Facile Synthesis of N-Substituted Amides from Alcohols and Amides

Abstract

A facile and versatile method for preparing N-substituted amides from alcohols and amides using a Brønsted acid and an alkali metal halide has been developed. Treatment of tertiary alcohols and amides in the presence of an alkali metal halide or methanesulfonic acid in trifluoroacetic acid at elevated temperature afforded the corresponding N-substituted amides in moderate to high yields. Tertiary alcohols with various functional groups such as ether, ester, imide, carbamate, and halogen groups were tolerated under these conditions. This method can be used for the efficient and practical synthesis of various N-substituted formamides without the use of unmanageable cyano compounds.

N-Substituted amides are a very important class of compounds that have been widely utilized as intermediates in the syntheses of peptide, isonitrile, and other organic compounds.[ ¹ ] In addition, some of these compounds have served as drugs, lead compounds in drug development, and insect repellents.[ ² ] One of the most common procedures for preparing N-substituted amides is the Ritter reaction, which is particularly useful for the synthesis of tertiary alkylamides;[ ³ ] however, cyano compounds such as sodium cyanide or trimethylsilyl cyanide are required to prepare N-substituted formamides using the Ritter reaction,[ ⁴ ] and the unmanageability of cyano reagents often makes this method inconvenient.

Nevertheless, these N-substituted formamides are well known as important and versatile intermediates for the synthesis of isocyanides. In particular, the dehydration of formamides is a standard method used for preparing isocyanides,[1c] [5] although this method is not necessarily convenient in the case of N-tertiary alkylformamides because of difficulties involved in obtaining an appropriate formamide precursor. It is therefore desirable to develop a simple, efficient method for synthesizing N-substituted formamides without cyano compounds. Shokova and co-workers have reported the conversion of 1-adamantanol into the corresponding amides in the presence of formamides and trifluoroacetic acid (TFA).[ ⁶ ] This simple method gives N-adamantylformamides in 92% yield; however, they also reported that tertiary alcohols of non-adamantane character such as tert-butyl alcohol were converted into the desired amides in only poor yield (16%). Encouraged by the results of their study, we attempted to modify this reaction in order to develop a versatile method for synthesizing N-substituted amides from alcohols and amides. Detailed investigation showed that the yield of the desired compounds could be improved by optimizing the reaction conditions, even if the reaction was carried out with alcohols of non-adamantane character. Although many methods for preparing N-substituted amides from alcohols and amides have been reported,[ ⁷ ] they are limited to the combination of alcohols with amides such as aryl, benzyl, or propargyl alcohol with benzamide or p-toluenesulfonamide. A useful method for converting alkanols into N-substituted amides with simple amides has not been reported so far to the best of our knowledge. We describe herein a facile and versatile method for preparing N-substituted amides from alcohols and amides in which nucleophilic substitution is carried out with a Brønsted acid and an alkali metal halide.

The results for the reactions of 2-methyl-2-dodecanol (1a) with formamide and Brønsted acids are summarized in Table 1. All reactions included in the table were carried out at 90 °C in a screw-cap tube, except for entries 7 and 8. The desired N-substituted formamide 1b was obtained in only 29% yield under the conditions given in entry 1, which are the optimal conditions for preparing N-adamantylformamides reported by Shokova and co-workers.[ ⁶ ] A dramatic improvement in the yield of the desired formamide 1b was achieved by optimizing the ratio and amounts of formamide and TFA. It was found that the mixture composed of formamide and TFA in a ratio of 1:2 afforded the desired product 1b most efficiently (entries 1–6). In addition, formamide 1b was obtained in good to high yield when more than 30.0 equivalents of TFA were used (entries 4–6). When the amount of TFA was decreased from 30.0 equivalents to 10.0 equivalents, the amount of byproducts increased and the yield of the desired product decreased considerably. Although the identities of these byproducts are unclear, many kinds of low polarity compounds were observed in a TLC analysis. ¹H NMR analysis of the crude product suggested that the corresponding 1,2-disubstituted alkenes and TFA esters of secondary alcohols were generated as byproducts through carbocation rearrangement. On the other hand, when the reaction temperature was lowered from 90 °C to 60 °C, the product yield decreased (entry 7). Furthermore, the N-substituted amide was not detected at room temperature (entry 8).

Table 1 Optimization of the Reaction Conditions^a

Entry	Formamide (equiv)	TFA (equiv)	MsOH (equiv)	Metal halide (equiv)	Yieldb (%)
1	2.0	10.0	–	–	29
2	5.0	10.0	–	–	51
3	7.0	10.0	–	–	33
4	15.0	30.0	–	–	74
5	25.0	50.0	–	–	81
6	50.0	100.0	–	–	93
7c	50.0	100.0	–	–	60
8d	50.0	100.0	–	–	n.d.e
9	5.0	5.0	5.0	–	71
10	15.0	15.0	15.0	–	86
11	15.0	21.0	9.0	–	85
12	25.0	25.0	25.0	–	91
13	50.0	50.0	50.0	–	87
14	5.0	–	10.0	–	15
15	15.0	–	30.0	–	10
16	25.0	–	50.0	–	4
17	50.0	–	100.0	–	6
18	15.0	30.0	–	KCl, 2.0	86
19	15.0	30.0	–	KBr, 2.0	85
20	15.0	30.0	–	LiCl, 2.0	88
21	15.0	30.0	–	LiBr, 2.0	94
22	15.0	30.0	–	LiI, 2.0	87
23	5.0	7.0	3.0	LiBr, 2.0	69
24	15.0	21.0	9.0	LiBr, 2.0	78

^a Reactions were carried out for 8 h.

^b Determined by GLC analysis.

^c The reaction was carried out at 60 °C.

^d The reaction was carried out at room temperature.

^e n.d. = not detected.

We also made numerous attempts to employ other Brønsted­ acids such as acetic acid, sulfuric acid, methanesulfonic acid (MsOH), and oxalic acid in addition to the TFA to decrease the amount of TFA required. Although combinations of TFA and other Brønsted acids were not efficient for this reaction in many cases, the combination of TFA and MsOH gave the desired product in good yield (Table 1, entries 9–13). In particular, the desired product 1b was obtained in high yield when 15.0, 25.0, and 50.0 equivalents each of formamide, TFA, and MsOH were used (entries 10–13). On the other hand, the desired reaction hardly proceeded at all when only MsOH was used without TFA (entries 14–17).

Further examination showed that the addition of alkali metal halides to the reaction mixture improved the yield of the desired N-substituted formamide. Thus, the same reaction was examined with 2.0 equivalents of various alkali metal halides along with 15.0 equivalents of form­amide and 30.0 equivalents of TFA (Table 1, entries 18–22). Among the various alkali metal halides (KCl, LiCl, KBr, LiBr, LiI), LiBr was the most effective, and 94% yield of 1b was obtained. On the other hand, addition of LiBr decreased the yield of the desired formamide at all in the presence of TFA/MsOH (entries 23 and 24). It is proposed that the role of alkali metal halides in the reaction system is as a source of halide ions. Halide intermediate was detected by GLC analysis, by monitoring the reaction performed under TFA/LiBr conditions (entry 21). The results indicate that alcohol 1a can be converted into form­amide 1b via a halide intermediate in the presence of alkali metal halides, and this halide intermediate may contribute to effective formamide formation. On the basis of these experiments, the conditions shown in entry 21 were chosen as the optimum conditions.

Subsequently, the scope and limitations of this reaction were investigated under the optimized conditions. Table 2 displays the results obtained for the formation of the corresponding formamides from various tertiary alcohols. Under the optimized conditions, all linear alcohols examined gave the corresponding formamides in moderate to good yields (entries 1–11). Various functional groups such as halide, ether, ester, imide, and carbamate groups were tolerated well under these conditions; however, when fluoride 2a and chloride 3a were used as the starting materials, two byproducts were observed that resulted from the nucleophilic substitution of bromide and trifluoroacetate anions for the fluoride and chloride moieties. Improvement of the yields of the reactions described in entries 1 and 4 was achieved by using MsOH instead of LiBr. When the TFA/MsOH conditions were used, the desired N-substituted amides were obtained in high yields of up to 84% (2b) and 86% (3b), whereas 2b and 3b were obtained in 73% and 74% yield, respectively, under simple TFA conditions. These results indicate that the TFA/MsOH conditions could become the optimal conditions when formamide formation is inefficient under the TFA/LiBr conditions. On the other hand, 1-dodecanol and 2-dodecanol, which are primary and secondary alcohols, afforded the corresponding trifluoroacetates as the main products under the standard TFA/LiBr conditions (data not shown).

Table 2 Reaction of Various Linear Alkyl Alcohols 2a–8a to the Corresponding Formamides^a

Entry	Substrate	R	Product	Yieldb (%)
1	2a	F	2b	66
2c	2a	F	2b	73
3d	2a	F	2b	84
4	3a	Cl	3b	72
5c	3a	Cl	3b	74
6d	3a	Cl	3b	86
7	4a	Br	4b	76
8	5a	OBz	5b	86
9	6a	OMe	6b	77
10	7a	phthalimidyl	7b	85
11	8a	NHFmoc	8b	55

^a Reaction conditions: alcohol 2a–8a (0.5 mmol), formamide (15.0 equiv), TFA (30.0 equiv), LiBr (2.0 equiv), 8 h.

^b Isolated yield.

^c LiBr was not added.

^d TFA (15.0 equiv) and MsOH (15.0 equiv) were used, without LiBr.

The stereoselectivity of the reaction was also examined using 1-methyl-1-cyclohexanol derivatives possessing a tert-butyl group (9a, 10a), a benzoyloxy group (11a, 12a), or a benzoyloxymethyl group (13a, 14a) at the 4-position, as shown in Table 3. The desired formamides 9b and 10b were obtained in good yield under TFA/LiBr and TFA/MsOH conditions. In addition, the stereoisomeric alcohols 9a and 10a gave the same products in approximately the same ratio (entries 1–6); however, the ratio of 9b to 10b changed for the different conditions: it was about 1:1 under TFA/LiBr conditions (entries 1 and 4) and 3:2 under TFA/MsOH conditions (entries 2 and 5). Furthermore, the ratio of 9b to 10b changed to 2:1 when 30% camphorsulfonic acid was used instead of MsOH under TFA conditions (entries 3 and 6). These results suggest that the stereoselectivity could change for different counteranions.

On the other hand, cyclohexyl benzoates 11a and 12a afforded the corresponding amides 11b and 12b in trace yields under TFA/LiBr conditions (data not shown). The yields of the desired formamides 11b and 12b from alcohols 11a and 12a were improved by switching to the TFA/MsOH conditions, although they were only 17% and 18% (Table 3, entries 7 and 8). In the case of cyclohexyl benzoates 11a and 12a, disubstituted internal alkene 18 and TFA ester 19 were observed as byproducts. It is proposed that the benzoyloxy group might be rearranged to carbocation intermediate 16 to afford these rearranged or eliminated byproducts 18 and 19, as shown in Scheme [1]. Based on this hypothesis, we prepared cyclohexylmethyl benzoates 13a and 14a, which possess one more methylene than alcohols 11a and 12a. As expected, the desired formamides 13b and 14b were obtained in good yields from alcohols 13a and 14a under the TFA/MsOH conditions (entries 9 and 10). This might be attributed to the greater stability of the benzoyloxymethyl group toward rearrangement to the carbocation compared to that of the benzoyloxy group. In contrast, the conversion of alcohol 14a into the corresponding amides was inefficient under the TFA/LiBr conditions, and the desired products 13b and 14b were obtained in only 49% yield (entry 11). Entries 7–11 show that the stereoisomeric alcohols also gave the same products in approximately the same ratio, as did alcohols 9a and 10a. However, the stereoselectivity was different for 11a and 12a than for 13a and 14a. The ratio of 11b and 12b was about 2:3 in the case of the cyclohexyl benzoates (entries 7 and 8), whereas alcohols 13a and 14a gave the corresponding formamides 13b and 14b in a ratio of about 3:1 (entries 9–11). These results suggest that the stereoselectivity is influenced by the functional group at the 4-position.

Table 3 Reaction of Various Cyclohexyl Alcohols 9a–14a to the Corresponding Formamides^a

Entry	Substrate	R	Productb	Yieldc (%)
1d	9a	t-Bu	9b/10b (1:1)	82
2e	9a	t-Bu	9b/10b (3:2)	80
3f	9a	t-Bu	9b/10b (2:1)	78
4d	10a	t-Bu	9b/10b (1:1)	77
5e	10a	t-Bu	9b/10b (3:2)	77
6f	10a	t-Bu	9b/10b (2:1)	79
7e	11a	OBz	11b/12b (2:3)	17
8e	12a	OBz	11b/12b (2:3)	18
9e	13a	CH2OBz	13b/14b (3:1)	77
10e	14a	CH2OBz	13b/14b (3:1)	76
11d,g	14a	CH2OBz	13b/14b (3:1)	49

^a Reaction conditions: alcohol 9a–14a (0.5 mmol), formamide (15.0 equiv), TFA (30.0 equiv), 8 h.

^b Determined by NMR analysis.

^c Isolated yield.

^d TFA (30.0 equiv) was used, and LiBr (2.0 equiv) was added.

^e TFA (15.0 equiv) and MsOH (15.0 equiv) were used.

^f TFA (21.0 equiv) and (+)-CSA (9.0 equiv) were used.

^g The reaction was carried out for 24 h.

Table 4 shows results of the reactions of various amides with alcohol 1a. The reaction conditions were the same as those used for synthesizing the N-substituted formamides. Treatment of the tertiary alcohol with acetamide or benz­amide afforded the corresponding amides 1c and 1d in moderate yields (entries 1 and 2). In addition, N,N-disubstituted amide 1e was obtained with the N-substituted form­amide, although the yield was not as good (entry 3); however, improvement in the yield of the desired 1e was observed when the amounts of starting amide and TFA were increased (entry 4). These results indicate that not only formamides but also other kinds of amides can be prepared using this method.

Table 4 Reaction of Various Amides with Alcohol 1a ^a

Entry	Amide	R1	R2	Product	Yieldb (%)
1	acetamide	Me	H	1c	69
2	benzamide	Ph	H	1d	40
3	N-methylformamide	H	Me	1e	16
4c	N-methylformamide	H	Me	1e	24

^a Reaction conditions: alcohol 1a (0.5 mmol), amide (15.0 equiv), TFA (30.0 equiv), LiBr (2.0 equiv), 8 h.

^b Isolated yield.

^c TFA (30.0 equiv) and N-methylformamide (60.0 equiv) were used.

In conclusion, we have developed a facile and versatile method for converting alcohols into the corresponding N-substituted amides using amides, Brønsted acids, and alkali metal halides. In particular, the combinations of TFA and LiBr or of TFA and MsOH are effective conditions for the synthesis of a wide range of N-substituted amides. The present method can provide a practical approach for preparing N-substituted or N,N-disubstituted amide compounds.

NMR spectra were obtained in CDCl₃ on a JEOL ECA-600 or JEOL ECS-400 spectrometer. All ¹H NMR data are reported in ppm relative to tetramethylsilane (TMS). All ¹³C NMR data are reported in ppm relative to the central line of the triplet for CDCl₃ at 77.0 ppm. ¹H and ¹³C NMR data for formamides are reported separately for each rotational isomer (major, minor) on the basis of ¹H NMR analysis. IR spectra were recorded on a JEOL WINSPEC-50 spectrometer. Electrospray ionization (ESI) was recorded on a JEOL JMS-T100 mass spectrometer. Chromatographic separations were carried out on a silica gel column (Kanto Chemical 60N, 63–210 μm) unless otherwise stated. The physical data for compounds 1a–4a, 2b–4b, and 6b–8b were identical to the data we previously reported.[1c] [8] The intermediates 1-methyl-1,4-cyclohexanediol and 4-(hydroxymethyl)cyclohexanone were prepared according to literature procedures.[ ^8,9 ]

Preparation of Amides from Alcohols; General Procedure

LiBr (87 mg, 1.0 mmol) and amide (7.5 mmol) were successively added to a mixture of alcohol (0.5 mmol) and TFA (1.15 mL, 15.0 mmol) in a screw-cap tube. After the reaction mixture was stirred at 90 °C for 8 h, sat. NaHCO₃ (30 mL) was added, and the resultant mixture was extracted with EtOAc (100 mL). The combined extracts were washed with sat. NaHCO₃ and brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by performing silica gel column chromatography to give the pure amide.

N-(2-Methyl-2-dodecyl)formamide (1b)

Purified by performing silica gel column chromatography (hexane–EtOAc, 1:1) to give amide 1b as a colorless oil; yield: 92.5 mg (81%).

IR (neat): 3282 (br), 3055, 2954, 2924, 2854, 2754, 1686, 1670, 1541, 1468, 1385, 1365, 1265 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.18 (d, J = 12.4 Hz, 1 H), 6.03 (br s, 1 H), 1.49–1.45 (m, 2 H), 1.34–1.20 (m, 22 H), 0.86 (t, J = 6.9 Hz, 3 H); δ (minor) = 8.01 (s, 1 H), 5.28 (br s, 1 H), 1.67–1.63 (m, 2 H), 1.34–1.20 (m, 22 H), 0.86 (t, J = 6.9 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 163.2, 52.9, 43.9, 32.0, 30.0, 29.8, 29.7, 29.7, 29.4, 28.8, 23.9, 22.8, 14.2; δ (minor) = 160.5, 54.1, 40.8, 32.0, 30.1, 29.8, 29.7, 29.7, 29.4, 27.1, 24.2, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₂₉NNaO: 250.2147; found: 250.2148.

N-(2-Methyl-2-dodecyl)acetamide (1c)

Purified by performing silica gel column chromatography (hexane–EtOAc, 3:2) to give amide 1c as a white solid; yield: 82.6 mg (69%); mp 54–55 °C.

IR (KBr): 3275, 3088, 2962, 2916, 2848, 1641, 1566, 1471, 1371, 1304 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 5.16 (br s, 1 H), 1.90 (s, 3 H), 1.67–1.63 (m, 2 H), 1.32–1.20 (m, 22 H), 0.87 (t, J = 6.9 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 169.4, 53.8, 40.5, 32.0, 30.1, 29.8, 29.8, 29.7, 29.5, 27.0, 24.6, 24.3, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₃₁NNaO: 264.2303; found: 264.2302.

N-(2-Methyl-2-dodecyl)benzamide (1d)

Purified by performing silica gel column chromatography (hexane–EtOAc, 10:1) to give amide 1d as a white solid; yield: 61.5 mg (40%); mp 63–64 °C.

IR (KBr): 3286 (br), 3064, 3028, 2956, 2922, 2850, 1633, 1540, 1470, 1329, 1308, 696 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.70 (d, J = 7.3 Hz, 2 H), 7.46 (t, J = 7.3 Hz, 1 H), 7.41 (t, J = 7.3 Hz, 2 H), 5.82 (br s, 1 H), 1.81–1.77 (m, 2 H), 1.43 (s, 6 H), 1.33–1.22 (m, 16 H), 0.87 (t, J = 6.9 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.9, 136.2, 131.1, 128.6, 126.8, 54.3, 40.7, 32.0, 30.2, 29.8, 29.8, 29.7, 29.5, 27.2, 24.3, 22.8, 14.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₃₃NNaO: 326.2460; found: 326.2458.

N-Methyl-N-(2-methyl-2-dodecyl)formamide (1e)

Purified by performing silica gel column chromatography (hexane–EtOAc, 1:1) to give amide 1e as a colorless oil; yield: 29.2 mg (24%).

IR (neat): 3481 (br), 2954, 2926, 2854, 1680, 1660, 1466, 1375, 1028 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.29 (s, 1 H), 2.79 (s, 3 H), 1.53–1.50 (m, 2 H), 1.34–1.19 (m, 20 H), 1.14–1.10 (m, 2 H), 0.86 (t, J = 6.9 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 161.7, 57.3, 40.2, 31.9, 29.8, 29.6, 29.6, 29.5, 29.3, 27.1, 25.9, 23.7, 22.6, 14.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₃₁NNaO: 264.2303; found: 264.2311.

11-Hydroxy-11-methyldodecyl Benzoate (5a)

Benzoic acid (352 mg, 2.88 mmol) and Et₃N (400 μL, 2.87 mmol) were added successively to a soln of 12-bromo-2-methyl-2-dodecanol (290 mg, 1.04 mmol) in DMF (7 mL). After the reaction mixture was stirred at 80 °C for 20 h, 1 M HCl (30 mL) was added, and the resultant mixture was extracted with hexane–EtOAc (2:1, 90 mL). The combined extracts were washed with 1 M HCl, sat. NaHCO₃, and brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by performing silica gel column chromatography (hexane–EtOAc, 3:1) to give alcohol 5a as a white solid; yield: 91 mg (27%); mp 43–44 °C.

IR (KBr): 3510 (br), 3398 (br), 3091, 3064, 3034, 2966, 2929, 2854, 1720, 1468, 1452, 1275, 1116, 712 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.03 (dd, J = 7.8, 1.4 Hz, 2 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 4.31 (t, J = 7.0 Hz, 2 H), 1.76 (quint, J = 7.0 Hz, 2 H), 1.47–1.25 (m, 16 H), 1.20 (s, 6 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.8, 132.9, 130.7, 129.6, 128.4, 71.1, 65.3, 44.1, 30.3, 29.7, 29.6, 29.4, 29.4, 29.4, 28.9, 26.2, 24.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₃₂NaO₃: 343.2249; found: 343.2251.

11-(Formylamino)-11-methyldodecyl Benzoate (5b)

Purified by performing silica gel column chromatography (hexane–EtOAc, 1:1) to give amide 5b as a white solid; yield: 149.2 mg (86%); mp 66–67 °C.

IR (KBr): 3209 (br), 3086, 2976, 2926, 2852, 1716, 1689, 1481, 1282, 1126, 717 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.20 (d, J = 12.4 Hz, 1 H), 8.05–8.02 (m, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 5.88 (br s, 1 H), 4.31 (t, J = 6.6 Hz, 2 H), 1.76 (quint, J = 6.6 Hz, 2 H), 1.51–1.47 (m, 2 H), 1.47–1.41 (m, 2 H), 1.38–1.22 (m, 18 H); δ (minor) = 8.05–8.02 (m, 3 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 5.24 (br s, 1 H), 4.31 (t, J = 6.6 Hz, 2 H), 1.76 (quint, J = 6.6 Hz, 2 H), 1.69–1.65 (m, 2 H), 1.47–1.41 (m, 2 H), 1.38–1.22 (m, 18 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 166.6, 163.0, 132.7, 130.5, 129.5, 128.2, 65.1, 52.8, 43.7, 29.8, 29.5, 29.4, 29.4, 29.2, 28.7, 27.0, 23.8; δ (minor) = 166.6, 160.3, 132.7, 130.5, 129.5, 128.2, 65.1, 54.0, 40.6, 29.9, 29.5, 29.4, 29.4, 29.2, 28.6, 26.0, 24.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₃₃NNaO₃: 370.2358; found: 370.2358.

N-(4-tert-Butyl-1-methylcyclohexyl)formamides 9b and 10b

Purified by performing silica gel flash column chromatography (Yamazen Corporation V003, 40 μm; hexane–EtOAc, 1:0 to 1:1) to give amides 9b [yield: 39.6 mg (40%)] and 10b [yield: 39.6 mg (40%)].

N-(cis-4-tert-Butyl-1-methylcyclohexyl)formamide (9b)

White solid; mp 83–85 °C.

IR (KBr): 3273 (br), 3251 (br), 3051, 2968, 2949, 2868, 2832, 1672, 1655, 1552, 1541, 1446, 1385, 1365 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.12 (d, J = 2.1 Hz, 1 H), 5.02 (br s, 1 H), 2.25–2.20 (m, 2 H), 1.66–1.54 (m, 3 H), 1.47–1.38 (m, 2 H), 1.33 (s, 3 H), 1.27–1.07 (m, 2 H), 0.86–0.83 (m, 9 H); δ (minor) = 8.24 (d, J = 13.0 Hz, 1 H), 5.56 (br s, 1 H), 1.85–1.79 (m, 2 H), 1.66–1.54 (m, 1 H), 1.47–1.38 (m, 3 H), 1.27–1.07 (m, 4 H), 1.01–0.95 (m, 2 H), 0.86–0.83 (m, 9 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 160.7, 53.3, 47.6, 37.2, 32.5, 28.1, 27.6, 22.7; δ (minor) = 163.5, 51.6, 47.5, 39.2, 32.5, 31.8, 27.6, 22.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₃NNaO: 220.1677; found: 220.1677.

N-(trans-4-tert-Butyl-1-methylcyclohexyl)formamide (10b)

White solid; mp 102–103 °C.

IR (KBr): 3275 (br), 3047, 2968, 2956, 2939, 2864, 1668, 1651, 1545, 1466, 1390 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.30 (d, J = 12.4 Hz, 1 H), 5.62 (br s, 1 H), 1.84–1.79 (m, 2 H), 1.74–1.47 (m, 5 H), 1.32 (s, 3 H), 1.23–1.12 (m, 2 H), 0.88–0.84 (m, 9 H); δ (minor) = 8.03 (d, J = 2.1 Hz, 1 H), 5.17 (br s, 1 H), 2.06–2.01 (m, 2 H), 1.74–1.47 (m, 3 H), 1.39 (s, 3 H), 1.23–1.12 (m, 2 H), 1.06–0.99 (m, 2 H), 0.88–0.84 (m, 9 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 162.6, 52.8, 47.6, 40.0, 32.4, 27.6, 24.6, 23.5; δ (minor) = 160.4, 54.1, 47.7, 37.7, 32.4, 27.7, 23.4, 22.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₃NNaO: 220.1677; found: 220.1675.

4-Hydroxy-4-methylcyclohexyl Benzoates 11a and 12a

Pyridine (1.5 mL, 19 mmol) was added to a soln of 1-methyl-1,4-cyclohexanediol (cis/trans mixture, 1.37 g, 10.6 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was cooled to ice bath temperature, and BzCl (1.5 mL, 13 mmol) was added dropwise to the solution. After the reaction mixture was stirred at 0 °C for 2 h, brine (30 mL) was added, and the resultant mixture was extracted with EtOAc (100 mL). The combined extracts were washed with 1 M HCl, sat. NaHCO₃, and brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by performing silica gel column chromatography (hexane–EtOAc, 3:1 to 2:1) to give alcohols 11a [yield: 345 mg (14%)] and 12a [yield: 233 mg (10%)].

cis-4-Hydroxy-4-methylcyclohexyl Benzoate (11a)

White solid; mp 83–87 °C.

IR (KBr): 3435 (br), 3410 (br), 3093, 3064, 2966, 2953, 2941, 2922, 2870, 2850, 1714, 1686, 1377, 1323, 1288, 1271, 1115, 1028, 989, 710 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.04 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 5.02–4.95 (m, 1 H), 1.98–1.84 (m, 4 H), 1.82–1.74 (m, 2 H), 1.62–1.53 (m, 2 H), 1.28 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.2, 132.9, 130.8, 129.6, 128.4, 72.6, 68.7, 36.7, 29.8, 27.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₈NaO₃: 257.1154; found: 257.1169.

trans-4-Hydroxy-4-methylcyclohexyl Benzoate (12a)

White solid; mp 67–68 °C.

IR (KBr): 3307 (br), 3238 (br), 3086, 3062, 3030, 2962, 2953, 2943, 2929, 2879, 2856, 1716, 1450, 1344, 1278, 1113, 917, 712 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.03 (d, J = 7.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 5.23–5.19 (m, 1 H), 2.06–1.99 (m, 2 H), 1.85–1.76 (m, 4 H), 1.62–1.55 (m, 2 H), 1.32 (s, 3 H), 1.16 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.0, 132.9, 131.0, 129.6, 128.4, 70.7, 69.4, 34.9, 30.3, 26.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₈NaO₃: 257.1154; found: 257.1156.

4-(Formylamino)-4-methylcyclohexyl Benzoates 11b and 12b

Purified by performing silica gel column chromatography (Fuji Silysia Chemical NH DM-1020, 100–200 mesh; hexane–EtOAc, 1:1) to give amides 11b [yield: 8.9 mg (7%)] and 12b [yield: 13.4 mg (10%)].

cis-4-(Formylamino)-4-methylcyclohexyl Benzoate (11b)

Colorless oil.

IR (neat): 3290 (br), 3061, 2943, 2868, 2758, 1712, 1682, 1535, 1450, 1275, 1115, 1026, 714 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.17 (d, J = 2.1 Hz, 1 H), 8.05–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.14 (s, 1 H), 5.07–4.97 (m, 1 H), 2.32–2.27 (m, 2 H), 1.99–1.91 (m, 2 H), 1.75–1.65 (m, 2 H), 1.59–1.53 (m, 2 H), 1.46 (s, 3 H); δ (minor) = 8.33 (d, J = 12.4 Hz, 1 H), 8.05–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.65 (br d, J = 12.4 Hz, 1 H), 5.07–4.97 (m, 1 H), 1.99–1.91 (m, 4 H), 1.84–1.79 (m, 2 H), 1.75–1.65 (m, 2 H), 1.41 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 166.1, 161.0, 133.0, 130.7, 129.6, 128.4, 72.2, 52.8, 34.3, 27.2, 26.4; δ (minor) = 166.0, 163.5, 133.1, 130.5, 129.6, 128.5, 71.3, 51.5, 35.9, 29.5, 26.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₉NNaO₃: 284.1263; found: 284.1263.

trans-4-(Formylamino)-4-methylcyclohexyl Benzoate (12b)

Colorless oil.

IR (neat): 3296 (br), 3059, 2947, 2860, 2756, 1716, 1682, 1533, 1450, 1275, 1115, 714 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.13 (d, J = 1.4 Hz, 1 H), 8.03–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 5.37 (br s, 1 H), 5.19–5.15 (m, 1 H), 2.07–2.01 (m, 2 H), 1.92–1.80 (m, 6 H), 1.48 (s, 3 H); δ (minor) = 8.30 (d, J = 12.4 Hz, 1 H), 8.03–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 6.16 (br s, 1 H), 5.19–5.15 (m, 1 H), 1.92–1.80 (m, 6 H), 1.75–1.71 (m, 2 H), 1.42 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 166.0, 161.0, 133.1, 130.8, 129.6, 128.5, 70.1, 53.3, 32.5, 26.5, 26.4; δ (minor) = 165.9, 163.4, 133.0, 130.7, 129.6, 128.5, 69.8, 51.8, 34.4, 29.9, 26.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₉NNaO₃: 284.1263; found: 284.1270.

(4-Hydroxy-4-methylcyclohexyl)methyl Benzoates 13a and 14a

MeLi (1.14 M in Et₂O; 29.5 mL, 33.6 mmol) was added dropwise to a soln of 4-(hydroxymethyl)cyclohexanone (1.43 g, 11.2 mmol) in THF (60 mL) at 0 °C under an argon atmosphere. After the reaction mixture was stirred at temperatures from 0 °C to r.t. for 16 h, sat. NH₄Cl (50 mL) was added, and the resultant mixture was extracted with EtOAc (100 mL). The combined extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give 4-(hydroxymethyl)-1-methylcyclohexanol [cis/trans mixture, yield: 1.54 g (95%)]. The obtained crude alcohol was used in the next step without further purification. Pyridine (3.0 mL, 37.0 mmol), BzCl (3.0 mL, 26.0 mmol), and DMAP (140 mg) were successively added to a soln of the above alcohol (cis/trans mixture, 1.66 g, 11.5 mmol) in CH₂Cl₂ (30 mL). After the reaction mixture was stirred at r.t. for 1 d, brine (30 mL) was added, and the resultant mixture was extracted with EtOAc (150 mL). The combined extracts were washed with 1 M HCl, sat. NaHCO₃, and brine, dried (MgSO₄), and concentrated under reduced pressure. The residue was purified by performing silica gel column chromatography (hexane–EtOAc, 3:1 to 2:1) to give alcohols 13a [yield: 575 mg (20%)] and 14a [yield: 217 mg (8%)].

cis-(4-Hydroxy-4-methylcyclohexyl)methyl Benzoate (13a)

White solid; mp 92–93 °C.

IR (KBr): 3352 (br), 3286 (br), 3062, 3034, 2964, 2931, 2914, 2860, 1712, 1450, 1280, 1117, 715 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.04 (d, J = 7.7 Hz, 2 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 2 H), 4.19 (d, J = 6.2 Hz, 2 H), 1.88–1.82 (m, 3 H), 1.76–1.71 (m, 2 H), 1.50 (dt, J = 12.7, 3.4 Hz, 2 H), 1.29–1.22 (m, 5 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.7, 133.0, 130.5, 129.6, 128.5, 70.8, 69.0, 39.1, 36.3, 26.9, 26.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₀NaO₃: 271.1310; found: 271.1322.

trans-(4-Hydroxy-4-methylcyclohexyl)methyl Benzoate (14a)

White solid; mp 71–72 °C.

IR (KBr): 3334 (br), 3282 (br), 3088, 3066, 3032, 2960, 2943, 2887, 2862, 1714, 1450, 1276, 1120, 711 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.04 (dd, J = 7.6, 1.4 Hz, 2 H), 7.55 (tt, J = 7.6, 1.4 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 4.18 (d, J = 6.4 Hz, 2 H), 1.78–1.65 (m, 5 H), 1.56–1.38 (m, 4 H), 1.24 (s, 3 H), 1.10 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 166.7, 132.9, 130.6, 129.7, 128.4, 69.8, 69.2, 38.1, 36.7, 31.6, 25.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₀NaO₃: 271.1310; found: 271.1310.

[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoates 13b and 14b

Purified by performing silica gel column chromatography (Fuji Silysia Chemical NH DM-1020, 100–200 mesh; hexane–EtOAc, 1:1) to give amides 13b [yield: 78.5 mg (57%)] and 14b [yield: 26.1 mg (19%)].

cis-[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoate (13b)

White solid; mp 139–140 °C.

IR (KBr): 3311, 3049, 2964, 2947, 2933, 2912, 2850, 2762, 1714, 1682, 1658, 1539, 1286, 1122, 717 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.13 (s, 1 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 5.14 (br s, 1 H), 4.16 (d, J = 6.2 Hz, 2 H), 2.29–2.24 (m, 2 H), 1.84–1.69 (m, 3 H), 1.42 (s, 3 H), 1.37–1.20 (m, 4 H); δ (minor) = 8.25 (s, 1 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 5.76 (br s, 1 H), 4.16 (d, J = 6.2 Hz, 2 H), 1.84–1.69 (m, 5 H), 1.50 (dt, J = 13.7, 3.4 Hz, 2 H), 1.37–1.20 (m, 5 H).

¹³C NMR (150 MHz, CDCl₃): δ (major) = 166.7, 160.8, 133.1, 130.4, 129.6, 128.5, 69.4, 53.4, 36.6, 35.9, 28.0, 25.0; δ (minor) = 166.6, 163.5, 133.1, 130.3, 129.6, 128.5, 69.2, 51.8, 37.8, 36.5, 31.9, 24.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₂₁NNaO₃: 298.1419; found: 298.1420.

trans-[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoate (14b)

Colorless oil.

IR (neat): 3292 (br), 3059, 2931, 2862, 2756, 1716, 1689, 1535, 1450, 1275, 1115, 714 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major) = 8.05 (d, J = 2.1 Hz, 1 H), 8.02 (d, J = 7.6 Hz, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 5.26 (s, 1 H), 4.21–4.18 (m, 2 H), 2.01–1.97 (m, 2 H), 1.91–1.67 (m, 5 H), 1.43 (s, 3 H), 1.39–1.29 (m, 2 H); δ (minor) = 8.32 (d, J = 12.4 Hz, 1 H), 8.02 (d, J = 7.6 Hz, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 5.86 (br s, 1 H), 4.21–4.18 (m, 2 H), 1.91–1.67 (m, 5 H), 1.63–1.57 (m, 2 H), 1.39–1.29 (m, 5 H).

¹³C NMR (100 MHz, CDCl₃): δ (major) = 166.7, 160.5, 133.0, 130.4, 129.6, 128.5, 68.9, 54.0, 36.3, 35.9, 25.4, 22.9; δ (minor) = 166.6, 162.7, 133.1, 130.3, 129.6, 128.5, 68.7, 52.7, 38.4, 36.2, 25.5, 25.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₂₁NNaO₃: 298.1419; found: 298.1409.

Acknowledgment

This work was partially supported by a Grant-in-Aid for the Accelerating Utilization of University IP Program from the Japan Science and Technology Agency.

• References

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• References

• 1a Allen CL, Williams JM. J. Chem. Soc. Rev. 2011; 40: 3405
  CrossrefPubMedSearch in Google Scholar
• 1b Humphrey JM, Chamberlin AR. Chem. Rev. 1997; 97: 2243
  CrossrefPubMedSearch in Google Scholar
• 1c Kobayashi G, Saito T, Kitano Y. Synthesis 2011; 3225
  Thieme Connect
• 1d Jo Y, Ju J, Choe J, Song KH, Lee S. J. Org. Chem. 2009; 74: 6358
  CrossrefPubMedSearch in Google Scholar
• 1e Carey JS, Laffan D, Thomson C, Williams MT. Org. Biomol. Chem. 2006; 4: 2337
  Search in Google Scholar
• 2a Cupido T, Tulla-Puche J, Spengler J, Albericio F. Curr. Opin. Drug Discovery Dev. 2007; 10: 768
  Search in Google Scholar
• 2b Ghose AK, Viswanadhan VN, Wendoloski JJ. J. Comb. Chem. 1999; 1: 55
  CrossrefSearch in Google Scholar
• 2c Gaudin JM, Lander T, Nikolaenko O. Chem. Biodiversity 2008; 5: 617
  CrossrefSearch in Google Scholar
• 3a Ritter JJ, Kalish J. J. Am. Chem. Soc. 1948; 70: 4048
  CrossrefSearch in Google Scholar
• 3b Ritter JJ, Minieri PP. J. Am. Chem. Soc. 1948; 70: 4045
  CrossrefSearch in Google Scholar
• 4a Chen HG, Goel OP, Kesten S, Knobelsdorf J. Tetrahedron Lett. 1996; 37: 8129
  CrossrefSearch in Google Scholar
• 4b Ho TL, Kung LR, Chein RJ. J. Org. Chem. 2000; 65: 5774
  CrossrefSearch in Google Scholar
• 4c Okada I, Kitano Y. Synthesis 2011; 3997
  Thieme Connect
• 5a Baldwin JE, O’Neil IA. Synlett 1990; 603
  Thieme Connect
• 5b Launay D, Booth S, Clemens I, Merritt A, Bradley M. Tetrahedron Lett. 2002; 43: 7201
  CrossrefSearch in Google Scholar
• 5c Porcheddu A, Giacomelli G, Salaris M. J. Org. Chem. 2005; 70: 2361
  CrossrefPubMedSearch in Google Scholar
• 5d Kim S, Yi KY. Tetrahedron Lett. 1986; 27: 1925
  CrossrefSearch in Google Scholar
• 6 Shokova EA, Musulu T, Luzikov TN, Kovalev VV. Russ. J. Org. Chem. 1999; 35: 844
  Search in Google Scholar
• 7a Das B, Reddy PR, Sudhakar C, Lingaiah M. Tetrahedron Lett. 2011; 52: 3521
  CrossrefSearch in Google Scholar
• 7b Wang GW, Shen YB, Wu XL. Eur. J. Org. Chem. 2008; 4367
• 7c Henneuse C, Boxus T, Tesolin L, Pantano G, Brynaert JM. Synthesis 1996; 495
  Thieme Connect
• 8 Kitano Y, Chiba K, Tada M. Synthesis 2001; 437
• 9 Kayser MM, Clouthier CM. J. Org. Chem. 2006; 71: 8424
  CrossrefSearch in Google Scholar

• Supplementary Material