Direct intermolecular aniline ortho- arylation via benzyne intermediates

Article abstract of DOI:10.1021/ol302875x

A method for direct, transition-metal-free ortho-arylation of anilines by aryl chlorides, bromides, fluorides, and triflates has been developed. This methodology provides the most direct approach to 2-arylanilines since no protecting or directing groups on nitrogen are required. The arylation is functional-group tolerant, with alkene, ether, trifluoromethyl, dimethylamino, carbonyl, chloro, and cyano functionalities tolerated. Phenylation of enantiopure binaphthyldiamine affords a product with >99% ee.

Full text of DOI:10.1021/ol302875x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Intermolecular Aniline
Ortho-Arylation via Benzyne
Intermediates
Thanh Truong and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003,
United States
olafs@uh.edu
Received October 18, 2012
ABSTRACT
A method for direct, transition-metal-free ortho-arylation of anilines by aryl chlorides, bromides, fluorides, and triflates has been developed. This
methodology provides the most direct approach to 2-arylanilines since no protecting or directing groups on nitrogen are required. The arylation is
functional-group tolerant, with alkene, ether, trifluoromethyl, dimethylamino, carbonyl, chloro, and cyano functionalities tolerated. Phenylation of
enantiopure binaphthyldiamine affords a product with >99% ee.
The most efficient routes to many structures involve direct
functionalization of carbonꢀhydrogen bonds. The past few
years have witnessed spectacular progress in developing
CꢀH bond functionalization methodologies.1 However,
some issues are still unresolved. For example, direct arylation
of aniline derivatives in most cases requires either a protecting
or directing group on nitrogen.2 Palladium-catalyzed ortho-
arylation of anilides offers a short pathway to 2-aminobi-
phenyls or terphenyls; however, installation followed by
removal of a directing group adds two steps to the synthetic
sequence.2aꢀc Additionally, directing group removal requires
harsh conditions. Gevorgyan has recently reported a method
for intramolecular palladium-catalyzed arylation of anilines
by employing a temporary silyl tether.2d The silyl group
removal can be performed under mild conditions. However,
several extra steps are required to install and remove the
tether. A recent paper by Greaney describes o-arylation of
N-tritylanilines by benzynes generated from silyl aryl triflates.
The reaction proceeds by an ene mechanism.2f However, the
reaction is not applicable for arylation of N- and o-substi-
tuted anilines. Additionally, only a few silyl aryl triflates are
commercially available thus limiting the practical applica-
tions of this procedure. Only a few articles describe direct
arylation of free anilines.3 Aminobiphenyls have been synthe-
sized by Ti-catalyzed arylation of free anilines by diazonium
salts.3a Isomer mixtures were obtained in many cases. A
selective transition-metal-free para arylation of N-substituted
anilines has been recently reported by employing diaryliodo-
nium salt electrophiles.3b Selective, direct o-arylation of
unprotected anilines has not yet been disclosed. We report
here a method for direct aniline o-arylation by aryl halides
that proceeds via aryne intermediates.
(1) Reviews: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792. (c) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (f) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (g) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Commun. 2010, 677. (i) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(2) (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44,
4046. (b) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720. (c)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (d) Huang, C.; Gevorgyan, V. J. Am. Chem. Soc.
2009, 131, 10844. (e) Phipps, R. J.; Gaunt, M. Science 2009, 323, 1593. (f)
Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.;
Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006. (g) Shi, Z.; Li,
B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew.
Chem., Int. Ed. 2007, 46, 5554. (h) Scarborough, C. C.; McDonald, R. I.;
Hartmann, C.; Sazama, G. T.; Bergant, A.; Stahl, S. S. J. Org. Chem.
2009, 74, 2613. (i) Brasche, G.; Garcıa-Fortanet, J.; Buchwald, S. L. Org.
Lett. 2008, 10, 2207.
We have recently reported direct C-arylation of hetero-
cycles, arenes, alkynes, and phenols proceeding via benzyne
(3) (a) Wetzel, A.; Ehrhardt, V.; Heinrich, M. R. Angew. Chem., Int.
Ed. 2008, 47, 9130. (b) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer,
F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458.
r
10.1021/ol302875x
XXXX American Chemical Society

intermediates. It was observed that the amount of C-aryla-
tion is dependent on the solvent.4 It is well-known that
N-arylation of NH-anilines can be accomplished by benzynes5a,b
and that the N-arylation products are sometimes accom-
panied by minor amounts of C-arylation.5c,d Since, as de-
scribed above, the ratio of C- vs O- or N-arylation can be
tuned by changing the reaction solvent, we decided to explore
aniline o-arylation. Arynes can be generated from silyl aryl
triflates under nearly neutral conditions at room tempera-
ture.6 Unfortunately, these starting materials are expensive,
and only a few of them are commercially available. To
increase the applicability of the arylation, we decided to use
readily accessible and cheap aryl chlorides as aryne sources.
Lithium 2,2,6,6-tetramethylpiperidide (LiTMP) base was
used to retard the reaction of arynes with base.7a
The optimization of reaction conditions was carried out
for the 2-naphthylamine 1 arylation by chlorobenzene
(Table 1). The ratio of C-arylation vs N-arylation was
found to be dependent on solvent, base, and 1/base ratio.
Reactions in THF afforded N-arylation with only minor
amounts of C-arylation product formed (entries 1 and 2).
Arylation in Et2O also gave predominately N-arylation
(entry 3). If LDA was used instead of LiTMP, clean forma-
tion of N-phenyl-2-naphthylamine was observed (entry 4).
Lowering the reaction temperature to ꢀ20 °C resulted
in good C-arylation selectivity in diethyl ether (entry 5).
Reactions in pentane at 40 °C gave substantial amount of
C-arylation (entries 6ꢀ7). However, competitive formation
of PhTMP was observed. Use of pentane/Et2O mixtures
increased the C/N-arylation ratio (entries 8ꢀ10). The best
results were obtained in cyclohexane/diethyl ether mixed
solvent at 25ꢀ50 °C (entries 11, 13, 14) by using 1/LiTMP
ratio of 1/1.8. Sensitive substrates can be arylated at low
temperature in diethyl ether.
Table 1. Optimization of Reaction Conditionsa
entry
1/PhCl/base
T, °C
solvent
2/3b
1
2
1/2/3.6
2/1/3.6
1/2/3.6
1/2/3.6
2/1/3.6
1/2/3.6
2/1/3.6
1/2/3.6
2/1/3.6
2/1/3.6
2/1/3.6
1/2/3.6
3/1/4.8
3/1/4.8
25
25
25
25
ꢀ20
40
40
25
25
25
25
25
50
50
THF
THF
1/8 (10)
1/3 (12)
1/5 (16)
1/50 (<2)
11/1 (27)
1/2 (29)
2/1 (35)
1.3/1 (43)
12/1 (27)
9/1 (64)
18/1 (74)
1/2.2 (25)
50/1 (78)
5/1 (50)
3
Et2O
4c
5
Et2O
Et2O
6
C5H12
7
C5H12
8
C5H12/Et2O 20:1
C5H12/Et2O 20:1
C5H12/Et2O 1:1
C6H12/Et2O 1:1
C5H12/Et2O 1:1
C5H12/Et2O 14:1
C5H12/Et2O 1:1
9
10
11
12
13
14
a Total volume of solvent 0.9 mL, 0.25 mmol scale, 24 h; 12 h for
entry 5. See the Supporting Information for details. b Ratio 2/3; GC yield
of 2 (%) in parentheses. c LDA base.
are reactive, and the corresponding arylation products were
obtained in good yields (entries 5ꢀ7). Arylation can also be
achieved by employing polycyclic aromatic chlorides
(entries 8 and 9). 2-Chlorodimethylaniline affords aryla-
tion product in moderate yield (entry 10). If introduction
of a chloro-substituted aryl moiety is required, 3-chlorophenyl
triflate at low temperature can be employed (entry 11).
Arylation by 3-bromobenzoate ester results in substitution
at 2-position of aryne, presumably by initial formation of
2-naphthylamide of 3-bromobenzoic acid (entry 12). 4-Chloro-
toluene gave nearly equal mixture of isomeric products
(entry 13).
The 2-naphthylamine arylation occurs selectively at the
1-position. In that context, observations by Pierini and
Rossi may be informative.8 They have reported the photo-
stimulated reaction of unactivated aryl bromides and
iodides with 2-naphthylamide. Substitution occurred at
N- and 1-positions of 2-naphthylamine. The authors ex-
plain the arylation selectivity by the relative basicities of
sites in an ambident naphthylamide anion.
The reaction scope with respect to aryl halides is pre-
sented in Table 2. Fluoro-, chloro-, and bromobenzene can
be used in the arylation of 2-naphthylamine (entries 1ꢀ3).
Interestingly, the arylations are selective for 1-position of
2-naphthylamine. 2-Chlorostyrene affords the arylation
product in a good yield (entry 4). As expected, substitution
occurs mainly at 3-position of the vinylphenyl group, with less
than 3% of 1-(2-vinylphenyl)-2-naphthylamine formed.7bꢀe
2-Chloroanisole, 2-chlorobenzotrifluoride, and 2-bromobiphenyl
(4) (a) Truong, T.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 4243.
(b) Truong, T.; Daugulis, O. Chem. Sci. 2012, Advance Article, DOI:
10.1039/C2SC21288A. (c) Truong, T.; Daugulis, O. Org. Lett. 2011, 13,
4172.
(5) (a) Scardiglia, F.; Roberts, J. D. Tetrahedron 1958, 3, 197. (b)
Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001,
66, 1403. (c) Bergstrom, F. W.; Wright, R. E.; Chandler, C.; Gilkey,
W. A. J. Org. Chem. 1936, 1, 170. (d) Haberfield, P.; Seif, L. J. Org.
Chem. 1969, 34, 1508.
Groups that can coordinate a lithium cation afford
reduced C/Nselectivities. Lower reaction temperatures have
to be used to obtain better yields and arylation selectivities.
For example, presence of the dimethylamino substituent
reduces C/N arylation selectivity from >50/1 (entry 2,
Table 2) to about 11/1 (entry 10, Table 2) even if the temper-
ature is lowered to ꢀ30 °C.
(6) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
8, 1211. (b) Chen, Y.; Larock, R. C. Arylation Reactions Involving the
Formation of Arynes. In Modern Arylation Methods; Ackermann, L., Ed.;
Wiley-VCH: New York, 2009; pp 401ꢀ473.
The reaction scopewithrespect toanilinesis presented in
Table 3. N-Alkyl- and arylanilines are reactive (entries
1ꢀ5). Specifically, anilines possessing N-methyl-, phenyl,
(7) (a) Olofson, R. A.; Dougherty, C. M. J. Am. Chem. Soc. 1973, 95,
582. (b) Huisgen, R.; Sauer, J. Angew. Chem. 1960, 72, 91. (c) Tadross,
P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2010, 12, 1224. (d) Im, G.-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton,
R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc.
2010, 132, 17933. (e) Gold, B.; Shevchenko, N. E.; Bonus, N.; Dudley,
G. B.; Alabugin, I. V. J. Org. Chem. 2012, 77, 75.
(8) Pierini, A. B.; Baumgartner, M. T.; Rossi, R. A. J. Org. Chem.
1991, 56, 580.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Arylation of 2-Naphthylaminea
a 2-Naphthylamine (1ꢀ2 mmol), ArX (0.5 mmol), LiTMP (1.8ꢀ3.4 mmol), solvent (1.4ꢀ3 mL), ꢀ85 to þ50 °C, 12ꢀ48 h. Yields are isolated yields.
b Cyclohexane/Et2O (14/1), 25 °C, <5% N-arylation product observed in crude reaction mixture. c Et2O, ꢀ25 °C, ca. 10% N-arylation. d Cyclohexane/
Et2O (14/1), 50 °C, <10% N-arylation. e Cyclohexane/Et2O (1/1), 25 °C, <5% N-arylation. f Et2O, ꢀ30 °C, 8% N-arylation. g THF, ꢀ85 °C, 7% N-
arylation. h Cyclohexane/Et2O (1/1), ꢀ35 °C, LDA base.
and benzyl substituents all give products in good to
excellent yields (entries 1, 3, and 5). 1,2,3,4-Tetrahydro-
isoquinoline is arylated at the 7-position in good yield
(entry 2). Unsubstituted anilines can be selectively and
efficiently monoarylated (entries 6ꢀ14). Thus, aniline can
be ortho-phenylated in a moderate yield (entry 6). Aryla-
tion of 3-aminobenzotrifluoride affords about 3/1 mixture
of isomers. 2-Phenyl-5-trifluoromethylaniline was isolated
in 50% yield (entry 9). 3,5-Dimethylaniline is arylated in the
ortho-position in a good yield (entry 8). Palladium-catalyzed
arylation of anilides that possess meta-substituents is not
efficient and thus structures such as the one generated in
entry 8 typically cannot be accessed by using transition-
metal catalysis.2a,b p-Substituted anilines are arylated in
good yields (entries 7, 10, and 11). 1-Naphthylamine is
arylated at the 2-position (entry 12). 2-Aminobiphenyl can
be arylated at 6-position affording 2,6-diphenylaniline
(entry 13). 2,6-Diarylanilines are used in the synthesis of
ligands for Brookhart-type transition-metal catalyzed olefin
polymerization.9 The reaction tolerates chloro- and cyano
substituents (entries 7 and 14). Arylation of enantiopure
binaphthyldiamine afforded the monoarylation product in
47% yield and >99% ee (eq 1).
The reaction is selective (>50/1) for ortho-arylation as
opposedtopara-arylation. Forentries 1, 6, and13, Table 3,
the crude reaction mixtures were analyzed by GC for the
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Arylamine Phenylationa
a Amine (1ꢀ2 mmol), PhCl (0.5 mmol), LiTMP (1.8ꢀ3.4 mmol), solvent (1.4ꢀ3 mL), ꢀ60 to þ50 °C, 24ꢀ48 h. Yields are isolated yields. See the
Supporting Information for C/N ratios. b Cyclohexane/Et2O (1/1), 25 °C. c Pentane/THF (36/1), 25 °C. d Cyclohexane/Et2O (14/1), 50 °C. e Pentane/
Et2O (1/1), ꢀ50 °C, PhOTf. f Isomeric 2-phenyl-3-trifluoromethylaniline also isolated (17%). g THF/Et2O (1:1), ꢀ60 °C.
presence of p-phenyl derivatives (comparison with authentic
commercial samples). No products arising from p-arylation
were observed.
chlorides, bromides, fluorides, and triflates. This metho-
dology provides the most direct approach to 2-arylanilines
since no protecting or directing groups on nitrogen are
required. Easily available aryl chlorides can be used as the
coupling partner. The arylation is functional-group toler-
ant, with alkene, ether, trifluoromethyl, dimethylamino,
carbonyl, chloro, and cyano functionalities tolerated.
The amount of N- vsC-arylation isdependent on solvent
coordination ability, aniline/LiTMP base ratio, and reac-
tion temperature. These features point to different reactiv-
ity of intermediate lithium anilide/LiTMP aggregates as
the reason for switch in arylation regioselectivity. Because
of the complexity of lithium anilide solution-state structures
and insolubility of LiCl additive in reaction mixture, further
mechanistic speculations are premature at this point.10
In conclusion, we have developed a method for direct,
transition-metal-free ortho-arylation of anilines by aryl
Acknowledgment. We thank the Welch Foundation
(Grant No. E-1571), NIGMS (Grant No. R01GM077635),
the A. P. Sloan Foundation, and the Camille and Henry
Dreyfus Foundation for supporting this research.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Schmid, M.; Eberhardt, R.; Klinga, M.; Leskelae, M.; Rieger, B.
Organometallics 2001, 20, 2321.
(10) (a) Clegg, W.; Horsburgh, L.; Mackenzie, F. M.; Mulwey,
€
R. E. J. Chem. Soc., Chem. Commun. 1995, 2011. (b) von Bulow,
R.; Gornitzka, H.; Kottke, T.; Stalke, D. Chem. Commun. 1996,
1639.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX