Overcoming naphthoquinone deactivation: Rhodium-catalyzed C-5 selective C-H iodination as a gateway to functionalized derivatives

Article abstract of DOI:10.1039/c6sc00302h

We report a Rh-catalyzed method for the C-5 selective C-H iodination of naphthoquinones and show that complementary C-2 selective processes can be achieved under related conditions. C-C bond forming derivatizations of the C-5 iodinated products provide a gateway to previously inaccessible A-ring analogues. The present study encompasses the first catalytic directed ortho-functionalizations of simple (non-bias) naphthoquinones. The strategic considerations outlined here are likely to be applicable to C-H functionalizations of other weakly coordinating and/or redox sensitive substrates.

Full text of DOI:10.1039/c6sc00302h

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Overcoming naphthoquinone deactivation:
rhodium-catalyzed C-5 selective C–H iodination as
a gateway to functionalized derivatives†
Cite this: DOI: 10.1039/c6sc00302h
ab
b
a
Guilherme A. M. Jardim, Eufranio N. da Silva Junior* and John F. Bower*
ˆ
´
We report a Rh-catalyzed method for the C-5 selective C–H iodination of naphthoquinones and show that
complementary C-2 selective processes can be achieved under related conditions. C–C bond forming
derivatizations of the C-5 iodinated products provide a gateway to previously inaccessible A-ring
analogues. The present study encompasses the first catalytic directed ortho-functionalizations of simple
Received 21st January 2016
Accepted 18th February 2016
DOI: 10.1039/c6sc00302h
(non-bias) naphthoquinones. The strategic considerations outlined here are likely to be applicable to
www.rsc.org/chemicalscience
C–H functionalizations of other weakly coordinating and/or redox sensitive substrates.
ability of the B-ring carbonyls (Scheme 1B). Indeed, we are
aware of only one protocol that enables catalytic carbonyl
Introduction
1
,4-Naphthoquinones function as redox cyclers and alkylating directed C–H functionalization of the naphthoquinone A-ring
1
agents in a wide range of biological processes. For example,
vitamin encompasses family of 2-methyl-1,4-naph-
K
a
thoquinones that act as cofactors for the post-translational
carboxylation of glutamic acid residues, a process that is
1e
essential to blood coagulation and bone metabolism. Other
2a
notable naphthoquinones include the juglomycins, dimeric
pyranonaphthoquinones, such as protoaphin- and proto-
2
b–e
2f
aphin-sl
and the lapachones (Scheme 1A). Because of their
biological importance, signicant efforts are devoted to the
synthesis and evaluation of a wide range of naphthoquinone
3
derivatives. While methods for the modication of the quinone
4
B-ring are reasonably well established, exible protocols that
allow the direct functionalization of the benzenoid A-ring are
5
rare (Scheme 1B). This situation is exacerbated by the limita-
6
tions associated with de novo naphthoquinone construction.
Consequently, medicinal studies on A-ring analogues are, in the
main, limited to simple derivatives of natural isolates.
Catalytic directed ortho-C–H metalation has emerged as
a powerful platform for the preparation of diverse aromatic
7
compounds. However, its application to the modication of
naphthoquinones is limited by (a) their susceptibility to
reduction, (b) their high electrophilicity, (c) the low nucleo-
philicity of the benzenoid A-ring and (d) the weak coordinating
a
School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK. E-mail: john.bower@
bris.ac.uk
b
Institute of Exact Sciences, Department of Chemistry, Federal University of Minas
Gerais, Belo Horizonte, MG, 31270-901, Brazil. E-mail: eufranio@ufmg.br
†
Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for all compounds are provided. CCDC
441683–1441694. For ESI and crystallographic data in CIF or other electronic
1
format see DOI: 10.1039/c6sc00302h
Scheme 1
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8
(
Scheme 1C). Here, Rh(III)-catalyzed C-5 vinylation required the and bis-iodinated product 4 (entry 2). Extensive optimization
strategic installation of a C-2 amino substituent, which was efforts were undertaken to identify an effective system, and, in
crucial for facilitating cyclometalation. part, these studies focussed on the use of other acetate ligated
Carbonyl directed ortho-metalation with late transition Lewis acids in combination with a range of Rh(III)-precatalysts
7,9
10
metals is usually a reversible process, where the equilibrium (entries 3–8). However none of these systems were especially
depends upon both the nucleophilicity of the arene and the effective, with the key issue being competitive degradation of the
coordinating strength of the directing group (Scheme 1B). iodinating agent under the reaction conditions. To resolve this,
11
Neither aspect is favorable for naphthoquinones, so an efficient microwave conditions were investigated. Pleasingly, by heating
ꢀ
process must necessarily rely upon fast trapping of the meta- at 65 W (50 C), a 54% yield of 2a was obtained aer just 2.5
lated intermediate. In considering this, we sought to introduce hours (entry 9). Under these conditions, the major byproduct
a synthetically versatile handle under conditions that avoid was bis-iodinated adduct 4, which was formed in 14% yield.
nucleophilic or reducing reagents. Consequently, we were Further renement led to the conditions outlined in entry 10,
drawn to the ortho-C–H iodination protocol reported by Glorius which deliver 2a in 69% yield and with high selectivity over 3a
9
12
and co-workers, which involves the trapping of cyclometalated and 4. The conversion of 1a to 2a has been achieved previously
aryl-Rh(III) complexes with NIS. This reagent is highly reactive, in 34% overall yield, but this required a substrate specic 5 step
13
oxidative and also non-nucleophilic, such that it seemed well sequence via a potentially hazardous diazonium intermediate.
suited to C-5 selective iodination. In this report, we outline the Thus, the efficiency and generality (vide infra) of the new protocol
development and scope of this protocol, which provides, for the described here is both notable and synthetically enabling.

rst time, a C–H activation-based gateway to diverse A-ring
The scope of the new process is outlined in Table 2. Naph-
analogues (Scheme 1D). Additionally, we disclose that, in thoquinones 1b–e possessing C-8 substitution underwent effi-
certain cases, ne tuning of the Rh-system enables a complete cient iodination to provide targets 2b–e in good to excellent
switch to C-2 selective iodination.
yield. As expected, the efficiency of the process decreases as the
benzenoid ring becomes more electron decient, and, accord-
ingly, nitro adduct 2f was generated in only 24% yield. Systems
with substituents at C-6 or C-7 can potentially deliver two
different regioisomeric products. Perhaps as a result of
secondary coordination by the methoxy group, naphthoquinone
Results and discussion
Preliminary studies involved exposing naphthoquinone 1a to
a variety of electrophilic iodine sources in the presence of in situ
generated cationic Rh(III)-systems (Table 1). These experiments
revealed that achieving both high conversion and high C-5
regioselectivity was likely to be challenging. [RhCp*Cl ] /AgNTf
2 2 2
in combination with NIS and Cu(OAc) resulted in only a 39%
1g afforded selectively adduct 2g, wherein iodination has
occurred at the more hindered ortho-position. Conversely,
methyl-substituted system 1h favored iodination at the less
hindered ortho-site to deliver iodide 2h in 63% yield. Halogen
substituents are tolerated and bromo- and chloro-naph-
thoquinones 1j–l were converted to targets 2j–l in synthetically
useful yields. For 2j, the high ortho-regioselectivity may reect
2
yield of 2a, albeit with 10 : 1 selectivity over C-2 regioisomer 3a
(entry 1). Other electrophilic iodine sources were less effective;
for example, DIH led to substantial quantities of C-2 adduct 3a
Table 1 Selected optimization results
+
ꢀ
Entry
Rh-source
X
Additive
I source
Y
Temp/ C
Z
2a : 3a : 4
1
2
3
4
5
6
7
8
9
[RhCp*Cl
[RhCp*Cl
[RhCp*Cl
[RhCp*Cl
[RhCp*Cl
2
]
]
]
]
]
2
2
2
2
2
(2.5%)
(2.5%)
(2.5%)
(2.5%)
(4%)
10
10
10
10
10
10
10
10
10
20
Cu(OAc)
Cu(OAc)
2
NIS
DIH
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
220
140
140
140
120
120
120
120
120
120
120
120
100
100
100
100
22
22
22
22
16
16
16
16
2.5
2
39 : 8 : 0
4 : 14 : 10
14 : 0 : 0
18 : 0 : 0
44 : 5 : 0
39 : 8 : 0
3 : 0 : 0
32 : 2 : 0
54 : 0 : 14
69 : 0 : 5
2
2
2
2
2
Cu(OPiv)
Zn(OAc)
2
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
i-pr
[RhCp* Cl
2
]
2
(4%)
(4%)
2
2
2
2
2
CF
3
[RhCp* Cl
[RhCp*(OAc)
2
]
2
2
] (4%)
a
[RhCp*Cl
[RhCp*Cl
2
]
]
2
(4%)
(3.75%)
120 50a
(65 W)
(60 W)
1
0
2
2
100 45
a
i-Pr
External temperature of the reaction vessel. NIS ¼ N-iodosuccinimide. DIH ¼ 1,3-diiodo-5,5-dimethylhydantoin. Cp*
¼ isopropyl
CF
3
tetramethylcyclopentadienyl. Cp* ¼ triuoromethyl tetramethylcyclopentadienyl.
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a
Table 2 Scope of the C-5 selective iodination protocol
Scheme 2 C-2 selective iodination. DIH ¼ 1,3-diiodo-5,5-dime-
t
thylhydantoin. Cp ¼ 1,3-di-tert-butylcyclopentadienyl.
In principle, the activation mode employed here should
enable other selective naphthoquinone C–H functionalizations.
However, as outlined in the introduction, efficient processes
likely require highly reactive and non-reducing coupling part-
ners. Accordingly, we have been unable to achieve direct C–H
19
activation based C–C bond formations. However, the iodin-
ated products described here provide a gateway to this impor-
tant goal (Fig. 1). Because of the synthetic inaccessibility of A-
ring halogenated naphthoquinones, Pd-catalyzed cross-
couplings involving the benzenoid ring have not been devel-
oped. This aspect is challenging because the quinone moiety
20
can act as an oxidant or ligand for Pd. For example, arylation
of 2a could not be achieved under Suzuki conditions and only
decomposition products were observed. Aer extensive inves-
21
tigation, we established that mild Stille cross-couplings are
effective and, using this approach, arylated derivative 5a was
isolated in high yield. Heck reactions are another promising
avenue and Pd(0)-catalyzed reaction of 2a with ethyl acrylate
22
delivered 5b in 66% yield. To date, alkynylation under Sono-
gashira conditions has not been fruitful but the use of stoi-
chiometric alkynyl copper(I) reagents is feasible and this
allowed the isolation of 5c in 64% yield. The studies outlined
in Fig. 1 validate short and diversiable entries to previously
challenging naphthoquinone targets.
a
<
5% bis-iodination was observed in all cases. NIS
¼
N-
were
iodosuccinimide. [a] 5 mol% [RhCp*Cl
used. [b] Run at 65 C and 75 W.
2
]
2
and 27 mol% AgNTf
2
13
ꢀ
Preliminary results suggest that other highly electrophilic
the higher basicity of the C-4 carbonyl of 1j. In all cases, only reagents might also be effective for C-5 selective functionaliza-
trace quantities (#5%) of bis-iodinated and C-2/3 iodinated tion (Scheme 3). Using DBH, Rh-catalyzed C-5 selective bromi-
products were observed (cf. 4 and 3a), and no signicant iodin- nation of 1a proceeded in 66% yield to afford a 7 : 2 mixture of
ation occurred in the absence of Rh-catalyst. Structural assign- C-5 and C-2 bromides 6/7; the structure of 6 was conrmed by
13
ments were based on detailed NMR analysis (DEPT, COSY, single crystal X-ray diffraction. The most direct previous entry
14
HSQC, HMBC) and X-ray structures of 2a–c, 2f, 2j and 2k.
to 6 involved oxidation of 2-bromonaphthalene, but this affor-
During optimization we noted that the regioselectivity of ded the target in only 15% yield and as a complex mixture of
23
iodination is strongly inuenced by the nature of the Lewis isomers. Alternative C-2 selective bromination can be achieved
acidic additive. Acetate based systems consistently provided by adapting the conditions outlined in Scheme 2 and this
high selectivity for C-5, likely via a Rh-acetate promoted enabled the selective formation of 7 in 88% yield from 1a.
concerted metalation–deprotonation mechanism (cf. Table 1,
15
entry 8). By switching from Cu(OAc) to CuSO we were able to
2
4
develop a complementary C-2 selective iodination protocol
10,16
(Scheme 2).
Under optimized conditions, iodination of 1a
generated 3a in 90% yield and with complete regioselectivity.
Perez and co-workers have shown that morpholine–iodine
complex can convert 1a to 3a, but in only 35% yield and as
17
a mixture of products. For unsymmetrical systems, such as 1h,
C-2 vs. C-3 selectivity was not readily controlled and 3h was
18
formed as a mixture of these two regioisomers. At the present
stage, C-3 selective iodination of systems possessing substitu-
tion at C-2 is not feasible, perhaps due to steric inhibition of the
C–H metalation event.
Fig. 1 C–C bond forming derivatizations of 2a. TBAC ¼ tetra-n-
butylammonium chloride, DMAc ¼ N,N-dimethylacetamide.
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A. W. Johnston, S. F. MacDonald and A. R. Todd, J. Chem.
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t
5
,5-dimethylhydantoin. Cp ¼ 1,3-di-tert-butylcyclopentadienyl.
Conclusions
In conclusion, we report an efficient and reliable methodology
for C-5 selective C–H iodination of naphthoquinoidal
compounds and show that complementary C-2 selective
processes can be achieved under related conditions. To the best
of our knowledge, the present study provides the rst method
for catalytic directed ortho-functionalization of simple (non-
bias) naphthoquinones. The iodinated products are amenable
to C–C bond forming derivatizations and this enables exible
modications to the naphthoquinone A-ring. The chemistry
opens up new avenues for biological investigation and is likely
to be of wide general interest. In broader terms, the strategic
considerations outlined here may guide the development of
catalytic C–H functionalizations involving other weakly coordi-
nating and/or redox sensitive substrates.
1
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1
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3
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Acknowledgements
G. A. M. J. thanks the CNPq Science without Borders program
for a scholarship. We thank the X-ray crystallography service at
the School of Chemistry, University of Bristol, for analysis of the
products described here. J. F. B. is indebted to the Royal Society
for the provision of a University Research Fellowship. E. N. S. J.
thanks the Royal Society of Chemistry for a JWT Jones Travelling
Fellowship, CAPES and CNPq for research support.
5
6
Aromatic substitution approaches are generally reliant on
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1 For reviews and discussion on the benets of microwave
1
heating for transition metal catalyzed processes, see: (a) 21 (a) T. J. Colacot and H. A. Shea, Org. Lett., 2004, 6, 3731; (b)
M. R. Rosana, Y. Tao, A. E. Stiegman and G. B. Dudley,
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S. Tomar, E. Van der Eycken and V. S. Parmar, Org. Process 22 P. M. Murray, J. F. Bower, D. K. Cox, E. K. Galbraith,
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Eycken, Eur. J. Org. Chem., 2008, 1133; (d) M. Larhed,
C. Moberg and A. Hallberg, Acc. Chem. Res., 2002, 35, 717.
2 A CEM Discover microwave was used in combination with
a customized, re-sealable reaction tube (see the ESI†).
J. S. Parker and J. B. Sweeney, Org. Process Res. Dev., 2013,
17, 397.
23 M. Periasamy and M. V. Bhatt, Synthesis, 1997, 330.
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