Silica-supported 5-(pyrrolidin-2-yl)tetrazole: Development of organocatalytic processes from batch to continuous-flow conditions

Article abstract of DOI:10.1039/c2gc16673a

5-(Pyrrolidin-2-yl)tetrazole functionalized silica prepared by photoinduced thiol-ene coupling is packed into a short stainless steel column. The resulting packed-bed microreactor is conveniently heated to perform environmentally benign continuous-flow al

Full text of DOI:10.1039/c2gc16673a

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PAPER
Silica-supported 5-(pyrrolidin-2-yl)tetrazole: development of organocatalytic
processes from batch to continuous-flow conditions†
Olga Bortolini,a Lorenzo Caciolli,a Alberto Cavazzini,*b Valentina Costa,b Roberto Greco,b
Alessandro Massi*a and Luisa Pastib
Received 27th December 2011, Accepted 19th January 2012
DOI: 10.1039/c2gc16673a
5-(Pyrrolidin-2-yl)tetrazole functionalized silica prepared by photoinduced thiol–ene coupling is packed
into a short stainless steel column. The resulting packed-bed microreactor is conveniently heated to
perform environmentally benign continuous-flow aldol reactions with good stereoselectivities, complete
conversion efficiencies, and long term stability of the packing material.
thereof. It is worth noting that while a (limited) number of
Introduction
notable examples of asymmetric syntheses in continuous-flow
have been reported,6 only a few studies have dealt with the use
In the context of a growing competition in which time, cost, and
of immobilized organocatalysts.7 Indeed, peculiar benefits of het-
sustainability issues of the synthesis play an increasingly impor-
tant role even at a research stage, chemical efficiency has
become one of the leading concepts for chemists working in
both industry and academia. Key criteria include intrinsic (yield,
(stereo)selectivity, atom economy) and extrinsic (time, waste,
equipment, environment, safety) factors of the synthetic
process.1 Hence, the booming field of asymmetric organocataly-
sis is opening, on the one hand, new and unique opportunities
towards efficient and highly stereoselective metal-free catalytic
syntheses.2 On the other hand, microreactor technology is offer-
ing safe, environmentally benign, and high-throughput processes
typically intensified by a fast postreaction phase (workup and
purification) and direct scalability.3 Very recently, we have
embarked on a research program aimed at preparing and testing
organocatalytic packed-bed microreactors4 to prove the potential
benefits arising from the combination of the above synthetic
methodology and production technology.5 Currently, this
program is being developed on the basis of the following general
thread: (i) heterogenization of a successful asymmetric organo-
catalyst on silica and optimization of its performance (yield and
stereoselectivity) under batch conditions; (ii) preparation of the
corresponding packed-bed microreactor and preliminary testing
in continuous-flow regime; (iii) development of a suitable in-line
analysis method and final optimization of the continuous-flow
process based on kinetic and thermodynamic characterization
erogeneous organocatalysis in conjunction with microreactor
technology are the absence of metal leaching (a problematic
issue especially in pharmaceutical applications), the enhanced
resistance of supports to mechanical degradation, and the poten-
tial long-term usage of (micro)reactors that is highly desirable
for complex and costly immobilized catalysts. As a matter of
fact, the main limitation encountered in our first investigation4
on the proline-catalyzed continuous-flow aldol reaction of cyclo-
hexanone with p-nitro benzaldehyde was the progressive loss of
catalytic activity of the packing material 1 (Fig. 1). Deactivation
of immobilized proline 1 occurred through irreversible decarbox-
ylation8 after 24 h on stream at room temperature and was
greatly accelerated by increasing the process temperature. Herein,
we report on the synthesis and catalytic activity under batch con-
ditions of immobilized proline mimetics, namely heterogeneous
prolyl amide 2,9 sulfonamide 3,10 and pyrrolidinyl tetrazole 4,11
which are not prone to the above deactivation pathway and
thus are expected to provide organocatalytic packed-bed
aDipartimento di Chimica, Laboratorio di Chimica Organica,
Università di Ferrara, Via L. Borsari 46, I-44121 Ferrara, Italy. E-mail:
alessandro.massi@unife.it; Fax: +39 0532 455183; Tel: +39 0532
455183
bDipartimento di Chimica, Laboratorio di Chimica Analitica, Università
di Ferrara, Italy. E-mail: alberto.cavazzini@unife.it; Fax: +39 0532
455133; Tel: +39 0532 455133
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra for new compounds, FT-IR spectra of silicas 2–4,
chiral HPLC chromatograms. See DOI: 10.1039/c2gc16673a
Fig. 1 Silica-immobilized proline and proline-like organocatalysts 1–4.
992 | Green Chem., 2012, 14, 992–1000
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microreactors with improved stability and, eventually, better
reaction profiles.9–11 Preliminary results on the continuous-flow
aldol reaction promoted by the best performing silica-supported
5-(pyrrolidin-2-yl)tetrazole catalyst 4 are finally presented.
immobilization strategies resulted equally effective producing,
after TFA-promoted Boc deprotection, the target prolyl amide
and sulfonamide functionalized silicas 2 and 3, respectively,
with a comparable degree of functionalization (0.75–0.70 mmol
g−1), as determined by elemental analysis (Scheme 2). A lower
loading (0.15 mmol g−1) was instead achieved for the tetrazole
functionalized silica 4 prepared by TEC (thermal or photo-
induced) of 14 with N-Cbz pyrrolidinyl tetrazole 13. This un-
satisfactory result was determined by the harsh acidic conditions
required for Cbz group removal (6N HCl, 80 °C). Nevertheless,
while milder Cbz deprotection procedures proved to be unsuc-
cessful on silica support, the synthetic sequence optimized for
the preparation of N-Cbz pyrrolidinyl tetrazole 13 was practi-
cable and effective for the synthesis of the N-Boc analogue 12 as
well (Scheme 1). Gratifyingly, TEC of 14 with 12 followed by
Boc deprotection afforded the tetrazole functionalized silica 4
with a suitable loading (0.76 mmol g−1; Scheme 2).
Next, on the basis of our previous experience with proline cat-
alyst 1, the activity of the newly prepared heterogeneous proline
mimetics 2–4 was evaluated in selected solvents (acetonitrile,
toluene, DMSO, and dichloromethane) by using the aldol con-
densation of cyclohexanone 15 with p-nitro benzaldehyde 16a as
the benchmark (Table 1). Proline amide 2 was the less active cat-
alyst in terms of both chemical yield and stereoselectivity
(entries 1–4). As already observed for immobilized proline 1,4
the use of the low-polarity toluene produced the best results for
the sulfonamide 3 and tetrazole 4 as well, the latter being much
more active than the former (entries 6 and 10). Different solvents
were then screened to further improve catalyst 4 profile (entries
13–15). Pleasingly, the utilization at room temperature of diiso-
propyl ether allowed isolation of the mixture of anti–syn adducts
(d.r. = 2 : 1) in quantitative yield and high enantioselectivity
(95% eeanti) after 12 h reaction time (entry 15). It is important to
note that tetrazole catalyst 4 outperforms the supported proline 1,
which promoted the formation of 17a (d.r. = 4 : 1) in lower yield
(67%) and enantioselectivity (78% eeanti; entry 16).4 Finally,
Results and discussion
The thermal/photoinduced thiol–ene coupling (TEC)12 was
chosen as the covalent immobilization strategy for the prep-
aration of heterogeneous proline-like organocatalysts 2–4 in
analogy with the synthesis of the previously reported immobi-
lized proline 1. Accordingly, the novel N-Boc pyrrolidine 2-car-
boxyamide 7 and sulfonamide 8 equipped with the ene
functionality (4-allyloxy group) were readily prepared in a single
step from (2S,4R)-N-Boc-4-O-allyl-hydroxyproline 54 by stan-
dard chemistry (Scheme 1). The tetrazolyl alkene 13 bearing a
Cbz protecting group at the pyrrolidine nitrogen atom was next
synthesized by adapting the procedures already optimized by
Ley et al.,11m Hartikka and Arvidsson,11i and Saito, Yamamoto
et al.11j for the synthesis of a N-Cbz protected pyrrolidinyl tetra-
zole analogue. Accordingly, (2S,4R)-N-Cbz-4-O-allyl-hydroxy-
proline 613 was almost quantitatively converted to the
corresponding amide 9 by in situ activation of the carboxylic
acid. Subsequent dehydration promoted by cyanuric chloride
gave the nitrile 11 in high yield (82%), which in turn was trans-
formed into the corresponding tetrazole 13 (85%) by cyclo-
addition with sodium azide.
The thermally (toluene, 90 °C) and photochemically (MeOH,
room temperature, λmax 365 nm) induced TECs of thiol–silica
1414 with alkenes 7 or 8 (3 equiv.) were next carried out under
the previously optimized conditions4 by using 2,2′-azobis(2-
methylpropionitrile) (AIBN) and 2,2-dimethoxy-2-phenyl-aceto-
phenone (DMAP) as the radical initiators, respectively. Both
Scheme 1 Synthesis of the ene-functionalized proline mimetics 7, 8,
12, and 13.
Scheme 2 Thermally and photochemically induced TEC of thiol silica
14 with 4-O-allyl-hydroxyroline derivatives 7, 8, 12, and 13.
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Table 1 Evaluation of catalysts 2–4 performance under batch
Table 2 Short study on the catalytic activity of 4 in model
conditionsa
organocatalytic reactionsa
Entry
Cat.
Solvent
Yieldb [%]
d.r. anti–sync
eeantid [%]
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
4
4
4
4
4
4
4
1
4
CH3CN
Toluene
DMSO
CH2Cl2
CH3CN
Toluene
DMSO
CH2Cl2
CH3CN
Toluene
DMSO
CH2Cl2
MeOH
Et2O
24
45
12
18
21
58
25
15
2 : 1
4 : 1
3 : 1
4 : 1
4 : 1
3 : 1
2 : 1
4 : 1
4 : 1
3 : 1
1 : 1
3 : 1
3 : 1
2 : 1
2 : 1
4 : 1
2 : 1
26
23
23
8
9
30
9
15
74
82
50
51
32
90
95
78
92
Entry
React.
Solvent
Yieldb [%]
d.r. anti–sync
eed [%]
1
a
a
b
b
c
(iPr)2O
DMSO
(iPr)2O
Toluene
(iPr)2O
DMSO
CH3CN
Toluene
DMSO
90 (17a)
92 (17a)
82f (18)
>95f (18)
80 (19)
2 : 1
1 : 1
1 : >19
1 : >19
1 : 15
1 : 9
—
95anti
50anti
90syn
95syn
55syn
45syn
42
2
3e
4e
6
9
75
10
11
12
13
14
15
16
17
>95
>95
84
5
c
92 (19)
7e
8e
9g
d
d
a
95f (20)
72f (20)
92 (17a)
45
>95
>95e
68
—
1 : 1
71
95anti
(iPr)2O
Toluene
(iPr)2Of
a Reactions performed at room temperature for 24 h in the stated solvent
with 0.25 mmol of acceptor (0.1 M), 0.75 mmol of cyclohexanone, and
0.075 mmol of 4. b Isolated yield of the stereomeric mixture of adducts.
c Estimated by 1H NMR analysis of crude reaction mixtures.
d Determined by chiral HPLC analysis. e Reaction performed with 20 vol
% of 15. Reaction time: 2 h. f Yield determined by 1H NMR analysis.
g Reaction performed under homogeneous conditions with (S)-5-
(pyrrolidin-2-yl)-1H-tetrazole catalyst (10 mol%).
>95
a Reactions performed in the stated solvent with 0.25 mmol of aldehyde
(0.15 M) and 0.75 mmol of ketone. b Isolated yield of the anti–syn
diastereomeric mixture. c Estimated by 1H NMR analysis of crude
reaction mixtures. d Determined by chiral HPLC analysis. e Reaction
time: 12 h. f Reactions performed with recycled catalyst.
a substantial maintenance of catalyst efficiency was detected in
diisopropyl ether for recycled 4 (entry 17). Indeed, the evalu-
ation of catalyst stability (recyclability) was a crucial experiment
to envisage the potential application of 4 in continuous-flow
processes.
Mechanistically, though the general mode of pyrrolidinyl tet-
razole catalysis is still the subject of debate and discussion,11a it
can be speculated that the suitable choice of low-polarity sol-
vents such as diisopropyl ether and toluene prevents the free
hydroxyls on the silica support of 4 from perturbing the hydro-
gen-bonding network responsible for the high selectivities
detected in homogeneous catalysis.17
Since its discovery,11g,h,j the unsupported (S)-5-(pyrrolidin-2-
yl)-1H-tetrazole has proven to be a successful catalyst due to its
efficacy in a wide range of organocatalytic reactions.11a There-
fore, with the aim to gain more information about the potential
applications of the supported analogue 4 in continuous-flow het-
erogeneous catalysis, the activity of 4 was tested in model
Mannich (eq. b, Table 2), Michael (eq. c), and α-amination
(eq. d) reactions. Table 2 summarizes the results of this short
study reporting for each transformation the best reaction profiles
based on product yield and/or stereoselectivity.15 Selected out-
comes of the model aldol reaction are also included in Table 2
(eq. a). It appears from these preliminary results that hetero-
geneous catalyst 4 behaves in a comparable manner to the un-
supported counterpart in terms of yield16 and diastereo- and
enantioselectivity. A direct comparison with literature data
was, in fact, possible for the Mannich,11c Michael,11c,16 and
α-amination reactions.11b As far as the aldol reaction is concerned
(entries 1–2), the observed poor diastereoselectivity was demon-
strated to be an intrinsic feature of tetrazole catalysis. Indeed, an
experiment (entry 9) performed in DMSO (room temperature,
24 h) with the unsupported (S)-5-(pyrrolidin-2-yl)-1H-tetrazole
catalyst (10 mol%) gave the mixture of aldol products in identical
quantitative yield and 1 : 1 diastereomeric ratio (entries 9 and 2).
As anticipated, the tetrazole catalyst 4 was finally tested in the
continuous-flow aldol reaction of cyclohexanone with p-nitro
benzaldehyde with the hope of setting up an effective process
with potential long term stability.18 Thus, a micro-HPLC was
suitably adapted for this study with minimized extra-columns
volumes. The packed-bed microreactor R4 (Table 3) was then
prepared by filling (packing by gravity) a stainless steel column
(50 mm length, 2.1 mm diameter) with tetrazole-functionalized
silica 4 (pore size 60 Å, particle size ∼50 μm, superficial area
500 m2 g−1, loading 0.76 mmol g−1). Main features of R4 were
determined by pycnometry and included the hold-up (dead)
volume (V0 = 125 μL), and the total porosity (0.72). The packing
amount of silica (154 mg) was calculated by weighing the
column before and after filling. In addition, chromatographic
retention factors k′ of cyclohexanone and p-nitro benzaldehyde
were measured under linear conditions in diisopropyl ether (DIP)
and toluene.19 These solvents, in fact, were selected as the
optimal reaction media for the subsequent continuous-flow
experiments (Table 3). Importantly, the determination of k′
values was crucial for roughly calculating the retention times (tr)
of the above reactants at different flow rates,19 and thus for
994 | Green Chem., 2012, 14, 992–1000
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Table 3 Optimization of continuous-flow aldol reaction in packed-bed microreactors R4 and short substrate scope studya
b
−1
Entry Solvent 16 (c [M]) k′16 tr(16)b (min) Temp.c [°C] Conv.d [%] Productivitye/103 [mmolh−1 mmolcat
]
d.r. anti–synf eeantig [%]
1
2
3
4
5
6
7
8
9
(iPr)2O 16a (0.03) 8.56 239
Toluene 16a (0.10) 0.91 48
25
25
25
50
50
50
50
50
50
65
62
58
>95
95
>95
95
>95
>95
50
2 : 1
3 : 1
2 : 1
1 : 1
2 : 1
3 : 1
3 : 1
3 : 1
2 : 1
95
82
85
92
80
75
78
82
68
159
149
77
256
256
256
256
236
(iPr)2Oh 16a (0.10)
—
—
(iPr)2Oi 16a (0.03) 8.56 239
Toluene 16a (0.10) 0.91 48
Toluene 16b (0.10) 0.60 45
Toluene 16c (0.10) 0.26 31
Toluene 16d (0.10) 0.27 32
Toluene 16e (0.10) 0.28 32
a See the Experimental section for a description of the experimental setup. All reactions were performed with a three-fold excess of cyclohexanone.
b Chromatographic retention factors k′ and retention times tr have been estimated at RT in the reaction solvent as described in ref. 19. k′15(DIP) = 0.84
(tr = 46 min); k′15(Tol) = 0.30 (tr = 33 min)). c All temperatures were measured by a thermometer placed inside the thermostatted unit containing the
microreactor. d Instant conversion in steady-state regime as established by 1H NMR analysis. e Productivities are measured in mmol(product) h−1
mmol(catalyst)−1 × 103. f Estimated by 1H NMR analysis of crude reaction mixtures. g Determined by chiral HPLC analysis. h Reaction performed
with 10 vol% of DMF. i The same reaction outcome was observed in a control experiment performed at the end of the substrate scope study.
estimating the duration of the process.20 An initial continuous-
flow experiment was performed in DIP by using a three-fold
excess of cyclohexanone in analogy to the batch study. The
optimal compromise between aldehyde solubility, conversion
efficiency, and productivity was obtained by pumping a 0.03 M
solution of aldehyde at 5 μL min−1 (residence time t0 = 25 min;
17b–e were produced in toluene at 50 °C with high conversion
efficiency (≥95%) and a satisfactory level of enantioselectivity
(68–82 eeanti). We would like to emphasize that the whole optim-
ization and substrate scope study was carried out with the same
packed-bed microreactor R4, which functioned at 50 °C for an
overall time of 80 hours. Remarkably, the packing silica 4 did
not show any evidence of deactivation during that period, as
demonstrated by a final control experiment that reproduced the
optimal 15/16a coupling outcome (entry 4). A progressive loss
of catalytic activity was observed, however, after 120 hours at
50 °C, with catalyst 4 fully deactivated after ca. 7 days on
stream.
t
r(16a): 239 min). As previously observed with proline catalyst 1,4
the stereoselectivity of the batch experiment with 4 (Table 1,
entry 15) was replicated (d.r. 2 : 1; 95 eeanti, Table 3, entry 1)
and maintained constant during the continuous process in
steady-state regime.20 The use of toluene or a 9 : 1 DIP–DMF
mixture as the solvent improved the process productivity because
of the higher concentration of reactants but, at the same time,
slightly lowered the reaction conversion and the level of enan-
tioselectivity (entries 2–3). Therefore, having in mind that reac-
tion completion is a fundamental goal in continuous process
optimization for easier product purification, the effect of temp-
erature on conversion efficiency was finally examined.21 To our
delight, we found that warming the microreactor R4 in the
HPLC oven set a 50 °C resulted in complete conversion and
selectivity (no formation of dehydration by-product was
detected) both in DIP and toluene, thus allowing the isolation of
the aldol product 17a by simple evaporation of the solvent and
excess cyclohexanone (entries 4 and 5). Notably, the increase of
the process temperature did not compromise the enantioselectiv-
ity of the process, which proceeded with higher productivity
(ca. 8 mg h−1) in toluene (entry 5).
Conclusions
In summary, we have synthesized a heterogeneous version of the
valuable Ley–Arvidsson–Yamamoto (S)-5-(pyrrolidin-2-yl)-1H-
tetrazole organocatalyst and ascertained that the utilization of
silica as the support and thiol–ene coupling (TEC) as the immo-
bilization strategy enables tetrazole organocatalyst 4 to maintain
the level of stereoselectivity of its homogeneous counterpart in
model batch transformations. Crucial for successful experiments
with supported tetrazole 4 was the selection of low-polarity reac-
tion solvents. In addition, we have provided a further example of
the effective combination of heterogeneous asymmetric organo-
catalysis and microreactor technology by preparing a packed-bed
microreactor filled with silica 4 and demonstrating its efficacy in
the continuous production of optically active aldol products.
Further improvements, in particular pertaining to process pro-
ductivity, are in progress through chemical optimization of the
The scope and the applicability of the method were shortly
investigated by reacting cyclohexanone with various aromatic
aldehydes having electron-withdrawing substituents (entries
6–9). Gratifyingly, the corresponding mixtures of aldol adducts
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(2S,4R)-tert-Butyl 4-(allyloxy)-2-(2-
nitrophenylsulfonylcarbamoyl)pyrrolidine-1-carboxylate (7)
described catalytic system and by taking advantage of a deeper
understanding of the kinetics and thermodynamics of the con-
tinuous-flow-process. Nevertheless, we believe this work may
represent a useful contribution to the current search for more
efficient, economic, and environmentally benign production
strategies of valuable chiral targets.
To a stirred solution of (2S,4R)-N-Boc-4-(allyloxy)proline 54
(500 mg, 1.85 mmol) in CH2Cl2 (8 mL) were added 2-nitroben-
zenesulfonamide (337 mg, 1.67 mmol), 4-(dimethylamino)pyri-
dine (DMAP, 61 mg, 0.50 mmol), and N,N′-
dicyclohexylcarbodiimide (DCC, 419 mg, 2.03 mmol). The
resulting mixture was refluxed for 72 h, then cooled to room
temperature, filtered, and washed with fresh portions of CH2Cl2
(4 × 5 mL). The combined filtrates were washed with cold 1 M
HCl (5 mL) and brine (5 mL) Then, the organic phase was dried
(Na2SO4), concentrated, and eluted from a column of silica gel
with 2.5 : 1 cyclohexane–AcOEt to give the sulfonamide 7
(631 mg, 75%) as a white amorphous solid. [α]D = −51.2 (c 1.6,
CHCl3). 1H NMR: δ = 8.50–8.38 (bm, 2 H, Ar), 7.85–7.62 (bm,
3 H, Ar), 5.90–5.78 (m, 1 H, CH2vCH), 5.28–5.15 (m, 2 H,
CH2vCH), 4.50–4.29 (bm, 1 H, H-2), 4.08–3.74 (bm, 3 H,
OCH2, H-4), 3.52 (bdd, 1 H, J4,5a = 2.0 Hz, J5a,5b = 8.5 Hz,
H-5a), 3.40 (bdd, 1 H, J4,5b = 5.0 Hz, J5a,5b = 10.5 Hz, H-5b),
2.50–2.00 (bm, 2 H, 2 H-3), 1.42 and 1.38 (2 s, 9 H, C(CH3)3).
13C NMR (major conformer): δ = 171.1, 157.0, 154.2, 148.1,
134.2, 133.3, 132.3, 124.7, 117.2, 82.3, 76.0, 70.1, 59.5, 51.9,
Experimental section
All moisture-sensitive reactions were performed under a nitrogen
atmosphere using oven-dried glassware. Solvents were dried
over standard drying agent and freshly distilled prior to use.
Flash column chromatograph was performed on silica gel 60
(230–400 mesh). Reactions were monitored by TLC on silica gel
60 F254 with detection by charring with sulfuric acid and/or nin-
hydrin. Flash column chromatography was performed on silica
gel 60 (230–400 mesh). Optical rotations were measured at 20
2 °C in the stated solvent; [α]D values are given in 10–1 deg cm2
g−1 1H (300 MHz) and 13C (75 MHz) NMR spectra were
.
recorded for CDCl3 solutions at room temperature unless other-
1
wise specified. Peak assignments were aided by H–1H COSY
and gradient-HMQC experiments. Enantiomeric excess (ee)
values were determined by HPLC. A two-pump high pressure
micro system (Agilent 1100 micro series) equipped with a DAD
detector was employed. The column was 150 × 2 mm Lux-1
Cellulose (from Phenomenex), 3 μm particle diameter. The
mobile phase was a binary mixture hexanes–i-PrOH 90 : 10
(v/v). ESI MS (LTQ-XL Linear Trap from Thermo Scientific)
analyses were performed in positive ion mode with samples dis-
solved in 10 mM solution of HCO2NH4 in 1 : 1 MeCN–
H2O. FT-IR analyses were performed with the Bruker Instrument
Vertex 70. Elemental analyses were performed with FLASH
2000 Series CHNS/O analyzer (ThermoFisher Scientific). Verti-
cal agitation was performed with the FirstMateTM synthesizer,
Argonaut Technology. The household UVA lamp apparatus was
equipped with four 15 W tubes (1.5 × 27 cm each). Photo-
induced reactions were carried out in a glass vial (diameter:
1 cm; wall thickness: 0.65 mm), sealed with a natural rubber
septum, located 2.5 cm away from the UVA lamp (irradiation on
sample: 365 nm, 1.04 W m−2). The system used for continuous-
flow reactions was composed of an HPLC pump (Agilent
1100 micro series), an in-line pressure transducer, a thermostated
microreactor holder (Peltier unit), a system to collect fractions
and a data acquisition system (Agilent ChemStation). The units
were connected by peek tubing (internal diameter 0.01 inch from
Upchurch Scientific). The system hold-up volume was smaller
than 80 μL. The temperature was controlled by inserting a
thermometer inside the Peltier unit (temperature measurement
error: 0.5 °C). Silica gel (grade 9385, pore size 60 Å, particle
size ∼50 μm, superficial area 500 m2 g−1) was purchased
from Sigma-Aldrich. (2S,4R)-N-Boc-4-(allyloxy)proline 54 and
(2S,4R)-N-Cbz-4-(allyloxy)proline 613 were synthesized as
described. Thiol–silica 1422 was prepared according to reported
procedures with minor modifications. For microreactor R4 prep-
aration and characterization see the ESI.† Adducts 17a–e, 18,
19, and 20 are known compounds. The self-disproportionation
of enantiomers (SDE) test for achiral chromatography23 has been
carried out for derivatives 17a–e, 19, and 20 without noting any
significant magnitude of SDE.
+
32.6, 28.2. ESI MS (455.1): 473.4 (M + NH4 ). Found: C,
50.02; H, 5.78; N, 9.51; S 7.22. C19H25N3O8S requires C,
50.10; H, 5.53; N, 9.23; 7.04%.
(2S,4R)-tert-Butyl 4-(allyloxy)-2-carbamoylpyrrolidine-1-
carboxylate (8)
To a stirred mixture of (2S,4R)-N-Boc-4-(allyloxy)proline 54
(1.28 g, 4.72 mmol), di-tert-butyl dicarbonate (1.54 g,
7.08 mmol,), NH4HCO3 (559 mg, 7.08 mmol), and anhydrous
CH3CN (20 mL) anhydrous pyridine (286 μL, 3.54 mmol) was
added in one portion. The mixture was stirred at room tempera-
ture until TLC analysis revealed the disappearance of the starting
acid (ca. 5 h), then the volume was reduced under vacuum to
approximately 5 mL. Subsequently, AcOEt (20 mL) and H2O
(20 mL) were added and the organic phase separated. The
aqueous phase was extracted further with AcOEt (2 × 20 mL)
and the combined organic phases washed with brine (10 mL),
dried (Na2SO4), and concentrated to give the amide 8 (1.21 g,
95%) at least 90% pure as judged by 1H NMR analysis. An
analytical sample of 8 was obtained by column chromatography
with 1 : 9 cyclohexane–AcOEt. [α]D = −58.8 (c 0.6, CHCl3). 1H
NMR: δ = 6.80 and 5.90 (2 bs, 1 H, NH), 6.00–5.80 (m, 1 H,
CH2vCH), 5.60–5.45 (bm, 1 H, NH), 5.35–5.15 (m, 2 H,
CH2vCH), 4.45–4.15 (bm, 2 H, H-2, H-4), 4.05–3.90 (bm, 2 H,
OCH2), 3.80–3.40 (m, 2 H, 2 H-5), 2.55–2.00 (bm, 2 H, 2 H-3),
1.42 (s, 9 H, C(CH3)3). 13C NMR (major conformer): δ = 173.9,
154.0, 134.3, 117.2, 80.8, 75.9, 70.2, 58.2, 51.8, 33.7, 28.3. ESI
MS (270.2): 309.8 (M + K+). Found: C, 57.48; H, 8.41; N,
10.09. C13H22N2O4 requires C, 57.76; H, 8.20; N, 10.36%.
(2S,4R)-Benzyl 4-(allyloxy)-2-carbamoylpyrrolidine-1-
carboxylate (9)
To a stirred mixture of (2S,4R)-N-Cbz-4-(allyloxy)proline 613
(1.00 g, 3.28 mmol), di-tert-butyl dicarbonate (1.07 g,
996 | Green Chem., 2012, 14, 992–1000
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4.92 mmol), NH4HCO3 (389 mg, 4.92 mmol), and anhydrous
CH3CN (15 mL) anhydrous pyridine (199 μL, 2.46 mmol) was
added in one portion. The mixture was stirred at room tempera-
ture until TLC analysis revealed the disappearance of the starting
acid (ca. 5 h), then the volume was reduced under vacuum to
approximately 5 mL. Subsequently, AcOEt (20 mL) and H2O
(20 mL) were added and the organic phase separated. The
aqueous phase was extracted further with AcOEt (2 × 20 mL)
and the combined organic phases washed with brine (10 mL),
dried (Na2SO4), and concentrated to give the amide 9 (917 mg,
92%) at least 90% pure as judged by 1H NMR analysis. An
analytical sample of 9 was obtained by column chromatography
cyclohexane–AcOEt to give 11 (1.23 g, 82%) as a white foam.
[α]D = −61.5 (c 0.7, CHCl3). H NMR: δ = 7.45–7.25 (m, 5 H,
1
Ar), 6.00–5.78 (m, 1 H, CH2vCH), 5.40–5.25 (m, 2 H,
CH2vCH), 4.80–4.58 (m, 1 H, H-2), 4.30–4.12 (m, 1 H, H-4),
4.10–3.80 (m, 2 H, OCH2), 3.80–3.72 and 3.64–3.50 (2 m, 2 H,
2 H-5), 2.60–2.20 (m, 2 H, 2 H-3). 13C NMR (major conformer):
δ = 162.0, 135.7, 133.8, 128.6, 128.3, 128.2, 128.1, 128.0,
118.7, 117.8, 75.9, 70.3, 68.1, 51.3, 45.5, 37.6. ESI MS (286.1):
309.5 (M + Na+). Found: C, 67.42; H, 6.60; N, 9.98.
C16H18N2O3 requires C, 67.12; H, 6.34; N, 9.78%.
1
with pure AcOEt. [α]D = −49.9 (c 1.4, CHCl3). H NMR: δ =
(2S,4R)-tert-Butyl 4-(allyloxy)-2-(1H-tetrazol-5-yl)pyrrolidine-1-
7.40–7.20 (m, 5 H, Ar), 6.65 and 5.82 (2 bs, 1 H, NH),
5.92–5.78 (m, 1 H, CH2vCH), 5.45–5.30 (bm, 1 H, NH),
5.28–5.10 (m, 2 H, CH2vCH), 4.50–4.35 (m, 1 H, H-2),
4.26–4.10 (m, 1 H, H-4), 4.00–3.90 (m, 2 H, OCH2), 3.86–3.50
(m, 2 H, 2 H-5), 2.60–2.40 and 2.30.2.00 (2 bm, 2 H, 2 H-3).
13C NMR (major conformer): δ = 173.4, 156.2, 136.1, 134.2,
128.5, 128.2, 127.8, 117.3, 76.1, 70.2, 67.5, 58.7, 51.7, 33.9.
ESI MS (344.1): 343.9 (M + K+). Found: C, 63.38; H, 6.51; N,
9.01. C16H20N2O4 requires C, 63.14; H, 6.62; N, 9.20%.
carboxylate (12)
A mixture of nitrile 10 (800 mg, 3.17 mmol), NaN3 (268 mg,
4.12 mmol), Et3N·HCl (567 mg, 4.12 mmol), and toluene
(5 mL) was stirred at 95 °C under an atmosphere of argon for
24 h. The mixture was then cooled to room temperature and
extracted with AcOEt (3 × 40 mL). The combined organic
phases were washed with brine (10 mL), dried (Na2SO4), con-
centrated, and eluted from a column of silica gel with 6 : 4 : 1
cyclohexane–AcOEt–AcOH to give 12 (701 mg, 75%) as a
1
white amorphous solid. [α]D = −92.0 (c 0.6, CHCl3). H NMR:
(2S,4R)-tert-Butyl 4-(allyloxy)-2-cyanopyrrolidine-1-carboxylate
(10)
δ = 6.02–5.88 (m, 1 H, CH2vCH), 5.37–5.22 (m, 2 H,
CH2vCH), 5.17 (dd, 1 H, J2,3a = 7.0 Hz, J2,3b = 7.5 Hz, H-2),
4.35–4.25 (m, 1 H, H-4), 4.15–4.00 (m, 2 H, OCH2), 3.64 (dd, 1
To a cooled (0 °C), stirred solution of crude amide 8 (1.21 g,
4.48 mmol) in anhydrous DMF (20 mL) cyanuric chloride
(537 mg, 2.91 mmol) was added in one portion. The mixture
was stirred at 0 °C for 1 h, then warmed to room temperature,
and stirred at that temperature for additional 24 h. The mixture
was then cooled to 0 °C, diluted with H2O (15 mL), and
extracted with AcOEt (3 × 50 mL). The combined organic
phases were washed with brine (10 mL), dried (Na2SO4), con-
centrated, and eluted from a column of silica gel with 4 : 1 cyclo-
hexane–AcOEt to give 11 (835 mg, 74%) as a pale yellow oil.
H, J4,5a = 3.0 Hz, J5a,5b = 11.5 Hz, H-5a), 3.48 (dd, 1 H, J4,5b
=
5.0 Hz, J5a,5b = 11.5 Hz, H-5b), 3.10–3.00 (m, 1 H, H-3a),
2.63–2.51 (m, 1 H H-3b), 1.42 (s, 9 H, C(CH3)3). 13C NMR
(major conformer): δ = 157.0, 155.9, 134.1, 117.3, 81.6, 76.0,
70.1, 52.0, 49.7, 35.5, 28.2. ESI MS (295.2): 296.6 (M + H+).
Found: C, 52.55; H, 7.41; N, 23.46. C13H21N5O3 requires C,
52.87; H, 7.17; N, 23.71%.
1
(2S,4R)-Benzyl 4-(allyloxy)-2-(1H-tetrazol-5-yl)pyrrolidine-1-
carboxylate (13)
[α]D = −65.4 (c 1.1, CHCl3). H NMR: δ = 5.98–5.82 (m, 1 H,
CH2vCH), 5.34–5.20 (m, 2 H, CH2vCH), 4.64–4.50 (m, 1 H,
H-2), 4.30–4.10 (m, 1 H, H-4), 4.08–3.90 (m, 2 H, OCH2),
3.70–3.60 and 3.58–3.48 (2 bm, 2 H, 2 H-5), 2.60–2.30 (bm,
2 H, 2 H-3), 1.48 and 1.4 (2 s, 9 H, C(CH3)3). 13C NMR (major
conformer): δ = 152.8, 133.7, 118.7, 117.2, 81.3, 74.9, 69.9,
50.5, 45.4, 37.0, 27.9. ESI MS (252.1): 275.7 (M + Na+).
Found: C, 61.67; H, 7.81; N, 11.28. C13H20N2O3 requires C,
61.88; H, 7.99; N, 11.10%.
A mixture of nitrile 11 (800 mg, 2.80 mmol), NaN3 (237 mg,
3.64 mmol), Et3N·HCl (501 mg, 3.64 mmol), and toluene
(5 mL) was stirred at 95 °C under an atmosphere of argon for
24 h. The mixture was then cooled to room temperature, diluted
with cold 1 M HCl until pH = 3, and extracted with CH2Cl2 (3 ×
40 mL). The combined organic phases were washed with brine
(10 mL), dried (Na2SO4), concentrated, and eluted from a
column of silica gel with 6 : 4 :1 cyclohexane–AcOEt–AcOH to
give 13 (783 mg, 85%) as a white amorphous solid. [α]D
=
(2S,4R)-Benzyl 4-(allyloxy)-2-cyanopyrrolidine-1-carboxylate
(11)
−42.2 (c 0.9, CHCl3). 1H NMR (DMSO-d6 + D2O, 120 °C): δ =
7.45–7.15 (m, 5 H, Ar), 6.00–5.84 (m, 1 H, CH2vCH),
5.32–5.05 (m, 2 H, CH2vCH), 5.29 (dd, 1 H, J2,3a = 5.0 Hz,
J2,3b = 5.5 Hz, H-2), 4.36–4.28 (m, 1 H, H-4), 4.04–3.98 (m, 2
H, OCH2), 3.72 (dd, 1 H, J4,5a = 5.0 Hz, J5a,5b = 11.5 Hz, H-5a),
3.64 (dd, 1 H, J4,5b = 1.5 Hz, J5a,5b = 11.5 Hz, H-5b), 2.42 (ddd,
1 H, J2,3a = 5.0 Hz, J3a,4 = 7.5 Hz, J3a,3b = 12.5 Hz, H-3a), 2.21
(ddd, 1 H, J2,3a = 5.5 Hz, J3a,4 = 6.0 Hz, J3a,3b = 12.5 Hz, H-3b).
13C NMR (major conformer): δ = 156.7, 156.3, 135.8, 134.1,
128.5, 128.2, 128.0, 127.8, 117.4, 75.7, 70.2, 67.7, 51.9, 50.3,
35.5. ESI MS (329.1): 330.5 (M + H+). Found: C, 58.62; H,
To a cooled (0 °C), stirred solution of crude amide 9 (1.60 g,
5.26 mmol) in anhydrous DMF (18 mL) cyanuric chloride
(630 mg, 3.41 mmol) was added in one portion. The mixture
was stirred at 0 °C for 1 h, then warmed to room temperature,
and stirred at that temperature for additional 12 h. The mixture
was then cooled to 0 °C, diluted with H2O (10 mL), and
extracted with AcOEt (3 × 40 mL). The combined organic
phases were washed with brine (10 mL), dried (Na2SO4), con-
centrated, and eluted from a column of silica gel with 2 : 1
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5.99; N, 21.58. C16H19N5O3 requires C, 58.35; H, 5.81; N,
21.26%.
and anhydrous CH2Cl2 (4 mL) was slowly added a solution of
TFA (4 mL) in anhydrous CH2Cl2 (4 mL). The mixture was then
warmed to room temperature, stirred for 12 h, and centrifuged
with 5 mL portions of CH2Cl2 (2×), 1 : 2/Et3N–CH2Cl2 (2×;
addition at 0 °C), CH2Cl2 (2×), MeOH (2×), CH2Cl2 (2×). The
resulting silica-supported proline mimetics 2, 3 or 4 was finally
dried at reduced pressure (0.1 mbar, 40 °C, 6 h).
Preparation of 3-mercaptopropyl silica gel 14
To preserve silica particles from mechanical degradation, this
derivatization step was carried out in a standard rotary evaporator
in which a two-necked flask was fitted with solvent condenser,
solvent collector, and nitrogen inlet for syringe addition of reac-
tant solutions under an inert atmosphere. Mixing was obtained
by spinning the flask around its axis and warming by means of a
standard oil-bath. Silica gel (grade 9385, pore size 60 Å, particle
size ∼50 μm, superficial area 500 m2 g−1) was dried before its
use (0.1 mbar, T = 110 °C, 2 h).
To a stirred slurry of silica gel (5.00 g), anhydrous toluene
(60 mL), and freshly distilled triethylamine (0.25 mL) was
slowly added a solution of (3-mercaptopropyl)-trimethoxysilane
(2.5 mL) in anhydrous toluene (10 mL). The resulting mixture
was then warmed to 60 °C and stirred for 20 h. Subsequently,
the mixture was refluxed until ca. 15 mL of solvent were col-
lected (eventually by the aid of a nitrogen stream). The mixture
was then refluxed for an additional 1 h, cooled to room tempera-
ture, and centrifuged with 20 mL portions of toluene, MeOH,
EtOH, and cyclohexane. The resulting thiol-functionalized silica
gel 14 was finally dried at reduced pressure (0.1 mbar, 60 °C,
6 h). FT-IR (KBr): ν 2577(SH) cm−1. Elemental analysis (%)
found: S 3.36 (estimated loading f = 1.05 mmol g−1).
Silica 2. Elemental analysis (%) found: N 2.10 (estimated
loading f = 0.75 mmol g−1). FT-IR (KBr): ν 2938 (CH), 1681
(CO) cm−1
.
Silica 3. Elemental analysis (%) found: N 2.94 (estimated
loading f = 0.70 mmol g−1). FT-IR (KBr): ν 2930 (CH), 1613
(CO), 1546 (SO2N), 1130 (SO2N) cm−1
.
Silica 4. Elemental analysis (%) found: N 5.32 (estimated
loading f = 0.76 mmol g−1). FT-IR (KBr): ν 2938 (CH), 1674
(CO), 1445 (CN) cm−1
.
General procedure for the synthesis of silica-supported proline
mimetics 2–4 via photoinduced TEC
To preserve silica particles from mechanical degradation, this
derivatization step was carried out with the FirstMateTM
synthesizer.
A vertically-agitated mixture of thiol–silica 14 (1.00 g,
1.05 mmol; f = 1.05 mmol S g−1), (4-allyloxy)pyrrolidine deriva-
tive 7, 8 or 12 (3.15 mmol), 2,2-dimethoxy-2-phenyl-aceto-
phenone (DMAP, 269 mg, 1.05 mmol), and MeOH (6 mL) was
irradiated at room temperature for 5 h, and then centrifuged with
5 mL portions of MeOH (4×). The resulting N-Boc protected
silica-supported proline mimetic N-Boc 2, N-Boc 3 or N-Boc 4
was finally dried at reduced pressure (0.1 mbar, 40 °C, 6 h).
Excess pyrrolidine derivative 7, 8 or 12 can be easily recycled
by column chromatography of the centrifugate. Silicas N-Boc 2,
N-Boc 3, and N-Boc 4 were obtained with levels of functionali-
zation which were comparable to those detected in the corre-
sponding thermally induced TECs.
To a cooled (0 °C), vertically-agitated mixture of silica-sup-
ported proline mimetic N-Boc 2, N-Boc 3 or N-Boc 4 (∼1.00 g)
and anhydrous CH2Cl2 (4 mL) was slowly added a solution of
TFA (4 mL) in anhydrous CH2Cl2 (4 mL). The mixture was then
warmed to room temperature, stirred for 12 h, and centrifuged
with 5 mL portions of CH2Cl2 (2×), 1 : 2/Et3N–CH2Cl2 (2×;
addition at 0 °C), CH2Cl2 (2×), MeOH (2×), CH2Cl2 (2×). The
resulting silica-supported proline mimetics 2, 3 or 4 was finally
dried at reduced pressure (0.1 mbar, 40 °C, 6 h). Silicas 2, 3, and
4 were obtained with levels of functionalization which were
comparable to those detected in the corresponding thermally
induced TECs.
General procedure for the synthesis of silica-supported proline
mimetics 2–4 via thermally induced TEC
To preserve silica particles from mechanical degradation, this
derivatization step was carried out with the FirstMateTM
synthesizer.
A vertically-stirred mixture of thiol–silica 14 (1.00 g,
1.05 mmol; f = 1.05 mmol S g−1), (4-allyloxy)pyrrolidine
derivative 7, 8 or 12 (3.15 mmol), 2,2′-azobis(2-methylpropio-
nitrile) (AIBN, 172 mg, 1.05 mmol), and anhydrous toluene
(8 mL) was degassed under vacuum, and saturated with argon
(by an Ar-filled balloon) three times. The mixture was then
warmed to 90 °C, stirred for 16 h, cooled to room temperature,
diluted with AcOEt (8 mL), and centrifuged with 5 mL portions
AcOEt (4×). The resulting N-Boc protected silica-supported
proline mimetic N-Boc 2, N-Boc 3 or N-Boc 4 was finally dried
at reduced pressure (0.1 mbar, 40 °C, 6 h). Excess pyrrolidine
derivative 7, 8 or 12 can be easily recycled by column chromato-
graphy of the centrifugate.
Silica N-Boc 2. Elemental analysis (%) found: N 2.15 (esti-
mated loading f = 0.77 mmol g−1). FT-IR (KBr): ν 1745 (CO),
1690 (CO), 1455 (t-Bu), 1370 (t-Bu) cm−1
.
Procedure for the model aldol reaction under batch conditions
(Table 1)
Silica N-Boc 3. Elemental analysis (%) found: N 3.18 (esti-
mated loading f = 0.76 mmol g−1). FT-IR (KBr): ν 1740 (CO),
1610 (CO), 1545 (SO2N), 1450 (t-Bu), 1370 (t-Bu) cm−1
.
A mixture of p-nitro benzaldehyde (38 mg, 0.25 mmol), cyclo-
hexanone (78 μL, 0.75 mmol), the stated catalyst (0.075 mmol),
and the stated solvent (1.7 mL) was vertically-stirred at room
temperature for 24 h, and then centrifuged with 2.5 mL-portions
of CH2Cl2 (2×). The combined centrifugates were concentrated
Silica N-Boc 4. Elemental analysis (%) found: N 5.45 (esti-
mated loading f = 0.78 mmol g−1). FT-IR (KBr): ν 1699 (CO),
1650 (CO), 1457 (t-Bu), 1396 (t-Bu) cm−1
.
To a cooled (0 °C), vertically-stirred mixture of silica-sup-
ported proline mimetic N-Boc 2, N-Boc 3 or N-Boc 4 (∼1.00 g)
1
and the resulting residue analyzed by H NMR to determine the
998 | Green Chem., 2012, 14, 992–1000
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Continuous-flow aldol reactions (Table 3)
diastereomeric ratio and conversion. Subsequently, the residue
was eluted from a column of silica gel with 5 : 1 toluene–AcOEt
to determine the yield of the anti–syn diastereomeric mixture
and obtain the pure anti-adduct 17a whose enantiomeric excess
value23 was determined by chiral HPLC analysis: Lux-1 cellu-
lose (hexanes–i-PrOH 98 : 2 v/v, 400 μL min−1; λmax = 258 nm);
tR (major) = 18.5 min; tR (minor) = 25.4).
Microreactor R4 was fed with a solution in the stated solvent of
cyclohexanone and the aromatic aldehyde 16a–e, and operated at
the stated temperature for 4 h (under steady-state conditions) at
5 μL min−1 (see Table 3 for molarity concentrations). Instant
conversion was determined (1H NMR analysis) every
30 minutes by taking a sample of the eluate. The collected sol-
ution was finally concentrated and eluted from a column of silica
gel with the suitable elution system to give the corresponding
mixture of anti–syn adducts whose diastereomeric ratio was
Procedure for the model Mannich reaction under batch
conditions (Table 2)
1
determined by H NMR analysis. The enantiomeric excess23 of
the anti-adducts 17a–e was evaluated by chiral HPLC analysis.
17b. Lux-1 cellulose (hexanes–i-PrOH 99 : 1 v/v, 500 μL
min−1; λmax = 220 nm); tR (major) = 30.5; tR (minor) =
46.2 min.
17c. Lux-1 cellulose (hexanes–i-PrOH 99 : 1 v/v, 100 μL
min−1; λmax = 220 nm); tR (major) = 57.8; tR (minor) =
77.9 min.
17d. Lux-1 cellulose (hexanes–i-PrOH 98 : 2 v/v, 500 μL
min−1; λmax = 220 nm); tR (major) = 5.3; tR (minor) = 7.3 min.
17e. Lux-1 cellulose (hexanes–i-PrOH 99 : 1 v/v, 500 μL
min−1; λmax = 220 nm); tR (major) = 5.4; tR (minor) = 6.8 min.
A mixture of N-p-methoxybenzyl-α-iminoglyoxalate (52 mg,
0.25 mmol), cyclohexanone (340 μL, 20 vol%), catalyst 4
(99 mg, 0.075 mmol), and the stated solvent (1.7 mL) was verti-
cally-stirred at room temperature for 2 h, and then centrifuged
with 2.5 mL-portions of CH2Cl2 (2×). The combined centrifu-
gates were concentrated and the resulting residue analyzed by 1H
NMR to determine the diastereomeric ratio and estimate the
yield of the syn–anti diastereomeric mixture. The enantiomeric
excess of the syn-adduct 18 was determined by chiral HPLC
analysis: Lux-1 Cellulose (hexanes–i-PrOH 99 : 1 v/v, 300 μL
min−1; λmax = 246 nm); tR (minor) = 16.5 min; tR (major) =
17.7).
Acknowledgements
We gratefully acknowledge the University of Ferrara (Progetto
FAR 2010) and the Italian Ministry of University and Scientific
Procedure for the model Michael reaction under batch
conditions (Table 2)
Research
(Progetto
FIRB
Chem-Profarma-Net
Grant
RBPR05NWWC 008, Progetto PRIN Grants 2009ZSC5K2 004
and 20098SJX4F 004) for financial supports. Thanks are also
given to Mr Paolo Formaglio for NMR experiments and to Mrs
Ercolina Bianchini for elemental analyses.
A mixture of trans-β-nitrostyrene (37 mg, 0.25 mmol), cyclohex-
anone (78 μL, 0.75 mmol), the stated catalyst (99 mg,
0.075 mmol), and the stated solvent (1.7 mL) was vertically-
stirred at room temperature for 24 h, and then centrifuged with
2.5 mL-portions of CH2Cl2 (2×). The combined centrifugates
were concentrated and the resulting residue analyzed by 1H
NMR to determine the diastereomeric ratio and conversion. Sub-
sequently, the residue was eluted from a column of silica gel
with 2 : 1 cyclohexane–AcOEt to determine the yield of the
anti–syn diastereomeric mixture and obtain the pure syn-adduct
19 whose enantiomeric excess value23 was determined by chiral
HPLC analysis: Lux-1 Cellulose (hexanes–i-PrOH 92 : 8 v/v,
50 μL min−1; λmax = 220 nm); tR (minor) = 34.8 min; tR (major)
= 36.3).
Notes and references
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and M. Beller, Chem.–Eur. J., 2003, 9, 4286–4294; (b) J. Andraos, Org.
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S. V. Ley and C. D. Smith, in Microreactors in Organic Synthesis and
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84–122; (e) I. R. Baxendale, J. J. Hayward and S. V. Ley, Comb. Chem.
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Procedure for the model α-amination reaction under batch
conditions (Table 2)
A mixture of diethyl azodicarboxylate (97% purity, 41 μL,
45 mg, 0.25 mmol), cyclohexanone (340 μL, 20 vol%), catalyst
4 (99 mg, 0.075 mmol), and the stated solvent (1.7 mL) was ver-
tically-stirred at room temperature for 2 h, and then centrifuged
with 2.5 mL portions of CH2Cl2 (2×). The combined centrifu-
gates were concentrated and the resulting residue analyzed by 1H
NMR to estimate the yield of 20. The enantiomeric excess of 20
was determined by chiral HPLC analysis: Lux-1 cellulose
(hexanes–i-PrOH 95 : 5 v/v, 200 μL min−1; λmax = 220 nm); tR
(minor) = 7.7 min; tR (major) = 10.4).
4 A. Massi, A. Cavazzini, L. Del Zoppo, O. Pandoli, V. Costa, L. Pasti and
P. P. Giovannini, Tetrahedron Lett., 2011, 52, 619–622.
5 In light of this new paradigm, Odera and Seeberger reported the first
homogeneous organocatalytic aldol and Mannich reactions in microflui-
dic devices: (a) A. Odedra and P. H. Seeberger, Angew. Chem., Int. Ed.,
2009, 48, 2699–2702. For a general discussion on the potential of this
approach in the field of fine chemicals and pharmaceuticals production,
see: (b) A. Kirschning, W. Solodenko and K. Mennecke, Chem.–Eur. J.,
2006, 12, 5972–5990; (c) A. El Kadib, R. Chimenton, A. Sachse,
This journal is © The Royal Society of Chemistry 2012
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F. Fajula, A. Galarneau and B. Coq, Angew. Chem., Int. Ed., 2009, 48,
4969–4972; (d) F. E. Valera, M. Quaranta, A. Moran, J. Blacker,
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Ed., 2010, 49, 2478–2485. For a recent review on the combination of het-
erogeneous catalysis with microreactor technology, see: (e) C. G. Frost
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16 It has to be pointed out that reactions considered in this comparison have
been optimized with a lower loading of homogeneous catalyst (typically,
5–15 mol% of unsupported tetrazole vs. 30 mol% of 4). Moreover,
modest enantioselectivities were also detected in Michael and α-amin-
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selectivities were achieved by Ley and co-workers in Michael additions
to nitro-olefins by using a homo-proline tetrazole catalyst (ref. 11f).
17 The effect on catalyst 4 activity of free hydroxyls capping with hydrophi-
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flow model aldol reaction promoted by either catalyst 1 or 4 will be
reported in due course along with a suitable in-line analysis method.
19 The equation for the experimental determination of the retention factor k′
is: k′ = (tr − t0)/t0, where tr is the retention time of the species under
evaluation and t0 is the hold-up time of the column. The hold-up time t0
can be easily calculated by dividing the hold-up volume V0 by the flow
rate. In microreactor technology literature, this is the so called residence
time.
20 Typically, the steady-state regime is reached ca. 30 minutes after the first
elution of the more retained aldehyde.
21 For a discussion on the beneficial effect of temperature on the catalytic
activity of unsupported (S)-5-(pyrrolidin-2-yl)-1H-tetrazole, see ref. 5d.
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1000 | Green Chem., 2012, 14, 992–1000
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