Agotf Catalyzed Amination Of Benzyl Alcohols With Sulfonamides Biology Essay


The catalytic formation of carbon-nitrogen bonds is of a broad interest to synthetic organic chemists since a large number of nitrogen-containing molecules are of importance for both the bulk and fine chemical industries, for example, for the production of solvents and emulsifiers. In addition, a variety of naturally occurring bio-active compounds such as alkaloids, amino acids and nucleotides contain amino groups, which are particularly useful for the development of new pharmaceuticals and agrochemicals.1, 2

However, these conventional reactions suffer disadvantages as follows; (1) the use of alkyl halides or strong reducing reagents is undesirable from an environmental point of view and (2) these reactions generate equimolar amounts of wasteful salts as co-products.

The N-alkylation of amines with alcohols (Scheme 1) is an attractive candidate for the synthesis of amines because, (1) it does not generate any harmful and/or wasteful co-products (only H2O as co-product), (2) alcohols are more readily available than corresponding halides or carbonyl compounds in many cases, and (3) if the reaction proceeds efficiently by the employment of equimolar amounts of starting materials, extremely high atom economical system6 can be realized. (6. Trost, B. M. Science 1991, 254, 1471.)

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Thus, the development of improved methods for the synthesis of amines continues to be a challenging and active area of research.2 (2. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785.)

Scheme 1. Substitution of benzyl alcohol by (a) catalytic hydrogen transfer (b) catalytic hydrogen transfer, and (c) direct catalytic substitution.

Review of literature

Amines are a versatile class of compounds used frequently in organic synthesis, especially in the construction of heterocycliccompounds.17 Therefore, transformation of alcohols to amines is an important reaction for the synthesis of a variety of organic compounds. The most common approach for their preparation involves a three steps protocol:

a) conversion of alcohols to corresponding halides or sulfonates,

b) nucleophilic substitution by azide anion18and

c) reduction of azide to amine by using various reagents19.

Alternatively they can be prepared by a two step methodology :

conversion of alcohol to azide by Mitsunobu reaction using hydrazoicacid, triphenylphosphine and diethylazodicarboxylate (DEAD)20,

reduction of azide to amine.

But, extra time is required to isolate intermediate products and leading to low overall yields, and involves the risk of handling explosive azides. In view of this, there is a need to develop one pot sequence. Although there is a report of one pot method21 involving the combination of Mitsunobu and Staudinger reactions, it is less attractive as it involves the usage of toxic and expensive reagents like HN3 and DEAD respectively.

Since the beginning of the 90's with the seminal articles of Trost14, 15 and Sheldon16, the attention of the organic chemists was drawn to the necessity to develop methods in agreement with the atom economy concept to fit with increasing environmental awareness. It is thus necessary to minimize or if possible, to eliminate the waste production. A complete re-thinking of the strategy in organic synthesis should be undertaken. To solve this waste problem, one should notably use more catalysis in organic synthesis, limit the utilization of hazardous and /or toxic chemicals and reexamine the question of solvent.

Some of the recent reports which describing the direct amination of alcohols with amines are:

Hiroshi shinokubo R have developed a direct amination of allyllic alcohols using palladium(0) as the catalyst. In this method direct use of allyl alcohol for the Tsuji-Trost reaction at room temperature is achieved in an aqueous system without any activator. The reaction conditions are neutral to basic, allowing the use of amines as nucleophile.

Matthias Beller et al have reported An improved method for the N-alkylation of primary amines with primary and secondary alcohols has been developed. Novel, effective catalyst systems, for example, Ru3(CO)12 combined with tri-o-tolylphosphine or n-butyl-di-1-adamantylphosphine, allow for aminations in a good yield under comparatively mild conditions. R

The reaction proceeds in a good yield in the presence of the ruthenium carbonyl cluster. With respect to the used ligands, there was no clear trend observed. For example electron-rich bulky phosphines such as tricyclohexylphosphine 1 and n-butyl-di-1-adamantyl-phosphine20 2 behaved quite differently. Similar divergent behaviour was observed with aryl phosphines 3. The best results were obtained with 2 and 3.

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The reactions can be performed under significantly milder conditions (110 oC) compared to the known ruthenium catalysts and proceed with good yields.

Damien Prim groupR have developed an efficient procedure to obtain benzylic amines starting from the corresponding alcohols under mild and environmentally benign catalytic conditions. This methodology tolerates various aromatic or heterocyclic substrates bearing electron-donating but also mild electron-withdrawing groups. Several catalytic systems were compared evidencing the higher selectivity of Au (III) over others. Among the nitrogen-based nucleophiles used, TMSN3 proved useful as intermediate in the amination-reduction sequence leading to the direct preparation of diarylmethylamines.

The formation of the carbon-nitrogen bond is assumed to proceed through an overall SN1-like mechanism including the generation of a benzylic cation as reactive intermediate, in a first step, and subsequent nucleophilic attack in a second step. This kind of mechanism and intermediate are consistent with the influence of the electronic effects of the substituents.

Takao Ikariya group have shown that the easily handled Pd-P(OC6H5)3 catalyst system provides convenient halidefree allylation reactions by directly using allylic alcohols. The reaction, even with low catalyst loading (0.2-1 mol %), smoothly proceeds to give the corresponding allylic ethers and the related C-C and C-N bond-forming products. Cocatalysts and bases are not required in the allylations, which is thus of great promise for achieving environmentally benign processes.

Y. Kayaki,T . Koda,T . Ikariya, J. Org. Chem. 2004, 69,2595 ;

Shigeki Matsunaga, and Masakatsu Shibasaki group have developed a bismuth-catalyzed direct substitution of allylic,propargylic,and benzylic alcohols with sulfonamides,carbamates ,and carboxamides. A combination of commercially available Bi(OTf)3 and KPF6 (1-5 mol%) catalyzed the reactions effectively,mostly at room temperature, to give the products in moderate to good yields.

Bi(OTf)3 alone promoted the reaction,albeit at a lower reaction rate. The reaction was much slower with BiCl3. KPF6 alone did not afford any of the product. Both Bi(OTf)3 and KPF6 were required for high reactivity at room temperature. With the Bi(OTf)3/KPF6 system, the catalyst loading was successfully decreased to 2 mol%. presence of the desiccant drierite CaSO4 increases rate of the reaction.

We present here an efficient method for the direct amination of benzyl alcohols with sulfonamides using silver triflate as catalyst, using no other additives (Scheme 2). The advantages of this type of amination are the ready availability of alcohols and high atom efficiency with the formation of water as the only by-product. Moreover, as opposed to typical reductive aminations, it is possible to run these reactions in the absence of additional hydrogen.

Scheme 2.

Results and Discussion

Initially, we examined the influence of different solvents using p-chlorobenzyl alcohol and p-toluenesulfonamide as model substrates in the presence of 5 mol % AgOTf as catalyst at 100 oC. The results are summarized in Table 1. It was observed that on using 1 equiv of alcohol and amine, mono- and disubstituted products (3aa and 4aa) were obtained in a ratio of 3:1 using toluene as the solvent in 60% yield (Table 1, entry 1). Reaction in DMF, DMSO or 1,4-dioxane resulted in lower yields (Table 1, entries 2-4), and there was no reaction in acetonitrile (Table 1, entry 5). In nitromethane, the products were obtained in a ratio of 3:2 in 72% yield (Table 1, entry 6). Variation of the alcohol and amine ratio changed the yields as well as selectivities of the products formed. The reaction with 1.5 or 2 equiv of amine resulted in monosubstituted product in high yields, whereas the presence of 2 equiv of alcohol afforded the disubstituted product in good yield.

Table 1. Optimization of reaction conditions for the reaction of 1a with 2aa

aReaction conditions as exemplified in the typical experimental procedure.10 bIsolated yields.

cAll products were characterized by IR,1H NMR, 13C NMR, mass spectroscopy.11

Various other Lewis acids were screened for the reaction under the optimized conditions. As can be seen from Table 2, Cu(OTf)2, Sc(OTf)3 and Bi(OTf)3 gave the corresponding products in 92, 90 and 90% yields, whereas La(OTf)3 and Ce(OTf)4 gave the products in only moderate yields (entries 4 and 5). Zn(OTf)2 and Ag(0) afforded the desired products in poor yields (entries 6 and 7) and there was no reaction with CuCl2 and Ag(NO)3 (entries 8 and 9). Among the several catalysts screened, AgOTf was the catalyst of choice and, as can be seen, the nature of the counter ion also plays a significant role in the amination reaction.

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Table 2. Screening of catalysts for the reaction of 1a with 2aa

aReaction conditions as exemplified in the typical experimental procedure.10

bIsolated yield.

Under the optimized reaction conditions (2 equiv of amine and nitromethane as solvent), various primary alcohols were subjected to amination with different sulfonamides and the results are given in Table 3. The reaction of electronically and structurally diverse benzyl alcohols such as o-chloro, p-fluoro, p-methyl and p-trifluoromethyl benzyl alcohols with 2a gave the desired products in good yields (entries 1-6), whereas the presence of a strong electron-withdrawing substituent (pnitrobenzyl) gave no product (entry 7). 2-Naphthyl methanol on reaction with 2a gave the product in low

yield (entry 8).

Reaction of 1a with benzenesulfonamide, methanesulfonamide and triisopropylbenzenesulfonamide gave the corresponding products in high yields (entries 9-11) and the reaction of 1a with N-substituted p-toluenesulfonamides gave the desired products in moderate yields (entries 12 and 13).


In conclusion, we have developed an efficient procedure to obtain benzylic amines from the corresponding primary alcohols and sulfonamides in the presence of silver triflate as catalyst. The methodology is straightforward and environmentally benign with the formation of water as the only by-product.

Table 3. Direct amination of different benzyl alcohols with p-toluene sulfonamidesa

a Reaction conditions as exemplified in the typical experimental procedure.10

bIsolated yields.

cAll products were characterized by IR,1H NMR, 13C NMR, mass spectroscopy.11

Table 3. Direct amination of 4-chlorobenzyl alcohol 1a with different sulfonamidesa

a Reaction conditions as exemplified in the typical experimental procedure.10

bIsolated yields.

cAll products were characterized by IR,1H NMR, 13C NMR, mass spectroscopy.11

Typical experimental procedure: A mixture of benzyl alcohol (1 mmol), sulfonamide (2.0 mmol) and silver triflate (5 mol %) in nitromethane (5 mL) was stirred at 100 oC for 8 h (Table 1). After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2X 10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel to afford the pure product.

Spectroscopic data for the products

N-(4-Chloro-benzyl)-4-methyl-benzenesulfonamide (Table 3, entry 1):

IR (KBr): ν 3053, 2924, 1596, 1344, 1185, 837cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.44 (s, 3H), 4.07 (d, 2H, J = 6.8 Hz), 4.81 (t, 1H, J = 6.8 Hz),

7.11 (d, 2H, J = 8.3 Hz), 7.20 - 7.28 (m, 4H), 7.70 (d, 2H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.49, 46.43, 127.08, 128.66, 129.16, 129.67, 133.56, 134.85, 136.64, 143.67. LC MS (m/z): 295.9 (M)+,318.0 (M+Na)+.

N-Benzyl-4-methyl-benzenesulfonamide (Table 3, entry 2):

IR (KBr): ν 3268, 3032, 1598, 1423, 1324, 1172, 1059, 742cm-1. 1H NMR (300 MHz, CDCl3): d (ppm)

2.41(s, 3H), 4.04 (d, 2H, J = 6.3), 5.03 (t, 1H, J = 6.3 Hz), 7.02(d, 2H, J = 8.3 Hz), 7.23- 7.36(m, 5H), 7.68 (d, 2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 20.91, 47.02, 125.46, 127.1, 127.5, 128.36, 129.24, 133.28, 139.54, 143.4. LC MS (m/z): 284 (M + Na)+.

N-(2-Chloro-benzyl)-4-methyl-benzenesulfonamide (Table 2, entry 3):

IR (KBr): ν 3059, 2934, 1607, 1490, 1301, 1165, 862 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.43(S, 3H), 4.20 (d, 2H, J = 6.6 Hz), 5.00 (t, 1H, J = 6.6 Hz), 7.13

- 7.31 (m, 6H), 7.68 (d, 2H, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.42, 37.27, 128.08, 126.28, 128.57, 129.16, 129.67, 132.31, 136.85, 141.64, 142.96. LC MS (m/z): 295.9 (M)+.

N-(4-Fluoro-benzyl)-4-methyl-benzenesulfonamide (Table 2, entry 4):

IR (KBr): ν 3246, 3043, 2866, 1607, 1509, 1317, 1167, 1066, 812, 728 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.46 (S, 3H), 4.05 (d, 2H, J = 6.3

Hz), 4.96 (t, 1H, J = 6.3 Hz), 6.93 (d, 2H, J = 8.5 Hz), 7.13 - 7.29 (m, 4H), 7.71 (d, 2H, J = 7.8 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.44, 46.51, 115.46 (d, J C-F = 19.7 Hz), 127.13, 129.60 (d, J C-F = 13.17 Hz), 136.76, 143.57, 160.65, 163.93. LC MS (m/z): 280 (M+H)+, 302 (M+Na)+.

4-Methyl-N-(4-methyl-benzyl)-benzenesulfonamide (Table 2, entry 5):

IR (KBr): ν 3266, 3059, 1598, 1322, 1154, 1093, 726, 685 cm-1.1H NMR (300 MHz, CDCl3): d (ppm) 2.30 (s, 3H), 2.44 (s, 3H), 4.03 (d, 2H, J = 6.0 Hz),

4.76 (t, 1H, J = 6.0 Hz), 6.85 - 7.04 (m, 4H), 7.25 (d, 2H, J = 8.1 Hz), 7.71 (d, 2H, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 20.94, 21.49, 47.01, 127.07, 129.34, 129.60, 133.18, 136.73, 137.54, 143.33. LC MS (m/z): 298.1 (M+Na)+.

4-Methyl-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide (Table 2, entry 6):

IR IR (KBr): ν 3436, 2942, 1317, 1175, 1132, 1069, 908, 815 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.45 (s, 3H), 4.03 (d, 2H, J = 6.3 Hz),

4.82 (t, 1H, J = 6.3 Hz), 7.09 (d, 2H, J = 8.3 Hz), 7.24 - 7.31 (m, 4H), 7.81(d, 2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.45, 47.2, 122.10, 124.94, 125.44 (q, J C-F = 3.3 Hz), 127.25, 128.93, 129.38, 132.9 (d, J C-F = 3.3 Hz), 136.37, 142.75. LC MS (m/z): 330 (M+H)+, 352 (M+Na)+.

4-Methyl-N-naphthalen-2-ylmethyl-benzenesulfonamide (Table 2, entry 8):

IR (KBr): ν 3032, 1529, 1423, 1288, 1093, 875 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.32 (s, 3H), 4.18 (d, 2H, J = 6.3 Hz), 5.34 (t, 1H, J = 6.3

Hz), 7.11 (d, 2H, J = 8.3 Hz), 7.22 - 7.26 (m, 1H), 7.36 - 7.40 (m, 2H), 7.61 - 7.71(m, 6H), 7.52 (S, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 21.37, 47.38, 125.56, 126.04, 126.19, 126.6, 127.09, 127.53, 127.64, 128.42, 129.57, 131.96, 132.04, 132.74, 133.06, 133.58, 136.90, 143.38. LC MS (m/z): 334.1 (M + Na)+.

N-(4-Chloro-benzyl)-benzenesulfonamide (Table 2, entry 9):

IR (KBr): ν 3452, 2875, 1601, 1567, 1314, 1179, 1070, 829 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 4.08 (d, 2H, J = 6.3 Hz), 5.04 (t, 1H, J = 6.3

Hz), 7.09 - 7.26 (m, 3H), 7.44 - 7.57 (m, 4H), 7.82 (d, 2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 47.04, 127.02, 127.63, 127.74, 128.50, 129.58, 143.3. LC MS (m/z): 281(M)+, 304 (M + Na)+.

N-(4-Chloro-benzyl)-methanesulfonamide (Table 2, entry 10):

IR (KBr): ν 3043, 2821, 1609, 1371, 1167, 1094, 813 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.81 (s, 3H),

4.26 (d, 2H, J = 5.9 Hz), 4.79 (t, 1H, J = 5.9 Hz), 7.12 (d, 2H, J = 8.3 Hz), 7.24 (d, 2H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 41.17, 46.40, 128.99, 129.23, 135.25, 140.91.LC MS (m/z): 242 (M + Na)+.

N-(4-Chloro-benzyl)-2,4,6-triisopropyl-benzenesulfonamide (Table 2, entry 11):

IR (KBr): ν 3312, 2958, 1603, 1567, 1322, 1174, 1092, 829, 656 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 1.25 (d, 18H, J = 6.8 Hz), 2.86 - 2.95 (m,

3H), 4.10 (d, 2H, J = 6.0 Hz), 4.53(t, 1H, J = 6.0 Hz), 7.14 (d, 2H, J = 7.5 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.25 (s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 23.62, 24.87, 29.67, 34.16, 46.33, 123.79, 128.81, 129.37, 132.28, 133.78, 138.05, 150.24, 153.02. LC MS (m/z): 430.1 (M+Na)+.

N-(4-Chloro-benzyl)-4-methyl-N-phenyl-benzenesulfonamide (Table 2, entry 12):

IR (KBr): ν 2922, 1453, 1355, 1132, 548 cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.43 (s, 3H), 4.65 (s, 2H), 6.91- 6.94 (m, 2H), 7.15 - 7.20 (m,

6H), 7.23 - 7.26 (m, 3H), 7.49 (d, 2H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.4, 53.51, 113.2, 118.3, 127.4, 128.5, 128.70, 129.02, 129.72, 132.8, 136.3, 141.51, 43.27, 143.75. LC MS (m/z): 372 (M+H)+, 394 (M+Na)+.

N-(4-Chloro-benzyl)-4,N-dimethyl-benzenesulfonamide (Table 2, entry 13):

White solid. IR (KBr): ν 3027, 1495, 1324, 1177, 1093, 742cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.41(s, 3H), 2.72 (s, 3H), 4.26 (s, 2H), 6.91

(d, 2H, J = 8.0 Hz), 7.18 - 7.23 (m, 4H), 7.48 (d, 2H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.46, 34.80, 53.21, 126.82, 128.89, 129.68, 133.28, 134.24, 136.48, 142.9. LC MS (m/z): 332 (M + Na)+.

N, N-Bis-(4-chloro-benzyl)-4-methyl-benzenesulfonamide (4aa):

IR (KBr): ν 3246, 2921, 1600, 1460, 1293, 1167, 812cm-1. 1H NMR (300 MHz, CDCl3): d (ppm) 2.47 (s, 3H), 4.23 (s, 4H), 6.842 - 7.07 (m, 8H), 7.31 (d, 2H J = 8.0 Hz), 7.72 (d, 2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 21.54, 47.26, 127.18, 127.91, 128.64, 129.70, 132.19, 133.4, 136.29, 143.54. LC MS (m/z): 420.1 (M)+, 443.0 (M+Na)+.