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Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19

1. History and Introduction Silberrad and Roy discover First reported Ronald Diegle, scientist Both Fe and Ru Hans Von Pechmann Cu dust decomposes death from CH N at Sepracor Canda dies began widespread adoption Theodore Curtius discovers CH N 2 2 O discovers diazoacetic acid 2 2 ethyldiazoacetate exposure from TMSCHN2 exposure

O2N N2

N 1858 NO2 1892 1898 1943 1973 2009 2011 2 1883 1894 1906 1949 2008 2010

Peter Griess William Will and German Hans Von Pechmann Gilman and Jones Rhodium carboxylates were Iridium-Salen complexes Gold rush begins discovers scientists begin investigating serendipitously discovers report deca-gram found to catalyze the also found to enable DDNP DDNP as explosive polyethylene synthesis of CF3CHN2 of olefins with from CH2N2 ethyldiazoacetate

Definition: Group Meeting includes: N N - Introduction to different classes of diazo compounds A diazo compound is an organic compound bearing two N N - Preparation and synthesis of diazoalkanes and stabilized derivatives atoms and neutrally charged. - Non-metal-mediated reactions R R R R - Transition metal-mediated reactions The term "diazo" is loosely used throughout the literature. For example, diazonium salts and azo - Common trends in C-H activation should be not be used when describing a diazo motif. Only the form (vide supra) bears the - Towards heterocyclic chemistry proper IUPAC name. - Naturally occuring natural products Stability:

Group Meeting does not include: In general, due to the tendency of these to liberate N2, care should be taken when preparing and - Extensive focus on any topic handling most diazo compounds. The more delocalization of negative charge, the more stability. - Azo compounds and azo dyes - Fischer (see GM Chen 2007) N2 N2 N2 N2 N2 - Diazonium chemistry (see GM Brückl, 2011) - Diazo compounds in photochemistry (see Gryko Org. Biomol. alkyl Ar RO2C RO2C Ar RO2C CO2R Chem., 2019, 17, 432) alkyl aryl (neutral) acceptor donor-acceptor acceptor-acceptor - Diazo compounds in chemical biology (see Raines ACS Chem. Biol. reactivity 2016, 11, 3233)

Quick search hits: Classic reactivity: - rearrangements (Wolff) N2 term diazo = 46275 R - ylide formation M - cyclopropanation term = 40333 R - cycloaddition O term diazo compound = 1154 - alkylating agent N white paper "diazo" process - dimerization Boc donor-acceptor by mcapdevila - fragmentation Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19

2. Diazo Preparation and Synthesis Diazald kits: 10-50 mmol scale 200-300 mmol scale modification X R3 H $1726.50/ea diazo H 1 N N R N2 1 2 fragmentation acylation 1 R N R system 45 generator R N2 up to 1 mmol $155/ea

H N2 NH2 diazo diazotization transfer R1 R2 R1 R2 R R multi-scale R= EWG up to 100 mmol $767/ea

alkaline On process scale: H2N N NO decomposition Isis pharma: 100 mmol dilute solutions oxidation N XHN 1 Aerojet batch process: up to 25000 mmol scale in batch US Patent: 58175778 R1 R2 N R H2C COR (SO2R) H R1 R2 SPh O NHtBu dehydration ACIE 2009, 48, 8186. Me O NH HO O N-alkyl-N-Nitroso compounds: N N H H properties: uses: H OH NHtBu + diazomethane • • yellow gas • methylating agent H SPh • musty odor • cycloaddition MsOH H2C N N H2C N N • bp: -23 °C • insertion • toxic • etc... • Nelfinavir Mesylate (BN: Viracept) CbzHN Cl • highly explosive • HIV-1 protease inhibitor OH • LD50 = 175 ppm • Developed Agouron and Eli Lilly • exposure: 0.2 ppm/ 8 hr • FDA approved in 1997 Can make without using diazo O O O O See: OPRD, 2002, 6, 49. S NO S N KOH Ar O OTs OH Ar N N Me N CH N O N OH 2 2 SPh NMP SPh SPh Me H Me +H2O EtCOCOCl CH2N2 OH OCO2Et OH CbzHN CbzHN CbzHN N "…it possesses highly toxic properties, which evoke respiratory 2 O O O depression… and make handling particularly unpleasant.” Common diazomethane precursors SPh SPh NH NH O O HCl NaBH4 S NO O N NO NO CbzHN Cl CbzHN Cl N 2 N N H N N 2 O OH Me H Me Me Me Diazald ® MNNG MNU Phoenix Pharmaceuticals: Continuous flow (50-60 tonnes/yr) OPRD, 2002, 6, 884. $0.80/g 3rd party sellers carcinogenic, mutagenic toxic, carcinogenic, mutagenic MeNC contamination Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19

2. Diazo Preparation and Synthesis cont'd. For mono carbonyls use Danheiser method: O O O O LiHMDS RSO2N3 Dehydrogenation of : N2 R1 Me R1 CF R1 other conditions: CF3CO2CH2CF3 3 Hydrolysis NH H NNH •H O 2 Me O 2 2 2 N MnO2 N2 Me -Hg2O, -Ag2O O 1 2 1 2 1 2 Me O R R R R CH2Cl2 R R -(COCl)2,DMSO, Et3N Me N2 filter used as solution O O O N2 O O O tBu Useful for nonstabilized diazoalkane synthesis: O Si H MeO O Me O Ag O, K CO Me N2 tBu NH 2 2 3 8 bar N 2 N 80% yield 47% yield 50% yield 2 TL, 2006 62, 3266 OL, 2013, 15, 3480 ACIE, 2012, 51, 10510 R1 R2 R1 R2 -20 °C to rt Choice of : New diazo transfer reagents are being reported | Safety main concern 0.5-4.3 mL/min quenched immediately i Pr PS MeO C CO Me SO2N3 2 2 O SO2N3 MsN N 3 N2 2 N2 H Me N N2 N2 N2 TsN3 i i H OS 1992, 70, 93 Pr Pr Me H TfN3 Me Me Me Me p-ABSA TIPSA good balance between SO2N3 reactivity & byproduct removal Di-substituted diazoalkanes mono-alkyl diazoalkanes Polymer-supported N3 Case studies: Safety first! - Diazo transfer reaction: • Touted as: Inexpensive, shelf stable salt with similar reactivity as TfN3 O O O O N N SO2N3 TsN3, Base • Stability: at 80 °C, insensitive to impact and vigorous grinding •HCl • Synthesis: SO Cl , NaN + imidazole + HCl R1 R2 R1 R2 2 2 3 + TsNH2 OL 2007, 9, 3797. 4 years N 2 most popular way • Salt determined to be hygroscopic leaching HN3 • An explosion was reported to access -carbonyl Base -NHTs • Further studies showed sensitivity SO Cl +RN diazo compounds JOC 2012, 77, 1760 2 3 was similar to RDX >70 examples + O O O O workup provides N NaN3 up to 95% purity 3 CO H R1 R2 R1 R2 • Reported as: Intrinsically safe and 2 H H N N insensitive to impact and friction tolerates: N N N N Ts N N Ts • Solid is stable up to 1 year MeO N OMe 7 months later CN, heterocycles, SO2, amide JOC 2018, 83, 10916 limitation: alkyl • Significant risk of runaway exotherm R EWG Tetrahedron Lett. 1964, 5, 1403 • Misinterpretation of DSC data sulfonyl-azide-free protocol (SAFE) J. Chem. Ber. 1968, 101, 1263. R= aryl, COR, CO2R • Precautions similar to other J. Org .Chem. 1990, 55, 1959 EWG = COR, CO2R, SO2R, PO(OR)2 JOC 2019, 84, 5893 should be taken Chem. Commun., 2019, 55, 5239 Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19 3. "TM-Metal-free" Reactivity H 1 N R1 R Tris N H General Reactivity H H Me Me Me 1 X R2 N2 R 1. KH (xs) XH X 2. NaI XH CO2Me addition H CO Me 3. MeOH/LiOH H H X= C,N,O,Si... insertion 2 CO2H Me name? Me Me R3 O ( )-isoclavukerin 3 R1 with alkyllithiums = decomposition N R R1 JACS, 1996, 118, 10094 light name? N 2 1 2 1 or R R R R2 N2 R R1 Wolff R Progression: CH2N2 TMSCHN2 • There tends to be no trend cycloadditions rearrangements R N2 • Various selectivity issues Ph nuc. ambiphilic character Me Me TMS N Me Me attack R1 susceptible to decomposition 1. 2 R1 R2 singlet vs. triplet carbene Me BF3•OEt2, CH2Cl2 N Me R N R1 Ph ( )-Frodonsin A O H 2. TBAF, MeCN azo compounds (not cyclopropanations OMe rt, 4h O covered) OMe MeO 54% -singlet carbenes tend be electrophilic name? MeO due to empty p-orbital -tend to act in concerted fashion JACS, 2007, 129, 11781 Cl Cl O H Me H Me HMe ClC(O)CCl3 1. CH N Cl -triplet carbenes usually participate Zn/Cu Me 2 2 Me singlet triplet Me in stepwise reactions/additions Me Me E+ diradical Me H 2. NaBH -tend to be stereoselective then CH2N2 H 4 H O excited state ground stable H 3. Cr(ClO4)2 60% 50-60% single isomer or mixture?

R CH2N2 R R R + aliph. > aryl O O O CHO h R R EtO2C N note: this is a general trend 2 86% vs 50% highly dependent on substituents Ph H SnCl (cat.) Ph OEt JACS, 1956, 78, 4496 Me 2 H -15 °C As nucloephiles with diazoalkanes Me name? H Cl O CH2N2 O O Me Me H OEt O Sn n n n can also be employed: R O Bu + Bu Bu + H H Cl nBu nBu LA nBu n n rac-Hirsutene O Bu Bu R R Me Me Me S N2 P N2 N2 TL, 1980, 21, 3059 O O R O homologation product ratios sensitive to L.A. employed. Bulky L.A. like MAD work best JOC, 1989, 54, 3258 Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19 3."Transition-Metal-free"cont'd.JACS, 2006, 128, 13072 4.TM-MediatedTransformations R O O R Via migratory insertion

Li N2 N Still underutilized in standard cross couplings NH migratory [M] R O N2 [M]-R insertion R [M] O R • protonolysis O N 2 R R1 R2 R1 R2 R1 R2 • cross-couplings N R N2 N [M] usually employed: Pd, Cu, Fe, Rh(III) migrating groups Metal-free reactions with organoboranes - 1960s Typical catalytic cycle via 2 1 aryl: ACIE, 2007, 46, 5587 O O R 2 0 R -X O R 1 -H B Pd vinyl: JACS 2007, 129, 8708 N 2 B R 1 2 + BR R2 1 R 3 1 R 2 R3 1 benzyl: TL, 2001, 57, 5219 -N2 R R 2 R R II acyl: EJOC, 2006, 563 N2 Pd low yielding 1 II allyl: Chem. Commun. 2008, 4198 JACS, 1968, 90, 5936 R Pd X 3 allenyl: CEJ, 2011, 17, 6918 2 R 2009 - much improved method with boroxines R alknyl: ACIE, 2011, 50, 3510 cyclopropyl: OL, 2012, 14, 922 O O DIPEA migratory N2 N2 Ph up to 84% yield 1 3 MeO + (PhBO)3 MeO insertion R II R DCE 60 °C Pd R2 N R R OL, 2009, 11, 1667 R3 2 R2 For review see: 2013 Reductive coupling with N- Acc. Chem. Res., , 46, 236 Despite the plethora of cross couplings, first acount in 2001: NNHTs K CO (1.5 equiv.) R3 Pd (dba) 2 3 18 examples 2 3 + R3B(OH) X AsPh 1 2 2 1 2 52-99% yield 3 R R dioxane, 110 °C R R + TMS N2 54-60% yields DIPEA, DCE, reflux Nat. Chem. 2009, 1, 433. Arylation quickly followed NaOMe, MeOH NNHTs Bpin N NHTs Ar + B2pin2 18 examples 2 4 Pd (dba) 2 1 PhMe, 90 °C 1 R + R 2 3 R 16 examples R R 52-99% yield R1 R1 LiOtBu, dioxane 52-98% yields R3 R3 X reflux Bpin Bpin Alkynes also amenable as migrating groups in presence of Cu C6H13 Bpin OMe NNHTs 56% 48% 14% CuI DIPEA ACIE, 2012, 51, 2943 H + H R OH mech? O R For adaption of this method into flow chemistry see: Nat. Chem., 2016, 8, 360 see migrating group references Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19 [3+3] 4. Metal-mediated cont'd. In Cycloaddition Chemistry OTBS [2+1] and [3+2] OSi Ph O CO2Me General Structure of RhII-Catalysts Rh2(S-TPA)4 for some initial reviews, see: EWG + N 12 examples face O up to 93% ee R MTBD, -30 °C N R Chem. Rev. 2003, 103, 977 N2 Ph OTBS Coord. Chem. Rev., 2008, 252, 545 [3+5] O O EWG Rh Tetrahedron, 2013, 69, 5765 OSi R O O R Ph N Rh2(Piv)4 Chem. Rev. 2017, 117, 11651 EWG + R N O O Organometallics 1984, 3, 53 R Rh R R CH2Cl2, rt N O Chem. Soc. Rev. 2009, 38, 3061 N2 N O mech? [3+1]-Metallo-enolcarbene-cycloaddition (MECC) Ph face OSi OSi [M] EWG EWG OSi 12 examples EWG N [M] 2 TIPSO up to 99% ee EWG TIPSO EWG [M] C2 I Cu [Cu] - SR2 3-atom C1 C2 D2 C4 synthon SR2 - Cu ROC SR Rh2(S-TCPTTL)3 2 ROC COR Taizhou Artex Machinery Rh2(S-PTPA)4 Rh2(S-DOSP)4 Rh2(S-PTTL)4 (PTAiB) Co., Ltd. Chem. Rev. 2017, 46, 5425 Catalysts, 2017, 7, 347 [M] [M] [M]

EWG EWG 5. C-H Activation Strategies EWG H EWG EDG Delicate balance R R R the three main classes of metal carbenoids For reviews see: R H R H R H R steric R R N effects Nature, 2008, 451, 417 2 H electronic Chem. Rev., 2010, 110, 624 R effects + Chem. Rev., 2010, 110, 704 EDG EWG R R EDG EWG Pop Quiz Chem. Rev., 1998, 98, 911 Chem. Rev., 2002, 102, 1731 Boc Si Hc Chem. Rev., 2003, 103, 2861 relative rates for C-H insertion of metal carbenoids N N O Si Hb H H Me Ha Me Ha Hb H H H Me b a H O 24,000 1700 0.66 0.011 H Ha O 26,000 2700 1.0 0.078 a O Hb Me Hb Hb Me Me Ph H H Hc H Me H a Ha N Me b Boc H JACS, 2016, 138, 3797 Chem. Rev. 2011, 40, 1857 Me Chem. Rev. 2011, 40, 1857 Hc Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19 6. Formation of Heterocycles Metal-Mediated Cascade strategies via C-H activation with Rh(III), Co(III), Ru(II) and Ir(III) Background: Jones (1949) CO2Et For review see: Adv.Synth.Catal.2019,361,919 Hans Von Pechmann (1895) Me CO Et N Me 2 N Isoquinoline synthesis - first development of chelated assisted cross-coupling CH2N2 CH2N2 N then [O] N [Cp*RhCl ] O O O 2 2 H H NH NH •H O, MnO OPiv + 2 2 2 2 Tetrazine formation NH N alykl R Het CO2Na CO2Na CO2Me Het H CsOAc, HOAc N CO Et R= aryl or heteroaryl THF, rt R 2 2 N N HN N HCl, MeOH N N alkyl + OL, 2015, 17, 2494 N N N NH [O] N N Fused pyrazoles NaOH(aq.) [Cp*RhCl2]2 N2 AgSbF (20 mol %) CO2Na CO2Na CO2Me 6 N R N Org. Synth., 1992, 70, 79 + EWG N THF, rt N P(O)Ph2 Diazotization/amidation strategy H O R= alkyl alkyl Me O N N Me CO2Et EWG = COR/CO2R EWG 1. NaNO2, HCl/acetone N N + NBn - 2H N N N Ar -N NH 2. BnNH2, NaOAc, 85 °C N 2 N O 2 O N P(O)Ph2 3. K2CO3 - Rh(III) H condensation Pharm. Chem., 1983, 17, 707 OH + 2H+ NH 2 N N NHTs EWG alkyl RSC Adv., 2017, 7, 20548 1. NaNO , HCl/H O NR CO Et 2 2 O 1 R2 O 2 [Cp*RhCl ] R N via: 2 2 2 CO2Et 2. 20% aq. Na CO O N R H 2 3 N 2 R1 Cu(OAc)2 Me or RNH2, 65 °C H N2 DMAC, 50 °C -H2O Farmaco, 1997, 52, 105 CO2Et N N O Rh(III) N NH O Ts Ts 2 iPr L L ONO N N NH RhL2 Rh L Rh NH N + diazo 2 2•H2O N AcOH, H2O N N N N -N2 65% Ph H H N -HOAc N N -H2O Liebigs Ann. Chem., 1986, 1012. Ts Ts Ts OL, 2016, 18, 5236 F azepinones O EtO C Ph TMS-CF3 2 N2 O Ph N2 [Cp*RhCl2]2 NH NaI, THF DMF, rt N CsOAc EtO2C N NHOPiv mech? R1O C + 110 °C, 2h 77% 2 MeCN, rt mech? 2 2 R 1 R R O2C Chem. Sci. 2013, 4, 3912 Diazo Chemistry Baran Group Meeting Kevin Rodriguez 6/8/19 N O 2 OH PNAS 2015, 113, 7. Naturally Occuring Diazo Compounds R1O Kinamycin A-D 2851 O O Et -isolated in 1970 as orange crystalline solids CO H by Omura and co-workers. 2 CO2H -known mainly by functionalization across D-ring O O H H OH O HO N2 NH2 N2 NH2 N OH O HO O OH O DON azaserine -1 N2 IR = 2150 cm Et N OAc 13 CO2H C: 78 ppm OR1 Lomaiviticin B Me CN ~ 100 ppm O NH2 OH OH O N2 isolated in 2001 O AcO DONV N2 O OH by He and Ireland OAc OH O N 1 2 R O Initial proposed structure OR R2O Et N Me OH O Putative Biosynthesis IR = 2240 cm-1 H O N O OR O H O HO 13 OH O OH O OH O 2 OH Me C: 112 ppm RO OR OR R1 O NMe2 Me Kinamycin A-F Et O 1 Me OMe R=H or Ac OR R2 HO RSH O OH Echavarren and co-workers OH O N2 OH O N N OH O N2 Lomaiviticin A S Porco's Synthesis of ( )-Kinamycin C Herzon's Synthesis of Kinamycin F (R = H) R -N2 Friedel-Crafts Me -RS• MOM Me OH O MOMO O MOMO OMOM OTBSOH O Me N2 O Me O 1. Na, NH3 OH O OAc OAc + O Me Me Me 2. AD-mix- OTIPS SnBu3 Br 55%, 66% ee OH OH O MOMO OMOM O OTIPS recrystallized >95% ee AcO 1. [O] OAc Stille coupling OAcOAc OH O 2. TMSCH 3. PG (88%) JACS 2006, 128, 14790 2 [O] DNA damage Nicolaou's Synthesis of ( )-Kinamycin C,F and J MOMO O Kinamycin F Me [Divergence point] Me Me OMe TASF(Et) BnO O 12 steps TMS O Me Benzoin 50% yield O + BnO O CHO MOMO O 79% O N2 3 steps Br Me Me Me Me OHO O O Me Me Br Me Me MOMO O MOMO O O O MeO O O Me Pd(OAc) O O Me O 2 MeO Me + O O Me Me O O TfN3 Me Ullmann coupling OTBS PPh3 Me O Br DIPEA, MeCN, Ag2CO3 2007 JACS 2010, 132, 2540 OH Me O O JACS , 129, 10356 I OTBS rt, 99% O 66%