Buttressing Salicylaldehydes: A Multipurpose Directing Group for C(sp3)?H Bond Activation

Article abstract of DOI:10.1002/anie.201610666

A palladium-catalyzed reaction of primary amines with iodoarenes produces γ-arylated primary amines. A bulky salicylaldehyde, which is marked as easily available, installable, removable, and recoverable, plays a key role in directing palladium to site-selectively activate the C?H bond located γ to the amino group.

Full text of DOI:10.1002/anie.201610666

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International Edition: DOI: 10.1002/anie.201610666
German Edition: DOI: 10.1002/ange.201610666
Arylation
Buttressing Salicylaldehydes: Multipurpose Directing Group for
3
À
C(sp ) H Bond Activation
Akira Yada, Wenqing Liao, Yuta Sato, and Masahiro Murakami*
Dedicated to Professor Tamejiro Hiyama on the occasion of his 70th birthday
Abstract: A palladium-catalyzed reaction of primary amines
with iodoarenes produces g-arylated primary amines. A bulky
salicylaldehyde, which is marked as easily available, instal-
lable, removable, and recoverable, plays a key role in directing
À
palladium to site-selectively activate the C H bond located g to
the amino group.
A
mines constitute an important and vast class of organic
compounds, and it ranges from biologically active compounds
to organic functional materials. It presents a valuable syn-
thetic maneuver if a functionality is installed selectively at
a specific site of an amine.[1] An amino group itself or
a nitrogen functionality derived thereof can coordinate to
a metal, thus acting as the directing group, as a complex-
induced proximity effect[2] arises between the metal and
a specific C H bond of the amine. In fact, specific C(sp ) H
bonds of primary[3] and secondary[4] amines are amenable to
transition metal catalyzed functionalization. It is much more
À
Scheme 1. Palladium-catalyzed C H bond functionalization using aux-
iliary directing groups. DG=directing group, FG=functional group.
2
À
À
3
2
À
À
difficult, however, to activate C(sp ) H bonds than C(sp ) H
The dehydration process of a primary amine with an
aldehyde to produce an aldimine is fascinating because it is
a reversible process and the equilibrium can be shifted in
either direction by setting appropriate reaction conditions.
There have appeared reports in which either an imine or an
bonds,[5] and thus, there are no examples reported so far for
3
À
the direct functionalization of C(sp ) H bonds of primary
amines. In contrast, various auxiliary directing groups have
been devised for this purpose.[6] They are installed on the
nitrogen atom prior to a metal-catalyzed functionalization
reaction and followed by an isolation/purification procedure.
The auxiliary directing groups are finally removed after the
functionalization reaction, and is again followed by an
isolation/purification procedure (Scheme 1a). It would dra-
matically augment the synthetic usefulness if a directing
group is easily installed and removed in the same reaction
vessel with that for the desired functionalization reaction
without intervention of an isolation/purification procedure.[7]
It would further increase the synthetic value from a practical
viewpoint if the directing group was readily available from
commercial sources, and could be recovered from the reaction
mixture.
À
oxime is used as an exo-directing group for C H bond
functionalization of primary amines.[8,9] Recently, a palla-
3
À
dium-catalyzed C(sp ) H bond arylation reaction of primary
amines was reported by two groups. Dong et al. used 8-
formylquinoline as a directing group which was installed in
situ,[10] and Ge et al. used a catalytic amount of glyocylic acid
as a transient directing group (Scheme 1b).[11] We directed
our attention to salicylaldehyde and its derivatives, which are
readily available from commercial sources and easily synthe-
sized and derivatized in a laboratory. They convert primary
amines into the corresponding salicylaldimines, which are also
called phenoxy-imines. Upon treatment with metals, salicyl-
aldimines chelate at the phenoxy group and the imino group,
instantly in most cases, to form six-membered ring complexes.
Once a chelate complex is formed, the rigid backbone of the
bidentate ligand places the metal in proximity of a specific site
of an amine for its activation.[12] Thus, we examined various
salicylaldehydes, which are sterically modified, as a directing
[*] Dr. A. Yada, W. Liao, Y. Sato, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University
Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
À
group for a palladium-catalyzed C C bond-forming reaction
Dr. A. Yada
of primary amines. Herein, we report that arylation with an
iodoarene successfully takes place to produce the correspond-
ing g-arylated primary amine and a buttressing salicylalde-
hyde[13] acts as the multipurpose, that is, easily available,
installable, removable, and recoverable, directing group for
palladium.[14]
Present address: Interdisciplinary Research Center for Catalytic
Chemistry, National Institute of Advanced Industrial Science and
Technology (AIST)
1-1-1 Higashi, Tsukuba, Ibaraki, 305-8565 (Japan)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201610666.
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Table 1: Screening of salicylaldehydes (2).
2
2a
2b
2c
2d
2e
2 f
2g
NMR yield
of 5 [%]
0
0
0
0
78
81
0
Our investigation set out with the examination of various
salicylaldehydes (2) for an arylation reaction of sec-butyl-
amine (1a; Table 1). Initially, salicylaldehyde (2a, 0.21 mmol)
was treated with 1a (0.20 mmol) at 1108C in 1,2-dichloro-
ethane. Dehydration was complete after 15 minutes to deliver
the salicylaldimine 3a quantitatively. Then, 4-iodotoluene
(4a; 0.60 mmol), Pd(OAc)2 (10 mol%), isobutyric acid
(20 mol%), and KHCO3 (0.40 mmol) were added to the
reaction vessel, and the resulting mixture was stirred at
1108C. After 24 hours, however, no formation of an arylated
product was observed and 3a was recovered. 3,5-Dimethyl-
salicylaldehyde (2b), 3,5-dichlorosalicylaldehyde (2c), and 5-
tert-butysalicylaldehyde (2d) all failed to afford an arylated
product. To our surprise, a contrasting result was obtained
when the tert-butyl group of 2d was relocated from the 5-
position to the 3-position (2e). The g-arylated imine 5e was
obtained in 78% yield along with 4% of the g bis(arylation)
product. The more-space-demanding 3,5-di-tert-butylsalicyl-
aldehyde (2 f) attained the best yield of 81%. These results
signify the importance of the tert-butyl group located at the 3-
position. In contrast, the arylation reaction shut down when
we used the methyl ether 2g where the hydroxy group of 2 f
was methylated. Thus, the hydroxy group is also indispensable
for the arylation to occur.
A proposed reaction mechanism is depicted in Scheme 2.
Dehydration from the amine 1a and the salicylaldehyde 2e
forms the salicylaldimene 3e. It acts as the bidentate chelating
ligand to replace the acetate ligands of Pd(OAc)2. The
generated chelate complex A possesses a planar core, to
which a tertiary butyl substituent as well as a secondary butyl
substituent appended. The sterically demanding tertiary butyl
group on the benzene ring exercises a buttressing effect, as it
blocks an open space which would otherwise be available for
the other pendant secondary butyl chain, and places it
a conformation for metalation, through a concerted metal-
ation deprotonation (CMD) mechanism.[15] Oxidative addi-
tion of the iodoarene 4a occurs on the resulting palladabi-
Scheme 2. Plausible reaction mechanism.
À
metalate the C H bond through
a
CMD mechanism
(Scheme 3). We assume that the secondary and tertiary
butyl groups located on the periphery of the central flat
core of 6e would buttress against each other. Thus, the
repulsive interaction arising between the peripheral butyl
groups would disfavor 6e, and instead, would induce its
dissociation into the mechanistically active A, thus mitigating
the repulsive interaction.
Next, we carried out a control experiment. The diimine-
palladium complexes 6a and 6 f (Scheme 3) were prepared
À
cycle B. The following reductive elimination forms a new C C
bond and exchange of the chelating salicylaldimine and iodide
ligands releases the arylated salicylaldimine 5e. Thus, A is
regenerated for the next catalytic cycle. It has been reported
that A possibly reacts with another molecule of the phenoxy-
imine 3e to form the bis(imine)/Pd complex 6e. The complex
6e lacks a carboxylate ligand, and therefore, is unable to
Scheme 3. Formation of the bis(phenoxy-imine)palladium complex 6e.
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from 2a and 2 f, respectively, and their catalytic activities were
compared in the arylation reaction of 3 f. The tert-butyl-
substituted 6 f worked well as the catalyst to afford 5 f in good
yield whereas the reaction using nonsubstituted 6a was
sluggish, even in the presence of an excess amount of 3 f.
These contrasting results are consistent with the mechanistic
interpretation mentioned above.
Figure 1. Other attempted primary alkyl amines.
À
We took advantage of the facile reversibility of the imine-
forming step to increase the practical usefulness. All the steps,
including hydrolysis of 5, were all executed in one reaction
vessel (Table 2). After the palladium-catalyzed reaction of 1a
with 4a was complete in 24 hours, conc. HCl and THF were
simply added to the same reaction vessel. The aqueous acidic
conditions allowed hydrolysis of the imino group at 808C. The
resulting 2 f was separated from the reaction mixture into an
organic phase by extraction, and recovered in 99%. The
remaining aqueous acidic layer was basified, and the follow-
ing extractive workup afforded the g-arylated primary amine
7a (4-(p-tolyl)-2-butylamine), which was directly subjected to
a standard procedure for Boc protection. Chromatographic
purification furnished the Boc-protected amine 8a in 72%
yield [bis(arylation) product 8a’ in 7%].
C H bond should be that of a methyl group. Substitution at
the nitrogen atom by a secondary alkyl group would bear
conformational constraints which are beneficial for the
metalation by a CMD mechanism. A palladium carboxylate
would be given better access in space to the C(sp ) H bond of
a methyl group than to that of a methylene group.
2-Aminonorbornane (1k) and 2-ethylaniline (1l), the
carbon skeletons of which are conformationally less flexible
than those of the primary amines 1h–j, made exceptions with
arylation of their methylene groups. The C(sp ) H bond of
the bridging methylene group of 1k was successfully arylated.
The benzylic methylene group of 1l was also amenable to the
g arylation.
For comparison, two phenoxy-imines, 9 and 10, were
prepared from propylamine and the corresponding carbonyl
compounds, and their reactivities toward the g-arylation were
examined (Scheme 4). Whereas 9 furnished no arylation
product, 10 gave the arylated amine 8m in 46% yield, albeit
under slightly modified reaction conditions (CsOAc in p-
xylene at 1308C). The additional phenyl group on the
periphery of the chelate complex formed from 10 would
generate an extra steric pressure and push the propyl
3
À
3
À
Table 2: Arylation of primary amines (1) with aryl iodides (4).[a]
À
substituent into the vicinity of the palladium to promote C
H activation.
[a] Yield of diarylated product is given within parentheses. [b] AcOH used
instead of aq. HCl. [c] 15% of monoarylated product. [d] Arylation run at
1208C. [e] CsOAc used instead of KHCO3 in chlorobenzene. Boc=tert-
butoxycarbonyl, THF=tetrahydrofuran.
Scheme 4. Arylation of the ketimine 10.
The scope and limitations were studied in terms of
iodoarenes and primary amines (alkyl-NH2) using the one-
pot procedure (Table 2). As for iodobenzenes, electron-
donating and electron-withdrawing substituents were both
tolerated on the benzene ring (4b–f). In the case of 1-bromo-
4-iodobenzene (4e), coupling occurred selectively at the
iodide moiety. 2-Iodothiophene (4g) also participated in the
reaction. The arylation products 8h–j were successfully
obtained from primary amines having a secondary alkyl
group (1h–j). In the case of 3-pentylamine (1i), the major
product was the bis(arylated) amine 8i. In contrast, propyl-
amine (1m) failed to react. Neither 2-pentylamine (1n) nor 4-
phenyl-2-butylamine (1o) gave arylation products (Figure 1).
These results highlight the limitations that 1) the alkyl group
on the nitrogen atom should be a secondary one, and 2) the g
Although the g-arylation reaction studied above was
catalytic in palladium, it used a stoichiometric amount of 2 f.
If the facile reversibility of the imine formation is taken into
account, however, turnover of 2 f was expected.[9–11,14,16] Thus,
we carried out the arylation reaction of 2-ethylaniline (1l)
using 20 mol% of 2 f as shown in Equation (1). The arylated
product 8l was obtained in 69% yield. This result suggested
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[5] O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902.
that the tandem-type catalytic cycle, which is shown in the
Supporting Information, could turnover more than three
times, although it is yet to be improved.
To conclude, a substituted salicylaldehyde serves as an
easily available, installable, removable, and even recoverable
À
[6] Reviews on auxiliary-directed C H bond functionalization
reactions: a) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed.
2013, 52, 11726; Angew. Chem. 2013, 125, 11942; b) O. Daugulis,
J. Roane, L. D. Tran, Acc. Chem. Res. 2015, 48, 1053; c) R. K.
Rit, M. R. Yadav, K. Ghosh, A. K. Sahoo, Tetrahedron 2015, 71,
4450; d) G. He, B. Wang, W. A. Nack, G. Chen, Acc. Chem. Res.
À
directing group for the C H bond arylation reaction of
primary amines.
À
2016, 49, 635; Selected examples of auxiliary-directed C H bond
functionalization of primary amines: e) V. G. Zaitsev, D. Shaba-
shov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154; f) G. He,
G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192; Angew. Chem.
2011, 123, 5298; g) N. Rodrꢀguez, J. A. Romero-Revilla, M. ꢁ.
Fernꢂndez-IbꢂÇez, J. C. Carretero, Chem. Sci. 2012, 4, 175; h) M.
Fan, D. Ma, Angew. Chem. Int. Ed. 2013, 52, 12152; Angew.
Chem. 2013, 125, 12374; i) K. S. L. Chan, M. Wasa, L. Chu, B. N.
Laforteza, M. Miura, J.-Q. Yu, Nat. Chem. 2014, 6, 146; j) J. Han,
Y. Zheng, C. Wang, Y. Zhu, D.-Q. Shi, R. Zeng, Z.-B. Huang, Y.
Zhao, J. Org. Chem. 2015, 80, 9297; k) K. K. Pasunooti, B.
Banerjee, T. Yap, Y. Jiang, C.-F. Liu, Org. Lett. 2015, 17, 6094;
l) J. Li, S. Warratz, D. Zell, S. D. Sarkar, E. E. Ishikawa, L.
Ackermann, J. Am. Chem. Soc. 2015, 137, 13894; Auxiliary
Acknowledgements
This work was supported in part by Grant-in-Aid for Scien-
tific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” (No. 22105005),
Grant-in-Aid for Scientific Research (S) (No. 15H05756), and
Challenging Exploratory Research (No. 26620083) from
JSPS, and the ACT-C program of the JST.
À
directed C H bond functionalization of secondary amines, see:
m) J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford,
Nature 2016, 531, 220.
Conflict of interest
[7] F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906.
[8] a) B. D. Dangel, K. Godula, S. W. Youn, B. Sezen, D. Sames, J.
Am. Chem. Soc. 2002, 124, 11856; b) L. V. Desai, K. J. Stowers,
M. S. Sanford, J. Am. Chem. Soc. 2008, 130, 13285; c) Z. Ren, F.
Mo, G. Dong, J. Am. Chem. Soc. 2012, 134, 16991.
The authors declare no conflict of interest.
À
Keywords: amines · arylation · C H activation · palladium ·
reaction mechanisms
À
[9] C H bond arylation of ketones and aldehydes with transient
imine directing groups: a) F.-L. Zhang, K. Hong, T.-J. Li, H.
Park, J.-Q. Yu, Science 2016, 351, 252; b) K. Yang, Q. Li, Y. Liu,
G. Li, H. Ge, J. Am. Chem. Soc. 2016, 138, 12775.
[1] a) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; b) M.
Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem.
Front. 2014, 1, 843.
[2] X. Chen, K. M. Engle, D. H. Wang, J.-Q. Yu, Angew. Chem. Int.
Ed. 2009, 48, 5094; Angew. Chem. 2009, 121, 5196.
[3] a) J. Vicente, I. Saura-Llamas, M. G. Palin, P. G. Jones, J. Chem.
Soc. Dalton Trans. 1995, 2535; b) J.-B. Sortais, N. Pannetier, A.
Holuigue, L. Barloy, C. Sirlin, M. Pfeffer, N. Kyritsakas,
Organometallics 2007, 26, 1856; c) A. Lazareva, O. Daugulis,
Org. Lett. 2006, 8, 5211; d) H. He, W.-B. Liu, L.-X. Dai, S.-L.
You, J. Am. Chem. Soc. 2009, 131, 8346; e) C. Suzuki, K. Hirano,
T. Satoh, M. Miura, Org. Lett. 2013, 15, 3990.
[10] Y. Xu, M. C. Young, C. Wang, D. M. Magness, G. Dong, Angew.
Chem. Int. Ed. 2016, 55, 9084; Angew. Chem. 2016, 128, 9230.
[11] Y. Liu, H. Ge, Nat. Chem. 2016, DOI: 10.1038/nchem.2606.
[12] a) K. Hiraki, S. Ibaraki, M. Onishi, Y. Ono, J. K. Kawashima, M.
Ando, J. Organomet. Chem. 1997, 547, 199; b) J. Dutta, M. G.
Richmond, S. Bhattacharya, Dalton Trans. 2015, 44, 13615; c) Z.
Ren, G. Dong, Organometallics 2016, 35, 1057.
[13] H. Makio, H. Terao, A. Iwashita, T. Fujita, Chem. Rev. 2011, 111,
2363.
[14] During preparation of this manuscript, a closely related work
appeared: Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate, J.-Q. Yu, J.
Am. Chem. Soc. 2016, 138, 14554.
[4] a) K. Orito, A. Horibata, T. Nakamura, H. Ushito, H. Nagasaki,
M. Yuguchi, S. Yamashita, M. Tokuda, J. Am. Chem. Soc. 2004,
126, 14342; b) A. McNally, B. Haffemayer, B. S. L. Collins, M. J.
Gaunt, Nature 2014, 510, 129; c) J. Calleja, D. Pla, T. W. Gorman,
V. Domingo, B. Haffemayer, M. J. Gaunt, Nat. Chem. 2015, 7,
1009.
[15] D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118.
[16] Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222.
Manuscript received: November 1, 2016
Final Article published: && &&, &&&&
4
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Angewandte
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Communications
Arylation
Added bulk: A palladium-catalyzed reac-
tion of primary amines with iodoarenes
produces g-arylated primary amines. A
buttressing salicylaldehyde, which is
marked as easily available, installable,
removable, and recoverable, plays a key
role in directing palladium to site-selec-
A. Yada, W. Liao, Y. Sato,
M. Murakami*
&&&& — &&&&
Buttressing Salicylaldehydes:
Multipurpose Directing Group for
3
À
À
C(sp ) H Bond Activation
tively activate the C H bond located g to
the amino group.
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