C-H borylation of diphenylamines through adamantane-1-carbonyl auxiliary by BBr3

Article abstract of DOI:10.1021/acs.orglett.0c02552

A method for ortho-C-H borylation of diphenylamines using BBr3 as the boron source has been reported. The noncatalytic adamantane-1-carbonyl directed reaction exhibited site exclusivity and good functional group tolerance. Generally, the borylation occurred at the more electron-rich aromatic ring and the borylated products could be converted to various useful intermediates. Besides, the derived arylation and removal of auxiliary of the product could be achieved in a one-pot fashion.

Full text of DOI:10.1021/acs.orglett.0c02552

pubs.acs.org/OrgLett
Letter
C−H Borylation of Diphenylamines through Adamantane-1-
carbonyl Auxiliary by BBr3
Gaorong Wu, Xiaopan Fu, Yangyang Wang, Kezuan Deng, Lili Zhang, Tao Ma,* and Yafei Ji*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02552
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A method for ortho-C−H borylation of diphenyl-
amines using BBr3 as the boron source has been reported. The
noncatalytic adamantane-1-carbonyl directed reaction exhibited
site exclusivity and good functional group tolerance. Generally, the
borylation occurred at the more electron-rich aromatic ring and the
borylated products could be converted to various useful
intermediates. Besides, the derived arylation and removal of
auxiliary of the product could be achieved in a one-pot fashion.
s a highly important class of chemicals, diphenylamines
are frequently found among drugs, dyes, agrochemicals,
Scheme 1. Borylation of Diphenylamines and Indoles
A
explosive stabilizers, and radical trapping antioxidants, such as
diclofenac sodium, mefenamic acid, and clausine E (Figure 1).1
Figure 1. Bioactive molecules of diphenylamine.
Arylboronates are useful synthetic intermediates in modern
organic synthesis due to the fact that the C−B bond can be
converted into different functionalities such as C−C, C−N,
C−O, and C−X (X = halogens) bonds.2 In recent years,
tremendous progress has been made in C−H borylation
reactions, but few synthetic methods for ortho-borylation of
diphenylamines have been developed.3 Prevalent methods
mainly involved transition-metal-catalyzed Miyaura borylation
(Scheme 1Aa) and Buchwald−Hartwig amination.4 These
reactions mostly rely on metal catalysts and harsh conditions.4
In addition, the difficulty in removal of toxic trace metals in
pharmaceutical products will limit its application.5 Thus, it is
highly desirable to develop a reliable access for ortho-borylation
of diphenylamines under mild, convenient, and eco-friendly
conditions.
C−H borylation using strong Lewis acids such as BX3 (X =
F, Cl, Br) or B(C6F5)3 has attracted more attention to
synthesize organoboranes.6 In 2019, Shi,7 Ingleson8 and their
co-workers reported pivaloyl group directed ortho-borylation of
indoles and anilines by just using BBr3 (Scheme 1Ab). It
offered an outstanding strategy for generating boron species
with simple, mild, and efficient conditions. More recently,
Iashin et al.6k achieved the C−H borylation of N-heteroarenes
by BF3, and the direct intramolecular aminoboration of allenes
with BCl3 was disclosed by Yang’s group.6l The above-
Received: July 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02552
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
mentioned reports all demonstrate that borylation using BX3 is
an effective measure to form C−B bonds in organic materials.
Inspired by the above achievements, we hope to develop a
new and more bioactive directing group in this simple system,
providing a general method for the preparation of diphenyl-
amine borates that could be used as viable substrates in
subsequent derivatization applications. Thus, we reported a
method for C−H borylation of diphenylamines through an
adamantane-1-carbonyl auxiliary by BBr3 (Scheme 1B). The
reaction exhibited site exclusivity and good functional group
tolerance. The obtained diphenylamine boronic esters were
shown to engage in C−X (X = C, O, Cl, Br) bond formation,
providing a reliable access to obtain diphenylamine derivatives.
Besides, we achieved the derived arylation and removal of
auxiliary of the product in a one-pot fashion.
Our initial study aimed at evaluating the different types of
acyl DGs (directing groups) for the borylation. The reaction
was carried out in the presence of substrates 1−5a (0.2 mmol)
and 1b (0.22 mL, 1.1 equiv) in dried DCM (1.5 mL) for 2 h at
room temperature under a N2 atmosphere, and then pinacol
(1.1 equiv) and Et3N (5.0 equiv) were added for 1 h (Scheme
2). To our delight, 1c and 2c were obtained in 67% and 69%
Table 1. Optimization of the Reaction Conditions
b
Entry
Mainly deviation from the “primary conditions”
Yield
1
2
3
4
5
6
None
75%
80%
78%
73%
72%
0%
1b (2.2 equiv)
1b (3.3 equiv)
c
d
DCE instead of DCM
e
TCM instead of DCM
f
ACN instead of DCM
a
Reaction conditions: 5a (0.20 mmol), 1b (0.44 mL, 1 M in DCM),
DCM (1.5 mL), N2, 2 h; then pinacol (0.44 mmol, dissolved in 1 mL
of dry DCM), Et3N (1.0 mmol), rt, N2, 1 h. Isolated yields. DCE =
b
c
d
e
1,2-dichloroethane. DCM = dichloromethane. TCM = Trichloro-
f
methane. ACN = acetonitrile.
with this procedure, producing the target compounds in 32−
95% yield (5c−29c). In general, the diphenylamines under
optimized reaction conditions gave the corresponding products
with excellent site selectivity. All the borylations occurred at
the ortho-position of diphenylamines, and most of them were
substituted on the more electron-rich aromatic ring. It might
due to the fact that the electron-donating group increases the
electron cloud density of the aromatic ring, which was
conducive to the electrophilic reaction.10 However, the
opposite results of 13c and 20c were obtained because
methoxy was deactivating toward SEAr when it was in the meta
position. Furthermore, the coordination of BBr3 to the MeO
rings was presumably deactivating the MeO substituted
aromatic rings with excess BBr3. para-Symmetrical substrates
afforded the borylated products (6c, 7c, 9c−11c) with good
yields; especially, the yield of 7c was up to 95%. But 8c was
obtained in only 32% yield, probably because ether cleavage
was a competing reaction.11 Of note, 11c was obtained in 85%
yield with 5.0 equiv of BBr3 for 2 h while the yield was slightly
increased with 2.2 equiv of BBr3 for 12 h, suggesting the
borylation may be slow with the more deactivated system. In
addition, para-asymmetrical diphenylamines bearing Me (12c),
F (15c), Cl (16c), Br (17c), and CF3 (18c) substituents could
also be borylated with excellent yields. The structure of
product 16c was confirmed by X-ray analysis. Of note, para-
phenyl-substituted substrate 14a gave a pair of isomers (6:5) in
high yield (see the Supporting Information). Likely, meta-Cl-
and Br-substituted substrates 21a and 22a also produced
isomers with 89% (1:1) and 87% (3:4) yields (see the SI).
ortho-Me Substrate provided highest yield of the correspond-
ing product (23c), while para-Me (12c) lowest. Besides, the
yield of the ortho- and para-dimethyl borylated product (24c)
was higher than that meta- and para-dimethyl product (25c).
Interestingly, when the diphenylamine 26a bearing two methyl
groups at different aromatic rings (ortho- and para-) was
treated in the system, the borylation occurred at the aromatic
ring with para-methyl. A good yield was obtained with N-1-
naphthylaniline (27a), but the yield of 28c was decreased and
the other six membered boracycle derived isomer was not
observed, suggesting the deprotonation may be slow.12
Moreover, indan-5-yl substituted 29a gave the borylated
products in 71% yield. The 4-(phenylamino)pyridine (30a)
and N-cyclohexylaniline (31a) substrates were not suitable for
a b
,
Scheme 2. Screening of Directing Groups
a
Reaction conditions: 1−5a (0.2 mmol), 1b (0.22 mL, 1 M in DCM),
DCM (1.5 mL), N2, 2 h; then pinacol (0.22 mmol, dissolved in 1 mL
of dry DCM), Et3N (1.0 mmol), rt, N2, 1 h. Isolated yields.
b
1
yields. However, there was no change in the H NMR spectra
before and after addition of BBr3 of 3a, indicating no adduct
formation, probably because of the strong electron-with-
drawing nature of the two fluorine atoms. When the aryl was
replaced with 3,5-dimethyl, the desired compound 4c was
obtained in 51% yield. In addition, the adamantane-1-carbonyl
DG delivered a better yield of the target compound 5c of 75%.
Although the isolated yields among 5c, 1c, and 2c were slightly
different, the adamantane moiety was commonly observed in
drugs and its derivates possessed multiple biological activities
such as antiviral, antidiabetic, antiparkinsonian, anticancer, and
antimycobacterial.9 Thus, adamantane-1-carbonyl was selected
as the optimal directing group for further surveys.
Having identified the optimal DG, we further evaluated the
parameters to optimize reaction conditions. The results were
summarized in Table 1. Upon increasing 1b to 2.2 equiv, the
desired product 5c was obtained in up to 80% yield (entries 1
and 2). However, further increasing 1b did not lead to a higher
yield (entry 3). In contrast to our initial solvent choice of
DCM, DCE and TCM diminished the yield (entries 4 and 5)
and ACN led to no desired compound (entry 6). Thus, entry 2
was established as the standard reaction conditions.
With the established reaction conditions, the scope of
diphenylamines was examined as shown in Scheme 3. Both
electron-rich and electron-deficient aromatics were tolerated
B
https://dx.doi.org/10.1021/acs.orglett.0c02552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
Scheme 3. Substrate Scope of Diphenylamines
Scheme 4. Gram-Scale Reaction and Synthetic Application
of Product 6c
radical quencher, were added under the standard reaction
conditions, it was found that TEMPO had negligible effect on
the yield of 5c, which did not evidence a radical pathway
(Scheme 5A). Subsequently, we conducted the intra- and
Scheme 5. Effect of TEMPO and Intra-/Intermolecular
Deuterium Labeling Experiments
a
Reaction conditions: 5−32a (0.20 mmol), 1b (0.44 mL, 1 M in
DCM), DCM (1.5 mL), N2, 2 h; then pinacol (0.44 mmol, dissolved
b
in 1 mL of dry DCM), Et3N (1.0 mmol), rt, N2, 1 h. Isolated yields.
c
d
Using BBr3 (5 equiv, 1.0 mL, 1 M in DCM). Using BBr3 (0.44 mL,
1 M in DCM), 12 h.
the reaction. However, the tetrahydroquinoline 32a afford the
borylated product in excellent yield.
The boryl groups could be transformed into a range of other
functional groups. To certify the utility of the current
borylation reaction, we performed the reaction on gram
scale. The borylated product 6c was provided in 82% yield.
Then we converted 6c to several useful intermediates as shown
in Scheme 4. With excess NaBO3·4H2O in THF/H2O at room
temperature, the hydroxylated product 33c was afforded in
87% yield.13 The C(sp2)−B bond of 6c was transformed into
the C−Cl bond with CuCl2 in 61% yield.14 Similarly,
bromination of 6c with CuBr2 furnished 35c in 53% yield.15
Moreover, in a one-pot fashion we realized the arylation of 6c
by Suzuki−Miyaura reaction with bromobenzene and the
removal of the directing group, which provided 36c in 67%
yield.16
intermolecular competition experiments with deuterium-
labeled diphenylamine to further investigate the mechanism.
The intramolecular competition reaction of 5a′ (D5) under the
standard conditions for 20 min gave a KIE value of 2.13 by 1H
NMR spectroscopic analysis (see the SI) (Scheme 5B). On the
other hand, the intermolecular competition reaction between
To obtain mechanistic insight into the reaction, a control
experiment was performed. When 3.0 equiv of TEMPO, a
C
https://dx.doi.org/10.1021/acs.orglett.0c02552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
5a (undeuterated) and 5a′′ (D10) under the standard
conditions for 10 min gave a KIE value of 2.45 (see the SI)
(Scheme 5C). These results were consistent with the
calculations by Houk on the electrophilic borylation of aniline,
indicating that C(sp2)−H bond cleavage was the rate-
determining step.7,17
Based upon the mechanistic experimental results and
relevant literature reports, a possible mechanism for this
reaction is depicted in Scheme 6.6c,i,k,l,7,8 First, complex A,
Yafei Ji − Engineering Research Centre of Pharmaceutical Process
Chemistry, Ministry of Education; School of Pharmacy, East
China University of Science and Technology, Shanghai 200237,
P. R. China; orcid.org/0000-0002-3562-6703;
Email: jyf@ecust.edu.cn
Authors
Gaorong Wu − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P. R. China
Scheme 6. Proposed Mechanism
Xiaopan Fu − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P. R. China
Yangyang Wang − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education;
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, P. R. China
Kezuan Deng − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P. R. China
Lili Zhang − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P. R. China
consisting of substrate and BBr3, was formed upon the addition
of BBr3. With another BBr3, the Br transferred from A to
generate a borenium cation B. Then the borenium cation
undergoes electrophilic reaction, attacking the ortho-carbon of
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02552
−
diphenylamine, and the deprotonation by BBr4 formed a six-
membered cyclic C. Subsequently, intermediate D was
generated. Finally, with pinacol, the B−Br bonds and B−O
bond of the acyl cleavage event provided the desired
compound 5c.
Notes
The authors declare no competing financial interest.
In summary, we have developed a method for C−H
borylation of diphenylamines using BBr3 as the boron source
with an adamantane-1-carbonyl auxiliary. This method shows
good functional group tolerance, high efficiency, and site
exclusivity. In view of the widespread application of diphenyl-
amine, it may serve as a significant tool to construct
structurally diversified diphenylamine derivatives for the
screening of potential pharmaceuticals in the future.
ACKNOWLEDGMENTS
■
We gratefully thank the National Natural Science Foundation
of China (Project No. 21676088) for financial support.
REFERENCES
■
(1) (a) Suwanprasop, S.; Nhujak, T.; Roengsumran, S.; Petsom, A.
Ind. Eng. Chem. Res. 2004, 43, 4973. (b) Kim, T. H.; Kwon, S. H.;
Choi, J. H. B. Kor. Chem. Soc. 2019, 40, 1229. (c) Yucel, A.; Inal, E.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02552.
■
K.; Akay, M. A. Cent. Eur. J. Energy Mater. 2011, 8, 183. (d) Haidasz,
E. A.; Shah, R.; Pratt, D. A. J. Am. Chem. Soc. 2014, 136, 16643.
(e) Parihar, J. A.; Dash, P.; Kudav, D. P. J. Chem. Res. 2004, 2004,
220. (f) Verma, V.; Ramamoorthi, M.; Morris, M. JDR Clin. Trans.
Res. 2016, 1, 178. (g) Lyons, B. M.; Poppenga, R. H.; Thawley, V. J. J.
Am. Anim. Hosp. Assoc. 2019, 55, e555-02. (h) Stip, E. Can. J. Psychiat.
2020, 0706743720934997.
sı
Experimental procedures and spectral data (PDF)
Accession Codes
(2) (a) Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (b) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Leonori, D.;
Aggarwal, V. K. Acc. Chem. Res. 2014, 47, 3174. (d) Leonori, D.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2015, 54, 1082. (e) Zweifel, G.
T.; Brown, H. C. Org. React. 1963, 13, 22. (f) Brown, H. C. Boranes in
Organic Chemistry; Cornell University Press: Ithaca, NY, 1972.
(g) Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem.
Soc. 2011, 133, 16794. (h) Scott, H. K.; Aggarwal, V. K. Chem. - Eur. J.
2011, 17, 13124.
(3) (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J.
M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (b) Hartwig, J. F. Chem.
Soc. Rev. 2011, 40, 1992.
(4) (a) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2007, 46, 5359. (b) Morris, S. A.; Nguyen, T. H.;
Zheng, N. Adv. Synth. Catal. 2015, 357, 2311.
CCDC 2011000 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Tao Ma − School of Chinese Materia Medica, Beijing University
of Chinese Medicine, Beijing 102488, P. R. China;
orcid.org/0000-0001-9856-2631; Email: mosesmatao@
163.com
D
https://dx.doi.org/10.1021/acs.orglett.0c02552
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(5) (a) Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889.
(b) Nair, D.; Scarpello, J.; White, L.; Freista dos Santos, L.;
Vankelecom, I.; Livingston, A. Tetrahedron Lett. 2001, 42, 8219.
(6) (a) Focante, F.; Camurati, I.; Nanni, D.; Leardini, R.; Resconi, L.
Organometallics 2004, 23, 5135. (b) Niu, L.; Yang, H.; Wang, R.; Fu,
H. Org. Lett. 2012, 14, 2618. (c) De Vries, T. S.; Prokofjevs, A.;
Vedejs, E. Chem. Rev. 2012, 112, 4246. (d) Bagutski, V.; Del Grosso,
A.; Carrillo, J. A.; Cade, I. A.; Helm, M. D.; Lawson, J. R.; Singleton,
P. J.; Solomon, S. A.; Marcelli, T.; Ingleson, M. J. J. Am. Chem. Soc.
2013, 135, 474. (e) Crossley, D. L.; Cade, I. A.; Clark, E. R.; Escande,
A.; Humphries, M. J.; King, S. M.; VitoricaYrezabal, I.; Ingleson, M. J.;
Turner, M. L. Chem. Sci. 2015, 6, 5144. (f) Yin, Q.; Klare, H. F. T.;
Oestreich, M. Angew. Chem., Int. Ed. 2017, 56, 3712. (g) Liu, Y. L.;
Kehr, G.; Daniliuc, C. G.; Erker, G. Chem. - Eur. J. 2017, 23, 12141.
(h) Tanaka, S.; Saito, Y.; Yamamoto, T.; Hattori, T. Org. Lett. 2018,
20, 1828. (i) Tanaka, S.; Saito, Y.; Yamamoto, T.; Hattori, T. Org.
̈
Lett. 2018, 20, 1828. (j) Liu, K.; Lalancette, R. A.; Jakle, F. J. Am.
Chem. Soc. 2019, 141, 7453. (k) Iashin, V.; Berta, D.; Chernichenko,
K. Chem. - Eur. J. 2020, DOI: 10.1002/chem.202001436. (l) Yang, C.;
Han, M.; Li, W.; Zhu, N.; Sun, Z.; Wang, J.; Yang, Z.; Li, Y. Org. Lett.
2020, 22, 5090. (m) Lv, J.; Zhao, B.; Yuan, Y.; Han, Y.; Shi, Z. Nat.
Commun. 2020, 11, 1316.
(7) Lv, J.; Chen, X.; Xue, X.; Zhao, B.; Liang, Y.; Wang, M.; Jin, L.;
Yuan, Y.; Han, Y.; Zhao, Y.; Lu, Y.; Zhao, J.; Sun, W.; Houk, K. N.;
Shi, Z. Nature 2019, 575, 336.
(8) Iqbal, S. A.; Cid, J.; Procter, R. J.; Uzelac, M.; Yuan, K.; Ingleson,
M. Angew. Chem., Int. Ed. 2019, 58, 15381.
(9) (a) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J. Med.
Chem. 2011, 46, 1949. (b) Sacksteder, K. A.; Protopopova, M.; Barry,
C. E.; Andries, K.; Nacy, C. A. Future Microbiol. 2012, 7, 823.
̈
(c) Goktas,̧ F.; Vanderlinden, E.; Naesens, L.; Cesur, N.; Cesur, Z.
Bioorg. Med. Chem. 2012, 20, 7155. (d) Khaziev, R.; Shtyrlin, N.;
Pavelyev, R. Lett. Drug. Des. Discovery 2019, 16, 1360. (e) Scherman,
M. S.; North, E. J.; Jones, V.; Hess, T. N.; Grzegorzewicz, A. E.;
Kasagami, T.; Kim, I. H.; Merzlikin, O.; Lenaerts, A. J.; Lee, R. E.;
Jackson, M.; Morisseau, C.; McNeil, M. R. Bioorg. Med. Chem. 2012,
20, 3255.
(10) Oliveira, F. G.; Rodrigues, F. L.; de Oliveira, A. V. B. Struct.
Chem. 2017, 28, 545.
(11) (a) Williard, P. G.; Fryhle, C. B. Tetrahedron Lett. 1980, 21,
3731. (b) Kosak, T. M.; Conrad, H. A.; Korich, A. L. Eur. J. Org.
Chem. 2015, 2015, 7460. (c) Ryu, I.; Matsubara, H.; Yasuda, S. J. Am.
Chem. Soc. 2002, 124, 12946. (d) Sumida, Y.; Harada, R.; Kato-
Sumida, T. Org. Lett. 2014, 16, 6240.
(12) Iqbal, S. A.; Pahl, J.; Yuan, K.; Ingleson, M. Chem. Soc. Rev.
2020, 49, 4564.
(13) Zou, X.; Zhao, H.; Li, Y. J. Am. Chem. Soc. 2019, 141, 5334.
(14) Dai, H.; Yu, J. J. Am. Chem. Soc. 2012, 134, 134.
(15) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 15434.
(16) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature 2014, 513,
367.
(17) Wang, J. B. Concise Course of Physical Organic Chemistry; Peking
University Press: 2013.
E
https://dx.doi.org/10.1021/acs.orglett.0c02552
Org. Lett. XXXX, XXX, XXX−XXX