Regioselective iridium(I)-catalysed remote borylation of oxygenated naphthalenes

Article abstract of DOI:10.1016/j.tetlet.2012.05.040

We present our investigations into the regioselective borylation and halogenation of polyoxygenated naphthalene systems that are key precursors to dimeric pyranonaphthoquinone natural products. A variety of oxygenated naphthalenes were successfully borylated with pinacolborane in high yield and excellent regioselectivity using [Ir(COD)OMe]₂ and di-tert-butylbipyridine (dtbpy). The boronates were also readily transformed into the corresponding halides, opening new avenues for the preparation of advanced Suzuki coupling substrates useful for the synthesis of natural products.

Full text of DOI:10.1016/j.tetlet.2012.05.040

Tetrahedron Letters 53 (2012) 3771–3773
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective iridium(I)-catalysed remote borylation
of oxygenated naphthalenes
⇑
Paul Hume, Daniel P. Furkert, Margaret A. Brimble
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
We present our investigations into the regioselective borylation and halogenation of polyoxygenated
naphthalene systems that are key precursors to dimeric pyranonaphthoquinone natural products. A vari-
ety of oxygenated naphthalenes were successfully borylated with pinacolborane in high yield and excel-
Received 19 March 2012
Revised 30 April 2012
Accepted 10 May 2012
Available online 16 May 2012
2
lent regioselectivity using [Ir(COD)OMe] and di-tert-butylbipyridine (dtbpy). The boronates were also
readily transformed into the corresponding halides, opening new avenues for the preparation of
advanced Suzuki coupling substrates useful for the synthesis of natural products.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Borylation
Pyranonaphthoquinone
C–H activation
Iridium catalysis
Dimeric pyranonaphthoquinones, such as cardinalin 3 (1,
Fig. 1) and crisamicin A (2),2 form an important subclass of the
pyranonaphthoquinone family of antibiotics in which our group
has a long-standing synthetic interest.3 Formation of the key
binaphthyl bond is one of the more challenging aspects of their
synthesis, for which the Suzuki coupling has proven most effective
to date. In some cases a late-stage cross- or homo-coupling using
advanced borylated or halogenated precursors has been possible
(Scheme 1). Direct borylation of a remote aromatic C–H bond
would remove the need for this latent phenol, simplifying the
synthesis of the monomeric naphthalene unit considerably. As an
additional benefit, the direct C–H activation approach would re-
duce the number of functional group interconversions required
to arrive at an activated coupling substrate.
1
To explore the potential of the iridium-catalysed C–H boryla-
tion, a variety of substituted naphthalene systems 7–12 (Table 1)
were submitted to conditions similar to those previously re-
(
e.g., 4, Scheme 1), while in others the coupling was performed
7
on simpler substrates such as 6 followed by a bi-directional elabo-
ration to the final target structures.4 In either case, the necessity
for suitable functionality to enable cross-coupling requires the
assembly of complex monomeric fragments via lengthy synthetic
sequences.
ported, and optimised to give complete conversion for our partic-
,5
8
ular substrates. We were pleased to discover that the reaction
proceeded cleanly and with perfect regioselectivity for the least
O
Remote functionalisation of unactivated C–H bonds offers a
direct and atom-efficient route to synthetic intermediates not
easily prepared using traditional methodology. In particular,
iridium-catalysed borylation of aromatic C–H bonds has become
an important synthetic method for effecting this type of transfor-
mation. Due to recent developments in the methodology for
selective functionalisation of aromatic C–H bonds,6 in particular
OMe
OH
O
O
O
O
OH
MeO
O
cardinalin 3 (1)
O
H
the remote borylation of arenes using iridium catalysts and
O
O
O
OH
,4 -di-tert-butylbipyridine (dtbpy),7 we envisaged that more
H
0
4
O
direct access to these cross-coupling precursors should be feasible.
Most preparative routes to date have involved a pendant phenol
that is selectively unmasked before transformation into a suitable
cross-coupling substrate such as a triflate, halide or boronate
O
O
H
H
O
OH
O
O
crisamicin A (2)
⇑
Corresponding author.
E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
Figure 1. Dimeric pyranonaphthoquinone natural products.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.040

3
772
P. Hume et al. / Tetrahedron Letters 53 (2012) 3771–3773
OMe
OMe
with a stoichiometric amount of pinacolborane (1.1 equiv) affor-
OMe O
OMe
ded a complex mixture of starting material, mono- and di-borylat-
ed products after 24 h. Silyl ether 12 is a potential intermediate en
route to dimeric crisamicin A (2), but although borylation pro-
ceeded in excellent chemical yield, disappointingly no differentia-
tion between the two remote C–H bonds on the naphthalene
system was observed. Boronates 18a and 18b were formed in an
equimolar ratio (entry 6), indicating that the bulky alkyl substitu-
ent at C2 is too distant to direct the iridium-catalysed activation.
The pinacol borate esters 13–18 are potentially useful Suzuki
coupling partners, but for our purposes it proved expedient to der-
ivatise the boron substituent to permit isolation of chromatograph-
ically stable products. To this end, unpurified borate esters 13–18
obtained via borylation, were directly treated with copper(II) bro-
OMe O
OMe
RO
X
OR
OR
(
1)
O
3
4
OHC
Et N
O
O
X
2
NEt2
CHO
NEt2
CHO
O
(
2)
5
6
Scheme 1. Retrosynthetic options for the dimeric pyranonaphthoquinone core of
the cardinalins using late-stage (Eq. 1) or early (Eq. 2) Suzuki coupling of naphthyl
triflates or derived boronate esters (X = OTf or Bpin).
9
mide in aqueous methanol to afford the corresponding bromides
1
9–23 in good yield over the two steps (Table 1). Chloride 22b
hindered arene C–H bond. 1H NMR analysis of the reaction mix-
tures showed quantitative conversion in most cases (entries 1, 2
and 4). In the case of 2,3-dimethoxynaphthalene (9), additional
pinacolborane (5 equiv in total) was required to achieve complete
conversion into the borate ester. Substrate 11, possessing two
equiv sites for borylation, afforded di-borylated 17 as the only
product under the standard conditions (entry 5). Treatment of 11
was also prepared from 16 in an analogous fashion to 22a using
copper(II) chloride in the halogenation step.
To examine further the scope of borylation in the context of
pyranonaphthoquinone synthesis, a small series of carbonyl-con-
taining substrates was also submitted to the borylation conditions.
Submission of ketone 24 to the standard borylation conditions
(Table 2, entry 1) resulted in only 20% conversion into a single
Table 1
Regioselective borylation–halogenation of complex napthalenes
BHpin (2.5 eq.)
[
Ir(COD)OMe] (1.5 mol%)
2
CuX
2
dtbpy (3 mol%)
MeOH-H O
2
OR
OR
OR
THF, 80 °C
OMe
pinB
Time (h)
X
Entry
1
Substrate
OMe
Product
Conv.a (%)
Halide
Yieldb (2 steps)
OMe
OMe
pinB
Br
7
13
1
9
24
100
79
OMe
OMe
OMe
OMe
OMe
2
0
2
3
4
8
72
96
48
100
77c
>90
63
1
4
MeO
MeO
MeO
pinB
Bpin
OMe
MeO
Br
Br
OMe
OMe
21
9
15
67
OMe
OMe
OMe
OMe
OMe
OMe
1
6
22a
2b
MeO
pinB
MeO
Br
10
28 (R = Br) 30 (R = Cl)d
2
Bpin
R
OMe
OMe
OMe
1
7
1
1
23
5
6
24
24
88
56
Bpin
Br
OMe
MeO OTBS
OMe
OMe
MeO OTBS
pinB
1
8a
1
2
OMe
OMe
95 (1:1)
Decomposition
—
MeO OTBS
1
8b
pinB
OMe
a
(1.5 mol %), dtbpy (3.0 mol %), THF, 80 °C. Conversion determined by 1H NMR spectroscopy.
Borylation conditions: HBpin (2.5 equiv), [Ir(COD)OMe]
Isolated yield over 2 steps after purification by flash chromatography; structures of 19–23 determined by H NMR spectroscopy; Bromination conditions: CuBr
2
b
1
2
, MeOH–
2
H O.
c
HBpin (5 equiv) used.
CuCl used instead of CuBr .
2 2
d

P. Hume et al. / Tetrahedron Letters 53 (2012) 3771–3773
3773
Table 2
ing convenient preparation of variously substituted naphthalene
systems for investigation of cross-coupling reactions. Carbonyl-
containing compounds were found to undergo predominantly
reduction under these reaction conditions. The methodology re-
ported herein will simplify access to key Suzuki coupling sub-
strates required for the total synthesis of naphthalene-derived
natural products including the dimeric pyranonaphthoquinone
antibiotics, and enable preparation of previously inaccessible sub-
stitution patterns.
Attempted borylation of carbonyl-containing substrates
Entry
1
Substrate
Product
Conv.a (%)
MeO
O
MeO
O
0b
pinB
2
27a
24
OMe
OMe
MeO OH
7
5c
References and notes
27b
OMe
1. (a) Gill, M.; Buchanan, M. S.; Yu, J. J. Chem. Soc., Perkin Trans. 1 1997, 919; (b) Gill,
M.; Buchanan, M. S.; Yu, J. Aust. J. Chem. 1997, 50, 1081.
O
OH
2
.
Nelson, R. A.; Pope, J. A.; Luedemann, L. E.; McDaniel, L. E.; Schaffner, C. P. Jpn. J.
Antibiot. 1986, 39, 335–344.
(a) Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267–281;
2
8
9
2
5
100d
2
3
3.
(
b) Sperry, J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep. 2008, 25, 376–400.
O
O
OH
O
4
5
.
.
Brimble, M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 2084.
Sperry, J.; Gibson, J. S.; Sejberg, J. J. P.; Brimble, M. A. Org. Biomol. Chem. 2006, 6,
4261–4270.
2
26
100 d
6.
Ishiyama, T.; Miyaura, N. Pure Appl. Chem. 2006, 78, 1369–1375.
O
O
7. Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924–
925.
8. General hydroborylation-bromination procedure: To [Ir(COD)OMe]
2
a
b
c
Borylation conditions: see Table 1.
After 24 h, only starting material 24 and borate ester 27a were present.
(7.3 mg,
0 0
11 lmol) and 4,4 -di-tert-butyl-2,2 -bipyridine (7.0 mg, 26 lmol) in a flame-
2
After 48 h.
dried vial under nitrogen were added THF (0.7 mL), pinacolborane (0.18 mL,
d
Complete after 4 h.
1.24 mmol) and 1,4-dimethoxynaphthalene (7) (188 mg, 1.0 mmol). The
Ò
mixture was stirred at 80 °C for 24 h then filtered through Celite an1 d
concentrated in vacuo to afford crude pinacol ester 13 (100% conversion by
H
NMR) that was used directly in the next step. 1H NMR (400 MHz, CDCl
Me, excess HBpin), 1.25 (12H, s, Me), 3.77 (3H, s, OMe), 3.78 (3H, s, OMe), 6.48
(1H, d, J = 8.4 Hz), 6.54 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.5, 1.0 Hz), 8.06 (1H,
d, J = 8.5 Hz), 8.63 (1H, s); 13C NMR (100 MHz, CDCl
) d 24.2 (CH , excess HBpin)
4.5 (CH , Bpin), 55.2 (CH , OMe), 55.3 (CH , OMe), 82.6 (quat, Bpin), 83.6 (quat,
3
) d 1.10
(
borate ester 27a after 24 h. Unambiguous determination of boryla-
tion regiochemistry (C6 vs C7) was not possible for 27a. We have
proposed the C7-borylated product here on the basis of the
electron-withdrawing properties of the C2 acetyl substituent.
Extension of the reaction time resulted solely in reduction of the
ketone to the corresponding secondary alcohol 27b. Our observa-
tions suggested that once a significant amount of the alcohol had
been formed, the desired borylation was suppressed and reduction
became the predominant reaction pathway. Use of pinacolborane
dimer as an alternative boryl donor gave identical results in this
case. Attempted borylation of naphthoquinone (25) (entry 2) and
chromone (26) (entry 3) only resulted in reduction, affording
hydroquinone (28) and chromanone (29), respectively, in quantita-
tive yields.
3
3
2
3
3
3
excess HBpin), 102.7 (CH, C-6 or 7), 104.3 (CH, C-6 or 7), 120.5 (CH, Ar, C-3),
125.3 (quat, C-4a or 8a), 127.6 (quat, C-4a or 8a), 129.6 (CH, Ar, C-5 or 8), 130.3
(
[
CH, Ar, C-5 or 8), 148.9 (quat, C-4a or 8a), 149.7 (quat, C-4a or 8a); HRMS
+
+
M+Na] found 337.1563, C18
4
H23BNaO requires 337.1585. A portion of crude
13 prepared as above (158 mg, 0.5 mmol) was taken up in MeOH (6.2 mL) and
2
an aqueous solution of CuBr (6.2 mL, 0.25 M, 1.55 mmol) was added dropwise.
The mixture was stirred at 80 °C for 6 h then cooled to rt and extracted with
EtOAc (3 ꢀ 10 mL). The combined organic phase was dried over MgSO
4
, filtered
through a plug of silica and concentrated in vacuo. Column chromatography
(20:1, hexanes–EtOAc) afforded bromide 19 as a pale pink solid (106 mg, 79%
1
over 2 steps): mp 48.9–50.9 °C; H NMR (400 MHz, CDCl
3
) d 3.92 (6H, s, OMe),
6
.65 (2H, s, H-2 and 3), 7.57 (1H, dd, J = 8.8, 2.0 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.39
13
(
3 3 3
1H, d, J = 2.0 Hz). C NMR (100 MHz, CDCl ) d 55.5 (CH , OMe), 55.6 (CH ,
OMe), 103.5 (CH, C-2), 104.3 (CH, C-3), 120.3 (quat, C-6), 123.8 (CH, C-5), 124.3
(CH, C-8), 124.6 (quat, C-4), 127.3 (quat, C-1), 128.9 (CH, C-7), 148.3 (quat, C-4a),
+
79
+
1
2
49.3 (quat, C-8a); HRMS [M+H] found 267.0026,
C
12
H
12 BrO
2
requires
In summary, we have established that the borylation of substi-
tuted naphthalenes with pinacolborane in the presence of the irid-
ium catalyst, [Ir(COD)OMe]
occurs in excellent yield and regioselectivity. The resulting borate
esters are readily converted into the corresponding halides, allow-
1281BrO
+
1
67.0015; found 269.0006, C12
H
2
requires 268.9995. H NMR data were
in agreement with that previously reported (Yajima, A.; Saitou, F.; Sekimoto, M.;
Maetoko, S.; Nukada, T.; Yabuta, G. Tetrahedron 2005, 61, 9162–9172).
. Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434–15435.
2
and di-tert-butylbipyridine ligand
9