This work is focusing on an investigation of the influence of the reaction parameters on the suppression of the undesired amide formation as a side reaction. As a standard reaction, dehydration of Boc-prolinal oxime 4 at a substrate concentration of 0.5 m, a catalyst loading of 2 mol % and the use of 10 equivalents of acetonitrile in ethyl acetate for 4 h at 70 °C was selected (Scheme 2 ).

2.1 Variation of Catalyst Loading and Temperature

First, the influence of the amount of copper acetate on the progress of the reaction and side product formation was studied by varying the catalyst loading between 0.5 and 5 mol % (see Supporting Information). While no difference was observed between 1 and 5 mol % with respect to the total conversion as well as to the amide formation, the total conversion at a catalyst loading of 0.5 mol % decreased to 38 % (28 % nitrile 5 and 10 % amide 6). Thus, a catalyst loading of 2 mol % was chosen for the subsequent study of the impact of the reaction temperature on conversion and amide formation. The temperature was varied in the range of 70 °C to −20 °C using the standard reaction conditions (Table 1). The dehydration of aldoxime 4 takes place at all selected reaction temperatures, although with different rates. While the conversions at 70 °C and 50 °C are quantitative after four hours, the reaction time must be extended at lower temperatures in order to achieve full substrate consumption. It is also noteworthy that a reaction at −20 °C, without stirring, also leads to the formation of both nitrile and amide. To evaluate the effect of the temperature on amide formation, the reactions were carried out until complete conversion of the oxime was observed. When comparing the results, only a small effect of temperature can be noted, but there seems to be a tendency for a higher degree of amide formation at lower temperature. After complete conversion at 70 °C, 29 % of amide 6 are formed, in contrast to 37 % at 30 °C and 32 % at room temperature. To gain insight into the amide formation as a side reaction, a reaction without acetonitrile at room temperature and at 70 °C was also studied (Table 1, entries 9, 10). While almost no conversion of prolinal oxime 4 after 18 h was observed at room temperature, 7 % of nitrile 5 and 13 % of amide 6 were detected at 70 °C. This supports the assumption that the formation of the amide side product proceeds, at least in part, through the reaction mechanism of the aldoxime to nitrile conversion (in which the formed nitrile 5 then acts as a nitrile acceptor). At the same time, the presence of acetonitrile leads to an increased formation of amide 6 at both studied temperatures. This can be explained by the formation of the desired cyanopyrrolidine 5 in higher amount, which then acts as an intermediate in the undesired formation of the proline amide side product 6.

Table 1. Screening of temperature in copper(II)-catalysed dehydration of prolinal oxime 4.

Entry

T [°C]

Time [h]

Aldoxime 4 [%]

Nitrile 5 [%]

Amide 6 [%]

1

70

4

–

71

29

2

50

4

–

67

33

3

30

4

7

64

30

4

30

18

–

63

37

5

rt

4

21

63

16

6

rt

18

–

68

32

7

rt[a]

18

2

65

32

8

−20[a]

18

81

14

5

9

rt[b]

18

97

2

1

10

70[b]

18

80

7

13

[a] Without stirring; [b] without acetonitrile. 2.2 Variation of the Excess of the Acceptor Nitrile

Since an influence of the acetonitrile on conversion and side-product formation could be observed, the used equivalents were subsequently varied in a standard reaction at 70 °C. In detail, the number of equivalents was varied between 235 and 10, which in most cases has also been associated with a change in substrate concentration (Table 2). By increasing the amount of acetonitrile, the formation of side product 6 in the dehydration of prolinal oxime 4 can be reduced or almost suppressed. For example, an increase from 10 to 38 equivalents of acetonitrile in a reaction at 0.5 m substrate concentration leads to a significant decrease of the formation of side product 6 (26 % to 11 %, entries 8, 9). By successively increasing the number of equivalents of acetonitrile up to 235, which corresponds to a substrate concentration of 80 mm of 4 in pure acetonitrile, led to a further decrease of formation of the undesired amide 6 to only 1 % at a complete conversion of the aldoxime after 4 h (entry 1).

Table 2. Influence of acetonitrile equivalents and substrate loading on copper(II)-catalyzed dehydration of prolinal oxime 4.

Entry

Equiv. MeCN

Substrate concentration [mm]

Aldoxime 4 [%]

Nitrile 5 [%]

Amide 6 [%]

1

235

80

–

99

1

2

150

127

–

96

4

3

125

152

–

96

4

4

100

190

–

95

5

5

75

253

–

94

6

6

64

300

–

93

7

7

48

400

–

91

9

8

38

500

–

89

11

9

10[a]

500

–

74

26

10

10[a]

300

–

73

27

11

10[a]

100

9

68

23

[a] Ethyl acetate was used as solvent.

In contrast, a reduction of the substrate concentration to 100 mm using 10 equivalents of acetonitrile in ethyl acetate as a solvent only leads to a reduced reaction rate, but not to a relevant reduction of the formed undesired proline amide 6 in the reaction mixture (entry 11).

These results also support the described mechanism of an amide formation via a nitrile intermediate. Accordingly, an increased amount of acetonitrile as acceptor nitrile and, thus, co-substrate decreases the probability of a further reaction of the desired Boc-protected nitrile 5 as such a co-substrate in the further course of the reaction.

With these findings on the impact of various reaction conditions on the dehydration of aldoxime 4 in hand, we next focused on the preparation of Boc-2 cyanopyrrolidine 5 within a one-pot process starting from aldehyde 3 (Scheme 3). The reaction was carried out at a substrate concentration of 0.1 m using an aqueous hydroxylamine solution in acetonitrile.

One-pot synthesis of N-Boc-(S)-2-cyanopyrrolidine (5) in pure acetonitrile.

Compared to the one-step dehydration of prolinal oxime 4, a longer reaction time was needed to achieve full conversion of the starting material. After 24 h, N-Boc-(S)-2-cyanopyrrolidine (5) was isolated in a yield of 85 %, whereas only 5 % conversion to amide 6 was observed (Scheme 3). Note that an optical rotation analysis revealed a full retention of the chiral information.

Although using a large excess of acetonitrile enables suppression of the side product and high conversion, the resulting substrate concentrations of 80 or 100 mm are not attractive for an industrial application. Thus, other options to inhibit amide formation have been considered and, in particular, we became interested in a fine-tuning of the electronic properties of the acceptor nitrile with respect to the ability to add water within the dehydration step with aldoxime 4 as a substrate. We envisioned that reducing the electron density at the carbon atom of the nitrile moiety of the “acceptor nitrile” by electron-withdrawing substituents could lead to a faster (formal) addition of water during the dehydration process of the aldoxime substrate. In addition, the electronic properties of the aldoxime substrate should then play a role on both conversion and side product formation. While a general influence of electron donating substituents in this type of reaction is mentioned, an influence on amide formation under the chosen conditions has not yet been described.24

In order to verify this hypothesis, at first the influence of the electron density at the aldoxime on amide formation in the standard reaction was investigated (Figure 2). For this purpose, besides n-octanal oxime, various p-substituted benzaldoximes were chosen based on their Hammett values and used as substrates in a dehydration reaction.

Influence of substrate structure on dehydration of aldoximes using acetonitrile as an acceptor nitrile.

Initially, the benzaldoximes 7 a–e with different substitution pattern in 4-position were prepared from the respective aldehydes in good to excellent yields. Similarly, amides 11 a-e were obtained from the corresponding aldoximes as reference compounds in low to moderate yields by a copper(II)-catalyzed rearrangement in toluene. The Hammett values σp of the aromatic aldoximes ranged from 0.78 for p-nitrobenzaldoxime 7 a to −0.83 for p-(N,N-dimethyl)aminobenzaldoxime 7 e, defining the electronic characteristics of the p-substituents. Furthermore, n-octanal oxime (8) was investigated as an aliphatic substrate. We were pleased to find that the dehydration reaction under standard conditions (Scheme 1) indeed proceeded for all selected substrates. However, there is a considerable difference in the selectivity of the reaction.

For the aliphatic substrate n-octanal oxime (8), only a small amount of the side product n-octanamide (12) (3 %) is observed at complete conversion of the aldoxime (Figure 2).

When using the 4-substituted benzaldoximes 7 a–e as substrates, there is a clear dependency of the selectivity on the Hammett parameter and, thus, on the electron density at the carbon atom of the aldoxime group (Figure 2). When using benzaldoxime 7 e containing the dimethylamino group as the most electron-donating substituent in this study as a substrate, formation of the resulting benzamide 11 e in only 9 % yield was observed. However, when reducing the degree of electron donation, associated with an increasing σp value, the selectivity decreases sharply. While in the dehydration of unsubstituted benzaldoxime 7 c to benzonitrile 9 c already 17 % amide is formed, the selectivity decreases further for electron-withdrawing substituents. An amide formation of 31 % and 35 % in the dehydrations towards p-chlorobenzonitrile 9 b (σp=0.23) and p-nitrobenzonitrile 9 a (σp=0.78), respectively, was observed, although only a conversion of 95 % was noted in the latter case. These observations confirm that the reactivity of the aldoxime and the resulting nitrile significantly influence the progress and selectivity of the reaction. The electron-withdrawing substituent in para-position lowers the electron density at the cyanocarbon of the in situ formed p-nitrobenzonitrile 9 a, favoring a nucleophilic attack in the dehydration of unreacted aldoxime 7 a compared to the higher electron density of acetonitrile, which served as the acceptor nitrile in the initial dehydration step. In the conversion of octanal oxime 8, this effect is only slightly observed, since the resulting octanenitrile 10 has a similar electron density at the reactive center as acetonitrile. Here, the 10-fold excess of acetonitrile plays a more significant role, which leads to the suppression of the undesired amide formation in this case.

2.3 Variation of Acceptor Nitrile

Based on these findings, a modification of the acceptor nitrile with regard to suppression of amide formation was investigated next. At first, different monosubstituted, aliphatic acceptor nitriles such as butyronitrile or octanenitrile were used, but these acceptor nitriles showed no positive influence on the selectivity in the dehydration of prolinal oxime 4 (see Supporting Information). However, when using more electrophilic acceptor nitriles we found a significant increase of the reactivity with respect to water addition, as expected. In detail, we tested two different acceptor nitriles with such an expected higher reactivity, namely trichloroacetonitrile and succinonitrile (Figure 3). Trichloroacetonitrile exhibits a strong electrophilicity due to the trifold chlorine substitution, whereas succinonitrile has just a slightly lower electron density at the cyano-carbon atom compared to acetonitrile, but has the advantage of a bifunctionality. This bifunctionality theoretically enables to halve the number of equivalents compared to those needed for acetonitrile.

Influence of different acceptor nitriles on dehydration of p-nitro benzaldoxime 7 a.

The reaction was first carried out for both acceptor nitriles under standard conditions with p-nitrobenzaldoxime 7 a as aldoxime substrate, which, in previous experiments, had shown the highest tendency to amide formation. Ten equivalents of the nitrile functionalities were used in each case in the first place, resulting in the conversion of aldoxime 7 a to nitrile 9 a in both cases. When five molar equivalents of succinonitrile are used, a significant improvement of the selectivity (12 % amide) was observed in comparison with acetonitrile (35 % amide). On the other hand, reduction to two molar equivalents of succinonitrile leads to a non-complete conversion (96 %) of 7 a after 4 h with a similarly high amide 11 a content (33 %) compared to the experiment with ten equivalents of acetonitrile. When using trichloroacetonitrile as a co-substrate, we were pleased to find that this compound showed even better properties as a nitrile acceptor (Figure 3). Here, a complete conversion of the para-substituted benzaldoxime 7 a to nitrile 9 a was observed in the presence of 10, 5 and 2 equivalents. Furthermore, extractive and column chromatographic work-up gave the resulting product 4-nitrobenzonitrile 9 a in 89 % yield, which is a considerable increase compared to the synthesis using acetonitrile (58 %). Only with just an equimolar use of this acceptor nitrile, analogous to succinonitrile, an incomplete conversion and, with 35 %, a high proportion of the undesired p-nitrobenzamide 11 a as a side product was observed.

With this improved nitrile acceptor in hand, these findings were applied to the dehydration of Boc-prolinal oxime 4 as a next step. When utilizing either ten equivalents (data not shown) or even just two equivalents of trichloroacetonitrile, we were pleased to find a complete conversion of the aldoxime without formation of the undesired amide side-product (Scheme 4). For the experiment with two equivalents of trichloroacetonitrile, work-up and product isolation were conducted, which led to the isolation of the desired N-Boc-(S)-2-cyanopyrrolidine 5 in 92 % yield. Furthermore, also in this case full retention of the absolute configuration was observed.

Dehydration of Boc-prolinal oxime 4 with trichloroacetonitrile as the optimized nitrile acceptor.