Sterically controlled, palladium-catalyzed intermolecular amination of arenes

Article abstract of DOI:10.1021/ja4032677

We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)₂ as an oxidant in the presence of Pd(OAc) ₂ as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation.

Full text of DOI:10.1021/ja4032677

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Communication
Sterically Controlled, Palladium-Catalyzed Intermolecular Amination of Arenes
Ruja Shrestha, Paramita Mukherjee, Yichen Tan, Zachary Charles Litman, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4032677 • Publication Date (Web): 16 May 2013
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Sterically Controlled, Palladium-Catalyzed Intermolecular
Amination of Arenes
Ruja Shrestha,‡ Paramita Mukherjee,‡ Yichen Tan, Zachary C. Litman and John F. Hartwig*
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Department of Chemistry, University of California, Berkeley, CA 94720-1460, U.S.A.
Supporting Information Placeholder
as under metal-free10 conditions, have been reported. How-
ABSTRACT: We report the palladium-catalyzed amination
ever, the metal-catalyzed reactions are limited to intramolec-
of arenes to form N-aryl phthalimides with regioselectivity
controlled predominantly by steric effects. Mono-, di-, and
tri-substituted arenes lacking a directing group undergo ami-
nation reactions with moderate to high yields and high regi-
oselectivities from sequential addition of iodosoben-
zene(diacetate) as oxidant. This sterically derived selectivity
contrasts that for analogous arene acetoxylation.
ular processes (Eq 1)9a-c,11a-d or intermolecular processes with
reactivity and regioselectivity governed by a directing group
(Eq 2).9d-e,11a,e-f A few uncatalyzed intermolecular reactions
with substrates lacking a directing group have been report-
ed.10 These reactions provide high yields of amination prod-
ucts but require high reaction temperatures and, most rele-
vant to the work reported here, occur with regioselectivity
dictated by the electronic effects that control electrophilic
aromatic substitution (Eq 3).
One method to conduct sterically controlled aminations
of arenes is the combination of arene borylation12 and Chan-
Lam amination of the resulting arylboronate ester.13 A direct,
intermolecular amination of arenes with this steric control of
regioselectivity would avoid the arylboronate intermediate,
but such a process has not been reported (Eq 4).
Here, we report a palladium-catalyzed intermolecular oxi-
dative amination of mono-, di- and tri-substituted arenes
with regioselectivities guided by steric effects.14 The selectivi-
ty contrasts that for related palladium-catalyzed acetoxyla-
tion of arenes,15 suggesting that a different species cleaves the
C-H bond in the two classes of reactions.
The abundance of amines in medicine, agroscience, and
material science makes them valuable synthetic targets.1
Conventional methods for the synthesis of aromatic amines
involve nitration of arenes, followed by reduction.2 To miti-
gate the harsh reaction conditions associated with these early
methods, alternative approaches such as copper-catalyzed3
and palladium-catalyzed coupling reactions4 of amines with
aromatic halides or pseudohalides were developed. These
approaches have been used widely in academia5 and indus-
try,6 but these reactions require pre-functionalization of
arenes to aromatic halides. Thus the regioselectivity of the
reaction reflects the regioselectivity for halogenation of the
arene.
O
O
10 mol % Pd(OAc)2
10 mol % t-Bu3P
Intramolecular C-H Amination
+
HN
(5)
N
cat. [Pd] or [Cu]
2.0 equiv PhI(OAc)2
Benzene
100 °C, 24 h
R
R
(1)
O
O
oxidant, heat
30%
RHN
N
R
Previously, we reported palladium-catalyzed intramolecu-
lar aminations of aromatic C-H bonds with oxime esters to
form substituted indoles;9c however, an intermolecular ver-
sion of this reaction has not been observed. As part of studies
to develop an intermolecular variant, we observed the for-
mation of N-phenyl phthalimide in 30-40% yield in the pres-
ence of a palladium catalyst, phthalimide, and iodosoben-
zene(diacetate) as oxidant in benzene at 100 °C (Eq 5).
Intermolecular Ortho C-H Amination
DG
DG
cat. [Pd] or [Cu]
+ RNH2
(2)
(3)
NHR
oxidant, heat
Intermolecular Metal-Free C-H Amination
R
R
PhI(OAc)2
+ RNH2
140 °C
O
O
R
NHR
R = electron donating; ortho-, para-isomers
R = electron withdrawing; meta-isomer
HN
N
+/- 10 mol% Pd(OAc)2
+/- 10 mol% ligand
O
O
R
Intermolecular Metal-Catalyzed C-H Amination
+
or
or
(6)
R
R
cat. [Pd]
PhI(OAc)2
2.0 equiv oxidant
100 µL solvent
100 °C, 24 h
O O
S
O
O
+ RNH2
(4)
R
S
100 °C
HN
N
NHR
R = electron donating and withdrawing;
meta-, para- isomers
O
O
Therefore, a sterically controlled direct amination of aro-
matic C-H bonds would complement cross-coupling.7 The
direct amination of arenes with Cu8 and Pd9 catalysts, as well
0.1 mmol 0.01 mmol
R = Me, t-Bu, OMe, CF3
Encouraged by this result, a series of ligands, oxidants, and
solvents were investigated by high-throughput experimenta-
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Page 2 of 5
tion (HTE) methods to identify variable(s) that affect the
10 mol % t-Bu3P, or 10 mol % of Pd(OAc)2 and t-Bu3P to-
yield of amination product.16 The reactions of electron-rich
and electron-poor arenes with phthalimide and saccharin as
the nitrogen source were conducted in the presence of cata-
lytic amounts of Pd(OAc)2 and mono- and bi-dentate nitro-
gen based ligands, catalytic amounts of Pd(OAc)2 alone, or
no catalyst in polar and non-polar solvents at 100 °C (Eq 6).
gether after Pd-black had formed (5 h reaction time) also did
1
2
3
4
5
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7
8
not increase the yield of the amination product.
These results suggested that catalyst deactivation is not re-
sponsible for the modest yields. Likewise, addition of an ex-
tra equivalent of phthalimide at 5 h did not increase the yield
of the amination product.16 In contrast, addition of an addi-
tional 2 equiv of PhI(OAc)2 after 5 h of reaction time revert-
ed the Pd-black to a soluble palladium species and increased
the yield of amination product from 35% to 55% based on
phthalimide. Additions of two further portions of 2 equiv of
oxidant at 5 h intervals, gave 83% yield of N-phenyl
phthalimide product.16
Our data from HTE revealed six general features of the re-
action: 1) electron-rich arenes reacted in higher yields than
electron-poor arenes; trifluoromethylbenzene reacted in low
yield (10-20%) while toluene, anisole and tert-butylbenzene
reacted in modest yield (30-50%); 2) reactions of arenes
with phthalimide provided the desired amination product,
but the reactions with saccharin gave several byproducts hav-
ing the same mass as that of the desired amination product;17
3) iodosobenzene(diacetate) provided the highest yield of
amination product among the oxidants tested, 4) reactions
run in neat arene occurred in higher yields and with higher
selectivities than those run in a solvent; 5) the observed se-
lectivities were similar in the presence or absence of a ligand;
and 6) the selectivities of reactions run in a solvent (1,2-DCE
and MeCN providing high yields) were the same when run
in the presence of palladium catalysts as in the absence of
catalyst.
With the knowledge gained from high-throughput exper-
imentation, we refined the factors that control reaction yield.
The reactions were run using phthalimide as the nitrogen
source in neat benzene at 100 °C with catalytic amounts of
Pd(OAc)2 and t-Bu3P, with catalytic amounts of Pd(OAc)2
alone, and without a palladium catalyst. Figure 1 shows the
kinetic profiles of these reactions. The reaction with
Pd(OAc)2 alone occurred more slowly than that conducted
with Pd(OAc)2 and t-Bu3P. However, both the reactions
with and without ligand were complete within 3 h and
formed 35-45% yield of the amination product. Upon further
heating, no additional amination product formed. Instead,
Pd-black formed. Reactions run under metal-free conditions
were slow at 100 °C and provided only 10% of the N-aryl
imide after 6 h.10d
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With conditions to form the amination product in high
yield, we turned our attention to the primary goal of this
work: identifying whether a direct amination could be con-
ducted with sterically controlled regioselectivity. Conditions
developed for the amination of benzene were applied to the
reaction of toluene (Table 1). With two sequential additions
of 2 equiv of PhI(OAc)2 at 9 and 24 h reaction times, 70%
yield of the amination product was observed with a sterically
controlled regioselectivity of 1:9:8 (o:m:p, entry 1).18,19 Re-
actions run under similar conditions with Pd(OAc)2 as cata-
lyst in the absence of ligand occurred in a similar yield and
selectivity as reactions run in the presence of ligand (entries
2 and 1 respectively). This result is consistent with those
observed in high-throughput experimentation.
Table 1. Regioselective Amination of Toluenea
1) 10 mol% Pd(OAc)2
10 mol % t-Bu3P
2.0 equiv PhI(OAc)2 Me
1 mL toluene, 100 °C
O
Me
O
+
HN
2) Add 2.0 equiv
PhI(OAc)2 at 9, 24 h
N
O
O
0.1 mmol
Selectivityc
Entry Conditions
Yieldb
70%
(o:m:p)
1
2
3
As above
1:9:8
1:6:6
2:1:1
No t-Bu3P added
65%
No Pd(OAc)2 or t-Bu3P 42%
added
4
As entry
1
with
8
equiv 56%
1:13:13
PhI(OAc)2 added initially
without sequential addition
As entry 1, on benchtop
5
6
68%
1:7:6
1:3:4
As above, with 10 equiv 34%
toluene in 1 mL 1,2-DCE
7
8
As above, with 10 equiv 38%
toluene in 1 mL MeCN
1:3:3
1:1:1
As above, with 10 equiv 10%
toluene in 1 mL mesitylene
Figure 1. Comparison of amination of benzene with phthalimide in
the presence of catalytic amounts of Pd(OAc)2/t-Bu3P (Ÿ), catalytic
amounts of Pd(OAc)2 alone (n) and without a palladium catalyst (w).
a
Reactions were assembled in a nitrogen-filled glove box on 0.1
mmol scale with 1 mL toluene and run for 33 h total. b Corrected
GC yield vs dodecane internal standard. c Crude GC selectivity.18
Due to the shorter reaction time, we focused on reactions
catalyzed by the combination of Pd(OAc)2 and t-Bu3P to
determine if catalyst deactivation or consumption of
phthalimide or PhI(OAc)2 in an undesired pathway were
responsible for the lack of full conversion. Reactions con-
ducted with activated 3-, 4-, and 5-Å molecular sieves, acetic
acid and bases (such as Cs2CO3, NaOAc and CsOH) gave
the amination product in yields that were comparable to or
lower than the reactions run without these additives, imply-
ing that the catalyst was not affected by adventitious water or
the acetic acid product.16 Addition of 10 mol % Pd(OAc)2,
In contrast, the uncatalyzed reaction with sequential addi-
tion of oxidant occurred in low yield with selectivity derived
from electronic effects (o:m:p = 2:1:1, entry 3).10 The reac-
tion catalyzed by Pd(OAc)2 and t-Bu3P with 8 equiv of the
oxidant at the beginning of the reaction occurred in lower
yield (entry 4). Finally, the presence of oxygen or moisture
introduced from reactions assembled on the benchtop did
not affect the yield of the product, but led to a slightly lower
regioselectivity (entries 1 vs 5).20 Likewise, reactions con-
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ducted with toluene and phthalimide in a 10:1 ratio in 1,2-
bon-halogen bonds in mono-, di-, and tri-substituted arenes
(3-6, 8-14, 22-25) underwent the C-H amination reaction
without any observed proto-dehalogenation or C-X amina-
tion.4 In all cases, the reactions were selective for the less
hindered meta-, and para-isomers. In some cases, (12, 13,
15, 16, 18, 20, 21, 24,) recrystallization of a mixture of
meta- and para- isomers from MeOH/hexanes allowed for
isolation of a single isomer. It is noteworthy that the trans-
formations can be conducted on the benchtop, at the ex-
pense of a slight decrease in selectivity (Table 1, entries 1 vs
5).
DCE, MeCN or mesitylene as a solvent at 100 °C occurred in
lower yield and with a lower selectivity for m-, p-isomers vs
o-isomer (entries 6-8) than reactions run in neat arene. In
summary, the reaction conditions described in Table 1 entry
1 lead to the direct oxidative amination of a substituted arene
in high yield with high regioselectivity derived from steric
effects.14
1
2
3
4
5
6
7
8
Having identified conditions for the amination of a substi-
tuted arene with steric control, we examined the selectivity
for the amination of a variety of mono-, di-, and tri-
substituted arenes with phthalimide using catalytic amounts
of Pd(OAc)2 and t-Bu3P, catalytic amounts of Pd(OAc)2,
and without a palladium catalyst.16 In all cases, the yield and
regioselectivity of the metal-catalyzed reactions were higher
than those observed for the uncatalyzed reactions. Slightly
higher yields and selectivities were observed with added t-
Bu3P in some cases.
The scope of the reactions of tri-, di-, and mono-
substituted arenes under conditions with the catalyst derived
from Pd(OAc)2 and t-Bu3P is shown in Schemes 1 and 2.
Reactions of 1,2,3-trisubstituted arenes and symmetric 1,2-
disubstituted arenes (1-8) gave the less hindered products as
the major constitutional isomer. A single isomer was isolated
upon purification by silica gel column chromatography. In
these cases, the regioselectivity observed with the catalyst
derived from Pd(OAc)2 and t-Bu3P is the opposite of the
selectivity from the electronically controlled amination of
arenes under uncatalyzed thermal conditions.10
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Scheme 2. Scope of the sterically controlled amination
of unsymmetrical di-substituted arenes and mono-
substituted arenesa
Me
OMe
F
X
I
I
13
14
9, X = F; 75% (1:1:50:29)
10, X = Cl; 67% (1:1:19:19)
11, X = Br; 85% (0:0:1:2)
12, X = I; 51% (0:0:1:1)
o-Me:o-X:m-Me:m-X
83%
(1:1:5:0)
o-OMe:o-I:
m-OMe:m-I
57%
(0:0:1:7)
o-F:o-I:
m-I:m-F
Me
i-Pr
t-Bu
Me
Me
CO2Me
CO2Me
15
16
17
18
78%
19
90%
60%
52%
78%
1:10:9
o:m:p
(1:1:50:15)
o-Me:o-X:
m-X:m-Me
(1:1:4:17)
o-Me:o'-Me:
o-X:m-Me
1:13:13 1:40:30
o:m:p
o:m:p
Scheme 1. Scope of the sterically controlled amination
F
Br
I
OMe
CF3
Cl
OAc
of symmetric arenesa
1) 10 mol% Pd(OAc)2
10 mol% t-Bu3P
2.0 equiv PhI(OAc)2
5 mL arene, 100 °C
R1
R1
O
O
22
23
24
25
26
20
21
R2
R3
R2
R3
62%
1:10:6
o:m:p
76%
1:6:6
o:m:p
82%
1:5:5
o:m:p
72%
1:4:3
o:m:p
58%
1:8:9
o:m:p
61%
1:1:5
o:m:p
72%
1:30:11
o:m:p
+
HN
N
2) Add 2.0 equiv
PhI(OAc)2 at 9, 24 h
O
O
aSame as in Scheme 1.
0.5 mmol
Expansion of the scope of nitrogen source has been chal-
lenging. Studies of the reactions with imides possessing dif-
ferent electronic properties showed that the reactions of
phthalimide and 4-methylphthalimide occurred in similar
yields and selectivity, but reactions of the electron-poor im-
ides 4-chlorophthalimide or 3,4,5,6-tetrachlorophthalimide
and reactions of maleimide, succinimide or saccharin oc-
curred to low conversion. The reactions of amides or amines
in place of imides occurred to low conversion.16 Neverthe-
less, our current results demonstrate that commercially avail-
able phthalimide can be used to generate a wide range of
protected anilines22 from readily available aromatic com-
pounds.
The selectivity of this amination of arenes is clearly dis-
tinct from that of the related acetoxylations of arenes.15 Crab-
tree showed that the acetoxylation of toluene, phenyl acetate,
anisole, chlorobenzene and iodobenzene occurs to form pre-
dominantly the ortho- and para-substituted products.15a
Many studies since then have suggested that the C-H bond is
cleaved by a concerted metalation-deprotonation (CMD)
sequence.23 For the amination to occur with regioselectivity
distinct from that of the acetoxylation process, the species
that cleaves the C-H bond in the two reactions must be dis-
tinct, or the C-H bond cleavage step must be reversible and
the amination step is faster for the less hindered arylpalladi-
um intermediate than for the more hindered arylpalladium
X
Me
X
OMe
X
Me
Me Me
Me Me
Me
1
2
46%
(0:1)
o:m
3, X = F; 46% (0:1)
7, X = Me;
72% (1:87)
8, X = Cl;
57% (0:1)
o:m
46%
(0:1)
o:m
4, X = Cl; 69% (1:19)
5, X = Br; 52% (1:24)
6, X = I; 65% (1:19)
o:m
a
Reactions were assembled in a nitrogen-filled glove box in 20 mL
scintillation vials on 0.5 mmol scale with 10 mol % Pd(OAc)2/t-Bu3P
in 5 mL arene and 2.0 equiv of PhI(OAc)2 at the beginning of the reac-
tion. Another 2.0 equiv of PhI(OAc)2 were added at 9, and 24 h of the
reaction. The reactions were run for 33 h total. Yield represents isolat-
ed yield after silica gel column chromatography. Selectivities are re-
ported based on GC analysis after isolation.18
The reaction also occurred with unsymmetrical 1,2-
disubstituted arenes (9-15) to provide good yields of the
two amination products containing the phthalimide group
meta to both the substituents (Scheme 2). Under the devel-
oped conditions, 1,2-disubstituted arenes were more reactive
than the corresponding 1,3-disubstited arenes (15 vs 16).21
In addition, the catalytic amination reaction occurred with
electron-rich and electron-poor monosubstituted arenes
(17-26) to provide mono-amination products exclusively
(Scheme 2). Substrates with larger substituents on the arene
reacted with higher selectivity for amination of the less hin-
dered C-H bonds (17 vs 18 vs 19). Arenes containing car-
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measured the kinetic isotope effect (KIE) from the reaction
of a mixture of C6H6 and C6D6. The KIE from these experi-
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1
2
3
4
5
6
7
8
ments was 4.10
0.06, implying that the C-H bond is
cleaved irreversibly.24 Thus, the species that cleaves the C-H
bond in the acetoxylation and the amination is different.
Studies to compare CMD pathways for reactions of
phthalimidate and acetate complexes will be the subject of
future work.
In conclusion, we have developed a regioselective, inter-
molecular Pd-catalyzed oxidative amination of arenes with
phthalimide. Sequential addition of oxidant allows the reac-
tions to occur in good yield in neat arene. This process
points to an avenue to develop alternatives to palladium-
catalyzed amination of aryl halides and the potential to con-
duct sterically controlled amination without initial boryla-
tion of the arene. Further studies to expand the scope of ni-
trogen sources based on mechanistic data are ongoing.
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Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M.
J. Am. Chem. Soc. 2008, 130, 16184. (d) Mei, T.-S.; Wang, X.; Yu, J.-Q. J.
Am. Chem. Soc. 2009, 131, 10806. (e) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-
J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (f) Sun, K.; Li, Y.; Xiong, T.;
Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental proce-
dures, supplementary tables of data, and full characterization of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864.
(13) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007, 9,
761.
AUTHOR INFORMATION
(14) For Pd-catalyzed oxidative coupling of arenes with regioselectivity
controlled by steric effects see Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2007, 129, 11904.
Corresponding Author
jhartwig@berkeley.edu
(15) (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A. 1996, 108, 35.
(b) Dick, A. R.; Hall, K. H.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300. (c) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew.
Chem., Int. Ed. 2011, 50, 9409.
Author Contributions
‡These authors contributed equally.
(16) See Supporting Information for more details.
(17) More than three products with m/z expected for the desired ami-
nation product were observed. Currently we hypothesize the by-product to
be arylation of the aromatic ring on saccharin ortho to the sulfimide func-
tional group. Related sulfonamide functional group is known to be an excel-
lent directing group. See: (a) Watanabe, H.; Gay, R. L.; Hauser, C. R. J.
Org. Chem. 1968, 33, 900. (b) Watanabe, H.; Schwartz, R. A.; Hauser, C.
R.; Lewis, J.; Slocum, D. W. Can. J. Chem. 1969, 47, 1543. (c) Slocum, D.
W.; Jennings, C. A. J. Org. Chem. 1976, 41, 3653.
ACKNOWLEDGMENT
Acknowledgments are made to the National Science Founda-
tion for financial support through the Center for Enabling New
Technologies through Catalysis (CENTC) and Johnson-
Matthey for a gift of Pd(OAc)2. We thank Prof. William D.
Jones and Prof. Karen I. Goldberg for helpful discussions.
(18) The constitutional isomer ratios were determined by comparison
to the authentic products synthesized according to the literature protocol:
Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Bioorg. Med. Chem. 2004,
12, 327.
(19) Experiments conducted to probe the stability of ortho-amination
product suggest that the ortho-amination product is stable under the ami-
nation reaction conditions. See Supporting Information.
REFERENCES
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(20) Additional experiments suggest that the decrease in selectivity can-
not be attributed to ligand oxidation. See Supporting Information.
(21) This observation was consistent with the reactivity of other 1,3-
disubstituted vs 1,2-disubstituted arenes reported in Scheme 1. Compari-
son of the crude GC traces of reactions conducted with a mixture of 1,2-
disubstituted arenes and 1,3-disubsituted arenes suggest that both reactions
produce comparable amounts of acetoxylation products. This observation
implies that competitive acetoxylation of 1,3-disubsituted arene is not
responsible for the lower yield of amination products with the 1,3-
disubstituted substrates. See Supporting Information for the primary data.
(22) Green, T. W.; Wutz, P. G. M. In Protective Groups in Organic Syn-
thesis, Wiley-Interscience: New York, 1999, 564-566, 740-743.
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Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (c)
Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Ec-
havarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (d) Gorelsky, S. I.;
Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (e)
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
(2) (a) Larock, R. C. In Comprehensive Organic Transformations;
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tions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, p 699.
(5) (a) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.;
Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123,
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(6) (a) Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem.
2003, 68, 644. (b) Damon, D. B.; Dugger, R. W.; Scott, R. W.
WO2002088085 A2, 30.4.2001; (c) Damon, D. B.; Dugger, R. W.; Scott, R.
W. WO 2002088069 A2, 30.4.2001; (d) Damon, D. B.; Dugger, R. W.;
Hubbs, S. E.; Scott, J. M.; Scott, R. W. Org. Proc. Res. Dev. 2006, 10, 472.
(7) For reviews of C-H amination, see: (a) Mueller, P.; Fruit, C. Chem.
Rev. 2003, 103, 2905. (b) Davies, H. M. L.; Long, M. S. Angew. Chem.,
Int. Ed. 2005, 44, 3518. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
(24) The observed KIE is identical to that for acetoxylation reported in
ref. 15a and slightly lower than that determined for the acetoxylation prod-
uct under our reaction conditions with phthalimide (5.7 0.2). The KIE
for the amination of
a mixture of protiated and deuterated 1,2-
dichlorobenzene with phthalimide under the conditions we developed was
2.8 0.1.
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Three portions
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26 examples
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regioselectivity
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