Kevin Rodriguez

Diazo Chemistry Baran Group Meeting

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 CH2N2 at Sepracor Canda dies began widespread adoption
Theodore Curtius discovers CH2N2
O discovers diazoacetic acid ethyldiazoacetate exposure from TMSCHN2 exposure
O2N N2

1858 NO2 1892 1898 1943 1973 2009 2011 N2

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 cyclopropanation of olefins with cyclopropanations
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 nitrogen 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 ylide 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 carbenes (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 carbene = 40333 R O
- cycloaddition
term diazo compound = 1154 N
- alkylating agent
white paper "diazo" process - dimerization Boc
donor-acceptor
by mcapdevila - fragmentation
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
6/8/19
2. Diazo Preparation and Synthesis Diazald kits:
10-50 mmol scale 200-300 mmol scale
modification X R3 $1726.50/ea
H H
diazo N N 2 fragmentation
acylation R1 N2 R1 N R system 45 generator
R1 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
oxidation Isis pharma: 100 mmol dilute solutions
XHN N N
R1 R2 R1H2C COR Aerojet batch process: up to 25000 mmol scale in batch US Patent: 58175778
(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
MsOH SPh
• musty odor • cycloaddition
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 KOH Ar S N N O OTs
Ar N OH
O Me N CH2N2
Me H Me N OH SPh NMP SPh SPh
+ H2O CH2N2
EtCOCOCl
OH OCO2Et
OH CbzHN CbzHN CbzHN N2
"…it possesses highly toxic properties, which evoke respiratory
O O O
depression… and make handling particularly unpleasant.”
Common diazomethane precursors SPh SPh
O O NH NH HCl NaBH4
S NO O2N NO NO CbzHN Cl CbzHN Cl
N N N H2N N
H O OH
Me 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
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
6/8/19
2. Diazo Preparation and Synthesis cont'd. For mono carbonyls use Danheiser method:
O O O RSO2N3 O
LiHMDS
Dehydrogenation of hydrazones: N2
other conditions: R1 Me CF CO CH CF R1 CF3 Hydrolysis R1
3 2 2 3
NH2
O H2NNH2•H2O N MnO2 N2 Me
-Hg2O, -Ag2O Me
Me O O
R1 R2 R1 R2 CH2Cl2 R1 R2 -(COCl)2,DMSO, Et3N Me
N2
filter used as solution O
N2 O O O O
t O
Useful for nonstabilized diazoalkane synthesis: Bu
O Me Si
H MeO O N2 t O
Ag2O, K2CO3 Me Bu
NH2 8 bar 80% yield 47% yield 50% yield
N N2
TL, 2006 62, 3266 OL, 2013, 15, 3480 ACIE, 2012, 51, 10510
R1 R2 R1 R2
-20 °C to rt Choice of azide: New diazo transfer reagents are being reported | Safety main concern
0.5-4.3 mL/min quenched immediately i
Pr PS
MeO2C CO2Me SO2N3
O SO2N3
MsN3
N2 N2 N2 H
N2 N2 N2 TsN3 Me N iPr iPr
H TfN H OS 1992, 70, 93
Me 3
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: SO2Cl2, NaN3 + imidazole + HCl
R1 R2 R1 R2 + TsNH2 OL 2007, 9, 3797. 4 years
N2 • Salt determined to be hygroscopic leaching HN3
most popular way
• An explosion was reported
Base to access -carbonyl
-NHTs • Further studies showed sensitivity SO2Cl
+RN3 diazo compounds JOC 2012, 77, 1760 was similar to RDX
>70 examples
+
O O O O workup provides
N3 NaN3 up to 95% purity
• Reported as: Intrinsically safe and CO2H
R1 R2 R1 R2
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 sulfonyl-azide-free
Tetrahedron Lett. 1964, 5, 1403 • Misinterpretation of DSC data
J. Chem. Ber. 1968, 101, 1263. • Precautions similar to other azides protocol (SAFE)
R = aryl, COR, CO2R
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
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
6/8/19
3. "TM-Metal-free" Reactivity H
R1 R 1 Tris N N H
General Reactivity H H Me Me Me
1
X R2 N2 R 1. KH (xs)
XH X
CO2Me 2. NaI
XH addition H 3. MeOH/LiOH H H
CO2Me
X = C,N,O,Si... insertion Me name? Me CO2H Me
R3 O ( )-isoclavukerin
R3 R1 with alkyllithiums = decomposition
N R1 light JACS, 1996, 118, 10094
name?
N R2 R1 R2
R 2 N2 R1 or
R1 Wolff R
Progression: CH2N2 TMSCHN2 • There tends to be no trend
cycloadditions rearrangements
R N2 • Various selectivity issues
nuc. Ph Me
ambiphilic character Me Me Me
attack R1
susceptible to decomposition 1. TMS N2
R1 Me BF3•OEt2, CH2Cl2
R2 singlet vs. triplet carbene
N Me
R N R1 Ph ( )-Frodonsin A
azo compounds (not O H 2. TBAF, MeCN
cyclopropanations rt, 4h
covered) OMe O
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
Cl
Zn/Cu Me 1. CH2N2 Me
-triplet carbenes usually participate Me
singlet triplet
in stepwise reactions/additions Me Me
E+ diradical Me H then CH2N2 2. NaBH4 O
-tend to be stereoselective H H
excited state ground stable H 3. Cr(ClO4)2
60% 50-60%
single isomer or mixture?
R CH2N2 R R
R + aliph. > aryl
h R R O EtO2C N2 O O CHO
note: this is a general trend 86% vs 50%
highly dependent on substituents JACS, 1956, 78, 4496 Ph H SnCl2 (cat.) Ph OEt
HMe -15 °C
As nucloephiles with diazoalkanes Me name? H Cl
O CH2N2 O O Me Me H OEt
O Sn
can also be employed: O
n n LA n
n
Bu + nBu n
Bu + H HR Cl
Bu Bu Bu n
Bu n
Bu rac-Hirsutene O
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
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
6/8/19
3. "Transition-Metal-free" cont'd. JACS, 2006, 128, 13072 4. TM-Mediated Transformations
R O
O R Via migratory insertion
Li N2 N Still underutilized in standard cross couplings
NH migratory
N2 [M]-R [M] R insertion
O O R [M] • protonolysis
R
O N2 1 2 1 2 1 2 • cross-couplings
R R R R R R R
N
R N2 N [M] usually employed: Pd, Cu, Fe, Rh(III)
migrating groups
Metal-free reactions with organoboranes - 1960s Typical catalytic cycle
via aryl: ACIE, 2007, 46, 5587
O O R2 2 -H B Pd0 R1-X
O R 1 vinyl: JACS 2007, 129, 8708
N2 2 B R
R1 + BR 3 R2 R1 benzyl: TL, 2001, 57, 5219
-N2 R1 R2 R3 R1
N2 R2 acyl: EJOC, 2006, 563
low yielding II PdII
JACS, 1968, 90, 5936 R1 Pd allyl: Chem. Commun. 2008, 4198
X
R3 allenyl: CEJ, 2011, 17, 6918
2
2009 - much improved method with boroxines R alknyl: ACIE, 2011, 50, 3510
cyclopropyl: OL, 2012, 14, 922
O O N2
DIPEA migratory
N2 Ph up to 84% yield 1
MeO + (PhBO)3 MeO insertion R R3
DCE 60 °C PdII R2
R R N2
OL, 2009, 11, 1667 R3 For review see:
R2
Reductive coupling with N-tosylhydrazones Acc. Chem. Res., 2013, 46, 236
Despite the plethora of cross couplings, first acount in 2001:
NNHTs K2CO3 (1.5 equiv.) R3 Pd2(dba)3
18 examples
+ R3B(OH) 2 X AsPh3
R1 R2 dioxane, 110 °C R1 R2 52-99% yield + TMS N2 54-60% yields
DIPEA, DCE, reflux
Nat. Chem. 2009, 1, 433.
Arylation quickly followed
NNHTs NaOMe, MeOH Bpin N NHTs Ar
+ B2pin2 18 examples R4 Pd2(dba)3
R1 PhMe, 90 °C R1 52-99% yield 1 R2 + R2 16 examples
R t R1 52-98% yields
LiO Bu, dioxane
R3 X R3
reflux
Bpin Bpin Alkynes also amenable as migrating groups in presence of Cu
C6H13 Bpin
OMe NNHTs
56% 48% 14% CuI
H DIPEA
ACIE, 2012, 51, 2943 + H R
OH mech? O R
For adaption of this method into flow chemistry see: Nat. Chem., 2016, 8, 360
see migrating group references
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
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
[3+5] Ph OTBS
O O Coord. Chem. Rev., 2008, 252, 545
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 O Chem. Soc. Rev. 2009, 38, 3061 N2 N
mech?
[3+1]-Metallo-enolcarbene-cycloaddition (MECC) Ph
face
OSi OSi
[M]
EWG EWG OSi
12 examples EWG
N2 [M]
TIPSO up to 99% ee
EWG TIPSO EWG [M]
C2
CuI [Cu] - SR2 3-atom
C1 C2 D2 C4 synthon
SR2 - Cu
Rh2(S-TCPTTL)3 ROC SR2 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]

5. C-H Activation Strategies EWG EWG H EWG EDG EWG 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
Nature, 2008, 451, 417 N2 effects electronic
H
Chem. Rev., 2010, 110, 624 R effects
EDG EWG + EDG EWG Pop Quiz
Chem. Rev., 2010, 110, 704 R R
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 Hb Ha
O Me
H
24,000 1700 0.66 0.011
Ha Ha O
26,000 2700 1.0 0.078 O
Hb
Me Hb Hb
Me Me
Ph H H Hc Ha Ha
Me Hb
N Me
Boc H
JACS, 2016, 138, 3797 Chem. Rev. 2011, 40, 1857 Me Chem. Rev. 2011, 40, 1857 Hc
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
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: CO2Et
Hans Von Pechmann (1895) Jones (1949) For review see: Adv.Synth.Catal.2019,361,919
Me
CO2Et Isoquinoline synthesis - first development of chelated assisted cross-coupling
CH2N2 N CH2N2 Me N
N then [O] N O [Cp*RhCl2]2 O
H H O
OPiv NH2NH2•H2O, MnO2
Tetrazine formation +
N alykl Het NH
CO2Na CO2Na CO2Me Het R CsOAc, HOAc
H
N2 CO2Et R = aryl or heteroaryl THF, rt R
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 AgSbF6 (20 mol %)
CO2Na CO2Na CO2Me
N + R N
Org. Synth., 1992, 70, 79 EWG THF, rt N
P(O)Ph2 N
Diazotization/amidation strategy H O
O R = alkyl alkyl
Me Me N N
CO2Et EWG = COR/CO2R EWG
1. NaNO2, HCl/acetone N N
NBn - 2H+ N
N N Ar - N2
NH2 2. BnNH2, NaOAc, 85 °C O N P(O)Ph2 N
O N H OH
3. K2CO3 - Rh(III) condensation
Pharm. Chem., 1983, 17, 707
+ 2H+
NH2 EWG
N N NHTs alkyl RSC Adv., 2017, 7, 20548
1. NaNO2, HCl/H2O NR O
CO2Et O R1 R2
N via: N [Cp*RhCl2]2 CO2Et
2. 20% aq. Na2CO3 N O 2 R2 Cu(OAc)2 Me
H R1
or RNH2, 65 °C H
N2 DMAC, 50 °C -H2O
Farmaco, 1997, 52, 105 CO2Et
N Rh(III) N N
O Ts
NH2 O L L Ts
iPr
ONO N NH RhL2 Rh L Rh
N
NH2 N + diazo
N N AcOH, H2O N N 2•H2O -N2
N Ph
65% H -H2O
H N -HOAc N N
Liebigs Ann. Chem., 1986, 1012. Ts Ts Ts OL, 2016, 18, 5236
F
Ph azepinones O
TMS-CF3 EtO2C N2 O
Ph N2 [Cp*RhCl2]2 NH
NaI, THF DMF, rt N CsOAc
EtO2C N + NHOPiv mech?
110 °C, 2 h 77% R1O2C
MeCN, rt
mech? R2 R2
R1O2C
Chem. Sci. 2013, 4, 3912
 Kevin Rodriguez
Diazo Chemistry Baran Group Meeting
6/8/19
N2 O OH
7. Naturally Occuring Diazo Compounds Kinamycin A-D PNAS 2015, 113,
R1O
-isolated in 1970 as orange crystalline solids 2851
O O Et
CO2H by Omura and co-workers.
CO2H -known mainly by functionalization across D-ring
O O
N2 NH2 N2 NH2 H H OH O HO N
OH O HO O OH O
DON N2 azaserine IR = 2150 cm-1
Et N OAc 13
C: 78 ppm
CO2H
OR 1
Lomaiviticin B Me CN ~ 100 ppm
O NH2 OH
OH O N2
isolated in 2001 O
DONV N2 O OH AcO OAc
OH O by He and Ireland
N2 1
R O Initial proposed structure
OR R2O
Et N
Me OH O Putative Biosynthesis
IR = 2240 cm-1
OR O H HO O HO N
O OH Me
13
C: 112 ppm OH O OH O
RO OR OH O OR2 R1
O NMe2
Et Me
Kinamycin A-F
Me OMe O
R = H or Ac OR1 R2 HO RSH
O OH OH O N2 OH O N N
N2 Lomaiviticin A Echavarren and co-workers
OH O
S
Porco's Synthesis of ( )-Kinamycin C Herzon's Synthesis of Kinamycin F (R = H) -N2 R
Me -RS•
MOM Friedel-Crafts Me
OH O MOM O O MOM O OMOM OTBS OH O Me
N2 O
Me O 1. Na, NH3 OH O
OAc OAc
+ O Me
Me Me 2. AD-mix-
SnBu3 Br OTIPS
55%, 66% ee
O OH MOM O OH OMOM O OTIPS recrystallized >95% ee
AcO OAc Stille coupling OAc OAc 1. [O]
3. PG (88%) OH O
2. TMSCH2
JACS 2006, 128, 14790 [O] DNA damage
Nicolaou's Synthesis of ( )-Kinamycin C,F and J Me MOMO O
Kinamycin F
[Divergence point] Me Me OMe TASF(Et)
BnO O 12 steps TMS O
Me Benzoin 50% yield O +
BnO O CHO MOMO O N2 3 steps 79%
O Br
Me Me Me Me
OHO Me O O
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 O PPh3
Me Br
DIPEA, MeCN, Me Ag2CO3
JACS 2007, 129, 10356 I OTBS JACS 2010, 132, 2540 rt, 99% OH O O
O 66%