Dual role of Rh(III) catalyst enables regioselective halogenation of (electron-rich) heterocycles

Article abstract of DOI:10.1021/jacs.5b00283

The Rh(III)-catalyzed selective bromination and iodination of electron-rich heterocycles is reported. Kinetic investigations show that Rh plays a dual role in the bromination, catalyzing the directed halogenation and preventing the inherent halogenation of these substrates. As a result, this method gives highly selective access to valuable halogenated heterocycles with regiochemistry complementary to those obtained using uncatalyzed approaches, which rely on the inherent reactivity of these classes of substrates. Furans, thiophenes, benzothiophenes, pyrazoles, quinolones, and chromones can be applied.

Full text of DOI:10.1021/jacs.5b00283

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Communication
Dual role of Rh(III)-catalyst enables regioselective
halogenation of (electron-rich) heterocycles
Nils Schroeder, Fabian Lied, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00283 • Publication Date (Web): 15 Jan 2015
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Dual role of Rh(III)-catalyst enables regioselective
halogenation of (electron-rich) heterocycles
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Nils Schröder, Fabian Lied and Frank Glorius*
OrganischꢀChemisches Institut, Westfälische WilhelmsꢀUniversität Münster, Corrensstrasse 40, 48149 Münster, Germany
Supporting Information Placeholder
Encouraged by previous Rh(III)ꢀcatalyzed halogenations of
arenes and alkenes,9,10 we started our study using N,Nꢀ
diisopropylfuranꢀ2ꢀcarboxamide (1) as the standard substrate.
Using 5 mol% of [RhCp*(MeCN)3](SbF6)2, Nꢀbromosuccinimide
(NBS) as the halogen source, pivalic acid as an additive and 1,2ꢀ
DCE as the solvent, we were able to get the desired product alꢀ
ready in a yield of 84% (see SI for further information), although
in a mixture with 8% of the dibrominated product. Screening of
different electrophilic brominating agents showed that the yield
could be increased to an excellent 95% with Nꢀbromoꢀphthalimide
(NBP) instead of Nꢀbromosuccinimide, while other reagents
proved to be less effective. Remarkably, unlike most other
Rh(III)ꢀcatalyzed C–H activations, no carboxylic acid or carboxꢀ
ylate was required to obtain high yields.11 Notably the reaction
works efficiently under air and no precaution needs to be taken to
exclude moisture from the glassware.
ABSTRACT: The Rh(III)ꢀcatalyzed selective bromination and
iodination of electronꢀrich heterocycles is reported. Kinetic invesꢀ
tigations show that rhodium plays a dual role in the bromination:
i) catalyzing the directed halogenation and ii) preventing the
inherent halogenation of these substrates. As a result, this method
gives highly selective access to valuable halogenated heterocycles
with complementary regiochemistry to those obtained using unꢀ
catalyzed approaches, which rely on the inherent reactivity of
these classes of substrates. Furans, thiophenes, benzothiophenes,
pyrazoles, quinolones and chromones can be applied.
Aromatic heterocycles are undoubtedly one of the most imꢀ
portant structural motifs in chemical synthesis.1 A major class of
building blocks for the synthesis of heterocycles are halogenated
compounds due to the versatility of the CꢀX group in a large
variety of functionalization reactions,2 especially cross couplings.3
While most heterocycles can be selectively halogenated at a wellꢀ
defined position due to their inherent selectivity resulting from the
electronic properties of the compound, the direct halogenation to
yield other isomers is often challenging and requires harsh reacꢀ
tion conditions and/or many synthetic steps. One prominent stratꢀ
egy is the directed ortho metallation (DoM), followed by a haloꢀ
gen quench.4
Gratifyingly, the more useful N,Nꢀdiethylamide 2 also works
effectively. Comparative reactions with 2 strikingly revealed that
in both reactions excellent selectivity for the 3ꢀ or the 5ꢀposition
was observed and no other isomers were detected by GCꢀMS
analysis (Scheme 1).
Scheme 1: Regioselectivity in the rhodium catalyzed halo-
genation compared to the standard reactivity.
Directed transition metalꢀcatalyzed C–H halogenation has
emerged as a powerful tool for the complementary synthesis of
halogenated building blocks.5 Within the last few years a plethora
of reports on the halogenation of benzene derivatives have been
described, highlighting the importance of this transformation. The
most often used metal for this transformation is palladium,6 howꢀ
ever other metals have also been applied.7 To the best of our
knowledge, only the group of Yu et al. has reported a transition
metalꢀcatalyzed C–H halogenation of aromatic heterocycles using
a palladium catalyst and molecular I2 as the oxidant.6r In this
excellent report pyrazoles, oxazoles, thiazoles and pyridines could
be used as suitable substrates. However, no directed halogenation
for the synthesis of electronꢀrich heterocycles such as furans and
thiophenes exists, which can override the inherent reactivity for
these substrates (Figure 1).8
Reaction conditions: 0.4 mmol scale in 1,2ꢀDCE (0.2 M), 1 equiv
of 1 and 1 equiv of NBP. 2 mol% [RhCp*(MeCN)3](SbF6)2 for
the catalyzed reaction. Isolated yields are reported.
With the optimized conditions in hand, we examined the scope
of different heterocycles with different substitution patterns,
bearing the directing group in the 2ꢀposition (Table 1). For all
substrates a control reaction omitting the catalyst was performed
(see SI for the results). With N,Nꢀdiethylamide 2-Br could be
isolated in a very good yield of 88%, iodination with Nꢀ
iodosuccinimide (NIS) gave a comparable yield of 87% (2-I).12 In
addition, a larger scale reaction (10 mmol scale) could be successꢀ
fully run. With electronꢀwithdrawing groups attached to the furan
the reactivity decreased significantly and higher temperatures
were needed to provide compound 3-Br in an acceptable yield of
57%. Methyl and phenyl substituents were readily tolerated and
the yield of the products were 88% for 5-Br and 95% for 4-Br.
Product 5-Br is a good example for the efficiency of the Rh(III)ꢀ
catalyzed reaction, suppressing two different side reactions which
Figure 1. Switch of selectivity.
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were found in the control reaction without any catalyst: the broꢀ
In comparison to furans with the amide moiety in the 3ꢀ
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mination in the 4ꢀposition occurred in 14% isolated yield, resultꢀ
ing most likely from an electrophilic pathway, and the brominaꢀ
tion of the methylꢀgroup occurred in 69% isolated yield, resulting
from a radical reaction under the uncatalyzed conditions. Switchꢀ
ing from furan to thiophene derivatives resulted in the same reacꢀ
tivity and excellent yields could be obtained. Several interesting
functional groups (methoxy, aldehyde, nitro, trifluoromethyl,
fluoro) were also well tolerated.13 However, the very electronꢀrich
pyrrole motif (13) could not be selectively halogenated under our
reaction conditions. In this case the inherent reactivity predomiꢀ
nated and the main product was the 5ꢀhalogenated derivative.
position, thiophenes such as 15 and 16 could be iodinated in
moderate to excellent yields. In addition benzothiophene 17 also
yielded the desired product 17-Br in a very good yield of 90%.
Applying the pyrazole 18 to the iodination conditions led to both
possible regioisomers in a 7:1 mixture in a combined yield of
80%.
Additionally other important benzannulated heterocycles were
tested under our reaction conditions (Table 3).14 Chromones 19
and 20 and the amide derivative of oxolinic acid 21, an antibiotic
of the quinolone class, underwent iodination in good yields.
Interestingly in the quinolone examples, iodination occurred at the
5ꢀposition rather than at the 2ꢀposition. This is most likely due to
the steric demand of the nitrogen substituent, blocking the 2ꢀ
position, as well as activation of the ring ketone group as a directꢀ
ing group through the nitrogen, which could be viewed as a viꢀ
nylogous amide. In addition to amides ester 22 (the free acid is a
precursor of Ciprofloxaxin, another quinolone type antibiotic)
also underwent iodination, albeit only in a lower yield of 69%. To
prove that the directing group is the vinylogous amide and the
amide or ester function is not of importance, the quinolone core
23 was subjected to the reaction conditions. First we observed
iodination of the 3ꢀposition, which is uncatalyzed due to the high
reactivity of the enamine. Applying this monoꢀiodinated species
to our reaction conditions led to a selective metalꢀcatalyzed ioꢀ
dination of the 5ꢀposition.
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Table 1. Scope of the halogenation of furans and thio-
phenes with the directing group in the 2-position
Table 3. Iodination of other heterocycles and arenes.
All reactions were performed on a 0.4 mmol scale under air.
a
Isolated yields are reported. Reaction was performed on a
10 mmol scale. b Reaction temperature was 100 °C and 1.2 equiv.
NBP were used. c Reaction was performed on a 0.2 mmol scale.
Unfortunately, N,Nꢀdiethylfuraneꢀ3ꢀcarboxamide 14 was not a
suitable substrate for our catalytic system (Table 2). With and
without the rhodiumꢀcatalyst, a mixture of the 2ꢀbrominated and
2,5ꢀdibrominated product was observed in a complex reaction
mixture.
All reaction were performed on a 0.4 mmol scale. Reaction
conditions: [RhCp*(MeCN)3](SbF6)2 (2 mol%), NBP/NIS
b
(1 equiv), 1,2ꢀDCE (0.2 M).a Reaction temperature was 100 °C.
5 molꢀ% [RhCp*(MeCN)3](SbF6)2.
Table 2. Scope of the halogenation of different heterocycles
with the directing group in the 3- or 4-position.
Due to the complementary reactivity of the metalꢀcatalyzed and
uncatalyzed halogenation we decided to see if these methods
could be combined in a oneꢀpot approach to synthesize highly
functionalized heterocyclic building blocks (Scheme 2).15 The
yields for this oneꢀpot procedure were generally very good; only
for product 2-Br/Br, where 2 brominations occurred, was a modꢀ
est yield of 67% observed. Due to the presence of the rhodiumꢀ
catalyst in this procedure, the second halogenation usually reꢀ
quired longer reaction times (see also Figure 2). A key feature is,
Scheme 2. One-Pot Synthesis of multi-halogenated prod-
ucts.
Reactions were performed on a 0.4 mmol scale under air, isoꢀ
lated yields are given. Conditions: [RhCp*(MeCN)3](SbF6)2 (2
mol%), NBP/NIS (1 equiv), 1,2 DCE (0.2 M).
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that for substrates with
3,4ꢀdihalogenation occured in good yield. Thus this method alꢀ
a blocked 5ꢀposition even the
Scheme 3: Bromination of 1 in the presence of AgSbF6.
1
2
lows the synthesis of the completely substituted furan 4-Br/I.
3
4
5
6
To get a better understanding for the origin of the high levels of
regioselectivity in the rhodiumꢀcatalyzed bromination of furan
and thiophene, a kinetic study of the inherent bromination of the
3ꢀbromoꢀsubstituted compound 2-Br, both in the absence and in
the presence of the rhodiumꢀcatalyst, was conducted (Figure 2).
7
could be observed, indicating that no external base (i.e. the
phthalimide) is needed for the C–Hꢀactivation step. A similar
result was observed when using MeOD as an external deuteriumꢀ
source (see SI).
8
9
The inherent, uncatalyzed bromination at the 5ꢀposition in the
absence of rhodium showed an induction period, suggesting that
the substrate does not directly react with NBP (The same effect
was observed with thiophene 6-I, see SI). We propose that the
reaction partner is in fact Br2, and that an initial reaction between
NBP and HBr (or Brꢀ), formed under the reaction conditions,
generates the active halogenating reagent. In the presence of the
rhodiumꢀcatalyst, the rate of the inherent bromination at the 5ꢀ
position is dramatically decreased. Presumably the rhodium comꢀ
plex acts as a bromide acceptor, retarding the formation of Br2.
This hypothesis is supported by the fact that AgSbF6 also supꢀ
presses the uncatalyzed reaction while the addition of HBr accelꢀ
erates the reaction (see SI for further kinetic studies). In addition
we were able to isolate the [RhCp*Br2]2ꢀcomplex upon heating
the cationic catalyst [RhCp*(MeCN)3](SbF6)2 with HBr. These
results suggest that for substrates with free sites at both the 3ꢀ and
the 5ꢀposition available for halogenation, the rhodiumꢀcatalyst
plays two roles in ensuring high levels of regioselectivity. On one
hand, rhodium catalyzes the directed halogenation at the 3ꢀ
position with NBP as the bromine source while, on the other hand,
suppressing the inherent reaction at the 5ꢀposition by retarding the
formation of Br2.
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Scheme 4. Mechanistic Experiments.
90
80
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standard conditions
20
with [Rh]
a0.20 mmol 2 and 0.17 mmol 1ꢀd1 were used. Deuterium distriꢀ
bution was analyzed by ESI.
10
with [Ag]
0
0
500
1000
1500
2000
A significant kinetic isotope effect was observed when measurꢀ
ing the rate constants of the reaction of 1 and 1-d1, indicating that
the C–H activation step is turnoverꢀlimiting. A competition experꢀ
iment between thiopheneꢀsubstrates 8 and 12 showed that elecꢀ
tronꢀpoor substrates react significantly slower. While the absence
of any carboxylate base and the preference for electronꢀrich subꢀ
strates speak in favor of an electrophilic aromatic substitution
pathway (EAS), the observance of a large kinetic isotope effect
time [min]
Figure 2: Inherent reactivity in the absence and in the presence of
[RhCp*(MeCN)3](SbF6)2. Yield determined by GCꢀanalysis.
We thought that the complexation of bromide by the rhodiumꢀ
catalyst is also the major decomposition pathway of the active
catalyst in our standard reaction. To prevent this pathway, we
performed the bromination of 1 in the presence of 5 mol%
AgSbF6 as an additive to remove the bromide. Indeed, it was
possible to perform the reaction with only 0.1 mol% catalyst,
resulting in an excellent turnover-number of 780 (Scheme 3).
argues against this pathway.16
A
concertedꢀmetallationꢀ
deprotonation (CMD) pathway may take place with the amide
moiety of the substrate acting as a base. However, at this point,
neither of the two mechanisms (CMD vs. EAS) can be ruled out.
To gain some mechanistic insight into this transformation difꢀ
ferent experiments have been performed (Scheme 4). To elucidate
the nature of the C–Hꢀactivation step, a crossꢀover experiment
between deuterium enriched diisopropylamide 1ꢀd1 and diethylaꢀ
mide 2 was conducted. In the presence of 2 mol% of the rhodiumꢀ
catalyst and no other additives, significant deuterium scrambling
Following the C–H activation event, two alternative scenarios
seem plausible:
A) oxidation of the Rh(III)ꢀintermediate with the halogenating
agent to generate a Rh(V)ꢀspecies, which releases the desired
product after reductive elimination, and
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(6) For selected examples, see: (a) Dick, A. R.; Hull, K. L.; Sanford, M.
B) direct nucleophilic attack of the rhodacycle at the halogenatꢀ
ing agent to deliver the desired product.
S. J. Am. Chem. Soc. 2004, 126, 2300. (b) Giri, R.; Chen, X.; Yu, J.ꢀQ.
Angew. Chem. Int. Ed. 2005, 44, 2112. (c) Kalyani, D.; Dick, A. R.;
Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483. (d) Kalyani,
D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (e)
Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am.
Chem. Soc. 2006, 128, 7416. (f) Whitfield, S. R.; Sanford, M. S. J. Am.
Chem. Soc. 2007, 129, 15142. (g) Li, J.ꢀJ.; Mei, T.ꢀS.; Yu, J.ꢀQ. Angew.
Chem. Int. Ed. 2008, 47, 6452. (h) Mei, T.ꢀS.; Giri, R.; Maugel, N.; Yu, J.ꢀ
Q. Angew. Chem. Int. Ed. 2008, 47, 5215. (i) Kakiuchi, F.; Kochi, T.;
Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.; Nishiyama, S.;
Tanabe, T. J. Am. Chem. Soc. 2009, 131, 11310. (j) Zhao, X.; Dimitriꢀ
jević, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466. (k) Bedford, R.
B.; Engelhart, J. U.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Dalton
Trans. 2010, 39, 10464. (l) Mei, T.ꢀS.; Wang, D.ꢀH.; Yu, J.ꢀQ. Org. Lett.
2010, 12, 3140. (m) Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal.
2010, 352, 329. (n) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webꢀ
ster, R. L. Angew. Chem. Int. Ed. 2011, 50, 5524. (o) Dubost, E.; Fossey,
C.; Cailly, T.; Rault, S.; Fabis, F. J. Org. Chem. 2011, 76, 6414. (p)
Sarkar, D.; Melkonyan, F. S.; Gulevich, A. V.; Gevorgyan, V. Angew.
Chem. Int. Ed. 2013, 52, 10800. (q) Sun, X.; Shan, G.; Sun, Y.; Rao, Y.
Angew. Chem. Int. Ed. 2013, 52, 4440. (r) Wang, X.ꢀC.; Hu, Y.; Bonacorꢀ
si, S.; Hong, Y.; Burrell, R.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2013, 135,
10326.
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In conclusion, a new method for the effective bromination and
iodination of different classes of electronꢀrich heterocyclic comꢀ
pounds has been described. Key to success is a Rh(III)ꢀcatalyst
that not only catalyzes the desired transformation, but also supꢀ
presses the inherent halogenation at the 5ꢀposition. It is likely that
a similar behavior is also operative in other catalytic transforꢀ
mations. In addition, the benzannulated six membered heterocyꢀ
cles chromones and quinolones were also successfully iodinated.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data, mechanistic exꢀ
periments (KIE, competition, deuteration, kinetics). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* F. Glorius: glorius@uniꢀmuenster.de
(7) Examples using Cu: (a) Chen, X.; Hao, X.ꢀS.; Goodhue, C. E.; Yu,
J.ꢀQ. J. Am. Chem. Soc. 2006, 128, 6790. (b) Wang, W.; Pan, C.; Chen, F.;
Cheng, J. Chem. Commun. 2011, 47, 3978. For an example using Ru, see:
(c) Wang, L.; Ackermann, L. Chem. Commun. 2014, 50, 1083.
(8) For a correction of ref. 6q that shows the superior inherent reactivity
of the 5ꢀposition of furan, thiophene and pyrrole, see:a) Sun, X.; Shan, G.;
Sun, Y.; Rao, Y. Angew. Chem. Int. Ed. 2014, 53, 7108. For related pseuꢀ
dohalogenations of electronꢀrich heterocycles, see: b) Gong, T.ꢀJ., Xiao,
B., Cheng, W.ꢀM., Su, W., Xu, J., Liu, Z.ꢀJ., Liu, L., Fu, Y. J. Am Chem.
Soc. 2013, 135, 10630, c) Liu, W., Ackermann, L. Chem. Commun. 2014,
50, 1878.
(9) For reviews on Rhꢀcatalyzed C–H functionalizations, see: (a) Colꢀ
by, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2009, 110, 624. (b)
Satoh, T.; Miura, M. Chem.– Eur. J. 2010, 16, 11212. (c) Patureau, F. W.;
WencelꢀDelord, J.; Glorius, F. Aldrichimica Acta 2012, 45, 31. (d) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (e) Kuhl, N.;
Schröder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443.
(10) (a) Schröder, N.; WencelꢀDelord, J.; Glorius, F. J. Am. Chem. Soc.
2012, 134, 8298. (b) Collins, K. D.; Glorius, F. Tetrahedron 2013, 69,
7817. (c) Kuhl, N.; Schröder, N.; Glorius, F. Org. Lett. 2013, 15, 3860. (d)
Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014, 136,
10770.
(11) It has to be noted that NaOAc suppresses the reaction, while
HOAc or Cu(OAc)2 have no influence on the reactivity. Propably this is
due to the fact that many free OAc anions coordinate to the Rh and thereꢀ
fore diminish its reactivity.
(12) In contrast to the bromination, the iodination was much slower the
in absence of the rhodiumꢀcatalyst. NIS, which is commercially available
in contrast to Nꢀiodophthalimide (NIP) showed a similar reactivity to NBP
and, thus, was used as reagent of choice for iodinations.
(13) For a more detailed robustness screen, see SI and: (a) Collins, K.
D.; Glorius, F. Nat. Chem. 2013, 5, 597. (b) Collins, K. D.; Glorius, F.
Tetrahedron 2013, 69, 7817.
(14) In most cases the iodination was shown to be more effective. The
bromination with NBP often led to only lower conversions to the desired
product.
(15) The rhodium catalyzed reaction was performed first, because the
reaction is cleaner than the nonꢀmetal catalyzed one. If the order was
changed, formation of side products and catalyst poisoning occured.
(16) There are some discussions concerning the observation of an KIE
in an electrophilic substitution pathway, however the reaction conditions
differ significantly from ours: (a) Boele, M. D. K.; van Strijdonck, G. P.
F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P.
W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (b) Campeau, L.ꢀC.; Parisꢀ
ien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2005, 128, 581. (c) Engle,
K. M.; Wang, D.ꢀH.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2010, 132, 14137.
ACKNOWLEDGMENT
We dedicate this manuscript to Prof. Günter Haufe (WWU) on the
occasion of his 65th birthday. We thank Daniel Paul for assistance
with the NMR experiments, Christian Vosse for experimental
support and Tobias Gensch, DaꢀGang Yu and Matthew Hopkinꢀ
son for helpful discussions. Generous financial support by the
DFG (IRTG MünsterꢀNagoya), the European Research Council
under the European Community's Seventh Framework Program
(FP7 2007ꢀ2013)/ERC Grant agreement no 25936 and the Alfried
Krupp von Bohlen und Halbach Foundation (Alfried Krupp Prize
for Young University Teachers) is gratefully acknowledged.
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