Toward the optimization of continuous-flow aldol and α-amination reactions by means of proline-functionalized silicon packed-bed microreactors

Article abstract of DOI:10.1016/j.tetlet.2010.11.157

The activity and stability under flow conditions of covalently and non-covalently silica supported proline and proline-like organocatalysts is herein described. The slow aldol reaction of cyclohexanone with p-nitro benzaldehyde and the fast α-amination of

Full text of DOI:10.1016/j.tetlet.2010.11.157

Tetrahedron Letters 52 (2011) 619–622
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward the optimization of continuous-flow aldol and
a-amination reactions
by means of proline-functionalized silicon packed-bed microreactors
Alessandro Massi a, , Alberto Cavazzini a, , Luisa Del Zoppo a, Omar Pandoli b, Valentina Costa a, Luisa Pasti a,
Pier Paolo Giovannini c
⇑
⇑
a Dipartimento di Chimica, Università di Ferrara, Via L. Borsari 46, I-44121 Ferrara, Italy
b National Key Laboratory of Micro/Nano Fabrication Technology, Shanghai Jiao Tong University, Shanghai, PR China
c Dipartimento di Biologia ed Evoluzione, Università di Ferrara, Corso Ercole I D’Este 32, I-44121 Ferrara, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The activity and stability under flow conditions of covalently and non-covalently silica supported proline
Received 21 October 2010
Revised 24 November 2010
Accepted 30 November 2010
Available online 5 December 2010
and proline-like organocatalysts is herein described. The slow aldol reaction of cyclohexanone with p-
nitro benzaldehyde and the fast
a-amination of isovaleraldehyde with dibenzyl azodicarboxylate have
been selected as model reactions for this study. Prospects and limitations of the disclosed continuous-
flow organocatalytic approach are widely discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Continuous-flow processes
Microreactors
Organocatalysis
Today, the combination of efficient synthetic methodologies
such as organocatalysis1 with high-throughput techniques such
as microreactor technology2 is actively pursued to create new syn-
thetic platforms for the sustainable, safe, and intensified produc-
tion of fine chemicals and pharmaceuticals.3 In light of this new
paradigm, Odedra and Seeberger recently reported the first homo-
geneous organocatalytic asymmetric aldol and Mannich reactions
performed in microfluidic devices.4 Pericàs and co-workers later
described the implementation of heterogeneous continuous-flow
Mannich reactions by using packed-bed microreactors filled with
a proline-functionalized polystyrene resin.5 For a broad range of
microreactor applications it would be desirable, however, that
the proline-functionalized packing material be compatible with a
wide array of reaction solvents. In general, lightly cross-linked
polystyrene resins appear inappropriate for microchannel packing
as they may cause high pressure drop along the microreactor and
lead to irreproducible flow when swollen with different solvents.6
Herein, we report on the preparation of proline-functionalized sil-
icas by a covalent immobilization strategy based on the photoin-
duced thiol-ene coupling (TEC).7 The synthesis of an ionic
counterpart is also described and the nature of immobilization
on catalyst activity and stability under batch and flow conditions
available (2S,4R)-N-Boc-4-hydroxyproline 1
(Scheme 1).8 The
thermally induced TEC of 2 (3 equiv) with commercial 3-mercapto-
propyl silica 4 was next performed by using 2,20-azobis(2-methyl-
propionitrile) (AIBN, 1 equiv) as the radical initiator and toluene as
the solvent (Scheme 2, route a).9 Full conversion into the adduct 5
was achieved under vigorous magnetic stirring at 90 °C in 20 h as
established by FT-IR analysis (disappearance of the SH stretching
band at 2577 cmꢀ1). The corresponding photochemically initiated
TEC was also investigated with the aim to set up a milder
procedure for proline immobilization. Indeed, the photoinduced
(365 nm) TEC of 4 with 3 (3 equiv) proceeded smoothly (25 °C,
3 h) in MeOH in the presence of 2,2-dimethoxy-2-phenyl-aceto-
phenone (DMAP) as the sensitizer (Scheme 2, route b).10
-
+
O
1. t-BuBr, Et3NBnCl
K2CO3 DMA, 55 ºC
,
CO2t-Bu
N
2. CH2CHCH2Br, NaH
DMF, -25 ºC to RT
HO
Boc
2 (72% overall)
CO2H
N
O
1. CH2CHCH2Br, NaH
DMF, -25 ºC to RT
Boc
1
duly evaluated by using model aldol and a-amination reactions.
The hitherto unreported 4-O-allyl-hydroxyproline derivatives 2
and 3 were readily synthesized in two steps from commercially
CO2H
2. NaOH
MeOH, 0 ºC to RT
N
Boc
3 (67% overall)
⇑
Corresponding authors.
E-mail address: msslsn@unife.it (A. Massi).
Scheme 1. Synthesis of 4-O-allyl-hydroxyproline derivatives 2 and 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.157

620
A. Massi et al. / Tetrahedron Letters 52 (2011) 619–622
Table 1
SiO2
SiO2
Optimization of catalysts 6 and 9 performance under batch conditionsa
S
S
3
3
O
O
1. TFA: CH2Cl2 2:1
2. Et3N: CH2Cl2 2:1
3
3
CHO
O
O
OH
cat. (10 mol%)
CO2t-Bu
CO2H
N
N
H
+
solvent, RT 24 h
Boc
NO2
5
6 (0.64 mmol N/g)
NO2
AIBN, 2
route a
Toluene, 90 ºC, 16 h
Entry
Cat.
Solvent
Yieldb (%)
dr anti/sync
eeanti (%)
d
1. DPAP, 3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6
6
6
6
6
6
DMSO
CH3CN
DMF
25
2:1
46
MeOH, RT, 365 nm, 3 h
6 (0.78 mmol N/g)
SiO2
52(31)e
11
3:1(3:1)e
1:1
42(42)e
SH
2. TFA: CH2Cl2 1:2
3. Et3N: CH2Cl2 1:2
32
40
4 (~50 µm, 60Å, 500 m2g-1
)
H2O
32
16
2:1
3:1
route b
CH2Cl2
Toluene
Toluene
DMSO
CH3CN
DMF
55
67(65)e
<5
4:1(4:1)e
—
78(78)e
1. aq. 35% H2O2
2. 0.05 MH2SO4
10f
9
9
9
9
9
—
52
5
45
38
47
N
92
52
95
78
1.5:1
2.5:1
2:1
N
H
-
N
8
SiO2
3 SO3
SiO2
3
SO3H
N
H
H2O
2:1
3:1
H+
.
CH3CN, RT, 2 h
CH2Cl2
Toluene
Toluene
44
7
9
7
>95(92)e
60
2:1(2:1)e
4:1
55(52)e
-
9 (0.74 mmol N/g)
Scheme 2. Thermally and photochemically induced TEC of thiol-silicas 4a with 4-
O-allyl-hydroxyproline derivatives 2 and 3.
a
Reactions performed in the stated solvent with 0.25 mmol of aldehyde (0.25 M)
and 0.75 mmol of ketone.
b
Isolated yield.
Considering the final deprotection step, it should be noted that
the harsher acid conditions required for simultaneous Boc and
t-butyl ester removal (route a) resulted in the partial loss (elemen-
tal analysis) of supported proline, thus confirming route b as the
optimal synthetic strategy toward the covalently proline-function-
alized silica 6. In a divergent approach, the non-covalently sup-
c
Estimated by 1H NMR analysis of crude reaction mixtures.
d
Determined by chiral HPLC analysis.
Reactions performed with recycled catalysts.
Catalyst 10 (0.8 mmol/g) prepared by capping the thiol-silica 4 with 1-hexene
e
f
under the photochemical conditions described in Scheme 2.
ported chiral amine catalyst
9 was readily prepared from
commercial thiol-silica 4 and (S)-(+)-1-(2-pyrrodinylmethyl)-pyr-
rolidine 8 by adapting a two-step procedure already reported for
chiral amine catalysts supported on polystyrene resins.11
promoted the model reaction in the apolar solvent toluene (entry
6), showing levels of activity (67% yield) and stereoselectivity
(anti/syn = 4:1; 78% eeanti) comparable to those observed for homo-
geneous proline catalysis.12a,13
Activity and stability of covalently and non-covalently anchored
organocatalysts
6
and
9
were first evaluated under batch
Bearing in mind the execution of a continuous-flow process as
the ultimate goal of this study, stability (recyclability) of catalyst
6 was also investigated. A progressive loss of activity was observed
with recycled 6 in the polar solvent acetonitrile (entry 2; only data
conditions in different solvents by using the aldol condensation
of cyclohexanone with p-nitro benzaldehyde as a benchmark
(Table 1). To our delight, we found that catalyst 6 efficiently
Table 2
Optimization of continuous-flow aldol reaction in packed-bed microreactors R1and R2a
functionalized silica
HPLC
pump
O
CHO
NO2
OH
O
flow rate:
6 or 9
5 µL min-1
SiO
3
N
H
2
N
H
NH
2
2
+
2
Toluene
NO
2
32 min (R1)
residence time:
34 min (R2)
ꢀ1
f
Entry Reactor (Cat.) Aldehyde (c [M]) Ketone (c [M]) Temperatureb (°C) Conversionc (%) Productivityd (mmol hꢀ1 mmolcat
)
dr anti/syne eeanti (%)
1
2
3
4
5
6
7
R1 (6)
R1 (6)
R1 (6)
R1 (6)
R1 (6)
R1 (6)h
R2 (9)
0.22
0.44
0.22
0.22
0.22
0.22
0.22
0.66
0.22
4.8
0.66
0.66
0.66
0.66
25
25
25
0g
50
70
25
60
18
88
38
82
>95
50
0.43
0.13
0.64
0.27
0.59
4:1
3:1
5:1
5:1
4:1
2:1
2:1
78
77
76
82
78
72
40
—
—
a
b
c
See note 15 for a description of the experimental setup.
All temperatures were measured by a thermometer placed inside the thermostated unit containing the microreactor.
Instant conversion as established by 1H NMR analysis of the eluate after 2 h reaction time.
d
e
f
Productivities are measured in mmolproduct hꢀ1 mmolcatalystꢀ1
Estimated by 1H NMR analysis of crude reaction mixtures.
Determined by chiral HPLC analysis.
.
g
h
Microreactor placed in a ice-bath.
Temperature determined a partial degradation of supported catalyst (see main text for discussion).

A. Massi et al. / Tetrahedron Letters 52 (2011) 619–622
621
of the second run are shown), whereas a substantial maintenance
of efficiency (yield and stereoselectivity) was detected in toluene
(entry 6). This evidence agrees with previous observations by Arm-
strong, Blackmond and their co-workers on the solvent/additive ef-
fect in the irreversible deactivation via decarboxylation of proline
or proline-like catalysts in the presence of electron-deficient aro-
matic aldehydes.14 Indeed, when the integrity of recycled 6 (entry
2, second run) was checked by FT-IR analysis, a much lower inten-
sity of the carbonyl band (1641 cmꢀ1) was observed. In a parallel
solvent screening, toluene resulted to be the best performing for
the ionic catalyst 9 as well (entry 13), activity and recyclability
of 9 being comparable to those previously detected for polysty-
rene-supported analogs.11 Control reactions were also carried out
in toluene in the presence of the 1-hexene-capped thiol-silica 10
(entry 7) and sulfonic acid silica 7 (entry 14). These experiments
demonstrated the absence of background conversion in the reac-
tion catalyzed by the covalently proline-functionalized silica 6
and highlighted the detrimental effect on stereoselectivity in case
of incidental amine leaching from ionic catalyst 9.
Continuous-flow experiments were then performed by means
of a micro-HPLC suitably adapted for this study with minimized
extra-column volumes. Reactors R1 and R2 were prepared by fill-
ing (packing by gravity) stainless steel columns (50 mm length,
2.1 mm diameter) with silicas 6 and 9, respectively (Table 2).15
The hold-up (dead) volumes (V0) of reactors R1 and R2 were deter-
mined by pycnometry. Residence times were calculated by divid-
ing V0 by the flow rate. A packed cartridge of commercially
available triamine-functionalized silica gel was placed down-
stream the reactors to selectively remove unreacted p-nitro benz-
aldehyde and thus facilitate isolation of the aldol product. The
study on continuous-flow model aldol reaction by using reactor
R1 started with the optimization of flow rate and aldehyde concen-
tration. After some experimentations, the optimal compromise be-
tween aldehyde solubility in toluene and conversion efficiency was
found by pumping a solution of aldehyde (0.22 M) and cyclohexa-
none (0.66 M) at 5 l
L minꢀ1 (residence time: 32 min). Gratifyingly,
the stereoselectivity of the batch process (Table 1, entry 6) was
replicated (dr 4:1; 78% eeanti, Table 2, entry 1) and maintained con-
stant during the entire flow process (overall time 4 h; Fig. 1).
The working concentrations were chosen by considering the
retention behavior of cyclohexanone and p-nitro benzaldehyde in
R1. Under steady-state conditions, the greater affinity of p-nitro
benzaldehyde for silica 6 (chromatographic retention factor k0 = 1
vs k0 = 0.45 for the ketone) causes the preferential occupancy of
the packing material by this component, thus limiting the forma-
tion of the reactive enamine intermediate and lowering the con-
version efficiency. This hypothesis seemed to be supported by
experiments conducted at different ketone/aldehyde ratios (entries
2 and 3) and by an in depth analysis of the conversion versus pro-
cess time profile (Fig. 1).
This shows a higher conversion (>95%) for the fraction eluted
immediately after the hold-up time (32 min) compared to the stea-
dy-state conversion (60%),16 thus confirming that enamine forma-
tion happens at maximum level when the less retained
cyclohexanone reacts with the bare immobilized proline (first
eluted fraction).17 The effect of temperature on process efficiency
was next investigated. A slight improvement of stereoselectivity
(dr 5:1; 82% eeanti, entry 4) accompanied by a marked decrease
of conversion was observed at 0 °C. Warming the reactor R1 in
Figure 1. Conversion of the model aldol reaction as a function of time (black lines)
in microreactors R1 (j) and R2 (N). Enantioselectivity of the anti-aldol as a function
of time (gray lines) in microreactors R1 (j) and R2 (N).
Table 3
Optimization of continuous-flow
a
-amination reaction in packed-bed microreactors R1a
HPLC
Cbz pump flow
silica 6
Cbz
N
O
O
N
rate
Cbz
+
H
N
H
N
solvent
H
i-Pr
i-Pr
Temp.
Cbz
Entry
Solvent
Flow rate (
l
L minꢀ1
)
Temperatureb (°C)
Productivityc
eed (%)
1e
2e
3f
Toluene
CH2Cl2
CH3CN
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
25
25
25
25
25
50
75
100
Batch
0
0
0
3.60
3.60
1.80
3.60
3.60
7.20
10.8
13.2
3.33
58
42
38
52
55
55
55
55
52
4e
5e
6e
7e
8g
9h
0
25
25
25
25
0
a
b
c
See note 15 for a description of the experimental setup. R1 fed with 0.22 M DBAD and 0.66 M aldehyde solution in the stated solvent.
Microreactor placed in a ice-bath for processes conducted at 0 °C.
Productivities are measured in mmolproduct hꢀ1 mmolcatalystꢀ1
Determined by chiral HPLC analysis.
.
d
e
f
Instant conversion: >95% (1H NMR analysis).
Instant conversion: 50% (1H NMR analysis).
Instant conversion: 92% (1H NMR analysis).
g
h
Reaction performed with 0.25 mmol of DBAD (0.25 M), 0.75 mmol of aldehyde, and 10 mol % of 6. Full conversion after 3 h.

622
A. Massi et al. / Tetrahedron Letters 52 (2011) 619–622
the HPLC column oven set at 50 °C produced an improvement of
conversion from 60% to 82% without altering the stereoselectivity
of the process (entry 5). Unfortunately, a further increase of tem-
perature (70 °C; entry 6) resulted in a fast (ca. 2.5 h) degradation
of packed-bed material, which occurred very likely through decar-
boxylation of supported proline as indicated by FT-IR analysis of
the recovered packing silica. In a parallel investigation, the long-
term stability of the covalent packed-bed 6 was also considered,
this issue being a key point for the development of effective contin-
uous-flow processes. Gratifyingly, silica 6 did not show any deacti-
vation in terms of productivity and selectivity at ambient
temperature for at least 24 h, whereas a progressive decreasing
yield with maintenance of stereoselectivity was observed after that
time (catalyst fully deactivated after 72 h on stream). Next we fo-
cused our attention on microreactor R2 filled with the ionic silica 9
(entry 7). Degradation of packed-bed catalytic activity took place
under flow conditions within 2 h owing to gradual amine 8 leach-
ing as confirmed by MS analysis of eluate samples. The racemic
background conversion, in fact, became predominant after that
time, thus determining a progressive loss of enantioselectivity of
the process (Fig. 1).
References and notes
1. (a)Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007; (b) Chem. Rev. (List, B. Guest Ed.) 2007, 107, 5413.; (c) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638–4670.
2. (a) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D. In
Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH:
Weinheim, 2008; pp 84–122. Chapter 4.2; (b) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300–
2318; (c) Geyer, K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 15, 2382–2391.
3. (a) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem. Eur. J. 2006, 12, 5972–
5990; (b) El Kadib, A.; Chimenton, R.; Sachse, A.; Fajula, F.; Galarneau, A.; Coq,
B. Angew. Chem., Int. Ed. 2009, 48, 4969–4972; (c) Valera, F. E.; Quaranta, M.;
Moran, A.; Blacker, J.; Armstrong, A.; Cabral, J. T.; Blackmond, D. G. Angew.
Chem., Int. Ed. 2010, 49, 2478–2485.
4. Odedra, A.; Seeberger, P. H. Angew. Chem., Int. Ed. 2009, 48, 2699–2702. For a
critical analysis of this study, see Ref. 3c..
5. Alza, E.; Rodríguez-Escrich, C.; Sayalero, S.; Bastero, A.; Pericàs, M. A. Chem. Eur.
J. 2009, 15, 10167–10172.
6. (a) Nikbin, N.; Watts, P. Org. Process Res. Dev. 2004, 8, 942–944; (b) Phan, N. T.
S.; Brown, D. H.; Styring, P. Green Chem. 2004, 6, 526–532.
7. (a) Lowe, A. B. Polym. Chem. 2010, 1, 17–36; (b) Jonkheijm, P.; Weinrich, D.;
Köhn, M.; Engelkamp, H.; Christianen, P. C. M.; Kuhlmann, J.; Maan, J. C.; Nüsse,
D.; Schroeder, H.; Wacker, R.; Breinbauer, R.; Niemeyer, C. M.; Waldmann, H.
Angew. Chem., Int. Ed. 2008, 47, 4421–4424.
8. Compound 2: [a]D = ꢀ26.6 (c 0.6, CHCl3). Compound 3: [a]D = ꢀ66.3 (c 0.9,
CHCl3).
9. In a similar approach, a styrene functionalized proline derivative was thermally
coupled with mercaptomethyl polystyrene resin: Gruttadauria, M.;
To broaden the scope of the methodology and reach higher lev-
els of productivity, the implementation of the fast proline-cata-
a
Giacalone, F.; Mossuto Marculescu, A.; Riela, S.; Noto, R. Eur. J. Org. Chem.
2007, 4688–4698.
10. Massi, A.; Pandoli, O.; Cavazzini, A.; Del Zoppo, L.; Giovannini, P. P.; Bendazzoli,
C. Italian Patent, Deposit 01. 03. 2010, No. BO2010A000119.
lyzed
a
-amination reaction12b,c of isovaleraldehyde with dibenzyl
azodicarboxylate (DBAD) in microreactor R1 was also investi-
gated.15 After a fast (non exhaustive) solvent screening carried
out under flow conditions (Table 3, entries 1–4), toluene was again
selected as the optimal solvent (entry 1). Full conversion was
11. Luo, S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273–1281.
12. (a) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580–591; (b)
List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657; (c) Bøgevig, A.; Juhl, K.;
Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002,
41, 1790–1793.
13. Under optimized conditions (Table 1, entry 6), the aldol reaction of
cyclohexanone with the electron-rich p-methoxy benzaldehyde gave the
corresponding adduct in lower yield (15%). Hence, the optimization study
was continued with the more reactive p-nitro benzaldehyde acceptor.
14. Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007,
129, 15100–15101.
achieved at 0 °C with a 5-fold faster flow rate (25
previous aldol reaction (entry 1). Quite surprisingly, the enantiose-
lectivity of the flow process (58% ee of the -hydrazino alcohol
l
L minꢀ1) than
a
generated in situ by NaBH4 reduction of the product aldehyde)
was noticeably lower compared to that of similar proline-catalyzed
homogeneous reactions.12b,c Fortunately, conducting the model
a-
15. Description of the experimental setup for the continuous-flow processes. 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), and either reactor R1 or R2 (containing
117 mg and 70 mg of packing material, respectively). In case of aldol reactions,
a glass OmnifitÒ column containing triamine-functionalized silica gel (500 mg,
ꢁ1.3 mmol gꢀ1) was placed downstream the reactor. Continuous-flow model
aldol reaction (Table 2, entry 1). Microreactor R1 was fed with a 0.22 M
aldehyde and 0.66 M ketone solution in toluene and operated for 8 h (under
amination at ambient temperature left the stereoselectivity of the
process almost unchanged (entry 5). On the other hand, complete
conversions could be also achieved at 25 °C with higher flow rates
(up to 75 l
L minꢀ1, entries 6 and 7), thus further increasing the
productivity of the flow process (10.8 mmol hꢀ1 molcatꢀ1; ca. three
times greater than the batch process, entry 9).
In conclusion, we have demonstrated here the potential of
packed-bed microreactors filled with covalently silica supported
proline to produce chiral targets under flow regime in a stereose-
lective manner and with a facilitated post reaction phase (workup
and purification). Actually, these features along with direct scala-
bility are important prerequisites of a synthetic process for its
industrial applications. The proof-of-principle results reported
herein are currently being extended to proline-like organocatalysts
with extended lifecycle and to other organocatalytic processes.
steady state conditions) at 5
to give the pure adduct (78 mg, 60%) as
diastereoisomers (eeanti = 78%). Chiral HPLC analysis: Lux-1 Cellulose (hexanes/
i-PrOH 90:10 v/v, 200 kmax = 258 nm); tR (major) = 10.9 min; tR
L minꢀ1
(minor) = 14.6. Continuous-flow model -amination reaction (Table 3, entry 7).
Microreactor R1 was fed with a 0.22 M DBAD and 0.66 M aldehyde solution in
toluene and operated for 8 h (under steady state conditions) at 75 L/min
l
L/min. The collected solution was concentrated
a
4:1 mixture of anti and syn
l
;
a
l
(25 °C). The collected solution was kept at 0 °C and then diluted with EtOH
(40 mL). To the resulting stirred, cooled (0 °C) mixture was then added NaBH4
(629 mg, 16.6 mmol) in one portion. The mixture was stirred at 0 °C for an
additional 30 min, then diluted with saturated aqueous NH4Cl (25 mL), filtered
over a pad of Celite, and extracted with Et2O (2 ꢂ 125 mL). The combined
organic phases were dried (Na2SO4), concentrated, and eluted from a column of
Acknowledgments
silica gel with 4:1 cyclohexane–AcOEt to give the target
a-hydrazino alcohol
(2.75 g, 90%, ee = 55%). Chiral HPLC analysis: Lux-1 Cellulose (hexanes/i-PrOH
L minꢀ1
;
kmax = 210 nm); tR (major) = 9.9 min; tR
We gratefully acknowledge the Italian Ministry of University
and Scientific Research (Progetto FIRB Chem-Profarma-Net Grant
RBPR05NWWC 008) for financial supports. Thanks are also given
to Professor F. Dondi for useful discussion and support, to Mr. P.
Formaglio for NMR experiments and to Professor A. Marchi and
Mr. M. Fratta for elemental analyses. We also acknowledge Eka
Chemicals for the kind donation of Kromasil silica gel.
90:10 v/v, 200
(minor) = 10.9.
l
16. For all packed-bed microreactors prepared the steady-state was reached
within 60 min process time.
17. The prior coverage of silica surface by flowing
a 0.66 M solution of
cyclohexanone before feeding R1 under optimized conditions (see note 15)
produced, in steady state regime, the same results of entry 1 (Table 2).