Palladium catalyzed selective arylation of: O -carboranes via B(4)-H activation: Amide induced regioselectivity reversal

Article abstract of DOI:10.1039/c8cc08193j

By changing the charge distribution of boron vertices via introducing an amide on cage B(9), the selective B(4) arylation of o-carboranes via Suzuki-Miyaura coupling has been developed. A series of o-carborane derivatives decorated with diverse active groups have been synthesized with moderate to good yields, which have been proved to be further transformed to a novel kind of tri-substituted nido-carborane fused oxazole with potential application in boron neutron capture therapy, organometallic as well as coordination chemistry.

Full text of DOI:10.1039/c8cc08193j

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Palladium catalyzed selective arylation of
o-carboranes via B(4)–H activation: amide
induced regioselectivity reversal†
Cite this: Chem. Commun., 2018,
54, 13603
Received 12th October 2018,
Accepted 14th November 2018
Tao-Tao Xu,a Ke Cao, *a Cai-Yan Zhang,a Ji Wu,a Linhai Jiangb and
Junxiao Yanga
DOI: 10.1039/c8cc08193j
rsc.li/chemcomm
By changing the charge distribution of boron vertices via introducing an on the pre-functionalized B–I or B–Br bonds,8 and opens a new
amide on cage B(9), the selective B(4) arylation of o-carboranes via era for carborane chemistry.
Suzuki–Miyaura coupling has been developed. A series of o-carborane
Since 2013, three strategies have been developed for selective
derivatives decorated with diverse active groups have been synthesized boron functionalization via B–H activation. Firstly, based on the
with moderate to good yields, which have been proved to be further preferential electrophilic activity of B(8,9,10,12), Xie and our
transformed to a novel kind of tri-substituted nido-carborane fused groups have developed selective tetrafluorination and mono-
oxazole with potential application in boron neutron capture therapy, functionalization on B(8) and B(9),9 respectively (Scheme 1a).
organometallic as well as coordination chemistry.
To achieve the selective functionalization of B(4,5,7,11) with weak
electrophilic activity, Xie and coworkers employed carboxylic acid
Carboranes are a class of boron hydride clusters with three as a directing group on cage carbon, and have made significant
dimensional aromaticity, which possess outstanding features
of high boron content and excellent thermal and chemical
stability, and have been proved to be the key frameworks in
pharmaceuticals for boron neutron capture therapy (BNCT),1
building blocks in functional materials2 and ligands in organo-
metallic as well as coordination chemistry.3 Therefore, the
regioselective functionalization of carboranes has drawn growing
interest from chemists.
For o-carboranes, the cage carbon functionalization could be
facilitated by nucleophilic substitution4 or transition metal
mediated/catalyzed cycloaddition of carboryne based on the
weak acidity of cage C–H bonds.5 On the other hand, the ten
cage B–H bonds are not fully equal and the electrophilic
reactivity is reduced in the following order: B(9,12) 4 B(8,10) 4
B(4,5,7,11) 4 B(3,6),6 which make the selective boron functionaliza-
tion more complicated and a challenging subject. The transition
metal catalyzed B–H activation for the selective construction of B–C
and B–X (X = N, O etc.) bonds developed in recent years7
displays much more superiority than pioneering works based
a State Key Laboratory of Environment-friendly Energy Materials & School of
Material Science and Engineering, Southwest University of Science and
Technology, 59 Qinglong Road, Mianyang, Sichuan, P. R. China.
E-mail: caoke@swust.edu.cn
b Instrumental Analysis Center, Shenzhen University (Xili Campus), P. R. China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, complete characterization data, copies of 1H, 13C and 11B NMR
Scheme 1 Strategies for the selective functionalization of o-carboranes
via B–H activation.
spectra, and cif files of 2f. CCDC 1859043. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c8cc08193j
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contributions to selective functionalization on B(4,5)10 (Scheme 1b). expected, the desired Suzuki–Miyaura coupling with B(4)–H bonds
Similar to Xie’s work, by introducing an aldehyde or aminomethyl could proceed in the presence of 10 mol% Pd(OAc)2 and
on cage carbon, Yan and coworkers have also achieved the selective 2 equivalents of Cu(OAc)2 at reflux temperature (entries 1–4),
1
functionalization on B(4,5) via a transient directing-group strategy11 and the expected product 2a was fully characterized using H,
(Scheme 1c).
13C and 11B NMR spectra. The yields show a slight increase
From these works, we can see that the selective boron when Pd(MeCN)2Cl2 was used, and Cu(OAc)2 was found to be
functionalization becomes more controllable by employing a more favorable for the coupling reaction (entries 5–7). Further-
directing group on cage carbon. However, the directing group more, we found that when Brønsted acid was added, the
anchored on cage boron is still unexploited. Amide as a versatile yields were enhanced distinctly (entries 8–10). Importantly,
directing group has been well developed in C–H activation of the coupling reaction could proceed smoothly even when
arenes.12 Therefore, we consider that when an amide with an carried out at 40 1C (entry 11). To our delight, the yield was
electron withdrawing effect is decorated on B(9), the charge distribu- further improved to 74% when Pd(MeCN)4(BF4)2 was used in
tion of the adjacent B(12), B(8,10) and B(4,5) could be changed and the presence of cyclohexanecarboxylic acid (entry 14).
an unusual regioselectivity delivered (Scheme 1d). With this idea in
With the optimized conditions, the scope of arylboronic acids
mind, the Mulliken charge analysis of 9-benzamide-o-carborane was was then examined. As can be seen from Table 2, arylboronic
performed with Dmol3 in Materials Studio.13 The calculated result acids substituted with electron withdrawing groups were all
demonstrated that the charge of B(4,5,8,10,12) was much more compatible with the coupling and gave the desired products
negative than that in o-carborane, and indicated that the electron with moderate to good yields (2b–2g), meanwhile, the exact
withdrawing effect of amide caused electron flow to the adjacent structure of 2f was further confirmed by X-ray crystallographic
boron vertices. More importantly, the B(4)–H and B(5)–H bonds were analysis15 (Fig. 1). On the other hand, the arylboronic acids
more polarized by comparing the relative charge change of other decorated with electron donating groups were found to be more
B–H bonds (Table S1, ESI†). This result implies that the B(4)–H and favorable for this transformation, and the expected products were
B(5)–H bonds would be activated prior to other adjacent B–H bonds afforded with good yields (2i–2m). However, when 2-methyl-
under appropriate conditions.
phenylboronic acid was subjected to the standard conditions,
To validate our predicted selectivity, Suzuki–Miyaura coupling, a the corresponding product 2h was obtained with lower yield,
powerful tool for the construction of C–C bonds in synthetic organic which indicated that the steric effect has slight influence on the
chemistry, was explored which displayed poor activity and limited
scope in the formation of C–B bonds based on boron-halogenated
Table 2 Selective arylation of 1a with various arylboronic acidsa,b
carboranes.14 To start our research, 9-benzamide-o-carborane and
phenylboronic acid were selected as model substrates to screen
conditions, and the results are summarized in Table 1. Just as we
Table 1 Optimized conditions for the selective arylation of 9-benzamide-
o-carboranea
Entry Catalyst
Oxidant
Additive Solvent
Yieldb
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
AgOAc
Cu(OAc)2 AcOH
Cu(OAc)2 TsOH
Cu(OAc)2 (+)CSAe
Cu(OAc)2 (+)CSAe
—
—
—
—
—
—
—
THF
Toluene
DCE
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
23
18
12
10
34
5
29
40c
9
33c
10
11
12
13
14
50c
48c,d
58c,d
59c,d
76 (74)c,d
Pd(MeCN)4(BF4)2 Cu(OAc)2 (+)CSAe
Pd(MeCN)4(BF4)2 Cu(OAc)2 AcOH
Pd(MeCN)4(BF4)2 Cu(OAc)2 CyHA f
a
All reactions were carried out using 0.1 mmol 1a, 0.2 mmol phenylboronic
acid, 10 mol% catalyst, 0.2 mmol oxidant and 1 mL solvent at reflux tem-
perature for 24 h under an argon atmosphere. b GC yields, and the isolated
a
All reactions were carried out on a 0.2 mmol scale in 1 mL of THF at
b
c
yield given in parentheses. c Adding 1 equivalent additive. d Reacted at 40 1C. 40 1C for 24 h under an argon atmosphere. Isolated yields. Using
e (+)-Camphorsulfonic acid. f Cyclohexanecarboxylic acid.
20 mol% catalyst.
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Scheme 2 Synthesis of nido-carborane fused oxazoles.
withdrawing groups were found to be more favorable for this
coupling and gave the expected products with good yields
(2u–2w). Additionally, 9-alkylamide-o-carboranes were well
compatible with the coupling, and the corresponding products
were afforded with moderate yields (2x–2za).
Recently, we have developed a facile route for the synthesis
of nido-carborane fused oxazoles from 9-amide-o-carboranes.16
To further validate the generality of this transformation, 2a was
then examined. To our delight, the deboronation/cyclization
reaction could proceed smoothly and gave the expected product
3a with 52% yield (Scheme 2). This transformation would give a
novel kind of tri-substituted nido-carborane fused oxazole
further expanding its application in metallacarboranes and
BNCT reagents.
Based on the experimental results and the Mulliken charge
calculation, a plausible mechanism is proposed in Scheme 3. Firstly,
the catalytic cycle is most likely initiated by the transfer of an acyloxy
group from cyclohexanecarboxylic acid to Pd(MeCN)4(BF4)2.17 Due to
the more polarized B(4)–H bond, which should be prior activated by
Pd(II) directed by amide to form intermediate A, intermediate B
would be formed by transmetalation with arylboronic acid. Then
reductive elimination would give the coupling product, and the
subsequent oxidation of the released Pd(0) to Pd(II) would facilitate
the next catalytic cycle.
In summary, by changing the charge distribution of boron
vertices via introducing an amide with an electron withdrawing
effect on cage B(9), we have realized the selective B(4) arylation
of o-carboranes via Suzuki–Miyaura coupling. A series of
o-carborane derivatives decorated with diverse active groups
Fig. 1 Crystal structure of 2f.
coupling reaction. Additionally, biphenylboronic acid and
1-naphthalene boronic acid were well compatible with this
coupling and gave the desired products with moderate yields
(2n–2o). Furthermore, 4-hydroxyphenylboronic acid and thiophene-
2-boronic acid were also suitable for the coupling despite providing
slightly lower yields (2p–2q). It is worth noting that bis-arylated
products on B(4,5) have not been obtained compared to Xie’s and
Yan’s works. Moreover, we found that even when 2a was subjected
to the standard conditions, the secondary arylation on B(5) could
not occur at all. This result demonstrated that the changed charge
distribution induced by the aryl on B(4) has vital influence on
further B–H functionalization, meanwhile, the steric effect might
also be included.
Subsequently, o-carboranes decorated with various amides were
explored. We can see that the coupling could proceed smoothly
when the amides were substituted with electron donating groups
(Table 3, 2r–2t). Meanwhile, the amides decorated with electron
Table 3 Selective arylation of 9-amide-o-carboranes with phenylboronic
acidsa,b
a
All reactions were carried out on a 0.2 mmol scale in 1 mL of THF at
b
c
40 1C for 24 h under an argon atmosphere. Isolated yields. The yield
is calculated based on the consumed o-carborane and the conversion
ratio is given in parentheses.
Scheme 3 Plausible mechanism for selective arylation of B(4)–H bond
with arylboronic acid.
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(g) Y. Zhang, Z.-X. Zhang, Y. Wang, H. Li, F.-Q. Bai and H.-X. Zhang,
Inorg. Chem. Front., 2018, 5, 1016–1025; (h) N. S. Hosmane and
J. A. Maguire, Comprehensive Organometallic Chemistry III, Elsevier,
Oxford, 2007, ch. 5, vol. 3.
have been synthesized with moderate to good yields, which
have been proved to be further transformed to a novel kind of
tri-substituted nido-carborane fused oxazoles with potential
application in metallacarboranes and BNCT reagents. This
work provides an alternative strategy for the selective B(4)
functionalization of o-carboranes and has important value in
the design and synthesis of o-carborane derivatives with mis-
cellaneous groups.
This work is supported by the NSFC (No. 21602182), Sichuan
Provincial Science and Technology Department (No. 2016TD0014),
Sichuan Provincial Education Department (No. 16ZB0133),
Longshan academic talent research supporting program of
SWUST (17LZX324, 18LZX305, and 18LZXT02) and the Project
of State Key Laboratory of Environment-friendly Energy Materials,
SWUST (17fksy0102). Prof. H.-P. Zhang at SWUST is highly
acknowledged for calculation of Mulliken charge. KeeCloud
Biotech is acknowledged for HRMS analysis.
4 V. I. Bregadze, Chem. Rev., 1992, 92, 209–223.
5 Z. Qiu, S. Ren and Z. Xie, Acc. Chem. Res., 2011, 44, 299–309.
6 (a) J. A. Potenza, W. N. Lipscomb, G. D. Vickers and H. Schroeder,
J. Am. Chem. Soc., 1966, 88, 628–629; (b) T. F. Koetzle and
W. N. Lipscomb, Inorg. Chem., 1970, 9, 2743–2748.
7 (a) Z. Qiu, Tetrahedron Lett., 2015, 56, 963–971; (b) W.-B. Yu, P.-F.
Cui, W.-X. Gao and G.-X. Jin, Coord. Chem. Rev., 2017, 350, 300–319;
(c) X. Zhang and H. Yan, Coord. Chem. Rev., 2019, 378, 466–482;
(d) S. Duttwyler, Pure Appl. Chem., 2018, 90, 733–744; (e) Y. Quan,
Z. Qiu and Z. Xie, Chem. – Eur. J., 2018, 24, 2795–2805.
8 (a) I. P. Beletskaya, V. I. Bregadze, K. Z. Kabytaev, G. G. Zhigareva,
P. V. Petrovskii, I. V. Glukhov and Z. A. Starikova, Organometallics, 2007,
26, 2340–2347; (b) Z. Zheng, W. Jiang, A. A. Zinn, C. B. Knobler and
M. F. Hawthorne, Inorg. Chem., 1995, 34, 2095–2100; (c) L. Eriksson,
¨
K. J. Winberg, R. T. Claro and S. Sjoberg, J. Org. Chem., 2003, 68,
˜
˜
3569–3573; (d) D. Olid, R. Nu´nez, C. Vinas and F. Teixidor, Chem. Soc.
Rev., 2013, 42, 3318–3336; (e) R. M. Dziedzic, L. M. A. Saleh, J. C. Axtell,
J. L. Martin, S. L. Stevens, A. T. Royappa, A. L. Rheingold and A. M.
Spokoyny, J. Am. Chem. Soc., 2016, 138, 9081–9084; ( f ) R. M. Dziedzic,
J. L. Martin, J. C. Axtell, L. M. A. Saleh, T.-C. Ong, Y.-F. Yang, M. S.
Messina, A. L. Rheingold, K. N. Houk and A. M. Spokoyny, J. Am. Chem.
Soc., 2017, 139, 7729–7732.
Conflicts of interest
9 (a) Z. Qiu, Y. Quan and Z. Xie, J. Am. Chem. Soc., 2013, 135, 12192–12195;
(b) K. Cao, Y. Huang, J. Yang and J. Wu, Chem. Commun., 2015, 51,
7257–7260; (c) J. Wu, K. Cao, T.-T. Xu, X.-J. Zhang, L. Jiang, J. Yang and
Y. Huang, RSC Adv., 2015, 5, 91683–91685; (d) K. Cao, T.-T. Xu, J. Wu,
L. Jiang and J. Yang, Chem. Commun., 2016, 52, 11446–11449; (e) T.-T. Xu,
C.-Y. Zhang, K. Cao, J. Wu, L. Jiang, J. Li, B. Li and J. Yang, ChemistrySelect,
2017, 2, 3396–3399; ( f ) T.-T. Xu, K. Cao, J. Wu, C.-Y. Zhang and J. Yang,
Inorg. Chem., 2018, 57, 2925–2932.
10 (a) Y. Quan and Z. Xie, J. Am. Chem. Soc., 2014, 136, 15513–15516;
(b) H. Lyu, Y. Quan and Z. Xie, Angew. Chem., Int. Ed., 2015, 54,
10623–10626; (c) Y. Quan and Z. Xie, Angew. Chem., Int. Ed., 2016, 55,
1295–1298; (d) H. Lyu, Y. Quan and Z. Xie, Angew. Chem., Int. Ed.,
2016, 55, 11840–11844; (e) H. Lyu, Y. Quan and Z. Xie, J. Am. Chem.
Soc., 2016, 138, 12727–12730; ( f ) Y. Quan, C. Tang and Z. Xie, Chem.
Sci., 2016, 7, 5838–5845; (g) H. Lyu, Y. Quan and Z. Xie, Chem. – Eur.
J., 2017, 23, 14866–14871.
11 (a) X. Zhang, H. Zheng, J. Li, F. Xu, J. Zhao and H. Yan, J. Am. Chem.
Soc., 2017, 139, 14511–14517; (b) X. Zhang and H. Yan, Chem. Sci.,
2018, 9, 3964–3969.
12 B.-J. Li, S.-D. Yang and Z.-J. Shi, Synlett, 2008, 949–957.
13 (a) B. Delley, J. Chem. Phys., 2000, 113, 7756–7764; (b) B. Delley, J. Chem.
Phys., 1990, 92, 508–517; (c) B. Delley, Phys. Rev. B: Condens. Matter
Mater. Phys., 2002, 66, 155125; (d) J. P. Perdew, K. Burke and
M. Ernzerhof, Phys. Rev. Lett., 1996, 77, 3865–3868; (e) H. J. Monkhorst
and J. D. Pack, Phys. Rev. B: Solid State, 1976, 13, 5188–5192.
14 (a) L. Eriksson, I. P. Beletskaya, V. I. Bregadze, I. B. Sivaev and
There are no conflicts to declare.
Notes and references
1 (a) M. F. Hawthorne, Angew. Chem., Int. Ed. Engl., 1993, 32, 950–984;
(b) A. H. Soloway, W. Tjarks, B. A. Barnum, F. G. Rong, R. F. Barth,
I. M. Codogni and J. G. Wilson, Chem. Rev., 1998, 98, 1515–1562;
(c) J. F. Valliant, K. J. Guenther, A. S. King, P. Morel, P. Schaffer,
O. O. Sogbein and K. A. Stephenson, Coord. Chem. Rev., 2002, 232,
173–230; (d) A. F. Armstrong and J. F. Valliant, Dalton Trans., 2007,
4240–4251; (e) F. Issa, M. Kassiou and L. M. Rendina, Chem. Rev.,
˜
2011, 111, 5701–5722; ( f ) A. N. Ay, H. Akar, A. Zaulet, C. Vinas,
F. Teixidor and B. Zumreoglu-Karan, Dalton Trans., 2017, 46,
3303–3310; (g) N. Kuthala, R. Vankayala, Y.-N. Li, C. S. Chiang
and K. C. Hwang, Adv. Mater., 2017, 29, 1700850; (h) G. Calabrese,
A. Daou, E. Barbu and J. Tsibouklis, Drug Discovery Today, 2018, 23,
63–75.
2 (a) N. S. Hosmane, Boron Science: New Technologies and Applications,
Taylor & Francis Group, 2012; (b) A. M. Prokhorov, T. Hofbeck,
R. Czerwieniec, A. F. Suleymanova, D. N. Kozhevnikov and H. Yersin,
J. Am. Chem. Soc., 2014, 136, 9637–9642; (c) K. O. Kirlikovali, J. C. Axtell,
A. Gonzalez, A. C. Phung, S. I. Khan and A. M. Spokoyny, Chem. Sci., 2016,
7, 5132–5138; (d) S. Mukherjee and P. Thilagar, Chem. Commun., 2016, 52,
1070–1093; (e) X. Wu, J. Guo, Y. Cao, J. Zhao, W. Jia, Y. Chen and D. Jia,
Chem. Sci., 2018, 9, 5270–5277.
¨
3 (a) Z. Xie, Acc. Chem. Res., 2003, 36, 1–9; (b) L. Deng and Z. Xie, Coord.
Chem. Rev., 2007, 251, 2452–2476; (c) A. M. Spokoyny, M. G. Reuter,
S. Sjoberg, J. Organomet. Chem., 2002, 657, 267–272; (b) K. Aizawa,
K. Ohta and Y. Endo, Heterocycles, 2010, 80, 369–377.
C. L. Stern, M. A. Ratner, T. Seideman and C. A. Mirkin, J. Am. Chem. 15 CCDC of 2f is 1859043†.
Soc., 2009, 131, 9482–9483; (d) A. M. Spokoyny, C. W. Machan, 16 C.-Y. Zhang, K. Cao, T.-T. Xu, J. Wu, L. Jiang and J. Yang, unpublished
D. J. Clingerman, M. S. Rosen, M. J. Wiester, R. D. Kennedy,
result, 2018.
C. L. Stern, A. A. Sarjeant and C. A. Mirkin, Nat. Chem., 2011, 3, 17 (a) W. Dong, L. Wang, K. Parthasarathy, F. Pan and C. Bolm, Angew.
590–596; (e) Z.-J. Yao and G.-X. Jin, Coord. Chem. Rev., 2013, 257,
2522–2535; ( f ) A. M. Spokoyny, Pure Appl. Chem., 2013, 85, 903–919;
Chem., Int. Ed., 2013, 52, 11573–11576; (b) T. K. Hyster and T. Rovis,
Chem. Sci., 2011, 2, 1606–1610.
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