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DOI: 10.1055/s-0034-1379961
Alkylation of Nitrogen-Containing Heterocycles via In Situ Sulfonyl Transfer
Publication History
Received: 03 November 2014
Accepted after revision: 05 December 2014
Publication Date:
03 February 2015 (online)
Abstract
A convenient synthesis of N-substituted heterocycles from primary and secondary alcohols and N-sulfonyl heterocycles is described. The reaction proceeds through sulfonyl transfer and in situ formation of activated alcohol derivatives. The formation of alkyl sulfonates as transient intermediates mitigates challenges associated with isolation of these reactive species. N-Sulfonyl heteroarenes were found to be stable over prolonged time, and efficiently coupled to a variety of alcohols.
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Pyrazoles and other azoles comprise a privileged motif in medicinal chemistry and are commonly found in biologically active molecules including agrochemicals and pharmaceutical agents.[1] To address the need for highly substituted pyrazoles, a range of synthetic routes have been developed utilizing either direct heterocycle functionalization or de novo synthesis.[2] N-Alkylation of pyrazoles and related heterocycles can often be accomplished through SN2 displacement or Mitsunobu reaction (equations 1 and 2 in Scheme [1]).[3] [4] [5] While approaches to N-alkylation featuring displacement of halides or sulfonates can be convenient, with compounds capable of neighboring-group participation or base-promoted elimination access to halides or sulfonates can be restricted by low stability and undesired reactivity.[6]
One strategy to overcome the difficulties associated with the use of unstable aliphatic halides or sulfonates is the generation of transient reactive intermediates during the reaction, as exemplified by the Mitsunobu reaction (intermediate II; equation 2 in Scheme [1]).[4] An analogous approach is the reaction of sulfonylated heterocycles with unactivated alcohols (equation 3 in Scheme [1]).[7] [8] In this reaction a transfer of the sulfonyl group from the heterocycle to the alcohol occurs, thereby generating the electrophile as an intermediate (III) and unveiling the nucleophile (equation 3 in Scheme [1]). This reactivity can be advantageous relative to Mitsunobu because of improved atom economy, generation of fewer by-products, and by avoiding the use of hazardous azodicarboxylate reagents.[9]
The intramolecular alkylation of sulfonylated indoles with pendant alcohols was reported as a side reaction in attempted C3 alkylations a number of years ago.[8a] [b] To date there are very few reports applying this reactivity in a general manner, most of which utilize strongly basic conditions in alkylations with only primary alcohols.[7a–c] In this report a protocol utilizing carbonate bases in the alkylation of substituted pyrazoles and other heterocycles is described, using both secondary and primary alcohols as substrates.
We undertook this investigation after encountering challenges with an unstable intermediate mesylate 5 (Scheme [2]). Although mesylation of alcohol 1a, and subsequent displacement was effective on small scale with freshly prepared mesylate, scale-up proved to be problematic because of decomposition of 5 upon concentration, leading to highly variable yields.[6] To overcome this problem we synthesized the mesylated pyrazole 4a and examined the in situ formation and reaction of the problematic electrophile. To our gratification, preliminary experiments showed not only that mesyl pyrazole 4a was a stable crystalline solid, but that mesyl transfer and SN2 displacement furnished the desired product 3a in 60% overall yield.
With an encouraging result in hand, a number of bases and solvents were screened (Table [1]). With unsubstituted mesyl pyrazole 4b the reaction proceeded efficiently in the presence of either alkoxide or carbonate bases (Table [1], entries 1–5 and 10–13). Sodium and potassium alkoxides yielded the products in slightly higher yields than lithium tert-butoxide (Table [1], entries 2, 4 and 5). MeCN and DMF were the optimal solvents. Tertiary amines failed to promote the reaction, while other bases examined yielded intermediate results (Table [1], entries 6–9). Carbonate base counterion appeared to be important for the success of the reaction, with Na2CO3 and K2CO3 giving inferior conversion, possibly as an outcome of lower solubility (Table [1], entries 11–13). The reaction conditions reported in the literature on sulfonyl transfer from indole derivatives were also examined (Table [1], entries 14 and 15).[7b] [d] The use of sodium hydride yielded some product, albeit in lower yield, and the addition of a phase-transfer catalyst (Bu4NBr) did not lead to improved yields.
a Mesyl pyrazole (0.72 mmol), the alcohol (0.6–0.72 mmol), and the base (1.2 equiv) were weighed into a vial. Solvent (0.3 M) was added. Vial was sealed with a screw cap and heated at 90 °C for 16 h.
b Yields were determined by NMR using 1,3,5-trimethoxybenzene as an internal standard.
c 1 M solution of the base in THF was used.
d Reaction was conducted at 110 °C, using Bu4NBr (5 mol%) as an additive.
e Reaction was conducted at 110 °C.
With suitable conditions in hand, pyrazoles bearing different substituents were compared (Table [2]). It was observed that in reactions of electron-poor pyrazoles (4a and 4c), conditions utilizing Cs2CO3 were more efficient and gave a cleaner reaction profile, while more electron-neutral pyrazoles (4b and 4d) led to product formation in higher yield when utilizing t-BuONa as the base. This difference in reactivity is consistent with the change in pK a and leaving group ability of the heterocycle. Thus, milder base can be utilized with more electron-deficient heterocycles, which mirrors some trends in reactivity of substituted indoles reported previously.[7d]
 |
|||||
|
Entry |
4 |
R |
Product |
Yield A (%)b |
Yield B (%)c |
|
1 |
4a |
CN |
3a |
79 |
47 |
|
2 |
4b |
H |
3b |
74 |
87 |
|
3 |
4c |
CF3 |
3c |
67 |
61 |
|
4 |
4d |
I |
3d |
70 |
79 |
a Conditions A: Cs2CO3 (1.2 equiv), MeCN, 90 °C, 16 h. Conditions B: t-BuONa (1.2 equiv), DMF, 90 °C, 16 h. See Table [1] for the protocol.
b Isolated yields using conditions A.
c Isolated yields using conditions B.
Next, the effect of the sulfonyl substituent on the outcome of the reaction was examined. Two different mechanisms for the sulfonyl transfer have been described in the literature.[10] It is typically assumed that the alkoxide adds directly to the sulfur atom leading to sulfonyl transfer. The alternative possibility is that the reaction can proceed through E1cB-type elimination of the mesylate to give a sulfene intermediate, which is then trapped by the alcohol. In the latter case, the presence of hydrogen atoms α to sulfur is necessary. A recent report from Sutton and co-workers, featuring mesyl transfer from phenols, suggested that both mechanisms were operative, with electron-poor phenols favoring E1cB pathway.[11] The presence of this pathway was also confirmed in the earlier work of Pregel and Buncel, where the transient sulfene intermediates could be trapped with enamines.[10b] Triflyl- and tosyl-functionalized pyrazoles were subjected to the reaction conditions (Scheme [3]). Both 4e and 4f afforded the product in similar yields to 4a, with tosyl pyrazole 4e furnishing the product in higher yield. These experiments suggested that α-protons were not essential for the reaction of 4-cyanopyrazole. Mesylated heterocycles were used for further studies out of convenience, although in some cases the tosylates yielded slightly better results (see Scheme [4]).
The substrate scope of the transformation was examined with both primary and secondary alcohols (Scheme [4]). Primary alcohols coupled to give product in high yield (3e, 3f, 3g), with the reaction with a diol being selective for primary over tertiary alcohol to afford compound 3g. Reaction proceeded efficiently in the presence of 2-chloropyridine with no SNAr by-products detected. Remarkably, a number of secondary alcohols reacted efficiently to give product in good yield (3h–3l), which is in contrast to earlier reports featuring sulfonyl transfer from phenol, indole, and pyrrolopyrimidine where only yields below 50% have been obtained with secondary alcohols.[7c] [d] [11] With a base-labile α-hydroxyamide substrate leading to 3j, some deterioration in the enantiomeric purity was observed under standard conditions. This problem could be remedied by carrying out the reaction at 70 °C, which facilitated product formation while maintaining a high enantiomeric ratio. In an attempt to improve the yield in a reaction with dianhydromannitol derivative 1k, we examined the reaction of N-tosyl pyrazole 4e in place of 4a. Under the standard conditions partial conversion was observed and a tosylated alcohol intermediate could be isolated. However by increasing the reaction temperature to 110 °C the product 3k could be obtained in excellent yield as a single diastereomer following inversion of the alcohol stereocenter. Utilizing tosyl pyrazole instead of mesyl pyrazole could furnish products in higher yields for some substrates [e.g., 3a (Scheme [3]), 3k], however the trend was not universal across other alcohols (e.g., 3i). The reaction was also tolerant of acidic protons, with Boc-protected secondary amines furnishing the products in good yield (3m, 3n, 3o). Considering the known challenges in regioselective alkylations of azoles, it was not surprising to observe mixtures of 3- and 5-regioisomers when 3-methyl or 3-phenylpyrazoles were utilized as substrates (3p and 3q).[3] [7a] The regioselectivity was dependent on the substrate structure and reaction conditions, and further optimization of the base and solvent, as well as application of more electronically or sterically biased substrates could lead to improved reaction outcomes.[12] [13]
Although numerous functional groups are compatible with this reaction, the reactivity is subject to an interplay between nucleophilicity and nucleofugality of the two substrates. As such, very nucleophilic or electrophilic functional groups interfere in the reaction in a predictable manner (Scheme [5]). While secondary and tertiary amides/carbonates as well as basic tertiary amines were well tolerated in the reaction (3a, 3j, 3m, 3n, 3o), substrate 1p bearing a basic secondary amine reacted with the sulfonyl group of 4a preferentially to the alcohol to give sulfonamide 5 as the major product (equation 1 in Scheme [5]). Conducting the reaction in the presence of 2 equivalents of 4a yielded 82% of protected compound 3r following two instances of mesyl transfer and a displacement of the mesylated alcohol (equation 2 in Scheme [5]). For electrophilic functional groups, 2-chloropyridine was well tolerated in the reaction of primary alcohol to give 3f (Scheme [4]). In a reaction of secondary alcohol 7, however, mesyl transfer onto the alcohol was observed followed by SNAr with the pyrimidinyl chloride to give compound 8 as the major product (equation 3 in Scheme [5]).
In addition to pyrazoles other sulfonylated heterocycles were subjected to the reaction conditions (Scheme [6]). Substituted benzimidazole afforded compound 9 in high yield. Pyrrolopyrimidine 10 was furnished in moderate yield, with some material lost likely to oligomer formation. Reaction of mesylindazole afforded the major product 11 in moderate yield, with some of the minor regioisomer detected. Tosylated indoles were also viable substrates, but the substitution pattern affected which conditions were optimal. In the case of unsubstituted indole, the reaction furnished better yields of 12 when using t-BuONa as the base. With more electron-deficient 3-acylindole, high yields of product 13 were obtained under milder conditions using Cs2CO3.
In conclusion, this work outlines the use of sulfonylated heterocycles in a desulfonylative alkylation of azoles. The reaction proceeds through sulfonyl transfer from the azole to the alcohol generating the electrophile in situ, which then undergoes displacement. Both primary and secondary alcohols perform well under the relatively mild reaction conditions. A number of different heterocycles bearing diverse substitution patterns can be utilized in this transformation.
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Acknowledgment
We thank Jason Ramsey and Justin Stroh for high resolution mass spectrometry determination, and Jason K. Smith for stereochemical purity determination.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1379961.
Included are procedures and characterization data for compounds 3a–3p, 4a–4n, and 8–13.
- Supporting Information
-
References and Notes
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- 1h Mowbray CE, Burt C, Corbau R, Gayton S, Hawes M, Perros M, Tran I, Price DA, Quinton FJ, Selby MD, Stupple PA, Webster R, Wood A. Bioorg. Med. Chem. Lett. 2009; 19: 5857
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- 13 See the Supporting Information for further experiments examining regioselectivity. General Procedure for Alkylation of Heterocycles through Sulfonyl Transfer (Procedure 2, SI): The alcohol (0.6 mmol, 1 equiv), sulfonylpyrazole (0.72 mmol, 1.2 equiv) and Cs2CO3 (0.72 mmol, 1.2 equiv) were weighed into a vial. The vial was fitted with a stirring bar and a screw cap with a septum. MeCN (2 mL, 0.3 M) was added, the vial was sealed and heated overnight at 90 °C. No special precautions to exclude air or moisture were taken. After a 16–18 h reaction time, the reaction was diluted with NH4Cl (aq) and EtOAc and, extracted into EtOAc. The aqueous phase was washed with EtOAc (2 ×). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give the reaction crude. The crude was purified through column chromatography to give the final product (typically 4-g cartridge, EtOAc and heptanes as solvents). tert-Butyl 4-[2-(4-Cyano-1H-pyrazol-1-yl)ethyl]piperazine-1-carboxylate (3a): yield: 78%; colorless oil (solidified over time); mp 75–76 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.72 (s, 1 H), 4.21 (t, J = 6.2 Hz, 2 H), 3.31–3.37 (m, 4 H), 2.75 (t, J = 6.0 Hz, 2 H), 2.36 (br m, 4 H), 1.39 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 154.5, 142.0, 134.8, 113.4, 91.9, 79.7, 57.0, 52.8, 50.1, 43.4 (br), 28.3. IR (neat): 3124, 2974, 2929, 2861, 2816, 2233, 1687, 1544, 1421, 1364, 1249, 1169, 1128, 1005 cm–1. HRMS (ESI): m/z [M + H+] calcd for C15H24N5O2: 306.1925; found: 306.1926. tert-Butyl 4-{2-[4-(Trifluoromethyl)-1H-pyrazol-1-yl]ethyl}-piperazine-1-carboxylate (3c): yield: 67%; colorless solid; mp 66–68 °C. 1H NMR (400 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.65 (s, 1 H), 4.22 (t, J = 6.2 Hz, 2 H), 3.37 (br t, J = 5.1 Hz, 4 H), 2.78 (t, J = 6.4 Hz, 2 H), 2.38 (br t, J = 4.7 Hz, 4 H), 1.42 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 154.6, 136.7 (q, J = 2.4 Hz), 128.9 (q, J = 3.7 Hz), 122.5 (q, J = 265.6 Hz), 113.3 (q, J = 38.1 Hz), 79.6, 57.3, 52.9, 50.1, 43.4 (br m), 28.3. 19F NMR (376 MHz, CDCl3): δ = –56.27 (s, 1 F). IR (neat): 2976, 2926, 2856, 2816, 1686, 1574, 1458, 1404, 1366, 1232, 1170, 1114, 1005, 968 cm–1. HRMS (EI): m/z [M + H+] calcd for C15H24F3N4O2: 349.1846; found: 349.1849. 1-[2-(Pyridin-4-yl)ethyl]-1H-pyrazole-4-carbonitrile (3e): yield: 66%; off-white solid; mp 99–101 °C. 1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 5.9 Hz, 2 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 6.94 (d, J = 6.2 Hz, 2 H), 4.37 (t, J = 6.8 Hz, 2 H), 3.16 (t, J = 6.8 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 149.8, 145.8, 142.3, 134.4, 123.6, 113.0, 91.7, 52.7, 35.1. IR (neat): 3121, 3069, 3032, 2994, 2954, 2233, 1603, 1544, 1462, 1438, 1417, 1385, 1358, 1158, 999 cm–1. HRMS (EI): m/z [M + H]+ calcd for C11H11N4: 199.0978; found: 199.0978. 1-[(3S,6R)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-yl]-1H-pyrazole-4-carbonitrile (3k): yield: 90%; colorless solid; mp 113–114 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.82 (s, 1 H), 7.28–7.40 (m, 5 H), 4.88–4.93 (m, 1 H), 4.82 (t, J = 4.7 Hz, 1 H), 4.79 (d, J = 11.3 Hz, 1 H), 4.70 (d, J = 4.7 Hz, 1 H), 4.59 (d, J = 11.7 Hz, 1 H), 4.37 (dd, J = 10.5, 5.5 Hz, 1 H), 4.26 (dd, J = 10.2, 2.0 Hz, 1 H), 4.12 (td, J = 6.6, 4.7 Hz, 1 H), 3.91 (dd, J = 9.0, 6.2 Hz, 1 H), 3.80 (dd, J = 9.4, 7.0 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 142.6, 137.4, 133.4, 128.4, 127.9, 127.8, 113.0, 92.8, 87.3, 81.1, 78.5, 72.8, 72.5, 71.0, 68.4. IR: 3121, 3065, 3031, 2928, 2878, 2234, 1544, 1495, 1454, 1388, 1359, 1324, 1211, 1134, 1099, 1082, 1058, 1021, 984 cm–1. HRMS (EI): m/z [M + H+] calcd for C17H18N3O3: 312.1343; found: 312.1342. tert-Butyl 4-{2-[5,6-Dichloro-2-(methylthio)-1H-benzo[d]-imidazol-1-yl]ethyl}piperazine-1-carboxylate (9): yield: 89%; pale yellow solid; mp 122–123 °C. 1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 1 H), 7.31 (s, 1 H), 4.08 (t, J = 6.6 Hz, 2 H), 3.38 (t, J = 4.7 Hz, 4 H), 2.75 (s, 3 H), 2.66 (t, J = 6.6 Hz, 2 H), 2.42 (br s, 4 H), 1.43 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 155.5, 154.5, 142.7, 135.5, 125.6, 125.4, 119.2, 109.9, 79.6, 56.4, 53.2, 43.4 (br), 42.2, 28.3, 14.7. IR (neat): 2974, 2932, 2861, 2815, 1687, 1457, 1428, 1363, 1300, 1245, 1168, 1127, 1091, 1050, 1005, 864 cm–1. HRMS (ESI): m/z [M + H+] calcd for C19H27Cl2N4O2S: 445.1226; found: 445.1229. tert-Butyl 4-[2-(3-Acetyl-1H-indol-1-yl)ethyl]piperazine-1-carboxylate (13): yield: 88%; yellow solid; mp 107–108 °C. 1H NMR (400 MHz, CDCl3): δ = 8.34–8.40 (m, 1 H), 7.81 (s, 1 H), 7.32–7.37 (m, 1 H), 7.26–7.32 (m, 2 H), 4.23 (t, J = 6.6 Hz, 2 H), 3.41 (br t, J = 4.3 Hz, 4 H), 2.77 (t, J = 6.4 Hz, 2 H), 2.50 (s, 3 H), 2.42 (br s, 4 H), 1.46 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 192.8, 154.5, 136.6, 135.3, 126.1, 123.1, 122.5, 122.4, 116.9, 109.5, 79.6, 57.1, 53.0, 44.5, 43.5 (br), 28.3, 27.4. IR (neat): 2975, 2932, 2861, 2814, 1684, 1641, 1527, 1461, 1419, 1389, 1365, 1291, 1243, 1220, 1167, 1127, 1003, 921 cm–1. HRMS (ESI): m/z [M + H+] calcd for C21H30N3O3: 372.2282; found: 372.2278.
For selected recent examples, see:
For reviews on the synthesis of pyrazoles, see:
For work on N-alkylation of heterocycles with halides and sulfonates, see:
The propensity of mesylates substituted with neighboring nucleophilic groups to react is well precedented. See:
For mechanism of sulfonyl transfer, see:
For N-alkylations of azoles examining regioselectivity, see ref. 3 and:
-
References and Notes
- 1a de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ. J. Med. Chem. 2006; 49: 3332
- 1b Lamberth C. Heterocycles 2007; 71: 1467
- 1c Vicentini CB, Romagnoli C, Andreotti E, Mares D. J. Agric. Food Chem. 2007; 55: 10331
- 1d Lahm GP, Cordova D, Barry JD. Bioorg. Med. Chem. 2009; 17: 4127
- 1e Wickens P, Kluender H, Dixon J, Brennan C, Achebe F, Bacchiocchi A, Bankston D, Bierer D, Brands M, Braun D, Brown MS, Chuang C.-Y, Dumas J, Enyedy I, Hofilena G, Hong Z, Housley T, Jones B, Khire U, Kreiman C, Kumarasinghe E, Lowinger T, Ott-Morgan R, Perkins L, Phillips B, Schoenleber R, Scott WJ, Sheeler R, Redman A, Sun X, Taylor I, Wang L, Wilhelm S, Zhang X, Zhang M, Sullivan E, Carter C, Miglarese M, Levy J. Bioorg. Med. Chem. Lett. 2007; 17: 4378
- 1f Fustero S, Román R, Sanz-Cervera JF, Simón-Fuentes A, Bueno J, Villanova S. J. Org. Chem. 2008; 73: 8545
- 1g Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O’Brien MA, O’Reilly M, Reule M, Saxty G, Seavers LC. A, Smith D.-M, Squires MS, Trewartha G, Walker MT, Woolford AJ.-A. J. Med. Chem. 2008; 51: 4986
- 1h Mowbray CE, Burt C, Corbau R, Gayton S, Hawes M, Perros M, Tran I, Price DA, Quinton FJ, Selby MD, Stupple PA, Webster R, Wood A. Bioorg. Med. Chem. Lett. 2009; 19: 5857
- 2a Fustero S, Simón-Fuentes A, Sanz-Cervera JF. Org. Prep. Proced. Int. U.S.A. 2009; 41: 253
- 2b Fustero S, Sánchez-Roselló M, Barrio P, Simón-Fuentes A. Chem. Rev. 2011; 111: 6984
- 2c Dadiboyena S, Nefzi A. Eur. J. Med. Chem. 2011; 46: 5258
- 2d Eicher T, Hauptmann S, Speicher A. The Chemistry of Heterocycles . Wiley & Sons; New York: 2004. 2nd ed. 179-184
- 2e Yet L. Progress in Heterocyclic Chemistry . Vol. 25. Gribble GW, Joule JA. Elsevier; Amsterdam: 2013: 217
- 2f Kumar V, Kaur K, Gupta GK, Sharma AK. Eur. J. Med. Chem. 2013; 69: 735
- 3a Benjes PA, Grimmett MR. Advances in Detailed Reaction Mechanisms . Vol. 3. Coxon JM. JAI Press; Greenwich (CT, USA): 1994: 199 ; and references therein
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- 13 See the Supporting Information for further experiments examining regioselectivity. General Procedure for Alkylation of Heterocycles through Sulfonyl Transfer (Procedure 2, SI): The alcohol (0.6 mmol, 1 equiv), sulfonylpyrazole (0.72 mmol, 1.2 equiv) and Cs2CO3 (0.72 mmol, 1.2 equiv) were weighed into a vial. The vial was fitted with a stirring bar and a screw cap with a septum. MeCN (2 mL, 0.3 M) was added, the vial was sealed and heated overnight at 90 °C. No special precautions to exclude air or moisture were taken. After a 16–18 h reaction time, the reaction was diluted with NH4Cl (aq) and EtOAc and, extracted into EtOAc. The aqueous phase was washed with EtOAc (2 ×). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give the reaction crude. The crude was purified through column chromatography to give the final product (typically 4-g cartridge, EtOAc and heptanes as solvents). tert-Butyl 4-[2-(4-Cyano-1H-pyrazol-1-yl)ethyl]piperazine-1-carboxylate (3a): yield: 78%; colorless oil (solidified over time); mp 75–76 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.72 (s, 1 H), 4.21 (t, J = 6.2 Hz, 2 H), 3.31–3.37 (m, 4 H), 2.75 (t, J = 6.0 Hz, 2 H), 2.36 (br m, 4 H), 1.39 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 154.5, 142.0, 134.8, 113.4, 91.9, 79.7, 57.0, 52.8, 50.1, 43.4 (br), 28.3. IR (neat): 3124, 2974, 2929, 2861, 2816, 2233, 1687, 1544, 1421, 1364, 1249, 1169, 1128, 1005 cm–1. HRMS (ESI): m/z [M + H+] calcd for C15H24N5O2: 306.1925; found: 306.1926. tert-Butyl 4-{2-[4-(Trifluoromethyl)-1H-pyrazol-1-yl]ethyl}-piperazine-1-carboxylate (3c): yield: 67%; colorless solid; mp 66–68 °C. 1H NMR (400 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.65 (s, 1 H), 4.22 (t, J = 6.2 Hz, 2 H), 3.37 (br t, J = 5.1 Hz, 4 H), 2.78 (t, J = 6.4 Hz, 2 H), 2.38 (br t, J = 4.7 Hz, 4 H), 1.42 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 154.6, 136.7 (q, J = 2.4 Hz), 128.9 (q, J = 3.7 Hz), 122.5 (q, J = 265.6 Hz), 113.3 (q, J = 38.1 Hz), 79.6, 57.3, 52.9, 50.1, 43.4 (br m), 28.3. 19F NMR (376 MHz, CDCl3): δ = –56.27 (s, 1 F). IR (neat): 2976, 2926, 2856, 2816, 1686, 1574, 1458, 1404, 1366, 1232, 1170, 1114, 1005, 968 cm–1. HRMS (EI): m/z [M + H+] calcd for C15H24F3N4O2: 349.1846; found: 349.1849. 1-[2-(Pyridin-4-yl)ethyl]-1H-pyrazole-4-carbonitrile (3e): yield: 66%; off-white solid; mp 99–101 °C. 1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 5.9 Hz, 2 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 6.94 (d, J = 6.2 Hz, 2 H), 4.37 (t, J = 6.8 Hz, 2 H), 3.16 (t, J = 6.8 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 149.8, 145.8, 142.3, 134.4, 123.6, 113.0, 91.7, 52.7, 35.1. IR (neat): 3121, 3069, 3032, 2994, 2954, 2233, 1603, 1544, 1462, 1438, 1417, 1385, 1358, 1158, 999 cm–1. HRMS (EI): m/z [M + H]+ calcd for C11H11N4: 199.0978; found: 199.0978. 1-[(3S,6R)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-yl]-1H-pyrazole-4-carbonitrile (3k): yield: 90%; colorless solid; mp 113–114 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.82 (s, 1 H), 7.28–7.40 (m, 5 H), 4.88–4.93 (m, 1 H), 4.82 (t, J = 4.7 Hz, 1 H), 4.79 (d, J = 11.3 Hz, 1 H), 4.70 (d, J = 4.7 Hz, 1 H), 4.59 (d, J = 11.7 Hz, 1 H), 4.37 (dd, J = 10.5, 5.5 Hz, 1 H), 4.26 (dd, J = 10.2, 2.0 Hz, 1 H), 4.12 (td, J = 6.6, 4.7 Hz, 1 H), 3.91 (dd, J = 9.0, 6.2 Hz, 1 H), 3.80 (dd, J = 9.4, 7.0 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 142.6, 137.4, 133.4, 128.4, 127.9, 127.8, 113.0, 92.8, 87.3, 81.1, 78.5, 72.8, 72.5, 71.0, 68.4. IR: 3121, 3065, 3031, 2928, 2878, 2234, 1544, 1495, 1454, 1388, 1359, 1324, 1211, 1134, 1099, 1082, 1058, 1021, 984 cm–1. HRMS (EI): m/z [M + H+] calcd for C17H18N3O3: 312.1343; found: 312.1342. tert-Butyl 4-{2-[5,6-Dichloro-2-(methylthio)-1H-benzo[d]-imidazol-1-yl]ethyl}piperazine-1-carboxylate (9): yield: 89%; pale yellow solid; mp 122–123 °C. 1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 1 H), 7.31 (s, 1 H), 4.08 (t, J = 6.6 Hz, 2 H), 3.38 (t, J = 4.7 Hz, 4 H), 2.75 (s, 3 H), 2.66 (t, J = 6.6 Hz, 2 H), 2.42 (br s, 4 H), 1.43 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 155.5, 154.5, 142.7, 135.5, 125.6, 125.4, 119.2, 109.9, 79.6, 56.4, 53.2, 43.4 (br), 42.2, 28.3, 14.7. IR (neat): 2974, 2932, 2861, 2815, 1687, 1457, 1428, 1363, 1300, 1245, 1168, 1127, 1091, 1050, 1005, 864 cm–1. HRMS (ESI): m/z [M + H+] calcd for C19H27Cl2N4O2S: 445.1226; found: 445.1229. tert-Butyl 4-[2-(3-Acetyl-1H-indol-1-yl)ethyl]piperazine-1-carboxylate (13): yield: 88%; yellow solid; mp 107–108 °C. 1H NMR (400 MHz, CDCl3): δ = 8.34–8.40 (m, 1 H), 7.81 (s, 1 H), 7.32–7.37 (m, 1 H), 7.26–7.32 (m, 2 H), 4.23 (t, J = 6.6 Hz, 2 H), 3.41 (br t, J = 4.3 Hz, 4 H), 2.77 (t, J = 6.4 Hz, 2 H), 2.50 (s, 3 H), 2.42 (br s, 4 H), 1.46 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 192.8, 154.5, 136.6, 135.3, 126.1, 123.1, 122.5, 122.4, 116.9, 109.5, 79.6, 57.1, 53.0, 44.5, 43.5 (br), 28.3, 27.4. IR (neat): 2975, 2932, 2861, 2814, 1684, 1641, 1527, 1461, 1419, 1389, 1365, 1291, 1243, 1220, 1167, 1127, 1003, 921 cm–1. HRMS (ESI): m/z [M + H+] calcd for C21H30N3O3: 372.2282; found: 372.2278.
For selected recent examples, see:
For reviews on the synthesis of pyrazoles, see:
For work on N-alkylation of heterocycles with halides and sulfonates, see:
The propensity of mesylates substituted with neighboring nucleophilic groups to react is well precedented. See:
For mechanism of sulfonyl transfer, see:
For N-alkylations of azoles examining regioselectivity, see ref. 3 and:
