Part 1. Introduction - Scripps Research Institute 1. Introduction Nitro Compounds R3N R1 R2 O N O R3...
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Hai Dao 11/22/2014 Baran Group Meeting Nitroso and Nitro Compounds Nitroso Compounds ( C -Nitroso Compounds) Part 1. Introduction Nitro Compounds R 3 N R 1 R 2 O N O R 3 R 1 R 2 N O R 3 R 1 R 2 R 3 N R 1 R 2 O N O R 3 R 1 R 2 R 3 = H ΔG = 10 Kcal mol -1 N OH R 2 R 1 monomer: blue color cis-dimer colorless trans -dimer colorless oxime n π ∗ Blue color: absorption band 630-790 nm R 3 = H: unstable (favor the oxime form), in situ generation IR: υ (N=O): 1621-1539 cm -1 , dimer υ (N−O): 1300 (cis), 1200 (trans ) cm -1 1 H NMR ( α-C-H) δ = 4 ppm: nitroso is an EWG CH 3 −NO CH 3 −NO 2 CH 3 −NH 2 D(Kcal/mol) d (Å) CH 3 − I 40 56 79 57 1.48 1.47 1.47 N O R 3 R 1 R 2 Nu R e Reaction Modes Nitroso vs. olefin: Diels-Alder reaction: as dienophiles Ene reaction Cope rearrangement Nitroso vs. carbonyl Nucleophilic addition Other reaction modes Radical addition Redox reaction Photochemical reaction h υ IR: υ (N=O): 1621-1539 cm -1 Nitro group is an EWG (both − I and −M) Ph NO 2 Ph N O OH a nitro compound b.p = 100 o C (8 mm) a nitronic acid m.p = 84 o C (pKa = 2−6) [O] Nitro group is a "sink" of electron Synthesis of C -Nitroso Compounds Substitution R NOBF 4 R NO - R = OH, OMe, Me, NR 2 , NHR - para-selectivity Me Me Kochi et al. J. Org. Chem. 1994, 59, 5573–5586. Chem. Rev. 2004, 104 , 3315–3340. or NaNO 2 /HCl With NO + sources: NaNO 2 /HCl, NOBF 4 , NOCl, NOSbF 6 , RONO... NO 2 − NO 2 O N O O N O O N O N O O high temp brown low temp color less O N O NO 2 + nitrite ion nitrolium ion N O NO + NO nitric oxide nitrosonium ion N O N O O R 1 R 3 R 2 e h υ Nu [H] EWG R Me + ON H Wheland intermediate rate determining step cellular signaling molecule in mammals
Transcript of Part 1. Introduction - Scripps Research Institute 1. Introduction Nitro Compounds R3N R1 R2 O N O R3...
Hai Dao11/22/2014Baran Group Meeting Nitroso and Nitro Compounds
Nitroso Compounds (C-Nitroso Compounds)
Part 1. IntroductionNitro Compounds
R3 N
R1R2
O
NO
R3
R1 R2NO
R3
R1 R2 R3 N
R1R2
O
NO
R3 R1R2
R3 = HΔG = 10 Kcal mol-1N
OHR2
R1
monomer: blue color cis-dimercolorless
trans-dimercolorless
oximen π∗Blue color: absorption band 630-790 nm
R3 = H: unstable (favor the oxime form), in situ generation
IR: υ(N=O): 1621-1539 cm-1, dimer υ(N−O): 1300 (cis), 1200 (trans) cm-1
1H NMR (α-C-H) δ = 4 ppm: nitroso is an EWG
CH3−NOCH3−NO2
CH3−NH2
D(Kcal/mol) d (Å)
CH3−I
40
567957
1.481.471.47
NO
R3
R1 R2
Nu
R
e
Reaction ModesNitroso vs. olefin: Diels-Alder reaction: as dienophiles Ene reaction Cope rearrangement Nitroso vs. carbonyl Nucleophilic additionOther reaction modes Radical addition Redox reaction Photochemical reaction
hυ
IR: υ(N=O): 1621-1539 cm-1
Nitro group is an EWG (both −I and −M)
Ph NO2Ph N
O
OHa nitro compound
b.p = 100 oC (8 mm) a nitronic acidm.p = 84 oC(pKa = 2−6)
[O]
Nitro group is a "sink" of electron
Synthesis of C-Nitroso Compounds
SubstitutionR
NOBF4
R
NO
- R = OH, OMe, Me, NR2, NHR- para-selectivity
Me Me
Kochi et al. J. Org. Chem. 1994, 59, 5573–5586.Chem. Rev. 2004, 104 , 3315–3340.
or NaNO2/HCl
With NO+ sources: NaNO2/HCl, NOBF4, NOCl, NOSbF6, RONO...
NO2− NO2
ON
O ON
OO
NO
NO O
high tempbrown
low tempcolor less
O N O
NO2+
nitriteion
nitroliumion
N O
NO+NO
nitric oxide nitrosoniumion
N O
NO
OR1
R3R2
e
hυNu
[H]EWG
R
Me+
ON HWheland intermediate
rate determining step
cellular signaling molecule in mammals
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BzOBzO Me
NOFe(acac)3 (10 mol%)PhSiH3, BuONO
Mukaiyama et al. Chemistry Letters 1992, 1137–1140.
2
OMe
NHAcMe
MeMeO
NOBF4, DCM95%
OMe
NHAcMe
MeMeONO
Aust. J. Chem. 1994, 47, 1483–1508.
OMe
NAcNO
via
Addition reactions to C=C double bonds
F3C
F
F
F NOCl, CsCl91% F3C
F
F
FON
ClJ Fluorine Chem., 1984, 26, 87.
Elimination reactions
OO
O
OO
CH2OH1. TsHN
OTBDMSDEAD, Ph3P
2. CsF
OO
O
OO
NO
90%
64%
Org. Lett. 2008, 10 , 2259.
Oxidation reactions
O CH2OH
OHNH3
HO
HOCl
mCPBA47%
O CH2OH
OHNO
HO
HO2
Me
iPrNOH
Me
iPrNOCl
Me
iPrClNO
Cl2, CHCl3Cl2, CHCl3Na2CO3
69% 42%
synthesis 2006, 3819.
Internal [NO] sources
Metal-NO complexes
[Co(Cp)(NO)]2NO68% N
Co(Cp)NN
(Cp)CoN
O
O
O
OOrganometallics 1983, 2, 787.
Reduction from Nitro group
Other external [NO] sources
H
H
H
Me Br
Me
NH
tBuLiAmNONO
H
H
H
MeNO
Me
NH
H
H
H
Me NOH
NH
HClH
H
H
Me O
NH
H
H
H
Me
NH
HNO
Lyconadin BFukuyama et al. J. Am. Chem. Soc. 2013, 135 , 3243.
75%
Barton reaction and other reactions with NO
tBuNO
tBu
Me
MeMe
hυ tBu
tBu
Me
MeMe
NOtBu
tBu
MeMeNO
dimer30-40%
Can. J. Chem. 1978, 56, 2665.
Hai Dao11/22/2014Baran Group Meeting Nitroso and Nitro Compounds
Lycoricidine
Hudlicky, et al. J. Am. Chem. Soc. 1992, 114 , 9694–9696.
Hetero Diels-Alder reaction
FOTMS Cl NO
+Et3N
NO
FOTMS
1. AcOH2. BzCl
N
F
OBz72%
overall
Schlosser, et al. Tetrahedron 1993, 49, 1445.
Me
Me Me
OAc CuCl (5 mol%)Py (12 mol%)
THF, air, rt87%
Me
Me
OAcCbzN
OH
Me Me
OAcNCbz
OH+
9:1J. Read de Alaniz, J. Am. Chem. Soc. 2011, 133 , 10430–10433.
Krebs et al. Chem. Rev. 2003, 103 , 4131–4146.
Regioselectivity nitroso compound vs. 1O2 and triazolinedione (TDA)
CbzNHOH+
with ArNO
Cope reactionTBDMSO
MeO CO2Me
OTBDMS
MeOCO2Me
NO
NO
OTBDMSH
H
CO2Me1. LDA
2. TMSCl3. AmONO
TiCl4
60%
O
Reaction of C-Nitroso Compounds
Br
O
OO
O
Me
Me
ONR
O
O
Br
O
NHOH
Bu4NIO4Br
Al(Hg)
+
OH
OH
OH
NH
O
O
O
=RNHOH
80% 91%
OH
O
O
NH
O
O
O
Br
Zakarian et al. J. Am. Chem. Soc. 2006, 128 , 5356–5357.
Ene reaction
OO
nPr4NIO4
Me
Me
then Δ OO
OO
NOH
OCON
O
CONHOH
OO
N
dl-crinane85% 2 steps Keck et al. J. Am. Chem. Soc. 1981, 103 , 3173.
BocHN
OH
BocNO
Mo(CO)6NaBH4
70% NNH
NH
NMe
OBr
O
H
HH
HO
agelastatin ATanaka et al. Org. Lett. 2008, 10 , 5457–5460.
[H-NO equivalent]
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O-Nitroso aldol vs. N-nitroso aldol reaction
O O
SAr
MeOtBuO NHOH
O+Cu(OTf)2 (10 mol%)
(RR)-PhBoxMnO2 (5 equiv)
61%, 97% ee
O O
SAr
MeOONHBoc
O O
SAr
MeOOH
O O
OMe
MeOOH
Mo(CO)6slow addition
AgTFA
MeOH(+)-Kjelmanianone
Yamamoto et al. J. Am. Chem. Soc. 2012, 134 , 18566.
Read de Alaniz, et al. J. Am. Chem. Soc. 2012, 134 , 18948–18951.
OEtMe
O O
MetBuO NHOH
O+
CuCl (5 mol%)CuOTf (5 mol%)
MeOH, air, rtNBoc
Me
O
Me CO2Et
OH
79%
DCM, rt
NS
OO
O
O
O1. NaHMDS
2.Cl NO
3. HCl
Me Me
NS
OO
O
N
Me
ONH
Me
Me piridinine80%
Davison et al. J. Chem. Soc. Perkin Trans. 1, 2002, 1494.
alkylnitroso (1-chloro-1-nitrosoalkanes): N selectivity with enolate
Aldol reaction (acyl and arylnitroso compound): steric and electronic factors
Other reactions
HexHex
Ni(cod)B2(pin)2
B(pin)
B(pin)
PhNOthen H2O2
H2O2
HexOH
HO
HexOH
OH
Morken et al. Org. Lett. 2010, 12 , 3796.
OMe
Me
TMSOMe
Me
OMe
Me
OH
PhNOHOAc60%
Yang et al. Org. Lett 2010, 12 , 5072–5074.
alotaketal A
NH
NHCO2Me
CO2MeHPhNOZrCl4
NH
NHCO2Me
CO2Me
82%
Baran et al. J. Am. Chem. Soc. 2006, 128 , 8678–8693.
TMSClFeCl3
MeMgBr
Reaction with radical
NN
Ph Ph
Δ or hυPhPh
PhNONO
PhPh
Ph
PhPh
NPh
O
Adam et al. Tetrahedron Letters 1991, 32, 4283.
N
N
O
ONO
N
Ofuroxan
Δ
Other nitroso compounds
O-Nitroso compounds (nitrite compounds)
Me
Me
ONO
amyl nitriteMe
Me
OH
HONO
esterification
Furoxans
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N-Nitrosoamine (secondary amine derivatives)
HNCN NaNO2
HClN
CN
ON
Fischer–Hepprearrangement
HNCN
NOD'Amico et al. J. Am. Chem. Soc. 1959, 81, 5957–5963.
S-Nitrosothiols (thionitrites)
HO NH
OH
O
NH2
O
O
OS
NO
S-Nitrosoglutathione (GSNO)
- NO is an important cellular signaling molecule- GSNO: endogenous NO carriers and donors
RSH HONO RSNOdeeply colored
compounds
RSSR + 2NO
R'SH R'SNO
Synthesis of nitro compoundsNitration with NO2+
OH
Br
NaNO3H2SO4
OH
BrNO2
OH
Br
O2N+
p-pdt: recrystalization in CHCl3
100g scale
Nitration with NO2-
AgNO2: Victor-Meyer reaction, NaNO2: Kornblum reaction, KNO2
Victor-Meyer test (primary vs. secondary vs. tertiary alcohol)
R OHHI
or P+I2R I
AgNO2R NO2
HONOR NO2
NOH
nitrolic acidR NO2
NONa
redcolor
R OHHI
or P+I2R I
AgNO2R NO2
HONOR NO2
NO
Pseudonitrolic acid
R R RR blue
color
NaOH
R OH
RR HI
or P+I2 R I
RR AgNO2 NR: colorless
Oxidation of amines, oximes or azides
O
IO
ON OCH2CCl3OC CO
1. NaN3
2. PPh33. O3
O
NO2O
ON OCH2CCl3OC CO
50%
Corey et al. J. Am. Chem. Soc. 1984, 106 , 3682–3683.
Reaction of nitro compoundsHenry reaction, Michael reaction: see refNef reaction, reduction: see ref
MeMe
AgNO2TEMPO
DCE70 oC69%
Nitration with nitro radical
MeMe
NO2
Maiti et al. J. Am. Chem. Soc. 2013, 135 , 3355
Radical chain nucleophilic substitution (SRN1)I
Na CH2NO2+CH2NO2
hυNaCH2COCH3
ICH2NO2
CH2NO2
68%
Rossi et al. J. Org. Chem. 1999, 64, 5826.
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OCH2I
OO
Me
Me
OO Me
Me
py(dmgH)Co Na82%
OCH2Co(dmgH)2py
OO
Me
Me
OO Me
Me
hυNaCH2NO2
then AcOH
OCH2CH2NO2
OO
Me
Me
OO Me
Me
76%
N N OON N OO
Co HH
R
Py
RCo(dmgH)2py =
Branchaud et al. Tetrahedron Letters 1991, 32, 3639.
Elimination of NO2NO2 is a good leaving group
R1
O
NC
+NO2
R3
R2
HNR2
R2
R1O
Barton-Zard pyrrole synthesis
base
tBuNO
+Ph NO2
KtBu
NO
Ph
nitronetBu
NO
Ph
NO2
77%
Russ. Chem. Bull. 1996, 45, 856.
removal of NO2 under radical conditions
NO2
OBnOHCO
BzONu NO2
OBnOHCO
BzON N
NN NHBz
78%Bu3SnHAIBN48% OBnOHCO
BzONu
Pd/C; H2
93%
NO2
OHHO
HON N
NN NH2
(-)-aristeromycinZanirato et al. Tetrahedron Letters 1996, 37, 7599.
Cycloaddition
Cl
O
O
OiPr
KONO2
OOiPr
ON
O
OO
ORO
OiPr
ON
O
OO ORH
O
NOO ORH
HH
O
iPrO2C
74%
MAPh
1. [H]2. Ni, H2 O
N
HH
HO
H
O
HO
OH
N
HH
HO
H
HO
(-)-rosmarinecine
MAPh: methylaluminum bis(2,6-diphenylphenoxide)
Denmark et al. J. Am. Chem. Soc. 1996, 118 , 8266.
NO
O PPh3AuTf2
O
N
O
O
68% OAu
ONO
Au
ON
OAu Liu et al. J. Am. Chem. Soc.
2011, 133 , 1769.
Photochemistrymeta-activation
NO2
OMeO14Me SN2Ar*
hυNaOMe, MeOH
NO2
OMeOMe
- direct substitution of the triplet state: meta-activation vs. SNAr- depend on: nucleophiles, solvent system
NO2
O14MeOMe
or
Φm = 0.21 vs Φp = 0.016
Havinga et al. J. Am. Chem. Soc. 1981, 103 , 7257–7262.
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NO2
OMeOMe
nHexNH2
NH
O2N OMe
NHnHex
O2N N
OMe
SN2Ar*
SR−N1Ar*
SR−N1Ar*: radical ion pair via ET from amine to nitro
hυ
hυ
NO2
OMeOMe
NO2
NH
OH
hυNaOH, H2O
NO2
NH
OH75%o and p < 20%
Photo-Smiles reactionOxman et al. J. Am. Chem. Soc. 1980, 102 , 4848.
Activation of nitro group
NO
O
tBu
HAThυ
MeOH
NOOH
tBu
CH2N OH
tBu
O
73%
Döpp et al. Eur. J. Org. Chem. 1979, 1979 , 554–563.
O OMeOMe
OO
OAc
AcOAcO OAcO2N
hυ O OMeOMe
OHO
OAc
AcOAcO OAc
Ar
O
Collins et al. J. Chem. Soc., Perkin Trans. 1 1983, 1879
60%
NO2Me
AcO
Mehυ
NaOMe MeOH
OHN O
78% 17%
NO
ON
O
Ohυ
hυ
activation of nitronic acid
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