Controlling hazardous chemicals in microreactors: Synthesis with iodine azide

Article abstract of DOI:10.3762/bjoc.5.30

Aromatic aldehydes have been converted into the corresponding carbamoyl azides using iodine azide. These reactions have been performed safely under continuous flow reaction conditions in microreactors.

Full text of DOI:10.3762/bjoc.5.30

Controlling hazardous chemicals in microreactors:
Synthesis with iodine azide
Johan C. Brandt and Thomas Wirth*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 30.
Cardiff University, School of Chemistry, Park Place, Cardiff CF10
3AT, UK.
doi:10.3762/bjoc.5.30
Received: 23 March 2009
Accepted: 04 June 2009
Published: 12 June 2009
Email:
Thomas Wirth* - wirth@cf.ac.uk
* Corresponding author
Guest Editor: A. Kirschning
Keywords:
© 2009 Brandt and Wirth; licensee Beilstein-Institut.
License and terms: see end of document.
azide; flow chemistry; hazardous reagents; microreactor;
rearrangement
Abstract
Aromatic aldehydes have been converted into the corresponding carbamoyl azides using iodine azide. These reactions have been
performed safely under continuous flow reaction conditions in microreactors.
Introduction
Microstructured devices have already found their way into moieties in organic synthesis as they can be transformed easily
organic synthesis, because they offer various advantages over into a large variety of other functional groups [5].
traditional large-scale chemistry performed in flasks or vessels
[1,2]. The high surface-to-volume ratio as their main character- Iodine azide is a very hazardous but valuable reagent that is
istic can result in rapid mixing of compounds, uniform reaction easier and much more safely handled under microreactor condi-
conditions due to precise temperature control as well as rate tions. Iodine azide is a solid compound, highly explosive and
enhancements because of short diffusion distances. In addition, toxic. It is known to add stereospecifically to carbon–carbon
the synthesis and use of potentially hazardous compounds is double bonds with high regioselectivity following an ionic
another advantage of microreactors as only very small amounts mechanism. This azido-iodination reaction is by far the most
of compounds/reagents are handled. Large inventories of common synthetic application of iodine azide [6-14]. Due to the
dangerous reagents and intermediates are not necessary.
weakness of the iodine–nitrogen bond iodine azide also reacts
in a radical manner upon heating, where this weak bond can be
Azides are among the most versatile reagents in modern organic homolytically cleaved and introduce azide moieties efficiently
chemistry however they are not often used to their full potential into molecules with weak carbon–hydrogen bonds such as
due to safety concerns. Especially azides with low molecular benzyl ethers [15,16] or aldehydes [17,18]. Recently some other
weights are difficult to handle because of their high disposition research groups have investigated the use of azides in
to detonate [3-5]. However, azides are extremely useful chemistries performed in microreactors [19-22].
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Beilstein Journal of Organic Chemistry 2009, 5, No. 30.
Results and Discussion
When using non-distilled p-bromobenzaldehyde 1c the reaction
The radical addition of azide to aldehydes 1 initially forms acyl stopped with the formation of the acyl azide 5 contrary to the
azides 2 which directly rearrange in a Curtius rearrangement to corresponding chloride derivative (Table 1). However when we
the corresponding isocyanates 3. Isocyanates are very reactive modified the protocol to only using freshly distilled aldehydes,
themselves and offer a wide range of possible conversions. An we also observed reaction and rearrangement of 1c via 5 to 4c
excess of azide leads to the formation of stable carbamoyl and increased yields for the other reactions.
azides 4 as shown in Scheme 1.
Table 1: Products and yields in the addition of iodine azide to alde-
hydes performed in a tubing microreactor at a flow rate of 7.5 µL/min
(26 min residence time) at 80 °C.
Entry
Aldehyde 1
Product
Yield
[%]
Scheme 1: Azide addition to aldehydes and formation of carbamoyl
azides.
1
44
As sodium azide is poorly soluble in organic solvents, we
decided to use tetrabutylammonium azide for the in situ genera-
tion of iodine azide. The reaction with iodine monochloride is
rapid and after several minutes (depending on the flow rate) the
aldehyde 1 was added to the reagent in the microreactor as
shown in Figure 1.
2
3
4
32
Figure 1: Microreactor setup for the in situ generation and use of
iodine azide (IN3).
24a
All reagents and the aldehyde 1 were used as solutions in acet-
onitrile. After mixing the aldehyde with the iodine azide reagent
the solution is passed through a capillary (volume: 196 µL) in a
heating zone to allow the Curtius rearrangement to occur. Flow
rates of 20 µL/min or higher led to very low or no conversion.
At slower flow rates the yields were enhanced but seemed to
stop growing at one point. Optimal yields were constant within
a range of 15 to 1.5 µl/min corresponding to residence times in
the heating zone of 13–130 minutes. For optimization experi-
ments benzaldehyde 1a was used. Slower flow rates are technic-
ally possible but not very attractive from a synthetic point of
view. The reaction would work best at 80 °C, just below the
boiling point of acetonitrile. Lower temperatures gave lower
conversions. A reaction at 65 °C produced the product 4a in
only 25% yield, whereas a reaction at room temperature did not
yield any product. An exchange of the solvent for propionitrile
allowed a temperature increase to 110 °C, but conversions were
found to be similar to reactions using acetonitrile. In the
original publication the solvent had already been optimized and
acetonitrile seemed to be the best solvent for this reaction [17].
not distilled
27
distilled
5
21
aNo carbamoyl azide is obtained when crude (non-distilled) aldehyde 1c
is used.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 30.
We could show that the quality of the tetrabutylammonium Lewis acid and accelerates the rearrangement. It is known that
azide is important for the success of the reaction. Its prepara- Lewis acid catalysts such as zinc triflate can accelerate Curtius
tion from tetrabutylammonium hydroxide and sodium azide in rearrangements and the sodium cation might serve a similar role
water and dichloromethane did not lead to dry, crystalline [34]. We obtained 67% yield of 4b when zinc triflate was used
material [23]. Unfortunately also the procedure using as catalyst in a flask reaction. Even the reaction of non-distilled
tetrabutylammonium chloride and sodium azide produced a p-bromobenzaldehyde 1c under these acidic conditions showed
product highly contaminated with DMF, which was not remov- traces of the corresponding carbamoyl azide according to 1H
able without decomposition of the product [24,25]. Highest NMR. But electron rich substrates such as 2,4-dimethoxybenza-
yields were obtained with commercially available tetrabutylam- ldehyde 1d showed decomposition and unidentifyable product
monium azide (Aldrich), although great care has to be taken as mixtures with this catalyst. Generally, the batch reactions all
this compound is very hygroscopic. Calculations indicate that proceeded less cleanly compared to the microreactor processes.
the synthesis of iodine azide from trimethylsilyl azide and
iodine monochloride is slightly endothermic (ΔH ≈ +15 kJ/mol) Conclusion
[26-29]. Geometry optimisations and frequency analyses on After initially promising results we were challenged with a
Me3SiN3, ICl, IN3 and Me3SiCl were performed using Gaus- complex optimization task, that included many more para-
sian 98 at the B3LYP/6-311+G(d,p) level using the LANL2DZ meters than usual in organic synthesis, due to the technical
basis set for iodine augmented with one p function and one d implications of our approach. There are phenomena in this reac-
function. NMR experiments showed a ratio of about 1:3 of tion that prevent complete conversion to complete by a long
trimethylsilyl azide and trimethylsilyl chloride upon reaction way, probably azide-consuming side reactions or lack of
with iodine monochloride. This mixture was not efficient in the activity of the substrate, lack of acid catalysis, or a combination
reaction with aldehydes, only an unidentifiable mixture of of these reasons. Additionally, the substitution pattern of the
products was obtained.
substrates led to an unexpected outcome of the reaction.
Experimental
The reactivity of carbamoyl azides is analogous to isocyanates,
compound 4a reacted with n-butyllithium to give amide 6 in Synthesis of tetrabutylammonium azide:
quantitative yields as shown in Scheme 2.
Procedure I [23]: Sodium azide (200 mmol, 13 g) was
dissolved in water (30 mL). Then tetrabutylammonium
hydroxide (100 mmol, 26 g) was added and the mixture was
stirred at room temperature for 90 min. Dichloromethane (50
mL) was added and stirring was continued for 10 min. The
organic layer was separated and dried over magnesium sulfate.
Finally the solvent was removed under reduced pressure and the
product was dried for 24 h under vacuum.
Scheme 2: Reaction of carbamoyl azide 4a with n-butyllithium.
Another way to form a stable iodine–azide bonds are hyper- Procedure II [24,25]: Sodium azide (79 mmol, 5.13 g) and
valent iodine compounds [30,31]. This source of reagent has tetrabutylammonium chloride (85 mmol, 22 g) were mixed in
indeed been used for radical azidonations in flask reactions [18] DMF (35 mL) and stirred overnight under argon at 50 °C. Dry
and resulted in an interesting approach using solid support [32], THF (70 mL) was added and stirring continued for 15 min. The
but these compounds are usually unsuitable for applications in reaction mixture was filtered and the solvent in the filtrate was
microreactors because of their poor solubility or they would removed under reduced pressure. The product was heated under
require a different microreactor set-up that would allow solid vacuum for 2 h to remove some DMF.
supported reagents [33].
Yields for these reactions cannot be given as the solvents could
For better comparison with literature procedures the reaction not be removed completely from the product. IR (Nujol, cm−1):
was then also investigated as a batch process. The reaction with ν = 3418, 2145 (azide), 1643.
commercial tetrabutylammonium azide and non-distilled alde-
hyde precursors would stop after the formation of the acyl azide General procedure for the synthesis of carbamoyl
with p-chlorobenzaldehyde and with p-bromobenzaldehyde. azides 4:
Rearrangement took place when sodium azide was used, but A twin syringe pump (KDS-200-CE) was charged with two 5
lower yields (34% yield of 4b) were observed than those given ml Hamilton syringes, one containing tetrabutylammonium
in literature (53–97%) [17]. Maybe the sodium ion acts like a azide (3 mmol, 853 mg) in dry acetonitrile (3.5 mL) and the
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Beilstein Journal of Organic Chemistry 2009, 5, No. 30.
other iodine monochloride (2 mmol, 102 µL) in dry acetonitrile 1H NMR (500 MHz, CDCl3): δ 7.45 (d, 3JHH = 8.7 Hz, 2H,
(4.8 mL). The outlets were connected by standard HPLC tubing H-3/H-5), 7.34 (d, 3JHH = 8.7 Hz, 2H, H-2/H-6) 6.84 (s, 1H,
to a T-junction, after 30 cm tubing a second T-junction was NH) ppm; 13C NMR (125 MHz, CDCl3): δ 154.1 (C-7), 136.0
connected to the third syringe containing the substrate aldehyde (C-4), 132.2 (C-1), 120.9 (C-2/C-6), 117.4 (C-3/C-5) ppm;
(1 mmol) in dry acetonitrile (2.4 mL). All HPLC equipment was EI-MS m/z (%): 242 ([M]+, 100), 240 ([M]+, 96), 231 (25), 229
purchased from CHM GmbH, Fridolfing, Germany. The HPLC (27), 214 (10), 212 (19). HRMS (EI): calc. for C7H5BrN4O:
tubing used as flow reactor was made of PTFE with the meas- 239.9641, found: 239.9639.
urements 1/16 × Ø 0.25 mm. The syringes containing the
reagents were connected to the flow system with PEEK 2,4-Dimethoxyphenylcarbamoyl azide (4d)
adapters (1/4- 28f – Luer, female) and 1/4 PEEK fittings. The The crude product was purified with a silica gel column using
T-mixers used were PEEK (1/4-28 with 1/16 fittings and Ø 0.5 hexane/CH2Cl2 1:4 as eluent. Yield: 47 mg (21%), colourless
mm) for low pressure applications. The third syringe was solid, mp: 65–67 °C.
loaded on a separate syringe pump. The flow rate was adjusted
to an overall flow rate of 7.5 µL/min. The source of heating for 1H NMR (500 MHz, CDCl3): δ 8.02 (d, 3JHH = 8.6 Hz, 1H,
the reaction was a PEG 600 oil bath. After passing the heating H-4), 7.22 (s, 1H, NH), 6.50–6.47 (m, 2H, H-1/H-3), 3.84 (s,
zone (80 °C) behind the second T-junction (4 m) the reaction 3H, H-13 or H-14), 3.80 (s, 3H, H-13 or H-14); 13C NMR (125
was terminated at the outlet with 5 mol% aq thiosulfate solu- MHz, CDCl3): δ 156.7 (C-10), 153.4 (C-2), 149.3 (C-6), 119.9
tion. For work-up, the mixture was extracted with dichloro- (C-4), 109.9 (C-3), 103.9 (C-5), 98.7 (C-1), 55.7 (C-13 or
methane (3 × 10 mL). The combined organic phases were C-14), 55.5 (C-13 or C-14) ppm; EI-MS m/z (%): 222 ([M]+,
separated, dried over magnesium sulfate and the solvent 10), 179 (100), 164 (31), 153 (18), 136 (52), 122 (10), 110 (11),
removed under reduced pressure.
95 (12); HRMS (EI): calc. for C9H10N4O3: 222.0753, found:
222.0755; IR (neat): 1531, 1711, 2144, 3415 cm−1.
Phenylcarbamoyl azide (4a)
The crude product was purified with a silica gel column using Azido(4-bromophenyl)methanone (5)[35]
hexane/CH2Cl2 15:1 as eluent. Yield: 71 mg (44%), colourless The crude product was purified with a silica gel column using
solid, mp: 106–107 °C (lit: 107.1 °C) [18].
hexane/CH2Cl2 1:1 as eluent. Yield: 54 mg (24%), light yellow
solid.
1H NMR (500 MHz, CDCl3): δ 7.44 (d, 3JHH = 7.9 Hz, 1H,
H-2), 7.33 (t, 3JHH = 7.9 Hz, 2H, H-1/H-3), 7.13 (t, 3JHH = 7.4 1H NMR (500 MHz, CDCl3): δ 7.87 (d, 3JHH = 8.8 Hz, 2H,
Hz, 2H, H-4/H-6), 6.97 (s, 1H, NH) ppm; 13C NMR (125 MHz, H-4/H-6), 7.59 (d, 3JHH = 8.8 Hz, 2H, H-1/H-3) ppm; 13C
CDCl3): δ 154.0 (C-8), 136.8 (C-5), 129.2 (C-1/C-3), 124.6 NMR (125 MHz, CDCl3): δ 171.7 (C-8), 132.0 (C-5), 130.8
(C-2), 119.2 (C-4/C-6) ppm; EI-MS m/z (%): 162 ([M]+, 7), 119 (C-1/C-3), 129.7 (C-2), 129.5 (C-4/C-6) ppm.
(100), 93 (64), 91 (56), 64 (32).
N-Phenylpentanamide (6)
4-Chlorophenylcarbamoyl azide (4b)
Phenylcarbamoyl azide 4a (0.12 mmol, 20 mg) was dissolved in
The crude product was purified with a silica gel column using dry THF (35 mL) and cooled to −78 °C under argon. Then
hexane/CH2Cl2 1:1 as eluent. Yield: 63 mg (32%), colourless n-BuLi (0.37 mmol, 0.15 mL, 2.5 M in hexane) was added care-
solid, mp: 103–105 °C.
fully dropwise into the solution via a syringe. After the addition
the cooling bath was removed and the flask was allowed to
1H NMR (500 MHz, CDCl3): δ 7.39 (d, 3JHH = 8.8 Hz, 2H, warm to r.t. The mixture was then diluted with AcOH/THF (20
H-4/H-6), 7.29 (d, 3JHH = 8.8 Hz, 6.86 (s, 1H, NH) ppm; 13C mL/20 mL) and aq sodium carbonate (20 mL). Then
NMR (125 MHz, CDCl3): δ 154.0 (C-9), 135.4 (C-5), 129.8 ethylacetate (60 mL) was added, the organic layer separated and
(C-2), 129.2 (C-1/C-3), 120.4 (C-4/C-6) ppm; EI-MS m/z (%): dried over magnesium sulfate. The crude product was purified
198 ([M]+, 2), 196 ([M]+, 4), 187 (2), 185 (5), 155 (12), 153 with a silica gel column using hexane/CH2Cl2 15:1 as eluent.
(100), 127 (23), 125 (21); HRMS (EI): calc. for C7H535ClN4O: Yield: 14 mg (quant.) colourless solid, mp: 60–61 °C (lit:
196.0146, found: 196.0145.
60–61.5 °C) [36].
4-Bromophenylcarbamoyl azide (4c)
1H NMR (500 MHz, CDCl3): δ 7.51 (d, 3JHH = 7.9 Hz, 2H,
The crude product was purified with a silica gel column using H-4/H-6), 7.32 (t, 3JHH = 7.9 Hz, 2H, H-1/H-3), 7.13 (s, 1H,
hexane/CH2Cl2 1:1 as eluent. Yield: 65 mg (27%), colourless NH), 7.10 (t, 3JHH = 7.4 Hz, 1H, H-2), 2.36 (t, 3JHH = 7.6 Hz,
crystals, mp: 77–78 °C.
2H, H-10), 1.72 (qn, 3JHH = 7.6 Hz, 2H, H-11), 1.41 (sext, 3JHH
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Beilstein Journal of Organic Chemistry 2009, 5, No. 30.
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13C NMR (125 MHz, CDCl3): δ 171.3 (C-8), 137.9 (C-5),
129.0 (C1/C-3), 124.2 (C-2), 119.7 (C-4/C-6), 37.6 (C-10), 27.7
(C-11), 22.4 (C-12), 13.8 (C-13) ppm.
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Acknowledgments
We thank Cardiff University for support and the EPSRC
National Mass Spectrometry Service Centre, Swansea, for mass
spectrometric data. We thank Dr. Robert Richardson, Cardiff
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