Cu(I)-catalyzed diamination of conjugated dienes. Complementary regioselectivity from two distinct mechanistic pathways involving Cu(II) and Cu(III) species

Article abstract of DOI:10.1021/ja207691a

Conjugated dienes can be diaminated at the internal and/or terminal double bonds using Cu(I) as catalyst and N,N-di-t-butyldiaziridinone (1) as nitrogen source. The regioselectivity is highly dependent upon the choice of Cu(I) catalyst and the substituent

Full text of DOI:10.1021/ja207691a

ARTICLE
pubs.acs.org/JACS
Cu(I)-Catalyzed Diamination of Conjugated Dienes. Complementary
Regioselectivity from Two Distinct Mechanistic Pathways Involving
Cu(II) and Cu(III) Species
Baoguo Zhao, Xingao Peng, Yingguang Zhu, Thomas A. Ramirez, Richard G. Cornwall, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S Supporting Information
b
ABSTRACT: Conjugated dienes can be diaminated at the internal and/
or terminal double bonds using Cu(I) as catalyst and N,N-di-t-butyldia-
ziridinone (1) as nitrogen source. The regioselectivity is highly dependent
upon the choice of Cu(I) catalyst and the substituents on diene substrates.
The diamination likely proceeds via two mechanistically distinct path-
ways. The NꢀN bond of N,N-di-t-butyldiaziridinone (1) is first homo-
lytically cleaved by the Cu(I) catalyst to form four-membered Cu(III) species A and Cu(II) radical species B, which are in rapid
equilibrium. The internal diamination likely proceeds in a concerted manner via Cu(III) species A, and the terminal diamination
likely involves Cu(II) radical species B. Kinetic studies have shown that the diamination is first-order in N,N-di-t-butyldiaziridinone
(1), zero-order in olefin, and first-order in total Cu(I) catalyst, and the cleavage of the NꢀN bond of 1 by the Cu(I) catalyst is the
rate-determining step. The internal diamination is favored by use of CuBr without ligand and electron-rich dienes. The terminal
diamination is favored when using CuClꢀL and dienes with radical-stabilizing groups.
Chart 1
’ INTRODUCTION
Present in many biologically active compounds and chiral
catalysts, 1,2-diamines are important functional moieties.1 The
synthesis of 1,2-diamines is of interest to organic chemists.1
Diamination of olefins, allowing direct installation of two nitro-
gen atoms across CꢀC double bonds, provides a straightforward
approach to prepare 1,2-diamines. Various metal-free,1,2 metal-
mediated,1,3,4 and metal-catalyzed4c,5ꢀ8 diaminations of olefins
have been developed. In our own studies, we have developed
Pd(0)-9ꢀ11 and Cu(I)-catalyzed12ꢀ15 diaminations of olefins
using three-membered rings 1ꢀ316ꢀ19 as nitrogen sources
(Chart 1). When Pd(0) was used as catalyst, various dienes were
efficiently diaminated at the internal double bonds with N,N-di-t-
butyldiaziridinone (1) (Scheme 1).9 Mechanistic studies suggest
this diamination likely proceeds via a concerted reaction path-
way.9f The Pd(0) catalyst inserts into the NꢀN bond of N,N-di-t-
butyldiaziridinone (1) to form four-membered Pd(II) species
6,20 which reacts with diene 4 to give π-allyl Pd species 7.21,22
Species 7 then undergoes reductive elimination to give internal
diamination product 5 and regenerate the Pd(0) catalyst.23
However, when the CuClꢀL complex was used as catalyst, the
terminal diamination product 8 was predominantly formed for
various conjugated dienes (Scheme 2).12a A radical mechanism
has been proposed for this Cu(I)-catalyzed diamination.12a The
Cu(I) first homolytically cleaves the NꢀN bond of N,N-di-t-
butyldiaziridinone (1) to give nitrogen radical species 9.24ꢀ28
Radical species 9 adds to the terminal double bond of the diene to
form allyl radical species 10, which then undergoes rapid CꢀN
bond formation to give terminal diamination product 8 and re-
generate the Cu(I) catalyst. The CuClꢀL catalyzed diamination
with N,N-di-t-butylthiadiaziridine 1,1-dioxide (2)14 and N,N-di-
t-butyl-3-(cyanimino)-diaziridine (3)15 also appears to proceed
via a stepwise radical mechanism based upon studies of deuter-
ated olefin substrates.
Very recently, we have found that various conjugated dienes
can be predominantly diaminated at internal double bonds when
CuBr without a ligand is used as catalyst, giving internal diamina-
tion product 5 ingood yield andhigh regioselectivity (Scheme3).29
The preliminary studies suggest that the Cu(I)-catalyzed diamina-
tion may proceed via two distinct pathways (Scheme 4). The
terminal diamination proceeds via a stepwise radical mechanism
involving Cu(II)30 intermediate (B), and the internal diamination
proceeds via a concerted mechanism involving a four-membered
Cu(III)31,32 species (A) similar to that of the Pd(0)-catalyzed
diamination.9f To better understand the Cu(I)-catalyzed dia-
mination,33,34 we have further investigated this reaction includ-
ing kinetics, substituent effect, and the effect of different nitro-
gen sources. Herein, we wish to report our detailed studies on
this subject.
Received: August 19, 2011
Published: November 14, 2011
r
2011 American Chemical Society
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Scheme 1. Pd(0)-Catalyzed Internal Diamination of Dienes
Scheme 4. Proposed Mechanisms for the Cu(I)-Catalyzed
Regioselective Diamination of Conjugated Dienes
Scheme 2. Cu(I)-Catalyzed Terminal Diamination of Dienes
diamination using CuBr or terminal diamination using CuCl-
PCy3 (Table 1, entries 1 and 2).
Kinetic Model and Analysis of the Cu(I)-Catalyzed Regio-
selective Diamination. Based on the mechanisms proposed in
Scheme 4, a kinetic model has been established for the Cu(I)-
catalyzed regioselective diamination (for the detailed derivation,
see Supporting Information). Using steady-state approximation,
the internal diamination and terminal diamination rates are ex-
pressed as eqs 1 and 2, respectively. The ratio of internal di-
amination product 5 to terminal diamination product 8 can be
expressed as eq 3, indicating that the diamination regioselectivity
is dependent on the equilibrium between A and B (K), the equi-
librium between A and D (k2/kꢀ2), and the rate constants of
CꢀN bond formation (k3 and k5):
Scheme 3. Cu(I)-Catalyzed Regioselective Diamination of
Dienes
k1k2k3½1ꢁ½4ꢁ½CuXLnꢁ
rate
¼
internal
k2k3½4ꢁ þ Kkꢀ2k5½4ꢁ þ kꢀ2k7ð1 þ KÞ
ð1Þ
’ RESULTS AND DISCUSSION
Kk1kꢀ2k5½1ꢁ½4ꢁ½CuXLnꢁ
rate
¼
terminal
k2k3½4ꢁ þ Kkꢀ2k5½4ꢁ þ kꢀ2k7ð1 þ KÞ
Various conjugated dienes have been investigated for the
internal diamination using CuBr29a and/or terminal diamina-
tion using CuCl-PCy3. As shown in Table 1, 1-monosubstituted
(entries 1, 3, and 4), 1,2-disubstituted (entries 7, 8, 10ꢀ14), 1,3-
disubstituted (entries 15ꢀ18), and 1,2,3-trisubstituted (entries
20 and 21) dienes can be efficiently diaminated at the internal
double bonds with 5ꢀ10 mol % CuBr and N,N-di-t-butyldiazir-
idinone (1), giving diamination product 5 in good yields and high
regioselectivities. 1-Arylbutadienes, such as (E)-1-phenyl-1,3-
butadiene, exhibited relatively low regioselectivity for internal
diamination usingCuBr(Table 1, entry 5) buthigh regioselectivity
for terminal diamination using CuCl-PCy3 (Table 1, entry 6).35
However, the regioselectivity for the internal diamination using
CuBr increased dramatically when additional alkyl substituent(s)
were introduced at the 2 and/or 3 positions (Table 1, entries 8,
18, and 21) of the diene substrates. For 1-alkylbutadiene sub-
strates, high regioselectivity can be obtained for either internal
ð2Þ
ð3Þ
½5ꢁ
½8ꢁ
k2k3
¼
Kkꢀ2k5
Kinetic Studies. The proposed diamination mechanism in
Scheme 4 involves the cleavage of the NꢀN bond of N,N-di-t-
butyldiaziridinone (1) by the Cu(I) catalyst and the subsequent
CꢀN formation with diene 4. In order to determine the rate-
determining step for the reaction, kinetic studies were carried out
using 1-methoxy-1,3-butadiene (4c) as substrate for internal
diamination (Scheme 5) and (E)-1-phenyl-1,3-butadiene (4d)
as substrate for terminal diamination (Scheme 6). The reactions
were monitored by 1H NMR spectroscopy using Si(SiMe3)4 as
internal standard. The concentrations of diaziridinone 1, internal
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Table 1. Cu(I)-Catalyzed Regioselective Diamination of Dienesa
a Method A (taken from ref 29a): All reactions were carried out with olefin 4 (0.20 mmol), N,N-di-t-butyldiaziridinone (1) (0.22 mmol), and CuBr
(0.010 mmol) in CDCl3 (0.4 mL) under Ar with vigorous stirring at 0 °C for 20 h unless otherwise stated. For entry 3, olefin 4b (0.19 mmol) was used.
For entry 4, olefin 4c (0.25 mmol, E:Z = 15.7:1, E isomer: 0.24 mmol) and 1 (0.20 mmol) were used. For entry 5, the reaction was carried out with 1
(0.24 mmol), CuBr (0.020 mmol), and CDCl3 (0.8 mL) for 24 h. For entry 12, the reaction was carried out on 0.40 mmol scale. For entry 14, CuBr
(0.020 mmol) was used. For entry 18, the reaction was carried out in CDCl3 (1 mL) at ꢀ20 °C for 40 h. Method B: All reactions were carried out with
olefin 4 (0.20 mmol), 1 (0.40 mmol), CuClꢀPCy3 (1:1.5) [0.020 mmol, prepared in situ from CuCl (0.020 mmol) and PCy3 (0.030 mmol) in C6D6
(0.20 mL) by stirring at room temperature for 1 h] in C6D6 (0.25 mL) under Ar at room temperature for 10 h unless otherwise stated. Entries 2 and 19
were taken from ref 29a. For entries 2 and 9, the reactions were carried out with olefin 4 (2.0 mmol) and 1 [0.20 mmol, dissolved in C6D6 (0.1 mL), slow
addition over 7 h] at room temperature for 10 h (total). b Isolated yield based on 4 except entries 2, 4, and 9 which were based on 1. c The ratio was
determined by 1H NMR analysis of the crude reaction mixture. The ratio of 5/8 is >99:1 unless otherwise indicated. For entries 6, 9, and 19, the ratio of
8/5 is >99:1. d The stereochemistry was tentatively assigned on the basis of sterics.
diamination product 5c, and terminal diamination product 8d
Reaction Order in N,N-Di-t-butyldiaziridinone (1). 1-Methoxy-
1,3-butadiene (4c) was chosen as test substrate for the
kinetic studies of internal diamination due to its high reactivity
and high regioselectivity for internal diamination. CuBr-P-
(OPh)3 (1:1.1) was used as catalyst instead of CuBr (Table 1,
method A) for the kinetic study because it was soluble in CDCl3
and also gave the internal diamination product for 4c. The
were calculated by integration of the signals corresponding to
1
their respective t-butyl groups. As judged by H NMR spec-
troscopy, internal diamination product 5c and terminal diami-
nation product 8d were formed with high regioselectivities
using 10 mol % CuBr-P(OPh)3 and 10 mol % CuCl-P(OPh)3 as
catalysts, respectively.
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Scheme 5
Scheme 7
Scheme 6
Figure 3. Plot of [1] against reaction time (min) in the Cu(I)-catalyzed
decomposition of N,N-di-t-butyldiaziridinone (1) (0.20 mmol) with
CuBr-P(OPh)3 (1:4.0) (0.020 mmol) in CDCl3 (total solution volume:
1.2 mL) in an NMR tube at room temperature.
Figure 1. Plot of ln([1]0/[1]) against reaction time (min) for the
Cu(I)-catalyzed internal diamination of 1-methoxy-1,3-butadiene (4c)
(E:Z = 15.7:1, E isomer: 0.24 mmol) with 1 (0.20 mmol) and CuBr-
P(OPh)3 (1:1.1) (0.020 mmol) in CDCl3 (total solution volume:
1.2 mL) in an NMR tube at room temperature. [1]0 stands for the
initial concentration of 1 in M, and [1] stands for the concentration of
1 in M at a particular time.
Figure 4. Plots of [5c] (M) against reaction time (min) for the Cu(I)-
catalyzed internal diamination of 1-methoxy-1,3-butadiene (4c) with
variable initial olefin concentrations. The diaminations were carried out
with 4c (E:Z = 15.7:1, E isomer: 0.080, 0.16, 0.24, 0.48, or 0.80 mmol),
N,N-di-t-butyldiaziridinone (1) (0.20 mmol), and CuBr-P(OPh)3
(1:1.1) (0.020 mmol) in CDCl3 (total solution volume: 1.2 mL) in an
NMR tube at room temperature.
analysis of the crude reaction mixture. No terminal diamina-
tion product and negligible amounts of byproduct from the
decomposition of 1 were observed. Since the internal diami-
nation predominates in this case, eq 1 can be simplified to eq 4
(for detailed derivation, see Supporting Information). Equa-
tion 4 can be further expressed as eq 5 if the cleavage of the
NꢀN bond of N,N-di-t-butyldiaziridinone (1) by the Cu(I)
catalyst is the rate-determining step (for detailed derivation,
see Supporting Information). The plot of ln([1]0/[1]) against
reaction time gave a straight line with kobs = 2.3 ꢂ 10ꢀ3 sꢀ1
(Figure 1), indicating first-order dependence on diaziridi-
none 1 in the internal diamination of 1-methoxy-1,3-buta-
diene (4c), which is consistent with the rate law shown in
Figure 2. Plot of ln([1]0/[1]) against reaction time (min) for the
Cu(I)-catalyzed terminal diamination of (E)-1-phenyl-1,3-butadiene
(4d) (0.72 mmol) with 1 (0.20 mmol) and CuCl-P(OPh)3 (1:1.5)
(0.020 mmol) in dry C6D6 (total solution volume: 1.2 mL) in an NMR
tube at room temperature. [1]0 stands for the initial concentration
of 1 in M, and [1] stands for the concentration of 1 in M at a
particular time.
reaction was carried out in an NMR tube at room tem-
perature (Scheme 5). Internal diamination product 5c was
1
cleanly formed during the reaction as judged by H NMR
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Figure 7. Plot of kobs against [CuCl]0 for the Cu(I)-catalyzed terminal
diamination of (E)-1-phenyl-1,3-butadiene (4d) with variable amounts
of total CuCl (0.020ꢀ0.10 mmol). The diaminations were carried out
with 4d (0.72 mmol), N,N-di-t-butyldiaziridinone (1) (0.20 mmol), and
CuCl-P(OPh)3 (1:1.5) (0.020, 0.040, 0.060, 0.080, and 0.10 mmol) in
C6D6 (total solution volume: 1.2 mL) in an NMR tube at room
temperature.
Figure 5. Plots of [8d] (M) against reaction time (min) for the Cu(I)-
catalyzed terminal diamination of (E)-1-phenyl-1,3-butadiene (4d) with
variable initial olefin concentrations. The diaminations were carried out
with 4d (0.12, 0.24, 0.48, or 0.72 mmol), N,N-di-t-butyldiaziridinone (1)
(0.20 mmol), and CuCl-P(OPh)3 (1:1.5) (0.020 mmol) in C6D6 (total
solution volume: 1.2 mL) in an NMR tube at room temperature.
Figure 6. Plot of kobs against [CuBr]0 for the Cu(I)-catalyzed internal
diamination of 1-methoxy-1,3-butadiene (4c) with variable amounts of
total CuBr (0.020ꢀ0.10 mmol). The diaminations were carried out with
4c (E:Z = 15.7:1, E isomer: 0.24 mmol), N,N-di-t-butyldiaziridinone (1)
(0.20 mmol), and CuBr-P(OPh)3 (1:1.1) (0.020, 0.040, 0.060, 0.080,
and 0.10 mmol) in CDCl3 (total solution volume: 1.2 mL) in an
NMR tube at room temperature.
Figure 8. EPR spectrum for the reaction between N,N-di-t-butyldiazir-
idinone (1) (0.050 mmol) and CuCl-P(OPh)3 (1:1.5) (0.0050 mmol)
in toluene (0.18 mL) at ꢀ50 °C. A similar triplet was also observed
when the reaction was performed in the presence of (E)-1-phenyl-1,3-
butadiene 4d (0.10 mmol).
eq 5:
indicates first-order kinetics in N,N-di-t-butyldiaziridinone (1) in
this case:
rate
¼ k1½1ꢁ½CuXLnꢁ
¼ k1½1ꢁ½CuXLnꢁ0
ð4Þ
ð5Þ
internal
internal
rate
¼ k1½1ꢁ½CuXLnꢁ0
ð6Þ
rate
terminal
The decomposition of N,N-di-t-butyldiaziridinone (1) was
investigated using CuBr-P(OPh)3 (1:4) complex as catalyst in
the absence of a diene substrate (Scheme 7). The reaction was
carried out in CDCl3 and monitored by 1H NMR spectroscopy.
N,N-di-t-butyldiaziridinone (1) rapidly decomposed to uniden-
tified compounds (Figure 3). Under the reaction conditions, Cu
species A or B cannot be detected by NMR spectroscopy even
with stoichiometric amounts of Cu(I) salt at low temperature,
which indicates the decomposition of A and B should be faster
than their formation. Under the diamination conditions, the re-
action between A and B with the diene substrate should be even
The diamination of 1-phenyl-1,3-butadiene (4d) with 10 mol %
CuCl-P(OPh)3 and 1 occurred regioselectively at the terminal
double bond as judged by the H NMR of the crude reaction
1
mixture. CuCl-P(OPh)3 was chosen as catalyst instead of CuCl-
PCy3 (Table 1, method B) for the kinetic study because the 1H
NMR signal of P(OPh)3 does not interfere with the signals of the
tert-butyl groups of 1 and 8d as PCy3 does. Equation 2 can be
similarly simplified to eq 6 if the cleavage of the NꢀN bond of N,N-
di-t-butyldiaziridinone (1) is also assumed to be the rate-determining
step. The straight line obtained for the plot of ln([1]0/[1])
against reaction time with kobs = 3.0 ꢂ 10ꢀ3 sꢀ1 (Figure 2) also
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Table 2. Studies of the Effect of Copper Salt on the Diamination of (E)-Nona-1,3-diene (4b)a
entry
catalyst
conv. (%)b
5b:8bc
1
2
3
4
5
6
CuCl-P(OPh)3
CuBr-P(OPh)3
CuIꢀP(OPh)3
CuOAc-P(OPh)3
CuCN-P(OPh)3
CuSPh-P(OPh)3
60
69
29
0
0.37:1
1.26:1
0.11:1
50
0
0:1
a The diamination was carried out with diene 4b (0.20 mmol), N,N-di-t-butyldiaziridinone (1) (0.30 mmol), and CuX-P(OPh)3 (1:1.5) (0.020 mmol) in
C6D6 (0.20 mL) in a 1.5 mL vial at room temperature under Ar for 10 h unless otherwise stated. b The conversion was based on diene 4b and determined
by 1H NMR analysis of the crude reaction mixture. c The ratio of 5b:8b was determined by 1H NMR analysis of the crude reaction mixture except for
entry 3. For entry 3, an accurate ratio of 5b to 8b was difficult to obtain by 1H NMR analysis of the crude reaction mixture due to the signal interference
with baseline noise and unknown byproducts. The ratio was thus obtained by 1H NMR analysis after flash chromatography (5b and 8b were nearly
inseparable by column).
Table 3. Studies of the Ligand Effect on the Cu(I)-Catalyzed Diamination of (E)-Nona-1,3-diene (4b)a
entry
ligand (L:Cu)
conv. (%)b
5b:8bc
1
2
3
4
5
6
7
8
9
(()-BINAP(1.5:1)
PPh3 (1.5:1)
0
72
60
92
77
99
94
87
99
0.76:1
0.35:1
1.59:1
0.33:1
2.9:1
P(4-MeOPh)3 (1.5:1)
P(4-CF3Ph)3 (1.5:1)
P(cyclohexyl)3 (1.5:1)
P(OPh)3 (1:1)
P(OPh)3 (1.5:1)
P(OPh)3 (4:1)
1.89:1
0.92:1
10:1
no ligand
a The diaminations were carried out with diene 4b (0.20 mmol), N,N-di-t-butyldiaziridinone (1) (0.30 mmol), and CuBr-ligand (0.020 mmol) in CDCl3
(0.2 mL) in a 1.5 mL vial at room temperature under Ar for 10 h. b The conversion was based on diene 4b and determined by analysis of the 1H NMR
spectrum of the crude reaction mixture. c The ratio of 5b:8b was determined by 1H NMR analysis of the crude reaction mixture.
faster than the decomposition of A and B, which also suggests the
formation of A and B is likely to be the rate-determining step.
Effect of Olefin Concentration. According to eqs 5 and 6, the
internal and terminal diamination reactions should be zero order
in olefin 4. The effect of olefin concentration on the internal and
the terminal diaminations was investigated using 1-methoxy-1,3-
butadiene (4c) and (E)-1-phenyl-1,3-butadiene (4d), respec-
tively. Similar reaction rates were observed for the CuBr-catalyzed
internal diamination when [4c]0 varied from 0.067 to 0.40 M
(Figure 4). The slightly reduced reaction rate observed with high
[4c]0 (0.67 M) is possibly due to the complexation of the Cu
catalyst with the diene substrate. For the CuCl-catalyzed terminal
diamination of (E)-1-phenyl-1,3-butadiene (4d), similar reaction
rates were also observed when [4d]0 varied from 0.10 to 0.60 M
(Figure 5). These results indicate that the potential involvement
of copper-diene complexes has little affect on the overall kinetic
profile, and the concentration of diene 4c or 4d has negligible
influence on the rate of diamination, which is consistent with the rate
law as expressed in eqs 5 and 6. The fact that the diamination is first
order in N,N-di-t-butyldiaziridinone (1) (Figures 1 and 2) and zero
order in diene 4(Figures 4 and 5) further indicates that the cleavage of
the NꢀN bond of 1 by the Cu(I) complex to form active Cu
species A and B is the rate-determining step of the diamination.
Effect of Total Cu Concentration. According to eqs 5 and 6,
the internal and terminal diaminations should be first order in
total Cu catalyst concentration. CuBr-catalyzed internal diami-
nation of 1-methoxy-1,3-butadiene (4c) and CuCl-catalyzed term-
inal diamination of (E)-1-phenyl-1,3-butadiene (4d) were then
investigated with variable amounts of initial Cu salts. The plots of
kobs against total Cu catalysts ([CuBr]0 and [CuCl]0) have found
to be straight lines, as shown in Figure 6 for the internal diamination
of 4c and in Figure 7 for the terminal diamination of 4d. This data
indicatethatthe internalandterminaldiaminations are firstorderin
total Cu catalyst as expressed in eqs 5 and 6.
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Table 4. Competition Experiments of CuCl-Catalyzed Terminal
EPR Studies. Intermediates A and B are proposed to be
involved in the Cu(I)-catalyzed diamination with N,N-di-t-
butyldiaziridinone (1) (Scheme 4). However, these intermedi-
ates could not be detected by the NMR spectroscopy. Elec-
tron paramagnetic resonance (EPR) spectroscopy was subse-
quently used to detect any radical species. A triplet with a 1:1:1
intensity ratio was observed when N,N-di-t-butyldiaziridinone
(1) was treated with CuCl-P(OPh)3 (1:1.5) at low tempera-
ture (Figure 8), which supports the existence of nitrogen radical
intermediate B.
Effect of Copper Salt and Ligand. The effect of copper salt on
the diamination was investigated in C6D6 using (E)-nona-1,3-diene
(4b) as substrate (Table 2). CuCl and CuBr exhibited the highest
catalytic activity for the diamination (Table 2, entries 1 and 2).
CuBr gave the highest regioselectivity for the internal diamina-
tion (Table 2, entry 2). Interestingly, CuCN gave only terminal
diamination product with moderate catalytic activity (Table 2,
entry 5). Apparently, the counteranion of the Cu(I) salt has a
dramatic effect on the reactivity and selectivity for the diamina-
tion. The counteranion could affect the reaction by altering the
relative stability and/or reactivity of four-membered Cu(III)
species A and Cu(II) radical species B.
Diamination of para-Substituted (E)-1-phenyl-1,3-butadienes 4a
b
entry
arylbutadiene (4)
ratio of [8]x/[8]H
1
2
3
4
5
6
X = Me, 4r
X = Ph, 4s
X = H, 4d
X = Cl, 4t
X = Br, 4u
X = NO2, 4v
1.18
1.33
1.00
1.13
1.08
1.55
a The competitive diaminations were carried out with 4d (1.0 mmol),
competing diene (4r, 4s, 4t, 4u, or 4v) (1.0 mmol), N,N-di-t-butyldia-
ziridinone (1) (0.10 mmol), and CuCl-P(OPh)3 (1:1.5) (0.020 mmol)
in C6D6 (1.0 mL) in a 3.0 mL vial under Ar at room temperature for 6 h.
1
b The ratio of [8]x/[8]H was determined by H NMR analysis of the
crude reaction mixture.
Figure 9. Plot of log(kX/kH) against radical substituent constant σ• for
the CuCl-catalyzed terminal diamination of para-substituted (E)-1-
phenyl-1,3-butadienes 4. The radical substituent constants σ• were
taken from ref 36b.
Figure 10. Hammett correlation of regioselectivity ([5]/[8]) for the
CuBr-catalyzed diamination of para-substituted (E)-1-phenyl-1,3-
butadienes 4. The radical substituent constants σ• were taken from ref
36b, and the substituent constants σp were taken from ref 38.
Table 5. Ratio of [5]/[8] for the CuBr-Catalyzed Diamination of para-Substituted (E)-1-Phenyl-1,3-butadienes 4a
entry
arylbutadiene (4)
[5]/[8]b
1
2
3
4
5
6
7
X = OMe, 4w
X = Me, 4r
X = Ph, 4s
X = H, 4d
X = F, 4x
0.94
0.80
0.29
0.37
0.37
0.21
0.18
X = Cl, 4t
X = Br, 4u
a The diamination was carried out with diene 4 (0.20 mmol), N,N-di-t-butyldiaziridinone (1) (0.24 mmol), and CuBr (0.020 mmol) in CDCl3 (0.80 mL)
in a 1.5 mL vial at 0 °C under Ar for 24 h. b The ratio of [5]/[8] was determined by 1H NMR analysis of the crude reaction mixture.
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Table 6. CuBr-Catalyzed Diamination of (E)-Nona-1,3-diene (4b) with Nitrogen Sources 1ꢀ3a
a The diamination was carried out with diene 4b (0.20 mmol), nitrogen source (1, 2, or 3) (0.30 mmol), and CuBr (0.020 mmol) in CDCl3 (0.4 mL) in a
1.5 mL vial at room temperature under Ar atmosphere for 20 h. b The conversion was based on diene 4b and determined by 1H NMR analysis of the
crude reaction mixture. c The ratio of [5]:[8] was determined by 1H NMR analysis of the crude reaction mixture.
Scheme 8
Various ligands were also investigated for the Cu(I)-catalyzed
diamination of (E)-nona-1,3-diene (4b) (Table 3). Bidentate
phosphine, such as BINAP, was found to be an ineffective ligand
for the diamination (Table 3, entry 1). Monodentate ligands
exhibited good activity for the reaction (Table 3, entries 2ꢀ8).
The regioselectivity was also greatly influenced by the ligand. It
appears that electron-rich ligands, such as tris(4-methoxyphenyl)-
phosphine and tricyclohexylphosphine, favored terminal diami-
nation (Table 3, entries 3 and 5), whereas electron-deficient
ligands, such as tris(4-trifluoromethylphenyl)phosphine, favored
internal diamination (Table 3, entry 4). The Cuꢀligand ratio
was also investigated. Increasing the amount of ligand lowered
the regioselectivity for internal diamination product (Table 3,
entries 6ꢀ8). CuBr without ligand gave the highest regioselec-
tivity for internal diamination (Table 3, entry 9). The ligand
could influence the relative amount and/or reactivity of four-
membered Cu(III) species A and Cu(II) radical species
B, consequently affecting the regioselectivity of the diamina-
tion. Coordination of a ligand (particularly a bulky ligand such as
PCy3) to the Cu could increase the steric congestion around the
Cu and cause the equilibrium to shift toward the sterically less
crowded Cu(II) radical species B, favoring terminal diamination.
At the same time, coordination of a ligand to the Cu could
disfavor the formation of complex D and subsequent internal
diamination.
Substituent Effect. The diamination of various para-substituted
(E)-1-phenyl-1,3-butadienes was carried out using CuCl-P-
(OPh)3 (1:1.5) in C6D6. Under these reaction conditions, the
diamination occurred essentially only at the terminal double
bond, as judged by 1H NMR spectroscopy. As shown in Table 4,
the diamination was accelerated by both electron-donating and
electron-withdrawing substituents (Table 4, entries 1, 2, 4ꢀ6 vs
entry 3). The Hammett plot of log(kX/kH) against radical sub-
stituent constant σ• for the reaction gave a straight line as shown
in Figure 9,36,37 which is consistent with the radical mechanism
proposed for the terminal diamination, as shown in Scheme 4
[for the Hammett plot of log(kX/kH) against σp, see: Figure 9a in
Supporting Information].
The diamination of para-substituted (E)-1-phenyl-1,3-buta-
dienes was also carried out with 10 mol % CuBr as catalyst. Under
these reaction conditions, a mixture of internal and terminal
diamination products (5 and 8) was formed. As shown in Table 5,
in all these cases the terminal diamination product (8) was the
major product. However, the relative amount of internal diami-
nation product increased with the electron-donating capability of
the substituents. A good correlation was obtained in the Hammett
plot of the regioselectivity ([5]/[8]) against 0.23σ• + 0.77σp
(Figure 10) using the best-fit approach (for the Hammett plots of
the regioselectivity against σ• and σp, see: Figures 10a and 10b in
Supporting Information).36ꢀ38 The regioselectivity of the dia-
mination appears to be more sensitive to substituent constant σp
(77%) than to radical-based substituent constant σ•. The nega-
tive slope suggests that radical-stabilizing and electron-withdrawing
substituents decrease the ratio of internal to terminal diamination
([5]/[8]) and that the internal diamination of diene 4 with
Cu(III) species A (Scheme 4) is likely to be electrophilic in
nature.
Effect of Nitrogen Source. The diamination of (E)-nona-1,3-
diene (4b) was investigated with 10 mol % CuBr as catalyst using
different nitrogen sources (1, 2, and 3). These three nitrogen so-
urces displayed very different regioselectivity in the diamination
reaction. While N,N-di-t-butyldiaziridinone (1) gave high regio-
selectivity favoring internal diamination (Table 6, entry 1), N,N-
di-t-butyl-3-(cyanimino)-diaziridine (3) afforded essentially only
the terminal diamination product (Table 6, entry 3). The high
regioselectivity for terminal diamination exhibited by 3 is likely
due to the fact that the CN group can stabilize the radical Cu(II)
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species G, thus steering the reaction toward the terminal diamination
(Scheme 8). At the same time, higher content of radical species G
likely leads to more rapid decomposition of 3 via the radical pathway,
thus giving relatively lower conversion for the diamination (44%).
sources, and characterization data along with NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
’ CONCLUSION
Corresponding Author
yian@lamar.colostate.edu
Mechanistic studies have shown that the Cu(I)-catalyzed di-
amination of conjugated dienes proceeds via two distinct
mechanistic pathways (Scheme 4). The reaction begins with
the cleavage of the NꢀN bond of N,N-di-t-butyldiaziridinone
(1) by the Cu(I) catalyst to form four-membered Cu(III) species
A and Cu(II) radical species B, which are in rapid equilibrium.
For the internal diamination, Cu(III) species A coordinates with
conjugated diene 4 to form olefin-Cu complex D, which under-
goes migratory insertion and subsequent reductive elimination to
form internal diamination product 5 and regenerates the Cu(I)
catalyst. For the terminal diamination, nitrogen radical B adds to
the terminal double bond of conjugated diene 4 to form Cu(II)
allyl radical species C, which undergoes the subsequent CꢀN
bond formation to give terminal diamination product 8 and re-
generates the Cu(I) catalyst. The existence of nitrogen radical
intermediate B was supported by EPR spectroscopy.
Kinetic studies have shown that the diamination is first order
in N,N-di-t-butyldiaziridinone (1), zero order in olefin, and first
order in total Cu(I) catalyst, suggesting that the cleavage of the
NꢀN bond of 1 by the Cu(I) catalyst is the rate-determining
step. Studies with para-substituted 1-phenyl-1,3-butadienes have
shown that the Cu(I)-catalyzed terminal diamination was fa-
vored by both electron-donating and electron-withdrawing sub-
stituents. A good correlation of the Hammett plot with radical-
based substituent constants σ• supports the proposed radical
mechanism for the terminal diamination. The CuBr-catalyzed
diamination of para-substituted 1-phenyl-1,3-butadienes af-
forded a mixture of terminal and internal diamination products
(5 and 8). The regioselectivity ([5]/[8]) had a good Hammett
correlation with 0.23σ• + 0.77σp (Figure 10), suggesting the sub-
stituent constant σp contributes more to regioselectivity than the
radical-based substituent constant σ• does. The negative slope
indicates that the internal diamination with Cu(III) intermediate
A is electrophilic. Conjugated dienes with good radical-stabilizing
groups, such as 1-aryl-1,3-butadienes, are effective substrates for
terminal diamination. Electron-rich dienes favor the internal
diamination. Besides diene substrates, the competition between the
terminal and internal diamination is also dependent upon reaction
conditions, such as Cu(I) catalyst and ligand29 as well as the nitrogen
source. N,N-di-t-butyldiaziridinone (1) is the most regioselective
nitrogen source for the CuBr-catalyzed internal diamination of con-
jugated dienes, and N,N-di-t-butyl-3-(cyanimino)-diaziridine
(3) exhibits the highest regioselectivity for terminal diamination.
The current mechanistic studies have shown that Cu(III) and
Cu(II) species can coexist in rapid equilibrium in the catalytic cycle of
the diamination. The Cu(III) species accounts for a concerted
reaction pathway leading to internal diamination, whereas the Cu(II)
species accounts for a radical reaction pathway leading to terminal
diamination. The extent of the involvement of the Cu(III) or Cu(II)
species depends upon reaction conditions and substrates used.
’ ACKNOWLEDGMENT
We are grateful for the generous financial support from the
General Medical Sciences of the National Institutes of Health
(GM083944-04).
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’ ASSOCIATED CONTENT
S
Supporting Information. Procedures for diamination, ki-
b
netic studies, EPR study, studies of substituent effect and nitrogen
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