Name: protocol for the synthesis of ortho-trifluoromethoxylated aniline derivatives
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우리는이 작업을 지원 스토니 브룩 뉴욕 주립 대학에서 관대 시작 자금을 인정합니다. 우리는 또한 Togni 시약 II의 합성에 대해 우리에게 TMSCF 3 시약을 제공 토소 F-테크, 주식 회사 감사합니다.

1. 전구체 제조 : 메틸 4- (N의 -hydroxyacetamido) 벤조 에이트 (1A)의 합성 <ol><li> 메틸 4- 니트로 벤조 에이트의 감소. <ol><li> 오븐 건조 된 250 ml의 2 차원에 메틸 4- 니트로 벤조 에이트 (27.6 밀리몰, 1.00 당량), 탄소 5 % 로듐의 159 mg의 로듐 (Rh / C, 0.300 몰 % RH) 및 자기 교반 바을 5.00 g을 넣고 (18 시간 동안 150 ℃에서 건조) 목 환저 플라스크. 참고 : 시약 주변 분위기에서 계량 할 수 있습니다. 그러나, 반응은 질소 분위기 하에서 수행 될 필요가있다. </li><li> 질소 / 진공 매니 폴드에 플라스크의 한 목을 연결하고 격막과 다른 목 모자. 세 진공 재충전 사이클을 수행 (즉, 플라스크 중 공기를 펌핑하고, 질소 가스로 인한 진공을 대체), 질소 가스와 함께 플라스크 내에서 공기를 교체. </li><li> 기밀 주사기를 사용하여 반응 플라스크에 138 ml의 무수 테트라 히드로 푸란 (THF, 0.200 M)를 첨가. 차가운 반응 믹스트를 저어15 분 동안 0 ℃에서 URE. </li><li> 기밀 주사기를 사용하여 0 ℃에서 반응 액에 히드라진 일 수화물 1.47 ㎖ (1.52 g, 30.4 밀리몰, 1.20 당량)를 적가. 박층 크로마토 그래피 (T​​LC)를 사용하여 반응을 모니터한다. 헥산을 사용하여 에틸 아세테이트 (EtOAc)에 (4 : 1 V / V, R의 F = 0.23)을 전개 용매로 TLC를 개발. </li><li> 메틸 4- 니트로 벤조 에이트가 완전히 소모되면, 진공 여과를 사용하여 부 흐너 깔때기를 프릿 60 ㎖ 중의 규조토의 짧은 패드 (즉, 셀 라이트, 5g)을 통하여 반응 혼합물을 필터. EtOAc로 필터 (20 ㎖ × 3 회)를 씻으십시오. 추가의 정제없이 직접 사용되는 조 메틸 4- (N의 -hydroxyamino) 벤조 에이트를 수득 회전 증발기로 감압 여과 액을 농축시켰다. </li></ol></li><li> 메틸 4- (N의 -hydroxyamino) 벤조산 아세틸 보호 <ol><li> 중탄산 나트륨 2.55 g을 추가 (의 NaHCO3, 30.4 밀리몰, 1.20 당량), 모든 조질이전 단계에서 수득 된 메틸 4- (N의 -hydroxyamino) 벤조 에이트, 및 오븐 건조 된 500㎖의 두 구 둥근 바닥 플라스크에 교반 바. </li><li> 격막 하나의 목을 모자와 질소 / 진공 매니 폴드에 다른 목을 연결합니다. 플라스크 내를 질소 가스로 공기를 대체하기 위해 세 진공 재충전 사이클을 수행한다. </li><li> 기밀 주사기를 사용하여 반응 플라스크에 138 ml의 무수을 디 에틸 에테르 (ET 2 O, 0.200 M)를 첨가. 냉각시키고 15 분 동안 0 ℃에서 반응 혼합물을 교반한다. </li><li> 무수을 Et2O (138 ㎖, 0.220 M)을 (2.17 ㎖, 2.39 g, 30.4 밀리몰, 1.20 당량), 아세틸 클로라이드의 용액을 제조 하였다. 10.0 ㎖ / 시간의 속도로 시린지 펌프를 이용하여 0 ℃에서 반응 혼합물에 용액을 첨가. </li><li> 첨가의 마지막에, 규조토의 짧은 패드를 ​​통해 반응 혼합물을 필터링 (즉, 셀 라이트, 5g) 60 ㎖ 중의 진공 여과를 사용하여 부 흐너 깔때기를 프릿. EtOAc로 필터 (20 ㎖ × 3 회)를 씻으십시오. 집중회전 증발기를 사용하여 진공 여과. </li><li> 헥산으로 플래쉬 컬럼 크로마토 그래피 (35) 용리와 조질 생성물을 정제 : EtOAc로를 (4 : 1 내지 1 : 1 (V / V)) (R의 F = 0.13, 헥산 :을 EtOAc (4 : 1 (V / V))로 5.31을 수득 밝은 황색 고체 (25.4 밀리몰, 수율 92 %)로서 메틸 4- (N의 -hydroxyacetamido) 안식향산의 g. </li></ol></li></ol> 벤조 에이트 (2A) - 메틸 4- ((트리 플루오 로메 톡시) 아세트 N) 2. 합성 <ol><li> 메틸 4- (N의 -hydroxyacetamido) 벤조 에이트 (1A) (9.56 밀리몰, 1.00 당량) 2.00 g, 세슘 2 CO 3의 311 mg의 (0.956 밀리몰, 10.0 몰 %), Togni 시약 II의 3.63 g (11.5 밀리몰 추가 1.20 당량), 및 글로브 박스 (질소 분위기 안에서 오븐 - 건조 된 250 mL의 둥근 바닥 플라스크에 자기 교반 바). 주 :이 반응은 또한 글로브 박스 밖에서 슈렌 기법을 사용하여 수행 될 수있다. 주의 : 순수 Togni 시약 II는 충격과 마찰에 민감한, 불꽃입니다S는, 불꽃 및 / 또는 그라인딩을 피해야한다. 부드럽고 광택이 도구는 조작을 위해 사용되어야한다. 또한, 반응 혼합물 안전 실드 뒤에 교반한다. 36 </li><li> 반응 플라스크에 건조 및 탈기 클로로포름 95.6 ㎖ (클로로포름, 0.100 M)를 첨가. </li><li> 중격 플라스크 캡 내부 또는 16 시간 동안 글러브 박스의 외부에 N 2 분위기 하에서 23 ℃에서 반응 혼합물을 저어. </li><li> 임의의 고체 잔류 물을 제거하기 위해 필터 깔때기를 통해 반응 혼합물을 필터. 회전 증발기를 사용하여 진공 하에서 여과 액을 농축시켰다. </li><li> 디클로로 메탄 (CH 2 CL 2) 플래시 칼럼 크로마토 그래피는 헥산으로 용출하여 조질 생성물을 정제 (7 : 0~3 : 1 (V / V)) (R의 F = 0.44 (CH 2 CL (2))을 수득 (- (트리 플루오 로메 톡시) 아세트 N) 벤조 에이트 (9.05 밀리몰, 수율 95 %)의 4- 메틸 2.51 g. 참고 : Togni 시약 II는 준비 협정이다문헌 절차 37, -35 ℃에서 냉동 글로브 박스에 저장하기에 보내고 장기간에 걸쳐 그 품질을 유지한다. 이 반응은 산소에 민감하다. 모든 시약을 실온에서 주위 분위기하에 칭량 할 수 있지만, 반응 플라스크로부터 모든 산소를 제거하여 매우 중요하다. 건조 및 동결 - 펌프 - 해동 절차의 3주기를 수행 한 다음, 질소 분위기 하에서 2 CAH에서 증류에 의해 제조된다 클로로포름 탈기. </li></ol> 3. 메틸의 합성 4- 아세트 아미도 -3- (트리 플루오 로메 톡시) 벤조 에이트 OCF 3 -migration (3A)를 통해 <ol><li> 50 ml의 압력 용기로 벤조 에이트 (9.05 밀리몰, 1.0 당량), 자기 볶음 바, 특산 2 (1.00 M)의 9.05 ml의 - 2.51 g의 메틸 4- ((트리 플루오 로메 톡시) 아세트 N)를 추가합니다. 스크류 캡으로 용기를 모자. </li><li> 20 시간 동안 안전 실드 뒤에 120 ℃에서 반응 혼합물을 교반한다. 주의 : 불순한 니트로 메탄폭발성이므로, 반응 혼합물 안전 실드 뒤에 교반한다. </li><li> RT 반응 액을 냉각. </li><li> 100㎖의 환저 플라스크에, 반응 혼합물을 전송. </li><li> 회전 증발기를 사용하여 진공 하에서 반응 혼합물을 농축시킨다. </li><li> 플래시 칼럼 크로마토 그래피는 헥산으로 용출하여 조질 생성물을 정제 : EtOAc로를 (9 : 1~7 : 3 (V / V)) (R의 F = 0.51 헥산 :을 EtOAc (4 : 1 (V / V))로 정제하여 메틸 -4- 아세트 아미도 -3- (트리 플루오 로메 톡시) 벤조산 2.13 g (7.69 밀리몰, 85 %). 주 :이 반응은 주변 대기 하에서 수행 될 수있다. 질소 분위기가 필요하지 않습니다. 물 응축기가 장착 된 둥근 바닥 플라스크를 대체 반응 장치로서 사용될 수있다. </li></ol> 신제품 4. 특성 <ol><li> 1 H, 13 C NMR 분광법 및 고해상도 질량 분광법으로 모든 신규 화합물을 특성화하고 19 F NMR 분광법을 사용불소 원자를 함유하는 화합물을 특성화. 34 </li></ol>

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Rev. 96, 1757-1777 (1996).</li><li>Umemoto, T., Adachi, K., Ishihara, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CF3+oxonium+salts,+O-(trifluoromethyl)dibenzofuranium+salts:+in+situ+synthesis,+properties,+and+application+as+a+real+CF3++species+reagent.">CF3 oxonium salts, O-(trifluoromethyl)dibenzofuranium salts: in situ synthesis, properties, and application as a real CF3+ species reagent.</a> J. Org. Chem. 72, 6905-6917 (2007).</li><li>Stanek, K., Koller, R., Togni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reactivity+of+a+10-I-3+hypervalent+iodine+trifluoromethylation+reagent+with+phenols.">Reactivity of a 10-I-3 hypervalent iodine trifluoromethylation reagent with phenols.</a> J. Org. Chem. 73, 7678-7685 (2008).</li><li>Koller, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Zinc-mediated+formation+of+trifluoromethyl+ethers+from+alcohols+and+hypervalent+iodine+trifluoromethylation+reagents.">Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents.</a> Angew. Chem. Int. Ed. 48, 4332-4336 (2009).</li><li>Trainor, G. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+preparation+of+O-trifluoromethyl+carbohydrates.">The preparation of O-trifluoromethyl carbohydrates.</a> J. Carbohydr. Chem. 4, 545-563 (1985).</li><li>Nishida, M., Vij, A., Kirchmeier, R. L., Shreeve, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+polyfluoro+aromatic+ethers+-+a+facile+route+using+polyfluoroalkoxides+generated+from+carbonyl+and+trimethysilyl+compounds.">Synthesis of polyfluoro aromatic ethers - a facile route using polyfluoroalkoxides generated from carbonyl and trimethysilyl compounds.</a> Inorg. Chem. 34, 6085-6092 (1995).</li><li>Kolomeitsev, A. A., Vorobyev, M., Gillandt, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Versatile+application+of+trifluoromethyl+triflate.">Versatile application of trifluoromethyl triflate.</a> Tetrahedron Lett. 49, 449-454 (2008).</li><li>Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+deeper+insight+into+direct+trifluoromethoxylation+with+trifluoromethyl+triflate.">A deeper insight into direct trifluoromethoxylation with trifluoromethyl triflate.</a> J. Fluorine Chem. 131, 200-207 (2010).</li><li>Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+and+direct+trifluoromethoxylation+of+aliphatic+substrates+with+2,4-dinitro(trifluoromethoxy)benzene.">A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-dinitro(trifluoromethoxy)benzene.</a> Adv. Synth. Catal. 352, 2831-2837 (2010).</li><li>Huang, C. H., Liang, T., Harada, S., Lee, E., Ritter, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Silver-mediated+trifluoromethoxylation+of+aryl+stannanes+and+arylboronic+acids.">Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids.</a> J. Am. Chem. Soc. 133, 13308-13310 (2011).</li><li>Rozen, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+fluorinations+by+reagents+containing+the+OF+group.">Selective fluorinations by reagents containing the OF group.</a> Chem. Rev. 96, 1717-1736 (1996).</li><li>Venturini, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Direct+trifluoro-methoxylation+of+aromatics+with+perfluoro-methyl-hypofluorite.">Direct trifluoro-methoxylation of aromatics with perfluoro-methyl-hypofluorite.</a> J. Fluorine Chem. 140, 43-48 (2012).</li><li>Hojczyk, K. N., Feng, P., Zhan, C., Ngai, M. -. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trifluoromethoxylation+of+arenes:+synthesis+of+ortho-trifluoromethoxylated+aniline+derivatives+by+OCF3+migration.">Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.</a> Angew. Chem. Int. Ed. 53, 14559-14563 (2014).</li><li>Still, W. C., Kahn, M., Mitra, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+chromatographic+technique+for+preparative+separations+with+moderate+Resolution.">Rapid chromatographic technique for preparative separations with moderate Resolution.</a> J. Org. Chem. 43, 2923-2925 (1978).</li><li>Fiederling, N., Haller, J., Schramm, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Notification+about+the+Explosive+Properties+of+Togni's+Reagent+II+and+One+of+Its+Precursors.">Notification about the Explosive Properties of Togni's Reagent II and One of Its Precursors.</a> Org. Process Res. Dev. 17, 318-319 (2013).</li><li>Matousek, V., Pietrasiak, E., Schwenk, R., Togni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-pot+synthesis+of+hypervalent+iodine+reagents+for+electrophilic+trifluoromethylation.">One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation.</a> J. Org. Chem. 78, 6763-6768 (2013).</li></ol>

The authors declare no competing financial interests.

인해 trifluoromethoxylated 아렌의 합성에 대해 일반적이고 사용자 친화적 인 절차의 부족, 많은 OCF 3 - 함유 방향족 화합물은 매우 고가이다. (34) 우리의 전략은 광범위한 관능기 허용 변위 각종 trifluoromethoxylated 아렌에 대한 쉬운 접근을 제공한다. 이들 화합물은 새로운 의약품, 농약, 및 재료의 발견과 개발을위한 가치있는 빌딩 블록을 제공 할 수있다. 히드라진 ?...

플루오 로메는 (OCF 3) 그룹이 때문에 높은 전기 음성도의 독특한 조합에 1935 년 2 트리 플루오로 에테르의 첫 번째 합성 이후의 삶과 재료 과학 연구에 지대한 영향을 만들었습니다 (χ = 3.7) 3과 우수한 친 유성 (Π X = 1.04), 4 플루오 로메 그룹은 의학, 농업, 및 재료 산업의 광범위한 응용 프로그램을 발견했다. 5-10 그러나, 유기 분자, 특히 방향족 화합물로 OCF 3 그룹의 손쉬운 도입은 합성 화학의 주요 과제로 남아. 지난 몇 년 동안이 문제를 해결하기 위해 노력 trifluoromethoxylated 아렌의 합성 변환의 소수의 개발을 주도 5-7,9-11 trichlorinated 전구체에 이러한 포함 (I) 염소 / 불소 교환,., 12 fluoroformates의 -17 (II) deoxyfluorination 18 </SUP&gt; (III) 산화 fluorodesulfurization; 19-21 (IV) 알코올의 친 전자 trifluoromethylation; 22-25 (V) 핵성 trifluoromethoxylation; 26-30, 아릴 스탄 난과 붕산염의 (VI), 전이 금속 - 매개 trifluoromethoxylation 31 및 (Ⅶ ) 라디칼 trifluoromethoxylation. 32,33 그러나 이러한 접근 방법 중 하나는 많은 열악한 기재 범위 고통 또는 높은 독성 및 / 또는 열적으로 불안정한 시약의 사용을 필요로한다. 따라서, OCF 3 인해 함유 화합물을 합성 일반 사용자 친화적 방법의 부족, OCF 3 그룹의 화학 전위는 충분히 악용되지 않았다. trifluoromethoxylation 반응에서 우리의 관심의 일환으로, 우리는 34 메틸 4- 아세트 아미도 -3- (트리 플루오 로메 톡시의 합성 본원 두 단계의 프로토콜 (예를 들어, 라디칼과 O의 -trifluoromethylation 열 유도 OCF 3 -migration)을 묘사메틸 4- (N의 -hydroxyacetamido) 벤조 에이트 (1A)에서 벤조 에이트 (3A)). 이 전략은 오르 -trifluoromethoxylated 아닐린 유도체의 넓은 범위의 합성에-작동하기 쉽고 적용 할 수있다.

<table><tbody><tr><td>5% Rhodium on carbon</td><td>Aspira Scientific</td><td>300835</td><td>5% wt% dry loading</td></tr><tr><td>Hydrazine monohydrate</td><td>Sigma-Alderich</td><td>13696HMV</td><td>Reagent grade, 98%</td></tr><tr><td>Acetyl chloride</td><td>Alfa Aesar</td><td>10176887</td><td>98%</td></tr><tr><td>Sodium bicarbonate</td><td>Fisher Scientific</td><td>134826</td><td>Chemical pure</td></tr><tr><td>Cesium carbonate</td><td>Alfa Aesar</td><td>12887</td><td>99.9%, metals basis</td></tr><tr><td>Togni Reagent II</td><td></td><td></td><td>Prepared according to the literature procedure (ref 37). Caution: Pure Togni reagent II is impact and friction sensitive, treat it with great care (see ref. 36).</td></tr><tr><td>Tetrahydrofuran</td><td>BDH</td><td>BDH1149-4LG</td><td>Distilled from deep purple sodium benzophenone ketyl.</td></tr><tr><td>Diethyl Ether</td><td>Fisher Scientific</td><td>148221</td><td>Distilled from deep purple sodium benzophenone ketyl.</td></tr><tr><td>Chloroform</td><td>Fisher Scientific</td><td>141739</td><td>Dried over CaH&lt;sub&gt;2&lt;/sub&gt; and distilled</td></tr><tr><td>Nitromethane</td><td>Alfa Aesar</td><td>J03z053</td><td>Dried over CaSO&lt;sub&gt;4&lt;/sub&gt; and distilled</td></tr><tr><td>Silica gel</td><td>SILICYCLE</td><td>60514</td><td>40-63 &amp;micro;m (230-400 mesh)</td></tr><tr><td>Celite</td><td>EMD</td><td>2012040674</td><td>Not acid washed</td></tr></tbody></table>

protocol for the synthesis of ortho-trifluoromethoxylated aniline derivatives

플루오 로메 (OCF 3) 그룹을 함유 분자들은 약리학 및 생물 학적 속성을 원하는 보여줍니다. 그러나 trifluoromethoxylated 방향족 화합물의 손쉬운 합성은 유기 합성의 강력한 도전 남아있다. 종래의 접근 방식은 종종 열악한 기재 범위 고통, 또는 높은 독성 어려운 핸들의 사용을 필요로, 및 / 또는 열적으로 불안정한 시약. 여기서, 우리가 사용한 메틸 -4- 아세트 아미도 -3- (트리 플루오 로메 톡시) 벤조 에이트의 합성을위한 사용자 친화적 인 프로토콜을보고 -1- 플루오로 메틸 -1,2- benziodoxol -3- (1H) - 온 (시약 Togni II). 탄산 세슘의 촉매량의 존재하에 Togni 시약 II와 메틸 4- (N의 -hydroxyacetamido) 벤조 에이트 (1A)을 치료하는 CS (2 CO 3) RT에서 클로로포름 메틸 -4-을 수득 하였다 (N - (트리 플루오 로메 톡시) 아세트 아미도) 벤조산 (2A). 이 중간이어서 최종 제품 메틸 -4- 아세트 -3- (트라이 플루오로 전환시켰다120 ° C에서 니트로 메탄에 thoxy) 벤조 에이트 (3A). 이 절차는 일반적이며 새로운 의약품, 농약, 기능성 재료의 발견과 개발을위한 유용한 합성 빌딩 블록을 제공 할 수 -trifluoromethoxylated 오르토 아닐린 유도체의 광범위한 스펙트럼의 합성에 적용될 수있다.

메틸 4- (N의 -hydroxyacetamido) 벤조 에이트 (1A)는, 즉, 촉매로서 5 % Rh / C를 사용하여 히드라진 메틸 -4- 니트로 벤조 에이트를 환원하여 메틸 4- (형성한다 (두 단계 절차를 통해 92 % 격리 수율로 합성 하였다 N의 -hydroxyamino) 벤조 에이트, 생성 된 히드 록실 아민의 아세틸 보호 하였다). 탄산 세슘의 촉매량의 존재하에 Togni 시약 II와 1A의</stro...

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Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

의 합성을위한 프로토콜<em&gt; 직교</em&gt; -trifluoromethoxylated 아닐린 파생 상품

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

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Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

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9.9K 조회수.  State University of New York at Stony Brook. An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

비디오: Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

생성 Cyanocarbenes의 응용 프로그램에 대한 고원자가 요오드 알키 트라이 플레이트의 합성

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

연구

화학

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes &#945;v and &#945;5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document. The modifications described here involve terminally (N&#969;) alkylated and acetylated guanidine groups. For the synthesis, tailor-made precursor molecules are synthesized, which are then subjected to a reaction with an orthogonally deprotected amine to transfer the pre-modified guanidine group. For the synthesis of alkylated guanidines, precursors based on N,N&#8242;-Di-Boc-1H-pyrazole-1-carboxamidine are used to synthesize acylated compounds, the precursor of choice being a correspondingly acylated derivative of N-Boc-S-methylisothiourea, which can be obtained in one- and two-step reactions.

A protocol for the synthesis of alkyl-modified guanidines based on the use of the corresponding precursors is presented.

맞춤형 선구자로 수정하고, 구아니딘 그룹의 기능화

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. ...

생화학

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

중간 과산화물을 통해 광화학 및 산 - 촉매 CH 기능화에 의한 항 바이러스 Tetrahydrocarbazole 유도체의 합성 (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Synthesis of Indoxyl-glycosides for Detection of Glycosidase Activities

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are rapidly oxidized, for example by atmospheric oxygen, to indigo type dyes. This reaction enables fast and easy screening in vivo without isolation or purification of enzymes, as well as rapid tests on agar plates or in solution (e.g., blue-white screening, micro-wells) and is used in biochemistry, histochemistry, bacteriology and molecular biology. Unfortunately the synthesis of such substrates proved to be difficult, due to various side reactions and the low reactivity of the indoxyl hydroxyl function. Especially for glucose type structures low yields were observed. Our novel approach employs indoxylic acid ester as key intermediates. Indoxylic acid esters with varied substitution patterns were prepared on scalable pathways. Phase transfer glycosylations with those acceptors and peracetylated glycosyl halides can be performed under common conditions in high yields. Ester cleavage and subsequent mild silver mediated glycosylation yields the peracetylated indoxyl glycosides in high yields. Finally deprotection is performed according to Zempl&#233;n.

Indoxyl glycosides are well-established and widely used tools for enzyme screening and enzyme activity monitoring. Especially for glucose type structures previous syntheses proved to be challenging and low yielding. Our novel approach employs indoxylic acid esters as precious intermediates to yield a considerable number of indoxyl glycosides in good yields.

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are ...

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

N의 준비-(2-alkoxyvinyl) sulfonamides N-토실기-1,2,3-triazoles 및 후속 변환 대체 Phthalans 및 Phenethylamines에서

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile ...

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

1-Iodoalkynes, 1, 2-Diiodoalkenes, 및 1,1,2 Triiodoalkenes 터미널 Alkynes의 산화 Iodination에 따라 Chemoselective 준비

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates

Maleimide-bearing bifunctional probes have been employed for decades for the site-selective modification of thiols in biomolecules, especially antibodies. Yet maleimide-based conjugates display limited stability in vivo because the succinimidyl thioether linkage can undergo a retro-Michael reaction. This, of course, can lead to the release of the radioactive payload or its exchange with thiol-bearing biomolecules in circulation. Both of these processes can produce elevated activity concentrations in healthy organs as well as decreased activity concentrations in target tissues, resulting in reduced imaging contrast and lower therapeutic ratios. In 2018, we reported the creation of a modular, stable, and easily accessible phenyloxadiazolyl methyl sulfone reagent &#8212; dubbed &#8216;PODS&#8217; &#8212; as a platform for thiol-based bioconjugations. We have clearly demonstrated that PODS-based site-selective bioconjugations reproducibly and robustly create homogenous, well-defined, highly immunoreactive, and highly stable radioimmunoconjugates. Furthermore, preclinical experiments in murine models of colorectal cancer have shown that these site-selectively labeled radioimmunoconjugates exhibit far superior in vivo performance compared to radiolabeled antibodies synthesized via maleimide-based conjugations. In this protocol, we will describe the four-step synthesis of PODS, the creation of a bifunctional PODS-bearing variant of the ubiquitous chelator DOTA (PODS-DOTA), and the conjugation of PODS-DOTA to the HER2-targeting antibody trastuzumab.

In this protocol, we will describe the synthesis of PODS, a phenyoxadiazolyl methyl sulfone-based reagent for the site-selective attachment of cargos to the thiols of biomolecules, particularly antibodies. In addition, we will describe the synthesis and characterization of a PODS-bearing bifunctional chelator and its conjugation to a model antibody.

합성 및 Bioconjugation의 Thiol 반응 시 약 사이트에 선택적으로의 창조에 대 한 수정 Immunoconjugates

Maleimide-bearing bifunctional probes have been employed for decades for the site-selective modification of thiols in biomolecules, especially antibodies. ...

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyl(tropone)iron

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyltroponeiron

Representative experimental procedures for the addition of amine nucleophiles to tricarbonyl(tropone)iron and subsequent demetallation of the resulting complexes are presented in detail.

트리카보닐(트로폰)철을 통한 6-아미노사이클로헵타-2,4-디엔-1-1-1 유도체 의 제조

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate ...

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

3-Aroyl-N-hydroxy-5-nitroindoles were synthesized by cycloaddition of 4-nitronitrosobenzene with a conjugated terminal alkynone in a one-step thermal procedure. Preparation of the nitrosoarene and of the alkynones were adequately reported and respectively through oxidation procedures on the corresponding aniline and on the alkynol.

알키논을 곁들인 4-니트로니트로소벤젠의 사이클로추가에 의한 3-Aroyl-N-hydroxy-5-니트로인돌의 직접, Regioselective 및 원자-경제적 합성

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ...

Synthesis of pH Dependent Pyrazole, Imidazole, and Isoindolone Dipyrrinone Fluorophores using a Claisen-Schmidt Condensation Approach

Methine-bridged conjugated bicyclic aromatic compounds are common constituents of a range of biologically relevant molecules such as porphyrins, dipyrrinones, and pharmaceuticals. Additionally, restricted rotation of these systems often results in highly to moderately fluorescent systems as observed in 3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidin-3-ones, xanthoglows, pyrroloindolizinedione analogs, BODIPY analogs, and the phenolic and imidazolinone ring systems of Green Fluorescent Protein (GFP). This manuscript describes an inexpensive and operationally simple method of performing a Claisen-Schmidt condensation to generate a series of fluorescent pH dependent pyrazole/imidazole/isoindolone dipyrrinone analogs. While the methodology illustrates the synthesis of dipyrrinone analogs, it can be translated to produce a wide range of conjugated bicyclic aromatic compounds. The Claisen-Schmidt condensation reaction utilized in this method is limited in scope to nucleophiles and electrophiles that are enolizable under basic conditions (nucleophile component) and non-enolizable aldehydes (electrophile component). Additionally, both the nucleophilic and electrophilic reactants must contain functional groups that will not inadvertently react with hydroxide. Despite these limitations, this methodology offers access to completely novel systems that can be employed as biological or molecular probes.

The Claisen-Schmidt condensation reaction is an important methodology for the generation of methine-bridged conjugated bicyclic aromatic compounds. Through utilizing a base-mediated variant of the aldol reaction, a range of fluorescent and/or biologically relevant molecules can be accessed through a generally inexpensive and operationally simple synthetic approach.

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