A two-step continuous-flow synthesis of n-(2-aminoethyl)acylamides through ring-opening/hydrogenation of oxazolines

Article abstract of DOI:10.1002/chem.201102772

Harnessing hydrazoic acid in flow! 2-Oxazolines can be ring-opened in a very efficient manner by treatment with in situ generated hydrazoic acid. Despite the toxic and explosive nature of hydrazoic acid, this process can be conducted safely in a continuou

Full text of DOI:10.1002/chem.201102772

DOI: 10.1002/chem.201102772
A Two-Step Continuous-Flow Synthesis of N-(2-Aminoethyl)acylamides
through Ring-Opening/Hydrogenation of Oxazolines
Bernhard Gutmann,[a] Jean-Paul Roduit,[b] Dominique Roberge,*[b] and
C. Oliver Kappe*[a]
2-Oxazolines are a readily available class of heterocycles
that are easily generated from aminoalcohols and carboxylic
acids, or through alternative synthetic procedures starting
from alkenes or epoxides as substrates.[1,2] The oxazoline
moiety is very resistant against a range of reagents, such as
nucleophiles, bases, or radicals, and is, therefore, heavily
used as protecting and/or directing group, or as a powerful
source of chirality in asymmetric synthesis.[1–3] Under acidic
conditions, however, oxazolines are susceptible to nucleo-
philic ring-opening. Thus, the SN2 attack of a nucleophile at
the ether carbon C5 of the ring leads to b-substituted car-
boxamides as products.[1,2,4–7] This reaction is extensively em-
ployed in glycoside synthesis, whereby an anomeric oxazo-
line is used as the glycopyranosyl donor.[1,2,4]
Scheme 1. Two-step synthesis of selectively monoacylated 1,2-diamines
starting from 2-oxazolines.
and, hence, these batch protocols are hardly suitable for re-
actions on scale. Therefore, alternative strategies that avoid
the use of TMSN3 to introduce the N-(2-aminoethyl)acyl-
Importantly, the ring-opening of oxazolines with an azide
source is a key step in the synthesis of neuraminic acid ana-
logues (e.g., neuraminidase inhibitors, such as Zanamivir
and Oseltamivir) and may attain equal importance for the
preparation of other pharmaceutically active compounds
that contain the N-(2-aminoethyl)acylamide scaffold.[5,6]
Here, the oxazoline 1 is first ring-opened with the azide ion
as nucleophile, and the ensuing azide 2 is subsequently re-
duced to the monoacylated 1,2-diamine 3 (Scheme 1). The
azide source is usually TMSN3 in a high-boiling alcohol,
such as tBuOH.[6,7] For example, the corresponding oxazo-
line-ring-opening reaction with TMSN3 in tBuOH to intro-
duce the N-(2-aminoethyl)acylamide moiety in the neurami-
nidase inhibitor Zanamivir (Scheme 1) was performed at
808C for 10.5 h on up to 600 g scale.[6c] It should be noted
that TMSN3 rapidly releases volatile hydrazoic acid (HN3,
b.p. 37 8C) in the presence of protic solvents, such as alco-
hols.[8b] HN3 is an extremely explosive and toxic material
AHCTUNGTRENNUNG
amide moiety have been developed.[8]
Recently, we have described a general and scalable
method for the synthesis of 5-substituted-1H-tetrazoles
through cycloaddition of organic nitriles with HN3 by using
continuous-flow technology.[9] Key to this protocol is the in
situ generation of HN3 from an aqueous solution of NaN3
and AcOH inside a microreactor environment by using a
two-feed concept. Driven by the ever increasing demand for
cost-effective and safe chemical processes, the interest in
continuous-flow and microreactor technology in the fine
chemical industry increased tremendously in recent
years.[10,11] A continuous-flow approach generally allows
more drastic reaction conditions (e.g., high temperatures/
pressures) to be used, even when hazardous reagents or in-
termediates are involved.[12] Heat and mass transfer is very
fast at the scales used in flow systems (channel or capillary
diameters of ꢀ50–1000 mm), and the volumes processed at
any time are kept very small.[10–13] Synthetic intermediates
can be generated and consumed in situ in a closed system
by combining multiple reagent streams, which eliminates the
need to handle or store toxic, reactive, or explosive inter-
mediates.[14] A further important advantage of microreaction
technology is the ease with which reaction conditions can be
scaled to production scale capacities, for example, through
the operation of multiple systems in parallel or related strat-
egies.[13]
[a] B. Gutmann, Prof. Dr. C. O. Kappe
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and Institute of Chemistry
Karl-Franzens-University Graz
Heinrichstrasse 28, A-8010 Graz (Austria)
Fax : (+43) 316-380-9840
E-mail: oliver.kappe@uni-graz.at
[b] Dr. J.-P. Roduit, Dr. D. Roberge
Microreactor Technology, Lonza AG
CH-3930 Visp (Switzerland)
As an extension of our earlier HN3 microreactor work,[9]
we herein report the ring-opening of various 2-oxazolines 1
to the corresponding b-azido carboxamides 2 with in situ
E-mail: dominique.roberge@lonza.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102772.
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Chem. Eur. J. 2011, 17, 13146 – 13150

COMMUNICATION
generated HN3 under continuous-flow conditions.[14] In con-
trast to our previous strategy, HN3 is now generated inside
the microreactor environment by solvolysis of TMSN3 with
MeOH and consumed inside the heated-coil reactor by a
SN2 ring-opening reaction with the oxazoline heterocycles.
TMSN3 was the reagent of choice for this reaction, in partic-
ular because it is highly soluble in a variety of organic sol-
vents. The effluent product mixture can be directly subject-
ed to hydrogenation in a continuous-flow-hydrogenation
device without the need to isolate and purify the intermedi-
ate azides 2. Any excess of HN3 is destroyed inside the flow
hydrogenation reactor, and monoacylated 1,2-diamines of
type 3 are isolated as the final products (Scheme 1).
Initial optimization experiments were performed by using
the commercially available and structurally very simple 2-
methyl-2-oxazoline (1a) as model substrate. Following the
“microwave-to-flow” paradigm,[15] our optimization studies
were first executed on a small scale (<1 mL reaction
volume) in a microwave batch reactor. Best results were ob-
tained by using MeOH as the solvent. The ring-opening was
considerably slower in iPrOH or tBuOH as the solvent, and
did not proceed at all in aprotic solvents, such as THF or
MeCN (for further details see Table S1 in the Supporting In-
formation). Our observations are in good agreement with
those made by Saito et al. and indicate that the reactive spe-
cies in this process is indeed HN3, which is generated in situ
from TMSN3 and the protic solvent.[7c] By utilizing MeOH
as the solvent and employing 1.2 equivalents of TMSN3, the
ring-opening reaction was accomplished within 5 min at
1308C (8 bar pressure) in the microwave batch reactor
(Table 1). The reaction was remarkably clean, and the prod-
uct was isolated in high purities (>99% by GC-FID and
1H NMR spectroscopy) and almost quantitative yield after
simple evaporation of the solvent and any excess of reagent
under vacuum. Similar results were obtained by using 2-
ethyl-2-oxazoline (1b) as the starting material. The 2-phenyl
derivative 1c and the 4-substituted 2-methyl oxazolines, 1d
and 1e, however, required somewhat harsher reaction condi-
tions and for the 4,5-substituted oxazolines, 1 f and 1g, the
amount of TMSN3 was increased to 1.3 equivalents
(Table 1). As expected, the ring-opening for oxazolines 1 f
and 1g occurred stereospecifically by inversion on carbon
C5 (for details and spectra, see the Supporting Informa-
tion).[6,7]
Table 1. Synthesis of N-(2-azidoethyl)acylamides 2a–2i under microwave
batch conditions.[a]
Substrate
t
T
[8C]
TMSN3
[equiv]
Yield
[%][b]
[min]
ACHTUNGTRENNUNG
1a
1b
1c
5
5
130
130
140
1.2
1.2
1.2
97
99
96
10
10
10
10
10
15
1d
1e
1 f
1g
1h
130
130
140
140
160
1.2
1.2
1.3
1.3
1.3
90
96
95
88
87[c]
1i
20
170
1.3
69[c]
[a] Conditions: oxazoline 1 (1.8 mmol), TMSN3 (1.2–1.3 equiv), MeOH
(300 mL), single-mode microwave reactor (Biotage Initiator). [b] Products
2a and 2b were isolated by removing the solvent and excess of reagent
under reduced pressure; products 2c–2i were further purified by extrac-
tion with 0.5n HCl/CHCl3. [c] TEA (10 mol%) was used as the catalyst.
tailed description of these investigations, see the Supporting
Information). The SN2 ring-opening of oxazolines is general-
ly catalyzed by electrophiles.[1,2] In particular, hard, oxophil-
ic Lewis acids, such as YbACTHNUTRGNE(UGN OTf)3, and electrophiles, such as
N-iodosuccinimide (NIS) and N-bromosuccinimide (NBS),
increased the reaction rate significantly. Unfortunately, the
purity of the reaction was somewhat compromised in the
presence of acidic catalysts. Ultimately, we discovered that
the reaction is considerably accelerated by catalytic amounts
(10 mol%) of triethylamine (TEA) without decreasing the
selectivity for the ring-opening reaction. Presumably, TEA
assists in the release of HN3 from TMSN3 (see the Support-
ing Information). The azides 2a and 2b could be isolated by
simple evaporation of the solvent, whereas azides 2c–2i
were further purified by extraction with 0.5n HCl/CHCl3 to
give products with high purity (>99% by GC-FID and
1H NMR spectroscopy, Table 1).
In the above batch-type experiments, HN3 could be de-
tected in the headspace above the solvent mixture immedi-
ately upon mixing TMSN3 with MeOH (Figure S1 in the
Supporting Information).[16] Given the numerous safety
issues in handling HN3,[8] we therefore envisaged a continu-
ous-flow strategy for the ring-opening of oxazolines, where-
by HN3 is generated in situ in a microreactor environment
Under these general reaction conditions, only the 4,4-di-
methyl substituted oxazolines 1h and 1i did not undergo
ring-opening in an acceptable reaction time. Full conversion
of these difficult substrates to the corresponding azides was
not obtained even at temperatures of 1608C (18 bar). After
heating for 20 min at 1608C, the conversion was 74% for
2,4,4-trimethyl oxazoline 1h with 1.2 equivalents of TMSN3,
and reaction with 4,4-dimethyl-2-phenyl derivative 1i gave
only 15% conversion after 25 min at 1608C with 1.3 equiva-
lents of TMSN3. Although the reactions remained fairly
clean even at these high temperatures, we screened a
number of different catalysts to accelerate the oxazoline
ring-opening reaction with these two substrates (for a de-
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C. O. Kappe, D. Roberge et al.
and subsequently consumed by the reaction with the oxazo-
line. This concept necessitates that the oxazoline starting
materials, dissolved in MeOH, and the TMSN3 reagent are
in two separate feeds. The hazardous and toxic HN3 is then
generated inside a suitable mixer upon combination of the
two streams. In a subsequent high-temperature coil reactor
the ring-opening reaction occurs, before the reaction mix-
ture is thermally quenched by a heat exchanger and exits
the continuous-flow system through a back-pressure regula-
tor (Table 2).
the consequent dilution of the reaction mixture.[17] These
issues do not arise, when the reactor is operated continuous-
ly (see below) or can be circumvented by “steady-state col-
lection” (see the Supporting Information).
By employing oxazoline 1h as the model substrate, the
flow reaction was repeated on a tenfold scale without chang-
ing or reoptimizing the other reaction parameters. Hence, a
solution of oxazoline (3.65m) in MeOH (20 mL) (oxazoline
1h (73 mmol) and TEA (7.3 mmol), feed A) and neat
TMSN3 (feed B) were pumped into the mixer at flow rates
of 0.80 and 0.50 mLminꢁ1, respectively. During this period,
TMSN3 (12.5 mL, 1.3 equiv) was consumed in the process.
The reaction mixture passed through the coil reactor heated
at 1708C and left the reactor via the heat exchanger and a
52 bar back-pressure regulator. Again, the whole reaction
mixture was collected (plus pre (5 mL) and post collection
(10 mL)) and the desired azide 2h was isolated in high
purity and yield (9.6 g, 84%), comparable to the results ach-
ieved under microwave batch conditions on a 1.8 mmol
scale (Table 1).[18] This corresponds to a productivity of ap-
proximately 0.5 kg of N-(2-azidoethyl)acylamide 2h per day.
Following our two-step continuous-flow ring-opening/hy-
drogenation strategy to access the desired N-(2-aminoethy-
l)acylamides 3 (Scheme 1), the synthesized N-(2-azidoethy-
l)acylamides 2a–i (Table 2) were reduced with H2 over Pd/C
in MeOH as the solvent in continuous-flow mode to the
monoacylated diamines 3a–i (Table 3). Monoacylated 1,2-di-
Table 2. Continuous-flow synthesis of N-(2-azidoethyl)acylamides.[a]
Substrate
Flow rate
A/B
c feed A
[m]
t
T
[8C]
TMSN3
[equiv]
Yield
[%][b]
[min]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG ]
[mLminꢁ1
1a
1b
1c
1d
1e
1 f
1g
1h
1i
2.45/1.55
2.45/1.55
1.25/0.75
1.35/0.65
1.35/0.65
1.40/0.60
1.25/0.75
0.80/0.50
0.70/0.30
4.0
4.0
3.8
3.05
3.05
2.5
3.5
3.65
2.5
5
5
10
10
10
10
10
15.4
20
130
130
140
140
140
150
150
170
180
1.2
1.2
1.2
1.2
1.2
1.3
1.3
1.3
1.3
93
95
94
74
91
91
67
77[c]
59[c]
[a] Conditions (Uniqsis FlowSyn reactor): feed A: oxazoline solutions
(2 mL); feed B: neat TMSN3; the applied equivalents of TMSN3 follow
from the concentration of the oxazoline in feed A and the relative flow
rates of the two feeds; reaction times refer to residence times in the
heated-coil reactor (20 mL stainless steel, 34 or 52 bar back-pressure reg-
ulator, see the Supporting Information for details). [b] For isolation con-
ditions see Table 1, footnote [b]; purities of the isolated azide products
were identical to those obtained under microwave-batch conditions.
[c] TEA (10 mol%) was used as the catalyst.
Table 3. Continuous-flow reduction of N-(2-azidoethyl)acylamides.[a]
Substrate
Yield [%][b]
96
2a
2b
2c
2g
99
95
95
The very high solubilities of the tested oxazolines 1a–i in
MeOH allowed the use of extremely concentrated mixtures
of the oxazoline starting materials (2.5–4m, feed A). The
TMSN3 was fed into the reactor as the neat reagent through
a second pump (feed B). For an initial proof-of-concept
study, we introduced 2 mL of the oxazoline solutions into
the flow reactor (Uniqsis FlowSyn) equipped with a 20 mL
stainless-steel coil (1.0 mm internal diameter, ca. 25 m
length). Flow rates of the two streams, A and B, were select-
ed to reproduce the microwave batch experiments. After
completion of the process, the whole reaction mixture was
collected (plus pre- (5 mL) and post-collection (10 mL)), an-
alyzed (GC-FID), and the azide products 2a–2i were isolat-
ed (Table 2). The reaction temperatures were adjusted
slightly for some of the ring-opening reactions to account
for dispersion/diffusion of the introduced reaction “plug”.
The somewhat reduced conversions and isolated product
yields, compared with the microwave batch experiments, are
mainly caused by axial dispersion of the reaction plug and
[a] Conditions (H-Cube, ThalesNano): N-(2-azidoethyl)acylamides
2
(0.1m solutions, 2 mmol scale) were reduced in a continuous-flow hydro-
genation reactor. [b] The products were isolated by removing MeOH
under reduced pressure.
amines are a particularly valuable class of substrates, as
highlighted in Scheme 1, but are often difficult to synthesize
selectively.[19] For hydrogenation reactions employing heter-
ogeneous catalysts, microreactor and continuous-flow tech-
nology are particularly attractive.[20] Here, the hydrogen/sub-
strate mixture is pumped through packed catalyst columns
by high-pressure pumps. Due to the large interfacial areas
and the short diffusion paths in the packed columns, very ef-
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Chem. Eur. J. 2011, 17, 13146 – 13150

A Two-Step Continuous-Flow Synthesis of N-(2-Aminoethyl)acylamides
COMMUNICATION
ficient gas–liquid–solid interactions, and thus hydrogenation,
takes place.[20] Reduction of the azides 2a–c and 2g follow-
ing a standard room-temperature-hydrogenation method[21]
in a continuous-flow hydrogenator (H-Cube) gave the pure
monoacylated diamines 3a–c and 3g after evaporation of
the solvent (Table 3).
Interestingly, the dimethyl-substituted azide 2h provided
a mixture of the two isomeric acylated diamines 3h and 3h’.
Apparently, the N-acetyl group migrates upon reduction
and/or during workup.[22] Small amounts of the rearranged
monoacyl-1,2-diamines were also detectable after reduction
of the other 4- or 4,5-substituted N-(2-azidoethyl)acylamides
efficient method to destroy excess/unreacted HN3 formed in
the ring-opening process. As exemplified for oxazoline sub-
strates 1a–c, this combined two-step continuous-flow strat-
egy provided the acylated amines 3a–c in excellent purities
and product yields (Scheme 3).
In conclusion, we have demonstrated that variously substi-
tuted 2-oxazolines 1 can be efficiently and safely ring-
opened to provide N-(2-azidoethyl)acylamides 2 by using a
high-temperature/pressure continuous-flow approach. Key
to the success of this protocol is the in situ generation of
toxic and explosive HN3 within the microreactor environ-
ment from TMSN3 and MeOH. The resulting N-(2-azido-
2d and 2e, and even the benzoyl group in 3i underwent mi-
gration under the chosen reaction conditions (see the Sup-
porting Information for details). Gratifyingly, the migration
of the acetyl group can be easily prevented by interception
of the freshly formed amino group by di-tertbutyl dicarbon-
ate (BOC2O) as demonstrated for the reduction of azide 2h
(Scheme 2). Hence, azide 2h and BOC2O (1.2 equiv) were
ACHTUNGTRENNUNG
Experimental Section
General synthesis of N-(2-aminoethyl)acylamides 3 (Scheme 3): Appro-
priate amounts of oxazolines 1a–c (Table 2) were weighed into a volu-
metric flask (2 mL), and the flask was filled to the mark with MeOH
(feed A). TMSN3 was added to a second flask (feed B). Streams A and B
were mixed together at the indicated flow rates in a T-mixer at RT, and
the resulting stream was passed through the stainless-steel reactor coil
(20 mL heated volume) heated at the indicated temperatures (Table 2).
After passing the coil reactor, the mixtures were cooled in the plate-heat
exchanger to RT and left the reactor through a 34 bar back-pressure reg-
ulator. The entire reaction mixtures were collected (plus pre (5 mL) and
post collection (10 mL)) in a graduated cylinder, and the product mix-
tures were diluted with MeOH to give a 0.1m solution. 20 mL of these
solutions were then pumped through the H-Cube (10% Pd/C, 208C,
1 mLminꢁ1 flow rate, full H2 mode). The effluent reaction mixtures were
collected, and the solvent removed under vacuum. This procedure afford-
ed the pure N-(2-aminoethyl)acylamides 3a and 3b (>99% by GC-FID)
in 94% yield. The crude N-(2-aminoethyl)benzamide 3c was isolated in
93% yield after washing with anhydrous Et2O (2ꢁ2 mL) to remove un-
reacted 2-phenyl-2-oxazoline 1c.
Scheme 2. Preparation of the BOC-protected N-(2-aminoethyl)acetyl-
ACHTUNGTRENNUNGamide 4h.
dissolved in MeOH and the mixture was pumped through
the continuous-flow hydrogenator (H-Cube). The crude
BOC-protected N-(2-aminoethyl)acetylamide 4h was isolat-
ed in excellent purities (98% by GC-FID), without any sign
of rearrangement, in 94% yield after evaporation of the sol-
vent and washing the crude product with petroleum ether.
From a processing standpoint, it is important to note that
the crude N-(2-azidoethyl)acylamide reaction streams, ob-
tained through continuous-flow ring-opening of 2-oxazolines
with HN3 (Table 2), can be used directly for the flow hydro-
genation step without prior isolation/purification of the
azide intermediates. For this purpose, the highly concentrat-
ed crude azide mixtures leaving the coil reactor (FlowSyn)
were diluted with MeOH and directly introduced into the
flow hydrogenator (H-Cube) (Scheme 3). Apparently,
Acknowledgements
This work was supported by a grant from the Christian Doppler Society
(CDG). We acknowledge the valuable input of Dr. Petteri Elsner to this
work.
Keywords: hydrazoic acid · hydrogenation · microreactors ·
oxygen heterocycles · synthetic methods
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Scheme 3. Two-step continuous-flow synthesis of N-(2-aminoethyl)acyl-
ACHTUNGTRENNUNGamides 3a–c.
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Chem. Eur. J. 2011, 17, 13146 – 13150
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C. O. Kappe, D. Roberge et al.
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Received: September 5, 2011
Published online: October 14, 2011
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