An Efficient and Waste-Minimized One-Pot Procedure for the Preparation of N-Boc-γ-amino Alcohols Starting from α,β-Unsaturated Ketones in Flow

Article abstract of DOI:10.1021/acs.oprd.5b00163

We report herein a clean multistep flow process that starting from α,β-unsaturated ketones 1 allows the preparation of N-Boc-γ-amino alcohols 3 in high yields. The final products have been isolated in pure form without any additional purification step. Th

Full text of DOI:10.1021/acs.oprd.5b00163

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An efficient and waste minimized oneꢀpot procedure
for the preparation of γꢀamino alcohols starting from
α,βꢀunsaturated ketones in flow
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Eleonora Ballerinia, Raimondo Maggib, Ferdinando Pizzoa, Oriana Piermattia, Dmitri
Gelman*c, and Luigi Vaccaro*a
a
Laboratory of Green Synthetic Organic Chemistry, CEMIN – Dipartimento di Chimica,
Biologia e Biotecnologie, Università di Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy; Fax:
+39 075 5855560; Tel: +39 075 5855541; Eꢀmail: luigi.vaccaro@unipg.it.
b“Clean Synthetic Methodology Group”, Dipartimento di Chimica dell’Università, Parco Area
delle Scienze 17A, Iꢀ43124 Parma, Italy
cInstitute of Chemistry, The Hebrew University, Edmond Safra Campus, Givat Ram, 91904
Jerusalem (Israel).
KEYWORDS. γꢀamino alcohols, α,βꢀunsatuirated ketones, multistep synthesis, wasteꢀ
minimization, flow conditions
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ABSTRACT: We report herein a clean multistep flow process that starting from α,βꢀunsaturated
ketones 1 allows the preparation of NꢀBocꢀγꢀamino alcohols 3 in high yields. The final products
have been isolated in pure form without any additional purification step. The cleanness and the
environmental efficiency achieved by using our protocol is proven by the calculation of green
metrics such as Eꢀfactors.
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INTRODUCTION
The term green/sustainable chemistry has been often used in several areas to introduce the
efforts of academic and industrial scientists towards the development of new tools to access a
cleaner and efficient chemical production by also considering the corresponding environmental
impact.1,2
In this scenario, it is evident the strategic role of scientists from both industries and research
institutions who should be able not only to develop new safer chemical tools but also to reach
common economic interests keeping the production highly efficient and environmentally
sustainable.
Great attention must be paid to waste production and accordingly, to the use of green metrics
that allow to better evaluate all the features of a synthetic procedure.3 Among these, one of the
simplest and very effective measurement consists in the Environmental factor (Eꢀfactor)
introduced by Sheldon.4 This simple value is the ratio between the kilograms of waste produced
per kilograms of desired product and gives the immediate idea of how an elegant and complex
chemistry may results in a highly environmentally costly process. According to Andraos work,
this factor can be further divided into its components for a better evaluation of the results.3a, d
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In modern chemical production of fine chemicals, technological advances may be truly helpful
to define a more productive synthetic route and to combine both the need for a chemical and
economic efficiency. In this context, definition of chemical processes in flow represents an
important tool for the replacement of classic reactor schemes based on stirring and open novel
routes towards the identification of modern protocols to develop highly efficient chemistry.5
Flow conditions may also offer a safer alternative to batch processes whenever
dangerous/unstable intermediates/reagents are involved in a chemical process. Besides, the
undoubted innovative contribution of flow chemistry for the definition of novel reaction
windows, the adoption of flow may also be of great advantage for designing a novel approach to
batchꢀlike reactors that allows a different and unique chemical outcomes to be reached.5f Flow
conditions may also be a safe alternative to batch processes whenever dangerous/unstable
intermediates/reagents are involved in a chemical process.
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In this contribution, we report the results obtained by applying our approach and by exploiting
flow mixing for the definition of a clean and sustainable protocol for the preparation of γꢀamino
alcohols, known as valuable fine chemicals.
γꢀAmino alcohols are interesting compounds because they are common motifs in many natural
products and biologically active molecules and are precursors of βꢀamino acids, βꢀlactams and
pyrrolidines.6 They also are useful as chiral ligands and auxiliaries.7
Racemic γꢀamino alcohols have been synthesized by reductions of βꢀamino ketones8 or βꢀ
hydroxy imines and oximes,9 by the addition of organometallic reagents to βꢀamino aldehydes
and ketones,10 and by borylationꢀreductionꢀoxidation of unsaturated imines.11
A large number of target molecules, including βꢀamino acids, γꢀamino alcohols,
pharmaceuticals and natural products,12 have been synthesized starting from βꢀamino carbonyl
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compounds.13 These versatile intermediates can be prepared by the conjugate addition of a Nꢀ
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ꢀ
nucleophile (e.g. N3 ) to α,βꢀunsaturated ketones and an useful method for the selective
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introduction of a primary amino group is represented by the addition of the azido ion and its
subsequent reduction.14
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Within the context of our research devoted to the development of ecoꢀfriendly protocols based
on the use of supported organocatalysts15 and the use of safer reaction media such as water16 and
solventꢀfree conditions (SolFC),17,18 we have previously reported two alternative protocols for
the βꢀazidation of α,βꢀunsaturated ketones 1 based on the use of recoverable Amberlite IRA900F
as catalyst under SolFC18 and of recoverable PSꢀDABCOF2 as catalyst in water.15h The proposed
protocols allowed the preparation of βꢀazido ketones 2 with the minimal production of waste
(low Eꢀfactor).
In addition, to further manipulate intermediates βꢀazido ketones 2, we have defined a
procedure for the oneꢀpot reduction of the azido group that could allow the multistep oneꢀpot
preparation of βꢀamino ketones. By exploiting the use of batchꢀlike flow mixing reactors, it has
been possible to optimize the azido group reduction of 2 and concomitant amino group
protection with the use of Pd/Al2O3 (5 mol%) and an equimolar amount of HCOOH as reducing
system in the presence of 1 equiv. of Boc2O as protective agent. In this manner, a multistep flow
mixed reactor system, has been set to combine the βꢀazidation and azido group reduction steps in
aqueous medium to prepare NꢀBocꢀγꢀamino ketones.15h,19
However, this approach is useful for reducing the azido group in βꢀazido ketones whereas does
not provide a suitable method for accessing γꢀamino alcohols 3 starting from unsaturated ketones
1, by the concomitant reduction of both azidoꢀ and ketoꢀgroups. For this reason, we directed our
attention to other reductive systems able to reduce both functionalities of βꢀazido ketones 2.
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We selected CoCl2·6H2O/NaBH4 as a reductive system that has successfully been used for the
first time by our research group for the chemoselective reduction of azides in water.20, 21 Critical
issues on its use on larger scale is related to the very fast reaction of borohydrides which
decompose to form hydrogen when in contact with a metal salt or its corresponding metal boride
producing high volumes of gas in very short time.21 This makes its use in flow very challenging
although interesting.
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As a continuation of our interest in the use of flow approach to reduce waste, in this
contribution we report our results on the use of CoCl2·6H2O/NaBH4 as an efficient reductive
system usable in flow to promote the reduction of both azidoꢀ and ketoꢀgroups of βꢀazido
ketones 2. At this aim, we have investigated the definition of a wasteꢀminimized and multistep
flow procedure for the preparation of NꢀBocꢀγꢀamino alcohols 3 based on the βꢀazidation of α,βꢀ
unsaturated ketones 1 and subsequent reduction/protection step of βꢀazido ketones 2 (Scheme 1).
Scheme 1. Multistep procedure for NꢀBocꢀγꢀamino alcohols synthesis.
RESULTS AND DISCUSSION
βꢀAzido ketones 2 were synthesized starting from α,βꢀunsaturated ketones 1, in agreement to
our previously reported procedure18 that used trimethylsilylazide (TMSN3) as source of azido
ions and Amberlite IRA900F (AmbꢀF) as catalyst in SolFC (Scheme 2).
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TMSN3 1.1-3 eq
Amb-F 0.1-0.5 eq
O
O
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6
7
N3
R1
SolFC, 30-60°C
R2
R1
R2
2
1
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Scheme 2. βꢀazidation of α,βꢀunsaturated ketones 1.
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Preliminary studies were directed to the selection of the best catalyst as well as reaction
conditions for the reduction of βꢀazido ketone (2a) and concomitant in situ selective NꢀBoc
protection of the resulting amino group.
In Table 1 are illustrated the results obtained for the reduction of 4ꢀazidoheptanꢀ2ꢀone (2a),
chosen as a representative compound.
Some metal salts such as CuCl2 and NiCl2 were not effective in achieving the conversion of βꢀ
azido ketones into the corresponding NꢀBocꢀγꢀamino alcohols 3.
CoCl2·6H2O/NaBH4, effectively promoted the transformation also in the presence of different
reaction media, such as water, ethanol, water/methanol or methanol, which occurs at room
temperature and in short times.
In the presence of this catalytic system, the reduction proceeded well with 3 and also with 2.5
equivalents (Table 1, entries 7 and 8) of NaBH4.
It should be noticed that, cobalt(II) salts when treated with NaBH4 in protic solvent uniformly
produce the corresponding borides, which are the actual catalytic active species. Different
cobalt(II) salts lead to different types of borides and generally, chlorides allow to prepare the
20, 21
most effective borides for hydrogen production.
When CoCl2 is treated with NaBH4, in
EtOH or MeOH for 10 min, a finely dispersed Co(B) is formed. This compound is an airꢀstable
black solid that can be easily isolated by filtration. Co(B) formula is not precisely defined and it
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is known that boron is present at different oxidation states.21 (Caution: Co(B) becomes
pyrophoric but only if dried under vacuum21).
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From these data, we then investigated the possibility of a a multistep protocol for the synthesis
of NꢀBocꢀγꢀamino alcohols 3aꢀg starting from α,βꢀunsaturated ketones 1aꢀg focusing on the
amount of organic solvent needed to isolate the final products in order to minimize waste.
We have directed our attention to the use of flow mixing as alternative to classic mechanical
stirring and as an effective approach for the optimal recovery and reuse of heterogeneous
catalysts while preserving their chemical and physical stability and also their chemical
efficiency.
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Table 1. Screening of the catalyst and medium in the reduction reaction of 2a.
Boc2O (1 equiv)
NaBH4 (3 equiv)
OH
NHBoc
O
N3
r.t., 20'
2a
3a
Entry
Catalyst (10 mol%) Mediuma
Yield (%)
1
CuCl2·2H2O
NiCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
CoCl2·6H2O
H2O
H2O
H2O
mixb
mix
90
2
3
4
H2O/MeOHc
89
5
EtOH
92
6
MeOH
91
7d
8d
EtOH
90
MeOH
90
a1M; bcomplex mixture of products; cH2O/MeOH 2:1;d2.5 equivalent of NaBH4;
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In our process, a major issue that makes difficult the definition of a flow procedure is related to
very fast production of gas (H2) when a NaBH4 solution gets in contact with Co(B). In addition,
clogging of the system is experienced due to the inevitable precipitation of inorganic salts during
the NaBH4 decomposition to hydrogen. Direct translation into flow conditions of the results
obtained in Table 1, were unsuccessful.
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Therefore, we have extended the study to different reducing agents which could allow to
perform the reaction in flow and avoid clogging of the reactor.
We have performed the flow reduction of 4ꢀazidoheptanꢀ2ꢀone (2a) in the presence of reducing
agents such as sodium cyanoborohydride (NaBH3CN), tetrabutylammonium borohydride
([CH3(CH2)3]4NBH4) and tetramethylammonium borohydride ((CH3)4NBH4). The results are
reported in Table 2.
With all the hydrides used the process proceeded with total conversion to the desired product
and no precipitate was formed during the reaction.
At the end of the reduction step, only when (CH3)4NBH4 was used as hydride, the product
could be efficiently isolated from the ethanolic reaction mixture by heptane extraction.
In addition, we attempted to reduce the equivalents of hydride used (Table 2, entries 4ꢀ7). We
have found that the reduction process of 2a in EtOH using 10 mol % of CoCl2·6H2O in the
presence of 2.2 equivalent of (CH3)4NBH4 and 1.0 equivalent of Boc2O allowed to obtain the
desired NꢀBocꢀγꢀaminoalcohol 3a in 84% yield (Table 2, entry 6). To deal with gas evolution,
optimal results were obtained by setting a purge valve at 2.5 atm to regulate the reactor pressure.
Starting from these optimized conditions, we defined the oneꢀpot multistep flow protocol for the
βꢀazidation/hydrideꢀreduction of α,βꢀunsaturated ketones 1. The reactor scheme set for the
preparation of pure NꢀBocꢀγꢀamino alcohols 3 in high yield is depicted in Fig. 1. It is worthy to
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highlight again that the reactor operating in flow mixing also allows the preservation of the
integrity (chemical and physical) of the solid catalysts (AmbꢀF and Co(B)), making their
recovery and reuse straightforward and efficient.
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Table 2. Flowꢀreduction of 4ꢀazidoheptanꢀ2ꢀone (2a) with different hydrides.
(10 mol%)
CoCl2
OH
NHBoc
O
N3
Boc2O (1 equiv)
borohydryde
r.t., 30'
2a
3a
Entrya Hydride (equiv)
Yield (%)
1
2
3
4
5
6
NaBH3CN (2.5)
85
85
85
85
83
84b
[(CH3(CH2)3]4NBH4 (2.5)
(CH3)4NBH4 (2.5)
(CH3)4NBH4 (2.5)
(CH3)4NBH4 (2.4)
(CH3)4NBH4 (2.2)
7
(CH3)4NBH4 (2.1)
mixb
aReaction conditions:EtOH, r.t., 30’; b in the absence of Co(B) 20% unreacted starting material
2a.
The flow reactor has been assembled by setting up two different lowꢀpressure glass columns
that have been labelled as AmbꢀF and Co(B) in Fig. 1. On a representative scale of 50 mmol,
reactant 1 and TMSN3 (1.1ꢀ3.0 equiv.) were charged into a third column used as a reservoir. The
equipment was connected, by using the appropriate valves, to a pump and installed into a
thermostated box (not shown in Fig. 1 for clarity).
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Figure 1. Reactor scheme for the synthesis of NꢀBocꢀγꢀaminoalcohols 3.
◦
After setting the temperature (30ꢀ60 C, according to βꢀazidation step requirements of
substrates 1aꢀg) the reactants were pumped continuously through the AmbꢀF catalyst at 1 mL
minꢀ1 flow rate for the time necessary to complete the βꢀazidation step. After this time the
air/solvent valve was opened and the pump was set to work at 5 mL minꢀ1 in order to transfer the
product 2 into the reservoir and empty the AmbꢀF column. To completely wash the AmbꢀF
column, some ethanol (0.1 mL/mmol) was pumped from the air/solvent valve and collected in
the reservoir as well.
Melted Boc2O (1 equiv.) was added into the reservoir containing intermediate azido ketone 2.
At this point, (CH3)4NBH4 was charged as a solution of tetramethylammonium borohydride in
ethanol. Two pumps were run in order to simultaneously direct the two ethanol solutions (one of
the βꢀazido ketone 2 and Boc2O and the other of (CH3)4NBH4) through the Co(B) column at 0.5
mL minꢀ1 flow rate for the time necessary to reach complete formation of 3. The pump connected
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to the reservoir was then left to run in order to recover again the overall reaction mixture. Then
additional EtOH was added from the air/solvent valve to wash the catalyst and then collected
into the reservoir; the solution of product in ethanol was transferred in a continuous liquid/liquid
extraction apparatus and product 3 was continuously extracted with immiscible heptane (10 mL)
and after phase separation isolated in pure form and high yields. EtOH and heptane were
recovered by simple distillation. A variety of α,βꢀunsaturated ketones 1aꢀg were successfully
screened to afford the corresponding NꢀBocꢀγꢀamino alcohols 3aꢀg in good to excellent yields.
Table 3 shows the results obtained.
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As expected, 3a and 3b have been obtained in an almost 1:1 syn/anti diasteroisomeric ratio
(Table 3, entries 1 and 2) while in the case of 3g a prevalent formation of the syn product was
observed (Table 3, entry 7). In the case of 1d, 1e and 1f, the cis diaseteroisomers of the
corresponding γꢀamino alcohols 3dꢀf were preferentially formed (Table 3, entries 4ꢀ6) and in the
case of 3f trans isomer could not actually be detected. In the case of 1e, βꢀazidation proceeds
with the formation of a 60:40 trans/cis mixture of βꢀazidoketone 2e subsequent reduction
produced the corresponding isomers (1S,2R,4R)/(1S,2S,4R) in 78/22 ratio and
(1R,2S,4R)/(1R,2R,4R) 98/2 ratio, respectively (Table 3, entry 5).
After the reduction step, Co(B) was washed with a small amount of ethanol; then it was
successfully reused for other four consecutive runs without observing a decrease of its catalytic
efficiency. In fact, according to the flow procedure, the catalysts are safely conserved in their
own glass columns and can be reused without loss in activity for five consecutive runs.
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Table 3. Multistep synthesis synthesis of NꢀBocꢀγꢀaminoalcohols 3aꢀg.
5
6
7
8
CoCl2 6H2O (0.1 equiv)
OH
R1
O
Boc2O (1 equiv)
AmbF-catayzed
azidation
O
(CH3)4NBH4 (2.2 equiv)
BocHN
N3
R1
R2
R2
R1 SolFC, 30-60°C
9
EtOH, r.t., 20'
R2
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2
3
1
Entry
1
Reagent
Product
Diastereoisomeric ratioa Yield (%)b
O
OH
NHBoc
53:47
84
3a
1a
OH
NHBoc
O
2
3
56:44
ꢀ
90
85
(CH2)4
(CH2)4
1b
3b
3c
OH
O
BocHN
OH
1c
O
87:13c
84
81
4
5
NHBoc
1d
3d
78:22ꢀ98:2d
OH
O
NHBoc
1e
3e
OH
O
>99:1e
70:30
85
82
6
7
NHBoc
1f
3f
O
OH
NHBoc
3g
1g
a
if not otherwise indicated syn/anti or cis/trans ratios were determined by GCꢀMS
analyses; isolated yield of the pure products; cis/trans ratio: determined by H
NMR analysis; From the reduction of the 60:40 trans/cis mixture βꢀazidoketone 2e
b
c
1
d
the corresponding isomers (1S,2R,4R)/(1S,2S,4R) in 78/22 ratio and
(1R,2S,4R)/(1R,2R,4R) 98/2 ratio, respectively; e Ref. 22.
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It should be noticed that a comparison with a larger scale protocol in batch using classic
mechanical stirring cannot be properly conducted, because on 10ꢀ50 mmol scale mechanical
stirring causes the crunching of the catalytic systems both in the case of organic polymer AmbꢀF
and inorganic Co(B). The finely dispersed catalysts cannot be easily filtered and then completely
recovered even since the first reuse.
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The reactions in flow have been performed on 50 mmol scale and it is noteworthy that this is
only a minimal representative scale, in fact on higher scale, the flow protocol can be intensified
and is even more efficient in terms of waste because the organic solvent needed for cleaning the
reactors system (columns, pumps connectors and tubes) and recovering the product can be
proportionally reduced. The procedure can be easily scaledꢀup without significant changes in the
equipment except the size of the columns containing the reactants and catalysts. Reproducibility
of the results at different scales is closely dependant on gas evolution and exothermic
phenomena. Our results have been obtained at a 2.5 atm pressure of hydrogen and measuring the
actual temperature of the catalysts columns to regulate the heating of the thermostated box.
Finally, after completing an optimization, cleanness and efficiency of the process must be
carefully evaluated by using appropriate metrics able to measure the mass of all the reagents
(including solvent at all stages) used.
We have calculated several representative parameters of green metrics as percent overall yield,
overall atom economy (AE),24 overall Eꢀfactor4 and its components and process mass intensity
(PMI).3d Data are reported in the Supporting Information. The quantitative influence of the
recovery of the solvents used for the reaction and the workꢀup (ethanol and heptane) on the Eꢀ
factor values is clearly visible. Overall Eꢀfactor values for the different substrates ranged from
2.02 to 6.58 (see Supporting Information for details).
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The flow approach, allowed to use the minimal amount of organic solvent to recover the pure
final products and consequently to reduce the reaction waste resulting in low values of Eꢀaux and
Eꢀtotal. A tentative comparison of our synthetic strategy to those of the already published
protocols for the synthesis of racemic γꢀaminoalcohols 3 has been reported in Supporting
Information.
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CONCLUSIONS
In conclusion, we have reported an efficient and clean multistep process performed by aa flow
reactor that, starting from α,βꢀunsaturated ketones 1, allows NꢀBocꢀγꢀamino alcohols 3 to be
produced in high yields. The final products have been isolated in pure form without any
additional purification step. The easy availability of the reducing system and the possibility to
recycle the catalyst make this procedure attractive and advantageous. Furthermore, it is the first
time that the system CoCl2·6H2O/NMe4BH4is used to catalyze the reactions in flow conditions..
The combination of SolFC for the first reaction step (βꢀazidation), highly concentrated
conditions for the second reaction step (azido group reduction) and recoverable solid catalysts,
together with the flow mixing technology, represents interesting practical examples of how
promising is flow approach for the minimization of the environmental cost of organic syntheses.
EXPERIMENTAL SECTION
Unless otherwise stated, all chemicals were purchased and used without any further purification.
GC analyses were performed by using HewlettꢀPackard HP 5890A equipped with a capillary
column DBꢀ35MS (30 m, 0.53 mm), a FID detector and hydrogen as gas carrier. GCꢀEIMS
analyses were carried out by using a HewlettꢀPackard HP 6890N Network GC system/5975
Mass Selective Detector equipped with an electron impact ionizer at 70 eV.
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NꢀBocꢀ βꢀaminoketones 3a, 3b, 3c, 3d, 3e and 3g are new compounds while 3f is a known
compound.23
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Characterization data are reported in the Electronic Supplementary Information (ESI).
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Representative batch procedure for βꢀazidation and subsequent reduction of α,βꢀ
unsaturated ketones 1aꢀg.
In a screwꢀcapped vial equipped with a magnetic stirrer, AmberlistꢀF (10 mol%, 0.026 g), (3E)ꢀ
heptꢀ3ꢀenꢀ2ꢀone (1a) (1 mmol, 0.112 g) and TMSN3 (1.1 mmol, 0.146 mL) were consecutively
°
added. The resulting mixture was left under stirring at 60 C for 2.5 h to reach the complete
conversion to 4ꢀazidoheptanꢀ2ꢀone (2a). Then ethyl acetate was added and the catalyst was
recovered by filtration and washed with ethyl acetate. The solvent was removed under vacuum to
furnish 4ꢀazidoheptanꢀ2ꢀone (2a). Then, in a screwꢀcapped vial equipped with a magnetic stirrer,
CoCl2·6H2O/NaBH4 (CoCl2·6H2O, 0.049 g, 0.09 mmol, NaBH4, 0.0068 g, 0.18 mmol), ethanol
(0.9 mL), 4ꢀazidoheptanꢀ2ꢀone (2a) and Boc2O (0.196 g, 0.9 mmol) were consecutively added;
then NaBH4 (0.085 g, 2.25 mmol) was slowly added and the resulting mixture was left under
stirring at room temperature. After 30 min, the catalyst was recovered by filtration and washed
with ethanol (0.5 mL). Water (1 mL) was added to the reaction mixture and then AcOEt (7 mL)
was added to extract the pure product. The organic phase was dried with Na2SO4 (2.5 g) and the
solvent was removed under vacuum to furnish tertꢀbutylꢀ2ꢀhydroxyheptanꢀ4ꢀylꢀcarbamate (3a)
in 84% yield (0.194 g, 0.84 mmol).
Representative flow procedure for multistep βꢀazidation/reduction of α,βꢀunsaturated
ketones 1aꢀg.
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(3E)ꢀHeptꢀ3ꢀenꢀ2ꢀone (1a) (50 mmol, 5.608 g) and TMSN3 (55 mmol, 7.3 mL) were charged
into a glass column functioning as a reservoir.
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AmberlistꢀF (10 mol%, 1.316 g), suitably dispersed in 1 mm diameter solid glass beads, was
charged on a glass column; the equipment was installed into a thermostated box and connected,
by using the appropriate valves, to a pump. The reaction mixture was continuously pumped (flow
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rate 1.0 ml/min) through the catalyst column at 60 C for 2.5 h to reach the complete conversion
to 4ꢀazidoheptanꢀ2ꢀone (2a). At this stage, the pump was left to run in order to recover the
reaction mixture into the reservoir. To completely recover the product and clean the reactor,
ethanol (2 x 2.5 mL at 1.5 mLminꢀ1) was cyclically pumped through the catalyst column for 10
min (each fraction) and then collected into the reservoir. Two columns labelled as Co2B and
(CH3)4NBH4 Were prepared.The first column was charged with previously prepared cobalt
boride from CoCl2·6H2O (10 mol %, 1.19 g) and NaBH4 (2 equiv. with respect to CoCl2·6H2O,
0.378 g), suitably dispersed in 1 mm diameter solid glass beads; the second one was charged
with (CH3)4NBH4 (110 mmol, 9.79 g) dissolved in EtOH (10 mL) and, by using the appropriate
valves, was connected to a syringe pump. Melted Boc2O (50 mmol, 10.91 g) was pumped into
the reservoir. The two pumps were run in order to continuously push the solution of βꢀazido
ketone and Boc2O and the solution of hydride through the catalyst column at 0.5 mL minꢀ1 flow
rate for the time necessary (20 min) for the complete conversion to tertꢀbutylꢀ2ꢀhydroxyheptanꢀ
4ꢀylꢀcarbamate (3a). At this stage, the pump was left to run in order to recover the reaction
mixture into the reservoir. Then EtOH (2 x 2.5 mL at 1.5 mLminꢀ1) was added from the
air/solvent valve to wash the catalyst and then was collected into the reservoir.
The solution of product in ethanol was transferred in a continuous liquid/liquid extraction
apparatus and the product was continuously extracted with heptanee (10 mL) to afford pure 3a in
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84% yield (42 mmol, 9.702 g). With this procedure the catalyst was left inside the reactor and
was successfully reused for five consecutive runs with the achieving identical results.
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ASSOCIATED CONTENT
Supporting Information. Full characterization of compounds 3aꢀg and copies of the 1H and 13C
NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Luigi Vaccaro CEMIN ꢀ Dipartimento di Chimica, Biologia e Biotecnologie, Università di
Perugia Via Elce di Sotto, 8; Perugia, Italia. Fax: +39 075 5855560; Tel: +39 075 5855541; Eꢀ
mail: luigi.vaccaro@unipg.it.
ACKNOWLEDGEMENTS
We gratefully acknowledge the Università degli Studi di Perugia, and the Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR) for financial support.
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An efficient and waste minimized oneꢀpot procedure for the preparation of γꢀamino
alcohols starting from α,βꢀunsaturated ketones in flow
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Eleonora Ballerinia, Raimondo Maggib, Ferdinando Pizzoa, Oriana Piermattia, Dmitri Gelman*c,
and Luigi Vaccaro*a
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A clean multistep flow process that starting from α,βꢀunsaturated ketones allows the preparation
of NꢀBocꢀγꢀamino alcohols 3 in high yields and with a significant waste minimization proven by
the calculation of green metrics
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