Selective Monoarylation of Primary Amines Using the Pd-PEPPSI-IPentCl Precatalyst

Article abstract of DOI:10.1002/anie.201502822

A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent^Cl catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination.

Full text of DOI:10.1002/anie.201502822

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502822
German Edition: DOI: 10.1002/ange.201502822
Cross-Coupling
Selective Monoarylation of Primary Amines Using the Pd-PEPPSI-
IPentCl Precatalyst**
Sepideh Sharif, Richard P. Rucker, Nalin Chandrasoma, David Mitchell, Michael J. Rodriguez,
Robert D. J. Froese, and Michael G. Organ*
Abstract: A single set of reaction conditions for the palladium-
catalyzed amination of a wide variety of (hetero)aryl halides
using primary alkyl amines has been developed. By combining
the exceptionally high reactivity of the Pd-PEPPSI-IPentCl
catalyst (PEPPSI = pyridine enhanced precatalyst prepara-
tion, stabilization, and initiation) with the soluble and non-
aggressive sodium salt of BHT (BHT= 2,6-di-tert-butyl-
hydroxytoluene), both six- and five-membered (hetero)aryl
halides undergo efficient and selective amination.
Scheme 1. Previously reported systems (1–4) for selective amination of
primary amines. The palladium precatalyst 5 is the focus of this study.
PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and
S
econdary amines are not only important synthetic inter-
mediates, but are also valuable commodities for investigation
in the fields of medicine, materials science, and drug discov-
ery.[1] Of the various routes available for preparing secondary
aromatic amines, the palladium-catalyzed amination of aryl-
(pseudo)halides[2,3] is one of the most robust methods
available and serves as a valuable complement to reductive
amination and substitution reactions.[4] Whereas the use of
secondary amines as nucleophiles in this transformation is
straightforward and leads to tertiary aniline products, the use
of primary amines can produce either secondary or tertiary
anilines resulting from mono- and diarylation, respectively, of
the amine.[5] In practice, such mixtures of mono- and diary-
lated amines are often observed, and these mixtures can be
difficult to separate and also have the disadvantage of
lowering the reactionꢀs efficiency for preparing the desired
secondary aniline. Fundamentally, the ratio of secondary to
tertiary aniline products observed for any particular amina-
tion is a consequence of the catalystꢀs ability to discriminate
between the starting primary amine and the secondary
aniline, which is the product of the initial catalytic cycle.
To address this selectivity problem, the steric and
electronic properties of ancillary ligands have been varied
initiation.
in an effort to enhance catalyst binding with the primary
amine over that of the secondary aniline product. This effort
has led to some notable successes, such as the BrettPhos
ligand 1 in conjunction with the BrettPhos precatalyst 2,[6] the
Josiphos ligand 3,[7,5a] the DalPhos family (4),[8] as well as
limited examples utilizing NHC (N-heterocyclic carbene)
ligands (Scheme 1).[9] Despite these efforts, no single univer-
sal catalyst, which is capable of promoting the amination of
aryl and five- and six-membered heteroaryl halides using
either simple or functionalized primary amines, has been
developed. We have previously reported that the Pd-PEPPSI-
IPent family[10] of palladium precatalysts has shown extremely
high reactivity for the coupling of secondary alkyl amines[11]
and primary and secondary anilines[12] with six-membered
aryl and heteroaryl chlorides and bromides. Herein, we
demonstrate the application of these catalysts in the selective
amination of six- and five-membered (hetero)aryl chlorides
and bromides using simple or functionalized primary aliphatic
amines governed under one general protocol.
In an initial experiment, we probed the reactivity of Pd-
PEPPSI-PentCl (5)[13] in the amination of 4-chloroanisole (6)
by using octyl amine (7) and cesium carbonate according to
the conditions we previously outlined for the analogous
amination of aryl chlorides by electron-deficient anilines
(Table 1, entry 1).[12a] While complete conversion of the halide
was observed at 808C, the reaction proceeded with low
selectivity for the desired monocoupled product 8. The use of
other inorganic bases (e.g., entry 3) did not improve selectiv-
ity. However, in a reaction utilizing sodium tert-butoxide,
which has been employed extensively by others,[14] the
product 8 was formed with moderate selectivity (entry 4).
We could improve the selective formation of 8 by lowering the
catalyst loading and decreasing the reaction concentration
such that 8 could be isolated in 90% yield with high selectivity
(65.6:1 8/9) after 90 min at 808C, and using just 0.5 mol% of
[*] S. Sharif,[+] Dr. R. P. Rucker,[+] Dr. N. Chandrasoma,
Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada)
E-mail: organ@yorku.ca
Dr. D. Mitchell, Dr. M. J. Rodriguez
Lilly Research Laboratories, A Division of Eli Lilly and Company
Indianapolis, IN 46285 (USA)
Dr. R. D. J. Froese
The Dow Chemical Company
Midland, MI 48674 (USA)
[+] These authors contributed equally to this work.
[**] This work was supported by NSERC Canada in the form of a CRD
grant and by the Eli Lilly Research Award Program (LRAP).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502822.
Angew. Chem. Int. Ed. 2015, 54, 9507 –9511
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9507

.
Angewandte
Communications
Table 1: Influence of basic additives on the selectivity and conversion of
4-chloroanisole 6 and octylamine (7) into 8 in the presence of 5.[a]
Table 2: Selective amination of aryl chlorides by 7 to give secondary
aniline products.[a]
X=4-OMe (14)
X=4-C(O)Me (15) 84% (32:1)
X=4-CN (16)
X=4-CO2Me (17)
90% (22:1)
X=4-CF3 (18)
X=2,6-Me2 (19) 90%
X=4-NO2 (20) 57%
X=3-(CF3) (21) 80%
85%
Base (equiv)
Solvent
8/9[c] ArCl
Conv.
8
(conc.)[b]
Conv.
[%]
92% (12:1)
92%
[%]
1[d] Cs2CO3 (3.0)
2[d] Cs2CO3 (3.0)
3[d] K3PO4·H2O (3.0)
4[d] NaOtBu (1.3)
5[e] NaOtBu (1.1)
DME (1.0)
DME (0.25)
DME (0.25)
3.3:1 100
5.3:1 100
3.0:1 89
71
77
34
[a] Yield of monoaryl product after purification of crude reaction mixture
by column chromatography using silica gel. Unless otherwise noted, only
the monocoupled product was observed in the 1H NMR spectrum of the
crude reaction mixture. See the Supporting Information for experimental
setup.
toluene (0.4) 4.9:1 86
toluene (0.1) 65.6:1 100
58
90[g]
32
6[g] K-Chromanoxide (10; toluene (0.1) 1.7:1 100
1.3)
7[g] K-BHT (11; 1.3)
8[h] Na-BHT (12; 1.3)
9[g] Na-BHT (12; 1.3)
toluene (0.1) 7.4:1 100
toluene (0.1) 28.6:1 100
63
but importantly they are much more soluble in organic
solvents. Despite these merits, there appear to be only
a limited number of examples where they are used as basic
additives in palladium-catalyzed amination reactions.[15a,18]
Using the productive results with Na-BHT, we were able
to develop a robust method for the amination of (hetero)aryl
halides with primary aliphatic amines catalyzed by Pd-
PEPPSI-IPentCl complex 5. The final conditions are shown
at the top of Table 2. We found that a variety of interesting
aryl chloride electrophiles with functionality including
methoxy (14), keto (15), cyano (16), carbomethoxy (17), 4-
trifluoromethyl (18), o-methyl disubstituted (19), and 4-nitro
(20) groups could all be coupled in very high yield for the
mono-aryl product, thus illustrating that the procedure is
highly monoselective and broadly functional-group tolerant.
In all instances where trace products were formed from over-
arylation, the desired mono-aryl product was readily isolated
in pure form after column chromatography on silica gel.
Having established that the reaction conditions outlined
above were effective in promoting the amination of simple
aryl chlorides using octyl amine, we next examined whether
more elaborate amines could be coupled as effectively. Under
the standard reaction conditions, benzylic, phenethyl, 2-
furylmethyl, and 2-thiophenethyl derivatives were all com-
petent nucleophiles in combination with activated and
deactivated ortho-, meta-, and para-substituted electrophiles
(22–29, Table 3).
These standard reaction conditions also facilitated the
effective amination of six-membered heterocyclic chlorides
and bromides, including 2- and 3-chloropyridines (30–36,
Table 3), 2-chloro-4-methylquinoline (37 and 38), and 1-
chloroisoquinoline (39) with simple or functionalized primary
amines. Compounds possessing tertiary alkyl amine function-
ality (35 and 37) could be isolated in high purity using a simple
extractive workup. Additionally, this single set of reaction
conditions utilizing 5 could also promote the amination of
electrophiles bearing multiple heteroatoms, such as 2-chloro-
pyrazine (40), 5-bromopyrimidine (41), as well as pyridazine
(42) and benzothiazole (43) derivatives.
81
toluene (0.1) 25:1
100
95[e]
[a] Unless otherwise noted, the conversion of 6 and conversion into 8
were determined using 1H NMR spectral analysis of the crude reaction
mixture containing 1,4-(CCl3)2-C6H4 as internal standard. [b] Concentra-
tion with respect to 6 given in [molLÀ1]. [c] The ratio of 8/9 represents the
ratio of desired monoarylation to the undesired diarylation. [d] Using
3 mol% of 5 and 1.3 equiv 7. [e] Using 0.5 mol% of 5, 1.1 mmol 7, and
1.0 mmol of 6. [f] Yield of 8 isolated after column chromatography.
[g] Using isolated phenolate salt stored and weighed in glove box.
[h] Using phenolate salt prepared in situ. DME=dimethyl ether.
catalyst (entry 5). Unfortunately, the use of sodium tert-
butoxide and other alkali alkoxides is often problematic when
functionalized aryl halides or amines are present.[15] To
address this deficiency, we next examined the ability of
phenolate derivatives to promote the selective formation of 8.
The use of potassium chromanoxide (10), previously reported
by us to affect the arylation of highly functionalized starting
materials with the Pd-PEPPSI-IPent catalyst,[15a] resulted in
complete conversion of 6 but with no selectivity for 8
(entry 6). However, the use of the isolated potassium salt of
BHT [2,6-di-tert-butyl hydroxytoluene (11)] did show
enhanced selectivity (7.4:1 8/9) with full conversion of the
electrophile. Unfortunately, there was only 63% conversion
into 8 (entry 7). In an analogous reaction conducted with the
isolated sodium BHT salt 12, both the conversion into 8
increased as well as the selectivity (entry 8). In the course of
these experiments, a significant increase in conversion into 8
was observed when 12 was prepared in situ rather than
isolated and stored in a glove box. Therefore, we designed
a simple procedure in which 12 is first prepared prior to
adding the other reagents and the reaction solvent. By using
this protocol, 8 was isolated in 95% yield and high selectivity
(25:1 8/9 in crude reaction mixture; entry 9) after purification
of the crude reaction mixture using silica gel column
chromatography. Although phenoxide derivatives have been
employed in carbonylation[16] and closely related etherifica-
tion reactions,[17] we did not observe the etherification
product of 12 with 6. Phenoxides such as 12 possess similar
pKb values as the inorganic carbonate and phosphate bases,
The amination of five-membered heteroaryl halides is
much more challenging than their six-membered heteroaryl
halide counterparts.[19] However, we found that simply
9508 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9507 –9511

Angewandte
Chemie
Table 3: Scope of amination of (hetero)aryl halides using primary
bromobenzothiophene (45), 2-bromobenzothiophene (46),
amines.[a]
and 4-bromo-1,3,5-trimethyl-1H-pyrazole (47 and 48) were
coupled nicely to primary alkyl amines with excellent mono-
selectivity.
The mild reaction conditions described above result from
the combination of the highly active and selective palladium
catalyst 5 with the soluble and nonaggressive basic additive
12, thus prompting us to investigate the possibility of halo-
(azido)benzene electrophiles participating in the amination
reaction. To the best of our knowledge, such electrophiles
have not been explored in any palladium- or nickel-catalyzed
aminations using primary aliphatic amines.[20] By using the
reaction conditions outlined in Scheme 2, the amine 50
reacted with both para- (49a) and meta-azidobromobenzene
(49b) participated to provide the products 51a and 51b,
respectively. The ortho derivative 49c generated only 5%
yield of the aminated product. In these cases, none of the
1
diarylation product was detected by H NMR spectroscopic
analysis of the crude reaction mixture.
Scheme 2. Selective monoarylation of primary amines with azide-
containing oxidative addition partners.
To extend the scope of the amination employing 5,
electrophiles bearing acidic functional groups were next
examined (Table 4). Possibly as a result of the complete
insolubility of the starting materials in this case, we found that
the amination worked best with LiHMDS as the base.[21,22]
The amination of benzoic acid and cyclopropanecarboxylic
acid derivatives (52–54) with a variety of primary amines
occurred smoothly in the presence of 1 mol% of 5 and an
Table 4: Representative amination of electrophiles bearing carboxylic
acid, alcohol, or 1H-indole functionality using 5 (1 mol%) in conjunction
with LiHMDS.[a]
[a] Unless otherwise indicated, only the monoaryl product was observed
by 1H NMR spectroscopic analysis of the crude reaction mixture. Yields
are those of the products isolated after purification by column
À
chromatography on silica gel. [b] 508C. [c] Using Ar Br. [d] 808C.
[e] Using 3 mol% of 5.
[a] Yield of product isolated after column chromatography using
0.5 mmol of (hetero)aryl halide. Unless otherwise indicated, only the
mono-aryl product was observed by analysis of the crude reaction
mixture using 1H NMR spectroscopy. See the Supporting Information for
experimental setup. [b] Using Ar-Br. HMDS=hexamethyldisilazide,
THF=tetrahydrofuran.
elevating the temperature to 808C, and in some cases
increasing the catalyst loading to 3 mol%, led to excellent
results without otherwise altering the standard conditions
(Table 3). Thus, the electrophiles 3-bromothiophene (44), 3-
Angew. Chem. Int. Ed. 2015, 54, 9507 –9511
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9509

.
Angewandte
Communications
extra equivalent of LiHMDS.[6a,7c,22] Through the same
approach, phenol (55) and even benzylic-alcohol-containing
electrophiles (56) were readily aminated. Finally, the amina-
tion of a free, unprotected indole (57) was also feasible
through this approach.
In conclusion, we have demonstrated that Pd-PEPPSI-
IPentCl[23] (5) is a highly effective catalyst for the amination of
both six- and five-membered (hetero)aryl halides in combi-
nation with the mild and soluble sodium salt of butylated
hydroxytoluene (Na-BHT; 12). By simply preparing 12, and
then adding the other components to the reaction flask,
a wide variety of functionalized aryl halides and amines
smoothly undergo coupling to selectively give secondary
anilines and heteroaromatic amines.
[8] a) For the BippyPhos ligand, see: S. M. Crawford, C. B. Lavery,
M. Stradiotto, Chem. Eur. J. 2013, 19, 16760 – 16771; b) R. J.
Lundgren, A. Sappong-Kumankumah, M. Stradiotto, Chem.
Eur. J. 2010, 16, 1983 – 1991.
[9] a) J. Broggi, H. Clavier, S. P. Nolan, Organometallics 2008, 27,
5525 – 5531; b) M. G. Organ, M. Abdel-Hadi, S. Avola, I.
Dubovyk, N. Hadei, E. A. B. Kantchev, C. J. OꢀBrien, M.
Sayah, C. Valente, Chem. Eur. J. 2008, 14, 2443 – 2452; c) G. A.
Grasa, M. S. Viciu, J. Huang, S. P. Nolan, J. Org. Chem. 2001, 66,
7729 – 7737; d) Others have observed modest selectivity using
specially modified NHC-ligated palladium precatalysts. See: Y.
Zhang, V. CØsar, G. Lavigne, Eur. J. Org. Chem. 2015, 2042 –
2050.
[10] M. G. Organ, S. C¸ alimsiz, M. Sayah, K. H. Hoi, A. J. Lough,
Angew. Chem. Int. Ed. 2009, 48, 2383 – 2387; Angew. Chem. 2009,
121, 2419 – 2423.
[11] a) K. H. Hoi, S. C¸ alimsiz, R. D. J. Froese, A. C. Hopkinson,
M. G. Organ, Chem. Eur. J. 2011, 17, 3086 – 3090.
Keywords: amination · cross-coupling · palladium · PEPPSI ·
[12] a) M. Pompeo, J. L. Farmer, R. D. J. Froese, M. G. Organ,
Angew. Chem. Int. Ed. 2014, 53, 3223 – 3226; Angew. Chem.
2014, 126, 3287 – 3290; b) K. H. Hoi, J. A. Coggan, M. G. Organ,
Chem. Eur. J. 2013, 19, 843 – 845; c) K. H. Hoi, S. C¸ alimsiz,
R. D. J. Froese, A. C. Hopkinson, M. G. Organ, Chem. Eur. J.
2012, 18, 145 – 151.
selectivity
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9507–9511
Angew. Chem. 2015, 127, 9643–9647
[13] M. Pompeo, R. D. J. Froese, N. Hadei, M. G. Organ, Angew.
Chem. Int. Ed. 2012, 51, 11354 – 11357; Angew. Chem. 2012, 124,
11516 – 11519.
[1] a) G. T. Hermanson, Bioconjugate Techniques, Elsevier Science,
Amsterdam, 2013; b) S. Kunugi, T. Yamaoka, Polymers in
Nanomedicine, Springer, Berlin, 2012; c) G. M. Cragg, P. G.
Grothaus, D. J. Newman, Chem. Rev. 2009, 109, 3012 – 3043;
d) L. Jiang, S. L. Buchwald, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 2008, pp. 699 – 760; e) J. F.
Hartwig, Modern Amination Methods, Wiley-VCH, Weinheim,
2007, pp. 195 – 262; f) D. A. Horton, G. T. Bourne, M. L. Smythe,
Chem. Rev. 2003, 103, 893 – 930; g) X.-G. Li, M.-R. Huang, W.
Duan, Y.-L. Yang, Chem. Rev. 2002, 102, 2925 – 3030.
[2] For the seminal investigation of the palladium-catalyzed cross-
coupling of simple amines (i.e., nonmetal amides) with aryl
halides, see: a) N. V. Kondratenko, A. A. Kolomeitsev, V. O.
Mogilevskaya, N. M. Varlamova, L. M. Yagupolꢀskii, J. Org.
Chem. USSR 1986, 22, 1547 – 1554; Translated from: Zh. Org.
Khim. 1986, 22, 1721 – 1729; For later pivotal studies, see:
b) A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem.
Int. Ed. Engl. 1995, 34, 1348 – 1350; Angew. Chem. 1995, 107,
1456 – 1459; c) J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36,
3609 – 3612.
[3] For reviews on paladium-catalyzed amination, see: a) C. Val-
ente, M. Pompeo, M. Sayah, M. G. Organ, Org. Process Res. Dev.
2014, 18, 180 – 190; b) R. J. Lundgren, M. Stradiotto, Aldrichi-
mica Acta 2012, 45, 59 – 65; c) I. P. Beletskaya, A. V. Cheprakov,
Organometallics 2012, 31, 7753 – 7808; e) C. Valente, S. C¸ alimsiz,
K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int.
Ed. 2012, 51, 3314 – 3332; Angew. Chem. 2012, 124, 3370 – 3388;
d) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27 – 50.
[4] a) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 –
3479; b) J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org.
Biomol. Chem. 2006, 4, 2337 – 2347.
[14] For references containing surveys of reaction conditions, see:
a) J. E. R. Sadig, M. C. Willis, Synthesis 2011, 1 – 22; b) C.
Fischer, B. Koenig, Beilstein J. Org. Chem. 2011, 7, 59 – 74;
c) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
6338 – 6361; Angew. Chem. 2008, 120, 6438 – 6461; d) S. Tasler, J.
Mies, M. Lang, Adv. Synth. Catal. 2007, 349, 2286 – 2300; e) B.
Schlummer, U. Scholz, Adv. Synth. Catal. 2004, 346, 1599 – 1626.
[15] a) K. H. Hoi, M. G. Organ, Chem. Eur. J. 2012, 18, 804 – 807;
b) N. Marion, E. C. Ecarnot, O. Navarro, D. Amoroso, A. Bell,
S. P. Nolan, J. Org. Chem. 2006, 71, 3816 – 3821.
[16] J. R. Martinelli, T. P. Clark, D. A. Watson, R. H. Munday, S. L.
Buchwald, Angew. Chem. Int. Ed. 2007, 46, 8460 – 8463; Angew.
Chem. 2007, 119, 8612 – 8615.
[17] a) G. Mann, C. Incarvito, A. L. Rheingold, J. F. Hartwig, J. Am.
Chem. Soc. 1999, 121, 3224 – 3225; b) N. Kataoka, Q. Shelby, J. P.
Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553 – 5566; c) A.
Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P. Sadighi, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 4369 – 4378; d) S.
Harkal, K. Kumar, D. Michalik, A. Zapf, R. Jackstell, F.
Rataboul, T. Riermeier, A. Monsees, M. Beller, Tetrahedron
Lett. 2005, 46, 3237 – 3240.
[18] a) A. X. Veiga, S. Arenz, M. ErdØlyi, Synthesis 2013, 777 – 784;
b) J. P. Schulte II, S. R. Tweedie, Synlett 2007, 2331 – 2336; c) The
[Pd(PtBu3)2]-catalyzed amination of three aryl chlorides using
the sodium BHT salt were studied by Hartwig and co-workers as
part of kinetic studies. See: S. Shekhar, J. F. Hartwig, Organo-
metallics 2007, 26, 340 – 351.
[19] a) M. Su, S. L. Buchwald, Angew. Chem. Int. Ed. 2012, 51, 4710 –
4713; Angew. Chem. 2012, 124, 4788 – 4791; b) M. W. Hooper,
J. F. Hartwig, Organometallics 2003, 22, 3394 – 3403; c) M. W.
Hooper, M. Utsunomiya, J. F. Hartwig, J. Org. Chem. 2003, 68,
2861 – 2873; d) K. Ogawa, K. R. Radke, S. D. Rothstein, S. C.
Rasmussen, J. Org. Chem. 2001, 66, 9067 – 9070.
[20] For copper-catalyzed methods, see: a) B. Yao, Y. Liu, L. Zhao,
D.-X. Wang, M.-X. Wang, J. Org. Chem. 2014, 79, 11139 – 11145;
b) Q. Liu, Y. Tor, Org. Lett. 2003, 5, 2571 – 2572.
[5] a) Q. Shen, T. Ogata, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130,
6586 – 6596; b) J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000,
65, 1144 – 1157; c) J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am.
Chem. Soc. 1996, 118, 7215 – 7216.
[6] a) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura, S. L.
Buchwald, Chem. Sci. 2011, 2, 57 – 68; b) B. P. Fors, D. A.
Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 2008,
130, 13552 – 13554.
[21] It is also possible that protic functional groups participate in
a rapid and reversible equilibrium with solvated LiHMDS
aggregates. See: B. L. Lucht, D. B. Collum, Acc. Chem. Res.
1999, 32, 1035 – 1042.
[7] a) Q. Shen, J. F. Hartwig, Org. Lett. 2008, 10, 4109 – 4112; b) J. F.
Hartwig, Acc. Chem. Res. 2008, 41, 1534 – 1544; c) Q. Shen, S.
Shekhar, J. P. Stambuli, J. F. Hartwig, Angew. Chem. Int. Ed.
2005, 44, 1371 – 1375; Angew. Chem. 2005, 117, 1395 – 1399.
9510
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9507 –9511

Angewandte
Chemie
[22] It has also been suggested that the in situ formation of a silylated
intermediate by LiHMDS may be partially responsible for its
high activity in electrophiles bearing protic functional groups.
See: M. C. Harris, X. Huang, S. L. Buchwald, Org. Lett. 2002, 4,
2885 – 2888.
[23] Pd-PEPPSI-IPentCl precatalyst is available through Total Syn-
thesis Ltd (http://www.totalsynthesis.ca).
Received: March 26, 2015
Published online: June 10, 2015
Angew. Chem. Int. Ed. 2015, 54, 9507 –9511
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9511