Catalytic nitrite was found to enable carbon–oxygen bond-forming reductive elimination from unstable alkyl palladium intermediates, providing dioxygenated products from alkenes. A variety of functional groups were tolerated, and high yields (up to 94 %) were observed with many substrates, also for a multigram-scale reaction. Nitrogen dioxide, which could form from nitrite under the reaction conditions, was demonstrated to be a potential intermediate in the catalytic cycle. Furthermore, the reductive elimination event was probed with ^(18)O-labeling experiments, which demonstrated that both oxygen atoms in the difunctionalized products were derived from one molecule of acetic acid

Grubbs, Robert H.

Guzmán, Pablo E.

Wickens, Zachary K.

Caltech Authors - Main

Supporting Information
 Wiley-VCH 2014
69451 Weinheim, Germany
Aerobic Palladium-Catalyzed Dioxygenation of Alkenes Enabled by
Catalytic Nitrite**
Zachary K. Wickens, Pablo E. Guzmn, and Robert H. Grubbs*
anie_201408650_sm_miscellaneous_information.pdf
 
 
 
 
Supporting Information 
 
All solvents, reagents and metal salts were obtained from Sigma-Aldrich and used without further 
purification. 1H and 13C NMR spectra were recorded on a Varian 500 MHz, Varian 400 MHz or a 
Varian 300 MHz spectrometer. High-resolution mass spectra were provided by the California 
Institute of Technology Mass Spectrometry Facility using JEOL JMS-600H High Resolution 
Mass Spectrometer. 
 
Procedure A for isolation scale (0.5 mmol) oxidation of 1-dodecene: 
PdCl2(MeCN)2 (0.025 mmol, 6.5 mg), CuCl2•2H2O (0.025 mmol, 4.5 mg) and AgNO2 (0.02 
mmol, 3.8 mg) were weighed into a 20 mL vial charged with a stir bar. The vial was sparged for 1 
minute with oxygen (1 atm, balloon). AcOH, Ac2O and MeNO2 were premixed in a 10:5:3 ratio 
and sparged with oxygen for 2 minutes. The oxygenated solvent mixture was then added to the 
vial (8 mL), followed by the alkene substrate (0.5 mmol) via syringe. After an additional 15 
seconds of sparging with oxygen, the reaction vessel was shielded with light using aluminum foil. 
The reaction was then allowed to stir at 35 ºC for 16 h under an atmosphere of oxygen (balloon). 
The reaction mixture was subsequently filtered and the solvent was removed under reduced 
vacuum. Dichloromethane was added and resulting mixture was washed three times with 
saturated NaHCO3. After drying the organics with Na2SO4, the solvent was removed under 
reduced pressure and the crude mixture was purified by silica gel chromatography. 
 
Procedure B for analytical scale oxidation of 1-dodecene (NMR analysis): 
PdCl2(PhCN)2 (0.01 mmol, 3.8 mg), CuCl2•2H2O (0.01 mmol, 1.8 mg) and AgNO2 (0.01 mmol, 
1.5 mg) were weighed into a 8 mL vial charged with a stir bar. The vial was sparged for 1 minute 
with oxygen (1 atm, balloon). AcOH, Ac2O and MeNO2 were premixed in a 10:5:3 ratio and 
sparged with oxygen for 2 minutes. The oxygenated solvent mixture was then added to the vial 
(3.2 mL), followed by the 1-dodecene (0.2 mmol) via syringe. After an additional 15 seconds of 
sparging with oxygen, the reaction vessel was shielded with light using aluminum foil. The 
reaction was then allowed to stir at 35 ºC for 16 h under an atmosphere of oxygen (balloon). The 
reaction mixture was subsequently filtered and the solvent was removed under reduced vacuum. 
Dichloromethane was added and resulting mixture was washed three times with saturated 
NaHCO3. After drying the organics with Na2SO4, the solvent was removed under reduced 
pressure, nitrobenzene (10 µL) was added as an internal standard and the mixture was dissolved 
in CDCl3 and subjected to NMR analysis (15 s relaxation delay was account for the t1 of 
nitrobenzene). 
 
 
 
 
 
 
 
 
Product characterization 
Me
9
OAc
AcO
 
dodecane-1,2-diyl diacetate (table 2, entry 1): 119 mg (83% yield) obtained using procedure A. 
1H NMR (500 MHz, CDCl3) δ 5.07 (dddd, J = 7.5, 6.6, 5.8, 3.3 Hz, 1H), 4.22 (dd, J = 11.9, 3.3 
Hz, 1H), 4.03 (dd, J = 11.9, 6.6 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.64 – 1.48 (m, 2H), 1.33 – 
1.22 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H). Spectral data were in accordance with the literature.1 
 
 
OPh
OAc
AcO
 
3-phenoxypropane-1,2-diyl diacetate (table 2, entry 2): 102 mg (81% yield) obtained using 
procedure A. 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.25 (m, 2H), 7.01 – 6.94 (m, 1H), 6.92 – 6.87 
(m, 2H), 5.40 – 5.34 (m, 1H), 4.48 – 4.39 (m, 1H), 4.30 (dd, J = 12.0, 6.0 Hz, 1H), 4.12 (d, J = 
5.1 Hz, 2H), 2.10 (s, 3H), 2.07 (s, 3H). Spectral data were in accordance with the literature.2 
 
 
NPht
OAc
AcO
 
3-(1,3-dioxoisoindolin-2-yl)propane-1,2-diyl diacetate (table 2, entry 3): 111mg (73% yield) 
obtained using procedure A. 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.84 (m, 2H), 7.76 – 7.71 (m, 
2H), 5.40 – 5.26 (m, 1H), 4.30 (dd, J = 12.1, 4.1 Hz, 1H), 4.20 – 4.12 (m, 1H), 3.96 (d, J = 5.2 Hz, 
2H), 2.08 (s, 3H), 2.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.47, 170.32, 168.00, 134.15, 
131.84, 123.46, 69.32, 63.08, 38.17, 20.85, 20.68. HRMS (EI+) calc'd for C15H16NO6 306.0978, 
found 306.0979. 
O
OEt
OAc
AcO
4  
7-ethoxy-7-oxoheptane-1,2-diyl diacetate (table 2, entry 4): 125mg (91% yield) obtained using 
procedure A. 1H NMR (400 MHz, CDCl3) δ 5.05 (dt, J = 9.9, 6.4 Hz, 1H), 4.21 (dd, J = 11.9, 3.3 
Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.02 (dd, J = 11.9, 6.5 Hz, 1H), 2.28 (t, J = 7.4 Hz, 2H), 2.05 (s, 
3H), 2.05 (s, 3H), 1.70 – 1.52 (m, 4H), 1.47 – 1.28 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR 
(101 MHz, CDCl3) δ 173.33, 170.70, 170.51, 71.26, 64.95, 60.25, 34.03, 30.38, 24.65, 21.01, 
20.73, 14.21. HRMS (EI+) calc'd for C13H23O6 275.1495, found 275.1484. 
 
 
                                                
1 Tetrahedron 2004, 60, 703–710 
 
2 J. Am. Chem. Soc. 2009, 131, 3846–3847 
 
7 CO2H
OAc
AcO
  
10,11-diacetoxyundecanoic acid (table 2, entry 5): 74% yield was obtained using procedure B 
on a 0.5 mmol scale (alkene). 
 
NHTs
OAc
AcO  
3-((4-methylphenyl)sulfonamido)propane-1,2-diyl diacetate (table 2, entry 6): 87 mg (53% 
yield) obtained using procedure A. 1H NMR (500 MHz; CDCl3) δ 7.74 (d, 2H, J = 8 Hz), 7.32 (d, 
J = 8 Hz, 2H), 5.10 (bs, 1H), 5.01 (p, J = 5 Hz, 1H), 4.22 (dd, J = 4.5, 12 Hz, 1H), 4.11 (dd, J = 
5.5, 12 Hz, 1H), 3.22-3.13 (m, 2H), 2.43 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H); 13C NMR (126 MHz, 
CDCl3) δ 170.5, 170.2, 143.7, 136.7, 129.8, 127, 69.8, 62.4, 43, 21.5, 20.8, 20.6; HRMS (FAB+) 
calc'd for C14H20O6NS 330.1011, found 330.1017. 
 
NO2
OAc
AcO
2  
5-nitropentane-1,2-diyl diacetate (table 2, entry 7): 96 mg (83% yield) obtained using 
procedure A. 1H NMR (500 MHz; CDCl3) δ 5.11-5.06 (m, 1H), 4.41 (td, J = 1.0, 7.0, 13.5 Hz, 
2H), 4.22 (dd, J = 3.5, 12.0 Hz, 1H), 4.05 (dd, J = 6.0, 12.0 Hz, 1H), 2.11-2.00 (m, 8H), 1.73-1.68 
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 170.6, 170.4, 74.8, 70.3, 64.5, 27.5, 23, 20.9, 20.7; 
HRMS (FAB+) calc'd for C9H15O6N 233.0899, found 233.0900. 
 
OBn
OAc
AcO  
3-(benzyloxy)propane-1,2-diyl diacetate (table 2, entry 8): 84 mg (63% yield) obtained using 
procedure A. 1H NMR (500 MHz; CDCl3) δ 7.36-7.27 (m, 5H), 5.24-5.20 (m, 1H), 4.54 (app q, J 
= 12 Hz, 2H), 4.33 (dd, J = 4.0, 12.0 Hz, 1H), 4.19 (dd, J = 6.0, 11.5 Hz, 1H), 3.59 (dd, J = 1.0, 
5.5 Hz, 2H), 2.08 (s, 3H), 2.03 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 170.6, 170.3, 128.4, 
127.8, 127.6, 73.2, 70.2, 68, 62.8, 21, 20.7; HRMS (FAB+) calc'd for C14H19O5 267.1232, found 
267.1224. 
 
 
5 Br
OAc
AcO
 
8-bromooctane-1,2-diyl diacetate (table 2, entry 9): 130mg (84% yield) obtained using 
procedure A. 1H NMR (500 MHz, CDCl3) δ 5.07 (dddd, J = 7.7, 6.6, 5.7, 3.3 Hz, 1H), 4.22 (dd, J 
= 11.9, 3.3 Hz, 1H), 4.03 (dd, J = 11.9, 6.6 Hz, 1H), 3.40 (t, J = 6.8 Hz, 2H), 2.07 (s, 3H), 2.07 (s, 
3H), 1.91 – 1.80 (m, 2H), 1.69 – 1.52 (m, 2H), 1.50 – 1.40 (m, 2H), 1.40 – 1.28 (m, 4H). 13C 
NMR (126 MHz, CDCl3) δ 170.77, 170.58, 71.41, 65.06, 33.80, 32.58, 30.57, 28.47, 27.92, 
24.93, 21.08, 20.79. HRMS (EI+) calc'd for C12H22O4Br 309.0701, found 309.0714. 
 
Ph
OAc
AcO
 
4-phenylbutane-1,2-diyl diacetate (table 2, entry 10): 113 mg (90% yield) obtained using 
procedure A. 3.56g (94% yield) was obtained upon increasing the reaction scale to 15.1 mmol. 1H 
NMR (500 MHz, CDCl3) δ 7.33 – 7.25 (m, 2H), 7.23 – 7.13 (m, 3H), 5.18 – 5.04 (m, 1H), 4.25 
(dd, J = 11.9, 3.4 Hz, 1H), 4.07 (dd, J = 12.0, 6.3 Hz, 1H), 2.76 – 2.57 (m, 2H), 2.06 (s, 3H), 2.05 
(s, 3H), 2.01 – 1.83 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.71, 170.52, 140.89, 128.48, 
128.27, 126.12, 71.12, 64.95, 32.38, 31.52, 21.01, 20.75. HRMS (EI+) calc'd for C14H19O4 
251.1283, found 251.1284. 
 
Stoichiometric reaction profiles 
 
Stoichiometric reaction with AgNO2: 
PdCl2(PhCN)2 (0.02 mmol, 7.7 mg), CuCl2•2H2O (0.02 mmol, 3.4 mg) and AgNO2 (0.02 mmol, 
3.1 mg) were weighed into a 8 mL vial charged with a stir bar. The vial was sparged for 1 minute 
with argon (1 atm, balloon. AcOH, Ac2O and MeNO2 were premixed in a 10:5:3 ratio and 
degassed with argon for 2 minutes. The solvent mixture was then added to the vial (3.2 mL), 
followed by the 1-dodecene (0.02 mmol) via syringe. After an additional 15 seconds of sparging 
with argon, the reaction vessel was shielded with light using aluminum foil. The reaction was 
stirred under an inert atmosphere (balloon). Aliquots (ca. 100 µL) were removed and subjected to 
GC analysis using tridecane as an internal standard.  
 
Stoichiometric reaction with nitrogen dioxide: 
First, nitrogen dioxide was condensed into a round bottom flask at -15 ºC. PdCl2(PhCN)2 (0.02 
mmol, 7.7 mg), CuCl2•2H2O (0.02 mmol, 3.4 mg) were weighed into a 8 mL vial charged with a 
stir bar. The vial was sparged for 1 minute with argon (1 atm, balloon). AcOH, Ac2O and MeNO2 
were premixed in a 10:5:3 ratio and degassed with argon for 2 minutes. The solvent mixture was 
then added to the vial (3.2 mL). A stock solution of NO2 was prepared by placing 2 mL of the 
degassed solvent mixture in a septum-capped 2 mL vial and adding condensed NO2 (12.7 µL, 0.4 
mmol) using a chilled gas tight microsyringe. Immediately after preparation, 100 µL of this 
solution (0.02 mmol NO2) was added to the vial containing palladium and copper followed by the 
1-dodecene (0.02 mmol) via syringe. The reaction vessel was shielded with light using aluminum 
foil. The reaction was stirred under an inert atmosphere (balloon). Aliquots (ca. 100 µL) were 
removed and subjected to GC analysis using tridecane as an internal standard. 
 
18O-labeling experiments: 
 
The procedure was modified to accommodate the high cost of the 18O-labeled AcOH:  
PdCl2(PhCN)2 (0.01 mmol, 3.8 mg), CuCl2•2H2O (0.01 mmol, 1.8 mg) and AgNO2 (0.01 mmol, 
1.5 mg) were weighed into a 2 mL vial charged with a stir bar. The vial was sparged for 1 minute 
with oxygen (1 atm, balloon). 18O-labeled AcOH (400 µL, 95% 18O specified by Sigma-Aldrich) 
and MeNO2 (100 µL) were added sparged with oxygen for 15 seconds. 1-dodecene (0.1 mmol) 
was next added via syringe. After an additional 10 seconds of sparging with oxygen, the reaction 
vessel was shielded with light using aluminum foil. The reaction was then allowed to stir at 35 ºC 
for 5 h under an atmosphere of oxygen (balloon). The reaction mixture was subsequently filtered 
and the solvent was removed under reduced vacuum. At this stage, a small amount of residue was 
set aside for mass spec analysis (FAB+). The remaining material was dissolved in 2M KOH in 
MeOH and was heated to 50 ºC for 8h. The mixture was diluted in dichloromethane and HCl (2 
M) was added. The aqueous layer was washed three times with dichloromethane. The combined 
organics were dried over MgSO4 and subsequently the volatiles were removed under reduced 
pressure. The residue was subjected to mass spec (FAB+) and the percentage of 18O-labeling was 
approximated by relative abundance of the molecular ions (+ sodium). 
 Experiment 1: 100% 18O-labeled HOAc 
Ph
O
OH
Ph
OH
O
O
Me
O
Me
+Ph
PdCl2(PhCN)2 (10%, 
CuCl2•2H2O (10%), AgNO2 (10%)
MeC18O2H / MeNO2 (4:1), O2
prominent peaks: m/z: 213 (M+H)
 (16O / 18O / 18O)
KOH (2 M), MeOH
Ph
OH
OH
prominent peaks: m/z: 213 (M+Na)
 (18O / 18O)  
Hydroxymonoacetate: 
 
Ph
O
OH
Ph
OH
O
O
Me
O
Me
prominent peaks
16O / 18O / 18O
m/z: 213
(M+H)
+
 
 
 
 
Diol: 
Ph
OH
OH
prominent peaks
 18O / 18O
m/z: 193
(M+Na)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Experiment 2: 50% 18O-labeled HOAc and 50% unlabeled HOAc 
Ph
O
OH
Ph
OH
O
O
Me
O
Me
+Ph
PdCl2(PhCN)2 (10%, 
CuCl2•2H2O (10%), AgNO2 (10%)
MeC18O2H / MeC16O2H / MeNO2 (2:2:1)
prominent peaks: m/z: 209 (M+H)
 (16O / 16O / 16O)
KOH (2 M), MeOH
Ph
OH
OH
prominent peaks: m/z: 189 (M+Na)
 (16O / 16O)
m/z: 213 (M+H)
 (16O / 18O / 18O)
m/z: 193 (M+Na)
 (18O / 18O)  
Hydroxymonoacetate: 
Ph
O
OH
Ph
OH
O
16O / 16O / 16O
m/z: 209
(M+H)
O
Me
O
Me
prominent peaks
16O / 18O / 18O
m/z: 213
(M+H)
+
 
 
Diol: 
Ph
OH
OH
prominent peaks
 18O / 18O
m/z: 193
(M+Na)
 16O / 16O
m/z: 193
(M+Na)  
  
 
 
Discussion: 
 
The diol (rather than the mono- or diacetate) products were of particular interest due to the clarity 
of the position of the 18O label. However, given that the diol oxygen atoms were the labeled 
positions, the masses observed in the monoacetate provides important evidence that the majority 
of the carbonyl oxygen atoms are not derived from the HOAc solvent. The likely source of 16O in 
the carbonyl oxygen is from H2O, upon hydrolysis of the acetoxonium ion. Relative abundance 
by FAB+ is not expected to provide quantitatively precise labeling percentages, however, the 
qualitative conclusions of the experiments are clearly supported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1H NMR spectra 
 
  
 
 
		





		



Me
9
OAc
AcO
OPh
OAc
AcO
  
 
 
 
		




	



NPht
OAc
AcO
O
OEt
OAc
AcO
4
  
NO2
OAc
AcO
2
NHTs
OAc
AcO
 
 
 		

 


OBn
OAc
AcO
5 Br
OAc
AcO
 
 
 
Ph
OAc
AcO
13C NMR spectra 
 
 
 
 
	
	



	
	



NPht
OAc
AcO
O
OEt
OAc
AcO
4
  
 
 
NHTs
OAc
AcO
NO2
OAc
AcO
2
 
 
 
 
 
	
	



OBn
OAc
AcO
5 Br
OAc
AcO
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
	
	



Ph
OAc
AcO


Aerobic Palladium-Catalyzed Dioxygenation of Alkenes Enabled by Catalytic Nitrite

https://authors.library.caltech.edu/51814/7/anie_201408650_sm_miscellaneous_information.pdf

Aerobic Palladium-Catalyzed Dioxygenation of Alkenes Enabled by Catalytic Nitrite

Abstract

Similar works

Full text

Available Versions

Caltech Authors - Main