Catalytic and stereoselective iodination of prochiral C-H bonds

Article abstract of DOI:10.1016/j.tetasy.2005.08.049

Oxazolines were employed as cyclic chiral directing groups for stereoselective C-H activation. Oxazoline-directed cleavage of the β-C-H bonds followed by reaction with I₂ gave a wide range of iodinated products. A large range of functional groups are tolerated. PdI₂ was isolated in the reaction and found to be converted to Pd(OAc)₂ upon treatment with a combination of I₂ and PhI(OAc)₂ in situ to achieve catalytic turnover. Diastereoselective iodination of prochiral C-H bonds were also investigated.

Full text of DOI:10.1016/j.tetasy.2005.08.049

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3502–3505
Catalytic and stereoselective iodination of prochiral C–H bonds
Ramesh Giri, Xiao Chen, Xue-Shi Hao, Jiao-Jie Li, Jue Liang,
Zi-Peng Fan and Jin-Quan Yu*
Department of Chemistry, Brandeis University, Waltham, MA 02454-9110, USA
Received 1 August 2005; accepted 29 August 2005
Available online 10 November 2005
Abstract—Oxazolines were employed as cyclic chiral directing groups for stereoselective C–H activation. Oxazoline-directed cleav-
age of the b-C–H bonds followed by reaction with I2 gave a wide range of iodinated products. A large range of functional groups are
tolerated. PdI2 was isolated in the reaction and found to be converted to Pd(OAc)2 upon treatment with a combination of I2 and
PhI(OAc)2 in situ to achieve catalytic turnover. Diastereoselective iodination of prochiral C–H bonds were also investigated.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
activation pathway to stereoselectively functionalize
sp3 C–H bonds in commonly used starting materials
remains a significant challenge.
Various approaches have been employed in order to
develop stereoselective C–H activation reactions.1 Ele-
gant syntheses of complex natural products have dem-
onstrated the power of C–H activation reactions.2 For
example, an oxazoline Schiff base complex (Me2PtL2)
was attached to a synthetic intermediate via an imine
linkage to dehydrogenate a remote ethyl group stoichio-
metrically and diastereoselectively in the synthesis of
(À)-rhazinilam.2a Recently, the well-established r-chela-
tion assisted stoichiometric C–H activation processes
have emerged into an exciting research area focused
on developing catalytic reactions.3 Cyclometallation
facilitated by pre-coordination to a r-chelating group
is one of the earliest observations of C–H activation.4
Activation of aryl C–H bonds directed by an ortho-
nitrogen chelating group to form dimeric cyclometal-
lated complexes has been extensively reviewed.5
Examples of cyclopalladation of aliphatic sp3 C–H
bonds to form the stable dimeric complexes have also
been observed.6 Interesting synthetic applications have
been also achieved based on a stoichiometric oxime
directed palladation, initially observed by Shaw in
1978.7 The mechanism of cyclometallation reactions
and application of palladacycles has been extensively
reviewed.8 Catalytic acetoxylation of C–H bonds using
O-methyl oxime as a chelating group has been recently
achieved.9 However, further exploitation of this C–H
From a viewpoint of synthetic utility, it is desirable to
develop chiral directing groups that can be readily
removed, after the C–H functionalization step, in order
to produce broadly useful compounds. Therefore, we
began to search for a combination of a removable chiral
directing group and a metal center that would form
reactive complexes and result in stereoselective C–H
cleavage. It is well established that r-chelation assisted
C–H activation takes place through a cyclic transition
state.8 We, therefore, reasoned that the use of a cyclic
chiral directing group could be advantageous in control-
ling the stereochemistry via a steric repulsion model
(Scheme 1).
stereogenic center
controls the
R2
R2
removable
linkage
R2
O
stereochemistry
R1
Me
R1
Me
Me
N
L
L
R1
M
H
3
tunable ligand
modulates the
reactivity
M
M
H
H
1
favored
2
disfavored
Scheme 1. Control of stereoselectivity in C–H activation.
2. Results and discussion
When R1 is larger than the Me group, 1 is favored over 2
due to the less steric repulsion between Me and R2 in 1,
thereby controlling the stereoselectivity in the C–H
*
Corresponding author. Tel.: +1 781 736 5201; fax: +1 781 736
2516; e-mail: yu200@brandeis.edu
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.049

R. Giri et al. / Tetrahedron: Asymmetry 16 (2005) 3502–3505
3503
activation step. This hypothesis led us to focus on exten-
sive exploration of a wide range of cyclic directing
groups with the following criteria: (a) facile formation
of either a three coordinate or square planar structure
with a metal center that is known to be reactive for
C–H cleavage,10 and (b) readily available chiral ana-
logues for diastereoselective C–H activation. Oxazo-
lines, as shown in 3, were initially selected to direct the
activation of a-methyl groups in carboxylic acids. 2-
Phenyloxazoline was previously observed to undergo
ortho-C–H activation by Pd(OAc)2 under reflux in
HOAc to form the stable dimeric arylpalladium com-
plex. A single case of stoichiometric activation of an
a-methyl group in an oxazoline to form the five-mem-
bered dimeric palladocycle, was also observed.6b How-
ever, the formation of these stable dimeric Pd
complexes has not been developed into a catalytic pro-
cess to date.
higher yields. It is worth noting that in the absence of I2,
the combination of Pd(OAc)2 and PhI(OAc)2 results in
an acetoxylation reaction in a similar manner to a
recently reported Pd-catalyzed acetoxylation reaction.9
It should be pointed out that, unlike in the acetoxylation
reaction, the role of PhI(OAc)2 in this iodination reac-
tion is not to oxidize PdII to PdIV. Instead, PhI(OAc)2
reacts with I2 to generate a new oxidant, which is
responsible for converting PdI2 into Pd(OAc)2 (Scheme
4).
unknown species
Pd(OAc)2
PhI(OAc)2
+
I2
unknown species
+
+
PhI
PdI2
Scheme 4. Catalytic turnover.
Next, we tested the diastereoselective iodination using
this catalytic protocol (for a typical procedure, see
Ref. 15). We found that substituents on the 4-position
of oxazolines have a dramatic impact on the reactivity
and stereoselectivity. Iodination of oxazoline 9 derived
from (S)-tert-leucinol gave the product 9a in 92% yield
and 25% de. Oxazoline 10 derived from (S)-valinol
was less reactive under the same conditions and a com-
plete loss of diastereoselectivity was observed. We also
synthesized oxazolines 11–13 to test how the substitu-
ents at the 4-position affect the reactivity and diastereo-
selectivity. The iodination of 11–13 gave low yields of
the iodinated products 11a–13a with poor diastereo-
selectivity. Oxazolines 14–15 were prepared in order to
further investigate how the reaction rate is influenced
by the oxazoline structure. The absence of a substituent
or the presence of a phenyl group at the 4-position was
found to decrease the reaction rate. From these results,
the presence of a bulky tert-butyl group at the 4-position
is crucial for both the reactivity and stereoselectivity.
Based on previous work on the oxidative addition of I2
onto Pt(II) or Pd(II) complexes coordinated to triden-
tate ligands,11 we explored the following proposed reac-
tion pathway to achieve diastereoselective iodination
(Scheme 2). The preliminary results have recently been
reported.12 Herein, we report further investigations into
functional group tolerance of the newly developed catal-
ytic system, and the influence of the oxazoline structures
on the reactivity and stereoselectivity.
I
I2 Oxa
Oxa
IV
PdII
5
I
PdII
Oxa C I
+
Pd
Oxa C H
4
HOAc
6
7
Scheme 2. Proposed reaction pathway for iodination of unactivated
C–H bonds.
Oxazolines were readily prepared from carboxylic acids
and amino alcohols using a three-step sequence in one
pot at room temperature.13 In order to establish the
C–H activation conditions, pivalic acid derived oxazo-
line 8 was initially tested. Stirring 8 (1 equiv) with
Pd(OAc)2 (1 equiv) and I2 (1 equiv) in CH2Cl2 at
24 °C for 24 h exclusively led to the iodination of the
methyl group to give mono-iodide 8a in 80% isolated
yield (Scheme 3). The quantitative formation of PdI2
(characterized by powder X-ray diffraction) was also
observed.
A variety of functional groups such as halides, esters,
ethers, and imides were found to be compatible with this
catalytic system (Table 1). We were pleased to find
that the presence of a bulky group at the a-position of
oxazolines drastically improved the diastereoselectivity
(entries 7 and 8). This is consistent with the proposal
that the steric repulsion between the a-substituent and
the 4-substituent on the oxazoline controls the stereo-
chemistry. The selective activation of methylene over
methyl group in oxazoline 24, although surprising, is
consistent with the previously reported amide directed
lithiation of a cyclopropyl group.16
Since PdI2 is not reactive, we screened various condi-
tions to convert PdI2 into Pd(OAc)2 in order to achieve
catalytic iodination reactions. Both Ag(OAc)2 and
The diastereoselective C–H activation of prochiral aryl
C–H bonds was also achieved using substrate 25. The
14
PhI(OAc)2 were found to be effective, the latter giving
I
Pd(OAc)2, 1 equiv
Me
I2, 1 equiv
N
N
+
Me
Me
Me
Me
PdI2
t-Bu
t
-Bu
CH2Cl2, 24 ˚C
24 h
O
O
8
8a, 80% yield
Scheme 3. Stoichiometric iodination.

3504
R. Giri et al. / Tetrahedron: Asymmetry 16 (2005) 3502–3505
Table 1. Diastereoselective iodinationa
I
I
Entry Substrate
Product
Yield de
N
N
Et
Me
Et
Me
t-Bu
(%)
(%)
i-Pr
O
O
9a
10a
Me Me
Me
I
60b
35
Cl
Cl
1
92% yield, 25% de
15% yield, 0% de
Oxa
Oxa
I
16
16a
I
N
N
Et
Me
Et
I
Me Me
Me
COOMe
Me
Me
41c
45d
50b
55
55
25
O
O
2
3
4
t-Bu
O
Oxa
t-Bu
O
Oxa
11a
12a
17
17a
20% yield, 0% de
46% yield, 14% de
Me Me
Me
TBSO
I
I
I
TBSO
Oxa
Oxa
N
N
Et
Me
Et
18
18a
CH2OTBS
Me
O
O
Me Me
Me
I
13a
14a
30% yield
MeOOC
Oxa MeOOC
Oxa
38% yield, 6% de
19
19a
I
N
O
O
Me
Me
Me Me
Oxa
Me
I
O
N
N
Oxa
5
6
60b
10
0
15a
15% yield
O
20
O
20a
Scheme 5. Ligand effect in iodination. Reagents and conditions:
Pd(OAc)2 (10 mol %), I2 (1 equiv), PhI(OAc)2 (1 equiv), CH2Cl2,
24 °C, 64 h (9a–11a, 14a and 15a); 50 °C, 48 h (12a–13a).
Me Me
Me
Me
I
Me
O
Oxa
Oxa
70e
O
O
O
21
21a
Me Me
Me
I
7
8
9
83f
62g
65h
82
87
99
t-Bu Oxa
t-Bu Oxa
Me
O
Me
O
22
22a
a, b
N
N
t
-Bu
t
-Bu
Me Me
Me
I
I
TBSO Oxa
TBSO Oxa
25a, 98% yield, >99% de
25
23
23a
I
Me
Me
H
H
Me
Me
H
Oxa
24
I
Oxa
N
a, c
N
24a
Me
Me
O
I
O
a Oxa = (S)-4-tert-Butyloxazoline-2-. Reaction conditions: Pd(OAc)2
(10 mol %) I2 (1 equiv), PhI(OAc)2 (1 equiv), CH2Cl2.
b 65 °C, PhI(OAc)2 (1 equiv) was added after 12 h, and stirring con-
26a, 62% yield
26
Scheme 6. Diastereoselective iodination of aryl C–H bonds. Reagents
and conditions: (a) Pd(OAc)2 (10 mol %), I2 (1 equiv), PhI(OAc)2
(1 equiv), CH2Cl2, 24 °C; (b) 13 h; (c) 48 h.
tinued for another 24 h.
c 50 °C, 41 h.
d 24 °C, 42 h.
e 24 °C, 24 h.
f 24 °C, 30 h.
g 50 °C, 48 h.
h 24 °C, 96 h.
decrease in steric bulkiness of the 4-substituent in sub-
strate 26 resulted in a complete loss of selectivity.
We observed that the iodination reaction can be influ-
enced by the structures of oxazolines (Schemes 5 and
6). It is especially intriguing that oxazoline 10 exhibits
poor reactivity in comparison with 9.17 To seek an
explanation for this experimental observation, we
decided to investigate how the methine C–H bond in
10 interacts with the Pd center. Since we were unable
to obtain crystal structures in the form of Pd(Oxa)2-
(OAc)2 using substrates listed in the table, Pd(Oxa)2TFA2
27a was prepared by stirring oxazoline 27 with
Pd(TFA)2 in CH2Cl2 at room temperature. The crystal
Figure 1.
structure showed that the methine C–H bond in the iso-
propyl group is pointing toward the Pd center (Fig. 1).
A downfield shift of the methine proton from 1.8 to

R. Giri et al. / Tetrahedron: Asymmetry 16 (2005) 3502–3505
3505
1
6. For various examples of stoichiometric cyclopalladation
reactions, see: (a) Canty, A. J. In Comprehensive Organo-
metallic Chemistry II: A Review of the Literature 1982–
1994; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon, 1995; pp 225–255; (b) Balavoine, G.; Clinet,
J. C. J. Organomet. Chem. 1990, 390, C84–C88.
7. (a) Constable, A. G.; McDonald, W. G.; Sawjins, L. C.;
Shaw, B. L. J. Chem. Soc., Chem. Commun. 1978, 1061–
1062; (b) Carr, K.; Sutherland, J. K. J. Chem. Soc., Chem.
Commun. 1984, 1227–1228; (c) Baldwin, J. E.; Jones, R.
H.; Najera, C.; Yus, M. Tetrahedron 1985, 41, 699–711; (d)
Bore, L.; Honda, T.; Gribble, G. W. J. Org. Chem. 2000,
65, 6278–6282.
2.9 ppm was also observed in the H NMR. The down-
1
field shift in H NMR and the distance (H atoms were
placed at idealized geometric positions) between the
methine C–H bond and the Pd center in the crystal
structure (27a)18 rules out the possibility of agostic inter-
actions.19 However, a weaker interaction between PtII
and C–H bonds reported by Pregosin was shown to
result in a downfield shift.20 At this stage, it is unclear
to us as to how this interaction may interfere the C–H
cleavage process. However, this preliminary study, in
combination with the experimental results obtained using
substrates 9–15 suggested that the C–H bonds in the
vicinity of the r-chelating group need to be appropriately
positioned or avoided.
8. (a) Gomez, M.; Granell, J.; Martinez, M. Eur. J. Chem.
2000, 217–224; (b) Dupont, J.; Consorti, C. S.; Spencer, J.
Chem. Rev. 2005, 105, 2527–2572.
9. (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542–9543; (b) Dick, A. R.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301.
10. (a) Stahl, S. S.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem.
Soc. 1996, 118, 5961–5976; (b) Fekl, U.; Goldberg, K. I.
J. Am. Chem. Soc. 2002, 124, 6804–6805.
11. (a) Canty, A. J.; Denney, M.; Koten, G.; Skelton, B. W.;
White, A. H. Organometallics 2004, 23, 5432–5439; (b)
Amijs, C. H. M.; Kleij, A. W.; van Klink, G. P. M.; Spek,
A. L.; van Koten, G. Organometallics 2005, 24, 2773–
2779.
We are currently in the process of obtaining crystal
structures of the Pd-alkyl intermediates using a wide
range of prochiral oxazoline substrates. Further optimi-
zation of the oxazoline structures using the structural
information will be carried out in our laboratory in
order to improve the diastereoselectivity with a broad
substrate scope.
Acknowledgments
12. Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem., Int. Ed. 2005,
44, 2112–2115.
13. For various protocols for the preparation of monodentate
oxazolines see: Gomes, M.; Muller, G.; Rocamora, M.
Coord. Chem. Rev. 1999, 193–195, 769–835.
We thank Brandeis University for financial support and
the Camille and Henry Dreyfus Foundation for a New
Faculty Award.
14. For the early use of PhI(OAc)2 as an oxidant for the
acetoxylation of benzene, see: Yoneyama, T.; Crabtree,
R. H. J. Mol. Catal. A-Chem. 1996, 108, 35.
References
15. Typical procedure: Oxazoline (1 mmol) was placed in a
20 mL scintillation vial and dissolved in CH2Cl2 (5 mL).
Palladium acetate (22.4 mg, 0.1 mmol), iodobenzene diac-
etate (322 mg, 1 mmol) and iodine (253.8 mg, 1 mmol)
were added to the solution. The vial was tightly sealed
with a polypropylene lined cap and the resulting violet
solution was either stirred at room temperature or heated
at 50–65 °C 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 iodobenz-
ene, and then with ethylacetate/hexane 1:20.
1. (a) Groves, J. T.; Viski, P. J. Am. Chem. Soc. 1989, 111,
8537–8538; (b) Punniyamurthy, T.; Katsuki, T. Tetra-
hedron 1999, 55, 9439–9454; (c) Zhou, X. G.; Yu, X. Q.;
Huang, J. S.; Che, C. M. Chem. Commun. 1999, 2377–
2378; (d) Jang, D. O.; Kim, D. D.; Pyun, D. K.; Beak, P.
Org. Lett. 2003, 5, 4155–4157; (e) Kennedy, M.; Mcker-
vey, M. A.; Maguire, A. R.; Roos, G. H. P. J. Chem. Soc.,
Chem. Commun. 1990, 361–362; (f) Doyle, M. P.; Proto-
popova, M. N.; Poulter, C. D.; Rogers, D. H. J. Am.
Chem. Soc. 1995, 117, 7281–7282; (g) Espino, C. G.;
When, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc.
2001, 123, 6935–6936; (h) Davies, H. M. L.; Beckwith, R.
E. J. Chem. Rev. 2003, 103, 2861–2903; (i) Muller, P.;
Fruit, C. Chem. Rev. 2003, 103, 2905–2919.
16. Eaton, P. E.; Daniels, R. G.; Casucci, D.; Cunkle, G. T.
J. Org. Chem. 1987, 52, 2100–2102.
17. Murai has previously tested oxazolines as directing groups
to activate ortho-aryl C–H bonds using a Ru(II) catalyst.
It was concluded that a chiral oxazoline bearing a
hydrogen a to the nitrogen is not suitable for C–H
activation, due to the preferential oxidation of this
hydrogen. For details see: Kakiuchi, F.; Sato, T.; Yama-
uchi, M.; Chatani, N.; Murai, S. Chem. Lett. 1999, 19–20.
18. CCDC number 287801.
2. (a) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc.
2002, 124, 6900–6903; (b) Hinman, A.; Du Bois, J. J. Am.
Chem. Soc. 2003, 125, 11510–11511.
3. (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1699–1712;
(b) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999,
121, 6616–6623; (c) Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826–834; (d) Kakiuchi, F.; Chatani, N. Adv.
Synth. Catal. 2003, 345, 1077–1101.
19. Crabtree, R. H.; Holt, E. M.; Lavin, M.; Morehouse,
S. M. Inorg. Chem. 1985, 24, 1986–1992.
20. Pregosin, P. S.; Wombacher, F. Magn. Reson. Chem. 1991,
29, S106–S117.
4. (a) Bennett, M. A.; Milner, D. L. J. Am. Chem. Soc. 1969,
91, 6983–6994; (b) Ibers, J. A.; Dicosimo, R.; Whitesides,
G. M. Organometallics 1982, 1, 13–20.
5. Ryabov, A. D. Synthesis 1985, 233–252.