Nickel or phenanthroline mediated intramolecular arylation of sp 3 C-H bonds using aryl halides

Article abstract of DOI:10.1021/ol402869h

The development of the intramolecular arylation of sp³ C-H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)₂ or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates.

Full text of DOI:10.1021/ol402869h

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Nickel or Phenanthroline Mediated
Intramolecular Arylation of sp3 CÀH
Bonds Using Aryl Halides
William C. Wertjes,‡ Lydia C. Wolfe,‡ Peter J. Waller, and Dipannita Kalyani*
Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield,
Minnesota 55057, United States
kalyani@stolaf.edu
Received October 4, 2013
ABSTRACT
The development of the intramolecular arylation of sp3 CÀH bonds adjacent to nitrogen using aryl halides is described. Arylation was
accomplished using either Ni(COD)2 or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of
electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates.
The direct functionalization of CÀH bonds is a powerful
method for the introduction of aryl groups into organic
molecules. The majority of known methods for the aryla-
tion of sp3 CÀH bonds utilize precious metal (e.g., Pd, Ru,
Rh) catalysts and/or expensive phosphine ligands.1,2 In
recent years a number of reports on Cu-3 and Fe-4 cata-
lyzed sp3 CÀH bond arylation using heteroarenes5 or
transmetallating reagents6 have been described. Addition-
ally, an example of Ni-catalyzed intermolecular oxidative
arylation of CÀH bonds adjacent to ether oxygen or amine
nitrogen atoms has been published.7 Although these re-
ports represent important advances toward general sys-
tems for alkyl CÀH arylations using inexpensive catalysts,
most of these protocols require the use of potentially
hazardous oxidants (e.g., TBHP, DDQ) at high tempera-
tures. This drawback could be addressed by replacing
transmetallating reagents with aryl halides, which can
serve as both the aryl source and the oxidant. To the best
‡ W.C.W. and L.C.W. contributed equally.
(1) For representative reviews on CÀH arylation, see: (a) Alberico,
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F.; Kochi, T. Synthesis 2008, 3013. (c) McGlacken, G. P.; Bateman,
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r
10.1021/ol402869h
XXXX American Chemical Society

of our knowledge, no examples of alkyl CÀH arylations
using aryl halides and substoichiometric amounts of first
row transition metals have been disclosed.1
the possible involvement of alkyl radicals in these reac-
tions. As would be expected, in this scenario the use of
radical scavengers such as TEMPO ((2,2,6,6-tetramethyl-
piperidin-1-yl)oxidanyl) and galvinoxyl led to lower yields
of 1b (entries 9 and 10).
Herein, we describe a method for the intramolecular
coupling of aryl halides (halide = Br, Cl) with alkyl CÀH
bonds adjacent to nitrogen in benzamide substrates using
substoichiometric Ni(COD)2. During the course of these
investigations we discovered that the same transformation
could often be effected using substoichiometric 1,10-
phenanthroline in place of Ni(COD)2. These latter results
are the first demonstration of the use of transition-metal-
free catalysts for the arylation of alkyl CÀH bonds adja-
cent to heteroatoms using aryl halides.8À11
Table 1. Optimization of the Intramolecular Arylation of 1-Bra
Our studies commenced with the investigation of reac-
tion parameters for the intramolecular arylation of amide
1-Br using the Ni(COD)2/PCy3 catalyst system (Table 1).
Although the use of carbonate and phosphate bases pro-
vided only trace cyclization product (entries 1À4), higher
conversion was obtained with NaOtBu in xylene or
dioxane (entries 5 and 6). Strikingly, in contrast to the
previously reported Pd-catalyzed reactions (which afford
1a),12 isoindolinone 1b was formed as the major product
via arylation of the cyclohexyl CÀH bond.
Control experiments revealed that the yield of 1b could
be improved to 45% in the absence of PCy3 (entry 7).
However, diminished product yields were obtained when
Ni(COD)2 was excluded (entry 8). The preferential aryla-
tion of the more substituted CÀH bond (cyclohexyl versus
methyl) using the Ni(COD)2/NaOtBu system suggested
a General conditions: Ni(COD)2 (0.1 equiv), PCy3HBF4 (0 or
0.2 equiv), base (1.5 equiv), solvent, 145 °C, 15 h. b Calibrated GC yields
against hexadecane as the internal standard. c Calibrated yield of
remaining 1-Br determined by gas chromatographic analysis of the
crude reaction mixtures. d General conditions, but with no Ni(COD)2.
e In the presence of TEMPO (0.5 equiv). f In the presence of galvinoxyl
(0.5 equiv).
(8) For recent examples on biaryl formation in the absence of
transition metal catalysts, see: (a) Buden, M. E.; Guastavino, J. F.;
Rossi, R. A. Org. Lett. 2013, 15, 1174. (b) Liu, W.; Tian, F.; Wang, X.;
Yu, H.; Bi, Y. Chem. Commun. 2013, 49, 2983. (c) Cheng, Y.; Gu, X.; Li,
P. Org. Lett. 2013, 15, 2664. (d) Mehta, V. P.; Punji, B. RSC Adv. 2013,
11957. (e) Wu, Y.; Wong, S. M.; Mao, F.; Chan, T. L.; Kwong, F. Y.
Org. Lett. 2012, 14, 5306. (f) Bhakuni, B. S.; Kumar, A.; Balkrishna,
S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838. (g)
De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett. 2012, 14,
4466. (h) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 15537. (i) Liu, W.; Cao, H.; Zhang, H.; Chung,
K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010,
132, 16737. (j) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu,
X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, J.-Z. Nat. Chem. 2010, 2,
1044.
The potential involvement of radicals and the require-
ment for strong bases is reminiscent of the recently re-
ported 1,10-phenanthroline catalyzed arylation of sp2
CÀH bonds using aryl halides.8,9 As shown in Scheme 1,
1,10-phenanthrolinecouldbeusedinplaceofNi(COD)2 to
afford 1b in comparable yield (38%) albeit with higher
catalyst loadings (20 mol %). Although complete conver-
sion of 1-Br is observed using either Ni(COD)2 or 1,10-
phenanthroline, the modest yield of 1b is in part due to
significant demethylation of the protodebrominated sub-
strate (producing a 2° amide). The observation of this
product suggested that 1° CÀH bonds are not amenable to
the desired arylation.
(9) For recent reviews on biaryl formation in the absence of transition
metal catalysts, see: (a) Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41,
130. (b) Yanagisawa, S.; Itami, K. ChemCatChem 2011, 3, 827. (c)
Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018. (d) Lei,
A.; Lei, W.; Liu, C.; Chen, M. Dalton Trans. 2010, 39, 10352.
(10) Metal-free intramolecular R-arylation adjacent to a carbonyl
using aryl halides has been reported. See: Khan, T. A.; Tripoli, R.;
Crawford, J. J.; Martin, C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971.
Arylations adjacent to heteroatoms using aryl halides in the presence of
radical initiators such as Bu3SnH/AIBN have been reported (see ref
11d).
Scheme 1. Arylation Using 1,10-Phenanthroline
(11) For other representative reports on sp3 CÀH arylation adjacent
€
to nitrogen atoms, see: (a) Dastbaravardeh, N.; Kirchner, K.; Schnurch,
M.; Mihovilovic, M. D. J. Org. Chem. 2013, 78, 658. (b) McNally, A.;
Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114. (c) Prokopkova,
H.;Bergman, S. D.;Aelvoet, K.;Smout, V.;Herrebout, W.;VanderVeken,
B.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2010, 16, 13063. (d)
Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (e) Pastine, S. J.; Gribkov,
D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (f) Campos, K. R.;
Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. Y. J. Am. Chem.
Soc. 2006, 128, 3538.
(12) (a) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 10692. (b) Rousseaux, S.; Davi, M.;
Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.;
Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706.
Consistent with this proposal, the dimethyl substrate
2-Br provided the desired product only in trace amounts
under both sets of conditions (Table 2, entry 1). Gratify-
ingly, substrates bearing only 3° CÀH bonds adjacent to
nitrogen led to higher yields of products than those bearing
1° or 2° CÀH bonds (entries 1À4).13
B
Org. Lett., Vol. XX, No. XX, XXXX

formation, as this SNAr product is detected at the end of
the reaction.
Table 2. Scope of Arylation Using Bromide Substrates
We next explored the efficiency of the analogous trans-
formations of aryl chlorides. As shown in Table 3, the use
of Ni(COD)2 generally led to significantly higher yields
than the phenanthroline conditions for aryl chlorides.
Overall the functional group tolerance and electronic
effects were similar to those observed with aryl bromides.
Table 3. Scope of Arylation Using Chloride Substrates
a Conditions A: Ni(COD)2 (0.1 equiv), NaOtBu (1.5 equiv), dioxane,
145 °C. b 1H NMR yields against 1,4-dinitrobenzene as the internal
standard. c Conditions B: 1,10-phenanthroline (0.2 equiv), NaOtBu
(1.5 equiv), dioxane, 145 °C. d Isolated yields (isolated yields were
generally within 5% of the crude 1H NMR yields).
a Conditions A: Ni(COD)2 (0.1 equiv), NaOtBu (1.5 equiv), dioxane,
145 °C. b Isolated yields (isolated yields were generally within 5% of the
crude NMR yields). c Conditions B: 1,10-phenanthroline (0.2 equiv),
NaOtBu (1.5 equiv), dioxane, 145 °C. d 1H NMR yields against 1,4-
dinitrobenzene as the internal standard.
Under the Ni-mediated conditions (Conditions A), the
isoindolinone products are formed in good yields from
electronically varied substrates. Although a good yield of
8a is obtained from 8-Br, competitive substitution of the
F and Br groups by the tBuOÀ ion was observed with this
substrate. In contrast to the Ni-mediated transformations,
the efficiency of the corresponding phenanthroline-
mediated reactions (Conditions B) is significantly influ-
enced by the substrate electronics. While substrates bear-
ing electron neutral aryl rings were transformed to the
desired products in excellent yields (entries 3À5), those
bearing substituents that are electron withdrawing with
respect to the ipso CÀBr position afforded only trace
cyclization products (7-Br and 8-Br, entries 6 and 7). The
observed poor reaction efficiencies of these substrates
is partly due to a faster rate of nucleophilic aromatic
substitution by tBuOÀ than the desired CÀC bond
The reaction of substrates bearing a substituent meta to
the amide moiety was next examined (Table 4). The
reaction of meta-Me, -OMe, and -F substituted benza-
mides revealed that CÀC bond formation does not take
place exclusively at the ipso (CArÀX) position. Instead a
mixture of isomeric products was formed, exhibiting a
slight preference for CÀC bond formation at the more
sterically hindered position on the aryl ring (i.e., ortho to
the preexisting aryl substituent, entries 1À3, 5, and 6).
This selectivity trend was upheld for both substrates
11-Br and 12-Br, which differ in the nature of the alkyl
groups on the amide. Interestingly however, the reaction of
dimethoxy substrate 13-Br displayed modest selectivity for
alkylation at the less sterically hindered ortho position,
para to one of the OMe groups (entry 4). The site selectivity
of the phenanthroline-mediated transformations was com-
parable to that of the Ni-mediated process described above
(entries 1À3, 6). Consistent with the poor reactivity of
(13) Product 3a has been isolated previously from the reaction of 3-Br
in the absence of any catalyst. In this report, 3a was isolated as a side
product in the context of a Pd-catalyzed reaction. MacNeil, S. L.; Gray,
M.; Gusev, D. G.; Brigs, L. E.; Snieckus, V. J. Org. Chem. 2008, 73,
9710.
(15) The mechanism in Scheme 2 is just one proposal. The regenera-
tion of Ni0 in step (v) cannot be excluded amongst other possibilities.
(14) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Site Selectivity of CÀC Bond Formation
Scheme 2. Plausible Mechanism
conditions, the 1 eÀ transfer steps (i and v) are mediated by
a phenanthroline/tBuOÀ adduct analogous to the propos-
als in previously documented in sp2 CÀH arylations.8,9,14
This mechanism is consistent with several observations
described above. First, radical scavengers such as TEMPO
and galvinoxyl inhibit the Ni-mediated transformation
(Table 1, entries 9 and 10). Second, the efficiency of the
arylation increases with more substituted alkyl CÀH
bonds, which is in accord with a mechanism involving
alkyl radical intermediates such as D. Third, meta-substi-
tuted amides lead to mixtures of isomeric products. This
latter result is expected for a mechanism involving the
proposed step iv (Scheme 2). Finally, the diminished
efficiencies of the reactions of aryl chloride substrates
(versus the analogous aryl bromides) under phenanthro-
line conditions parallel the trend in reduction potentials of
aryl halides (ArÀBr > ArÀCl).14,15
a Reaction conditions: Ni(COD)2 (0.1 equiv), NaOtBu (1.5 equiv),
dioxane, 145 °C. b Reaction conditions: 1,10-phenanthroline (0.2 equiv),
NaOtBu (1.5 equiv), dioxane, 145 °C. c Isolated yields (all isolated yields
were within 5% of the crude NMR yields). d 1H NMR yields against 1,4-
dinitrobenzene as the internal standard. e Selectivities determined by 1H
NMR spectroscopic analysis of the crude reaction mixtures.
In summary, this paper describes the development of
intramolecular arylation of sp3 CÀH bonds adjacent to an
amide nitrogen using ArÀX (X = Br, Cl) with substoi-
chiometric Ni(COD)2 or 1,10-phenanthroline. Preliminary
studies suggest the involvement of aryl and alkyl radical
intermediates.
substrates 7-Br and 8-Br under phenanthroline conditions
(Table 2), substrates 13-Br and 14-Br led to a trace of
product with phenanthroline, while displaying good reac-
tivity with Ni(COD)2 (Table 4, entries 4À5).
Acknowledgment. This work was supported by St. Olaf
College, the American Chemical Society Petroleum Re-
search Fund (PRF#52224-UNI3), and the NIH NIGMS
(R15GM107892). L.C.W. is thankful for the SURF fel-
lowship from ACS, Division of Organic Chemistry.
A plausible mechanism for the Ni-mediated intramole-
cular arylation involves (i) an initiation step via single
electron transfer from Ni0 to the substrate to generate
radical anion B, (ii) loss of BrÀ to form the aryl radical C,
(iii) intramolecular H-atom abstraction to provide the
stabilized alkyl radical D, (iv) radical addition into the
arene to generate isomeric aryl radical intermediates E and
F, and finally (v) rearomatization to afford the cyclized
product with concomitant regeneration of the radical
anion B (Scheme 2). Alternatively, under phenanthroline
Supporting Information Available. Experimental de-
tails and spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX