Ritter reactions in flow

Article abstract of DOI:10.1002/cssc.201100372

Flow me a Ritter: Ritter reactions are performed in a simple microreactor setup using tert-butylacetate as versatile carbocation source. The protocol avoids the handling of large amounts of hot concentrated sulfuric acid as low concentrations are optimal for rapid access tert-butyl- or diphenylmethyl- protected amides. Copyright

Full text of DOI:10.1002/cssc.201100372

DOI: 10.1002/cssc.201100372
Ritter Reactions in Flow
Logan Audiger,[a] Kevin Watts,[a] Simon C. Elmore,[a] Richard I. Robinson,[b] and Thomas Wirth*[a]
Modern organic synthesis is undergoing a period of rapid
change due to the many demands challenging it today. The in-
troduction of more general platforms to perform reactions
under continuous flow rather than in batch mode has led to
improvements regarding safety and sustainability. Many reac-
tions can benefit from the physical properties of microreactors,
including short diffusion distances, enhanced mass and heat
transfer due to very large surface-to-volume ratios, as well as
regular flow profiles, leading to improved yields with increased
selectivities and better reproducibility.[1]
concentrated sulfuric acid, which are the conditions of the
original work.[6] The Ritter reaction is therefore a challenging
subject for microreactor technology,[13] and we report here that
this approach is advantageous with regards to safety, produc-
tivity, and tolerance towards substrate functionalities.
Initial optimizations using different solvents were performed
using cyclohexanol 1 (Scheme 1, R=C6H11) as alcohol and ace-
tonitrile 2 (R’=Me). It was found that highest yields of amide 3
could be obtained using acetic acid, although other solvents
such as nitrobenzene or dioxane have also been described in
successful Ritter reactions.[14]
Microreactors are ideally suited to the use of hazardous re-
agents or for the generation of dangerous intermediates. This
has been recognized by many research groups and we have
contributed to this area, also. Recently, we described Ritter re-
actions in flow chemistry and will give a full account of this
work herein.[2] In addition, we describe the use of tert-butyl
acetate as a convenient alternative to tert-butanol as cation
source and also employ diphenylmethanol as a versatile cation
precursor to the corresponding diphenylmethyl-substituted
amides.
Scheme 1. Procedure A: Ritter reaction with alcohols (R=alkyl, R’=alkyl,
alkenyl, aryl).
The nucleophilic attack of a nitrile or cyanide to a carbenium
ion followed by hydrolysis of the resulting intermediate to
amides is known as the Ritter reaction.[3] The fast access to
amides has been advantageous for the synthesis of natural
products, pharmaceuticals, and heterocyclic compounds.[4] Pro-
tonation of alkyl alcohols or alkenes will lead to the required
carbenium ions. The generation of primary carbenium ions is
difficult as it requires rigorous reaction conditions.[5] Secondary
and tertiary alcohols are best suited as starting materials in the
Ritter reaction.[6] Strong acidic conditions, hazards such as tox-
icity, especially for the use of cyanides, and the strongly exo-
thermic character of the reaction are of concern, es-
Concentrated sulfuric acid was found to be the most effi-
cient acid for the Ritter reactions described here; other Lewis
acids such as BF3 led to the exclusive formation of acetic acid
cyclohexyl ester. On the basis of these first experiments, a pro-
tocol with reaction times of about 1 min at 458C (858C for sec-
ondary alcohols) was established. Also 2-methyl-2-butene was
evaluated as a substrate in the Ritter reaction and exposed to
different solvents and reaction conditions. Yields of up to 60%
were obtained using acetonitrile as solvent and 75% sulfuric
acid at 858C. Reactions at lower temperatures or at lower sul-
pecially when operating on a large scale. The occur-
rence of hot-spots or even thermodynamic runaways
have to be considered in batch-mode reactions, es-
pecially with increasing batch size.[7] Several proto-
cols that show improved and optimized processes
have been published. For example, the use of mild
Lewis acids or microwave irradiation,[8] even without
solvents,[9] in ionic liquids,[10] and diastereoselective
Ritter reactions using trifluoromethane sulfonic acid
have been described,[11] as well as fluoro-Ritter reactions in mi-
croreactors.[12] Best conversions are achieved with excess of
Scheme 2. Ritter reaction with alkene 4.
furic acid concentrations were less efficient. In order to make a
comparison between the original Ritter procedure and the
flow process, the Ritter reaction shown in Scheme 2 was also
performed in a flask, where a yield of 66% was obtained.
In addition to amide 5, a side product 6 was observed in the
reactions under flow conditions (ratio 5/6~15:1) as a result of
a methyl group cleavage under the strong acidic conditions.
Details of this side reaction and a possible mechanistic explan-
ation have already been published.[2] The side product 6 was
not observed in the batch reaction.
[a] L. Audiger, K. Watts, S. C. Elmore, Prof. T. Wirth
School of Chemistry, Cardiff University
Park Place, Cardiff CF10 3AT (UK)
Fax: (+44)29-2087-6968
E-mail: wirth@cf.ac.uk
[b] Dr. R. I. Robinson
Novartis Horsham Research Centre, Global Discovery Chemistry
Wimblehurst Road, Horsham, West Sussex, RH12 5AB (UK)
ChemSusChem 2012, 5, 257 – 260
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257

tert-Butylcations can also be generated from tert-butylace-
tate 7 and this approach has already been successfully used in
batch-type Ritter reactions.[15] A similar reaction, which uses
tert-butylacetate 7 as cation source, was performed in flow
using benzonitrile 2a. N-tert-Butyl benzamide 8a was obtained
in yields up to 77%. A reaction time of 6 min at 458C using
concentrated sulfuric acid diluted in acetic acid as reaction sol-
vent proved to be optimal (Table 1, entry 2) when using 7 as
Table 2. Different nitriles 2 for the Ritter reaction with tert-butylacetate.[a]
Entry
Nitrile 2
Product 8
Yield
[%]
1
H2C=CHÀCN
H5C2ÀCN
2b
2c
2d
8b
8c
8d
30
42
10
2
3[b]
NCÀCH2ÀCN
Table 1. Optimization of the Ritter reaction in Scheme 3 using tert-butyla-
cetate as carbocation source.[a]
4
4-FÀC6H4ÀCN
2e
2 f
8e
8 f
70
60
Entry
H2SO4 concentration in
reaction mixture [M]
Solvent AcOH/H2O
ratio
T
[8C]
Yield 8a
[%]
5[c]
2-MeÀC6H4ÀCN
1
2
3
4
5
6
7
8
9
2.2
2.2
2.2
4
4
4
3.3
3.3
3.3
100:0
100:0
100:0
100:8
100:8
100:8
100:15
100:15
100:15
25
45
80
25
45
80
25
45
80
63
77
46
55
62
35
52
10
10
[a] 2 Equiv 7, 458C, 96% H2SO4, residence time 6 min. [b] 4 Equiv 7 were
used. [c] Performed as batch experiment.
as nitrile did not lead to the expected amide, instead the hy-
drolysis of the nitrile to pyridine-2-carboxylic acid was ob-
served under the reaction conditions.
[a] 2 Equiv 7, residence time 6 min.
As we have already shown before, secondary and tertiary al-
cohols can be used similarly well in Ritter reactions as shown
in Scheme 1. We have investigated a series of nitriles in the
Ritter reaction using diphenylmethanol (Ph2CHOH) as sub-
strate. All products 9 of these reactions had to be purified by
column chromatography and are listed in Table 3. Using excess
diphenylmethanol leads to the formation of acetic acid diphe-
nylmethyl ester in variable amounts.[17] Variation of the reaction
conditions and using the nitrile as solvent instead of acetic
acid led to the formation of a clean Ritter reaction product not
requiring purification. Compound 9c was obtained in 72%
tert-butylcation precursor. The dilution of lower concentrated
sulfuric acid in acetic acid as reaction solvent (entries 4–6:
85%; entries 7–9: 70%) resulted in a considerable amount of
water being present in the reaction mixture, which is leading
at higher or lower temperatures to much lower yields of reac-
tion product 8a as shown in Table 1.
In all Ritter reactions in flow, a Teflon micromixer[16] (A in
Figure 1, internal volume 29 mL) was connected to PTFE tubing
(B in Figure 1, 2 m length, 0.5 mm inner diameter, 393 mL
volume).
Table 3. Different nitriles 2 used in the Ritter reaction with diphenyl-
methanol.[a]
Entry
Nitrile 2
Product 9
Yield
[%]
1
PhÀCN
2a
2b
2c
2d
9a
9b
9c
9d
43
Figure 1. Schematic set-up of the flow reaction. A: micromixer, B: PTFE
tubing, C: aq. NaOH.
2
H2C=CHÀCN
H5C2ÀCN
75
3
21,72[c]
29
Different nitriles 2 have the been used together with 7 in
Ritter reactions (Scheme 3). The products 8 shown in Table 2
have been obtained in moderate yields. Only 2-cyanopyridine
4[b]
NCÀCH2ÀCN
5
6
4-FÀC6H4ÀCN
2e
2g
9e
9 f
44
MeCN
81[d]
[a] 2 Equiv diphenylmethanol, 458C, 96% H2SO4, residence time 6 min.
[b] 4 Equiv diphenylmethanol. [c] Reaction performed in propionitrile 2c
as solvent. [d] Reaction performed in acetonitrile 2g as solvent.
Scheme 3. Procedure B: Ritter reaction using tert-butylacetate 7.
258
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ChemSusChem 2012, 5, 257 – 260

N-tert-Butyl-propanamide 8c:[10] yield: (135 mg, 1.05 mmol, 42%);
colorless solid: m.p.: 848C; H NMR (CDCl3, 400 MHz): d=1.10 (3H,
t, J=7.5 Hz), 1.33 (9H, s), 2.10 (2H, q, J=7.5 Hz), 5.25 ppm(1H, br
s); 13C NMR (CDCl3, 100 MHz): d=9.8, 28.8, 30.5, 51.0, 173.1 ppm.
yield on a 7.5 mmol scale and 9 f was isolated in 81% yield
when a 30 mmol scale reaction was performed.
1
Diphenylmethyl-substituted amides have been important for
the characterization of amides, as they usually provide solid
compounds.[18] The N-diphenylmethyl substituent is also being
used as an amine or amide protection group with a higher sta-
bility to acidic conditions than the trityl (triphenylmethyl)
moiety.[19] An adaption of the reaction conditions to perform
carboxylations of the carbocations described herein (Koch-Haaf
reaction)[20] in flow were not yet successful.
N,N’-di-tert-butyl-malonamide 8d:[9b] yield: (51 mg, 0.24 mmol,
10%); colorless solid: m.p.: 1188C; 1H NMR (CDCl3, 400 MHz): d=
1.28 (18H, s), 2.94 (2H, s), 6.76 ppm (2H, s); 13C NMR (CDCl3,
100 MHz) d=29.0, 45.6, 51.8, 167.4 ppm.
N-tert-Butyl-4-fluorobenzamide 8e:[21] yield: (342 mg, 1.75 mmol,
70%); colorless solid: m.p.: 1278C; 1H NMR (CDCl3, 400 MHz): d=
1.45 (9H, s), 5.95 (1H, br, s), 7.02–7.07 (2H, m); 7.68–7.73 ppm (2H,
m); 13C NMR (CDCl3, 100 MHz): d=29.3, 52.1, 115.8 (J=22 Hz),
129.4 (J=9 Hz), 132.4 (J=3 Hz), 164.9 (J=249 Hz), 166.3 ppm.
In conclusion, we have used a series of nitriles and shown
that they react under flow conditions with tert-butyl acetate or
with diphenylmethanol as convenient sources for carbocations
to yield the corresponding amides. This protocol avoids the
handling of large amounts of hot concentrated sulfuric acid as
reaction concentrations of 2.3m were found to be optimal to
rapidly access tert-butyl- or diphenylmethyl-protected amides.
N-tert-Butyl-2-methylbenzamide 8 f:[22] 1H NMR (CDCl3, 400 MHz):
d=1.49 (9H, s), 2.45 (3H, s), 5.57 (1H, br, s), 7.21 (2H, m); 7.28–
7.35 ppm (2H, m).
N-(Diphenylmethyl)-benzamide 9a:[23] yield: (158 mg, 0.55 mmol,
44%); colorless solid: m.p.: 1728C; 1H NMR (CDCl3, 400 MHz): d=
6.47 (1H, d, J=7.6 Hz), 6.66–6.68 (1H, m), 7.24–7.50 (13H, m) 7.80–
7.86 ppm (2H, m); 13C NMR (CDCl3, 100 MHz): d=57.9, 127.5, 127.9,
128.0, 129.1, 129.2, 132.2, 134.6, 141.9, 166.9 ppm.
Experimental Section
General: Melting points were obtained in open capillary tubes and
1
are uncorrected. H NMR and 13C NMR spectra were recorded on a
N-(Diphenylmethyl)-acrylamide 9b:[24] yield: (223 mg, 0.94 mmol,
75%); colorless solid; m.p.: 1768C; 1H NMR (CDCl3, 400 MHz): d=
5.65–5.70 (1H, m), 6.09–6.38 (4H, m), 7.23–7.37 ppm (10H, m);
13C NMR (CDCl3, 100 MHz): d=57.5, 127.8, 127.9, 128.0, 129.1,
130.9, 141.7, 165.0 ppm.
AV-400 Bruker using the solvents indicated at 400 and 100 MHz, re-
spectively. Mass spectra (m/z) and HRMS were recorded under the
conditions of electron impact (EI) and electrospray (ES) and chemi-
cal ionization (CI). All reactions were monitored by thin-layer chro-
matography that was performed on precoated sheets of silica gel
60, and flash column chromatography was performed with silica
gel 60 (Merck, 230–400 mesh). Eluting solvents are indicated. All
experiments were performed under an inert atmosphere of argon.
All purchased chemicals were used without further purification.
N-(Diphenylmethyl)-propaneamide 9c:[24] yield: (63 mg, 0.26 mmol,
21%). Reaction using 7.5 mmol diphenylmethanol performed in
propionitrile: yield: 1.29 g, 5.4 mmol, 72%. colorless solid; m.p.:
1448C; 1H NMR (CDCl3, 400 MHz): d=1.20 (3H, t, J=7.5 Hz), 2.30
(2H, q, J=7.5 Hz), 6.03 (1H, d, J=7.8 Hz) 6.26 (1H, d, J=7.8 Hz),
7.20–7.36 ppm (10H, m); 13C NMR (CDCl3, 100 MHz): d=9.8, 29.7,
56.7, 127.3, 127.4, 128.6, 141.6, 172.7 ppm.
General procedure: Syringe A was loaded with concentrated
H2SO4 (96%: 0.24 mL, 85%: 0.5 mL, 70%: 0.5 mL), diluted with
acetic acid to 1 mL. tert-Butyl acetate 7 (5 mmol, 0.671 mL) or
diphenylmethanol (5 mmol, 920 mg) and nitrile 2 (2.5 mmol) were
diluted with acetic acid to 1 mL and loaded to syringe B. The PTFE
micromixer and the attached PTFE tubing (2 m, 0.5 mm inner di-
ameter) were inserted into the heating bath and the temperature
was adjusted to the desired temperature (458C). The flow rate was
set at 50 mLminÀ1 (reaction time: 6 min) and the solutions were de-
livered to the micromixer using a syringe pump (KD Scientific Inc).
The crude product was quenched by dropping into excess of ice/
2m NaOH. After the reaction, the tube was flushed with acetic acid
and the addition of an aqueous solution of 2M aq. CH3CO2Na
(5 mL) allowed the precipitation of the product. The reaction mix-
ture was filtered, washed with water and the product was collect-
ed and dried under vacuo. The crude product was purified by flash
chromatography with petroleum ether/ethyl acetate (4:1). For the
reactions performed without acetic acid the acetic acid was re-
placed with the nitrile used, no product purification by chromatog-
raphy was necessary in these reactions.
N,N’-Bis(diphenylmethyl)-propanediamide 9d:[24] yield: (162 mg,
0.37 mmol, 29%); colorless solid; m.p.: 1678C; 1H NMR (CDCl3,
400 MHz): d=3.26 (2H, s), 6.20 (2H, d, J=8.1 Hz), 7.19–7.30 (20H,
m), 7.79 ppm (2H, d, J=8.0 Hz); 13C NMR ([D6]DMSO, 100 MHz): d=
43.8, 56.5, 127.4, 127.6, 128.2, 142.7, 166.5 ppm.
N-(Diphenylmethyl)-4-fluorobenzamide 9e:[23] yield: (337 mg,
1.1 mmol, 44%); colorless solid; m.p.: 2148C; 1H NMR (CDCl3,
400 MHz): d=6.42 (1H, d, J=7.6 Hz), 6.69 (1H, d, J=7.2 Hz), 7.06–
7.12 (2H, m), 7.27–7.33 (10H, m), 7.79–7.82 ppm (2H, m); 13C NMR
(CDCl3, 100 MHz): d=58.0, 116.1 (J=22 Hz), 127.5, 127.7, 127.9,
129.2, 129.9 (J=8 Hz), 129.9, 141.7, 165.3 (J=248 Hz), 165.9 ppm.
N-(Diphenylmethyl)-acetamide 9 f:[9b] use of 30 mmol (5.52 g) di-
phenylmethanol. Yield 9 f: (5.49 g, 24.4 mmol, 81%); colorless
1
solid; m.p.: 154–1558C; H NMR (CDCl3, 250 MHz): d=2.04 (3H, s),
6.26 (2H, s), 7.19–7.38 ppm (10H, m); 13C NMR (CDCl3, 63 MHz): d=
23.3, 57.0, 127.4, 128.7, 141.5, 169.1 ppm.
N-tert-Butyl-benzamide 8a:[21] yield: (340 mg, 1.92 mmol, 77%); col-
1
orless solid, m.p.: 1368C; H NMR (CDCl3, 400 MHz): d=1.29 (9H, s),
Acknowledgements
7.03 (1H, m), 7.25 (3H, m), 7.45 ppm (2H, m); 13C NMR (CDCl3,
100 MHz): d=27.6, 39.6, 120.0, 124.2, 129.0, 138.0, 176.6 ppm.
Financial support by Novartis, the EPSRC, and the School of
Chemistry, Cardiff University, is gratefully acknowledged. We also
thank the University of Nantes, France (L.A.) for support.
N-tert-Butyl-acrylamide 8b:[9b] yield: (95 mg, 0.75 mmol, 30%); col-
orless solid; m.p.: 1298C; 1H NMR (CDCl3, 400 MHz): d=1.39 (9H,
s), 5.55 (dd, J=10.0, 1.0 Hz, 1H), 5.82 (1H, br s), 6.02–6.16 (1H, m),
6.16–6.29 ppm(1H, m); 13C NMR (CDCl3, 100 MHz): d=28.8, 51.3,
125.4, 132.2, 165.0 ppm.
ChemSusChem 2012, 5, 257 – 260
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www.chemsuschem.org
259

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Keywords: amides · carbocations · medicinal chemistry ·
microreactors · Ritter reactions
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