Synthesis of sterically encumbered C10-arylated benzo[h]quinolines using ortho-substituted aryl boronic acids

Article abstract of DOI:10.1039/c2ob26806j

The challenging coupling of 10-halobenzo[h]quinolines with ortho-substituted aryl boronic acids has been achieved using Pd(OAc) ₂/P(O)Ph₃ as the catalytic system. High yields were obtained for diversely functionalised substrates unde

Full text of DOI:10.1039/c2ob26806j

Organic &
Biomolecular
Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Synthesis of sterically encumbered C10-arylated benzo-
[h]quinolines using ortho-substituted aryl boronic
acids†
Cite this: Org. Biomol. Chem., 2013, 11, 31
Received 14th September 2012,
Accepted 4th October 2012
DOI: 10.1039/c2ob26806j
Marko Weimar and Matthew J. Fuchter*
www.rsc.org/obc
The challenging coupling of 10-halobenzo[h]quinolines with agents under both C–H arylation and more conventional coup-
ortho-substituted aryl boronic acids has been achieved using Pd- ling conditions.
(OAc)2/P(O)Ph3 as the catalytic system. High yields were obtained
Initially we screened a significant number of published pro-
for diversely functionalised substrates under mild reaction cedures to examine the feasibility of arylating benzo[h]quino-
conditions.
line directly with ortho-substituted halobenzenes. In all cases
we found that, in the case of such substrates, C–H arylation
chemistry was not successful. The only procedure we found to
be preparatively viable (to prepare 3a), was palladium-catalyzed
C–H arylation using mixed aryl iodonium salts as reported by
Sanford and co-workers.8 Since this procedure requires prior
preparation of bespoke iodonium arylating agents however,
the advantages of using direct arylation as opposed to more
conventional coupling conditions is less clear. Consequently,
we decided to study whether the Suzuki–Miyaura reaction
would stand up to these challenging substrates.
The Suzuki–Miyaura cross-coupling reaction is a highly reliable
method to form aryl–aryl bonds starting from an aryl boronic
acid and an aryl halide under palladium catalysis.1 It has
already reached an upper level of maturity and is ubiquitously
applied in synthetic chemistry, facts recently recognised by the
award of a Nobel prize for one of its discoverers.2 In contrast,
the highly researched field of C–H arylation is comparatively
still in its infancy.3 The advantage of this methodology over
standard cross-coupling reactions is the fact that it allows the
coupling of (at least one) non-functionalised aromatic com-
pounds, thus potentially saving preparative steps and chemical
waste.
Benzo[h]quinoline represents a prevalent substrate for the
development of new directed C–H arylation protocols.4
However, there is a dearth of examples of reactions using
ortho-substituted arylating agents,4b,e which would afford
highly sterically encumbered heterobiaryls. Through restricted
rotation about the aryl–aryl bond, such bulky products would
likely exist as isolatable atropoisomers and therefore be of sig-
nificant interest in further conformational and stereochemical
studies.5 We were surprised by this omission from C–H aryl-
ation methodology, given that in the field of conventional
cross-coupling chemistry,6 especially the Suzuki–Miyaura reac-
tion,7 the coupling of bulky substrates is an actively investi-
gated topic. We therefore elected to study the C10-arylation of
benzo[h]quinoline with bulky ortho-substituted arylating
Using 10-halobenzo[h]quinoline9 substrates (1a or 1b), no
cross-coupling with o-toluene boronic acid (2a) occurred under
standard Suzuki–Miyaura reaction conditions (10 mol% Pd-
(PPh3)4, 2 equiv. CsF, dioxane–H2O, 100 °C).
We reasoned that the failure of the reaction may be due to
stability of the oxidative addition product,10 shutting down
catalysis. Since it has been known for some time that p-benzo-
quinone (BQ) can function as a useful additive to promote
transmetallation and reductive elimination of organopalla-
dium complexes,11 we decided to test the effect it would have
on this Suzuki reaction. To our delight, we found that the
addition of 0.5 equiv. of BQ to the reaction mixture lead to the
formation of 3a in 67% isolated yield (Scheme 1). While con-
ducting control experiments, we made the surprising
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
E-mail: m.fuchter@imperial.ac.uk; Fax: +44 (0) 2075945805; Tel: +44 (0) 2075945815
†Electronic supplementary information (ESI) available: Experimental procedures
and 1H and 13C NMR spectra for all new compounds. See DOI:
10.1039/c2ob26806j
Scheme 1 Suzuki–Miyaura cross-coupling reaction with BQ.
Org. Biomol. Chem., 2013, 11, 31–34 | 31
This journal is © The Royal Society of Chemistry 2013

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Optimisation of reaction conditionsa,b
observation that an old batch of Pd(PPh3)4 furnished the
desired product without additional BQ. We therefore con-
cluded that one role of BQ may be the oxidation of the PPh3
ligands to P(O)Ph3 during the course of the reaction
(cf. slow aerobic degradation of Pd(PPh3)4). Moreover, we
found that PPh3 suppressed the reaction: An experiment with
the “old” Pd(PPh3)4 catalyst and additional PPh3 did not yield
any product.
In light of these results, we turned our attention to phos-
phine-free palladium precatalysts and found that a combi-
nation of Pd(OAc)2 and P(O)Ph3 led to a fast reaction with
complete consumption of 1a within 10 min at 100 °C (Table 1,
entry 2). Denmark and co-workers have previously reported the
beneficial effect of P(O)Ph3 in cross-coupling reactions of elec-
tron-rich arylsilanolates.12 At this temperature, comparable
results were obtained when a Pd(0) or a Pd(II) source was used
(Table 1, entries 3 and 4). Only the heterogeneous catalyst Pd
black afforded an incomplete conversion even after 18 h
(Table 1, entry 5). Interestingly, with a Pd(0) source (Pd(dba)2)
as the catalyst, the addition of P(O)Ph3 was not necessary for
the reaction to occur at 100 °C (Table 1, entry 7) whereas with
a Pd(II) source (Pd(OAc)2) only traces of 3a were formed in the
Entry X Catalyst
Base
Solvent
Time (h) Yieldc (%)
1
2
3
4
5
6
7
Br Pd(OAc)2 CsF
Br Pd(dba)2 CsF
Cl Pd(OAc)2 CsF
Dioxane–H2O 2 : 1 18
Dioxane–H2O 2 : 1 18
Dioxane–H2O 2 : 1 0.5
98
52
100
99
92
Cl Pd(OAc)2 Na2CO3 Dioxane–H2O 2 : 1 2
Cl Pd(OAc)2 Na2CO3 Dioxane
Cl Pd(OAc)2 d Na2CO3 MeOH
Cl Pd(OAc)2 Na2CO3 MeOH
18
5 min
0.25
100
84
a Reactions were performed on a 0.1 mmol scale with 1.05 equiv. 2a in
0.75 ml dioxane–H2O 2 : 1 or 0.5 ml dioxane or 0.5 ml MeOH. b For
more results, see ESI.† c Isolated yield. d 1 mol% Pd(OAc)2.
In terms of suitable solvents, we found that under non-
absence of P(O)Ph3 (Table 1, entry 6). Upon lowering the reac- aqueous conditions (for example anhydrous dioxane) the reac-
tion took up to 18 h to go to completion (Table 2, entry 5),
whereas it was fastest in MeOH where the reaction was com-
tion temperature however, we observed that a quantitative
yield of 3a was afforded even at ambient temperature when a
Pd(II) precatalyst and P(O)Ph3 was used (Table 2, entry 1), plete after about 5 min (Table 2, entry 6). Pleasingly, when the
catalyst loading was reduced to 1 mol%, the reaction was still
suitably fast, although the product yield dropped slightly
whereas the use of a Pd(0) source (Pd(dba)2) was far less
effective (Table 2, entry 2). This result highlights the prepara-
tive usefulness of a Pd(II) source combined with P(O)Ph3. Fur- (Table 2, entry 7). While we surveyed other phosphine oxide
additives, for example P(O)Cy3 or XPhos(O), we found these to
be less effective than P(O)Ph3. Additional optimisation con-
thermore, to our surprise chlorobenzo[h]-quinoline 1b gave a
much faster reaction time than with bromo compound 1a.
Indeed, the coupling of substrate 1b proceeded quantitatively ditions can be found in Table S1, ESI.†
Next, the scope of the coupling reaction was examined
within 0.5 or 2 h, respectively, with CsF or Na2CO3 as the base
(Table 2, entries 3 and 4), while for 1a stirring overnight was
necessary to reach full conversion.
(Table 3). A variety of ortho-substituents were tolerated. In
general, electron donating (Me, OMe) and electron withdraw-
ing substituents (CF3 and Cl) all furnished a high product
yield (Table 3, entries 1 to 4). To our surprise, 2-bromobenzene-
boronic acid (Table 3, entry 5) was also a suitable substrate,
giving the corresponding product in 99% yield; the ortho-
bromo group proving inert to the reaction conditions.
Additional substituents on the aromatic ring did not generally
alter the reactivity of the boronic acids (compare Table 3, entry
1 with entry 7) unless the 6-position was occupied in addition
to the 2-position. For example, 2,6-dimethylbenzeneboronic
acid (Table 3, entry 8) only underwent coupling when the reac-
tion was performed at elevated temperature. Indeed, more
sterically encumbered substrates reduced the reaction rate
and, depending on the solvent used, led to a side reaction
where 1a or 1b were converted to the 10-methoxy derivative (in
methanol) or the 10-hydroxy derivative (in dioxane–H2O),
respectively. Pleasingly, this side reaction could be avoided
simply by switching to THF as solvent. While 10 mol% catalyst
was arbitrarily selected from our optimisation studies, we were
delighted to observe that analogous results were obtained
using 5 mol% (Table 3, entries 4 and 12). The robustness of
our method could be demonstrated when the reaction of
Table 1 Initial screening of reaction conditionsa
Entry
Catalyst
Additive (equiv.)
Time (h)
Conversionb (%)
1
2
3
4
5
6
7
Pd(PPh3)4
Pd(OAc)2
PdCl2
Pd(dba)2
Pd black
Pd(OAc)2
Pd(dba)2
BQ (0.5)
2
67c
86
98
83
64
1
P(O)Ph3 (0.2)
P(O)Ph3 (0.2)
P(O)Ph3 (0.2)
P(O)Ph3 (0.2)
—
10 min
0.5
0.5
18
1
0.5
—
86
a Reactions were performed on a 0.2 mmol scale with 1.05 equiv. 2a in
1.5 ml dioxane–H2O 2 : 1. b Determined by NMR based on the ratio of
1a and 3a. c Isolated yield.
32 | Org. Biomol. Chem., 2013, 11, 31–34
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 3 Scope of the cross-coupling reactiona,b
Entry
Boronic acid
Solvent
Base
T (°C)
Time (h)
Yieldc (%)
1
2
2a
Dioxane–H2O 2 : 1
Dioxane–H2O 2 : 1
CsF
CsF
rt
rt
0.5
18
100
74
3
Dioxane–H2O 2 : 1
Dioxane–H2O 2 : 1
Dioxane–H2O 2 : 1
THF
CsF
rt
18
100
93 (96d)
99
4
CsF
rt
10 min
2 min
18
5
CsF
rt
6
Na2CO3
CsF
60
rt
51
7
Dioxane–H2O 2 : 1
THF
0.5
100
84
8
CsF
60
rt
18
9
Dioxane–H2O 2 : 1
THF
Na2CO3
CsF
18
85
10
60
2
88
11e
12
2j
THF
THF
CsF
CsF
60
60
2
18
92
72 (84d)
a Reactions were performed on a 0.1 mmol scale with 1.2 equiv. boronic acid in 0.75 ml dioxane–H2O 2 : 1 or 0.5 ml THF. b For more results, see
ESI.† c Isolated yield. d Isolated yield using 5 mol% Pd(OAc)2. e On gram scale (4.2 mmol 1b).
2-methoxy-1-naphthylboronic acid with 1b was conducted on oxidative addition of a Pd(0) species into the carbon–halide
gram scale affording the coupling product in 92% isolated bond.13 Future studies will be aimed at elucidating the
yield (Table 3, entry 11).
mechanistic nature of this interesting transformation and its
In conclusion, we have developed a highly robust and versa- use in target based synthesis.
tile method to prepare bulky C10-arylated benzo[h]quinoline
We would like to thank the Leverhulme Trust (grant
products. We envisage these products will be of significant F/07058/BG) for funding this work.
interest in the study of dynamic conformation chemistry and
as stereochemical switches. In the developed method, the use
of P(O)Ph3 as an additive enabled the formation of a number
of sterically encumbered, functionalised products. It is worth
Notes and references
reiterating that use of chlorobenzo[h]quinoline (1b) lead to
shorter reaction times than the bromo compound (1a), a fact
that is counterintuitive for the known reactivity profile of
1 (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147;
(b) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(c) A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 31–34 | 33

View Article Online
Communication
Organic & Biomolecular Chemistry
ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinheim,
Germany, 1998, p. 49.
2 X.-F. Wu, P. Anbarasan, H. Neumann and M. Beller, Angew.
Chem., Int. Ed., 2010, 49, 9047.
J. Am. Chem. Soc., 2009, 131, 5331; (c) M. S. Betson,
A. Bracegirdle, J. Clayden, M. Helliwell, A. Lund,
M. Pickworth, T. J. Snape and C. P. Worrall, Chem.
Commun., 2007, 18, 754.
3 For reviews discussing C–H arylation, see: (a) S. H. Cho,
J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011,
40, 5068; (b) C. S. Yeung and V. M. Dong, Chem. Rev.,
2011, 111, 1215; (c) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792;
(d) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094; (e) G. P. McGlacken and L.
M. Bateman, Chem. Soc. Rev., 2009, 38, 2447;
(f) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev.,
2007, 107, 174.
6 (a) C. Valente, S. Çalimsiz, K. H. Hoi, D. Mallik, M. Sayah
and M. G. Organ, Angew. Chem., Int. Ed., 2012, 51, 3314;
(b) G. C. Fortman and S. P. Nolan, Chem. Soc. Rev., 2011,
40, 5151; (c) G. C. Fu, Acc. Chem. Res., 2008, 41, 1555;
(d) W. Su, S. Urgaonkar, P. A. McLaughlin and
J. G. Verkade, J. Am. Chem. Soc., 2004, 126, 16433.
7 (a) A. Chartoire, M. Lesieur, L. Falivene, A. M. Z. Slawin,
L. Cavallo, C. S. J. Cazin and S. P. Nolan, Chem.–Eur. J.,
2012, 18, 4517; (b) R. Martin and S. L. Buchwald, Acc.
Chem. Res., 2008, 41, 1461.
4 (a) L. Ilies, M. Kobayashi, A. Matsumoto, N. Yoshikai and
E. Nakamura, Adv. Synth. Catal., 2012, 354, 593;
(b) T. W. Lyons, K. L. Hull and M. S. Sanford, J. Am. Chem.
Soc., 2011, 133, 4455; (c) B. Li, Z.-H. Wu, Y.-F. Gu, C.-L. Sun,
B.-Q. Wang and Z.-J. Shi, Angew. Chem., Int. Ed., 2011, 50,
8 D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford,
J. Am. Chem. Soc., 2005, 127, 7330.
9 (a) D. Kalyani, A. R. Dick, W. Q. Anani and M. S. Sanford,
Tetrahedron, 2006, 62, 11483; (b) A. R. Dick, K. L. Hull and
M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 2300.
1109; (d) H. Miura, K. Wada, S. Hosokawa and M. Inoue, 10 M. Alami, C. Amatore, S. Bensalem, A. Choukchou-Brahim
Chem.–Eur. J., 2010, 16, 4186; (e) N. Luo and Z. Yu, Chem.– and A. Jutand, Eur. J. Inorg. Chem., 2001, 2675.
Eur. J., 2010, 16, 787; (f) W. Jin, Z. Yu, W. He, W. Ye and 11 (a) C. Sköld, J. Kleimark, A. Trejos, L. R. Odell,
W.-J. Xiao, Org. Lett., 2009, 11, 1317; (g) M. Kim, J. Kwak
and S. Chang, Angew. Chem., Int. Ed., 2009, 48, 8935;
(h) X. Zhao and Z. Yu, J. Am. Chem. Soc., 2008, 130, 8136;
S. O. Nilsson Lill, P.-O. Norrby and M. Larhed, Chem.–Eur.
J., 2012, 18, 4714; (b) K. L. Hull and M. S. Sanford, J. Am.
Chem. Soc., 2009, 131, 9651 and references cited therein.
(i) K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2007, 12 S. E. Denmark, R. C. Smith and S. A. Tymonko, Tetra-
129, 11904. hedron, 2007, 63, 5730.
5 (a) J. Clayden, S. P. Fletcher, S. J. M. Rowbottom and 13 (a) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002,
M. Helliwell, Org. Lett., 2009, 11, 2313; (b) J. Clayden,
S. P. Fletcher, J. J. W. McDouall and S. J. M. Rowbottom,
41, 4176; (b) V. V. Grushin and H. Alper, Chem. Rev., 1994,
94, 1047.
34 | Org. Biomol. Chem., 2013, 11, 31–34
This journal is © The Royal Society of Chemistry 2013