Straightforward hetero Diels-Alder reactions of nitroso dienophiles by microreactor technology

Article abstract of DOI:10.1016/j.tetlet.2010.08.117

The hetero Diels-Alder reactions of 2-nitrosotoluene and some representative acylnitrosodienophiles with a selected set of 1,3-dienes were studied under microflow conditions. The main assets of the technology, that is, an accurate control of the reaction

Full text of DOI:10.1016/j.tetlet.2010.08.117

Tetrahedron Letters 51 (2010) 5830–5833
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Straightforward hetero Diels–Alder reactions of nitroso dienophiles
by microreactor technology
Jean-Christophe M. R. Monbaliu a, , Ana Cukalovic a, Jacqueline Marchand-Brynaert b, Christian V. Stevens a,
⇑
a SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University,
Coupure links 653, B-9000 Gent, Belgium
b Institute of Condensed Matter and Nanosciences, IMCN, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2010
Revised 11 August 2010
Accepted 31 August 2010
Available online 7 September 2010
The hetero Diels–Alder reactions of 2-nitrosotoluene and some representative acylnitrosodienophiles
with a selected set of 1,3-dienes were studied under microflow conditions. The main assets of the tech-
nology, that is, an accurate control of the reaction parameters and continuous operating, led to an
increased efficiency of this reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Microreactor
Hetero Diels–Alder reaction
Nitroso dienophiles
Flow conditions
The hetero Diels–Alder (HDA) reactions of nitroso dienophiles
have gained a considerable attention in the last decade.1 At pres-
ent, it becomes a privileged tool in heterocyclic organic synthesis.
This reaction leads to polyfunctional 3,6-dihydro-1,2-oxazine scaf-
folds (Fig. 1) comprising of at least three different entries for selec-
tive chemical modifications.2 Among these, oxidation reactions,
ring opening or ring contraction of 1,2-oxazines have been used
in numerous total syntheses of nitrogen-containing bioactive nat-
ural products or synthetic analogs.3
acid under oxidative conditions can lead to acylnitroso dimerization
and degradation according to Kirby.8 The main assets of the microre-
actor technology, namely efficient heat-exchange and strictly con-
trolled local stoichiometry, therefore look attractive for further
optimization of such a HDA reaction. Commercial microreactor sys-
tems are being increasingly and successfully used to improve organ-
ic synthesis, due to the above-mentioned and other benefits such as
an easy control of reaction and operating parameters, adequate mix-
ing, efficient processing of unstable intermediates, the possibility of
continuous processing without time delays characteristic for batch
conditions, and the use of dangerous reagents, etc.9 Even though
some recent reports are dedicated to continuous Diels–Alder reac-
tions,10 to thebestof our knowledgethere is norecord of flownitroso
DA reactions. As a part of our ongoing research in flow chemistry, the
microreactor technology has been investigated to continuously pro-
duce 1,2-oxazine synthons from a selected set of available dienes. In
this Letter, we report the flow synthesisof 1,2-oxazines derived from
nitrosotoluene (1) or acylnitroso derivatives (3a–c) and a set of
dienes (4) (Table 1).
Two main classes of nitroso compounds are predominantly
used, namely aryl- (1) and acylnitroso (3) dienophiles ( Fig. 1),
although some studies emphasized the synthetic utility of vinyl-
nitroso,4 -chloro-5 and -acyloxynitroso dienophiles.2b 2-Nitroso-
a a
toluene (1) is generated from its stable commercial dimer by
solvation. Acylnitrosodienophiles (3a–c) are generated in situ in
the presence of the guest diene from stable precursors, mainly
hydroxamic acids (2a–c) under oxidative conditions.6 On the other
hand, some recent improvements in acylnitroso generation were
reported, using metal catalysts; however under environmentally
unfriendly conditions.7
These cycloaddition reactions are exothermicand stoichiometry-
sensitive, hence demanding accurate thermal and stoichiometric
control to avoid side-reactions. Indeed, a local excess of hydroxamic
The CPC College System from Cytos11a (47 mL total volume) and
the X-Cube from ThalesNano11b (6 mL total volume) were used for
this project. Experiments requiring higher pressures have been car-
ried out using the X-Cube microsystem. The cycloaddition reactions
of 2-nitrosotoluene (1) were first investigated using a microreactor
setup A as described in Figure 1. A temperature ranging from 0 to
95 °C, a pressure ranging from 1 to 100 bar, and flow rates ranging
from 0.2 to 1 mL minÀ1 were considered for equimolar solutions
(0.15 N). Several solvents were investigated: acetone, methanol,
⇑
Corresponding author. Tel.: +32 9 264 59 50; fax: +32 9 264 62 43.
E-mail address: Chris.Stevens@UGent.be (C.V. Stevens).
Jean-Christophe M. R. Monbaliu is Postdoctoral Fellow of the Research Founda-
tion-Flanders (FWO-Vlaanderen).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.117

Jean-Christophe M. R. Monbaliu et al. / Tetrahedron Letters 51 (2010) 5830–5833
5831
NHOH
O
N
R1
0.2-1 mL.min-1
0.2-0.5 mL.min-1
R2
+
n
2a (R1=Ac)
2b (R1=Boc)
2c (R1=Bz)
4
O
1
R1
R2
N
solvent
0-95°C
water/acetone
25-30°C
n
1-100 bar
n=0,1,2
1,2-oxazine
NaIO4
R2
0.2-1 mL.min-1
0.2-0.5 mL.min-1
n
4
in situ
Setup A
Setup B
O
R
N
O
3a-c
Figure 1. Setups A–B of the microreactor and HDA reactions of nitrosodienophiles.
Table 1
Cycloadditions of nitroso dienophiles 1, 3a–c with dienes 4a–g under microflow conditions (standard pressure conditions)12
Entry
Dienophiles
Diene
Adduct
Microflow conditions
Batch
rta (min)
Scale (g hÀ1)
Yieldb (%)
Yield (%)
1
2
3
1
3a
3c
47
117.5
117.5
0.90
0.19
0.25
92
94
87
673e
573h
O
R
R
R=2-tolyl (5)
R=Ac (6)
N
N
933i
R=Boc (7)
4a
4b
4
5
6
7
1
3a
3b
3c
/
/
0
85
72
70
0
O
R=2-tolyl (8)
R=Ac (9)
117.5
117.5
117.5
0.33
0.47
0.48
84–993g
787a
683h
R=Boc (10)
R=Bz (11)
8
9
10
11
1
3a
3b
3c
/
/
0
90
92
81
0
O
117.5
117.5
117.5
0.33
0.40
0.41
903j
R
N
R=2-tolyl (12)
R=Ac (13)
728d
823h
R=Boc (14)
R=Bz (15)
4c
12
13
14
1
3a
3c
47
117.5
117.5
0.91
0.19
0.26
96
87
85
92
82
O
R=2-tolyl (16)
R=Ac (17)
767a
N
R=Boc (18)
R
4d
15
16
17
1
3a
3c
47
117.5
117.5
0.85
0.17
0.23
91c
72d
89
75
O
R=2-tolyl (19)
R=Ac (20)
65e
657a
N
R=Boc (21)
R
4e
18
19
20
1
3a
3c
117.5
/
/
0.56
/
/
89
0
0
957a
0
0
PO(OEt)2
PO(OEt)2
O
R=2-tolyl (22)
R=Ac (23)
N
R
R=Boc (24)
4f
21
22
23
1
3a
3c
47
/
/
1.0
/
/
75
0
0
80
0
0
CO2H
CO2H
O
R=2-tolyl (25)
R=Ac (26)
N
R
R=Boc (27)
4g
a
b
c
Residence time.
Isolated.
1/4 mixture of regioisomers.
1/8 mixture of regioisomers.
1/1 mixture of regioisomers.
d
e

5832
Jean-Christophe M. R. Monbaliu et al. / Tetrahedron Letters 51 (2010) 5830–5833
THF, acetonitrile, and dimethylformamide. The optimized condi-
tions and results obtained under standard pressure are listed in Ta-
ble 1 (entries 1, 4, 8, 12, 15, 18, and 21).12
withtotalconversionofthedieneandexcellentyields(87–94%)with
a residence time of 117.5 min (0.4 mL minÀ1 total flow rate). The use
of shorter residence times (i.e., higher flows) significantly decreased
theconversion. Undersimilaroperatingconditions, cyclopentadiene
(4b) underwent cycloaddition with Ac-, Boc-, and Bz-nitroso deriva-
tives (3a–c) in moderate to good yields (70–85%, after extraction).
No dimerization of the diene was observed. Total conversion was ob-
served for the cycloadditions of 9,10-dimethylanthracene (4c) with
3a–c within 117.5 min of residence time. The instability of the corre-
sponding cycloadducts lowers the yield and prevents any purifica-
tion on silica gel column. Similarly to the results obtained in the
cyclic series, 2,3-dimethylbutadiene (4d) reacted under flow condi-
tions with acylnitroso dienophiles 3a and 3b yielding 1,2-oxazines
1718 and 18 in 85% and 87%, respectively. Isoprene (4e) led to a 1/8
and 1/1 mixtures of regioisomers with dienophiles 3a and 3b,
respectively.19 The yields were moderate (65–72%). No cycloaddi-
tions are observed for dienes 4f and 4g, even under 100 bar (X-Cube)
and using an excess of hydroxamic acid.20
In conclusion, the cycloadditions of a selected set of dienes with
representative nitrosodienophiles have been successfully con-
ducted under microflow conditions, leading to the first example
of a continuous lab-scale production of 1,2-oxazines (0.2–1 g h
À1). Using equimolar solutions of reagents, similar and in several
cases higher yields to the corresponding batch reactions were ob-
tained. The continuous process however offers a range of advanta-
ges over batch reactions, namely the efficient heat exchange, the
easy control of the reaction stoichiometry and shorter residence
(reaction) times. Moreover, no metal catalysts or specific additives
were necessary to achieve good yields.
The cycloaddition of 1 was relatively insensitive toward solvent
polarity. For example, using cyclohexadiene (4a) at 55 °C and
1 mL minÀ1 total flow (i.e., 47 min residence time), the conversion
was complete in THF, acetonitrile, and methanol. In DMF, under
the same flow conditions, total conversion was reached at 95 °C
(92% yield). Doubling of the flow rate (i.e., shortening the reaction
time by a factor two) led to 85% conversion. Using the X-Cube
microsystem with a backpressure of 100 bar led to a significant
reduction in residence time (15 min) leading to 95% conversion.
For the reaction of 1 and 4b,13 the dimerization of cyclopentadiene
was the major phenomenon observed. At 0 °C and with
a
0.4 mL minÀ1 total flow, no reaction occurred. As expected, no
cycloaddition was observed for 9,10-dimethylanthracene (4c) and
2-nitrosotoluene.14 2,3-Dimethylbutadiene (4d) gave its corre-
sponding N-2-tolyl-1,2-oxazine cycloadduct 16 in 96% yield (after
extraction) in DMF at 95 °C and 1 mL minÀ1 total flow.15 At lower
temperatures, the conversion of 4d was lower than for cyclohexa-
diene (4a), even with lower flow rates. The reaction of isoprene
(4e) and 1 gave a 1:4 (LC) mixture of regioisomers in 91% yield.
No modification of the regioselectivity is observed in comparison
to batch conditions. Next, the cycloadditions of functionalized
dienes 4f and 4g with 1 led to the corresponding cycloadducts
22 and 25, respectively, in moderate to good yields after extraction.
In both cases, the regioselectivity is total. The longer residence
time needed to complete the reaction of 1 and 4f emphasizes the
lower reactivity of diene 4f.16 These results can be interpreted
within the electrophilicity scale as introduced by Domingo.17 Nitr-
osotoluene has a high electrophilicity power (
x
= 2.82 eV) and will
Acknowledgments
consequently react through polar Diels–Alder reaction toward
electron rich dienes (i.e., nucleophilic ones). For instance, the rela-
This work is supported by the Long Term Structural Methusa-
lem Funding by the Flemish Government, the BOF (Bijzonder Ond-
erzoeksfonds Universiteit Gent, Research Fund Ghent University)
and the FWO (Fonds voor Wetenschappelijk Onderzoek Vlaander-
en, Research Foundation - Flanders). J.M.-B. is a senior research
associate of F.R.S.-FNRS (Fonds de la Recherche Scientique-Belgi-
que, National Funds for Scientific Research-Belgium).
tively low
4d–e emphasize their higher nucleophilic nature. For 9,10-dimeth-
ylanthracene (4c), the computed equals 1.61 eV. This, combined
x values ranging from 0.83 to 1 eV for dienes 4a,b, and
x
with the high reversibility of its Diels–Alder reaction with nitroso
dienophiles, explains the lack of reactivity observed. The presence
of electron-withdrawing substituents onto the butadienyl moiety
(dienes 4f–g) increases their relative electrophilicity (and thus re-
duces their intrinsic nucleophilicity), as showed by their higher
References and notes
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agreement with the observed lower conversions.
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Further on, the cycloaddition reactions of acylnitroso dienophiles
(3a–c) were studied. The transient acylnitroso species were gener-
ated in situ in the mixing unit of the reactor by pumping separately
theoxidantand thehydroxamic acids (2a–c) (Setup B,Fig. 1). Sodium
metaperiodate is preferred over tetrabutylammonium periodate, as
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ucts that clogged the micrometric channel of the reactor. Several sol-
vent mixtures were investigated, the best results being realized with
a 3/1 water/acetone mixture, and the optimum temperature being
30 °C (except for 9,10-dimethylanthracene (4c), which reacted best
in DMF at 65 °C). By using the ThalesNano X-Cube (total flow rates
ranging from 0.2 to 1 mL minÀ1), no beneficial effect of the increased
pressure has been observed. Several attempts were performed using
the ThalesNano X-Cube using catalyst cartridges filled with sup-
ported NaIO4 to convert in situ the hydroxamic acid into the nitroso
derivative in order to avoid the extraction step; however these
experiments gave poor results. Flow rates ranged from 0.2 to
0.5 mL minÀ1 with the CPC College System from Cytos for 0.1 N equi-
molar solutions of diene/hydroxamic acid (in a 1/1 water/acetone
mixture) and sodium periodate (in water). The optimized conditions
and results are listed below (Table 1).
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extractor (ethyl acetate/water). Compound 16: 1H NMR (300 MHz, CDCl3) d
7.23–7.01 (m, 4H), 4.24 (s, 2H), 3.47 (s, 2H), 2.29 (s, 3H), 1.66 (s, 3H), 1.58 (s,
3H) ppm. 13C NMR (75 MHz, CDCl3) d 148.27, 133.04, 131.01, 126.52, 125.37,
124.87, 123.21, 118.22, 72.30, 56.19, 18.50, 16.18, 13.81 ppm.
11. (a) Schwalbe, T.; Golbig, K.; Hohmann, M. et al. Miniaturized Reaction
Apparatus. YMC Co Ltd, EP 1123734, 2001; (b) www.thalesnano.com.
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and is relative to the diene. The yield is calculated after extraction. The
regioisomer ratio is determined by analytical HPLC. The physical
characterizations of all obtained products were in agreement with the
reported data in the literature. See for example Ref. 7a and: Monbaliu, J.-C.;
Marchand-Brynaert, J. Tetrahedron Lett. 2008, 49, 1839–1842.
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dimer.
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73, 8791–8799. and references cited therein.
18. Typical procedure of setup B: freshly prepared equimolar 0.1 N solutions of 2,3-
dimethylbutadiene/acetohydroxamic acid (in acetone/water 1/1) and sodium
metaperiodate (in water) are injected with a 0.2 mL minÀ1 flow each through
the CPC microsystem (setup B). After 188 min stabilization at 30 °C, the outlet
is connected to a continuous extractor (ethyl acetate/water). Compound 17: 1
H
NMR (300 MHz, CDCl3) d 4.15 (s, 2H), 3.96 (s, 2H), 2.07 (s, 3H), 1.61 (s, 3H), 1.53
(s, 3H) ppm. 13C NMR (75 MHz, CDCl3) d 169.54, 122.63, 122.13, 72.92, 44.93,
19.88, 15.43, 13.91 ppm.
15. Typical procedure of setup A: freshly prepared equimolar 0.15 N solutions of 2,3-
dimethylbutadiene and 2-nitrosotoluene in DMF are injected with
a
0.5 mL minÀ1 flow each through the CPC microsystem (setup A). After 75 min
19. The same regioisomeric ratio was reported in the literature.7a
20. Under similar conditions, no cycloadditions are observed in batch either.
stabilization at 95 °C, the outlet is connected to a continuous liquid–liquid