Continuous-flow synthesis of nitriles from aldehydes via Schmidt reaction

Article abstract of DOI:10.1016/j.cclet.2019.01.006

A continuous-flow synthesis of nitriles by Schmidt reaction has been developed. Using this procedure, a variety of aldehydes could be smoothly transformed into the desired nitriles in good to excellent yields. The mild reaction conditions and the flowing reaction system greatly improved the safety and make the reaction easy to scale up.

Full text of DOI:10.1016/j.cclet.2019.01.006

Accepted Manuscript
Title: Continuous-flow synthesis of nitriles from aldehydes via
Schmidt reaction
Authors: Wei Zhan, Meng Tong, Ling Ji, Han Zhang, Zemei
Ge, Xin Wang, Runtao Li
PII:
DOI:
Reference:
S1001-8417(19)30023-3
https://doi.org/10.1016/j.cclet.2019.01.006
CCLET 4774
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
13 December 2018
2 January 2019
8 January 2019
Please cite this article as: Zhan W, Tong M, Ji L, Zhang H, Ge Z, Wang X, Li R,
Continuous-flow synthesis of nitriles from aldehydes via Schmidt reaction, Chinese
Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.01.006
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Communication
Continuous-flow synthesis of nitriles from aldehydes via Schmidt reaction
Wei Zhan, Meng Tong, Ling Ji, Han Zhang, Zemei Ge, Xin Wang*, Runtao Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Graphical Abstract
Continuous-flow synthesis of nitriles from aldehydes via Schmidt reaction
Wei Zhan, Meng Tong, Ling Ji, Han Zhang, Zemei Ge, Xin Wang*, Runtao Li*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191,
China
Using continuous-flow synthesis of nitriles by Schmidt reaction, a variety of aldehydes could be smoothly transformed into the
desired nitriles in good to excellent yields. The mild reaction conditions and the flowing reaction system greatly improved the
safety and make the reaction easy to scale up.
ARTICLE INFO
ABSTRACT
A continuous-flow synthesis of nitriles by Schmidt reaction has been developed. Using this
procedure, a variety of aldehydes could be smoothly transformed into the desired nitriles in good
to excellent yields. The mild reaction conditions and the flowing reaction system greatly
improved the safety and make the reaction easy to scale up.
Article history:
Received 13 December 2018
Received in revised form 2 January 2019
Accepted 4 January 2019
Available online
———
 Corresponding authors.
E-mail addresses: lirt@bjmu.edu.cn (R. Li), xinwang@bjmu.edu.cn (X. Wang).

Keywords:
Continuous-flow reaction
Aldehydes
Schmidt reaction
Nitriles
Safety
Nitriles are versatile important organic synthesis intermediates
in organic chemistry. They can be easily transformed into amides [1,2], amines [3,4], ketones [5,6], carbonic acids [7,8], esters [9] and
other important functional group [10-13]. Furthermore, the cyano group, as a key pharmacophore, widely exists in the structure of many
bioactive compounds and drugs (Scheme 1) [14-18]. Classical synthetic methods of nitriles are Sandmeyer reaction [19] and Rosenmund-
von Braun reaction [20] which require highly toxic cyanide salts and produce large amounts of inorganic salts as waste. Also some
metal-catalyzed oxidative synthesis of nitriles from primary amines or alcohols have been developed and achieved great success [21,22].
Direct synthesis of nitriles from aldehydes via the Schmidt reaction was a promising way [23-25], while it has not received wide
acceptance by the synthetic community likely due to the use of highly toxic and dangerous azide compounds. Recently, Rokade and
Prabhu [26] reported that NaN3/TfOH provides a superior medium for selective conversion of aromatic aldehydes to nitriles, whereas it
still produces the toxic HN3 and excessive amounts of TfOH was needed (Scheme 2a). Laali [27] has also successfully achieved the
selective Schmidt reaction of aldehydes in ionic liquids (Scheme 2b).
Scheme 1. Nitriles in bioactive natural products, pharmaceuticals and pesticide.
Scheme 2. Selective Schmidt reaction.
In the past decade, micro-reactor technology has emerged as a powerful tool for solving synthetic problems in the field of
pharmaceutical and fine chemical research due to its environmental friendliness, efficiency and safety [28-36]. The recent special issue
in Bioorganic & Medicinal Chemistry has reported the organic synthesis in flow for medicinal chemistry [37]. The azides have been
successfully applied in several reactions in continuous flow mode [38-41]. For example, Yanada and co-workers developed an efficient
one-pot synthesis of 1,2,3-triazole-fused isoindoles from o-alkynylbenzaldehydes and trimethylsilyl azide (TMSN3) through the
formation of a diazide intermediate and a subsequent intramolecular azide-alkyne cycloaddition in high yields [42]. Yakambram reported
a simple and convenient metal free procedure for the synthesis of 5-substituted 1H-tetrazoles using various nitriles and sodium azide in
the presence of urea and acetic acid with good to high yields [43]. A microreactor setup was developed in which methyl azide (MeN3)

was successfully generated and performed, demonstrating that the flow method serves as a safe method for handling hazardous explosive
methyl azide [44].
Therefore, we envisioned to synthesize nitriles from aldehydes via the classical Schmidt reaction in flow mode in order to improve the
safety and make it easy to scale up.
In this experiment, 1H and 13C NMR spectra were recorded on Bruker NMR spectrometer (1H 400 MHz, 13C 100 MHz). HPLC analysis
was performed on Agilent 1260 (DAD: 254 nm; column: agilent zorbax eclipse ZORBAX SB-C18 (4.6 × 150 mm, I.D. 5 µm); mobile
phase: MeCN-water, 30% MeCN within 20 min, flow rate 1.0 mL/min). Selective hydrolysis of nitriles was performed in a Labtrix S1
continuous flow system equipped with a SOR-mixer reactor 3222 (Width channel: 300 μm, Depth channel: 120 μm, Reactor Volume: 5
μL) and a back pressure regulator (0-20 bar). The pictures of Labtrix S1 and SOR-mixer reactor 3222 are shown in Supporting
information. Syringes were purchased from SGE Analytical science (I.D. = 4.610 mm, volume = 1 mL).
General procedure for synthesis of nitriles from aldehydes in continuous flow is as follows. Take benzaldehyde as an example,
benzaldehyde (0.6 mmol) and TfOH (0.9 mmol) were dissolved in 3 mL MeCN and pumped into inlet A. TMSN3 (0.6 mmol) was
dissolved in 3 mL MeCN and pumped into inlet B (flow rate A: B = 54 μL/ min:65 μL/ min for 5 s residence time). The whole system
was maintained at 25 C. The flow system was equilibrated (about 5 min), then the product stream was quenched and collected in a glass
vessel with saturated aqueous NaClO in it. The flow system was stopped after the inlet A reduced 0.5 mL. The crude mixture was
dissolved in ethyl acetate and washed with saline solution. The combined organic layers were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel with hexane and
EtOAc as eluent to afford the product (details seeing Supporting information).
Firstly, benzaldehyde was chosen as a model reaction substrate, acetonitrile as solvent, different acids and azides were tested in
microreactors. As shown in Table 1, NaN3 and TMSN3 were both capable for conducting this reaction in the presence of TfOH.
Comparing to TMSN3, NaN3 is more toxic and need DMSO as solvent, so TMSN3 was selected to the following screening. Considering
TfOH is costly, a mixed acids of TfOH and acetic acid with different ratio were also examined and the conversion ratio was not good
enough (Table 1, entries 10-12). Hence, TMSN3 and TfOH was chosen to establish the following flow-platform: Benzaldehyde and TfOH
were taken up in MeCN and pumped into inlet A, while TMSN3 was pumped into inlet B. The reaction stream was pressurized by a 10
bar back pressure regulator (BPR) and the outflow was collected. After being filtered, the outflow was analyzed by HPLC to determine
the conversion (Scheme 3).
Table 1
Different combination of acids and azides.a
Entry
1
2
3
4
5
6
7
Acids (equiv.)
POCl3 (3.0)
POCl3 (3.0)
POCl3 (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
CH3COOH (3.0)
H2SO4 (3.0)
HCl (3.0)
RN3
Solvent
MeCN
MeCN
DMSO
MeCN
MeCN
DMSO
MeCN
MeCN
MeCN
MeCN
Conversion (%)
0
TMSN3
DPPAb
NaN3
TMSN3
DPPAb
NaN3
TMSN3
TMSN3
TMSN3
TMSN3
7.6
35
100
15
100
0
0
0
13
8
9
10
CH3COOH (2.8) +
TfOH (0.2)
11
12
CH3COOH (2.5) +
TfOH (0.5)
CH3COOH (2.0) +
TfOH (1.0 )
TMSN3
TMSN3
MeCN
MeCN
40
93
a Reaction condition: solution A: 0.6 mmol benzaldehyde and 1.8 mmol acids dissolved in 3 mL MeCN or DMSO, solution B: 0.6 mmol RN3 dissolved in 3 mL
MeCN, flow rate A: B = 54 μL/ min:65 μL/ min, residence time t = 150 s, T = 150 C.
b DPPA: diphenylphosphoryl azide.

Scheme 3. A simple set-up for flow platform.
Next, we turned our attention to the optimization of the reaction parameters in a continuous-flow microreactor (Table 2). It can be
seen that the conversion ratio was quantitative even if the residence time decreased from 120 s to 5 s (Table 2, entries 1-7). The change
of temperature did not affect the reaction, either. The conversion rate of the reaction maintained 100% when the reaction temperature
dropped from 100 C to 25 C (Table 2, entries 6, 8-13). Reducing the amount of TfOH to 1.1 equiv. would not cause any loss of
conversion (Table 2, entries 13-18). Taking into account the difference of substrate activity and some follow-up exploratory experiments,
we confirmed that the final response parameters were the reaction temperature of 25 C, the residence time of 5-15 s and the TfOH of
1.5 equiv.
Table 2
Optimization of residence time, temperature and the equivalent of TfOH.a
Entry
1
2
3
4
5
6
7
8
Residence time (s)
X
Conversion (%)
100
Temperature (C)
100
100
100
100
100
100
100
80
60
50
40
30
25
25
25
25
25
25
120
60
30
15
10
5
2
5
5
5
5
5
5
5
5
5
5
5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.5
1.1
0.5
0.2
100
100
100
100
100
99.5
100
100
100
100
100
100
100
100
100
40
13
9
10
11
12
13
14
15
16
17
18
a Reaction condition: solution A: 0.6 mmol benzaldehyde and 0.6x mmol TfOH dissolved in 3 mL MeCN, solution B: 0.6 mmol TMSN3 dissolved in 3 mL MeCN,
flow rate A: B = 54 μL/ min:65 μL/ min.
With the optimized reaction conditions in hand, we next surveyed the scope of this approach. As shown in Scheme 4, all tested
substrates produced the expected nitriles in good to excellent yields. For substituted benzaldehydes, whatever it bearing electron-donating
or electron-withdrawing groups, i.e., halogen, methoxyl, trifluoromethyl, amino and nitro, were all tolerated in this transformation (1b-
1g, 88%-95%). The position of substituent had little effect on the reaction (1g-1l). The substrates bearing aryl substitution or
polysubstitution could also react well to provide the desired nitriles as long as the residence time was prolonged to 10 s (1m-1n). The
presence of extra functional group such as hydroxyl or cyano on benzaldehydes had no effect on the reaction (1o-1p). Heteroaromatic
aldehydes were suitable as well, leading to the corresponding products 1q-1s in excellent yields. Notably, phenyl acetaldehyde and
cinnamaldehyde could also be smoothly transformed into the desired nitriles 1t and 1u in 98% and 88% yields, respectively.
In summary, we have successfully carried out the synthesis of nitriles via Schmidt reaction in a continuous-flow microreactor. The
advantages of this method include broad substrate scope, high yields, rapid reaction, simplicity and convenience. Most importantly, this
procedure greatly improves the safety and is easy to scale up. Thus, the approach will be very useful in the preparation of various nitriles.

Scheme 4. Substrate scope under optimized condition. Reaction condition: solution A: 0.6 mmol substituted benzaldehyde and 0.9 mmol TfOH
dissolved in 3 mL MeCN, solution B: 0.6 mmol TMSN3 dissolved in 3 mL MeCN. Flow rate A: B = 54 μL/ min:65 μL/ min, residence time t =
5 s, T = 25 C. aResidence time is 10 s.
Acknowledgment
The authors thank the National Natural Science Foundation of China (No. 21877005) for financial support.
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