Direct ortho -Selective C-H Functionalization of Carboxybenzyl-Protected Arylalkylamines via Ir(III)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.8b00797

A convenient and practical approach to synthesize ortho-alkynylated arylalkylamines through ortho-selective C-H functionalization has been developed using Cbz-amide as the directing group and Ir(III) as the catalyst. Various substrates were well tolerated, affording the corresponding products in moderate to good yields. Moreover, preliminary mechanistic study revealed the role of the amide as the coordination center to cooperate with the Ir(III) complex during C-H activation. Development of this Cbz-amide-promoted C_Ar-H functionalization offers a practical approach with potential applications in organic synthesis.

Full text of DOI:10.1021/acs.orglett.8b00797

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct ortho-Selective C−H Functionalization of Carboxybenzyl-
Protected Arylalkylamines via Ir(III)-Catalyzed C−H Activation
Guobao Li, Jundie Hu, Runsheng Zeng,* Da-Qing Shi, and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A convenient and practical approach to
synthesize ortho-alkynylated arylalkylamines through ortho-
selective C−H functionalization has been developed using
Cbz-amide as the directing group and Ir(III) as the catalyst.
Various substrates were well tolerated, affording the
corresponding products in moderate to good yields. Moreover,
preliminary mechanistic study revealed the role of the amide as
the coordination center to cooperate with the Ir(III) complex during C−H activation. Development of this Cbz-amide-promoted
CAr−H functionalization offers a practical approach with potential applications in organic synthesis.
rylalkylamines are very significant molecular scaffolds in
synthetic chemistry, due to their prevalence in biologically
removing the directing groups have limited their further
application in synthetic chemistry. Recently, an in situ directing
strategy, which can avoid the prefunctionalization and
deprotection steps, has provided a straight route to access
functionalized amines.10 However, these reactions usually
required further treatment with di-tert-butyl dicarbonate
(Boc2O) or 2,2,2-trifluoroacetic anhydride to facilitate the
isolation or further transformation.
A
active compounds, natural products, and approved drugs.1 In
this context, various approaches to construct the arylalkylamine
derivatives have been extensively studied in the past decades.2,3
One of the most efficient strategies is the transition-metal-
catalyzed direct C−H functionalization of arylalkylamines
because the prefunctionalization of the substrate could be
avoided.3 Further, the research groups of Daugulis,4 Chen,5 and
Ma6 have developed diverse N,N-bidentate directing groups to
assist the site-selective C−H functionalization reactions
(Scheme 1a). Yu and co-workers have demonstrated the
On the other hand, the use of benzyl chloroformate (Cbz-Cl)
as the protecting group is one of the common and convenient
strategies to protect active amine groups in the construction of
complex synthetic molecules.11 Consequently, the development
of Cbz-amide-assisted C−H functionalization reactions is of
great significance in synthetic chemistry. So far, there have been
no reports on the utility of Cbz-amide as a directing group to
assist C−H functionalizations. Although the Pd(II) catalyst
displayed excellent catalytic ability in promoting the C−H
activation reactions, there are only a few examples of using
simple amide directly as the substrate for the C−H
functionalization reaction. It is probable that the strong
coordination ability of the amide suppresses the C−H
activation step. Recently, significant developments have been
achieved in the Ir(III)-catalyzed C−H functionalizations, thus
greatly enriching the substrate scope and the type of
reactions.12−14 In 2013, Chang and co-workers developed an
Ir(III)-catalyzed C−H amidation of benzamide employing acyl
azides as the nitrogen source.15 Inspired by this result, we
speculated that Cbz-amide could be used as the coordination
center in assisting C−H activations in combination with an
Ir(III) catalyst.
Scheme 1. Protecting-Group-Directed C−H
Functionalization
efficiency of trifluoromethanesulfonamide as a directing group
in combination with N-protected amino acid ligands.7,8 In
addition, our group has previously reported that oxalyl amide is
an effective N,O-bidentate directing group in assisting the
remote C−H functionalization of amines.9 Even though these
methods have greatly enriched the approaches to functionalize
arylalkylamines, the additional steps required for installing and
Herein, we report the first example of the Ir(III) complex as
an efficient catalyst in promoting C−H activation of Cbz-
Received: March 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. C(sp2)−H Alkynylation of Benzylamine
protected arylalkylamines (Scheme 1b). These Ir(III)-catalyzed
Cbz-amide-assisted ortho-selective C−H alkynylation reactions
yielded the corresponding alkynylated products in moderate to
good yields. Further, preliminary mechanistic studies have
exposed that the amide is the coordination center to assist the
Ir(III) complex in C−H activation.
a
Derivatives
At the outset of our study, the alkynylation of Cbz-protected
benzylamine was set as the model reaction. Accordingly, the
Cbz-protected benzylamine 1a was treated with bromoalkyne 2
in the presence of [Cp*Ir(III)Cl2]2, Cs2CO3, and pivalic acid in
cyclohexane at 80 °C for 8 h. We were delighted to find that an
excellent isolated yield of ortho-alkynylated 3a was obtained
(Table 1, entry 1). Further screening revealed that when
a
Table 1. Optimization of the Reaction Conditions
a
entry
various from the “standard” conditions
yield of 3a (%)
b
a
1
2
82(79 )
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), catalyst (4 mol
[Cp*RhCl2]2 instead of [Cp*IrCl2]2
Pd(OAc)2 instead of [Cp*IrCl2]2
no [Cp*IrCl2]2
45
0
%), additive (0.3 equiv), base (1 equiv) in cyclohexane (1 mL) at 80
°C for 12 h under air in a sealed tube; isolated yields. For 8 h. At 100
°C, 24 h.
b
c
3
4
0
5
no Cs2CO3
0
6
no PivOH
17
31
54
trace
0
substituted with MeO, Me, F, and CF3 selectively took place at
the less sterically hindered position, providing the correspond-
ing products in good yields (3h−3l).
7
DCE as solvent
8
toluene as solvent
9
DMF as solvent
Particularly, the amide group was also tolerated in this
protocol, affording the alkynylated product in synthetically
acceptable yield (3m). The para-substituted Cbz-protected
benzylamine afforded a mixture of both mono- and
dialkynylated products in good yields, which were easily
separated by silica gel chromatography (3n−3r). The 2,5-
dimethyl-substituted benzylamine was also compatible in this
reaction, giving the alkynylated product in a lower yield due to
the steric effect (3t). In addition, the heterocyclic furan also
performed well, affording the alkynylated product in excellent
yield (3u).
10
11
12
13
Ag2CO3 instead of Cs2CO3
K2CO3 instead of Cs2CO3
CsOAc instead of Cs2CO3
60 °C
46
8
51
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), catalyst (4 mol
%), additive (0.3 equiv), base (1 equiv) in solvent (1 mL) at 80 °C for
8 h under air in a sealed tube. Yields were based on GC analysis using
tridecane as an internal standard. Isolated yield of monoalkynylated
product.
b
[Cp*Ir(III)Cl2]2 was replaced by [Cp*Rh(III)Cl2]2, a dramat-
ically decreased yield of 3a was obtained (entry 2). As expected,
there was no yield of the alkynylated product 3a when
Pd(OAc)2 was used as the catalyst, along with the starting
material being completely recovered (entry 3). Several other
solvents such as DCE, toluene, and DMF were screened, which
all afforded decreased yields of the product (entries 7−9).
Particularly, Cs2CO3 was crucial for the reaction; the yields
decreased dramatically when the bases such as CsOAc or
K2CO3 were used instead of Cs2CO3 (entries 11 and 12). The
addition of pivalic acid was essential for this reaction for
promoting C−H activation.16
With the optimized reaction conditions in hand, we
proceeded to investigate the substrate scope to illustrate the
versatility of this Cbz-enabled ortho-selective C−H alkynylation
protocol (Scheme 2). In general, Cbz-protected benzylamines
substituted with both electron-deficient and electron-rich
functional groups performed well under the optimized reaction
conditions, affording the corresponding products in moderate
to excellent yields. A wide variety of functional groups such as
Me, MeO, F, Cl, Br, CF3, CN, and CO2Me were all tolerated in
this Cbz-assisted C−H alkynylation reaction. The ortho-
alkynylation of substrates, in which the meta-position was
Encouraged by the promoting effect of the Cbz-amide with
Ir(III) as the catalyst, we next explored whether the
alkynylation could be achieved with the Cbz-protected
arylethylamines. To our great delight, the ortho-alkynylations
have proceeded well by a slight modification of the reaction
conditions (Scheme 3). An elevated temperature of 100 °C was
essential for the reactions to proceed. It is worth noting that the
reaction might undergo a six-membered cyclometalation, which
is unusual in the Ir(III)-catalyzed C−H functionalization
reactions. Interestingly, para-substituted substrates only
provided the monoalkynylated products in good yields, whereas
the dialkynylated products were observed in trace amounts.
This might be due to the weak cooperating effect of the triple
bond of the substrate with the Ir(III) catalyst, which hindered
the highly unstable six-membered complex formation during
the catalytic cycle.
Next, we demonstrated the synthetic utility of this Cbz-
amide-assisted C−H alkynylation reaction. First, gram-scale
reactions were effortlessly achieved, affording the correspond-
ing products in good yields (Scheme 4). Second, selective
cleavage of the protecting group (i.e., TIPS) could be
accomplished by carrying out the typical deprotection reaction
procedure under mild reaction conditions.17 Herein, a valuable
B
DOI: 10.1021/acs.orglett.8b00797
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Organic Letters
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Scheme 3. C(sp2)−H Alkynylation of Phenylethylamine
subjected to the standard reaction conditions to explore the
feasibility of the ketone as the coordination center. However,
only the starting materials were recovered, without the
formation of any alkynylated product (Scheme 5a). This result
supports the role of the amide moiety as the coordination
center, rather than the oxygen in the Cbz-protected benzyl-
amines. Further, a control experiment was carried out by using
Cbz-protected N-benzylmethylamine as the substrate under the
standard reaction conditions (Scheme 5b). In this case, no
alkynylated product was observed, and the starting material was
completely recovered. This may suggest the significance of the
formation of a N−Ir bond to realize the ortho-selective C−H
functionalization. To further support this hypothesis, the Cbz-
protected aniline was also investigated, but no alkynylated
product was obtained under the standard reaction conditions.
Subsequently, the deuteration experiment was explored by
directly adding D4-acetic acid into the reaction (Scheme 5c).
The result from this experiment might suggest the formation of
a N−Ir bond during the catalytic cycle.
a
Derivatives
To further understand the electronic and steric effects of the
coordination center on the reaction pathway, several other
protected benzylamines were subjected to the optimized
reaction conditions (Scheme 6). For instance, the sterically
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), catalyst (8 mol
%), additive (0.3 equiv), base (1 equiv) in cyclohexane (0.5 mL) at
100 °C for 24 h under air in a sealed tube, isolated yields. 2 (0.4
mmol), [Cp*Ir(III)Cl2]2 (10 mol %), 48 h.
b
Scheme 6. Screening of Different Protecting Groups
Scheme 4. Gram-Scale Reaction and Further Transformation
in the Alkynylation
synthetic protocol for the synthesis of ortho-alkynylated
benzylamines has been developed.
In order to elucidate the mechanism of this Cbz-amide-
assisted Ir(III)-catalyzed C−H functionalization reactions,
additional experiments were performed (Scheme 5). Initially,
benzylacetone and 4-methyl-1-phenyl-2-pentanone were both
hindered pivaloyl-protected substrate provided the alkynylated
product in only 8% yield, whereas the less sterically hindered
acetyl- or Boc-protected substrates afforded comparatively
higher yields. In contrast, both the p-toluenesulfonyl and p-
nitrobenzenesulfonyl were ineffective as directing groups for
this reaction. It is likely that the electron-deficient protecting
groups reduced the electron-donating effect of the N atom,
resulting in its weak coordinating ability with the Ir(III)
catalyst. Unfortunately, all of these substrates only afforded
poorer yields, compared to that of Cbz-protected benzylamines.
Even though the clear reason for the optimum performance of
the Cbz-protected benzylamines in these C−H alkynylation
reactions is not well understood, we might speculate that the
phenyl ring may form weak coordination with the active Ir(III)
catalyst.
Scheme 5. Preliminary Mechanistic Study
Based on the experimental results and previous reports,18,19
a
probable catalytic cycle was proposed for this Cbz-amide-
assisted C−H alkynylation reaction, as shown in Scheme 7.
Initially, the dimeric precursor [Cp*Ir(III)Cl2]2 was converted
into the complex I with the assistance of Cs2CO3 and substrate
1a. Subsequently, the cyclometalated Ir(III) complex was
generated with the aid of the proton shuttle PivO− additive,
followed by oxidation and reductive elimination, affording the
complex IV, which would then produce the complex I by
reacting with substrate 1a and Cs2CO3.
C
DOI: 10.1021/acs.orglett.8b00797
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Organic Letters
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Scheme 7. Plausible Catalytic Cycle
DEDICATION
■
Dedicated to Professor Xiyan Lu on the occasion of his 90th
birthday.
REFERENCES
■
(1) (a) Diez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166. (b) Palisse,
A.; Kirsch, S. F. Org. Biomol. Chem. 2012, 10, 8041. (c) Alabugin, I. V.;
Gold, B. J. Org. Chem. 2013, 78, 7777. (d) Hu, R.; Lam, J. W. Y.; Tang,
B. Z. Macromol. Chem. Phys. 2013, 214, 175. (e) Chinchilla, R.; Najera,
C. Chem. Rev. 2014, 114, 1783.
(2) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084.
(3) For selected recent reviews, see: (a) Yamaguchi, J.; Yamaguchi, A.
D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (b) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236. (c) Engle, K.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2012, 45, 788. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf,
P. H. Chem. Rev. 2012, 112, 5879. (e) Zhang, C.; Tang, C.; Jiao, N.
Chem. Soc. Rev. 2012, 41, 3464. (f) Brand, J. P.; Waser, J. Chem. Soc.
Rev. 2012, 41, 4165. (g) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(i) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885. (j) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (k) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Chem. Soc. Rev. 2009, 38, 3242. (l) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439. (m) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (n) Daugulis, O.; Roane, J.; Tran, L. D.
Acc. Chem. Res. 2015, 48, 1053.
(4) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154.
(5) (a) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850. (b) Zhang, S.;
He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc.
2012, 134, 7313. (c) Zhao, Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett.
2012, 14, 2948.
(6) Fan, M.; Ma, D. Angew. Chem., Int. Ed. 2013, 52, 12152.
(7) Chu, L.; Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J.
Am. Chem. Soc. 2013, 135, 16344.
(8) (a) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura,
M.; Yu, J.-Q. Nat. Chem. 2014, 6, 146. (b) Chu, L.; Xiao, K.-J.; Yu, J.-
Q. Science 2014, 346, 451. (c) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. J. Am.
Chem. Soc. 2015, 137, 2042.
In conclusion, we have demonstrated a convenient and
practical protocol employing Cbz-amide as the directing group
and an Ir(III) complex as the catalyst for the synthesis of ortho-
alkynylated arylalkylamines. Herein, we have also explored the
effectiveness of Cbz-amide as a directing group in assisting the
C−H functionalization reactions of arylalkylamines. Further,
various substrates were well tolerated in this protocol, affording
the alkynylated products in moderate to good yields. The
reactions also produced optimal yields on the gram scale. Thus,
the utilization of Cbz-amide as the directing group would offer
an effective approach for the synthesis of ortho-functionalized
arylalkylamines in the laboratory as well as large-scale
syntheses. Further applications and mechanistic studies
including DFT calculations are now in progress.
ASSOCIATED CONTENT
* Supporting Information
■
(9) (a) Wang, C.; Chen, C.; Zhang, J.; Han, J.; Wang, Q.; Guo, K.;
Liu, P.; Guan, M.; Yao, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2014, 53,
9884. (b) Wang, Q.; Han, J.; Wang, C.; Zhang, J.; Huang, Z.; Shi, D.;
Zhao, Y. Chem. Sci. 2014, 5, 4962. (c) Wang, C.; Zhang, L.; Chen, C.;
Han, J.; Yao, Y.; Zhao, Y. Chem. Sci. 2015, 6, 4610.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00797.
(10) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
(b) Miura, M.; Feng, C.-G.; Ma, S.; Yu, J.-Q. Org. Lett. 2013, 15, 5258.
(c) Yada, A.; Liao, W.; Sato, Y.; Murakami, M. Angew. Chem., Int. Ed.
2017, 56, 1073. (d) Wu, Y.; Chen, Y.-Q.; Liu, T.; Eastgate, M. D.; Yu,
J.-Q. J. Am. Chem. Soc. 2016, 138, 14554. (e) Xu, Y.; Young, M. C.;
Wang, C.; Magness, D. M.; Dong, G. Angew. Chem., Int. Ed. 2016, 55,
9084.
(11) (a) Bergmann, M.; Zervas, L. Ber. Dtsch. Chem. Ges. B 1932, 65,
1192. (b) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag:
Stuttgart, 1994; pp 192−205. (c) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2nd ed.; John Wiley: New York,
1991; pp 315−348.
(12) (a) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.;
Jung, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 1132. (b) Hwang, H.;
Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014, 136, 10770.
(c) Kim, J.; Chang, S. Angew. Chem., Int. Ed. 2014, 53, 2203. (d) Kang,
T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136,
4141.
(13) (a) Xie, F.; Qi, Z.; Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136,
4780. (b) Kim, H.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2014, 136,
5904. (c) Zhou, J.; Shi, J.; Qi, Z.; Li, X.; Xu, H. E.; Yi, W. ACS Catal.
2015, 5, 6999. (d) Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org.
Chem. 2015, 80, 223.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zengrunsheng@suda.edu.cn.
*E-mail: yszhao@suda.edu.cn.
ORCID
Da-Qing Shi: 0000-0003-2262-8491
Yingsheng Zhao: 0000-0002-6142-7839
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Natural
Science Foundation of China (Nos. 21772139 and 21572149).
Project of Scientific and Technologic Infrastructure of Suzhou
(SZS201708) and the PAPD Project are also gratefully
acknowledged.
D
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Letter
(14) (a) Becker, P.; Pirwerdjan, R.; Bolm, C. Angew. Chem., Int. Ed.
2015, 54, 15493. (b) Ebe, Y.; Nishimura, T. J. Am. Chem. Soc. 2015,
137, 5899. (c) Kim, H.; Park, G.; Park, J.; Chang, S. ACS Catal. 2016,
6, 5922. (d) Hermann, G. N.; Becker, P.; Bolm, C. Angew. Chem., Int.
Ed. 2016, 55, 3781.
(15) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc.
2013, 135, 12861.
(16) (a) Kim, H.; Chang, S. ACS Catal. 2015, 5, 6665. (b) Gao, P.;
Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. J. Am. Chem. Soc.
2015, 137, 12231.
(17) Guan, M.; Chen, C.; Zhang, J.; Zeng, R.; Zhao, Y. Chem.
Commun. 2015, 51, 12103.
(18) (a) Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2014, 53, 2722.
(b) Landge, V. G.; Midya, S. P.; Rana, J.; Shinde, D. R.; Balaraman, E.
Org. Lett. 2016, 18, 5252. (c) Tan, E.; Konovalov, A. I.; Fernandez, G.
́
A.; Dorel, R.; Echavarren, A. M. Org. Lett. 2017, 19, 5561. (d) Viart, H.
M.-F.; Bachmann, A.; Kayitare, W.; Sarpong, R. J. Am. Chem. Soc.
2017, 139, 1325.
(19) (a) Cera, G.; Haven, T.; Ackermann, L. Chem. - Eur. J. 2017, 23,
3577. (b) Ruan, Z.; Sauermann, N.; Manoni, E.; Ackermann, L. Angew.
Chem., Int. Ed. 2017, 56, 3172.
E
DOI: 10.1021/acs.orglett.8b00797
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