Remote C-H bond functionalization reveals the distance-dependent isotope effect

Article abstract of DOI:10.1016/j.tet.2008.03.026

Iodination of remote aryl C-H bonds has been achieved using palladium acetate as the catalyst and iodoacetate (IOAc) as the oxidant. Systematic kinetic isotope studies imply a mechanistic regime shift as the number of bonds separating the directing heteroatom and the target C-H bond increases. Both isotope and electronic effects observed in remote C-H bond activation are consistent with an electrophilic palladation pathway in which the initial palladation is slower than the C-H bond cleavage.

Full text of DOI:10.1016/j.tet.2008.03.026

Tetrahedron 64 (2008) 6979–6987
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Remote C–H bond functionalization reveals the distance-dependent
isotope effect
,
Jiao-Jie Li a, Ramesh Giri b, Jin-Quan Yu b
*
a Department of Chemistry, MS015, Brandeis University, 415 South Street, MA 02454, USA
b Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodination of remote aryl C–H bonds has been achieved using palladium acetate as the catalyst and
iodoacetate (IOAc) as the oxidant. Systematic kinetic isotope studies imply a mechanistic regime shift as
the number of bonds separating the directing heteroatom and the target C–H bond increases. Both
isotope and electronic effects observed in remote C–H bond activation are consistent with an electro-
philic palladation pathway in which the initial palladation is slower than the C–H bond cleavage.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 January 2008
Received in revised form 5 March 2008
Accepted 7 March 2008
Available online 12 March 2008
Keywords:
Oxazoline
Palladium
Iodination
Iodoacetate
Remote C–H bond activation
1. Introduction
formation of five-membered palladacycles.16 Both isotope and
electronic effects have been used to investigate the mechanistic
Development of synthetically useful C–H bond activation re-
actions has received considerable interest in recent years.1 In par-
ticular, palladium catalysts have been extensively used in sp2 and
sp3 C–H bond functionalizations.2 While direct hydrocarbon C–H
functionalization remains a significant challenge,3 chelation-assis-
ted stoichiometric metal insertion into inert C–H bonds, namely
cyclometalation, is relatively well-established.4 C–H cleavages di-
rected by heteroatom-containing functional groups such as ox-
imes,5 oxazolines,6 pyridines,7 and amides8 have been extensively
explored. Various approaches using simple functionalities such as
N-Boc,9 carboxyl,10,11 and amino12 groups as directing groups have
also been developed. These chelates share a common feature of
forming a five-membered palladacycle with the proximal C–H
bonds separated by three bonds from the coordinating atoms as
a prelude to the subsequent functionalization.13 However, palla-
dium-catalyzed activation of C–H bonds farther away from the
directing group remains a difficult problem. Activation of such re-
mote C–H bonds would require the formation of six- or higher-
membered palladacycles, hitherto only little is known in the realm
of chelation-assisted palladium-catalyzed C–H bond functionali-
zations (Scheme 1).14,15 Furthermore, the mechanism of palladium-
catalyzed C–H bond activation has primarily focused on the
subtleties. However, lack in the general methodology to function-
alize remote C–H bonds has prevented the evaluation of such
mechanistic pathways in the activation of C–H bonds that would
involve the formation of six- or higher-membered palladacycles.
Herein we report a palladium-catalyzed ortho-iodination of aryl
C–H bonds that are located four, five and six bonds away from the
directing heteroatom. Systematic kinetic isotope studies imply
a change in mechanism as the number of bonds separating the
directing heteroatom and the target C–H bond increases.
( )n
( )n
DG
H
DG
Pd(II)
DG
Pd(II)
Pd(II)
DG
n = 1, 2, 3
Pd(II)
H
1a
1
2
2a
current remote C-H activation
traditional C-H activation
DG = directing group
Scheme 1. Activation of remote C–H bonds.
Selective functionalizations of remote C–H bonds have repre-
sented a great challenge in organic synthesis since the term ‘remote
functionalization’ was coined by Breslow in the seventies.17 While
such processes are common to enzymes that anchor a functional
group and recognize a specific site of the substrate,18 these strate-
gies are rarely reported in solution chemistry where such principles
* Corresponding author. Tel.: þ1 858 784 7942; fax: þ1 858 784 7949.
E-mail address: yu200@scripps.edu (J.-Q. Yu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.026

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J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
may be applied. Crabtree et al.19 have recently uncovered a re-
markable example of molecular recognition by a synthetic catalyst
that selects a reaction site on carboxylic acid substrates through
hydrogen bonding mimicking enzymatic reactions. Directed C–H
activation has long been practiced for remote functionalization in
electrophilic20 radical processes without the assistance of metal
catalysts. Oxidation of specific remote C–H bonds on steroid skel-
etons is achieved via a radical relay mechanism by attaching an
iodoaryl template to the substrate.21 Corey and Hertler have de-
scribed an efficient and selective method for functionalizing a re-
mote C18 angular methyl group by the free radical chain
decomposition of an N-chloro-20-aminosteroid in acid solution.22
intermediates less stable and hence the reductive elimination
faster.35 Indeed the five-membered cyclopalladated Pd(IV) com-
plexes are remarkably stable and isolable.35 Thus, substrates with
the target C–H bonds separated from the directing group by four to
six bonds were selected to test for the palladium-catalyzed remote
C–H bond functionalization. Stirring the substrate 9 with 10 mol %
Pd(OAc)2 and 2 equiv of IOAc in CH2Cl2 at room temperature for 72 h
provided the selectively mono-iodinated product 9a in 95% isolated
yield through the activation of ortho-aryl C–H bonds involving a six-
membered palladacycle (Table 1, entry 5). The iodination protocol
was also applicable for the substrates 12 and 13 in which the target
C–H bonds are separated from the directing group by five and six
bonds, respectively (Table 1, entries 8–10). Although 2-tert-butyl-
4,4-dimethyloxazoline can be iodinated on the methyl group
through a five-membered palladacycle at mild temperature,6a the
aryl C–H bonds are preferred over the methyl C–H bonds in general
even if seven- and eight-membered palladacycles are involved.
The yields can be increased at the expense of the selectivity for
mono- and di-iodinations by raising the reaction temperature to
100 ꢀC (Table 1, entry 10). We also found that yields are improved
when sterically bulky oxazoline is employed as the directing group
(Table 2, entries 1–3).
´
Suarez reagent (I2/iodobenzene diacetate) has also been widely
used to functionalize remote C–H bonds in steroids where a hy-
droxyl23 or amide24 group functions as a radical inductor under
photochemical conditions. An alkylborane intermediate obtained
from the hydroboration of tetrasubstituted alkenes with BH3$THF
has been shown to intramolecularly activate a remote C–H bond.25
However, the remote activation of C–H bonds by transition metals
is very rare. Few examples of remote C–H bond activation by ‘na-
ked’ Feþ, Mnþ, Coþ, and Crþ ions (ligand and counterion-free) in the
gas phase have been reported by Schwarz26 where functional
groups such as nitrile,27 isonitrile,28 amine,29 ketone,30 alcohol,31
alkyne,32 and allene32c provide an anchor to the metal ions. Such an
inadequate investigation into transition metal-catalyzed remote C–
H bond activations provided the impetus to develop our iodination
reaction6c for remote functionalization.
2.2. Mechanistic investigation
Extensive effort has been invested in determining the mecha-
nistic pathway for the activation of C–H bonds leading to the for-
mation of metalacycles. However, the exact nature of the activation
step, especially whether it involves electrophilic activation, carbo-
palladation,36 oxidative addition,37 or s-bond metathesis,38 re-
mains the subject of debate. Ryabov et al. proposed an electrophilic
mechanism via the Wheland intermediate for the palladium-
promoted cyclometalation of dimethylbenzylamine in which the
acetate acts as an intramolecular base for deprotonation through
a six-membered transition state 18 (Scheme 3).16 A similar work on
imine cyclometalation has, however, suggested a four-membered
transition state 19.39
Canty and van Koten have proposed the likelihood of oxidative
addition of the aryl C–H bond to the electrophilic palladium(II) to
form a palladium(IV) intermediate in which the acetate may or may
not participate as a base.40 Crabtree has put forward the in-
termediacy of agostic C–H complex or transition state 20 in which
the sp2 C–H bond being broken assumes an out-of-plane formation
by partial rehybridization to sp3 (Scheme 4).41 The involvement of
an agostic C–H complex and the participation of the acetate as an
intramolecular base via a six-membered transition state have been
further supported by computational studies in the case of cyclo-
metalation by palladium acetate.42 Milstein et al. have indeed
characterized by X-ray analysis an h2 aromatic C–H agostic com-
plex, which can be deprotonated by weak organic bases to give the
corresponding cyclometalated product.43
Investigation into the mechanism of C–H bond activation by
palladium catalysts using physical organic approaches has pri-
marily focused on the formation of five-membered palladacycles.16
Both isotope and electronic effects have been used to support one
pathway over the others. Our current remote iodination protocol
has provided us an opportunity to evaluate these mechanistic
pathways to the palladium-catalyzed functionalization of remote
C–H bonds. We anticipated that the remote C–H bond activation
may go through a different pathway44 from that of the five-mem-
bered cyclopalladation process. We carried out a systematic intra-
molecular isotope effect on the ortho-iodination of substrates 21–
24 (Scheme 5). The large intramolecular isotope effect (kH/kD¼3.5)
with substrate 21 is consistent with the previous reports on
cyclopalladation reactions.15f,g,45 Interestingly, the value of the
intramolecular isotope effect gradually decreases to 1.0 when the
2. Results and discussion
2.1. Remote C–H bond activation
Recently, we found that the b-methyl groups of aliphatic carb-
oxylic acids could be iodinated via sp3 C–H bond activation under
mild conditions using oxazoline as the auxiliary and IOAc33 as the
terminal oxidant.6c Considering the broad utility of aryl iodides in
a variety of organic reactions,34 we anticipated that the ortho-io-
dinated aryl carboxylic acids could provide synthetically valuable
building blocks. However, the initial attempts to functionalize
simple oxazoline 3 derived from benzoic acid gave poor yields
under the standard reaction conditions (Scheme 2).6c We believe
that the five-membered palladacycle intermediate resulting from
ortho-palladation could be very stable and consequently not re-
active toward the oxidant. Accordingly, the reaction temperature
was increased to 100 ꢀC and the mono-iodinated product 3a was
obtained in 60% yield. Enhancing the steric bulkiness of the palla-
dacycle by using tert-butyl oxazoline 4 only increased the product
yield marginally.
I
10 mol% Pd(OAc)2
IOAc
N
Me
Me
N
Me
Me
CH2Cl2
O
O
22% yield at 24 °C
3
3a
60% yield at 100 °C
I
10 mol% Pd(OAc)2
IOAc
N
N
t-Bu
t-Bu
CH2Cl2, 24 °C
30% yield
O
O
4a
4
Scheme 2. Iodination of unactivated aryl C–H bonds.
We reasoned that six- or seven-membered cyclometalated
complexes could be more reactive since they would make Pd(IV)

J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
6981
Table 1
Pd-catalyzed iodination of remote aryl C–H bonds at room temperaturea
Entry
Substrate
Product
Yieldb (%)
I
I
Me
Me
N
O
Me
Me
N
O
5
5a
1
15
81
Me
Me
Me
Me
N
O
N
O
6
6a
2
3
4
5
I
Me
N
N
Me
7a
7
76 (91)c
Me
O
Me
O
Me
F
Me
F
I
Me
Me
N
Me
N
8
8a
86
Me
O
O
I
9
9a
Me
Me
Me
Me
N
N
95
O
O
I
Me
Me
Me Me
N
Me
10
N
Me
10a
6
7
72
Me
O
Me
O
I
Me
Me
O
Me
Me
O
Me
N
Me
N
11
11a
58 (65)c
Me
Me
Cl
Cl
Me
Me
Me
Me
Me
N
Me
N
12
12a
13a
13a
8
9
40d
29
Me
Me
I
O
O
I
I
Et
Et
Et
Et
Et
Et
Me
N
Me
Me
N
13
Me
O
O
Et
N
N
Me
Me
Et
O
O
Me
Me
N
13
10
87e (a/b 2:1)
I
Et
Et
O
Me
Me
13b
I
a
Pd(OAc)2 (10 mol %), IOAc (2 equiv), 24 ꢀC, 72 h.
Isolated yield.
In parenthesis: microwave, 100 ꢀC, 2 h.
Unidentified side product (30%).
Condition: 100 ꢀC, 24 h.
b
c
d
e
C–H bonds are further away from oxazoline groups as shown by
substrates 21–24; a clear indication of the mechanistic regime shift
for the activation of remote C–H bonds.
bond activation (Fig. 1) in which the directing group is independent
of any electronic perturbation in the aryl moiety. The negative slope
of the Hammett plot (s¼ꢁ1.6) with substrate 16 (kH/kD¼1.5) and its
derivatives 25–27 indicates that electron-donating groups facilitate
the cyclometalation process in the activation of the remote C–H
bonds (Fig. 2).
The large value of the intramolecular isotope effect alone is in-
sufficient to define whether a particular type of mechanism, such as
an electrophilic activation or carbopalladation, is operative in the
functionalization of proximal C–H bonds since the initial pallada-
tion process can be reversible and faster than the C–H bond
cleavage in both cases. An alternative mechanism for the
While this intriguing data may prompt a number of in-
terpretations, we further carried out a brief study on electronic
effects in the parent substrate 16 (Scheme 6). Previous study of
electronic effects on C–H bond activation has focused on those
substrates in which the coordinating ability of the directing group
is also influenced by the substituents on the aryl ring.45 This
influence could complicate the interpretation of the electronic
effects. The current remote C–H activation protocol has allowed an
unprecedented investigation into the electronic effects on C–H

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J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
Table 2
Pd-catalyzed iodination of remote aryl C–H bonds at room temperature using chiral oxazolinea
Entry
Substrate
Product
Yieldb (%)
I
N
O
14a
t-Bu
N
O
14
t-Bu
t-Bu
1
85c (a/b 4:1)
I
I
N
O
14b
t-Bu
t-Bu
I
I
N
O
N
O
14
14b
2
3
77d
N
O
N
t-Bu
t-Bu
15
15a
79e
O
I
I
Me
Me
Me
O
Me
O
N
N
16
16a
t-Bu
t-Bu
4
5
a
70f
38
I
I
Et
Et
Et
Et
O
N
N
17
17a
t-Bu
t-Bu
O
Pd(OAc)2 (10 mol %), IOAc (2 equiv), 24 ꢀC, 72 h.
b
c
d
e
f
Isolated yield.
IOAc (0.6 equiv), 50 h.
16 h.
24 h, 24 ꢀC, 16 h.
IOAc (0.5 equiv).
a high degree of freedom and the reaction system would have to
compensate for the high entropy cost to bring the target C–H bond
in proximity to the palladium. In other words, the palladation
process during the electrophilic activation of the remote C–H bond
Me
N
Me
OAc
N
X
L
δ+
Pd
O
Pd
H
Me
O
H
O
O
H
Me
I
18
19
H
kH / kD = 3.5
Scheme 3. Deprotonation by intramolecular acetate as a base.
N
N
t-Bu
N
t-Bu
O
D
H
O
21
H(D)
21a
functionalization of proximal C–H bonds would be an oxidative
addition or s-bond metathesis. However, the complete loss of
intramolecular isotope effect in the functionalization of the remote
C–H bonds implies that the oxidative addition and s-bond me-
tathesis pathways, which involve a direct scission of the C–H bonds,
are less likely to be operative.46 Therefore, the electrophilic
mechanism can be invoked to explain the observed results. The
experimental observations can be rationalized based on the fact
that, unlike the proximal C–H bonds, the remote C–H bonds have
(D)H
k
H / kD = 2.9
N
t-Bu
t-Bu
O
O
D
I
22a
22
H
Me
H(D)
Me
Me
O
Me
k
H / kD = 1.5
N
N
t-Bu
t-Bu
D
H
I
O
23
23a
H
I
M
N
Et
Et
Et
Et
kH / kD = 1.0
N
N
t-Bu
t-Bu
O
O
H(D)
24a
D
20
24
Scheme 4. Agostic C–H complex.
Scheme 5. Isotope effects on proximal and remote C–H bond activation.

J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
6983
X
3. Conclusions
X
10 mol% Pd(OAc)2
IOAc
CH2Cl2, 24 °C
Me
Me
O
Me
Me
O
N
N
Iodination of aryl C–H bonds located four, five or six bonds away
from the directing group has been achieved using palladium ace-
tate as the catalyst and IOAc as the oxidant. The current remote
iodination protocol has allowed an unprecedented investigation
into the mechanism of remote C–H bond activation. Systematic ki-
netic isotope studies imply a mechanistic regime shift as the num-
ber of bonds separating the directing heteroatom and the target C–H
bond increases. Although the mechanisms for the activation of
proximal C–H bonds are still uncertain, our experimental results
suggest that an electrophilic pathway in which the initial pallada-
tion is slower than the C–H bond cleavage can be operative in the
palladium-catalyzed functionalization of remote aryl C–H bonds.
t-Bu
t-Bu
I
16, X = H
25, X = Me
26, X = Cl
16a, X = H
25a, X = Me
26a, X = Cl
27a, X = CF3
27, X = CF3
Scheme 6. Iodination of substrates with substituents meta to the target C–H bonds.
40
25(Me)
16(H)
26(Cl)
27(CF3)
35
30
25
20
15
10
5
4. Experimental
4.1. General experimental
Solvents were obtained from Acros and used directly without
further purification. 1H and 13C NMR spectra were recorded on
a Varian instrument (400 and 100 MHz, respectively) and internally
referenced to the SiMe4 signal. Exact mass spectra for new com-
pounds were recorded on a VG 7070 high-resolution mass spec-
trometer. Analytical GC–MS was performed on a Hewlett–Packard
G1800C instrument connected to an electron ionization detector
using an MS-5 GC column (30ꢂ0.25 mm). Infrared spectra were
recorded on a Perkin–Elmer FT-IR Spectrometer.
Carboxylic acids were purchased from Aldrich and Acros, and
were used as received without further purification. PhI(OAc)2 was
procured from Acros. Pd(OAc)2 and I2 were received from Aldrich.
The carboxylic acids for substrates 12, 16, and 25–27 were prepared
by [1,3] sigmatropic rearrangement of the corresponding ketene
silyl acetals and subsequent hydrolysis.47 Carboxylic acids for sub-
strates 13 and 17 were prepared by ethylation48 of 4-phenylbutyric
acid.
0
0
1
2
3
4
5
Reaction time (h)
6
7
8
Figure 1. Electronic effect on the rate of remote C–H bond activation.
0.2
4.2. Preparation of oxazoline substrates
25(Me)
0.1
Carboxylic acids were converted to their acid chlorides using
either oxalyl chloride47 (3, 4, 6, 9, and 10) or thionyl chloride49 (5, 7,
8, 11–17, and 25–27). The acid chlorides were then reacted with
2-amino-2-methyl-1-propanol or (S)-tert-leucinol to form am-
ides,50 which were subsequently cyclized to oxazolines using
triphenylphosphine.51
16(H)
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.1
0
0.1
0.2
0.3
0.4
0.5
y = -1.6044x + 0.0361
2 = 0.9953
4.3. General procedure for palladium-catalyzed ortho-
iodination of remote C–H bonds
R
Oxazoline (0.2 mmol) was placed in a 20-mL scintillation vial
and dissolved in CH2Cl2 (1 mL). Palladium acetate (4.4 mg,
0.02 mmol), iodobenzene diacetate (64.4 mg, 0.2 mmol), and io-
dine (50.7 mg, 0.2 mmol) were added to the solution. The vial was
tightly sealed with a polypropylene lined cap and the resulting
violet solution was stirred at the specified temperature until black
palladium iodide precipitated out. The solvent was removed in
a rotary evaporator. The product was purified by silica gel column
chromatography eluting first with hexane to remove iodine and
iodobenzene, and then with ethylacetate/hexane 1:20.
26(Cl)
27(CF3)
m
Microwave-assisted protocol: in a 20-mL septum-capped micro-
wave vial (Microwave model: DiscoverÒ LabMateÔ), oxazoline
(0.2 mmol), palladium acetate (2.2 mg, 0.01 mmol), iodobenzene
diacetate (64.4 mg, 0.2 mmol), and iodine (50.7 mg, 0.2 mmol)
were dissolved in CH2Cl2 (1 ml) under atmospheric air. The vial was
stirred at 100 ꢀC for 2 h at 100 W. The solvent was removed in
a rotary evaporator. The product was purified by silica gel column
Figure 2. Hammett plot in the iodination of remote C–H bonds.
is likely to be slower than C–H cleavage. The negative slope of the
Hammett plot (s¼ꢁ1.6) with substrate 16 (kH/kD¼1.5) and its de-
rivatives 25–27 further indicates that the electrophilic palladation
can be operative for the activation of the remote C–H bonds.

6984
J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
chromatography eluting first with hexane to remove iodine and
iodobenzene, and then with ethylacetate/hexane 1:20.
chromatography. 1H NMR (400 MHz, CDCl3) d 1.33 (s, 6H), 1.65–1.75
(m, 2H), 1.83–1.95 (m, 2H), 2.13–2.23 (m, 2H), 2.56–2.66 (m, 2H),
3.96 (s, 2H), 6.74 (td, J¼8.2, 3.2 Hz, 1H), 7.12 (dd, J¼11.0, 3.0 Hz, 1H),
7.85 (dd, J¼8.6, 6.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 24.4, 28.0,
37.8, 54.7, 67.3, 79.5, 91.2 (d, JF¼3.8 Hz, 1C), 115.5 (d, JF¼49.4,
22.8 Hz, 1C), 143.0 (d, JF¼7.5 Hz, 1C), 148.6 (d, JF¼6.9 Hz, 1C), 161.4,
163.8, 168.5; IR (neat) n 2963, 2872, 1656, 1596, 1577, 1456, 1271,
1015, 1002, 878, 864, 809 cmꢁ1; HRMS (EI) calcd for C16H20FINO
(MHþ) 388.0574, found 388.0574.
4.3.1. 2-(2-Iodophenyl)-4,4-dimethyl-4,5-dihydrooxazole (3a)
Palladium iodide precipitated out at 72 h and 3a was obtained as
an orange-red oil (13.5 mg, 22% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.43 (s, 6H), 4.15 (s,
2H), 7.10 (td, J¼7.6, 1.6 Hz, 1H), 7.37 (td, J¼7.2, 1.2 Hz, 1H), 7.57 (dd,
J¼7.6, 1.4 Hz, 1H), 7.90 (dd, J¼8, 1.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 28.2, 68.2, 79.4, 94.7, 127.8, 130.5, 131.5, 134.2, 140.1, 162.8;
IR (neat) n 2918, 1656, 1585, 1462, 1308, 1082, 1016, 963 cmꢁ1
;
4.3.7. 4,5-Dihydro-2-(1-(2-iodophenyl)cyclohexyl)-4,4-
dimethyloxazole (9a)
HRMS (EI) calcd for C11H13INO (MHþ) 302.0042, found 302.0027.
Palladium iodide precipitated out at 72 h and 9a was obtained as
a pale yellow solid (72.7 mg, 95% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.34 (s, 6H), 1.40–1.61
(m, 4H), 1.74–1.85 (m, 2H), 2.17–2.26 (m, 2H), 2.36–2.45 (m, 2H),
3.92 (s, 2H), 6.88 (td, J¼7.5, 1.6 Hz, 1H), 7.34 (t, J¼7.8 Hz, 1H), 7.50
(dd, J¼8.4, 1.6 Hz, 1H), 7.96 (dd, J¼7.8, 1.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 22.6, 25.8, 28.1, 34.6, 46.7, 67.2, 78.7, 96.8, 127.8,
128.0, 128.7, 143.0, 145.3, 168.7; IR (neat) n 2929, 2863, 1655, 1462,
1452, 1363, 1249, 1112, 1004, 975 cmꢁ1; HRMS (EI) calcd for
4.3.2. (S)-4-tert-Butyl-2-(2-iodophenyl)-4,5-dihydrooxazole (4a)
Palladium iodide precipitated out at 72 h and 4a was obtained as
an orange-red oil (19.7 mg, 30% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.02 (s, 9H), 4.13 (dd,
J¼10, 8.4 Hz,1H), 4.26 (t, J¼8.2 Hz, 1H), 4.39 (dd, J¼10.4, 8.4 Hz, 1H),
7.098 (td, J¼7.6,1.7 Hz,1H), 7.37 (t, J¼7.6 Hz,1H), 7.62 (dd, J¼7.2, 2 Hz,
1H), 7.93 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.1, 34.1,
69.0, 76.8, 94.7,127.8,130.7,131.5,133.9,140.5,163.7; IR (neat)n 2955,
1658, 1586, 1477, 1353, 1305, 1244, 1095, 1014, 963, 903, 760 cmꢁ1
HRMS (EI) calcd for C13H17INO (MHþ) 330.0355, found 330.0342.
;
C
17H23INO (MHþ) 384.0824, found 384.08411.
4.3.8. 2-(2-(2-Iodophenyl)propan-2-yl)-4,4-dimethyl-4,5-
dihydrooxazole (10a)
4.3.3. 2-(1-(2-Iodophenyl)cyclopropyl)-4,4-dimethyl-4,5-
dihydrooxazole (5a)
Palladium iodide precipitated out at 72 h and 10a was obtained
as an orange-red oil (49.7 mg, 72% yield) after purification by col-
umn chromatography. 1H NMR (400 MHz, CDCl3) d 1.33 (s, 6H), 1.73
(s, 6H), 3.97 (s, 2H), 6.91 (td, J¼7.6, 1.7 Hz, 1H), 7.35 (td, J¼7.6, 1.2 Hz,
1H), 7.43 (dd, J¼8.0,1.2 Hz,1H), 7.94 (dd, J¼8.0,1.2 Hz,1H); 13C NMR
(100 MHz, CDCl3) d 27.8, 28.0, 43.6, 67.3, 79.56, 97.7, 127.1, 128.3,
128.3, 142.3, 146.2, 169.9; IR (neat) n 2973, 2889, 1658, 1462, 1384,
1363, 1296, 1112, 1008, 974, 931, 757 cmꢁ1; HRMS (EI) calcd for
Palladium iodide precipitated out at 72 h and 5a was obtained as
an orange-red oil (10.2 mg, 15% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.18 (s, 2H), 1.26 (s,
6H), 1.73 (s, 2H), 3.88 (s, 2H), 6.94–7.01 (m, 1H), 7.30–7.35 (m, 2H),
7.85 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 18.0, 28.2, 28.6,
67.2, 79.6, 103.5, 128.0, 128.9, 131.8, 139.5, 143.2, 166.7; IR (neat) n
2967, 2927, 1655, 1498, 1364, 1329, 1192, 1137, 1082, 933 cmꢁ1
HRMS (EI) calcd for C14H17INO (MHþ) 342.0355, found 342.0340.
;
C
14H19INO (MHþ) 344.0511, found 344.0499.
4.3.4. 4,5-Dihydro-2-(1-(2-iodophenyl)cyclopentyl)-4,4-
dimethyloxazole (6a)
4.3.9. 2-(2-(4-Chloro-2-iodophenyl)propan-2-yl)-4,4-dimethyl-
4,5-dihydrooxazole (11a)
Palladium iodide precipitated out at 72 h and 6a was obtained as
a pale yellow solid (59.5 mg, 81% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.31 (s, 6H), 1.64–1.70
(m, 2H),1.82–1.92 (m, 2H), 2.18–2.28 (m, 2H), 2.57–2.67 (m, 2H), 3.91
(s, 2H), 6.90 (td, J¼7.3,1.9 Hz,1H), 7.32 (td, J¼7.6,1.2 Hz,1H), 7.38 (dd,
J¼8.0, 1.6 Hz, 1H), 7.94 (dd, J¼7.8, 1.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 24.5, 28.0, 37.8, 54.7, 67.2, 79.5, 98.6,127.7,127.7,128.1,142.1,
146.0,169.0; IR (neat) n 2932,1655,1468,1120, 971 cmꢁ1; HRMS (EI)
calcd for C16H21INO (MHþ) 370.0668, found 370.0666.
Palladium iodide precipitated out at 25 ꢀC after 48 h and 11a
was obtained as an orange-red oil (44.1 mg, 58% yield) after puri-
fication by column chromatography. The title compound 11a was
also obtained in 65% isolated yield by heating the reaction mixture
at 100 ꢀC for 2 h under microwave. 1H NMR (400 MHz, CDCl3) d 1.32
(s, 6H), 1.70 (s, 6H), 3.97 (s, 2H), 7.31–7.33 (m, 2H), 7.93 (d, J¼2 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 27.8, 28.0, 43.3, 67.4, 79.6, 97.5,
127.7, 128.2, 132.9, 141.4, 144.9, 169.5; IR (neat) n 2926, 2855, 1660,
1364, 1295, 1125, 1110, 1022, 974, 817 cmꢁ1; HRMS (EI) calcd for
C
14H18ClINO (MHþ) 378.0122, found 378.0114.
4.3.5. 2-(1-(2-Iodo-4-methylphenyl)cyclopentyl)-4,4-dimethyl-4,5-
dihydrooxazole (7a)
4.3.10. 2-(1-(2-Iodophenyl)-2-methylpropan-2-yl)-4,4-dimethyl-
4,5-dihydrooxazole (12a)
Palladium iodide precipitated out at 25 ꢀC after 72 h and 7a was
obtained as an orange-red oil (58.5 mg, 76% yield) after purification
by column chromatography. The title compound 7a was also
obtained in 91% isolated yield by heating the reaction mixture at
100 ꢀC for 2 h under microwave. 1H NMR (400 MHz, CDCl3) d 1.31 (s,
6H), 1.60–1.73 (m, 2H), 1.79–1.91 (m, 2H), 2.15–2.24 (m, 2H), 2.25 (s,
3H), 2.54–2.65 (m, 2H), 3.91 (s, 2H), 7.11 (d, J¼7.6 Hz, 1H), 7.25 (d,
J¼8.0 Hz, 1H), 7.78 (s, 1H); 13C NMR (100 MHz, CDCl3) d 20.1, 24.4,
28.03, 37.9, 54.3, 67.2, 79.5, 98.5, 127.3, 128.5, 138.0, 142.6, 142.9,
169.2; IR (neat) n 2962, 2872, 1654, 1478, 1460, 1363, 1192, 1137,
1003, 965, 813 cmꢁ1; HRMS (EI) calcd for C17H23INO (MH)þ
384.0824, found 384.0832.
Palladium iodide precipitated out at 72 h and 12a was obtained
as a pale yellow oil (28.6 mg, 40% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 1.26 (s, 6H), 1.27 (s,
6H), 3.11 (s, 2H), 3.96 (s, 2H), 6.87 (t, J¼7.6 Hz, 1H), 7.15–7.25 (m,
2H), 7.83 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.1, 28.7,
38.8, 48.9, 67.2, 79.1, 103.2, 128.0, 128.3, 130.5, 130.6, 140.0, 170.66;
IR (neat) n 2929, 2358, 1560, 1496, 1456, 1266, 876, 668 cmꢁ1; GC–
MS (Mþ) found 357.
4.3.11. 2-(3-Ethyl-1-(2-iodophenyl)pentan-3-yl)-4,4-dimethyl-4,5-
dihydrooxazole (13a)
Palladium iodide precipitated out at 25 ꢀC after 72 h and 13a
was obtained as pale yellow oil (23.2 mg, 29% yield) after purifi-
cation by column chromatography. The title compound 13a was
also obtained in 58% isolated yield by heating the reaction mixture
at 100 ꢀC for 24 h. Diiodinated product 13b was also observed in
4.3.6. 2-(1-(3-Fluoro-2-iodophenyl)cyclopentyl)-4,4-dimethyl-4,5-
dihydrooxazole (8a)
Palladium iodide precipitated out at 72 h and 8a was obtained as
an orange-red oil (66.8 mg, 86% yield) after purification by column

J.-J. Li et al. / Tetrahedron 64 (2008) 6979–6987
6985
29% yield by 1H NMR and was not isolated. 1H NMR (400 MHz,
4.3.16. (S)-4-tert-Butyl-2-(3-ethyl-1-(2-iodophenyl)pentan-3-yl)-
CDCl3) d 0.87 (t, J¼7.6 Hz, 6H), 1.30 (s, 6H), 1.68 (q, J¼7.6 Hz, 4H),
1.74–1.80 (m, 2H), 2.55–2.62 (m, 2H), 3.93 (s, 2H), 6.86 (t, J¼7.4 Hz,
1H), 7.15–7.24 (m, 2H), 7.78 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 8.2, 26.5, 28.7, 34.7, 35.6, 43.2, 67.0, 78.6,100.3,127.6,128.4,
129.4, 139.4, 145.3, 169.4; IR (neat) n 2927, 2361, 1557, 1496, 1454,
1259, 1049, 874, 824, 668 cmꢁ1; GC–MS (Mþ) found 399. The title
compound 13a was also obtained as a pale yellow oil (23.2 mg, 29%
yield) when the reaction was carried out at room temperature.
4,5-dihydrooxazole (17a)
Palladium iodide precipitated out at 72 h and 17a was obtained
as an orange-red oil (32 mg, 38% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 0.84–0.91 (m, 6H),
0.92 (s, 9H),1.63–1.72 (m, 4H),1.73–1.80 (m, 2H), 2.59–2.66 (m, 2H),
3.88 (dd, J¼12.0, 7.6 Hz, 1H), 4.04 (t, J¼8.2 Hz, 1H), 4.16 (dd, J¼10.4,
8.4 Hz, 1H), 6.86 (td, J¼7.6, 2.0 Hz, 1H), 7.16–7.25 (m, 2H), 7.78 (dd,
J¼7.8, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 8.4, 26.8, 26.8, 33.6,
35.1, 35.7, 43.5, 67.9, 75.7, 100.3, 127.6, 128.4, 129.5, 139.4, 145.5,
4.3.12. (S)-4-tert-Butyl-2-(1-(2-iodophenyl)cyclopropyl)-4,5-
dihydrooxazole (14a)
170.7; IR (neat) n 2961, 2902, 1658, 1466, 1363, 1122, 984 cmꢁ1
;
HRMS (EI) calcd for C20H31INO (MHþ) 428.1450, found 428.1440.
The title compound 14a was obtained when the reaction was
carried out with 0.6 equiv of IOAc under the standard reaction con-
ditions. Palladium iodide precipitated out at 50 h and 14a was
obtained as a pale yellow solid (48.1 mg, 65% yield) along with 14b
(12.6 mg, 17.1% yield) after purification by column chromatography.
1H NMR (400 MHz, CDCl3) d 0.87 (s, 9H),1.12–1.19 (m,1H),1.20–1.28
(m, 1H), 1.67–1.75 (m, 1H), 1.76–1.84 (m, 1H), 3.79 (dd, J¼10, 6.8 Hz,
1H), 4.00–4.13 (m, 2H), 6.97 (td, J¼7.1, 2.6 Hz,1H), 7.28–7.35 (m, 2H),
7.85 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 18.6, 26.0, 28.7,
34.0,69.3,75.6,103.0,128.0,128.8,132.3,139.4,143.3,168.1;IR(neat)n
2953, 2917, 1660, 1468, 1434, 1361, 1157, 1014, 983, 929 cmꢁ1; HRMS
(EI) calcd for C16H21INO (MHþ) 370.0668, found 370.0651.
4.4. General procedure for the measurement of kinetic
isotope effects on the rate of ortho-iodination
of remote aryl C–H bonds
The deuterated oxazoline substrates 21–24 were prepared as
follows.52 To a stirred solution of the corresponding mono-iodin-
ated oxazoline (0.2 mmol) and Cu2Cl2 (19.8 mg, 0.1 mmol) in
MeOH-d4 (1 ml) was added NaBD4 (1.2 mmol) in small portions
over a period of 30 min at 0 ꢀC. After stirring for 10 min, the
resulting black precipitate was removed by filtration and the filtrate
was concentrated in a rotary evaporator. The product was purified
by silica gel column chromatography eluting with ethylacetate/
hexane 1:20.
Deuterated oxazoline (0.1 mmol) was placed in a 20-mL scin-
tillation vial and dissolved in CH2Cl2 (1 mL). Palladium acetate
(2.2 mg, 0.01 mmol), iodobenzene diacetate (32.2 mg, 0.1 mmol),
and iodine (25.4 mg, 0.1 mmol) were added to the solution. The vial
was tightly sealed with a polypropylene lined cap and the resulting
violet solution was stirred at room temperature. The reactions were
terminated at 1, 2, 3, 4, 5, 6, and 7 h and the products were analyzed
by 1H NMR. The reactions were carried out in triplicates and the
average value was used for plotting the graph.
4.3.13. (S)-4-tert-Butyl-2-(1-(2,6-diiodophenyl)cyclopropyl)-4,5-
dihydrooxazole (14b)
The title compound 14b was also obtained as a pale yellow solid
(76 mg, 77% yield) when the reaction was carried out under the
standard condition using 2.0 equiv of IOAc. 1H NMR (400 MHz,
CDCl3) d 0.88 (s, 9H), 1.17–1.30 (m, 2H), 1.97–2.09 (m, 2H), 3.80 (dd,
J¼9.6, 6.8 Hz, 1H), 4.03–4.14 (m, 2H), 6.59 (t, J¼8.0 Hz, 1H), 7.88 (m,
2H); 13C NMR (100 MHz, CDCl3) d 25.3, 25.9, 33.1, 34.1, 69.3, 75.7,
103.4, 103.6, 129.9, 140.0, 144.0, 166.7; IR (neat) n 2952, 2898, 1659,
1539, 1475, 1415, 1360, 1160, 1101, 981, 767 cmꢁ1; HRMS (EI) calcd
for C16H20I2NO (MHþ) 495.9634, found 495.9614. The title com-
pound 14b was also obtained as a pale yellow solid (76 mg, 77%
yield) when the reaction was carried out under the standard con-
dition using 2 equiv of IOAc.
4.5. General procedure for the measurement of the electronic
effects on the rate of ortho-iodination of remote aryl C–H
bonds and the Hammett plot
4.3.14. (S)-4-tert-Butyl-2-(20,60-diiodobiphenyl-2-yl)-4,5-
dihydrooxazole (15a)
Oxazoline substrate 16, 25, 26 or 27 (0.1 mmol) was placed in
sealed NMR tubes and dissolved in CD2Cl2 (1 mL). Palladium acetate
(2.2 mg, 0.01 mmol), iodobenzene diacetate (32.2 mg, 0.1 mmol),
and iodine (25.4 mg, 0.1 mmol) were added to the solution. The
NMR tubes were tightly sealed and the resulting violet solution was
stirred at room temperature. The reactions were monitored at 1, 2,
3, 4, 5, 6, and 7 h by 1H NMR. The reactions were carried out in
triplicates and the average value was used for plotting the graph.
Palladium iodide precipitated out at 24 h and 15a was obtained
as a pale yellow solid (83.9 mg, 79% yield) after purification by
column chromatography. 1H NMR (400 MHz, CDCl3) d 0.74 (s, 9H),
3.84 (dd, J¼9.8, 8.6 Hz, 1H), 3.95 (t, J¼8.6 Hz, 1H), 4.12 (dd, J¼9.8,
8.6 Hz, 1H), 6.63 (t, J¼8.0 Hz, 1H), 7.08 (d, J¼8.0 Hz, 1H), 7.48 (td,
J¼7.6, 1.2 Hz, 1H), 7.56 (td, J¼7.5, 1.2 Hz, 1H), 7.86 (m, 2H), 7.99 (d,
J¼8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 25.9, 33.8, 68.1, 76.6,
98.0, 98.7, 126.3, 128.3, 129.4, 129.8, 130.1, 130.7, 138.1, 148.0, 150.2,
161.2; IR (neat) n 3059, 2955, 2902, 1654, 1540, 1477, 1416, 1352,
Acknowledgements
1249, 1191, 1040, 969, 901, 773 cmꢁ1
19H20I2NO (MHþ) 531.9634, found 531.9645.
; HRMS (EI) calcd for
We thank The Scripps Research Institute, Brandeis University
and the U.S. National Science Foundation (NSF CHE-0615716) for
financial support, and the Camille and Henry Dreyfus Foundation
for a New Faculty Award.
C
4.3.15. (S)-4-tert-Butyl-2-(1-(2-iodophenyl)-2-methylpropan-2-
yl)-4,5-dihydrooxazole (16a)
Palladium iodide precipitated out at 16 h and 16a was obtained
as a pale yellow oil (54.0 mg, 70% yield) after purification by column
chromatography. 1H NMR (400 MHz, CDCl3) d 0.88 (s, 9H), 1.27 (s,
6H), 3.13 (d, AB, J¼14.2 Hz, 2H), 3.84 (dd, J¼10, 7.2 Hz, 1H), 4.10 (t,
J¼8.0 Hz, 1H), 4.19 (t, J¼9.4 Hz, 1H), 6.83–6.89 (m, 1H), 7.17–7.25 (m,
2H), 7.83 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 25.7, 25.8,
33.8, 38.8, 48.6, 68.4, 75.4, 103.1, 127.8, 128.0, 130.5, 139.8, 141.5,
172.0; IR (neat) n 2956, 2927, 1662, 1466, 1364, 1124, 1010, 981,
917 cmꢁ1; HRMS (EI) calcd for C17H25INO (MHþ) 386.0981, found
386.0973.
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