 equiv.), [Ag(IPr)2]PF6 (4 mol-%), MeOH (2 mL), microwave irradiation, 110 °C.
[b] Piperazine (0.55 equiv.). [c] Aldehyde (1.0 mmol), piperidine (1.2 equiv.), phenylacetylene (1.5 equiv.). [d] Reaction was performed at room temperature.
microwave irradiation within 30 min or at room temperature for synthesized under ambient atmosphere by using technical-
longer reaction times.
The efficient synthesis of propargylamines 24 and 25 by
treatment of heptanal with 1,2,3,4-tetrahydroisoquinoline/
grade MeOH and without any purification of the reagents, giv-
ing additional ease to this user-friendly protocol.
To study the scalability of these reaction conditions, the syn-
phenylacetylene and piperidine/2-ethynylpyridine, respectively, thesis of propargylamines 1 and 23 was tested under continu-
further extended the scope of this approach. Owing to their ous flow.[4d,26] Indeed, as both microwave and continuous-flow
lower reactivity, ketones are less studied than aldehydes in the synthesis allow efficient heating/cooling and generation of a
A3-coupling reaction. Delightfully, the [Ag(IPr)2]PF6/microwave superheated solvent, high-temperature microwave synthesis
reaction conditions were also applicable to ketones, as treat- should be easily transferred to continuous-flow synthesis.[27]
ment of 2-pentanone with pyrrolidine and phenylacetylene in Thus, two separate solutions, one containing benzaldehyde
the presence of [Ag(IPr)2]PF6 furnished propargylamine 26 in (2
88 % yield (Table 2). Of note, all of these propargylamines were ing piperidine (2.2
N
) and [Ag(IPr)2]PF6 (0.08
N
) in MeCN and the other contain-
), were pumped
N
) and phenylacetylene (2.2
N
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of the reaction vial. Continuous-flow experiments were performed
by using Uniqsis Flowsyn Multi-X equipment. High-temperature
PTFE coil reactors (10 or 20 mL) were set up. Flow rates were
adapted to ensure an appropriate residence time in the reaction
coil. The synthesis of the NHC–AgI catalysts was performed with a
Retsch MM200 or MM400 vibrating ball mill (vbm) operated at 25–
30 Hz or with a Retsch PM100 planetary mill (pbm) operated at
450 rpm, according to a previously reported procedure.[24b] Analy-
ses were performed at the “Plateforme Technologique Laboratoire
de Mesures Physiques” (IBMM, Université de Montpellier). 1H NMR
in a 20 mL polytetrafluoroethylene (PTFE) coil heated up to
130 °C at a flow rate of 0.17 mL min–1 to ensure a 2 h residence
time. An experimental setup with two pumps was necessary to
avoid the fast formation and precipitation of the intermediate
N-cyclohexylbenzaldimine. After classical workup and purifica-
tion, propargylamine 1 was isolated in 80 % yield (Scheme 1),
in the same range as that obtained for the reaction performed
in MeOH at 110 °C under microwave irradiation (81 %; Table 1,
Entry 12). On the other hand, pumping a single MeCN solution of
heptanal (1
[Ag(IPr)2]PF6 (0.04
N
), piperidine (1.1
N), phenylacetylene (1.1 N), and spectra were recorded in CDCl3 or [D6]DMSO with a Bruker Avance I
300 MHz or a Bruker Avance III HD 400 MHz spectrometer. Chemical
shifts are reported in ppm and are referenced to the residual protio
solvent signal (CHCl3 at δ = 7.26 ppm or DMSO at δ = 2.50 ppm).
Data are reported as s = singlet, d = doublet, t = triplet, q = quadru-
plet, quint = quintuplet, sept = septuplet, m = multiplet; coupling
constant in Hz; integration. 13C NMR spectra were recorded with a
Bruker Avance I 75 MHz or a Bruker Avance III HD 101 MHz spec-
trometer. Chemical shifts are reported in ppm and are referenced
to the solvent signal (CDCl3 at δ = 77.2 ppm or [D6]DMSO at δ =
39.5 ppm). 31P NMR spectra were recorded with a Bruker Avance III
HD 162 MHz spectrometer and 19F NMR spectra with a Bruker
Avance III HD 376 MHz instrument. HRMS analyses were performed
with a UPLC Acquity H-Class from Waters hyphenated to a Synapt
G2-S mass spectrometer with a dual ESI source from Waters.
N
) into a 10 mL PTFE coil heated up to 130 °C
was possible and produced propargylamine 23 in 89 % yield
(Scheme 1). Of note, MeCN was used instead of MeOH because
of clogging and blockage of the system due to the poor solubil-
ity of [Ag(IPr)2]PF6 in MeOH. These results show that these reac-
tion conditions are totally compatible with the production of
propargylamines at a much higher scale.
[Ag(IPr)2]PF6: 1,3-Bis(2,6-diisopropylphenyl)imidazolium hexa-
fluorophosphate (140.1 mg, 0.262 mmol, 1.00 equiv.), Ag2O
(30.3 mg, 0.131 mmol, 0.50 equiv.), and NaOH (11.5 mg, 0.288 mmol,
1.10 equiv.) were introduced into a 10 mL stainless-steel grinding
bowl with one stainless-steel ball (10 mm diameter). The bowl was
closed and subjected to grinding in the vibrating ball mill operated
at 30 Hz for 3 h. The black powder was recovered with CH2Cl2, and
the suspension was filtered through Celite. The filtrate was concen-
trated under vacuum. The white solid was dissolved in a minimum
amount of CH2Cl2, washed with water (3 ×), and concentrated un-
der vacuum. The solid was washed with water and Et2O and dried
under vacuum to afford bis[1,3-bis(2,6-diisopropylphenyl)imidazol-
2-ylidene]silver hexafluorophosphate (96.9 mg, 94.1 μmol, 72 %) as
a white solid. 1H NMR (400 MHz, [D6]DMSO): δ = 7.77 (d, J = 0.9 Hz,
4 H), 7.51 (t, J = 7.8 Hz, 4 H), 7.18 (d, J = 7.8 Hz, 8 H), 2.20 (sept.,
J = 6.9 Hz, 8 H), 1.01 (d, J = 6.9 Hz, 24 H), 0.75 (d, J = 6.9 Hz, 24 H)
ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 181.4 (dd, J = 201.6,
14.5 Hz), 144.6, 134.5, 130.3, 125.7, 125.6, 124.0, 28.1, 24.0,
23.7 ppm. 31P NMR (162 MHz, [D6]DMSO): δ = –144.2 (sept, J =
711.3 Hz) ppm. 19F NMR (376 MHz, [D6]DMSO): δ = –70.2 (d, J =
711.3 Hz) ppm.
Scheme 1. Continuous-flow synthesis of propargylamines 1 and 23.
Conclusions
The homoleptic and cationic [Ag(IPr)2]PF6 complex was found
to be a highly versatile and efficient catalyst for the production
of a wide range of propargylamines under microwave irradia-
tion or continuous flow. This represents one of the rare exam-
ples of successful catalysis involving homoleptic silver–NHC
complexes. Propargylamines were synthesized in short reaction
times with low catalyst loadings and by using low-toxic, techni-
cal-grade MeOH, all of which make the methodology easy and
user-friendly. This approach is versatile and compatible with
N-(1,3-Diphenylprop-2-yn-1-yl)piperidine (1). By Microwave Ir-
radiation: Benzaldehyde (103 μL, 1.00 mmol, 1.00 equiv.), piper-
idine (109 μL, 1.10 mmol, 1.10 equiv.), phenylacetylene (116 μL,
1.10 mmol, 1.10 equiv.), [Ag(IPr)2]PF6 (41.4 mg, 0.04 mmol,
both aliphatic and aromatic aldehydes and alkynes, including 0.04 equiv.), and MeOH (2 mL) were introduced into a sealed reac-
tor. The suspension was heated under microwave irradiation at
110 °C for 1 h. After cooling to room temperature, the mixture was
filtered through Celite and concentrated under reduced pressure.
The crude mixture was purified by flash column chromatography
(gradient cyclohexane/EtOAc) to afford N-(1,3-diphenyl-2-
propynyl)piperidine (211 mg, 0.77 mmol, 77 %) as a yellow oil. By
Continuous Flow: A solution of benzaldehyde (103 μL, 1.00 mmol,
1.00 equiv.), [Ag(IPr)2]PF6 (41.4 mg, 0.04 mmol, 0.04 equiv.), and
MeCN (500 μL) was prepared and connected to pump A. Similarly,
a solution of piperidine (109 μL, 1.10 mmol, 1.10 equiv.), phen-
highly hindered aromatic aldehydes, and less reactive ketones
reacted efficiently. Finally, a continuous-flow approach was de-
veloped, which thus allowed a facilitated scale-up.
Experimental Section
General Information: All reagents were purchased from Aldrich
Chemical Co., Fluka, and Alfa Aesar and were used without further
purification. Reactions performed under microwave irradiation were
performed with a Biotage® Initiator+ microwave synthesizer. The ylacetylene (116 μL, 1.10 mmol, 1.10 equiv.), and MeCN (500 μL)
temperature was measured with an IR sensor on the outer surface was prepared and connected to pump B. After setting the tempera-
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1
ture to 130 °C, both valve positions were switched to place the phenylethynyl)heptyl]piperidine (252 mg, 0.89 mmol, 89 %). H
mixture inline. Solutions A and B were pumped towards a T-shaped
mixer, then into the 20 mL PTFE residence coil, and then through a
back-pressure regulator (BPR) rated to 6.9 bar (100 psi) at a flow
rate ensuring a 2 h residence time (0.17 mL min–1). The mixture
NMR (300 MHz, CDCl3): δ = 7.48–7.45 (m, 2 H), 7.34–7.28 (m, 3 H),
3.48 (dd, J = 9.0, 5.8 Hz, 1 H), 2.77–2.62 (m, 2 H), 2.57–2.43 (m, 2 H),
1.77–1.69 (m, 3 H), 1.67–1.53 (m, 5 H), 1.51–1.42 (m, 3 H), 1.38–1.27
(m, 6 H), 0.94–0.86 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
was recovered and concentrated under reduced pressure. The crude 131.9, 128.3, 127.9, 123.8, 88.4, 85.7, 58.8, 50.7, 33.6, 31.9, 29.2, 27.0,
mixture was purified by flash column chromatography (gradient cy-
clohexane/EtOAc) to afford N-(1,3-diphenyl-2-propynyl)piperidine
(220 mg, 0.80 mmol, 80 %) as a yellow oil. 1H NMR (300 MHz, CDCl3):
δ = 7.65 (d, J = 7.2 Hz, 2 H), 7.53 (dd, J = 6.6, 3.0 Hz, 2 H), 7.40–7.30
(m, 6 H), 4.82 (s, 1 H), 2.58 (t, J = 5.1 Hz, 4 H), 1.66–1.57 (m, 4 H),
1.46 (q, J = 5.7 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 138.8,
131.9, 128.7, 128.4, 128.2, 127.6, 123.5, 88.0, 86.2, 62.5, 50.8, 26.3,
24.9 ppm.
26.3, 24.7, 22.8, 14.2 ppm.
Acknowledgments
Université de Montpellier, Centre National de la Recherche Sci-
entifique (CNRS), and French Ministry of Higher Education and
Research (grant to A. B.) are acknowledged for funding.
N-[1-(2,4,6-Trimethoxyphenyl)-3-phenylprop-2-yn-1-yl]piper-
idine (20): 2,4,6-Trimethoxybenzaldehyde (196 mg, 1.00 mmol,
1.0 equiv.), piperidine (119 μL, 1.20 mmol, 1.2 equiv.), phenylacet-
ylene (158 μL, 1.50 mmol, 1.5 equiv.), [Ag(IPr)2]PF6 (41.4 mg,
0.04 mmol, 0.04 equiv.), and MeOH (2 mL) were introduced into a
sealed reactor. The suspension was heated under microwave irradia-
tion at 110 °C for 4 h. After cooling to room temperature, the mix-
ture was filtered through Celite and concentrated under reduced
pressure. The crude mixture was purified by flash column chroma-
tography (gradient cyclohexane/EtOAc) to afford N-[1-(2,4,6-tri-
methoxyphenyl)-3-phenylprop-2-yn-1-yl]piperidine (330 mg,
0.90 mmol, 90 %) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ =
7.47–7.41 (m, 2 H), 7.27–7.24 (m, 3 H), 6.17 (s, 2 H), 5.24 (s, 1 H),
3.84 (s, 6 H), 3.82 (s, 3 H), 2.70–2.57 (m, 4 H), 1.63–1.55 (m, 4 H),
1.42–1.34 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.9, 160.0,
131.8, 128.2, 127.5, 124.6, 124.4, 108.0, 91.8, 89.7, 56.3, 55.4, 51.6,
26.3, 24.5 ppm. HRMS: calcd. for C23H28NO3 [M + H]+ 366.2069;
found 366.2064.
Keywords: Alkynes · Amines · Carbenes · Silver ·
Multicomponent reactions · Continuous flow
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N-[1-(2-Phenylethynyl)heptyl]piperidine (23). By Microwave Ir-
radiation: Heptanal (140 μL, 1.00 mmol, 1.0 equiv.), piperidine
(109 μL, 1.10 mmol, 1.10 equiv.), phenylacetylene (116 μL,
1.10 mmol, 1.1 equiv.), [Ag(IPr)2]PF6 (41.4 mg, 0.04 mmol,
0.04 equiv.), and MeOH (2 mL) were introduced into a sealed reac-
tor. The suspension was heated under microwave irradiation at
110 °C for 30 min. After cooling to room temperature, the mixture
was filtered through Celite and concentrated under reduced pres-
sure. The crude mixture was purified by flash column chromatogra-
phy (gradient cyclohexane/EtOAc) to afford N-[1-(2-phenyleth-
ynyl)heptyl]piperidine (261 mg, 0.92 mmol, 92 %) as a yellow oil. By
Agitation at Room Temperature: Heptanal (140 μL, 1.00 mmol,
1.0 equiv.), piperidine (109 μL, 1.10 mmol, 1.10 equiv.), phenylacet-
ylene (116 μL, 1.10 mmol, 1.1 equiv.), and [Ag(IPr)2]PF6 (41.4 mg,
0.04 mmol, 0.04 equiv.) were dissolved in MeOH (2 mL), and the
mixture was agitated at room temperature for 12 h. The mixture
was filtered through Celite and concentrated under reduced pres-
sure. The crude mixture was purified by flash column chromatogra-
phy (gradient cyclohexane/EtOAc) to afford N-[1-(2-phenyleth-
ynyl)heptyl]piperidine (223 mg, 0.79 mmol, 79 %) as a yellow oil.
By Continuous Flow: Heptanal (140 μL, 1.00 mmol, 1.00 equiv.),
piperidine (109 μL, 1.10 mmol, 1.10 equiv.), phenylacetylene
(116 μL, 1.10 mmol, 1.10 equiv.), and [Ag(IPr)2]PF6 (41.4 mg,
0.04 mmol, 0.04 equiv.) were dissolved in MeCN (1 mL) and placed
in a vial. After setting the temperature to 130 °C, the valve position
was switched to place the mixture inline. The mixture then flowed
into the 10 mL PTFE residence coil and then through a back-pres-
sure regulator (BPR) rated to 6.9 bar (100 psi) at a flow rate ensuring
a 30 min residence time (0.33 mL min–1). The mixture was then
concentrated under reduced pressure and purified by flash column
chromatography (gradient cyclohexane/EtOAc) to afford N-[1-(2-
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Received: July 13, 2017
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