N-Isopropylidene-N′-2-Nitrobenzenesulfonyl Hydrazine. A Reagent for Reduction of Alcohols via the Corresponding Monoalkyl Diazenes

Abstract

The reagent N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine (IPNBSH) is used in the reduction of alcohols via the loss of dinitrogen from transiently formed monoalkyl diazene intermediates accessed by sequential Mitsunobu displacement, hydrolysis and fragmentation under mild reaction conditions.

The loss of dinitrogen from monoalkyl diazene intermediates is common in a wide range of transformations in organic chemistry.^1,2 Several powerful methodologies for carbonyl reduction involve initial condensation with an arenesulfonyl hydrazine followed by reduction of the corresponding hydrazone leading to the loss of dinitrogen. In 1996, Myers reported a highly efficient, mild, and stereospecific conversion of a variety of propargylic alcohols to the corresponding allenes^3a via a Mitsunobu⁴ reaction using the reagent 2-nitrobenzenesulfonyl hydrazide⁵ (NBSH). Subsequent reports discussed the use of NBSH in the reduction of allylic, benzylic, and saturated alcohols.^3b–c This direct reduction of alcohols via the corresponding monoalkyl diazene intermediates under mild reaction conditions presents a highly versatile methodology for organic synthesis.⁶ We recently reported the use of the related reagent N-isopropylidene- N′-2-nitrobenzene-sulfonyl hydrazine (IPNBSH) for a difficult allylic reductive transposition step in our total syntheses of (−)-acylfulvene and (−)-irofulven.⁷ Herein we report our results on the general utility of IPNBSH, a complimentary reagent to NBSH, for conversion of alcohols to the corresponding monoalkyl diazene intermediates.

The stereospecific displacement of an alcohol by the reagent NBSH under the Mitsunobu reaction conditions affords the corresponding 1,1-disubstituted sulfonyl hydrazine 2 (Scheme 1).³

SCHEME 1.

Warming of the reaction mixture to ambient temperature provides the corresponding monoalkyl diazene 3 by elimination of 2-nitrobenzenesulfinic acid. Sigmatropic3a–b loss of dinitrogen from the unsaturated monoalkyl diazene, or expulsion of dinitrogen via a free-radical^3c pathway from the saturated monoalkyl diazene, affords the corresponding reduction product. The thermal sensitivity of NBSH in solution and the corresponding Mitsunobu adduct 2 necessitate the execution of the initial step in these transformations at sub-ambient temperatures (−30 to −15 °C). Lower reaction temperatures obviate a competitive and undesired Mitsunobu reaction of the alcohol substrate with 2-nitrobenzenesulfinic acid, the thermal decomposition⁸ product of NBSH or adduct 2.³ For less reactive alcohols, the use of higher substrate concentrations and excess reagents in N-methyl morpholine has been described.^3b–c

We recently found the use of the reagent IPNBSH to be advantageous over NBSH in a surprisingly difficult⁹ reductive allylic transposition reaction.⁷ In reduction of the substrate in entry 1 of Table 1, IPNBSH provided greater flexibility with respect to solvent choice, reaction temperature, order of addition, and concentration of substrate and reagents. As shown in Scheme 1, the Mitsunobu displacement of an alcohol with IPNBSH results in the stable and isolable arenesulfonyl hydrazone 4. We developed mild reaction conditions for in situ hydrolysis of hydrazone 4 to the same hydrazine 2 accessed using NBSH (Scheme 1).

TABLE 1.

Reduction of Alcohols using IPNBSH^a

Entry	Substrate	Product	Yield(%)b
1			71c
2			84d
3			82d,e
4			69f
5			60g
6			70
7			87
8			87h
9			35h

^aConditions: Ph₃P (1.2 equiv), DEAD (1.2 equiv), IPNBSH (1.2 equiv), THF [0.1M], 0→23°C, 2h; TFE–H₂O (1:1), 2h.

^bAverage of two experiments.

^cReference ⁷.

^dHydrolysis step required 3 h.

^eThe Mitsunobu reaction was complete in 15 min.

^fE:Z = 93:7.

^g2.0 equiv of reagents was used; contains <8% of C5-diastereomer.

^h1.6 equiv of reagents was used; PhNHNH₂ (5.0 equiv) was used in place of TFE–H₂O.

(1)

IPNBSH can be prepared by dissolution of the readily available NBSH⁵ in acetone (eq 1). For optimal results, IPNBSH is triturated with hexanes to give the desired reagent as a white solid. Comparison of the X-ray structure of IPNBSH¹⁰ with that of the closely related acetone p-toluenesulfonyl hydrazone¹¹ reveals longer C–S (1.774 vs. 1.753 Å) and slightly shorter N(2)–S (1.636 vs. 1.637 Å) bonds consistent with greater interaction between the nitrogen(2) and sulfur in IPNBSH. The smaller N–N–S bond angle found in IPNBSH (112.4° vs. 114.1°) was expected to reduce the steric interaction of the syn-coplanar N–H and C-Me groups.

Significantly, the greater thermal stability of IPNBSH compared to NBSH was expected to provide flexibility for the Mitsunobu reaction while offering equally rapid thermal fragmentation after hydrolysis of the adduct 4 (Scheme 1). For comparison, heating a solution of IPNBSH in DMSO-d₆ [0.02M] at 50 °C for 30 minutes did not result in decomposition while a significant quantity of NBSH (~60%) was found to fragment under the same conditions. Solutions of IPNBSH as described above did not decompose at 75 or 100 °C after 30 min whereas considerable decomposition was observed at 150 °C within minutes. The greater thermal stability of IPNBSH allows it to be stored at room temperature for several months.^{5b–c, 12}

The utility of IPNBSH in the challenging⁷ reductive allylic transposition mentioned above prompted our evaluation of this reagent’s broader utility for organic synthesis. Addition of diethylazadicarboxylate (DEAD, 1.20 equiv) to a solution of trans,trans-farnesol (1a, 1 equiv, Scheme 2), IPNBSH (1.21 equiv), and triphenylphosphine (Ph₃P, 1.21 equiv) in THF (9.0 mL) rapidly (15 min) provided the desired Mitsunobu adduct 4a in 86% isolated yield. The isolation of 4a is not necessary and its direct hydrolysis under optimal conditions was achieved by introduction of trifluoroethanol–water (TFE–H₂O, 1:1) upon completion of the Mitsunobu reaction.¹³ The hydrolysis step results in fragmentation of 2-nitrobenzenesulfinic acid followed by sigmatropic loss of dinitrogen to give the triene 5a in 87% isolated yield. The ease of hydrolysis of these hydrazones under mild conditions is likely due to the rapid fragmentation of the corresponding sulfonyl hydrazine derivatives at room temperature.¹⁴

SCHEME 2.

A uniform set of reaction conditions proved effective for a single-step reduction of a range of alcohols (Table 1). Allylic alcohols (Table 1, entries 1–5) and propargylic alcohols (Table 1, entries 6–7) provided the desired reduction products via the expected sigmatropic loss of dinitrogen from the intermediate monoalkyl diazenes generated by in situ hydrolysis. For unhindered primary alcohols the reaction could be conducted at even lower concentration (0.05M) and sub-ambient temperatures with equal efficiency. The use of IPNBSH allowed the use of other solvents (e.g., toluene, fluorobenzene, and chlorobenzene) in place of THF with similar results.

Interestingly, while the Mitsunobu reaction with the primary alcohol in entry 8 of Table 1 proceeded smoothly under standard conditions (adduct isolated in 93% yield), the hydrolysis of the corresponding hydrazone adduct 4 under the conditions used for propargylic and allylic substrates proved ineffective, affording less than 20% yield of the desired reduction product.¹⁵

We reasoned that while slow hydrolysis and generation of unsaturated (propargylic and allylic) monoalkyl diazenes led to an efficient sigmatropic loss of dinitrogen, the loss of dinitrogen from saturated monoalkyl diazenes would be optimal at higher concentrations of the diazene intermediate.¹⁶ The replacement of the hydrolysis step with a hydrazone exchange reaction (phenylhydrazine), reduced the time for the complete consumption of the Mitsunobu adduct from 4h to 30 min (TLC analysis).¹⁷ The limitation of IPNBSH is its greater sensitivity toward sterically hindered substrates as compared to NBSH. For example, the Mitsunobu reaction with the saturated secondary alcohol in entry 9 of Table 1 proved difficult as compared to the reaction of unsaturated secondary alcohols (Table 1, entries 4–7).¹⁸ The use of more forcing reaction conditions with the alcohol in entry 9 of Table 1 did not increase the isolated yield of the desired product and returned the starting alcohol.¹⁹

The thermal stability of IPNBSH allows for unique transformations such as the one shown in equation 2. N-Alkylation of the corresponding sodium sulfonamide of IPNBSH with allylic bromide 6 followed by in situ hydrolysis afforded the desired terminal alkene 5a via sigmatropic loss of dinitrogen. This single-step N-alkylation–reduction strategy offers a valuable alternative to the approach based on the Mitsunobu reaction.^9a

(2)

In addition to IPNBSH, we examined a series of other hydrazone derivatives as potential reagents for the conversion of alcohols to the corresponding monoalkyl diazenes. These included the 2-nitrobenzenesulfonyl hydrazones of trifluoroacetone, dichloroacetone, cyclobutanone, benzaldehyde, acetaldehyde, and trimethylacetaldehyde, in addition to methanesulfonyl hydrazones of acetone and benzaldehyde. IPNBSH was identified as the best reagent based on optimal reactivity in the Mitsunobu reaction and ease of hydrolysis of the corresponding adduct. Interestingly, while the Mitsunobu reaction of the aldehyde hydrazone derivatives proceeded with equal efficiency as IPNBSH their hydrolysis gave the corresponding carbonyl hydrazide and not the expected reduction product (Scheme 3). This is likely due to isomerization²⁰ of transient α-hydroxyalkyldiazene intermediates 10a–b.

SCHEME 3.

In conclusion, the reagent IPNBSH serves as a complementary reagent to NBSH for conversion of alcohols to the corresponding reduction products via monoalkyl diazene intermediates. Attractive features of this reagent include ease of preparation, storage, and use due to excellent thermal stability. IPNBSH offers flexibility with respect to choice of reaction solvent, reaction temperature, order of addition, and concentration of substrate and reagents in the Mitsunobu reaction. We expect IPNBSH will find applications in unique transformations such as that illustrated in equation 2.

Experimental Section

(E)-3,7,11-Trimethyldodeca-1,6,10-triene (5a, Table 1, entry 3)

DEAD (74 μL, 0.47 mmol, 1.2 equiv) was added drop-wise to a solution of IPNBSH (122 mg, 0.474 mmol, 1.21 equiv), trans,trans-farnesol (1a, 0.100 mL, 0.393 mmol, 1 equiv), and triphenylphosphine (124 mg, 0.473 mmol, 1.21 equiv) in anhydrous THF (9.0 mL) at 0 °C under an argon atmosphere. After 5 min, the reaction mixture was allowed to warm to 23 °C. After 20 min, a mixture of trifluoroethanol and water (1:1, 4.5 mL) was added to the reaction mixture to enable formation of the allylic diazene intermediate. After 3 h, the reaction mixture was partitioned between diethyl ether (25 mL) and water (25 mL), and the aqueous layer was extracted with diethyl ether (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated. The residue was purified by flash column chromatography on silica gel (100% ⁿpentane) to give triene 5a (71 mg, 87%). All spectroscopic data were in agreement with literature.²¹ TLC (40% ethyl acetate in hexanes), Rf: 0.8 (CAM, KMnO₄). ¹H NMR (400 MHz, CDCl₃, 20 °C): 5.25–5.15 (m, 1H), 5.13–5.10 (m, 2H), 4.99 (t, 1H, J = 2.0 Hz), 4.94–4.91 (m, 2H), 2.14–1.98 (m, 7H), 1.69 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.36–1.33 (m, 2H), 0.99 (d, 3H, J = 8 Hz). ¹³C NMR (500 MHz, CDCl₃, 20 °C): 145.0, 135.1, 131.5, 124.7, 124.6, 112.7, 39.9, 37.5, 36.9, 26.9, 25.9, 25.8, 20.4, 20.4, 17.9, 16.2. MS (m/z) C₁₅H₂₆ [M]⁺: 206. FTIR (thin film): 3077 (m), 2966 (s), 2915 (s), 2856 (s), 1640 (m), 1453 (s), 1376 (s).

5-Phenylpenta-1,2-diene (Table 1, Entry 6)

DEAD (67.5 μL, 0.429 mmol, 1.20 equiv) was added drop-wise to a solution of IPNBSH (110 mg, 0.429 mmol, 1.20 equiv), 5-phenylpent-1-yn-3-ol (57 mg, 0.36 mmol, 1 equiv), and triphenylphosphine (112 mg, 0.428 mmol, 1.20 equiv) in anhydrous THF (3.5 mL) at 0 °C under an argon atmosphere. After 5 min, the reaction mixture was allowed to warm to 23 °C. After 2 h, a mixture of trifluroethanol and water (1:1, 1.7 mL) was added to the reaction mixture to enable the formation of the propargylic diazene intermediate. After 2 h, the reaction mixture was partitioned between ⁿpentane (25 mL) and water (25 mL). The organic layer was washed with water (2 × 25mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated. The residue was purified by flash column chromatography on silica gel (100% ⁿpentane) to give the allene (36 mg, 70%). All spectroscopic data were in agreement with the literature.^{22 1}H NMR (400 MHz, CDCl₃, 20°C): 7.31–7.28 (m, 2H), 7.22–7.21 (m, 3H), 5.17 (tt, 1H, J = 13.2, 6.8 Hz), 4.69 (dt, 2H, J = 6.8, 3.2 Hz), 2.75 (t, 2H, J = 7.6 Hz), 2.35–2.32 (m, 2H). ¹³C NMR (500 MHz, CDCl₃, 20°C): 208.8, 142.0, 128.7, 128.5, 126.1, 89.6, 75.3, 35.6, 30.2. MS (m/z) C₁₁H₁₂ [M]⁺: 144. FTIR (thin film): 3027 (s), 2922 (s), 2855 (s), 1955 (s), 1495 (m), 1453 (m).