Propargyl amine synthesis catalysed by gold and copper thin films by using microwave-assisted continuous-flow organic synthesis (MACOS)

Article abstract of DOI:10.1002/chem.200902396

An effective multi-component reaction (MCR) protocol has been developed for the construction of propargyl amines from aldehydes, amines and terminal alkynes by using microwave-assisted continuous-flow organic synthesis (MACOS). The process is catalysed by

Full text of DOI:10.1002/chem.200902396

DOI: 10.1002/chem.200902396
Propargyl Amine Synthesis Catalysed by Gold and Copper Thin Films by
Using Microwave-Assisted Continuous-Flow Organic Synthesis (MACOS)
Gjergji Shore,[a] Woo-Jin Yoo,[b] Chao-Jun Li,*[b] and Michael G. Organ*[a]
Abstract: An effective multi-compo-
nent reaction (MCR) protocol has
been developed for the construction of
propargyl amines from aldehydes,
amines and terminal alkynes by using
microwave-assisted continuous-flow or-
ganic synthesis (MACOS). The process
is catalysed by thin films of either
copper or gold that achieve tempera-
tures in excess of 9008C when irradiat-
ed with low levels of microwave power.
The process works equally well for pre-
mixed solutions of the three starting
materials, or as three separate streams,
which improves the combinatorial effi-
ciency of the method. The process tol-
erates a wide variety of functional
groups and heterocycles, and conver-
sion over these diverse substrates
ranges from 70–90%.
Keywords: amines · copper · gold ·
microwave chemistry · thin films
Introduction
quent drop of product should be the same over time, which
is not the case with batch reactions. The physical separation
of reactive intermediates from the starting materials (and
products) until the point of contact at the start of the flow
tube minimises side reactions. Continuous removal of prod-
ucts from the reaction zone limits the formation of by-prod-
ucts owing to prolonged unnecessary exposure to heat, cata-
lysts or other reaction-promoting elements. The potential to
couple in-line analysis into a continuously moving flow
stream allows for instantaneous changes to reaction condi-
tions for process optimisation, and once ideal conditions
have been achieved, larger quantities of product can be ob-
tained by flowing reactions for longer and/or in parallel
tubes without the need for time-consuming, scale-up process
optimisation.
Microwave-assisted organic synthesis (MAOS) has become
an important tool in the hands of synthetic organic chemists
in the recent years. Some of the advantages of MAOS over
conventional heating methods (e.g., oil baths) include a sig-
nificant reduction of reaction times and the generation of
cleaner product mixtures.[1] However, batch-reactor MAOS
requires that transformations be conducted in sealed, high-
pressure vials; this necessitates the manual handling of each
individual transformation that slows down the overall syn-
thetic process. Over the last five years, the development of
microwave-assisted continuous-flow organic synthesis
(MACOS) has also rapidly progressed.[2,3] Continuous-flow
technology also offers numerous advantages over traditional
batch reactors.[4] A synthetic process can be rapidly opti-
mised because the results of any set of reaction parameters
can be assessed from the first drop of eluent. Every subse-
We have demonstrated that homogeneous reaction mix-
tures flowed through capillary-size glass reactors while
being constantly irradiated with microwave irradiation can
lead to excellent conversions. This can be done by flowing
premixed solutions through a single lead into the reactor or
by flowing the reactants into the reactor through separate
inlets where they mix under microwave radiation.[5] More
recently we have shown that coating the glass capillary reac-
tors with thin layers of metals can tremendously accelerate
flowed reactions.[6] This rate acceleration can be a result of
direct catalysis by the thin film itself, the extremely high
temperatures achieved by microwaving the film or by a
combination of the two. Pd thin films have been shown to
be capable of catalysing Suzuki–Miyaura and Heck reaction-
s,[6a] whereas gold films can very efficiently catalyse hydrosi-
[a] G. Shore, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
[b] Dr. W.-J. Yoo, Prof. C.-J. Li
Department of Chemistry, McGill University
801 Sherbrooke Street West
Montreal, Quebec, H3A2K6 (Canada)
Fax : (+1)514-398-3797
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902396.
lylation and benzannulation reacACHTUNGTRNEUNG
tions.[6b,c] All of these trans-
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FULL PAPER
formations proceed without any additional catalyst being
added to the reaction mixture. In the absence of microwave
irradiation, none of these reactions proceeded, indicating
that heating supplied by the thin films under microwave ir-
radiation plays a fundamental role in the process.
ic fine structure, and by energy-dispersive X-ray (EDX)
analysis to determine chemical composition.
The SEM analysis of film morphology indicated a very de-
veloped microstructure (with the exception of the Ag mirror
film) consisting of porous clusters of metal nanoparticles
that are closely held together (Figure 1a–e). The existence
of such clusters could increase the catalytic activity of the
film under microwave irradiation as previously suggested.[6]
Further, irregularities of morphology such as steps or sharp
corners on the metal–film surface have been postulated to
lead to the formation of hot spots that are much higher than
the bulk temperature of the film as recorded by the infrared
(IR) sensor in the microwave cavity.[6] This could lead to a
large increase in reactivity under MACOS conditions be-
cause the flowing reaction mixture contacts these areas in
the structure of the film through the formation of micro-
scopic (or larger) pockets of super-heated, vapour-phase re-
actants. This would be analogous to flash vacuum thermoly-
sis (FVT) in which compounds are warmed into the gas
phase under high vacuum and drawn into contact with the
walls of a super-heated (e.g., 500–7008C) quartz reaction
tube.
Propargylamines are versatile synthetic intermediates in
organic synthesis[7] and are also key structural elements in
natural products and therapeutic drug molecules.[8] The tra-
ditional approach for synthesising propargylamines involves
the nucleophilic attack of lithium acetylides or Grignard re-
agents on imines and their derivatives.[9] This method neces-
sitates the use of strictly moisture-free reaction conditions
and prohibits the presence of sensitive functionalities (e.g.,
alcohols, amines and esters), thus limiting its wider applica-
tion. Over the last decade there has been increasing interest
in the development of transition-metal catalysts to accom-
plish the synthesis of propargyl amines by using the Man-
nich-type three-component coupling reaction of aldehydes,
À
secondary amines and terminal alkynes through C H bond
activation. Several late transition-metal salts such as Au, Ag,
Ir, Ru–Cu, Ru–In and Fe were reported by Li and others to
[10]
À
promote this transformation through C H activation. En-
vironmentally friendly strategies have also been carried out
in water, ionic liquids and even under solvent-free condi-
tions.[10c,d,11] Recently, the Mannich three-component cou-
pling strategy has been shown to be promoted by supported
nanoparticles including Ag,[12a] Au[12b,c] and Cu,[12d,e] and by
oxides CuO[12f] and Ag2O.[12 g] In all cases the metal–acet-
EDX analysis illustrated that the films are primarily met-
allic in composition (Figure 1 f–h). The films are not pro-
duced with the exclusion of oxygen, thus oxygen detected
by the method could exist in the form of metal oxides on
the surface of the film. The role of these metal oxides,
which surely exist in all metal films, has yet to be examined.
Further, it has not yet been determined if these oxides are
reduced back to the metallic form because at least some of
the reactions that have been done with metal films in
MACOS, such as cross coupling reactions, are conducted in
a potentially reducing environment.[6] Although Pd readily
changes oxidation state during the various catalytic cycles in
which it is employed, Au resists such changes. Further, CuO
and Ag2O nanoparticles have already been shown to cata-
lyse the reaction under investigation in this report, so it
could very well be that it is the oxidised form of the metal
that is mediating the transformations in this study.
With the metal-coated capillaries in hand, we embarked
on the development of a general MACOS method for the
preparation of propargyl amines. With some optimisation by
using a Cu-coated capillary, a general protocol by using pre-
mixed solutions of 1, 2 and 3 was developed (Table 1,
entry 1). Attempted runs by using either Pd or Ag films
(Table 1, entries 2 and 3) failed to provide any conversion
whatsoever. However, Au films were shown to be reactive
in the transformation, although conversions with the Au
films were slightly lower when compared directly with the
identical transformation that used Cu.
ACHTUNGTRENNUNGylide intermediate has been assumed to play a key role in
the reaction sequence.
Multi-component reaction (MCR) protocols have been
successfully developed for MACOS in the past.[13] However,
those protocols were not metal-catalysed. In an effort to in-
crease the applications of MACOS, we envisioned that the
three-component coupling reaction to form propargyl
amines described above would be a good system to investi-
gate the catalytic role of transition-metal films in the
MACOS system. Further, bridging the gap between homo-
geneous and heterogeneous catalysis can lead to more effi-
cient methods for chemical synthesis.[14]
Results and Discussion
The investigation of the three-component, MACOS-facilitat-
ed synthesis of propargyl amines began with an assessment
of the catalytic properties of several metal films. Recent lit-
erature reports have demonstrated that metallic Au, Ag and
Cu nanoparticles can serve as useful catalysts for this reac-
tion,[12] thus we prepared thin films of these metals inside
our flow tubes (capillaries) and analysed their composition.
The protocols that we have developed for preparing these
films (detailed in the Experimental Section) all involve
either thermal reduction of a homogeneous solution of
metal salts or reduction with hydrazine. Analysis of the re-
sultant films was done by scanning electron microscopy
(SEM) to examine both general morphology and microscop-
To improve combinatorial efficiency when collecting a
larger number of compounds for biological evaluation, for
example, it would be desirable to infuse the starting materi-
als into the mixing chamber separately, rather than as pre-
mixed solutions that would require a separate flask for
every molecular combination desired. To examine how this
would work for the current MACOS setup, compound 4a
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127

M. G. Organ, C.-J. Li et al.
Figure 1. SEM images of all of the 6 mm metal films that were used in this study and their corresponding EDX analysis: a) Au film supported on a very
thin Ag lining taken at ꢁ50000 magnification, b) Cu film taken at ꢁ60000 magnification, c) Ag colloidal film taken at ꢁ30000 magnification, d) Pd film
taken at ꢁ30000 magnification, e) side view of Ag mirror film attached to the glass wall taken at ꢁ60000 magnification. The EDX spectra of f) the Au
film from (a), g) the Cu film from (b), h) the colloidal Ag film from (c).
was prepared by flowing 1, 2 and 3 into the mixing chamber
from three separate syringes (Table 1, entry 4). The reaction
proceeded equally well as when premixed solutions were
used (Table 1, entry1). From this we can conclude that if the
flow is laminar when it passes through the irradiation zone
of the microwave, it does not effect conversion. Certainly
flow through the MACOS reactor in the absence of micro-
wave irradiation is indeed laminar, which we confirmed by
using two dye solutions prepared with the same solvent.
However, we strongly believe that there is no laminar flow
while our reactions are being irradiated (see below).
An issue that has been frequently raised about microreac-
tors is their capacity to prepare compounds on a larger
scale, for example, beyond 1–20 mg of final product. To ad-
dress this we performed the reactions shown in Table 1, en-
tries 10 and 11. The substrates gave good conversion to 4e
when run for 40 min by using the standard conditions in
Table 1, entry 10, which after purification yielded 213 mg of
4e. To improve throughput, we doubled the concentration
of the starting materials and also doubled the flow rate
(Table 1, entry 11), which lowered conversion, but allowed
for the collection of half a gram of product in just 40 min.
Running the reaction for a longer period of time and/or
through multiple capillaries in parallel (scaling out) will lead
to the production of enough material to do most, if not all
preclinical work if this was a drug candidate. The rest of the
results in Table 1 illustrate that the process works well for a
wide variety of chemical structures, both with the Cu or Ag
films.
In past MACOS studies from our group, an important re-
action parameter that could only be estimated is the temper-
ature of the metal film, therefore, we have not had an accu-
rate measure of the actual temperature at which the conver-
sion is taking place.[6] The problem with the built-in IR
sensor in the Biotage Initiator Synthesiser is that it was de-
signed to read the temperature of the vials that were de-
signed for the irradiation chamber. The sensor is comprised
of a number of individual pixels and the temperature that is
read is the average of all of the pixels. When a standard mi-
crowave vial is used, the temperature is very accurate be-
cause the sensor is small relative to the diameter of the
tube. However, the capillaries only cover approximately
20% of the area of the sensor, which means that most of the
pixels are targeting the air surrounding the tube.
To better assess the temperature, we machined a window
into the end of the irradiation waveguide of the initiator
(Figure 2, left) through which we focused a FLIR Systems
ThermovisionTM A320 high definition IR camera. The field
of view measured by this camera can be focused down to
the level of only a few pixels, which is far narrower than the
diameter of the capillary, meaning that the temperature of
isolated areas within the film can be accurately assessed.
The temperature recorded by the built-in sensor for the re-
actions in Table 1 was 1858C; the temperature recorded by
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Microwave-Assisted Continuous-Flow Organic Synthesis
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Table 1. A three-component MCR procedure for the preparation of
propargyl amines by MACOS by using an Au- or Cu-coated capillary
flow tube.
matic reductions in conversion were observed, which sup-
ports the notion that the bulk of the film is well above the
1858C recorded by the internal temperature sensor. Further,
when the field of view of the external camera was widened
(Figure 2, right), it became clear that the temperature in the
middle of the capillary exceeds 9008C, and although the
temperature steadily decreases when moving away from the
middle of the waveguide, it is never less than 7008C.
We have speculated in the past that these reactions may
be, at least in part, gas-phase reactions. With these new tem-
perature findings in hand, it does seem unlikely that reac-
tion streams are a continuous column of homogeneous
liquid. There is visual evidence for this because the stream
of liquid entering the mixing chamber contained newly cre-
ated, small gas bubbles that were observed to move up and
down slightly, despite the constant force of the syringe
pumps pushing the material forward into the mixing cham-
ber. Movement of the solvent, and perhaps some of the re-
agents, to the gas phase would create higher local pressure
areas than that supplied by the pumps, which would account
for why the gas bubbles would be moving upstream against
the direction of flow. Indeed, the effluent exiting the micro-
wave chamber is not a continuous liquid stream, but rather
gives the appearance of liquid plugs in the tubing. So, what
is happening at the molecular level? We speculate that the
reactions are similar to flash vacuum thermolysis (FVT) in
which reactants are brought into the gas phase under typi-
cally very high vacuum and flowed through super-heated
(usually quartz) reaction tubes. Contact with the tube walls
provides the energy necessary for reactions with high transi-
tion-state barriers such as retro Diels–Alder reactions. If
this is true in the case of MACOS using metal films, several
major advantages can be realised. The system that we have
developed does not require high vacuum, in fact, no vacuum
is required at all. The metal film can supply extremely high
temperatures to address high-transition-state-barrier trans-
formations; it can also provide a catalytically active metal
surface to catalyse a vast array of transformations. In terms
of sustainability, microwave reactors have been argued both
positively and negatively in terms of how much energy they
consume. What we can say in the MACOS set up is that the
temperatures attained are reached with the lowest possible
power setting currently available on the Biotage Initiator
Synthesiser. In the batch reaction mode, it typically requires
full power (300–400 Watts) to attain sustained temperatures
of 200–2508C in solvents such as DMF or DMSO; with the
MACOS set up the average power setting is 30 Watts, which
is still far too much power and this leads to capillary failure
if reactions are not monitored. To address this we are de-
signing and constructing our own microwave applicator to
control power down to the level of one single Watt.
Entry
A
Aldehyde Amine Alkyne Cu film
Au film
%conversion[a] % conversion[a]
(% yield)
(2)
(3)
AHCTUNGTRENNUNG
1 (4a)
1a
1a
1a
1a
1a
1b
1c
1c
1d
1e
1e
1 f
1 f
1 f
1b
1a
1b
1a
1e
1b
1a
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2c
2c
2a
2b
2c
2a
2c
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
82 (76)
– (0)
75
–
–
–
8
78
70
11
68
90
–
–
–
–
73
70
–
65
–
2 (4a)[b]
3 (4a)[c]
4 (4a)
– (0)
80[d]
5 (4a)[e]
6 (4b)
– (29)
84 (78)
90 (84)
– (34)
7 (4c)
8 (4c)[e]
9 (4d)
85 (74)
82 (76)
60 (55)[f]
90 (82)
81 (75)
80 (75)
83 (74)
90 (82)
78 (70)
75 (67)
68 (60)
74 (68)
72 (65)
72 (67)
10 (4e)
11 (4e)
12 (4 f)
13 (4g)
14 (4h)
15 (4i)
16 (4j)
17 (4k)
18 (4l)
19 (4m)
20 (4n)
21 (4o)
22 (4p)
–
–
–
[a] Unless noted otherwise, all reaction mixtures were premixed, taken
up into a single syringe and infused through the MACOS capillary reac-
tor. [b] Performed with Pd-coated capillary. [c] Performed with Ag-
coated capillary. [d] All three reaction components were dissolved sepa-
rately, taken up into three separate syringes and infused into a MACOS
reactor head equipped with three inlet ports. The streams mixed at the
point of contact and then flowed down the attached capillary through the
microwave chamber. The concentrations of the aldehyde, amine and
alkyne were 3.0, 3.6 and 4.5 mmolmLÀ1, respectively. The flow rate of
each syringe was set at 7 mLminÀ1 and the transformation was run long
enough to collect 800 mL of effluent. [e] Performed with oil bath at
1858C. [f] A larger-scale run was performed by infusing the aldehyde
(2.0 mmolmLÀ1), amine (2.4 mmolmLÀ1
) )
and alkyne (3.0 mmolmLÀ1
into the reactor at a rate of 40 mLminÀ1 for 40 min leading to the isola-
tion of 4e (495 mg).
the external IR camera was 9508C! To assess whether this
was a localised or bulk heating effect, the reactions in
Table 1, entries 1 and 7 were repeated (Table 1, entries 5
and 8, respectively) by using an oil bath. Metal-film-coated
capillaries were allowed to sit in an oil bath set to 1858C for
20 min to come to temperature, after which time the reac-
tion mixtures were flowed through them in the usual way
and the product was collected. With both Au and Cu, dra-
Conclusion
In summary, we have demonstrated for the fist time that
temperatures can exceed 9008C when a strongly microwave-
Chem. Eur. J. 2010, 16, 126 – 133
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129

M. G. Organ, C.-J. Li et al.
Figure 2. Thermal IR imaging of Cu-coated capillary while the flowed reaction is irradiated with microwaves. The left picture shows a small portal (white
arrow) that has been machined into the end of the Biotage Initiator Synthesiser waveguide through which the FLIR Systems ThermovisionTM A320
camera is focused on the metal-coated capillary can be seen. No microwave irradiation escapes the irradiation zone, which is constantly monitored with
a microwave sensor. The right picture shows the thermal image of the Cu-coated capillary The central point of the capillary in the irradiation zone
(SP04) shows a temperature of approximately 9508C.
The reactors were rinsed with acetone and then calcinated in the same
furnace at 4008C (3ꢁ1 min) before use in MACOS.
conducting thin-metal film is irradiated. Au and Cu films
Ag film coating (the “silver mirror” layer): Tollensꢂ reagent was prepared
by adding NaOH solution (2.0 mL of 4m) drop-wise into AgNO3 solution
(20 mL of a 3% solution), forming a grey precipitate that was titrated
with a solution of NH4OH (4m) until the solution became clear. Tollensꢂ
have been shown to be very proficient at catalysing the
three-component coupling of terminal alkynes, amines and
aldehydes to produce propargyl amines. The process can be
conducted by using three separate streams of reactants, or
by premixing the reaction components and infusing the reac-
tion through one single syringe, and larger quantities of
product can be attained readily by scaling out the process.
reagent (0.5 mL) was added to a 2 mL vial containing d-glucose solution
(0.5 mL of a 5% solution). The glass reactors (1700 mm ID) were filled
with this mixture, capped at both ends with Teflon tape and left to devel-
op at RT. After the Ag coating was fully developed (5–10 min), the capil-
laries were rinsed with acetone and placed inside a muffle furnace for
calcination at 4008C before use.
Ag film coating (the “colloidal silver” layer): The glass capillaries
(1700 mm ID) were filled with a colloidal solution of silver oxide in ethyl-
ene glycol (0.5 mmolmLÀ1) and then capped at both ends with Teflon
tape. They were then placed inside a muffle furnace and the temperature
was gradually increased to 1408C. After the Ag coating was fully devel-
oped (30 min), the capillaries were rinsed with acetone and placed inside
a muffle furnace for calcination at 4008C before use.
Experimental Section
Microwave irradiation experiments: All MACOS experiments were per-
formed in borosilicate glass tubes (1700 mm internal diameter, ID), by
using a single-mode Biotage Smith Creator Synthesiser, operating at a
frequency of 2.45 GHz with irradiation power from 0 to 300 W. The glass
reactor was fed reactants from Hamilton gastight syringes attached to a
Harvard 22 syringe pump pre-set to the desired flow rate. The system
was connected to a sealed collection vial, where a pressurised airline was
attached to create backpressure (pressure inside the system reached
75 psi). The temperature read on the surface of the capillary by the built-
in IR sensor of the microwave was used to control the operation of the
magnetron. All reagents and solvents were purchased from commercial
sources and were used without additional purification. Column chroma-
tography purifications were carried out by using the flash techniques on
silica gel 60 (200–400 mesh). NMR spectroscopy was run by using a
Bruker Advance 400 MHz instrument. Proton NMR spectra were cali-
brated to 7.26 ppm for the signal from the residual proton of the deuter-
ated chloroform solvent, whereas carbon NMR spectra were calibrated
to 77.00 ppm for the signal from the central peak in the triplet for deuter-
ated chloroform.
General procedure for creating the Cu film coating inside of the glass ca-
pillaries (1700 micron ID): Borosilicate glass capillaries (1700 mm ID)
were filled with a solution of [CuACHTUNGTRNEUNG
(OAc)2] in hydrazine (0.5 mmolmLÀ1),
capped at both ends and placed inside a muffle furnace (1208C). After
10 min, metallic Cu was gradually released from the solution and deposit-
ed on the inner side of capillary wall. After rinsing with acetone, the ca-
pillaries were placed inside a muffle furnace for calcination at 4008C (3ꢁ
1 min) before use in MACOS.
General procedure for creating the gold-on-silver film coating inside of
the glass capillaries (1700 micron ID): Tollensꢂ reagent (0.5 mL) was
added to a 2 mL vial containing d-glucose solution (0.5 mL of a 5% solu-
tion). The glass capillaries (1700 mm ID) were filled with this mixture,
capped at both ends, and left to develop at RT. After the Ag coating was
fully developed (15 min), the capillaries were rinsed with acetone and
placed inside a muffle furnace for calcination at 5008C (3ꢁ1 min). The
gold coating solution was prepared by mixing an aqueous solution of
AuCl3 (0.5 mL, 0.4 mmolmLÀ1) with aqueous Na3C6H5O7·2H2O (0.5 mL
of a 2% solution). The Ag-lined capillaries were filled with the mixture,
capped at both ends, and left to develop at RT for 30 min. After empty-
ing the reactors and rinsing them with acetone, they were calcinated at
5008C (3ꢁ1 min) before use in MACOS.
General procedure for creating the Pd and Ag film coating inside of the
capillaries (1700 micron ID)
Pd film coating: The glass capillaries (1700 mm ID) were filled with a so-
lution of palladium acetate in DMF (0.1 mmolmLÀ1), capped at both
ends with Teflon tape and placed inside a muffle furnace. The tempera-
ture was increased to 1208C. After 10–30 min metallic Pd began to be re-
leased from the solution was and deposited on the inner side of the glass.
General procedure for the synthesis of propargyl amines: A stock solu-
tion containing the substituted benzaldehyde
1
(1.0 mmolmLÀ1
,
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Microwave-Assisted Continuous-Flow Organic Synthesis
FULL PAPER
1.0 equiv), secondary amine 2 (1.2 mmolmLÀ1, 1.2 equiv) and alkyne 3
(1.5 mmolmLÀ1, 1.5 equiv) in toluene was prepared. The continuous-flow
microwave system was primed with toluene and an aliquot from the ho-
mogenous stock solution (1–3 mL) was taken up in a Hamilton gastight
syringe that was connected to the reactor system with the aid of Micro-
tightTM fittings. The syringe was placed in a Harvard 22 syringe pump
that was set to deliver 20 mLminÀ1 and the single-mode microwave was
programmed so as to keep the temperature constant at a specified level.
The output from the reactor was fed into a sealed vial under backpres-
sure (75 psi). The percentage conversion was determined by 1H NMR
spectroscopy on an aliquot taken directly from this vial. Typically 0.8–
0.9 mL of the crude reaction mixture was collected and the product was
purified by silica gel column chromatography and the percent yield deter-
mined.
1.70–1.57 (m, 4H), 1.53–1.45 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
ACTHNUTRGNEUNG
d=143.0, 131.8, 129.7 (q, 2J(13C,19F)=32.2 Hz), 128.7, 128.4, 128.3, 125.1,
ACTHNUTRGNEUNG
124.3 (q, 1J(13C,19F)=271.9 Hz), 123.0, 88.6, 84.9, 62.0, 50.8, 26.2,
24.4 ppm (the spectra matched that found in the literature).[10b]
[1-(4-Methoxyphenyl)-3-phenyl-2-propynyl]piperidine (4e): Following the
general procedure, 4-methoxybenzaldehyde, piperidine and phenylacety-
lene were reacted and 0.92 mL of the
crude reaction mixture was collected.
Purification by flash chromatography
(20% ethyl acetate in hexane) afford-
ed 4e (213 mg, 76% yield). 1H NMR
(400 MHz, CDCl3): d=7.61–7.54 (m,
4H), 7.38–7.33 (m, 3H), 6.96–6.91 (m,
2H), 4.78 (s, 1H), 3.85 (s, 3H), 2.63–
(1,3-Diphenyl-2-propynyl)piperidine (4a):
Following the general procedure, benzal-
2.53 (m, 4H), 1.69–1.55 (m, 4H),
1.54–1.46 ppm (m, 2H); 13C NMR
dehyde, piperidine and phenylacetylene
(100 MHz, CDCl3): d=158.9, 131.8,
were reacted and 0.95 mL of the crude re-
action mixture was collected. Purification
130.7, 129.6, 128.3, 128.0, 123.4, 113.4, 87.6, 86.5, 61.8, 55.3, 50.6, 26.2,
24.5 ppm (the spectra matched that found in the literature).[10b]
by flash chromatography (14% ethyl ace-
1-(1-Isobutyl-3-phenyl-prop-2-ynyl)piperidine (4 f): Following the general
procedure, isovaleraldehyde, piperidine and phenylacetylene were react-
ed and 0.72 mL of the crude reaction mixture was collected. Purification
by flash chromatography (14% ethyl
tate in hexane) afforded 4a (201 mg, 76%
yield). 1H NMR (400 MHz, CDCl3): d=
7.71–7.68 (m, 2H), 7.59–7.54 (m, 2H),
7.48–7.31 (m, 6H), 4.86 (s, 1H), 2.65–2.58
(m, 4H), 1.69–1.61 (m, 4H), 1.52–
acetate in hexane) afforded 4 f
(148 mg, 82% yield). 1H NMR
1.44 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=140.9, 132.1, 128.9,
128.6, 128.3 (two signals overlap), 127.8, 123.4, 87.9, 86.1, 62.4, 50.7, 26.2,
24.4 ppm (the spectra matched that found in the literature).[10b]
(400 MHz, CDCl3): d=7.50–7.44 (m,
2H), 7.35–7.28 (m, 3H), 3.63–3.57 (m,
1H), 2.76–2.68 (m, 2H), 2.56–2.47 (m,
(1-(4-Bromophenyl)-3-phenyl-2-propynyl)piperidine (4b): Following the
general procedure, 4-bromobenzaldehyde, piperidine and phenylacety-
lene were reacted and 0.90 mL of the crude reaction mixture was collect-
ed. Purification by flash chromatography
2H), 1.92 (septet, J=7.1 Hz, 1H),
1.75–1.54 (m, 6H), 1.52–1.44 (m, 2H),
1.03–0.96 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=131.7, 128.2,
(18% ethyl acetate in hexane) afforded 4b
127.7, 123.6, 88.1, 85.6, 56.7, 50.6, 42.3,
26.2, 25.4, 24.6, 23.2, 22.1 ppm (the spectra matched that found in the lit-
erature).[15]
(247 mg, 78% yield). 1H NMR (400 MHz,
CDCl3): d=7.60–7.56 (m, 4H), 7.54–7.50
(m, 2H), 7.41–7.34 (m, 3H), 4.78 (s, 1H),
N-Benzyl-N-ethyl-5-methyl-1-phenylhex-1-yn-3-amine (4g): Following the
general procedure, isovaleraldehyde, N-ethylbenzylamine and phenylace-
tylene were reacted and 0.75 mL of the crude reaction mixture was col-
lected. Purification by flash chroma-
2.62–2.54 (m, 4H), 1.66–1.58 (m, 4H),
1.53–1.47 ppm
(m,
2H);
13C NMR
(100 MHz, CDCl3): d=137.9, 131.8, 131.1,
130.2, 128.3, 128.1, 123.1, 121.4, 88.2, 85.3,
61.8, 50.7, 26.2, 24.4 ppm (the spectra
matched that found in the literature).[10b]
tography (6% ethyl acetate in pen-
tane) afforded 4g as a colourless oil
(172 mg,
75%
yield).
1H NMR
[1-(3-Bromophenyl)-3-phenyl-2-propynyl]piperidine (4c): Following the
(400 MHz, CDCl3): d=7.56–7.50 (m,
general procedure, 3-bromobenzaldehyde, piperidine and phenylacet-
2H), 7.48–7.44 (m, 2H), 7.42–7.34 (m,
A
5H), 7.32–7.28 (m, 1H), 3.97 (d, J=
lected. Purification by flash chromatography (14% ethyl acetate in
hexane) afforded 4c (237 mg, 84% yield). 1H NMR (400 MHz, CDCl3):
d=7.88 (s, 1H), 7.65–7.62 (m, 1H), 7.60–
14.2 Hz, 1H), 3.82 (t, J=8.2 Hz, 1H),
3.53 (d, J=14.2 Hz, 1H), 2.79–2.68 (m,
1H), 2.63–2.54 (m, 1H), 1.98 (septet,
7.56 (m, 2H), 7.47–7.43 (m, 1H), 7.40–
J=7.1 Hz, 1H), 1.78–1.69 (m, 1H),
7.35 (m, 3H), 7.28–7.24 (m, 1H), 4.81 (s,
1.67–1.59 (m, 1H), 1.17 (t, J=7.2 Hz,
1H), 2.64–2.54 (m, 4H), 1.69–1.57 (m,
3H), 0.98–0.91 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=140.5,
131.8, 128.8, 128.3, 128.1, 127.8, 126.7, 123.7, 88.9, 84.7, 55.1, 50.9, 45.0,
43.1, 24.8, 22.8, 22.3, 13.7 ppm; elemental analysis calcd for C22H27N: C
86.51, H 8.91, N 4.59; found: C 86.61, H 9.13, N 4.72.
4H), 1.55–1.48 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=141.3, 131.9,
131.4, 130.9, 129.9, 128.4, 128.2, 127.1,
123.1, 122.4, 88.4, 85.1, 61.9, 50.7, 26.2,
4-(5-Methyl-1-phenylhex-1-yn-3-yl)morpholine (4h): Following the gener-
al procedure, isovaleraldehyde, morpholine and phenylacetylene were re-
acted and 0.75 mL of the crude reaction mixture was collected. Purifica-
tion by flash chromatography (20% ethyl acetate in pentane) afforded
4h as a pale-yellow oil (144 mg, 75%
24.7 ppm (the spectra matched that
found in the literature).[10b]
[1-(4-Trifluoromethylphenyl)-3-phenyl-2-propynyl]piperidine (4d): Fol-
lowing the general procedure, 4-(trifluoromethyl)benzaldehyde, piperi-
dine and phenylacetylene were reacted
yield). 1H NMR (300 MHz, CDCl3):
and 0.80 mL of the crude reaction mix-
d=7.49–7.41 (m, 2H), 7.34–7.27 (m,
ture was collected. Purification by flash
3H), 3.84–3.70 (m, 4H), 3.64–3.57 (m,
chromatography (16% ethyl acetate in
1H), 2.82–2.72 (m, 2H), 2.64–2.54 (m,
hexane) afforded 4d (203 mg, 74%
2H), 1.93 (septet, J=6.8 Hz, 1H),
yield). 1H NMR (400 MHz, CDCl3): d=
1.72–1.52 (m, 2H), 1.03–0.94 ppm (m,
7.81 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.1,
6H); 13C NMR (100 MHz, CDCl3): d=
2H), 7.58–7.54 (m, 2H), 7.39–7.34 (m,
131.7, 128.2, 127.9, 123.2, 87.1, 86.2,
3H), 4.86 (s, 1H), 2.62–2.55 (m, 4H),
67.2, 56.2, 49.7, 41.8, 25.2, 23.0,
Chem. Eur. J. 2010, 16, 126 – 133
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
131

M. G. Organ, C.-J. Li et al.
22.2 ppm; HRMS calcd for C17H23NO: 258.1858; found: 258.1851; ele-
mental analysis calcd for C17H23NO: C 79.33, H 9.01, N 5.44; found: C
79.53, H 8.82, N 5.48.
of the crude reaction mixture was col-
lected. Purification by flash chromatog-
raphy (30% dichloromethane in pen-
tane) afforded 4m as
(132 mg, 60% yield).
a
yellow oil
1H NMR
N-Benzyl-1-(4-bromophenyl)-N-ethyl-3-phenylprop-2-yn-1-amine
Following the general procedure, 4-bromoaldehyde, N-ethylbenzylamine
and phenylacetylene were reacted and
(4i):
(400 MHz, CD2Cl2): d=7.68–7.62 (m,
2H), 7.60 (d, J=3.0 Hz, 1H), 7.47–7.41
(m, 2H), 7.40–7.33 (m, 3H), 7.30–7.26
(m, 2H), 6.97–6.91 (m, 2H), 4.98 (s,
1H), 3.87 (d, J=14.1 Hz, 1H), 3.84 (s,
3H), 3.53 (d, J=14.1 Hz, 1H), 2.61 (q, J=7.1 Hz, 2H), 1.14 ppm (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=158.9, 140.3, 131.6, 130.1,
129.3, 128.7, 128.5, 128.1, 126.7, 125.4, 122.3, 113.3, 85.2, 82.6, 55.9, 55.2,
54.6, 44.3, 13.3 ppm. HRMS calcd for C23H23NOS: 361.1500; found:
361.1508; elemental analysis calcd for C23H23NOS: C 76.42, H 6.41, N
3.87; found: C 76.12, H 6.65, N 4.02.
0.70 mL of the crude reaction mixture
was collected. Purification by flash
chromatography (10% ethyl acetate in
pentane) afforded 4i as a pale-brown
oil (199 mg, 74% yield). 1H NMR
(400 MHz, CD2Cl2): d=7.70–7.60 (m,
4H), 7.58–7.52 (m, 2H), 7.49–7.41 (m,
5H), 7.40–7.34 (m, 2H), 7.32–7.27 (m,
1H), 4.99 (s, 1H), 3.88 (d, J=14.2 Hz,
1H), 3.56 (d, J=14.2 Hz, 1H), 2.68–
2.57 (m, 2H), 1.16 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CD2Cl2):
d=139.9, 139.0, 131.8, 131.1, 130.1, 128.8, 128.4, 128.3, 128.2, 126.9, 123.0,
121.1, 88.3, 84.7, 56.1, 54.9, 44.5, 13.4 ppm; HRMS calcd for C24H22BrN:
403.0936; found: 403.0908.
4-[1-(4-Bromophenyl)-3-(thiophen-3-yl)prop-2-ynyl]morpholine (4n): Fol-
lowing the general procedure, 4-bromobenzaldehyde, morpholine and 3-
ethynylthiophene were reacted and 0.86 mL of the crude reaction mix-
ture was collected. Purification by flash chromatography (18% ethyl ace-
tate in pentane) afforded 4n as a yellow oil (212 mg, 68% yield).
1H NMR (400 MHz, CD2Cl2): d=7.60–
4-(1,3-Diphenylprop-2-ynyl)morpholine (4j): Following the general pro-
cedure, benzaldehyde, morpholine and phenylacetylene were reacted and
0.75 mL of the crude reaction mixture was collected. Purification by flash
chromatography (15% ethyl acetate in
7.52 (m, 5H), 7.39–7.35 (m, 1H), 7.24–
7.21 (m, 1H), 4.78 (s, 1H), 3.76–3.66
(m, 4H), 2.64–2.56 ppm (m, 4H);
pentane) afforded 4j (170 mg, 82%
13C NMR (100 MHz, CD2Cl2): d=
yield). 1H NMR (400 MHz, CD2Cl2):
137.3, 131.2, 130.3, 129.9, 128.9, 125.5,
d=7.72–7.67 (m, 2H), 7.61–7.56 (m,
121.7, 121.5, 84.0, 83.7, 67.0, 61.4,
2H), 7.46–7.33 (m, 6H), 4.86 (s, 1H),
49.8 ppm;
C17H16BrNOS:
HRMS
calcd
for
found:
3.79–3.69 (m, 4H), 2.70–2.64 ppm (m,
4H); 13C NMR (100 MHz, CD2Cl2):
361.0136;
361.0131; elemental analysis calcd for
C17H16BrNOS: C 56.36, H 4.45, N 3.87;
found: C 56.22, H 4.46, N 3.66.
d=138.0, 131.7, 128.6, 128.4, 128.3,
128.2, 127.7, 123.0, 88.3, 85.2, 67.0,
61.9, 49.9 ppm (the spectra matched
that found in the literature).[11c]
1-[3-(1-Methyl-1H-imidazol-5-yl)-1-phenylprop-2-ynyl]piperidine
(4o):
4-[1-(4-Bromophenyl)-3-phenylprop-2-ynyl]morpholine (4k): Following
the general procedure, 4-bromoaldehyde, morpholine and phenylacety-
lene were reacted and 0.82 mL of the crude reaction mixture was collect-
ed. Purification by flash chromatography (15% ethyl acetate in pentane)
afforded 4k (202 mg, 70% yield).
Following the general procedure, benzaldehyde, piperidine and 5-ethyn-
yl-1-methyl-1H-imidazole were reacted and 0.80 mL of the crude reac-
tion mixture was collected. Purifica-
tion by flash chromatography (10%
methanol in acetonitrile) afforded 4o
1H NMR (400 MHz, CDCl3): d07.61–
as
a colourless oil (145 mg, 65%
yield). 1H NMR (400 MHz, CD2Cl2):
7.47 (m, 6H), 7.40–7.32 (m, 3H), 4.77
(s, 1H), 3.81–3.69 (m, 4H), 2.68–
d=7.67–7.62 (m, 2H), 7.47 (s, 1H),
7.44–7.38 (m, 2H), 7.36–7.31 (m, 1H),
2.59 ppm
(m,
4H);
13C NMR
(100 MHz, CDCl3): d=137.0, 131.8,
131.3, 130.3, 128.5, 128.4, 122.7, 121.8,
88.9, 84.3, 67.1, 61.4, 49.8 ppm (the
spectra matched that found in the lit-
erature).[11c]
7.28 (s, 1H), 4.91 (s, 1H), 3.74 (s, 3H),
2.60–2.54 (m, 4H), 1.69–1.55 (m, 4H),
1.52–1.46 ppm (m, 2H); 13C NMR
(100 MHz, CD2Cl2): d=138.4, 138.2,
133.8, 128.3, 128.1, 127.6, 116.2, 93.0, 75.9, 62.5, 50.7, 32.1, 26.2, 24.4 ppm;
HRMS calcd for C18H21N3: 279.1735; found: 279.1731; elemental analysis
calcd for C18H21N3: C 77.38, H 7.58, N 15.04; found: C 77.45, H 7.72, N
14.89.
1-(1-Phenyl-3-(thiophen-3-yl)prop-2-ynyl)piperidine (4l): Following the
general procedure, benzaldehyde, piperidine and 3-ethynylthiophene
were reacted and 0.82 mL of the crude reaction mixture was collected.
Purification by flash chromatography (20% dichloromethane in pentane)
afforded 4l as a yellow oil (154 mg, 67% yield). 1H NMR (400 MHz,
CDCl3): d=7.69–7.64 (m, 2H), 7.52 (d,
4-[1-(4-Bromophenyl)-3-(1-methyl-1H-
imidazol-5-yl)prop-2-ynyl]morpholine
(4p): Following the general procedure,
4-bromobenzaldehyde, morpholine and
5-ethynyl-1-methyl-1H-imidazole were
reacted and 0.88 mL of the crude reac-
tion mixture was collected. Purification
by flash chromatography (10% metha-
J=3.1 Hz, 1H), 7.43–7.36 (m, 2H),
7.35–7.29 (m, 2H), 7.23–7.20 (m, 1H),
4.81 (s, 1H), 2.64–2.52 (m, 4H), 1.69–
1.56 (m, 4H), 1.53–1.44 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=
138.6, 130.2, 128.5, 128.4, 128.0, 127.4,
125.2, 122.3, 85.7, 82.7, 62.5, 50.7, 26.2,
24.4 ppm; HRMS calcd for C18H19NS:
281.1238; found: 281.1211; elemental
nol in dichloromethACTHNUTRGNEUGNane) afforded 4p as
a colourless oil (213 mg, 67% yield).
1H NMR (400 MHz, CD2Cl2): d=7.58–
7.51 (m, 4H), 7.48 (s, 1H), 7.30 (s, 1H), 4.86 (s, 1H), 3.76–3.66 (m, 7H),
2.64–2.55 ppm (m, 4H); 13C NMR (100 MHz, CD2Cl2): d=138.4, 136.9,
134.3, 131.3, 130.2, 121.7, 115.6, 91.6, 76.8, 66.9, 61.5, 49.8, 32.2 ppm;
HRMS calcd for C17H18BrN3O: 359.0633; found: 359.0630; elemental
analysis calcd for C17H18BrN3O: C 56.68, H 5.04, N 11.66; found: C 56.50,
H 5.05, N 11.22.
analysis calad for C18H19NS: C 76.82, H 6.81, N 4.98; found: C 76.90, H
6.82, N 5.04.
N-Benzyl-N-ethyl-1-(4-methoxyphenyl)-3-(thiophen-3-yl)prop-2-yn-1-
amine (4m): Following the general procedure, 4-methoxybenzaldehyde,
N-ethylbenzylamine and 3-ethynylthiophene were reacted and 0.62 mL
132
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 126 – 133

Microwave-Assisted Continuous-Flow Organic Synthesis
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Received: August 31, 2009
Published online: November 30, 2009
Chem. Eur. J. 2010, 16, 126 – 133
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