transition metal-catalyzed 1,2-diamination of · pdf filepalladium catalyzed oxidative...
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Transition Metal-Catalyzed
1,2-Diamination of Alkenes
Group Meeting
Timothy Chang
04-27-10
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Valuable 1,2-Diamine Motif
NH
Pt
HN
O
O O
O
Eloxatin(Anticaner)
H2N
AcHN
OCHEt2
O
OEt
Tamiflu(Antiviral)
NCl
CO2H
HN
O
Ph
O
Lorabid(Antibacterial)
Ph Ph
S
NHHN COOH
O
Biotin
For a review on various synthetic methods of vicinal diamines, see
Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580.
For a review on the transition-metal catalyzed diamination, see
Cardona, F.; Goti A. Nature Chemistry 2009, 1, 269.
N N
Ph PhMe Me
RuCl
PhPy
Cl Py
Metathesis Catalyst(Grubbs)
N N
O O t-Bu
t-But-Bu
t-BuMn
Cl
Epoxidation Catalyst(Jacobsen)
P
P
PhPh
PhPh
HN
RuNH
Ph
Ph
Cl
Cl
Hydrogenation Catalyst(Noyori)
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Osmium Mediated Diamination
OOsO
Nt-Bu
Nt-BuOsO4 Ph3P Nt-Bu
2 equiv
+CH2Cl2
reflux, 48 h
OOsO
Nt-Bu
Nt Bu+
CO2Et NOsN
O
O
t-BuCO2Et
DCMrt, 5 h
63%
Chong, A. O.; Oshima, K. Sharpless, K. B. 1977 J. Am. Chem. Soc. 99, 3420.
For a review on osmium mediated diamination, see Muñiz, K. New J. Chem. 2005, 29, 1371.
O Nt-Bu EtO2C NO
t-BuCO2Et
rt, 5 h
1.5 equiv
84%
recovered unchanged frompreparative GLC at 250 oC
- Cis-disubstituted olefins react sluggishly.- Different amounts of hydroxyaminated products were observed for otherolefins such as styrene and 1-decene.
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Palladium Mediated Diamination
2 equvMe2NH(9 equiv)-40oC45 min
THF, 0oC, 5 min
mCPBA(10 equiv)15 min
then rt, 3 h
1. KBH42. NaOH NH2
NH2
77%(based on Pd)
PdCl2(PhCN)2
Bäckvall, J.-E. C. Tet. Lett. 1978, 19, 163.
Ph
D Me2N NMe2
PhH D
H
PdCl2(PhCN)2
Proposed Mechanism:
Me2N
PhH
DH Me2N
PhH
DH
[PdIV][PdII]
Me2NH
[O]
Me2NH
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Palladium Catalyzed Oxidative Intramolecular Diamination
Conditions:A: Pd(OAc)2 (5 mol %), PhI(OAc)2 (2.2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 12 h.B: Pd(OAc)2 (25 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2, RT, 48 h.C: Pd(OAc)2 (10 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2, RT, 12 h.
NH
NH
O
RNN
O
R
( )n
( )n
Conditions
O O O OO
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2005, 127, 14586.
NN
O
Tos
RR
R = Me, 92% (A)R = Ph, 95% (A)
NN
O
TosNN
O
Tos
91% (A) 86% (B)
NN
O
Tos
89% (C)
NN
O
Tos
MeMe Me
94% (A)
- Base is required (generated in situ from NMe4Cl/NaOAc) for reactivity (A).
- No reactivity difference by using Me4NOAc.
- Chlorinated intermediate may not be involved.
- Sulfamide substrates gave aminoacetoxylated product.
NN
Nt-Bu
Tos
95% (A)PhI(OAc)2 (2 equiv)
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The Overall Stereochemistry of Diamination
The acetoxy intermediate is not involved.
Anti diamination
Conditions:
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (2 equiv)
NMe4Cl/NaOAc (1 equiv)
CH2Cl2, RT, 12 h
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
Anti diamination
Anti diamination
Which step involves
the inversion of the
configuration?
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Stereochemistry of Aminopalladation and Titration Experiment
Not isolable
Syn aminopalladation due
to geometric constraint of
the urea.
1b
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
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Stereochemistry of Aminopalladation and Titration Experiment
Not isolable
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
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Modes of Syn Aminopalladation
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
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Rate Determining Step
NH
NH
O
Tos
X
X = H, t-Bu, Cl, Br, F, CN
Aminopalladation is the RDS.
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
EWGEDGNN
O
TosX
Pd(OAc)2 (5 mol%)PhI(OAc)2 (2 equiv)NMe4Cl/NaOAc (1 equiv)CH2Cl2, RT, 3 h
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Proposed Mechanism for the Second C-N Bond Formation
Conditions: Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 2 h
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
The second C-N bond formation is not the RDS.
Conditions: Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 2 h
Ion pair
Electrophilicity of -CH2-[PdIV]+ is enhanced
SN2 type
reductive elimination
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Proposed Catalytic Cycle
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
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An Example of Syn Diamination
Conditions: Pd(OAc)2 (10 mol%), PhI(OAc)2 (1.4 equiv), NMe4Cl/NaOAc (1.1 equiv), DMF, RT, 14 h
Syn diamination
89% yield
R = Tol
Muñiz, K. J. Am. Chem. Soc. 2007, 129, 14542.
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Nickel-Catalyzed Diamination Using Sulfamide
Muñiz, K.; Streuff, J.; Hövelmann, C. H.; Núñez, A. Angew. Chem. Int. Ed. 2007, 46, 7125.
Terminal alkenes are
good substrates.
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Pd-Catalyzed Diamination of Terminal Alkenes Using NFBS
RO
Byproducts
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
NHMe
Me
R
Me4a
NMe
Me
O
R
OC(O)CF3
5a
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Proposed Catalytic Cycle
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
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The Overall Stereochemistry of Diamination
Mechanistic implications of the
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Mechanistic implications of the
two C-N bond formations from
the overall syn diamination:
1. Anti aminopalladation
followed by SN2 displacement
of the C-Pd bond.
2. Syn aminopalladation
followed by C-N reductive
elimination (retentive).
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Stereochemistry of the Aminopalladation (1st C-N Bond Formation)
Chelation from the acetamide minimizes
β-hydride elimination.
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Inversion is required for the
2nd C-N bond formation for
the overall syn diamination.
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Proposed Mechanism for the 2nd C-N Bond Formation
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
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Challenges in the Palladium Catalyzed Alkene Diamination
Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. l. J. Am. Chem. Soc. 2005, 127, 7308.
Challenges:
1. Catalyst poisoning
2. Protonation of amine source 2
3. Oxidation of amine source 2
4. β-hydride elimination (route I)
5. Activation of Pd-C bond for a second attack by amine 2
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Pd-Catalyzed Intermolecular 1,2-Diamination of Conjugated Dienes
Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. l.
J. Am. Chem. Soc. 2005, 127, 7308.
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Pd-Catalyzed Diamination of Conjugated Alkenes
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762.
- Conjugated dienes are effective substrates.
- Highly stereoselective and regioselective at the internal double bond.
- Z isomers do not react.
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Synthesis of Di-tert-butyldiaziridinone
Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969, 34, 2254.
Du, H.; Zhao, B.; Shi, Y. Org. Synth. 2009, 86, 315.
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Properties of Diaziridinones
N
O
R N N
O
R R
O
C=O
R R
cyclopropanones aziridinones diaziridinones
amidesketones(saturated, aliphatic)
1813-1840 1837-1850 1855-1880
1650-1690~1710 1660-1695
ureas
C=O
cm-1
cm-1
Greene et. al. JOC 1969, 34, 2254.; JOC 1978, 43, 922.; JOC 1976 41 2813.
Heine, H. W. The Chemistry of Heterocyclic Compounds; Hassner, A., Ed; John Wiley & Sons, Inc: New York, 1983; pp 547.
N N
O
Me MeMeMe
Br Br
1.325 Å, typical amides (~1.33 Å)
F2N-NF2 (1.47 Å)H2N-NH2 (1.45 Å)
1.601 Å
The angle between the N-substituent andthe diaziridinone plane is 56o.
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Proposed Catalytic Cycle
Pd(0)t-BuN Nt-Bu
O
O
Nt B
O
NN
O
t-But-Bu
R
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762.
t-BuN
Pd
Nt-Bu
R
t-BuN
Pd
Nt-Bu
O
Pd
Nt-But-BuN
R
R
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Possible Reasons for High Stereoselectivity and Reactivity of E-Isomer
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NMR Study of the Stoichiometric Reaction
1.36 ppm
1.32 ppm
1.59 ppm
177.3 (13C) 159.3 (13C)
58.1
33.6
59.327.2
19.8 (31P)
A is consumed in 1 min when
(E)-1-methoxybutadiene (6g)
was added at 85 min.
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Pd(PPh3)4 (0.03 mmol)
5 (0.02 mmol)
C6D6, 40oC
(0.04 mmol)1.05 ppm
Stoichiometric Reaction monitored by 1H NMRA is a possible intermediate.
Oxidative Addition is likely the RDS.
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Kinetic Studies
MeOt-BuN Nt-Bu
O+
Pd(PPh3)4 (0.02 mmol)C6D6, 40
oCNN
O
t-But-Bu
E:Z = 15.7:10.24 mmol E
5
7g
6g
0.2 mmol
MeO
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
1st order in diaziridinone 5.No induction period.
PPh3 dissociates rapidly.
Quantitative conversion . No side reaction. 1st order in Pd(PPh3)4 (not shown).
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Kinetic Studies
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Inverse 1st-order in PPh3.Zero-order in diene 6g.
6g (0.12 mmol E isomer),
5 (0.1 mmol), Pd(PPh3)4 (0.01 mmol)
6g (0.12 mmol E isomer),
5 (0.1 mmol), Pd(PPh3)4 (0.01 mmol)
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Kinetic Studies
+C6D6, 40
oCNN
O
t-But-Bu
7
6 MeO
RPd
NN
O
t-Bu t-Bu
Ph3P PPh3
A
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
- A can be observed using 6i under catalytic reaction conditions ([A] is independent of PPh3).
C-N bond formation is slower for e-deficient dienes.
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Refining the Catalytic Cycle
7-membered urea
was not observed
RDS for e-rich dienes.
- Rational for high regioselectivity?
- Why is cis-alkene unreactive?
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Associative displacement?
The olefin insertion into Pd-N is
slower for electron-deficient dienes.
Details of insertion?
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Catalytic Asymmetric Diamination of Conjugated Alkenes
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
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Diamination at Allylic and Homoallylic Carbons
R2
R1
t-BuN Nt-Bu
O+
Pd(PPh3)4 (10 mol%)neat
65oC, 12 h55-93% yield
NN
O
t-But-Bu
R2
NN
O
t-But-Bu
2
NN
O
t-But-Bu NN
O
t-But-Bu
Et
2.75 equivslow addition R1
NN
O
t-But-Bu
Et
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
R2
76%R2
PhEt
n-C6H13CH2OBn
CH2On-C6H13
Yield (%)90 (7 h)68749078
55%
Et
NN
O
t-But-Bu
PhMeO
NN
O
t-But-Bu
64%
MeO
n-Bu
92%
EtPh
93%
n-C6H13
- Highly stereoselective.
- No reactions for olefins with internal double bonds
(e.g. trans-5-decane and cis-cyclooctene).
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Bisdiamination
A single diastereomer
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
A single diastereomer
Using 5 mol% Pd(PPh3)4:
10a (14%) and
10b (20%) were isolated
after 12 h.
10a and 10b gave 11
under the diamination
reaction condition.
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Proposed Catalytic Cycles
2 equiv
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
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Asymmetric Diamination at Allylic and Homoallylic Carbons
Rt-BuN Nt-Bu
O+
Pd2(dba)3 (5 mol%)L* (22 mol%)
neat65oC, 6 h50-85% yield89-94% ee
NN
O
t-But-Bu
R2.5 equivslow addition
O
OP N
Me Me
Me MeL*
REtn-C5H11CH2Ph
ee (%)909193
Yield (%)507167
NN
O
t-But-Bu NN
O
t-But-Bu
n-C6H13O
NN
O
t-But-Bu
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 8590.
CH2Phi-PrPh
939490
675180 80% (92% ee)
6 3
85% (91% ee)
67% (92% ee)
NMeBn
NN
O
t-But-Bu
70% (97:3 dr)
NN
O
t-But-Bu
81% (90% ee)
n-C5H11
NN
O
t-But-Bu
69% (89% ee)
n-C5H11 MeOTMS
NN
O
t-But-Bu
66% (94:6 dr)
MeOTMS
Ligand control overrides substrate control
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Diamination using Thiadiaziridine
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
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Preliminary Studies on Mechanism
Diamination may not proceed Initial allylic amination is possible.
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
Diamination may not proceed
via a diene species
Initial allylic amination is possible.
No cyclization was observed
without 4.
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Proposed Catalytic Cycle
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
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Cu(I)-Catalyzed Diamination of Conjugated Dienes (1)
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
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Cu(I)-Catalyzed Diamination of Conjugated Dienes (2)
Me+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h Me
NN
O
MeN
N
Ot-Bu
t-Bu
t-Bu
t-Bu+
1:1.365%
+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, 65
oC, 6 h NN
Ot-Bu
t-Bu
MeMe
58%
1.5 equiv
1 5 equiv
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h N
N
Ot-Bu
t-Bu
PhPh Z/E = 3.3/1
76%
Ph+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h
PhN
N
Ot-Bu
t-Bu
1.5 equiv
1.5 equiv
1.5 equiv
D
DD
DH
65:3573%
PhN
N
Ot-Bu
t-BuD
HD
+
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Proposed Catalytic Cycle
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
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Cu(I)-Catalyzed Asymmetric Diamination of Conjugated Dienes
Du, H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231.
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Cu(I)-Catalyzed Diamination with Other Nitrogen Sources
R +t-BuN Nt-Bu
S
CuCl-P(n-Bu)3(10-20 mol%, 1:1)CDCl3, rt - 65
oC7-48 h R
NSN
t-Bu
t-Bu
R = arylheteroarylalkynealkylether
O O
1.2 equiv
OO
45-91% yield
- Electron-deficient olefin (ethyl acrylate) andaliphatic substituted olefin (1-octene) are not reactive.
Zhao, B.; Yuan, W.; Du, H.; Shi, Y. Org. Lett. 2007, 9, 4943.
Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2008, 10, 1087.
R +t-BuN Nt-Bu
CuCl-P(n-Bu)3(10 mol%, 1:2)CDCl3, 50 - 65
oC24 h R
NN
t-Bu
t-Bu
R = arylheteroarylalkynealkenediene
1.2 equiv 48-86% yield
- No multiple diaminations with dienes or trienes.- Selective at the terminal olefin.- Electron-deficient olefin (ethyl acrylate) andaliphatic substituted olefin (1-octene) are not reactive.
NCN NCN
t-BuN Nt-Bu
Nt-Bu
No reaction
t-BuN Nt-Bu
NTs
Decomposed rapidly
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Conclusions
- Transition-metal catalyzed 1,2-diamination allows rapid access to protected diamines
from alkenes. However, deprotection conditions are quite harsh (e.g. LAH, reflux con. HCl).
- High catalyst loadings are often required.
- Limited enantioselective approach available.
- The dinitrogen source has a strong influence on the reaction at the terminal or the - The dinitrogen source has a strong influence on the reaction at the terminal or the
internal alkene.
- Some mechanistic details are elucidated. More studies are required (e.g. nickel catalyzed
and copper catalyzed diaminations).
- Much work remained to be done to make this methodology general and practical.