[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

Article abstract of DOI:10.1016/j.tetlet.2009.12.071

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous fl

Full text of DOI:10.1016/j.tetlet.2009.12.071

Tetrahedron Letters 51 (2010) 1026–1029
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[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under
continuous flow conditions
*
Mark Grafton, Andrew C. Mansfield, M. Jonathan Fray
Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor
benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence
of catalytic trifluoroacetic acid are examined under continuous flow conditions (20–100 °C, 10–60 min
residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide
and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77–83% yields, whereas less
reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59–63%).
Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrol-
idine-3-carboxylate (30 g, 87%) in 1 h.
Received 13 November 2009
Revised 27 November 2009
Accepted 11 December 2009
Available online 21 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The [3+2] cycloaddition of an unstabilised azomethine ylide
with an electron-deficient alkene1 offers a succinct entry into
substituted pyrrolidines (Scheme 1), which are considered valu-
able templates for the design of pharmaceuticals. A popular way
to generate the required azomethine ylide 2 is from the silylated
aminal ether 12 in the presence of an alkene which traps the ylide
to form the product pyrrolidine 3. The reaction is concerted, conse-
quently, the relative stereochemistry in the dipolarophile (E or Z) is
carried forward into adduct 3 (trans or cis).
As an illustration of the ways in which the pyrrolidine structural
motif has been employed in pharmaceuticals, a few recent exam-
ples are shown in Figure 1, including PDE9,3 factor Xa,4 rho kinase5
and AKT protein kinase6 inhibitors, H47 and NK38 antagonists, anti-
viral compounds9 and MC4 agonists.10
mixing of reactants is reproducible and precise control of stoichi-
ometry can be achieved. The relatively small reaction volume
means greater safety through lower amounts reacting at any one
time, particularly for highly hazardous reagents or exothermic
reactions. The high surface area to volume ratio of narrow-gauge
tubing helps rapid heat transfer and therefore control of reaction
temperature.15,16
Rapid heat transfer aids exothermic reactions requiring high
reactant concentrations for optimum yields. The major limitation
in many continuous flow set-ups is the need for a homogeneous
medium throughout the system; precipitates or insoluble reactants
affect flow rates or cause blockages. Insoluble reagents or catalysts
Usually ylide generation is promoted by an acid or fluoride
source.11,12 One of the earliest and simplest of these consists of
adding 10 mol % trifluoroacetic acid (TFA) to a mixture of the other
reactants in toluene or dichloromethane solvent, with cooling if
appropriate. Whilst these conditions have been safely scaled at
Pfizer to >400 g for cinnamic ester derivatives (i.e., X = aryl, W =
CO2Me), the reaction becomes dangerously exothermic with more
reactive dipolarophiles such as methyl crotonate and N-methylma-
leimide.13 One way around this problem is to pre-mix the dipolaro-
phile and the TFA, and add the azomethine ylide precursor slowly
to control the reaction temperature. Alternatively, the reaction can
be moderated by a suspension of LiF in acetonitrile.
H2C
CH2
H+ or F-
source
N+
Me3Si
N
OMe
2
1
Y
X
Y
W
X
W
N
Reactions conducted under conditions of continuous flow can
W = CO2Et, CN, NO2
X, Y = H, alkyl, Ar, CO2Et
offer advantages over conventional batch reactions.14 For example,
3
* Corresponding author. Tel.: +44 1304 649175; fax: +44 1304 651817.
E-mail address: jonathan.fray@pfizer.com (M.J. Fray).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.071

M. Grafton et al. / Tetrahedron Letters 51 (2010) 1026–1029
1027
O
Me
Me
Me
Cl
N
Me
N
Me
HN
H
N
N
O
N
N
O
N
N
N
N
N
N
NMe
N
N
N
H
H2N
AKT protein kinase inhibitor
PDE9 Inhibitor
H4 antagonist
O
Cl
N
O
Cl
O
Cl
N
N
H
Cl
O
O
O
N
N
N
H
N
F
CF3
N
H
N
O
N
N
O
Cl
CN
CHF2
O
Factor Xa Inhibitor
Antiviral (HCV)
O
NK3 antagonist
Ac
HN
F
N
Cl
Me
OH
Ph Cl
Me
Et
O
H
N
N
S
N
F
Cl
NH
N
N
F
N
N
N
Me
Me
Me
Me
H2N
Me
Me
Rho kinase inhibitor
MC4 agonist
MC4 agonist
Figure 1.
can be introduced via in-line reagent cartridges, and excess reac-
tants may be removed in a similar way, thereby facilitating product
purification.17 Finally, once the optimum reaction conditions have
been developed, increased scale is achieved by running the reac-
tion for longer or employing multiple reaction modules in parallel,
whereas re-optimisation of batch reactions is frequently required
as the scale is increased. Equipment is now commercially available
for performing reactions on micro-,18 meso-19 and macro-scales.
We describe herein our investigations of the [3+2] cycloaddi-
tions of 2 with various dipolarophiles under conditions of continu-
ous flow, since this would permit a high degree of control over the
reaction temperature and stoichiometry, thereby reducing the
inherent hazard and long addition time.
it had the most immediate relevance to a project in progress
(Fig. 2). The reaction set-up was very simple. Compound 1
(2.4 mmol, 1.2 equiv, 1.2 M in solvent) was introduced into a
2 ml loading loop, and a mixture of ethyl acrylate (2.0 mmol,
1 equiv, 1 M in solvent) and TFA (0.1 equiv) was introduced into
another. The solutions were pumped at equal rates through the
mixing T-piece into 2 Â 10 ml heated reactor loops linked in series.
The tubing was perfluoroalkoxyethylene of 1 mm internal diame-
ter throughout. The reaction mixture was collected in a flask
containing aqueous NaHCO3 to neutralise the acid. The product
was extracted into methyl tert-butyl ether, washed with brine,
dried and concentrated. The yield and purity of the product were
estimated by 1H NMR spectroscopy by using a standard solution
of sym-trioxane in CDCl3. Isolated yield refers to the yield following
purification by flash chromatography, however, for the initial
survey we used calculated yields.
The reaction between 1 and ethyl acrylate in anhydrous toluene
with 10 mol % TFA was used to survey various reaction tempera-
tures and flow rates in a Vapourtec™ R2+/R418a flow reactor, as
ylide precursor 1
Vapourtec R2+/R4
1.2 M in
solvent
convection
heating
100 psi back
pressure
mixing
T-piece
2 ml
regulator
pumps
loading
loops
product
collection
solvent
temp
flow rate
variable
variable
dipolarophile
1 M in solvent
+ TFA (0.1 M)
aq. NaHCO3
quench
Figure 2. Schematic apparatus set-up for conducting [3+2] cycloaddition reactions using the Vapourtec R2+/R4 reactor.

1028
M. Grafton et al. / Tetrahedron Letters 51 (2010) 1026–1029
Table 1
Survey of reaction conditions
Me
N
Me
CN
CN
CO2Et
Me3Si
N
OMe
CO2Et
10 mol% TFA
CH2Cl2, 16 h,
Me3Si
N
OMe
N
10 mol% TFA
toluene
62%
or 1 eq. LiF,
MeCN, 24 h,
85%
3i
1
3a
1
a
Isolated yieldb
(%)
Scheme 2. Batch synthesis of 3i.
Entry Residence time
(min)
Temp
(°C)
Calcd yield
(%)
1
2
3
4
5
6
7
8
60
30
60
30
10
30
15
5
20
20
70
70
70
100
100
100
89
74
99
93
89
93
86
54
70–100 °C, with a slight trend to better yields with longer resi-
dence times. Even with a residence time as short as 10 min at
70 °C (entry 5), the yield was satisfactory, although with only
5 min residence time at 100 °C (entry 8), it was significantly lower.
As we wanted to maximise product throughput, we subse-
quently focussed on heated reactions with a fast flow rate. Some
of the reactions were repeated with dichloromethane and acetoni-
trile as solvents, though the former could not be pumped satisfac-
torily. Since the yields were marginally better with acetonitrile
(Table 2, entry 1), this solvent was used in further experiments
with other dipolarophiles.
83
From the 1H NMR spectrum of the crude product, sym-trioxane internal
standard.
a
b
After flash chromatography.
The flow rate was varied to give a residence time from 5 to
60 min, and a temperature range between 20–100 °C with a typical
operating pressure of 7–9 bar. The overall reagent concentration
was kept at 0.5 M. The results are shown in Table 1.
The reaction proceeded at room temperature (entries 1 and 2),
with a lower yield of product under a shorter residence time. This
was to be expected, as Achiwa et al.21 performed similar cycload-
ditions at 0–20 °C for 3 h to obtain high yields. From heated reac-
tions (entries 3–7), we found that the yields of 3a were good at
The more reactive (and therefore more potentially hazardous)
dipolarophiles, such as diethyl fumarate, diethyl maleate and N-
methylmaleimide (Table 2, entries 2–4) gave high yields (>80%)
under the same conditions as ethyl acrylate (entry 1, 10 min,
70 °C). Other diploarophiles that gave good yields (>65%) were
(E)-ethyl cinnamate, (E)-2-nitrostyrene and ethyl 4,4,4-trifluoro-
crotonate (entries 9, 14 and 15). Yields were more modest (39–
56%) with ethyl crotonate, ethyl methacrylate, crotononitrile and
methacrylonitrile (entries 5, 7, 10 and 12). In an attempt to im-
Table 2
Cycloaddition reactions of 1 with various dipolarophiles in acetonitrile
Y
Y
X
W
X
W
Me3Si
N
OMe
N
MeCN
1
3a-l
Reaction time (min) Temp (°C) Calculated yielda (%) Isolated yieldb (%) Ref.
Entry Dipolarophile
Product
W
X
Y
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ethyl acrylate
3a
3b
3c
3d
3e
CO2Et
CO2Et CO2Et
H
H
CO2Et Me
CO2Et
CO2Et Ph
H
H
H
10
10
70
70
70
70
70
70
70
100
70
70
100
70
70
70
70
92
98
89
86
59
52
37
62
72
34
62
56
28
82
79
85
85
83
81
11e,12
19
19
20
21
Diethyl fumarate
Diethyl maleate
N-Methylmaleimide
(E)-Ethyl crotonate
CO2Et CO2Et 10
CON(Me)CO
10
10
30
10
10
10
10
10
10
30
10
10
H
52
NDc
42
d
Ethyl methacrylate
3f
H
Me
63
65
39
(E)-Ethyl cinnamate
(E)-Crotononitrile
3g
3h
H
H
22
23
CN
Me
59e
71e
NDc
77
Methacrylonitrile
3i
CN
H
Me
24
(E)-2-Nitrostyrene
(E)-Ethyl 4,4,4-
3j
3k
NO2
CO2Et CF3
Ph
H
H
25
26
74
trifluorocrotonate
(E)-Ethyl 4-bromocrotonate
d
16
3l
CO2Et CH2Br
H
10
70
85
56
From the 1H NMR spectrum of the crude product, sym-trioxane internal standard, accurate to 3% as samples weighed to nearest 0.1 mg (the accuracy of the calculated
a
yields was limited by the accuracy of weighing the NMR samples, hence in entries 7, 8 and 10 they appear marginally greater than the isolated yields).
b
After flash chromatography, purity >95% unless stated otherwise.
ND = not determined.
Novel compounds were characterised by spectroscopic means.
Purity <90% due to the presence of decomposition products of the azomethine ylide precursor.
c
d
e

M. Grafton et al. / Tetrahedron Letters 51 (2010) 1026–1029
1029
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higher temperature was employed. This sometimes increased the
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flow on a reasonable scale, the Vapourtec™ R2+/R4 was equipped
with four heated reaction loops (total volume 40 ml) so that we
could react compound 1 with ethyl acrylate under the previously
optimised conditions (0.5 M overall in MeCN, 70 °C, 10 min). From
a reaction on 30 g scale, we obtained compound 3a in 87% yield,
after chromatography in only 1 h.
We have described the feasibility of a potentially hazardous
cycloaddition reaction under conditions of continuous flow. After
optimisation, uniformly high yields of cycloadducts were obtained
for certain reactive electron-deficient alkenes, and a multi-gram
synthesis was demonstrated for compound 3a. For less reactive
dipolarophiles such as methacrylonitrile, lithium fluoride-pro-
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aware. (a) N-methylmaleimide (40 g, 1 equiv) and
1 (103 g, 1.2 equiv) in
CH2Cl2 (600 ml) at À20 °C were treated with a solution of TFA (4.1 g, 0.1 equiv),
dropwise. On completion of the addition, the reaction temperature rose very
quickly and the contents of the flask were ejected. (b) A mixture of trans-
methyl crotonate (1 equiv), 1 (1536 g, 1.05 equiv) in CH2Cl2 (ꢀ12 L) at 0 °C was
treated with a solution of TFA (0.1 equiv) dropwise. There was then a delayed
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