Catalytic discrimination between formyl groups in regio-and stereoselective intramolecular cross-Aldol reactions

Article abstract of DOI:10.1039/c5sc04594k

Catalytic discrimination between inequivalent formyl groups was achieved using an aniline-Type acid-base catalyst for the regio-, diastereo-, and enantioselective intramolecular cross-Aldol reactions of enolizable dials. Although l-proline gave a mixture of the regio-and stereoisomeric products in the presence of an N-containing 1,6-dial, the aniline-Type catalyst afforded anti-3,4-disubstituted pyrrolidine in high regio-, and stereoselectivity beyond the background reaction, which led to the regioisomeric 2,3-disubstituted products. The mild reactivity of the aniline-Type amine facilitated catalytic discrimination between the inequivalent formyl groups. Kinetic isotope effect studies and reductive amination experiments suggested that the regioselectivity was controlled under the enamine-forming steps.

Full text of DOI:10.1039/c5sc04594k

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EDGE ARTICLE
Overcoming Naphthoquinone Deactivation: Rhodium-Catalyzed
C-5 Selective C-H Iodination as a Gateway to Functionalized
Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
b
a
Guilherme A. M. Jardim, Eufrânio N. da Silva Júnior, * and John F. Bower *
DOI: 10.1039/x0xx00000x
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.
www.rsc.org/
substituent, which was crucial for facilitating cyclometalation.
Introduction
1
,4-Naphthoquinones function as redox cyclers and alkylating
1
agents in a wide range of biological processes. For example,
vitamin K encompasses a family of 2-methyl-1,4-naphthoquinones
that act as cofactors for the post-translational carboxylation of
glutamic acid residues, a process that is essential to blood
coagulation
naphthoquinones
1e
and
bone
metabolism.
Other
notable
dimeric
2a
include
the juglomycins,
pyranonaphthoquinones, such as protoaphin-fb and protoaphin-
2b-e
2f
sl and the lapachones (Scheme 1A). Because of their biological
importance, significant efforts are devoted to the synthesis and
3
evaluation of a wide range of naphthoquinone derivatives. While
methods for the modification of the quinone B-ring are reasonably
4
well established, flexible protocols that allow the direct
5
functionalization of the benzenoid A-ring are rare (Scheme 1B).
This situation is exacerbated by the limitations associated with de
6
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 modification of
naphthoquinones is limited by (a) their susceptibility to reduction,
(
b) their high electrophilicity, (c) the low nucleophilicity of the
benzenoid A-ring and (d) the weak coordinating ability of the B-ring
carbonyls (Scheme 1B). Indeed, we are aware of only one protocol
that enables catalytic carbonyl directed C-H functionalization of the
8
naphthoquinone A-ring (Scheme 1C). Here, Rh(III)-catalyzed C-5
vinylation required the strategic installation of a C-2 amino
a.
School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom. E-
mail: john.bower@bris.ac.uk.
Institute of Exact Sciences, Department of Chemistry, Federal University of Minas
b.
Scheme 1
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. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Chemical Science
Carbonyl directed ortho-metalation with late transition metals selectively adduct 2g, wherein iodination has occurred at the more
View Article Online
DOI: 10.1039/C5SC04594K
7,9
is usually a reversible process, where the equilibrium depends hindered ortho-position. Conversely, methyl-substituted system 1h
upon both the nucleophilicity of the arene and the coordinating favored iodination at the less hindered ortho-site to deliver iodide
strength of the directing group (Scheme 1B). Neither aspect is 2h
favorable for naphthoquinones, so an efficient process must
necessarily rely upon fast trapping of the metalated intermediate.
Table 1 Selected optimization results.
In considering this, we sought to introduce a synthetically versatile
handle under conditions that avoid nucleophilic or reducing
reagents. Consequently, we were drawn to the ortho-C-H iodination
9
protocol reported by Glorius and co-workers, which involves the
trapping of cyclometalated aryl-Rh(III) complexes with NIS. This
reagent is highly reactive, oxidative and also non-nucleophilic, such
that it seemed well suited to C-5 selective iodination. In this report,
we outline the development and scope of this protocol, which
provides, for the first time, a C-H activation-based gateway to
diverse A-ring analogues (Scheme 1D). Additionally, we disclose
that, in certain cases, fine tuning of the Rh-system enables a
complete switch to C-2 selective iodination.
Results and discussion
Preliminary studies involved exposing naphthoquinone 1a to a
variety of electrophilic iodine sources in the presence of in situ diiodo-5,5-dimethylhydantoin. Cp* = isopropyl tetramethylcyclopentadienyl. Cp*
generated cationic Rh(III)-systems (Table 1). These experiments trifluoromethyl tetramethylcyclopentadienyl.
[
a] External temperature of the reaction vessel. NIS = N-iodosuccinimide. DIH = 1,3-
i-Pr
CF3
=
revealed that achieving both high conversion and high C-5
regioselectivity was likely to be challenging. [RhCp*Cl ] /AgNTf in
2
2
2
Table 2 Scope of the C-5 selective iodination protocol.
combination with NIS and Cu(OAc) resulted in only a 39% yield of
2
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 and bis-iodinated
product 4 (Entry 2). Extensive optimization efforts were undertaken
to identify an effective system, and, in part, these studies focussed
on the use of other acetate ligated Lewis acids in combination with
10
a range of Rh(III)-precatalysts (Entries 3-8). However none of
these systems were especially effective, with the key issue being
competitive degradation of the iodinating agent under the reaction
conditions. To resolve this, microwave conditions were
11
o
investigated. Pleasingly, by heating at 65 W (50 C), a 54% yield of
a was obtained after just 2.5 hours (Entry 9). Under these
2
conditions, the major byproduct was bis-iodinated adduct 4, which
was formed in 14% yield. Further refinement led to the conditions
outlined in Entry 10, which deliver 2a in 69% yield and with high
1
2
selectivity over 3a and 4. The conversion of 1a to 2a has been
achieved previously in 34% overall yield, but this required a
substrate specific 5 step sequence via a potentially hazardous
1
3
diazonium intermediate. Thus, the efficiency and generality (vide
infra) of the new protocol described here is both notable and
synthetically enabling.
The scope of the new process is outlined in Table 2.
Naphthoquinones 1b-e possessing C-8 substitution underwent
efficient iodination to provide targets 2b-e in good to excellent
yield. As expected, the efficiency of the process decreases as the
benzenoid ring becomes more electron deficient, and, accordingly,
nitro adduct 2f was generated in only 24% yield. Systems with
substituents at C-6 or C-7 can potentially deliver two different
<
5% Bis-iodination was observed in all cases. NIS = N-iodosuccinimide. [a] 5 mol%
o
[
RhCp*Cl
2
]
2
and 27 mol% AgNTf
2
were used. [b] Run at 65 C and 75 W.
regioisomeric products. Perhaps as
a result of secondary
coordination by the methoxy group, naphthoquinone 1g afforded
2
| Chem. Sci., 2015, 00, 1-3
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in 63% yield. Halogen substituents are tolerated and bromo- and
ARTICLE
Preliminary results suggest that other highlyVieewleAcrtticrloepOhnliilnice
chloro-naphthoquinones 1j-l were converted to targets 2j-l in reagents might also be effective for C-5 selDeOctI:iv1e0.1fu03n9c/tCio5nSaCl0iz4a5t9io4Kn
synthetically useful yields. For 2j, the high ortho-regioselectivity (Scheme 3). Using DBH, Rh-catalyzed C-5 selective bromination of
may reflect the higher basicity of the C-4 carbonyl of 1j. In all cases, 1a proceeded in 66% yield to afford a 7:2 mixture of C-5 and C-2
only trace quantities (≤5 %) of bis-iodinated and C-2/3 iodinated bromides 6/7; the structure of 6 was confirmed by single crystal X-
13
products were observed (cf. 4 and 3a), and no significant iodination ray diffraction. The most direct previous entry to 6 involved
occurred in the absence of Rh-catalyst. Structural assignments were oxidation of 2-bromonaphthalene, but this afforded the target in
23
based on detailed NMR analysis (DEPT, COSY, HSQC, HMBC) and X- only 15% yield and as a complex mixture of isomers. Alternative C-
14
ray structures of 2a-c, 2f, 2j and 2k.
2 selective bromination can be achieved by adapting the conditions
During optimization we noted that the regioselectivity of outlined in Scheme 2 and this enabled the selective formation of 7
iodination is strongly influenced by the nature of the Lewis acidic in 88% yield from 1a.
additive. Acetate based systems consistently provided high
selectivity for C-5, likely via a Rh-acetate promoted concerted
15
metalation-deprotonation mechanism (cf. Table 1, Entry 8). By
switching from Cu(OAc)2 to CuSO4 we were able to develop a
10,16
complementary C-2 selective iodination protocol (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
17
only 35% yield and as a mixture of products. For unsymmetrical
systems, such as 1h, C-2 vs C-3 selectivity was not readily controlled
18
and 3h was formed as a mixture of these two regioisomers. At the Figure 1 C-C bond forming derivatizations of 2a. TBAC = tetra-n-butylammonium
chloride, DMAc = N,N-dimethylacetamide.
present stage, C-3 selective iodination of systems possessing
substitution at C-2 is not feasible, perhaps due to steric inhibition of
the C-H metalation event.
Scheme 2 C-2 selective iodination. DIH = 1,3-diiodo-5,5-dimethylhydantoin. Cpt = 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 Scheme
3
C-5 and C-2 selective bromination. DBH
=
1,3-dibromo-5,5-
dimethylhydantoin. Cpt = 1,3-di-tert-butylcyclopentadienyl.
reactive and non-reducing coupling partners. Accordingly, we have
been unable to achieve direct C-H activation based C-C bond
19
formations. However, the iodinated products described here Conclusions
provide a gateway to this important goal (Figure 1). Because of the
synthetic inaccessibility of A-ring halogenated naphthoquinones,
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 first 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 flexible modifications 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 coordinating and/or redox sensitive substrates.
Pd-catalyzed cross-couplings involving the benzenoid ring have not
been developed. This aspect is challenging because the quinone
20
moiety 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. After extensive
21
investigation, 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 delivered 5b
22
in 66% yield. To date, alkynylation under Sonogashira conditions
has not been fruitful but the use of stoichiometric alkynyl copper(I)
reagents is feasible and this allowed the isolation of 5c in 64%
1
3
yield. The studies outlined in Figure 1 validate short and
diversifiable entries to previously challenging naphthoquinone
targets.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2015, 00, 1-3 | 3
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Chemical Science
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. Aromatic substitution approaches are generVaiellwyArreticlilaenOtnloinne
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(
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1. For reviews and discussion on the benefits of microwave
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ARTICLE
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2. A CEM Discover microwave was used in combination with
a customized, re-sealable reaction tube (see the ESI).
Under optimized conditions, a constant power input of
6
0W was applied and the outer wall of the reaction tube
o
was maintained at 45 C using a cooling flow of N . For
2
the conversion of 1a to 2a, very similar results (71% yield
of 2a) were achieved using a Biotage Initiator 8
o
microwave reactor. Heating at 45 C under conventional
thermal conditions (oil bath) gave only an 8% yield of 2a,
which is consistent with microwave conditions providing
more efficient heating (see reference 11).
1
3. N. V. Ivashkina, V. S. Romanov, A. A. Moroz, M S.
Shvartsberg, Izvestiya Akademii Nauk SSSR, Seriya
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1
4. CCDC 1441683-1441694 contain the supplementary
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provided free of charge by The Cambridge
Crystallographic Data Centre.
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6. Rh(III)-catalyzed C-2 selective C-C bond forming processes
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004, 34, 3389.
1
8. For systems that possess electron donating groups on the
B-ring (e.g. 1b) this counterion effect is overridden and
iodination occurs preferentially at C-5.
1
9. For example, attempted C-5 vinylation of 1a under the
conditions outlined in reference 8 proceeded in <5% yield.
0. This issue has been noted in studies on the direct
functionalization of quinones: (a) Y. Fujiwara, V. Domingo,
I. B. Seiple, R. Gianatassio, M. Del Bel, P. S. Baran, J. Am.
Chem. Soc., 2011, 133, 3292; (b) S. E. Walker, J. A. Jordan-
Hore, D. G. Johnson, S. A. Macgregor, A.-L. Lee, Angew.
Chem. Int. Ed., 2014, 53, 13876.
2
2
2
2
1. (a) T. J. Colacot, H. A. Shea, Org. Lett., 2004, 6, 3731; (b) S.
P. H. Mee, V. Lee, J. E. Baldwin, Angew. Chem. Int. Ed.,
2
004, 43, 1132.
2. P. M. Murray, J. F. Bower, D. K. Cox, E. K. Galbraith, J. S.
Parker, J. B. Sweeney, Org. Process Res. Dev., 2013, 17,
397.
3. M. Periasamy, M. V. Bhatt, Synthesis, 1997, 330.
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