A versatile approach to ullmann C-N couplings at room temperature: New families of nucleophiles and electrophiles for photoinduced, copper-catalyzed processes

Article abstract of DOI:10.1021/ja4060806

The use of light to facilitate copper-catalyzed cross-couplings of nitrogen nucleophiles can enable C-N bond formation to occur under unusually mild conditions. In this study, we substantially expand the scope of such processes, establishing that this approach is not limited to reactions of carbazoles with iodobenzene and alkyl halides. Specifically, we demonstrate for the first time that other nitrogen nucleophiles (e.g., common pharmacophores such as indoles, benzimidazoles, and imidazoles) as well as other electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) serve as suitable partners. Photoinduced C-N bond formation can be achieved at room temperature using a common procedure with an inexpensive catalyst (CuI) that does not require a ligand coadditive and is tolerant of moisture and a variety of functional groups.

Full text of DOI:10.1021/ja4060806

Article
pubs.acs.org/JACS
A Versatile Approach to Ullmann C−N Couplings at Room
Temperature: New Families of Nucleophiles and Electrophiles for
Photoinduced, Copper-Catalyzed Processes
Daniel T. Ziegler, Junwon Choi,† Jose María Munoz-Molina,† Alex C. Bissember, Jonas C. Peters,*
́
̃
and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: The use of light to facilitate copper-catalyzed cross-couplings
of nitrogen nucleophiles can enable C−N bond formation to occur under
unusually mild conditions. In this study, we substantially expand the scope of
such processes, establishing that this approach is not limited to reactions of
carbazoles with iodobenzene and alkyl halides. Specifically, we demonstrate
for the first time that other nitrogen nucleophiles (e.g., common
pharmacophores such as indoles, benzimidazoles, and imidazoles) as well
as other electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an
aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) serve as suitable partners. Photoinduced C−N
bond formation can be achieved at room temperature using a common procedure with an inexpensive catalyst (CuI) that does
not require a ligand coadditive and is tolerant of moisture and a variety of functional groups.
INTRODUCTION
■
The discovery of mild and versatile methods for the formation
of Caryl−N bonds can have an impact on fields ranging from
biology to natural-product synthesis to materials science.1,2 An
array of powerful approaches have been developed, including
Ullmann couplings3,4 and Buchwald−Hartwig reactions.5
Because aromatic nitrogen heterocycles are a particularly
common motif in bioactive compounds,6 developing effective
methods for their elaboration remains an important objective.
Carbon−nitrogen bond-forming processes between nucleo-
philic nitrogen heterocycles and aryl electrophiles provide an
Figure 1. Outline of a possible pathway for photoinduced, copper-
catalyzed C−N coupling reactions.
attractive, convergent strategy for synthesizing derivatives, and
such reactions can be accomplished with good efficiency with
the aid of catalysts based on copper, palladium, and other
metals.1,4,5,7 The use of copper can be advantageous from the
standpoints of cost8 and/or toxicity,9 although an elevated
the para substituents of a copper−diarylamido complex,
temperature is almost always required10 and a plethora of
(Ph3P)2Cu(NAr2), results in a substantial change in photo-
catalyst/ligand combinations have been described that are often
luminescence properties.11 It was therefore unclear if effective
specific to certain families of nucleophiles.
C−N bond formation would be possible with nitrogen
nucleophiles other than carbazoles.15 In this paper, we describe
the development of a unified set of reaction conditions for the
N-arylation of a variety of aromatic nitrogen nucleophiles,
thereby achieving C−N bond construction at an unusually mild
temperature (room temperature)10 with a simple and
inexpensive method (10% CuI, without a ligand coadditive,
eq 1).
Building on our previous studies of the photophysics of a
copper−carbazolide complex,11 we recently reported that
photoinduced, copper-catalyzed C−N bond formation between
carbazole and iodobenzene12 and several carbazoles and alkyl
halides13 can be achieved. We postulated that these photo-
induced couplings may proceed through initial photoexcitation
of a copper−carbazolide complex (Figure 1).14
If this hypothesis is correct, then the structure of the
nucleophile would be expected to have a significant impact on
photoexcitation/electron transfer of the copper−nucleophile
complex (as well as subsequent steps); indeed, a change in the
identity of NAr2 (e.g., NPh2 vs carbazolide) or even simply in
Received: June 17, 2013
© XXXX American Chemical Society
A
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Table 2. N-Arylation of Benzimidazoles at Room
a
Temperature
RESULTS AND DISCUSSION
■
Because indoles bear a structural resemblance to carbazoles and
are a privileged scaffold in natural products and medicines,6,16
they were a natural starting point for our efforts to expand the
scope of photoinduced Ullmann C−N couplings.17,18 In an
initial study, we determined that the method that we had
developed for the N-arylation of carbazole12 was not useful for
the arylation of indole with iodobenzene (<20% yield). As
might be anticipated, the wavelength of light that is employed
has proved to be important, and by irradiating at 254 nm, rather
than at 350 nm, we were able to achieve the desired C−N bond
formation in good yield at room temperature (entry 1 of Table
1).10,19
a
b
For the reaction conditions, see eq 1. Yield of purified product
c
(average of two experiments). A 1.1:1 mixture of isomers.
similar rates (entry 4).23 A hindered 2-substituted benzimida-
zole is a suitable coupling partner, even with an ortho-
substituted aryl iodide and with 3-iodopyridine (entries 5−7).24
Furthermore, the standard conditions for photoinduced C−
N coupling can be employed for room-temperature N-
arylations of imidazoles (Table 3).6,10,21,22 Whereas the
a
Table 1. N-Arylation of Indoles at Room Temperature
a
Table 3. N-Arylation of Imidazoles at Room Temperature
a
b
For the reaction conditions, see eq 1. Yield of purified product
(average of two experiments).
Ullmann reaction of a hindered electrophile proceeds in
acceptable yield (entry 2), a sterically demanding nucleophile
cross-couples with modest efficiency (entry 3).
The fourth and final family of aromatic nitrogen heterocycles
that we have examined as coupling partners are carba-
zoles.6,25,26 In our original paper, we had described the
photoinduced, copper-catalyzed arylation of carbazole itself
with iodobenzene.12 The method that we have developed
herein for Ullmann reactions of indoles, benzimidazoles, and
imidazoles is also effective for cross-coupling an array of
carbazoles and aryl iodides at room temperature (Table 4),
including deactivated (entry 3), hindered (entries 4, 6, and 7),
and heteroaryl (entry 5) electrophiles.10
In our initial study of photoinduced Ullmann reactions, only
an aryl iodide was employed as an electrophile in the copper-
catalyzed process, although an aryl bromide and an aryl chloride
served as partners in stoichiometric couplings with a preformed
copper−carbazolide complex.12 We have now determined that
copper-catalyzed arylations of a range of nitrogen heterocycles
can be achieved at room temperature with an unactivated aryl
bromide as well as an activated aryl chloride (Table 5).10
We were interested in exploring the selectivity of photo-
induced Ullmann reactions with respect to both the
nucleophilic and electrophilic coupling partners. With regard
to the nucleophile, we have observed in competition experi-
ments that, in the presence of 1.0 equiv of base (relative to one
of the nucleophiles), good-to-excellent selectivity can be
a
b
For the reaction conditions, see eq 1. Yield of purified product
(average of two experiments).
These conditions can be applied to room-temperature
couplings of an array of indoles with iodobenzene (entries 1,
4, 6, 8, and 9 of Table 1). An ortho-substituted (entry 5) and a
deactivated (entry 7) aryl iodide serve as suitable coupling
partners. This method for Ullmann coupling is not highly
water-sensitive: the addition of 10 mol% H2O leads to only a
small loss in yield (for the reaction of indole with iodobenzene,
−7%).
This method for photoinduced, copper-catalyzed Ullmann
coupling reactions can also be applied to a second family of
nitrogen heterocycles, benzimidazoles, which are a common
subunit in bioactive compounds (Table 2).6,20−22 Thus, at
room temperature, benzimidazole cross-couples with iodoben-
zene, as well as with an activated and a deactivated aryl iodide,
in good yield (entries 1−3).10 Not surprisingly, the two
nitrogens of a 5-substituted benzimidazole are arylated at
B
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a
Table 4. N-Arylation of Carbazoles at Room Temperature
a
b
For the reaction conditions, see eq 1. Yield of purified product
(average of two experiments).
to one-electron reduction (Figure 1)28 (as well as the weakness
of the C−X bond and the proclivity toward concerted oxidative
addition).
Table 5. An Unactivated Aryl Bromide and an Activated Aryl
Chloride as Electrophiles
We have examined the functional-group compatibility of the
photoinduced Ullmann coupling method. As illustrated in
Tables 1−4, cross-coupling proceeds in the presence of an
ether, a nitrile, a pyridine, and an aryl fluoride, as well as a
relatively weak C−H bond (e.g., benzylic or α to oxygen) that
could be susceptible to reaction with an intermediate aryl
radical (Figure 1). We have further determined that photo-
induced Ullmann couplings occur in the presence of an array of
stoichiometric additives (Table 7). Thus, an ester, amide,
ketone, secondary amine, primary amine, aryl chloride, trans-
a
Table 7. Functional-Group Tolerance
a
Yield of purified product (average of two experiments).
obtained (Table 6). The propensity of a heterocycle to be
arylated parallels its acidity.27
With regard to the electrophile, competition experiments
reveal that an aryl bromide and an aryl chloride are substantially
less reactive toward indole than is an aryl iodide (eq 2). This
observation correlates with the susceptibility of the aryl halide
Table 6. Relative Reactivity of Nucleophilic Coupling
a
Partners
a
All ratios are the average of two experiments. pKa values (DMSO)
a
are provided in parentheses.
All data are the average of two experiments.
C
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alkene (<2% isomerization), cis-alkene (<2% isomerization),
and alkyne can be recovered largely intact at the end of a cross-
coupling, with at most a modest impact on the efficiency of the
desired C−N bond-forming process. The small inhibitory effect
of an additive on N-arylation can be partly offset by running the
reaction for a longer period of time; for example, in the case of
benzylacetone and CyNH2, the yield increases from 62% to
68% and from 58% to 66%, respectively, upon further
irradiation.
Table 8. New Families of Electrophiles: Alkenyl and Alkynyl
Halides
For each family of photoinduced coupling processes
described herein, we have conducted control reactions that
establish that, in the absence of light, CuI, or light and CuI,
essentially no C−N bond formation is observed (<2%).
Photoredox catalysis, wherein metal complexes such as
[Ru(bpy)3]X2 shuttle electrons but are not directly involved
in inner-sphere bond-forming processes, has emerged as an
increasingly powerful tool in synthetic organic chemistry;29 in
control experiments, we have determined that [Ru(bpy)3]-
(PF6)2 does not function as a replacement for CuI under our
standard, or under related, conditions (eq 3).
a
Yield of purified product (average of two experiments).
expanding the scope and on exploring the mechanism of these
and related photoinduced processes.
Finally, we have begun to explore the possibility of expanding
these photoinduced C−N bond-forming reactions beyond
arylation and alkylation processes. Because enamines and
ynamines are important targets in organic synthesis,30 we have
pursued couplings of nitrogen heterocycles with both alkenyl
and alkynyl halides. For example, we have established that
photoinduced alkenylations can be achieved at room temper-
ature with both an iodide and a bromide as electrophiles
(entries 1−4 of Table 8).31−33 Furthermore, we have
determined that coupling a nitrogen heterocycle with an
alkynyl halide is possible under the same conditions (entry 5).34
Collectively, these observations provide an indication of the
potential versatility of photoinduced, copper-catalyzed coupling
processes.
EXPERIMENTAL SECTION
■
General Procedure (Arylation). The nitrogen heterocycle (1.00
mmol), LiOt-Bu (112 mg, 1.40 mmol), and CuI (19.0 mg, 0.10 mmol)
were added to an oven-dried 10 mL quartz test tube that contained a
stir bar. The test tube was fitted with a rubber septum, the joint was
wrapped with electrical tape, and the test tube was evacuated and
backfilled with nitrogen (three cycles). Then, CH3CN (4.0 mL) and
the aryl iodide (1.40 mmol) were added in turn via syringe. The test
tube was detached from the nitrogen manifold, and the puncture holes
in the septum were covered with vacuum grease. The resulting mixture
was stirred for 5 min, and then the test tube was transferred to a
Luzchem LZC-4V photoreactor (a Honeywell ultraviolet air treatment
system (model RUVLAMP1), available for ∼$110 from retail outlets
such as Amazon or The Home Depot, furnishes a comparable yield),
where it was irradiated at 254 nm for 24 h. Next, the mixture was
passed through a long plug of silica gel (monitored by TLC), the
solvent was removed, and the residue was purified by column
chromatography.
CONCLUSIONS
■
The scope of photoinduced, copper-catalyzed C−N couplings
has been expanded substantially with respect to both the
nucleophile and the electrophile. Whereas our initial reports
were limited to reactions of carbazoles with iodobenzene and
alkyl halides, we have now determined that nitrogen
nucleophiles other than carbazoles (e.g., common pharmaco-
phores such as indoles, benzimidazoles, and imidazoles) and
electrophiles other than iodobenzene and alkyl halides (e.g.,
hindered/deactivated/heterocyclic aryl iodides, an aryl bro-
mide, an activated aryl chloride, alkenyl halides, and an alkynyl
bromide) also serve as useful coupling partners. Photoinduced
C−N bond formation can be accomplished using a common
procedure with a simple and inexpensive catalyst (CuI, without
a ligand coadditive) under unusually mild conditions (room
temperature) with tolerance of moisture and a range of
functional groups. Current investigations are focused on further
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
jpeters@caltech.edu; gcfu@caltech.edu
■
Author Contributions
†J.C. and J.M.M.-M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
D
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J.-Y.; Cao, Z.-L.; Li, H.; Zhang, Y.-F. Synthesis 2010, 1280−1284.
(d) Huang, Y.-B.; Yang, C.-T.; Yi, J.; Deng, X.-J.; Fu, Y.; Liu, L. J. Org.
Chem. 2011, 76, 800−810 (one example).
ACKNOWLEDGMENTS
■
This work was supported by the Gordon and Betty Moore
Foundation (grant to J.C.P.), the Kwanjeong Educational
Foundation (fellowship to J.C.), and the Council for Interna-
tional Exchange of Scholars (Fulbright Scholar award to
J.M.M.-M.). We thank the Caltech Center for Catalysis and
Chemical Synthesis for use of instrumentation. D.T.Z. and J.C.
are graduate students in the Department of Chemistry at the
Massachusetts Institute of Technology.
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Y.; Zhang, L.; Xi, C. J. Org. Chem. 2009, 74, 6371−6373.
(32) For the mildest methods of which we are aware for the coupling
of an indole with an unactivated alkenyl halide, as well as references to
the utility of the reaction products, see: (a) Taillefer, M.; Ouali, A.;
Renard, B.; Spindler, J.-F. Chem.Eur. J. 2006, 12, 5301−5313. (60
°C). (b) Kabir, M. S.; Lorenz, M.; Namjoshi, O. A.; Cook, J. M. Org.
Lett. 2010, 12, 464−467 (60−80 °C). See also ref 30a.
(33) Mixtures of isomeric products are observed when olefins such as
1-iodo-1-octene are employed as coupling partners.
(34) We are not aware of previous reports of N-alkynylations of
carbazoles. (a) For copper-catalyzed syntheses of N-alkynylindoles via
aerobic oxidative couplings of terminal alkynes with indoles, see:
Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833−835
(70 °C). (b) For copper-catalyzed syntheses of N-alkynylindoles via
couplings of alkynyl bromides with indoles, see: Zhang, Y.; Hsung, R.
P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6,
1151−1154 (70−80 °C).
F
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