Rh[III]-catalyzed C-H amidation using aroyloxycarbamates to give N-Boc protected arylamines

Article abstract of DOI:10.1021/ol401209f

The Rh(III)-catalyzed amidation of C(sp²)-H bonds by the use of electron-deficient aroyloxycarbamates as efficient electrophilic amidation partners is reported. The reaction proceeded under mild conditions with broad functional group tolerance, and pyridine and O-methyl hydroxamic acids serve as efficient directing groups, giving access to valuable N-Boc protected arylamines (also Fmoc and Cbz). Preliminary mechanistic experiments are discussed.

Full text of DOI:10.1021/ol401209f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rh[III]-Catalyzed CÀH Amidation Using
Aroyloxycarbamates To Give N‑Boc
Protected Arylamines
Christoph Grohmann, Honggen Wang, and Frank Glorius*
€
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstr. 40,
€
48149 Mu€nster, Germany
glorius@uni-muenster.de
Received April 29, 2013
ABSTRACT
The Rh(III)-catalyzed amidation of C(sp2)ÀH bonds by the use of electron-deficient aroyloxycarbamates as efficient electrophilic amidation
partners is reported. The reaction proceeded under mild conditions with broad functional group tolerance, and pyridine and O-methyl hydroxamic
acids serve as efficient directing groups, giving access to valuable N-Boc protected arylamines (also Fmoc and Cbz). Preliminary mechanistic
experiments are discussed.
The relevance of the arylamine/aniline motif in chem-
istry is reflected by its ubiquity in natural products,
pharmaceuticals, and countless other compounds.1 To
date, the most powerful methods for the construction of
the core CarylÀN bonds are represented by Ullmann and
BuchwaldÀHartwig couplings, using Cu or Pd catalytic
systems and preactivated aryl halides.2 With the advent
andcontinuousadvancementoftransition-metal catalyzed
CÀH activation methods in recent years,3 considerable
research interest toward the development of metal cata-
lyzed direct CÀH amination processes has been effected.4
Despite the continuous search for new catalytic systems, the
intermolecular transformation of a CarylÀH bond into the
valuable arylamine CÀN bond still remains challenging,
being reported for activated aromatics5aÀf and few directing
group-assisted arenes under oxidative conditions.5gÀk
As an attractive alternative, the effective use of electro-
philic nitrogen sources (chloroamines, hydroxylamines,
azides) containing a weakNÀX bondasa couplingpartner
with (hetero)arenes has been demonstrated in efficient
Pd6aÀc and Cu6d,e catalyzed intermolecular C(sp2)ÀH
amination and amidation reactions under redox-neutral
(1) (a) Rappoport, Z., Ed. The Chemistry of Anilines; Wiley-VCH:
Weinheim, 2007. (b) Amino Group Chemistry: From Synthesis to the Life
Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008.
(2) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41,
1534. (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954. Also see ChanÀEvansÀLam coupling: (d) Qiao, J. X.; Lam,
P. Y. S. Synthesis 2011, 829.
(3) Selected recent reviews on CÀH activation: (a) Giri, R.; Shi,
B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242.
(b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Xu,
L.-M.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (e)Ackermann, L.
(5) Selected examples of intermolecular CÀH aminations of activated
(hetero)arenes: (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A.
Org. Lett. 2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009,
11, 5178. (c) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2009, 48, 9127. (d) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S.
Angew. Chem., Int. Ed. 2010, 49, 9899. (e) Zhao, H.; Wang, M.; Su, W.;
Hong, M. Adv. Synth. Catal. 2010, 352, 1301. (f) Miyasaka, M.; Hirano,
K.; Satoh, T.; Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13,
359. For Pd-catalyzed intermolecular oxidative CÀH amidation, see:
(g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048. (h) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem.
Soc. 2011, 133, 1466. (i) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q.
J. Am. Chem. Soc. 2011, 133, 1694. For a polynuclear Ru/Cu catalytic
system: (j) Louillat, M.-L.; Patureau, F. W. Org. Lett. 2013, 15, 164.
For a Ag/Cu catalytic system: (k) Tran, L. D.; Roane, J.; Daugulis, O.
Angew. Chem., Int. Ed. 2013, 52, 6043.
€
Chem. Rev. 2011, 111, 1315. (f) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (g) Neufeldt, S. R.; Sanford,
M. S. Acc. Chem. Res. 2012, 45, 936. (h) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (i)
Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012,
51, 8960. (j) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
(4) Selected reviews on CÀH amination: (a) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Collet, F.;
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061. (c) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d) Stokes, B. J.;
Driver, T. G. Eur. J. Org. Chem. 2011, 4071.
r
10.1021/ol401209f
XXXX American Chemical Society

conditions. Recently, directed Rh-catalyzed methods employ-
ing chloroamines,6f,g aryl azides6h and arylsulfonyl azides,6i,j
and NFSI6k have been reported to give access to arylamines
and arylsulfamides. Herein, we wish to report on a mild
Rh(III)-catalyzed directed ortho-amidation with aroyloxy-
carbamates giving access to N-Boc protected arylamines
using pyridine or O-methyl hydroxamic acid as directing
groups (DGs). In our continued interest to develop broadly
applicable, mild, and efficient CÀH activation methods
using the Cp*Rh(III) catalyst,7,8 we initially investigated
the formation of primary aromatic amine derivatives via
Rh-catalyzed CÀH activation followed by electrophilic
amination, inspired by a recent report on the amination of
boronic acids with O-(2,4-dinitrophenyl)hydroxylamine.9
While this reagent was not suitable, we found that the reac-
tion of 2-phenylpyridine (1a) with 2.5 mol % [RhCp*Cl2]2,
10 mol % AgSbF6, 1.0 equiv of KOAc, and 1.0 equiv of
Scheme 1. Initial o-CÀH Amination of 2-Phenylpyridine
Scheme 2. Survey of the Different Electrophilic Amidation
Partnersa
PivONH2 HOTf10 (2a), in MeCN at 100 °C, produced the
3
corresponding free aniline 3 in 40% yield (Scheme 1).
(6) Selected examples of electrophilic nitrogen sources in CÀH
activation: Using Pd catalyst: (a) Ng, K.-H.; Chan, A. S. C.; Yu,
W.-Y. J. Am. Chem. Soc. 2010, 132, 12862. (b) Liu, X.-Y.; Gao, P.; Shen,
Y.-W.; Liang, Y.-M. Org. Lett. 2011, 13, 4196. (c) Yoo, E. J.; Ma, S.; Mei,
T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. Using
Cu catalyst: (d) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M.
J. Am. Chem. Soc. 2010, 132, 6900. (e) Matsuda, N.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 13, 2860. Using Rh catalyst: (f) Ng,
K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2011, 14, 272. (g) Grohmann, C.;
Wang, H.; Glorius, F. Org. Lett. 2011, 14, 656. (h) Ryu, J.; Shin, K.;
Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904.
(i) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S.
J. Am. Chem. Soc. 2012, 134, 9110. (j) Shi, J.; Zhou, B.; Yang, Y.; Li, Y.
Org. Biomol. Chem. 2012, 10, 8953. (k) Tang, R.-J.; Luo, C.-P.; Yang, L.;
Li, C.-J. Adv. Synth. Catal. 2013, 355, 869. Using Ru catalyst and
arylsulfonyl azides: (l) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Org. Lett.
2013, 15, 1638. (m) Kim, J.; Kim, J.; Chang, S. Chem.;Eur. J. 2013, 19,
7328.
a Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), [RhCp*Cl2]2
(2.5 mol %), AgSbF6 (10 mol %), KOAc (0.12 mmol), MeCN, 60 °C,
16 h. The corresponding yields of 4a were determined by crude 1H NMR
analysis using CH2Br2 (7.0 μL) as an internal standard and are given in
parentheses.
(7) Reviews on Rh(III)-catalyzed CÀH activations: (a) Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 11212. (b) Song, G.; Wang, F.; Li,
X. Chem. Soc. Rev. 2012, 41, 3651. (c) Patureau, F. W.; Wencel-Delord,
J.; Glorius, F. Aldrichimica Acta 2012, 45, 31. See also: (d) Morimoto,
K.; Itoh, M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka, K.; Miura, M.
Furthermore, the analogous reaction with tert-butyl pivaloyl-
oxycarbamate (2b) afforded the N-Boc protected deriva-
tive 4, which can be readily deprotected to give the primary
amine 3.11 This promising finding led us to investigate the
nature of the leaving group in the amination agent in order
to increase its efficiency in the desired CarylÀN bond
formation. A survey of electronically different tert-butyl
aroyloxycarbamates and tert-butyl arylsulfonyloxycar-
bamates12 2 revealed the electron-deficient 4-nitrobenzoyl
(2f) and 2,4,6-trichlorobenzoyl (2g) groups as effective
substituents on the N-atom, giving the amidation product
in excellent yield under relatively mild reaction conditions
(Scheme 2). The sulfonyl derivatives (2h, 2i) showed only
low conversion, although nosyloxycarbamates have been
reported to be effective in a related Pd-catalyzed CÀH
amidation of anilides.6a The potential of this mild
€
Angew. Chem., Int. Ed. 2012, 51, 5359. (e) Hyster, T. K.; Knorr, L.;
Ward, T. R.; Rovis, T. Science 2012, 338, 500. (f) Ye, B.; Cramer, N.
Science 2012, 338, 504. (g) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y.
J. Am. Chem. Soc. 2012, 134, 13565. (h) Zhen, W.; Wang, F.; Zhao, M.;
Du, Z.; Li, X. Angew. Chem., Int. Ed. 2012, 51, 11819. (i) Kwak, J.; Ohk,
Y.; Jung, Y.; Chang, S. J. Am. Chem. Soc. 2012, 134, 17778. (j) Li, B.-J.;
Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51,
3948. (k) Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482. (l) Lian, Y.;
Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Angew. Chem.,
Int. Ed. 2013, 52, 629. (m) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.;
Lan, J.; You, J. Angew. Chem., Int. Ed. 2013, 52, 580. (n) Neely, J. M.;
Rovis, T. J. Am. Chem. Soc. 2013, 135, 66.
(8) (a) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2154. (b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius,
F. J. Am. Chem. Soc. 2011, 133, 2350. (c) Wang, H.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 7318. (d) Wang, H.; Grohmann, C.; Nimphius,
€
C.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (e) Schroder, N.;
Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298. (f)
Kuhl, N.; Hopkinson, M. N.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 8230. (g) Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius, F.
(11) Deprotection of 4 using TFA in CH2Cl2 for 3 h at rt afforded 3 in
95% isolated yield (see Supporting Information, SI).
€
Angew. Chem., Int. Ed. 2012, 51, 13001. (h) Wang, H.; Schroder, N.;
Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5386. (i) Shi, Z.; Grohmann,
C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5393.
(9) Transition-metal-free amination of boronic acids: (a) Zhu, C.; Li,
(12) Selected reviews on O-acylhydroxylamines as electrophilic
amination agents in organic synthesis: (a) Erdik, E. Tetrahedron 2004,
60, 8747. (b) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.
For original reports on their preparation: (c) Carpino, L. A.; Giza, C. A.;
Carpino, B. A. J. Am. Chem. Soc. 1959, 81, 955. (d) Carpino, L. A. J. Am.
Chem. Soc. 1960, 82, 3133. (e) Marmer, W. N.; Maerker, G. J. Org.
Chem. 1972, 37, 3520. For a recent example employing alkyl 4-chloro-
benzoyloxycarbamates: (f) Harris, L.; Mee, S. P. H.; Furneaux, R. H.;
Gainsford, G. J.; Luxenburger, A. J. Org. Chem. 2010, 76, 358.
€
G.; Ess, D. H.; Falck, J. R.; Kurti, L. J. Am. Chem. Soc. 2012, 134, 18253.
See also the highlight: (b) Coeffard, V.; Moreau, X.; Thomassigny, C.;
Greck, C. Angew. Chem., Int. Ed. 2013, 52, 5684.
(10) This reagentwas introduced by Fagnoufor the installation of the
CONHOPiv directing group: Guimond, N.; Gorelsky, S. I.; Fagnou, K.
J. Am. Chem. Soc. 2011, 133, 6449.
B
Org. Lett., Vol. XX, No. XX, XXXX

Rh(III)-catalyzed CÀH amidation using tert-butyl(2,4,6-
trichlorobenzoyl)oxycarbamate 2g as an efficient electro-
philic amidation partner was investigated next.13,14
Scheme 3. Scope of 2-Phenylpyridine Derivativesa
As a start, different phenylpyridine derivatives were sub-
mitted to the established reaction conditions (Scheme 3).
Both ortho- (4bg) and meta-methyl (4cg) substituents
reacted smoothly, giving the products in high yields and
as a single regioisomer in the case of 4cg. The electron-
donating para-methoxy group was tolerated well (4dg);
however, a nitrile group in this position showed only
negligible conversion. Encouragingly, the olefinic CÀH
of 2-vinylpyridine could also be amidated by this protocol,
albeit in low yield (4eg). In addition to the N-Boc group,
other prominent N-protecting groups such as the Cbz (4aj)
and Fmoc (4ak) group, being removable under orthogonal
conditions,15 could also be installed via this Rh(III)-cata-
lyzed CÀH amidation. Of interest, a methyl substituent on
the nitrogen of the coupling partner shuts down the reactiv-
ity, providing none of the respective secondary arylamide.
Next, we were interested in the replacement of the
pyridine directing group by a more common and synthet-
ically useful moiety. N-Methoxybenzamides have been
showntobe powerfulincombination withtheCp*Rh(III)-
catalyst.8b,i,16 To our delight, a broad scope of substrates
bearing various functional groups proved to be suitable
(Scheme 4). Slightly modified reaction conditions (2.5 mol %
[RhCp*Cl2]2, 1.2 equiv of KOAc and aroyloxycarba-
mate 2g, MeCN, 50 °C) were used. ortho-Substituents like
methyl, phenyl, and halides (including iodide) afforded
high yields of the N-Boc protected arylamines (6aÀe).
The methoxy substituent (6f) in this position proved to
be troublesome, possibly by competing inhibitory chela-
tion of the Rh-catalyst. The R-naphthyl derivative also
gave the corresponding product in 77% yield (6g). A 2,5-
dihalide substituted N-methoxybenzamide (6h), as well as
substrates bearing a nitro (6i) or styryl (6j) moiety, also
smoothly underwent the amidation. Again, we were
pleased to find that O-methyl hydroxamic acids bearing
olefinic CÀH bonds undergo the directed amidation: 6k
and 6l were obtained in good yields even from the reaction
at rt. Among heterocyclic substrates, thiophene (6m) and
benzothiophene (6p) bearing the DG in the 2-position
reacted with high conversion, whereas the corresponding
3-position proved less efficient (6r). In the cases of sub-
strates derived from the more challenging heterocycles
furan (6n), pyrrol (6o), and indole (6q), a higher catalyst
loading and increased temperature of 60°C were appliedto
a PG = Protecting group. Reaction conditions: 1 (0.25 mmol), 2g
(0.3 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), KOAc
(0.3 mmol), MeCN (2.5 mL), 60 °C, 16 h. Isolated yields are given. b With
2j (1.2 equiv), [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), 80 °C. c With
2k (1.5 equiv), KOAc (1.0 equiv), [RhCp*Cl2]2 (5 mol %), AgSbF6
(20 mol %), 100 °C. d With 2n (1.2 equiv).
Scheme 4. Scope of the O-Methylhydroxamic Acidsa
(13) The coupling partner 2g was chosen over 2f due to possible
complications arising from competing coordination to the nitro group
and available o-CÀH bonds in 2f.
(14) In analogy to 2a, the corresponding triflate salts of O-mesitoyl-
hydroxylamine (2l) and O-(2,4,6-trichlorobenzoyl)hydroxylamine (2m)
(see SI) were prepared from 2c and 2g, respectively, to improve the yield
of the free aniline 3. However, no improvement (2l, 35% yield of 3) or
very poor conversion (2m, 5%) were observed.
(15) Greene, T. W.; Wuts, P. W. G. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(16) For the pioneering use of O-methyl hydroxamic acids as DGs in
CÀH activation chemistry, see: (a) Wang, D.-H.; Wasa, M.; Giri, R.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. Introduced to Rh CÀH
activation: (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem.
Soc. 2010, 132, 6908.
a Isolated yields. Reaction conditions: 5 (0.25 mmol), 2g (0.3 mmol),
[RhCp*Cl2]2 (2.5 mol %), KOAc (0.3 mmol), MeCN (2.5 mL), 50 °C, 16 h.
b Run at rt. c With [RhCp*Cl2]2 (5mol%), 60°C. d RuninMeOH(2.5mL),
40 °C. e 2g (2.5 equiv, 0.625 mmol), KOAc (4.0 equiv, 1.0 mmol), 80 °C, 16 h.
f 2g (2.5 equiv, 0.625 mmol), KOAc (2.5 equiv, 0.625 mmol), 40 °C, 16 h.
obtain the amidated products in acceptable to moderate
yields. For meta- and para-substituted benzhydroxamic
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Deuterium Labeling Experiments and DKIE Study
Scheme 6. Mechanistic Considerations
effect (DKIE) of 2.1 was observed in a parallel experiment
and a DKIE of 3.4 in an intermolecular competition experi-
ment19 of 1a/d5-1a (Scheme 5, c), suggesting CÀH bond
activation to be the rate-determining step.
A preliminary mechanistic pathway is postulated
(Scheme 6): Coordination of the nitrogen directing group
(pyridine-N or hydroxamate-N) to the rhodium catalyst
precedes the CÀH activation step, which gives rhodacycle A
upon proton abstraction. Next, the aroyloxycarbamate 2
coordinates to the rhodacycle via its deprotonated nitro-
gen to afford rhodacycle B. The next step delivers the CÀN
bond: a concerted mechanism involving a 1,2-aryl migra-
tion on the amide nitrogen with concomitant NÀO cleav-
age is conceivable. Alternatively, a stepwise reaction via a
Rh(V) nitrenoid species (obtained by O-acylmigration)
followed by reductive elimination to give complex C is
possible.20 The product 4 is deliberated by protodemetala-
tion, restoring the Rh(III)-catalyst.
In conclusion, a novel Rh(III)-catalyzed C(sp2)ÀH ami-
dation using electron-deficient aroyloxycarbamates as an
efficient electrophilic nitrogen source to give access to
N-carbamate protected arylamines under mild reaction
conditions has been described. We expect this method to
find applications in the synthesis of biologically active
arylamine compounds.
acids, diamidation was observed, leading to product mix-
tures.17 For the meta-methyl substituted substrate 5s, evalua-
tion of the reaction parameters led to a maximum isolated
yield of 55% of the monoamidated product 6s. Furthermore,
using 2.5 equiv of 2g, the observed diamidation can be utilized
to generate 2,6-diaminobenzamide derivatives, as demon-
strated for 6u. Upon additional heating and an excess amount
of base, a cyclization is promoted, providing the interesting
3-methoxy-1H-quinazoline-2,4-dione structure,18 in the case
of 6t in 85% yield. The synthetic exploitation of this finding
might be of interest for future studies.
To shed light on the mechanism, deuterium labeling experi-
ments were conducted with 2-phenylpyridine (Scheme 5).
H/D scrambling in MeOD-d4 revealed a reversible CÀH
rhodation in the absence of 2g, albeit this process is slow
(Scheme 5a). However, in the presence of 2g, there is no
D-incorporation observed in 4ag (at a conversion of 60%)
and only a negligible amount of d1-1a formed (Scheme 5b),
indicating the amidation process to be much faster than
the deuteration. Furthermore, a deuterium kinetic isotope
Acknowledgment. We thank Cornelia Weitkamp for
preparation of substrates. Generous financial support by
(17) A possible hydrogen bonding between the carbonyl oxygen of
the DG and the amide NÀH in the first-formed monoamidated product
might account for the observed diamidation reactivity when two o-CÀH
bonds are available:
€
the DFG (IRTG Munster-Nagoya; Leibniz award) and by
the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007-
2013)/ERC Grant Agreement No. 25936 is gratefully
acknowledged.
(18) For related biologically active compounds: O.; Catarzi, D.;
Varano, F.; Squarcialupi, L.; Costagli, C.; Galli, A.; Ghelardini, C.;
Pugliese, A. M.; Maraula, G.; Coppi, E.; Pellegrini-Giampietro, D. E.;
Pedata, F.; Sabbadin, D.; Moro, S. Eur. J. Med. Chem. 2012, 54, 470.
(19) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) For computational elucidation of a related process: Xu, L.; Zhu,
Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org. Chem. 2011, 77, 3017.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX