New Strategies for Sulfate-Free Synthesis of Lactams from Cycloalkanes Using NHPI as a Key Catalyst

Yasutaka Ishii*, Satoshi Sakaguchi, and Yasushi Obora

Department of Chemistry and Material Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University,Suita, Osaka 564-8680, Japan

(Received June 27,2008; E-mail: [email protected])

Abstract: New strategies for lactams synthesis from cycloalkanes without formation of sulfates have been

proposed. The synthesis of lactams from cycloalkanes through a one-pot reaction was successfully per- formed using N-hydroxyphthalimide (NHPI) as a key catalyst. The strategy involves nitrososation of cycloalkanes with tert-butyl nitrite under the influence of NHPI followed by isomerization to oximes and then the Beckmann rearrangement to lactams. For example, e-caprolactam and laurolactam were prepared from cyclohexane and cyclododecane in 74% and 78% yields, respectively, in one-pot. An alternative approach for sulfate-free lactam synthesis includes the nitration of cyclohexane with NO2 to nitrocyclohex- ane in the presence of NHPI under mild conditions followed by the hydrogenation to cyclohexanone oxime. The Beckmann rearrangement to ƒÃ-caprolactam was found to be achieved in quantitative yields by a very

small amount of cyanuric chloride in a mixed solvent of trifluoroacetic acid and toluene.

amount of ammonium sulfate waste in both the hydroxyl- 1. Introduction amine production and the Beckmann rearrangement processes. The development of an innovative methodology for the About 2.8 kg of ammonium sulfate is generated per kil- production of bulk and commodity chemicals, in particular ogram of cyclohexanone oxime produced. Recently, ones that take account of effects on the environment, Sumitomo Chemical Co. have industrialized vapor-phase becomes more and more important in industrial chemistry Beckmann rearrangement of cyclohexanone oxime derived from wordwide.1'2 For instance, lactams are very important raw cyclohexanone, H,02 and NH3 on TS-1 catalyst without materials for the synthesis of polyamides like nylon-6 and formation of sulfate (Route D).5 However, the development nylon-12. In particular, e-caprolactam is one of the of sulfate-free lactams synthesis still remains an important monomers most widely used for the production of nylon-6; subject. Particularly, the direct synthesis of lactams from in 2005, worldwide production of e-caprolactam amounted cycloalkanes without formation of any sulfate is a goal of the to about 4 X 106 tons. Currently, several different ways are lactams synthesis in industrial chemistry. employed for the production of e-caprolactam (Scheme 1). Scheme 1. The route currently used for the manufacture of The most popular route to lactam involves the following e-caprolactam. sequential reactions: (i) aerobic oxidation of cyclohexane to a mixture of KlA-oil (a mixture of cyclohexanone and cyclo- hexanol), (ii) dehydrogenation of alcohol to ketone, (iii) oxi- mation of cyclohexanone with hydroxylamine, and (iv) the Beckmann rearrangement of oxime to lactam with oleum (Route A). The Toray method (PNC process) is the oxima- tion using the photochemically initiated reaction of cyclohex- ane with NOC1 followed by treatment of the resulting oxime by oleum (Route B). This involves the direct conversion of cyclohexane to e-caprolactam precursor, but the PNC pro- cess must use very corrosive NOCI combined with HCl as a key compound.' In addition, cyclohexanone oxime is obtained as hydrochloric acid salt and the formation of NOCI is very troublesome. Another possibility is nitrosation of cyclohexane carboxylic acid with NOHSO4 (Route C). Of these technologies, Route A is most commonly employed and Recently, we have developed a novel catalytic method for accounts for about 70% of total production of e-caprolactam the generation of alkyl radicals from saturated hydrocarbons worldwide. However, this method incurs several drawbacks. using N-hydroxyphthalimide (NHPI) which serves as the rad- Cyclohexanone is now supplied by the aerobic oxidation of ical catalyst,6 and showed that the phthalimide N-oxyl cyclohexane which results in a mixture of cyclohexanone and (PINO) radical generated in situ from NHPI and 02, which cyclohexanol, but the conversion of cyclohexane must be kept lies in a triplet state, abstracts the hydrogen atom from the at only 3-6% to avoid the formation of further oxidation saturated hydrocarbons, forming the corresponding alkyl rad- products such as adipic acid and glutaric acid.3 Another seri- icals which are readily trapped by 02 under aerobic condi- ous drawback of this method is the co-production of a large tions to give oxygen-containing compounds like alcohols,

1066 (30) J. Synth. Org. Chem., Jpn. ketones and carboxylic acids. Thus, our attention is directed this nitrosation (entry 8). When the amount of l a or toward the development of the NHPI-catalyzed nitrosation CD3000D was halved, 2a was formed in slightly lower yield and nitration of cycloalkanes which provides new strategies (entries 9 and 10). The reaction did not take place at all in for lactams synthesis without the formation of sulfate. In this the absence of CD3000D (entry 11). Almost no reaction review, we disclose innovative strategies for lactams synthesis occurred when CD3CN was employed in place of acetic acid from cycloalkanes employing the NHPI as a key catalyst. (entry 12).

2. Nitrosation of Cycloalkanes with t-BuONO by NHPI Table 1. Nitrosation of cyclohexane (1a) with t-Bu0N0 catalyzed by NHPI. 2.1 Nitrosation of Cycloalkanes in Acetic Acid In the course of our studies on the NHPI-catalyzed func- tionalization of cycloalkanes, we found that the nitrosation of cycloalkanes with tert-butyl nitrite (t-BuONO) is first suc- cessfully achieved without photo-irradiation under halogen- free conditions by using NHPI as a catalyst (Eq. 1).8

Cyclohexane (la) was allowed to react with t-BuONO in

the presence of NHPI (0.1 equiv) in acetic acid at 80 •Ž for 2 a (4 mmol, 0.5 mL) was allowed to react with t-BUONO (0.5 mmol) h under argon (standard conditions). Evaporation of the sol- in the presence of NHPI (0.05 mmol) in CD3000D (0.5 mL) at 80 •Ž

vent and the unreacted starting materials followed by a short for 2 h under argon. The yield of 2a based on 2 used was determined by 'H-NMR using a known amount of nitromethane as an internal column chromatography on acidic alumina (hexane : ethyl standard and was average of two runs. b The abbreviations refer to the acetate = 5 : 1) gave nitrosocyclohexane (2a) (51%) which structures shown below. ` Reaction was carried out at 70 •Ž d The exists in dieter form. This is the first catalytic transformation recovered catalyst from the reaction in entry 1 was used. C la (2 mmol, 0.25 mL) was used. f CD3000D (0.25 mL) was used. g In the absence of la to 2a under relatively mild conditions (at 80 •Ž for 2 h). of CD3COOD. " CDICN (0.5 mL) instead of CD3000D was used. Most of the tent-butyl moiety of t-BuONO was found to be ' Reaction was carried out under 0 2 atmosphere. Reaction was carried converted into tert-butyl alcohol (vide infra). Since tert-butyl out under dark. k n-BUONO (0.5 mmol) was used instead of alcohol is known to react with NO2 or sodium nitrite to pro- t-BuONO.' Reaction time was 6 h.

duce t-BuONO,9 the nitrite may be regenerated from the

tert-butyl alcohol formed. This suggests that the present

nitrosation of la using t-BuONO provides a green route to

2a (Scheme 2).

Scheme 2. A new route to e-caprolactam precursor.

The reaction under 02 atmosphere was accompanied by Additionally, an independent LC-MS analysis of the 2a (28%) and considerable amounts of cyclohexanone oxime reactants showed that most of the NHPI catalyst exists in the (3a) (19%) as well as oxygenated products (<5%) such as reaction mixture without decomposition after the reaction. In cyclohexanol and cyclohexanone (entry 13). This may be due fact, 80% of the NHPI catalyst used could be recovered from to the fact that the cyclohexyl radical generated was trapped the reaction mixture. by NO2 derived from NO and 02, or by 02 itself to form 3a Table 1 summarizes the representative results for the and the oxygenated products, respectively. The reaction under nitrosation of la with t-BuONO to 2a under various reaction dark conditions led to the same results, indicating that the conditions. The yield of 2a was determined by H-NMR present nitrosation is not initiated by photo-irradiation using a known amount of nitromethane as an internal stan- (entry 14). When la was allowed to react with n-butyl nitrite dard. Among the N-hydroxyimide analogues, NHPI and 4- (n-BuONO) instead of t-BUONO, only a trace amount of 2a chloro-N-hydroxy-phthalimide (4C1-NHPI) were found to was formed due to the formation of n-butyl acetate by the be effective catalysts (entries 1-6). In particular, 2a was easy reaction of n-BuONO with acetic acid (entry 15). A obtained in 51% yield within only 1 h when 4Cl-NHPI was prolonged reaction time (6 h) led to a complex mixture of used as a catalyst (entry 3). The reaction proceeded even at products other than 2a (18%) and cyclohexanone oxime (3a) 70 •Ž (entry 7). The recovered catalyst was also efficient for (8%) (entry 16).

Vo1.66 No.11 2008 (31) 1067 On the basis of these results, the reaction of several cyclohexyl radical and N H PL Subsequently, the cyclohexyl cycloalkanes with t-BuONO catalyzed by NHPI under stan- radical formed is trapped by NO to produce 2a. dard conditions was examined (Eq. 2). Cyclopentane (lb) According to this reaction pathway, nitrosation of la was nitrosated in a similar manner to l a to afford nitrosocy- under an NO atmosphere instead of Ar should improve the clopentane (2b) in 49% yield. In this reaction, a small yield of 2a. However, it was found to be difficult to obtain 2a amount (2%) of cyclopentanone oxime (3b) was obtained. with selectivity by the NHPI-catalyzed reaction of la with t-

Interestingly, the reaction of cyclooctane (Id) produced BuONO under N0. When la was allowed to react with t- cyclooctanone oxime (3d) as a major product (56°/x). A BuONO in the presence of NHPI at 80 •Ž for 2 h under a longer reaction time (4 h) led to 3d in 65~/ yield. It is note- NO atmosphere, the reaction resulted in a complex mixture worthy that the direct transformation of cycloalkanes to of several products. We have previously shown that the reac- cycloalkanone oximes, which has been very difficult to carry tion of an alkane in the presence of the NHPI catalyst under out by the conventional methods so far, was thus achieved. It a NO atmosphere proceeded through the formation of an seems likely that nitrosocyclooctane (2d) formed is rapidly alkyl cation intermediate that is produced when the alkyl rad- isomerized into 3d under these reaction conditions, probably ical generated from the alkane is oxidized by excess amounts as a result of the lower stability of nitroso dimer 2d com- of NO.10 We therefore suggest that transformation of the pared to 3d. cyclohexyl radical into the cyclohexyl cation may occur as a side reaction in the nitrosation of la with t-BuONO in the

presence of excess amounts of NO. The cyclohexyl cation

generated could be converted into cyclohexyl acetate by trap-

ping with AcOH, into cyclohexene by $-proton elimination, and into several reaction products of the resulting cyclohex-

ene. As a consequence, the reaction of la with t-BUONO in a

NO atmosphere would lead to a complex mixture of the

products. 2.2 Nitrosation of Cycloalkanes in a Mixed Solvent ESR measurement was made to obtain information on Since the nitrosation of cyclododecane (le) with t- the reaction pathway. After reaction of t-BUONO with NHPI BuONO by NHPI in acetic acid led to nitrosation products, for 15 min under the standard conditions, ESR measurement nitrosocyclododecane (2e) (5%) and lauroxime (3e) (28%), in of the reaction mixture showed a triple signal at g = 2.0073 low yields, the nitrosation of le was further examined to having AN = 4.23 G, which we attributed to the phthalimide improve the yield of 2e and 3e. Decomposition of t-BUONO N-oxyl radical (PINO). The nitrosation process is complex by NHPI into PING, NO, and tart-butyl alcohol seemed to and the reaction pathway is difficult to explain clearly at this be facilitated in acetic acid. In fact, the reaction did not stage, but a plausible reaction path is outlined in Scheme 3. occur without acetic acid. In addition, the resulting NO In this suggested pathway, the reaction is initiated by the for- reacts readily with the dissolved oxygen in solvents like acetic mation of PINO and NO by the reaction of NHPI with t- acid to form NO2 which inhibits the nitrosation. The reaction BuONO. Since NHPI is easily oxidized with a weak oxidizing was examined in a mixed solvent after frozen-evacuation to agent, t-BUONO may serve as an oxidizing agent for NHPI and allow the formation of PINO and NO. In fact, evolution Table 2. Nitrosation of le with t-BUONO by NHPI under various of a brown gas by heating t-BuONO with NHPI in acetic conditions. acid in the presence or absence of la suggests t-BUONO was decomposed to NO followed by reaction with a small amount of the dissolved dioxygen to form NO2. The PINO thus generated abstracts the hydrogen atom from la giving a

Scheme 3. A plausible reaction pathway for the reaction of la with t-BUONO catalyzed by NHPI.

1068 (32) J.. Synth . Org. Chem., Jpn. remove strictly the oxygen dissolved in the reaction system . Table 2 shows the representative results for the nitrosation of le under various conditions.

Cyclododecane le (5 mmol), t-BuONO (1 mmol) and

NHPI (0.5 mmol) in benzene (2 mL) containing a small

amount of acetic acid (0.5 mL) were charged to a 20-mL

Schlenk tube under Ar. After frozen-evacuation below I Torr

at liquid nitrogen temperature, the reaction solution was

brought to room temperature and allowed to react at 75 •Ž

for 2 h to produce 2e in 75%, yield based on t-BuONO used

(entry 1). The reaction under normal pressure (760 Torr) of Ar resulted in a considerable decrease of 2e (37%) along with

nitrocyclododecane (4e) in 13% yield (entry 2). Since the

pressure of the reaction system was found to be an important factor to obtain 2e selectively, all reactions except entry 2

were carried out after frozen-evacuation below 1 Torr. The

reaction in benzene without acetic acid afforded 2e in low

yield (16%,) (entry 3), while the nitrosation in acetic acid without benzene gave 2e in relatively good yield (50%,) and 4e

(13%) (entry 4). The best yield (83%) of 2e was obtained when fluorobenzene containing a small amount of acetic acid

was employed (entry 5). However, the use of chlorobenzene

in place of fluorobenzene resulted in a considerable decrease

of 2e (from 83%) to 48(Y,,), whereas the yield of 4e increased

from 1%o to I1% (entry 6). Only trace amounts of 2e were

formed when using AIBN in place of NHPI as a radical ini-

tiator (entry 7). It is important to recover the NHPI from the reactant. In a previous paper, we showed that 80%% of NHPI can be recov- ered from the reaction solution after the nitrosation of cyclo-

hexane.7 Efforts will continue indefinitely to reduce the Figure 1. Effect of Ar pressure on NHPI-catalyzed nitrosation of amount of the catalyst used and to develop more efficient la and le with t-BuONO. Reaction conditions: la (10 mmol) or le (4 mL) were reacted with t-BuONO (I catalyst systems. mmol) and NHPI (0.1 mmol) in fluorobenzene (2 rL) To investigate the effect of NO gas, the reaction was and AcOH (0.1 mL) or AcOH (0.5 mL) at 75 •Ž for 2 h examined by adding NO (ca. 0.2 mmol) after frozen-evacua- under varying pressures of Ar. tion. The yield of 2e was decreased to 60% and the formation of 4e was increased to 10% yield (entry 8). This shows that the nitrosation of cycloalkanes. It seems reasonable to the concomitant generation of NO and PINO from t- assume that the solubility of NO, evolved from t-BuONO by BuONO and NHPI is important to obtain 2e.8 the action of NHPI, in the reaction solution is influenced by As the nitrosation of le with t-BuONO in the presence of the pressure of the reaction system. In the present reaction NHPI was considerably affected by the initial pressure, the system, in which a strong interaction between the solvent nitrosation of la and le was examined under varying Ar molecule (acetic acid) and a radical molecule like NO is pre- pressures (Figure 1 (a) and (b)) by freezing the reaction mix- dicted, Henry's law no longer fails and the solubility of NO ture and degassed in vacuo. in the reaction solution probably increases with pressure. As The yields of nitrocycloalkanes, nitrocyclohexane (4a) a result, the NO concentration in the reaction solution under and 4e, were considerably affected by the initial Ar pressure, higher Ar pressure may become higher than that under lower but the effects of the reaction pressure on the nitrosation of pressure. It is reported that 2a reacts with NO to lead to la and le were almost the same as each other. The yields of nitrocyclohexane 4a and a complex mixture of by-products.' 2a and 2e gradually decreased by increasing the Ar pressure Therefore, if the concentration of NO in the reaction solution in contrast to an increase in the yield of 4a and 4e. Under is high, the amount of nitrocycloalkanes, 4a and 4e, may be the nitrosation below I Torr, the yields of 2a and 2e attained increased in the present reaction. The results shown in Figure 88% and 83% respectively, based on t-BuONO use. 1 (a) and (b) well reflect the influences of the NO concentra- Previously, we showed sequential reaction pathways for tion on the nitrosation of cycloalkanes under varying Ar the nitrosation of la with t-BuONO by NHPI,s and the most pressures. These results indicate that the concentration of NO important step is the concomitant generation of NO and in acetic acid solution is an important factor to obtain PINO, since the resulting PINO abstracts the hydrogen atom nitrosocycloalkanes in high selectivity. from la to give the cyclohexyl radical which readily reacts 3. Catalytic Beckmann Rearrangement of Cycloalkanone with NO, producing nitrosocyclohexane 2a. Therefore, the Oximes concentration of NO in the reaction solution seems to be a very important factor governing the formation of 2a. As nitrosocycloalkanes are isomerized to oximes by treat- It is difficult to clearly account for the pressure effect in ing, then with amines, 2a and 2e were reacted with triethyl- amine in ethyl acetate to form cyclohexanone oxime 3a and new efficient catalyst for the Beckmann rearrangement of cyclododecanone oxime 3e respectively, in quantitative yields cycloalkanone oximes to lactams. The Beckmann rearrange- (Eqs. 3 and 4). ment of cyclododecanone oxime 3e to laurolactam 6e was

examined using several candidate catalysts which seem to

promote the rearrangement of oximes (Table 3))6 The activity of various catalysts for the rearrangement of

3e to 6e was compared with that of cyanuric chloride (CNC)

reported by Ishihara et al. 5 The reaction of 3e by CNC (1

mol%) in acetonitrile (2 mL) at 70 •Ž for 2 h afforded 6e in

22% yield (entry 1), while the same reaction by 1,3,5-triazo-

2,4,6-triphosphorine-2,2,4,4,6,6-chloride (TAPC) (1 mol%)

gave 6e in 64% (entry 2). In order to improve the catalytic efficiency of the reaction, we examined the effect of various

solvents in this transformation. From the reaction in various

solvents, the rearrangement was found to proceed smoothly

Recently, Giacomelli et al. have reported that cyanuric by allowing the reaction in fluorinated solvents. For instance, chloride (CNC) induces stoichiometrically the Beckmann the reaction in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) rearrangement of ketoximes to lactams.14 Thereafter, this instead of acetonitrile gave 6e in quantitative yields by both method was extended to a catalytic reaction by combining CNC and TAPC catalysts (entries 3 and 4). However, when

CNC with an acid like ZnCl2 or HCl in acetonitrile.15 How- the amount of CNC or TAPC was reduced to 0.1 mol% with ever, the yield of 6a from 2a was up to 300/ even with the use respect to 3e, the yield of 6e was 47% by CNC and 86% by of 10 mol%) of CNC under refluxing acetonitrile. On the TAPC (entries 6 and 7). By the use of 0.3 mol% of TAPC, 3e basis of these reports, we focused on the development of a was completely rearranged to 6e for 6 h (entry 8). The reac-

tion of 3e by CNC (1 mol%) In 2,2,3,3,3-pentafluoro-l-

Table 3. The Beckmann rearrangement of la to 2a by various propanol resulted in 6e (11 %) and cyclododecanone (5e)

catalysts.' (4%), while by TAPC 6e was obtained in 71% yield and 5e was 1 % (entries 9 and 10). The reaction in common solvents

like acetic acid and t-butyl alcohol led to 6e in poor yields

(entries 11-14). Several catalysts other than CNC and TAPC for the rearrangement of 3e to 6e were examined in HFIP

and acetonitrile (entries 15-20). Among the catalysts

employed, trichloroisocyanuric acid (TICNA) indicated rela-

tively high catalytic activity in HFIP but low in acetonitrile

(entries 16-17). However, 1,3,5-triazo-2,4,6-triphosphorine- 2,2,4,4,6,6-fluoride (TAPF) which is an analogue of TAPC

was found to be inactive, and the starting TAPF was recov-

ered unchanged after the reaction (entry 15). Cyanuric acid

(CNA) was inactive, but NBS and NCS indicated low catalyt- ic activities (entries 18 and 20). The most attractive application of TAPC and CNC to the Beckmann rearrangement is the reaction of cyclohexanone oxime 3a to s-caprolactam 6a. Thus, 3a was allowed to react

Table 4. The Beckmann rearrangement of cyclohexanone oxime (3a) by TAPC or CNC under various conditions.

1070 (34) J. Synth. Org. Chem., Jpn. in the presence of TAPC under several reaction conditions Table 5. Beckmann rearrangement of 3e in the presence of triazine 8 (or 9) to give 6e.`` (Table 4). Treatment of 3a with 1-2 mol% of TAPC in HFIP led to only small amounts of 6a (7-13%) and its condensate (7a) (3-7%), as well as cyclohexanone (5a) (1%) (entries 1 and 2). When the amount of TAPC was increased to 5 mol%, 3a was rearranged to 6a (40%) and 7a (26%) for 4 h (entry 4). In order to compare the catalytic activity of TAPC with that of CNC, the reaction using CNC was carried out under the same conditions, but giving only 6a (16%), 7a (7%), and 5a (1%) (entry 5). These results indicate that TAPC is more active than CNC for the Beckmann rearrangement of 3a to 6a under these conditions. The condensate product 7a was found to be easily hydrolyzed to two equivalents of 6a in quantitative yield (98% isolated yield) (Eq. 5). This means that 3a can be rearranged to 6a in an overall yield of 92% by TAPC.

the former case, however, the HCl was trapped by triethyl- amine as triethylamine hydrochloride and the subsequent We next examined the conversion of 3a to 6a through reaction of cyanurate with 3e may be inhibited. In contrast, one-pot. The reaction of 3a under the same conditions as in the reaction using HFIP, a transient active cyanuric inter- those described in Table 4 entry 4, followed by the hydrolysis mediate like 8 may be derived from cyanuric compounds and gave 6a in 82% isolated yield (Eq. 6). HFIP during the reaction course, and the reaction of the active cyanuric species with 3e was probably assisted by HFIP which serves as a weak acid to give 6e. On the other hand, by the use of 9 in place of 8, no rearrangement of 3e was observed at all, even in the presence of p-TsOH in HFIP (entry 9). This indicates that the reaction between 9 and HFIP, as well as oxime 3a has difficulty occurring because of the poor reactivity of 9. In fact, the catalyst 9 was recovered It is important to clarify the role of HFIP for the rear- unchanged after this reaction, while it was difficult to recover rangement of 3a to 6a and its condensate 7a by CNC and catalyst 8 as such. TAPC. Thus, 2,4,6-tris[2,2,2-trifluoro-I-(trifluoromethyl)- On the basis of these results, it is probable that the hexa- ethoxy]-1,3,5-triazine (8) and 2,4,6-trimethoxy-1,3,5-triazine fluoroisopropoxy group in 8 undergoes rapid exchange by the (9) were prepared by the reaction of cyanuric chloride with hydroxyl group in 3e to form a transient intermediate which HFIP and methanol, respectively. The Beckmann rearrange- is entirely converted to 6e, while the methoxy group in 9 is ment of 3a by 8 and 9 under several conditions is summa- stable and has difficulty reacting with 3e or HFIP. rized in Table 5. Scheme 4 shows a plausible reaction path for the Beck-

The reaction of 3e in the presence of 8 (1 mol%) in HFIP mann rearrangement of 3a by TAPC in HFIP. It was found at refluxing temperature for 2 h afforded 6e in 17% yield that no product was formed by the reaction of TAPC with (entry 1). When 8 (5 mol %) was used, the yield of 6e was HFIP at 70 •Ž for 2 h. Rosini et al. reported that a stoichio- improved to 80% (entry 2). By adding p-TsOH to this sys- metric reaction of oxime 3a with TAPC affords 0-(pen- tem, the yield of 6e was obtained in 94% yield even by the tachlorocyclotriphosphazatriene)cyclohexanone (A) in 63% use of 1 mol% of 8 (entry 3). To avoid the use of expensive yield.l7 Therefore, we thought that the compound A is a key HFIP as a solvent, the reaction was carried out using toluene intermediate to lactam 6a. Thus, 3a was allowed to react in instead of HFIP in the presence or absence of p-T5OH to the presence of a catalytic amount (0.1 equiv) of A prepared give 6e in 63% and 1% yields respectively, and small amounts independently by modified Rosini's procedure. It is interest- of cyclododecanone (entries 4 and 5). It is interesting to note ing to note that the reaction of 3a (1 mmol) in the presence that the rearrangement of 3e by cyanuric chloride in acetoni- of A (0.1 equiv) in HFIP (2 mL) at 70 •Ž for 2 h afforded 6a trile was found to be inhibited by adding triethylamine to the (47%) and 7a (15%), while the same reaction in McCN gave a catalytic system, but the same reaction in HFIP proceeded very low yield of 6a (5%). smoothly even in the presence of triethylamine (entries 7 and The rearrangement from A to lactam 6a is considered to 8). This shows that the HCl may be formed by the reaction proceed through the formation of nitrilium ion B followed by of 3e with cyanuric chloride and the resulting HCl serves as a nucleophilic attack of H2O to produce 6a. The dimeric con- an important promoter for the rearrangement of 3e to 6e. In densate 7a seems to be formed through the reaction of the

Vol.66 No.11 2008 (35) 1071 Scheme 4. A plausible reaction path for the Beckmann rearrangement by TAPC.

difficult to carry out selectively because of their exceedingly

low reactivity. Currently, nitrations are carried out at fairly

high temperatures (250-400 •Ž) using nitrogen dioxide or

nitric acid, and they proceed via free radical chain reactions resulting 6a with B. In fact, the addition of water in HFIP involving C-H bond homolysis.1s"9 Under such high temper- resulted in a considerable decrease of the condensate 7a. We atures, higher alkanes undergo not only the homolysis of the confirmed that 7a is not produced by the reaction of oxime C-H bonds but also the cleavage of the C-C skeletons. 3a with lactam 6a even in the presence of HFIP (Eq. 7). Therefore, the large-scale nitration of alkanes has been limit-

ed to several lower alkanes such as methane and ethane.19

For instance, the nitration of propane produces all of the

possible nitroparafins, namely, nitromethane, nitroethane, 1- nitropropane, and 2-nitropropane. 8.20 The development of

selective nitration of cyclohexane is very attractive, since

nitrocyclohexane is easily converted into cyclohexanone

oxime which is the raw material of e-caprolactam leading to

nylon-6.21 As the first trial, to a benzene solution dissolving NO2 4. One-pot Synthesis of Lactams from Cycloalkanes was added NHPI under stirring at room temperature, and the A salt-free one-pot synthesis of Lactams, 6a and 6e, from ESR measurement of the solution indicated a triplet signal cycloalkanes, la and le respectively, would be very attractive. which is assigned to the PINO radica1.22 This is believed to Thus, we tried the one-pot synthesis of 6a and 6b, which are be due to the fact that NO2 possesses stronger oxidizing abili- very important raw materials of nylon-6 and nylon-12, from ty than 02. Thus, the nitration of cyclohexane (la) was exam- la and 1e respectively (Scheme 5). ined using NO2 in the presence of a catalytic amount of The reaction of la with t-BuONO under the same condi- NHPI under selected reaction conditions (Eq. 8 and Table tions as Figure 1(a) and the isomerization of the resulting 2a 6). 23 with triethylamine followed by the Beckmann rearrangement using CNC in HFIP led to -caprolactam 6a (33%) and its condensate 7a (20%) which corresponds to 40% of 6a. Simi- larly, from cyclododecane le and t-BUONO, laurolactam 6e (72%) was obtained. This is the first successful one-pot syn- thesis of Lactams 6a and 6e from cycloalkanes la and le respectively, without any formation of undesired salts like The nitration of la with NO2 by NHPI proceeded ammonium sulfate. smoothly at 70 •Ž to give nitrocyclohexane (4a) (70%, based It is noteworthy that the conversion of cycloalkanes to on NO2 used) and cyclohexyl nitrite (IOa) (7%) along with a lactams was completed within 5 h of total reaction times. small amount of an oxygenated product, cyclohexanol (11a)

5. Lactam Synthesis through Nitration of Cycloalkanes (5%) (entry 1). As discussed later, it is important that the NHPI-catalyzed nitration can be carried out under air (O2),

In contrast to the nitration of aromatic hydrocarbons since NO generated in the course of the reaction can be reox- which is easily performed using nitric acid in the presence of idized to NO2 by air. In the same nitration of la in the sulfuric acid, the nitration of aliphatic hydrocarbons is very absence of air, the yield of 4a was decreased to 43% (entry 2).

1072 (36) J . Synth . Org . Chem . , Jpn. Table 6. NHPI-catalyzed nitration of la with NO2 under presence of air (02) under mild conditions. Under a higher selected conditions.a concentration of NO2 than that of air employed in the pre-

sent nitration, the alkyl radicals formed can react selectively

with NO2 rather than air (02) to give nitroalkanes in prefer-

ence to oxygenated products. In contrast, by the conventional

nitration operated at higher temperature (250-400 •Ž), the

nitration is difficult to carry out in the presence of air (02),

since under such temperatures the resulting alkyl radicals

react not only with NO2, but also with 02 to result in a com-

plex mixture of products.l9b

Scheme 7. A possible path for the NHPI-catalyzed alkane nitration with NO2 under air.

Needless to say, it was difficult to achieve the nitration of la without NHPI under these conditions (entry 3). The nitration took place even at 50 •Ž to give 4a in 39% yield (entry 5).

When the amount of NHPI was halved (0.3 mmol), 4a was formed in a slightly lower yield (56%) (entry 6). The nitration of 4a using the recovered NHPI produced 4a in 63% yield

(entry 7). Large-scale nitration afforded 4a in 53% isolated yield (entry 8). The catalytic reduction of nitocyclohexane with H225 or Scheme 6 shows the reaction pathway for the vapor- C026 is reported to give cyclohexanone oxime 3a in high phase nitration of alkanes by NO2. 9 According to this mech- yields. We tried the hydrogenation of nitrocyclohexane 4a anism, 113 of the NO2 employed is converted into NO with H2 in the presence of CuCI, which produced 3a in 93% through HNO2. Hence, the maximum yield of nitroalkanes yield (Eq. 9). by this method cannot, in theory, rise as high as 66.7%. In fact, the nitration of I a by NO2 under Ar led to 4a in 43% yield as shown in entry 2 in Table 6.

Scheme 6. A reaction path for the conventional alkane nitration with NO2.

The treatment of 3a with a small amount of CNC in a mixed solvent of trifluoroacetic acid (TFA) and toluene (3:2) under mild conditions gave a salt of 6a with TFA (6a •TFA) (Eq. 10). The 6a •TFA salt easily liberated 6a and TFA on sil- ica gel with a mixture of ethyl acetate and methanol (10 :1) or with water as eluents (Figure 2 (a) and (b)). The silica gel It is noteworthy that the present nitration of la by NO2 column can be used repeatedly, and the results were almost under air catalyzed by NHPI afforded 4a (70%) yield over the same after 5 times separation of the 6a •TFA salt as 66.7% corresponding to the theoretical yield by the conven- shown in Table 7. Therefore, the nitration method of la with tional nitration by NO2 alone. Owing to the complexities of the present nitration, it is an uncertain reaction pathway at this stage. A plausible reaction path is proposed in Scheme 7. The nitration may be initiated by the hydrogen atom abstrac- tion from the hydroxyimide group of the NHPI by NO2 to generate a PINO radical as described previously. The PINO readily abstracts the hydrogen atom from an alkane to form an alkyl radical which undergoes nitration with NO2 to give a nitroalkane. It is reported that HNO2 is converted into HNO3, H2O and NO.24 Under our conditions, the NO Table 7. Isolation of 6a from 6a-TFA salt by using formed is expected to be oxidized by 02 to NO2, and the gen- recycled silica column (Si02 20 g, 6a-TFA erated NO2 is reused in the present nitration. Therefore, the 1.1 g, eluent: AcOEt:MeOH (10:1)). yield of 4a seems to be over 66.7%. In fact, when the reaction mixture was extracted with water after the reaction, the aque- ous phase was acidified probably because of the formation of HNOh. The most promising feature of the NHPI-catalyzed nitra- tion of alkanes by NO2 is that the nitration is operated in the

Vol.66 No.11 2008 (37) 1073 Figure 2. Isolation of 6a from 6a-TFA salt by column chromatography on silica gel ((a) Si02 20 g, 2a-TFA 1.1 g, eluent: AcOEt:MeOH (10:1). (b) Si02 50 g, 6a-TFA salt 1.1 g, eluent: H20).

NO2 under air assisted by NHPI is an attractive alternative 8) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. Angew Chem. Int. Ed. 2004, 43, 1120. to sulfate-free e-caprolactam synthesis from cyclohexane. 9) (a) The Merck Index, 13th ed. (Eds: O'Neil, M. J.; Smith, A.; In conclusion, we summerized new strategies for lactams Heckelman, P. E.), MERCK & CO., Whitehouse Station, 2001, synthesis from cycloalkanes using NHPI as a key catalyst. P. 266. (b) J. C. Tracy (Notre Dame Ind.), US 2739166, 1956 These methods provide an enviromentally benign route to [Chem. Abstr. 1956, 50, 82174]. (c) F. S. Olan, US 4980496, 1990, [Chem. Abstr. 1991, 114, 121474]. lactams from cycloalkanes which are very important polymer 10) (a) Sakaguchi, S.; Eikawa, M.; Ishii, Y. Tetrahedron Lett. 1997, materials of nylon-6 and nylon-12. 38, 7075. (b) Eikawa, M. Sakaguchi, S.; Ishii, Y. J. Org Chem. 1999, 64, 4676. Acknowledgments 11) Hashimoto, M.; Sakaguchi, S.; Ishii, Y. Chem. Asian J. 2006, 1, 712. We acknowledge that these studies were carried out in 12) Donaruma, L. G.; Carmody, D. J. J. Org. Chem. 1957, 22, 635. collaboration with co-workers at Kansai University. These 13) Giacomo, A. D. J. Org Chem. 1965, 2614. studies were supported in part by a Grant-in-Aid for Scien- 14) De Luca, L.; Giacomelli, G.; Procheddu, A. J. Org Chem. 2002, 67, 6272. tific Research from the Ministry of Education, JSPS 15) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. Research for the Future Program of Japan Society for the 2005,127, 11240. promotion of Science, and Daicel Chemical Industries, Ltd. 16) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008, 73, 2894. 17) Rosini, G.; Baccolini, G.; Cacchi, S. J. Org. Chem. 1973, 38, References 1060. 1) (a) Luedeke, V. D. in Encyclipedia of Chemical Processing and 18) Albright, F. L. Chem. Eng. 1966, 73, 149 and references therein Design (Ed.: J. J. Mcketta), Marcel Dekker, New York, 1978, p. 19) (a) Markofsky, S. B., in Ulmann's Encyclopedia of Industrial 73. (b) Fisher, W. N.; Crescentini, L. in Kirk-Othmer Encyclope- Organic Chemicals, Vol. 6 (Eds.: Elvers, B.; Hawkins, S), Wiley- dia of Chemical Technology,4th ed., Vol. 4 (Ed.: J. I. Kroschwitz), VCH, Weinheim, 1999, pp. 3487-3501. (b) Albright, L. F., in John Wiley & Sons, New York, 1990, p. 829. (c) Ritz, J.; Fuchs, Kirk-Otluner Encyclopedia of Chemical Technology, Vol. 17 (Eds.; H.; Kiecza, H.; Moran, W. C. in Ullmann's Encyclopediaof Indus- Kroschewite, J. I.; Howe-Grant, M.), Wiley, New York, 1995, trial Organic Chemicals, Vol. 2 (Eds.: Elvers, B.; Hawkins, S.), pp. 68-107. Wilcv-VCH. Weinheim. 1999. p. 1013. 20) (a) Bachman, G. G.; Hass, B. H.; Addison, M. L. J. Org Gem. 2) For selected recent papers: (a) Neumann, R.; Dahan, M. 1952, 17, 914. (b) Bachman, G. G.; Hass, B. H.; Addison, M. Nature 1997, 388, 353. (b) Sato, K.; Aoki, M.; Noyori, R. Sci- L. J Org Chem. 1952, 17, 928. (c) Bachman, G. G.; Hewett, V. ence 1998, 281, 1646. (c) Thomas, M.; Raja, R.; Sankar, G.; J.; Millikan, A. J Org. Chem. 1952, 17, 935. (d) Bachman, G. Bell, R. G. Nature 1999, 398, 227. (d) Brink, G.-J.; Arends, I. G.; Kohn, L. J. Org Chem. 1952, 17, 942. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636. (e) Ishihara, 21) (a) Rita, J.; Fuchs, H.; Kieczka, H.; Moran, W C. in Ullmann's K.; Ohara, S.; Yamamoto, H. Science 2001, 290, 1140. (f) Encyclopedia Industrial Organic Chemicals, Vol. 2, Wiley-VCH, Zuwei, X.; Ning, Z.; Yu, S.; Kunlan, L. Science 2001, 292, 1139. Weinheim, 1999, p. 1013. (b) Fisher, W B.; Crescen'tini, L. in 3) (a) Davis, D. D. in Ullmann's Encyclopediaof Industrial Chemistry, Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 4 (Eds.: 5th ed., Vol. Al (Ed.: Gerhartz, W), John Wiley and Sons, New Kroschwite, J. I.; Howe-Grant, M.), John Wiley and Sons, York, 1985, p. 270. (b) Davis, D. D.; Kemp, D. R. in Kirk-Oth- New York, 1995, p. 827. (c) Luedeke, V. D. in Encyclopedia of arer Encyclopedia of Industrial Chemistry, 4th ed., Vol. 1 (Ed.: Chemical Processing and Design. Vol. 6 (Eds.: McKetta, J. J.; Kroschwitz, J. I.), John Wiley and Sons, New York, 1990, p. Cunningham, W. A.), Marcel Dekker, Inc., New York, 1978, pp 471, and references therein. 73-9. 4) Bellussi, G.; Perego, C. Cattech,2000, 4, 4. 22) Macker, A.; Wajer, A. J.; de Boer, J. Tetrahedron 1968, 24, 1623. 5) Mantegazza, M. A.; Petrini, G.; Cesana, A., EP 0564040, 1993. 23) Sakaguchi, S.; Nishiwaki, Y.; Kitamura, T.; Ishii, Y. Angew. 6) For a review, see: Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Chem. Int. Ed. 2001, 40, 222. Synth. Catal. 2001. 343. 393. 24) Jones, K. in ComprehensiveInorganic Chemistry (Ed.: Trotman- 7) (a) Yoshino, Y.; Hayashi, T.; Iwahama, T.; Sakaguchi, S.; Ishii, Dickenson), Pergamon, New York, 1973, p. 147. Y. J. Org. Chem. 1997, 62, 6810. (b) Ishii, Y.; Iwahama, T.; 25) Knifton, J. F. J. Catal. 1974, 33, 289. Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J Org. Chem. 26) Knifton, J. F. J Org. Chem. 1973, 38, 3296. 1996, 61, 4520.

1074 (38) J. Synth . Org . Chem ., Jpn. PROFILE Yasushi Obora was born in 1969 in Shizuoka and received his B.Sc. (1991) Yasutaka Ishii was born in Osaka, and Ph.D. degree (1995) from. Gifu Uni- Japan, in 1941. He received his BA. versity. After working as a postdoctoral (1964) and MS. (1967). In 1967, he was fellow (1995-1997) at Northwestern appointed Assistant Professor at Kansai University with Professor T. J. Marks, University. In 1971, he received his he moved to the National Institute of Ph.D. degree under the supervision of Materials and Chemical Research, AIST Prof. Masaya Ogawa. He was a postdoc- (1997-1999). In 1999, he joined the toral fellow with Professor Louis S. research group of Professor Yasushi Hegedus at Colorado State University in Tsuji at Catalysis Research Center at 1980-1981. Since 1990 he has been a full Hokkaido University as Research Asso- Professor at Kansai University. He ciate. In 2006, he was appointed to received the Japan Petroleum Institute Associate Professor and joined the Award for Distinguished Papers in 1987, research group of Professor Yasutaka Divisional Award (Organic Synthesis) of Ishii at Kansai University. He received the Chemical Society of Japan in 1999, the Shionogi Co. Ltd. Award in Synthet- Award of the Synthetic Organic Chem- ic Organic Chemistry Award, Japan, istry, Japan (Yu-uki Gosei Kagaku 2007. His current research interests Kyokai) in 1999, Award of the Japan include the development of new homo- Petroleum Institute in 2002, Green & geneous catalysis and organometallic Sustainable Chemistry (GSC) Award: chemistry. Minister of Education, Sports, Culture, Science and Technology Prize in 2003, and Award for Technical Development of the Chemical Society of Japan in 2004. His current research interests include the development of practical oxidation reactions using molecular oxy- gen and hydrogen peroxide, homoge- neous catalysis, petrochemistry, organometallic chemistry directed towards organic synthesis.

Satoshi Sakaguchi was born in 1970 in Nishinomiya, Japan, completed his undergraduate study and graduate study for his master's degree at Kansai Univer- sity in 1993 and 1995, respectively. He joined Kansai University, Faculty of Engineering, as an Assistant Professor in 1995. He received his Ph.D. from Kansai University in 2001 under the direction of Professor Yasutaka Ishii. In 2006, he became an Associate Professor. His research interest is the development of new synthetic reactions using a tran- sition metal complex as a catalyst.

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