Palladium-catalyzed oxidation of Boc-protected N-methylamines with IOAc as the oxidant: A Boc-directed sp3 C-H bond activation

Article abstract of DOI:10.1021/ol061384m

Pd-catalyzed selective oxidation of Boc-protected N-methylamines with IOAc as the oxidant is described. Evidence for the involvement of a Boc-directed C-H activation process is provided.

Full text of DOI:10.1021/ol061384m

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3387-3390
Palladium-Catalyzed Oxidation of
Boc-Protected N-Methylamines with
IOAc as the Oxidant: A Boc-Directed
sp3 C
−H Bond Activation
Dong-Hui Wang, Xue-Shi Hao, Di-Fu Wu, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
yu200@brandeis.edu
Received June 6, 2006
ABSTRACT
Pd-catalyzed selective oxidation of Boc-protected N-methylamines with IOAc as the oxidant is described. Evidence for the involvement of a
Boc-directed C H activation process is provided.
−
Selective functionalization of C-H bonds adjacent to a
nitrogen atom in simple amines and amides is of great
importance for the synthesis of nitrogen-containing com-
pounds and understanding enzymatic oxidations.1 Mura-
hashi’s pioneering work on the oxidation of 3° amines using
Pd0 and RuII catalysts mimics amine oxidase type (eq 1) and
cytochrome P-450 type (eq 2) reactivity.2 Transition metal-
catalyzed oxidation of N,N-dialkylanilines to iminium ions3
(eq 3) followed by nucleophilic capture has been utilized
by Murahashi and Li to form C-C bonds with selected
substrates.4
genated compounds as precursors for Ν-acyliminium ions
has been widely used in natural product synthesis.6 A novel
method of generating N-sulfonyliminium ions by a nitriene
insertion into C-H bonds adjacent to an oxygen atom was
also reported.7
In our effort to enhance the efficiency and practicality of
directed C-H activation reactions, we have strategically
selected to develop C-H functionalizations directed by
synthetically useful protecting groups. Herein, we describe
(1) (a) For a minireview on activation of sp3 C-H bonds in the R-position
to a nitrogen atom see: Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351.
(b) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J. Organometallics 1983,
2, 161. (c) Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882. (d) Yi, C. S.;
Yun, S. Y. Organometallics 2004, 23, 5392. (e) Li, Z.; Li, C. J. J. Am.
Chem. Soc. 2004, 126, 11810.
(2) (a) Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443.
(b) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.;
Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820.
(3) Lu, C. C.; Peters, J. C. J. Am. Chem. Soc. 2004, 126, 15818.
(4) (a) Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem.
Soc. 2003, 125, 15312. (b) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2004, 126,
11810. (c) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 3672.
(5) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648.
Pd0
R1R2N-CHR3R4 y z R1R2N+dCR3R4 + PdH- (1)
RuVdO
R1R2N-CHR3R4 y
z R1R2N+dCR3R4 + RuIII(OH) (2)
Cu(I), Ru(II)
ArR1N-CHR2R3 y peroxides z ArR1N+dCR2R3
(3)
Recently, Doyle described an efficient alkylation of C-H
bonds adjacent to nitrogen atoms with a wide range of N,N-
dialkylanilines using dirhodium caprolactamate.5 The elec-
trochemical oxidation of cyclic amides to provide R-oxy-
(6) Moeller, K. D. Tetrahedron 2000, 56, 9527.
(7) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 2028.
10.1021/ol061384m CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/30/2006

a PdII-catalyzed highly selective acetoxylation of R-methyl
groups in a wide range of aliphatic and aromatic Boc
-protected 2° N-methylamines using IOAc as the stoichio-
metric oxidant. The exclusive selectivity toward methyl
groups is a characteristic feature of our catalytic system in
contrast to the previously reported iminium ion pathway.3-5
The observed isotope effect, regioselectivity, and stereose-
lectivity are consistent with an unusual Boc-directed Pd
insertion into sp3 C-H bonds.
I2 + PhI(OAc)2 f PhI + IOAc
(4)
Thus, stirring 1 with 1 equiv of PhI(OAc)2 and I2 in the
presence of 10 mol % of Pd(OAc)2 in CH2Cl2 at 50 °C in a
sealed tube for 40 h gives the acetoxylated product 1a in
70% yield (Scheme 1).
Scheme 1. Selective Acetoxylation of N-Methylcarbamates
Amide-directed palladation of sp2 C-H bonds has been
extensively explored to develop C-C bond and C-hetero-
atom bond-forming reactions since the early examples
reported by Horino and Tremont using PdII/PdIV catalysis.8
Remarkably, Buchwald achieved an amide-directed C-H
activation/C-N bond-forming sequence involving PdII/Pd0
catalysis in which practically useful oxidants (CuII/air) were
employed.9 However, Boc-directed activation of sp3 C-H
bonds ajacent to the nitrogen atom has not been achieved
despite the potential synthetic utility due to the low coordina-
tion ability of the Boc group.10 Inspired by Beak’s carbamate-
directed lithiation reactions,11 Crabtree’s carbonyl-directed
cycloiridation of aryl C-H bonds12 and the early efforts from
Murai, Chatani, and Kakiuchi,10 we decided to identify
conditions that would oxidize Boc-protected N-methylamines
via a Boc-directed C-H activation catalyzed by Pd(OAc)2.
Boc-protected N-methylbutan-1-amine 1 was used to
screen for a catalytic oxidation system. We have previously
shown that Pd-alkyl or Pd-aryl complexes react with I2 to
give the iodinated products and PdI2.13a,b Unfortunately,
stirring 1 with 1 equiv of Pd(OAc)2 and I2 in CH2Cl2 at room
temperature or 50 °C led to a full recovery of the starting
material. We further tested various inexpensive peroxide
oxidants that were recently used in our C-H bond oxidation
reactions.13c No significant reaction was observed under these
reaction conditions. We were pleased to find that the use of
1 equiv of IOAc as the oxidant generated in situ by reacting
AgOAc with I2 gave the actoxylated product 1a in 90% yield
in the presence 1 equiv of Pd(OAc)2. Following a procedure
reported by Lusztyk,14 IOAc is more efficiently produced
by reacting I2 with PhI(OAc)2 (eq 4).
with IOAc as a Crucial Oxidant
PhI(OAc)2 has been previously used as a stoichiomertic
oxidant in Pd-catalyzed acetoxylation of C-H bonds.15
However, control experiments showed that no reaction was
observed when PhI(OAc)2 or I2 was used alone. This result
suggests that IOAc is critical for the Boc-directed oxidation
of the C-H bonds. It is worth noting that our previously
reported Pd-mediated iodination reaction directed by oxazo-
lines can occur in the presence of either I2 alone or IOAc,13a,b
which made it difficult to determine whether the oxidation
of the Pd-C bonds involves I2 or IOAc.
Table 1. Pd-Catalyzed Acetoxylation of Boc-Protected
N-Methylaminesa
(8) (a) Horino, H.; Inoue, N. J. Org. Chem. 1981, 46, 4416. (b) Tremont,
S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759. (c) Kametani,
Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000, 41, 2655.
(d) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586. (e) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 4156.
(9) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560.
(10) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. J. Am. Chem. Soc. 2001, 123, 10935.
(11) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206.
(12) Li, X.; Chen, P.; Faller, J. W.; Crabtree, R. H. Organometallics
2005, 24, 4810.
(13) (a) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Giri, R.; Chen, X.; Hao, X. S.; Li, J. J.; Fan, Z. P.; Yu, J. Q.
Tetrahedron: Asymmetry 2005, 16, 3502. (c) Giri, R.; Liang, J.; Lei, J. G.;
Li, J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.;
Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7420.
(14) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett. 1994,
35, 1003.
a 10 mol % of Pd(OAc)2, 1.6 equiv of I2, 1.6 equiv of PhI(OAc)2, DCE,
60 °C, 40 h.
3388
Org. Lett., Vol. 8, No. 15, 2006

Screening of the reaction conditions identified CH2ClCH2-
Cl (DCE) as a better solvent. The yield of the acetoxylation
of 1 was increased to 83% at 60 °C (Table 1, entry 1). Pd
loading was reduced to 5 mol % by extending the reaction
time to 72 h. The substrate scope was tested by using a
variety of N-methylamines. The N-methyl groups are oxi-
dized highly selectively to give the acetoxylated products in
good yields (Table 1). The successful acetoxylation of
substrate 9 also provides a potential means for functional-
ization of primary amines as both the Boc and OMe can be
readily deprotected to release the primary amine.
substrate 16 was prevented (Table 2, entry 7). However, the
p-iodination of 15 cannot be prevented completely at room
temperature. Intriguingly, no N-methyl oxidation was ob-
served with substrates containing an electron-donating group
on the para-position (Table 2, entry 8).16 Notably, we also
found that the pivaloyl group is as effective as the Boc group
for this reaction (Table 2, entry 9), although the less hindered
acetyl group displayed poor reactivity.
On the basis of characterizations of a number of PdIV
complexes obtained by oxidizing PdII with MeI (X-ray),17
(PhCO2)2 (1HNMR),18 and PhI(O2CPh) (X-ray)19 and our
recently developed C-H bond iodination reaction using PdII/
PdIV catalysis,12a we propose an unusual Boc-directed C-H
insertion pathway to account for the acetoxylation of the
N-methyl groups (Scheme 2). The IOAc serves as a sto-
This oxidation protocol was successfully applied to a wide
range of Boc-protected N-methylanilines (Table 2). Func-
Table 2. Pd-Catalyzed Acetoxylation of Boc-Protected
N-Methylanilinesa
Scheme 2. Proposed Reaction Pathway
ichiometric oxidant to oxidize the unstable PdII complex 1b
to a PdIV complex 1c.20 Our previous iodination reaction
prompts us to assume a preferential reductive elimination
of the iodide other than the acetate. It is also possible that
the reductive elimination of the acetate occurs to give the
acetoxylated product directly.
A number of mechanistic observations support our hy-
pothesis. First, the high selectivity for primary C-H bonds
and lack of reactivity of benzylic C-H bonds in 19 and 20
and secondary C-H bonds in 21 (Figure 1) cannot be
Figure 1. Unreactive substrates.
a 10 mol % of Pd(OAc)2, 1 equiv of I2, 1 equiv of PhI(OAc)2, DCE, 60
explained by the reaction pathways proposed for amine
oxidations (eq 1-3) or a radical pathway.21
°C, 40 h. b 24 °C, 72 h.
Second, the acetoxylation of a mixture of diastereomers
22 in 1:1 ratio gave 22a in 2:1 ratio at 40% conversion
tional groups such as amides, ketones, esters, and sulfonates
are tolerated and good yields are consistently obtained. In
the absence of a para-substituent, electrophilic iodination by
IOAc took place simultaneously to give the p-iodinated
acetoxylation product 15a (Table 2, entry 6). By carrying
out the reaction at room temperature, the p-iodination of
(16) The formation of a mixture of both o- and m-iodinated products is
most likely due to an electrophilic substitution. The lack of reactivity of
the N-methyl group in 17 could be explained by a bisdentate coordination
from the Boc and the electron-rich aryl ring, which positions the N-methyl
group away from the Pd(II) center. The presence of a p-methyl group also
inhibits the N-methyl oxidation.
(17) Byers, P. K.; Canty, A. J.; Skelton, B. W.; White, A. H. J. Chem.
Soc., Chem. Commun. 1986, 1722.
(15) For the direct involvement of PhI(OAc)2 in C-H bond oxidation
see: (a) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem. 1996, 108,
35. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300.
(18) Canty, A. J.; Denney, M. C.; Skelton, B. W.; White, A. H.
Organometallics 2004, 23, 1122.
(19) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 12790.
Org. Lett., Vol. 8, No. 15, 2006
3389

Scheme 3. Diastereoselective Acetoxylation
Scheme 5. Synthetic Applications
(Scheme 3). The diastereoselectivity obtained is consistent
with a cyclic transition state formed via the coordination of
the Boc group to the Pd center.
The isotope effects observed in both intermolecular (kH/D
) 2.9) and intramolecular (kH/D ) 3.2) competition experi-
ments are consistent with the C-H cleavage being the rate-
limiting step (Scheme 4).
In summary, we have developed a Pd-catalyzed acetoxy-
lation of a wide range of N-methylamines directed by a Boc
or pivaloyl group. Mechanistic data obtained are consistent
with a σ-chelation-assisted sp3 C-H insertion. The acetoxy-
lated products are useful building blocks for further synthetic
transformations.
Acknowledgment. We thank Brandeis University for
financial support and the Camille and Henry Dreyfus
Foundation for a New Faculty Award. D.F.W is grateful to
Pfizer for a Fellowship.
Scheme 4. Isotope Effects
Supporting Information Available: Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061384M
(20) For a Boc-coordinated alkylpalladium complex formed from the
Heck reaction see: Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem.
Soc. 2005, 127, 10323.
(21) For nonselective radical oxidation of tertiary amines with peroxide
oxidants see: Ochiai, M.; Kajishima, D.; Sueda, T. Heterocycles 1997, 46,
71.
Finally, the synthetic utility of both Boc- and pivaloyl-
protected products is demonstrated by allylation with allyl-
trimethylsilane, using a literature procedure (Scheme 5).4
3390
Org. Lett., Vol. 8, No. 15, 2006