Oxaphosphole-based monophosphorus ligands for palladium-catalyzed amination reactions

Article abstract of DOI:10.1002/adsc.201000878

A novel class of C-2-substituted oxaphosphole-based monophosphines 1-4 has been synthesized. Palladium complexes derived from these ligands and their C-2-unsubstituted analogs provide general catalysts for amination reactions of challenging aryl and heteroaryl halides with sterically hindered anilines and alkylamines.

Full text of DOI:10.1002/adsc.201000878

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DOI: 10.1002/adsc.201000878
Oxaphosphole-Based Monophosphorus Ligands for Palladium-
Catalyzed Amination Reactions
Sonia Rodriguez,a,* Bo Qu,a Nizar Haddad,a Diana C. Reeves,a Wenjun Tang,a,*
Heewon Lee,a Dhileepkumar Krishnamurthy,a and Chris H. Senanayakea
a
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, U.S.A.
Fax : (+1)-203-791-6130; phone: (+1)-203-798-9988; e-mail: sonia.rodriguez@boehringer-ingelheim.com or
wenjun.tang@boehringer-ingelheim.com
Received: November 22, 2010; Revised: December 23, 2010; Published online: March 2, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000878.
Abstract: A novel class of C-2-substituted oxa-
phosphole-based monophosphines 1–4 has been
synthesized. Palladium complexes derived from
these ligands and their C-2-unsubstituted analogs
provide general catalysts for amination reactions of
challenging aryl and heteroaryl halides with steri-
cally hindered anilines and alkylamines.
Palladium-catalyzed aminations have also been devel-
oped utilizing continuous flow chemistry.[16] Despite
all these advances, the arylation of hindered aryl-
AHCTUNGTREGUNaNN mines with hindered aryl halides has been less ex-
plored.[3a,17] Few successful results have been shown
for the preparation of tetra-ortho-substituted diaryla-
mines from such extremely hindered partners. There-
fore, the development of new, efficient and general li-
gands for amination reactions is important for dealing
with the challenging substrates in this area such as de-
activated hindered (hetero)aryl halides, sterically hin-
dered arylamines and alkylamines. Herein, we report
a new series of trans-C-2-substituted oxaphosphole-
based monophosphorus ligands 1–4 (Figure 1) and
À
Keywords: N-arylamination; C N coupling; palladi-
um
The development of new, general methodology for
the formation of aromatic carbon-nitrogen bonds is of
great significance in many areas of organic synthesis.
Due to the versatility and high functional group toler-
ance of most palladium catalysts, the palladium-cata-
lyzed amination of aryl halides has evolved as a
viable alternative to traditional nucleophilic aromatic
substitution and various other classical methods of in-
troducing arylamines.[1] Recent advances have focused
on the development of novel catalysts to provide
broad substrate scope, wide functional group toler-
ance and at low catalyst loadings. Examples of novel
families of ligands include Liꢀs POPd complexes,[2]
Nolanꢀs N-heterocyclic carbenes,[3] Verkadeꢀs triami-
nophosphines,[4] Singerꢀs N-phenylpyrrole and pyra-
zole phosphines,[5] Bellerꢀs N-substituted heteroaryl-
phosphines,[6] Zhangꢀs triazole phosphines,[7] Kwongꢀs
benzamine-derived phosphines,[8] Suzukiꢀs tri-tert-al-
kylphosphines,[9] and Swamyꢀs cyclodiphosphozane.[10]
Extensions of well established catalytic systems such
as Bellerꢀs, Buchwaldꢀs, Hartwigꢀs and Kwongꢀs have
also been reported to include aryl tosylates,[11] aryl
mesylates,[12] and heteroaryl systems[13] as electro-
philes, and ammonia[14] and amides[15] as nucleophiles. Figure 1. Novel oxaphosphole-based ligands.
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their application in palladium-catalyzed amination re-
To evaluate the effectiveness of these ligands in the
actions of challenging aryl and heteroaryl halides with Pd-catalyzed amination of challenging aryl halides, we
sterically demanding aryl- and alkylamines. first investigated the reaction between 2,4,6-triisopro-
Recently, we described a novel class of biaryl pylbromobenzene and 2,6-diisopropylaniline
monophosphorus ligands, that is, 5–7 (Figure 1), con- (Table 1). Standard conditions for the reactions were
taining 2,3-dihydrobenzo[d][1,3]oxaphosphole
a
ACHTUNGTRENNUNG
core.[18] The effectiveness of ligand 6 (BI-DIME) was
demonstrated in palladium-catalyzed Suzuki–Miyaura
coupling reactions of various aryl and heteroaryl bro-
mides and chlorides with sterically congested and
electron-poor arylboronic acids. The application of
monophosphines 5–7 in amination reactions was also
the subject of the present investigation.
Table 1. Amination of 2,4,6-triisopropylbromobenzene with
various ligands.[a]
The syntheses of C-2-substituted ligands 1–4 were
accomplished in two steps from aryl methyl ether 8 or
biphenyl 9 (Scheme 1), which was prepared from
Entry
Ligand
Conversion [%][b]
Yield [%][c]
1
2
4
5
6
7
8
9
10
11
12
13
1
2
3
4
5
6
7
24
61
24
100
72
100
70
0
–
–
–
96
–
98
–
–
–
–
BINAP
Xantphos
JohnPhos
XPhos
SPhos
46
0
5
–
–
18
[a]
Conditions: aryl bromide (1.0 equiv.), amine (1.2 equiv.),
Pd/Ligand 1:3, NaO-t-Bu (1.5 equiv.), toluene, 1108C,
20 h.
Conversion by HPLC at 220 nm.
Isolated yields.
[b]
[c]
2,4,6-triisopropylbromobenzene (1 equiv.), 2,6-diiso-
propylaniline (1.2 equiv.), NaO-t-Bu (1.5 equiv.),
Pd2ACTHNUTRGNE(UGN dba)3/phosphine (Pd/L 1:3) in toluene (0.5M solu-
tion relative to aryl halide) at 1108C. While common-
ly used commercially available ligands such as
BINAP, xantphos, JohnPhos, XPhos and SPhos af-
forded low conversions at 0.1 mol% Pd loading, li-
gands 4 and 6 provided superior performance with ex-
cellent conversions and yields. It is noteworthy that
the cross-coupling product is one of the most sterical-
Scheme 1. Synthesis of C-2-substituted oxaphosphole mono-
phosphine ligands 1–4.
methyldichlorophosphine at kilogram scale using our ly congested secondary amines reported to date via
previously reported procedure.[19] The CuCl2-mediated palladium-catalyzed aminations with all four
oxidative cross-coupling of lithiated 8 or 9 with vari- branched ortho-substituents.[23] The high performance
ous aryl organometallic reagents provided phosphine of ligands 4 and 6 clearly demonstrated the advance-
oxides 10a–c in approximately 50% yield.[20] For the ment of dihydrobenzooxaphosphole-based ligands for
synthesis of the C-2-methyl substituted ligand 4, the amination of sterically demanding substrates. Both
lithiated 9 was reacted with MeI to afford 10d in 61% Pd2ACHTNUGTRENNUG(dba)3 and PdACHTUNGTREN(NGUN OAc)2 could be used as palladium
isolated yield. Reduction of the phosphine oxides sources although the latter provided slightly lower
with polymethyl hydrosiloxane (PMHS) in the pres- yields of the arylated amine.
[21]
ence of Ti
G
Subsequently, the scope of the amination reaction
mic ligands 1–4 which proved to be air-stable solids at between various aryl halides and aryl- or alkylamines
room temperature.[22]
was studied with the simpler ligand 6 (BI-DIME).
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Oxaphosphole-Based Monophosphorus Ligands for Palladium-Catalyzed Amination Reactions
Table 2. Amination reactions of aryl bromides and chlorides.[a]
[a]
Conditions: halide (1.0 equiv.), amine (2 equiv.), Pd
10 mol%), NaO-t-Bu (2 equiv.), toluene, 1108C, 20 h.
Isolated yields.
2ACHTUNGTNER(NUNG dba)3 (0.05–2.5 mol%), ligand 6 (0.3–
[b]
[c]
m-Xylene, 1308C.
Particular emphasis was given to sterically demanding pling products in high yields (Table 2, entries 2–5, 10–
substrate combinations. The results are summarized in 11). Thus, tetra-ortho-substituted diarylamines were
Table 2. Sterically hindered aniline derivatives were prepared in 90–99% yields (Table 2, entries 3–5 and
efficiently converted (Table 2, entries 1–6 and 11). 11). These results demonstrate the broad substrate
Furthemore, high yields of isolated product were ob- scope of the Pd2ACTHNUTRGNEU(GN dba)3/oxaphosphole systems for ami-
tained with electron-rich, thereby electronically deac- nation reactions and its particular effectiveness for
tivated, aryl chlorides and bromides. ortho-Substitu- sterically demanding substrates.
ents on the aryl bromides and chlorides were tolerat-
We also evaluated the scope of the oxaphosphole
ed as well, leading to the corresponding hindered cou- monophosphine ligands in amination reactions of het-
Adv. Synth. Catal. 2011, 353, 533 – 537
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Sonia Rodriguez et al.
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Table 3. Amination reactions of heteroaryl halides.[a]
[a]
[b]
Conditions: halide (1.0 equiv.), amine (2 equiv.), Pd2ACTHNUTRGENUN(G dba)3 (2.5 mol%), ligand 6
(10 mol%), NaO-t-Bu (2 equiv.), toluene, 1108C, 12–20 h.
Isolated yields.
NaO-t-Bu (356 mg, 3.71 mmol, 1.5 equiv.) in toluene (4 mL)
under argon was added 2,4,6-triisopropylbromobenzene
(0.62 mL, 2.47 mmol) and 2,6-diisopropylamine (0.56 mL,
2.96 mmol, 1.2 equiv.). The resulting mixture was stirred at
1108C for 20 h, and after cooling to room temperature, the
mixture was filtered through a pad of celite washing with
EtOAc. The filtrate was concentrated to give a residue,
which was purified by column chromatography (silica gel, 0–
20% EtOAc in hexanes) to provide N-(2,4,5-triisopropyl-
phenyl)-N-(2,6-diisopropylphenyl)amine as white solid;
eroaryl halides (Table 3). 2-, 3- and 4-chloropyridines
were viable substrates for catalytic amination reac-
tions using ligand 6 (entries 1–5). A variety of amines
proved to be suitable coupling partners including acy-
clic alkylamines which are usually difficult substrates
due to b-hydride elimination of their palladium amide
complexes (Table 3, entry 3) and hindered 2,4,6-trime-
thylaniline (Table 3, entry 4). 5-Bromopyrimidine also
reacted with N-methylaniline to form the desired cou-
pling product in 78% isolated yield (Table 3, entry 6). yield: 919 mg (2.42 mmol, 90%). 1H NMR (400 MHz,
CDCl3): d=7.06 (d, J=7.6 Hz, 2H), 6.96 (t, J=7.6 Hz, 1H),
6.93 (s, 1H), 4.77 (s, 1H), 3.11 (sept, J=6.8 Hz, 2H), 3.05
(sept, J=6.8 Hz, 2H), 2.86 (sept, J=6.8 Hz, 1H), 1.23 (d,
J=6.8 Hz, 6H), 1.08 (d, J=6.8 Hz, 12H), 1.07 (d, J=6.8 Hz,
12H).
See Supporting Information for experimental details, char-
acterization of products and copies of product 1H and
13C NMR spectra.
In summary, we have developed a series of dihydro-
benzooxaphosphole-based monophosphorus ligands
1–4 bearing a C-2-substituted oxaphosphole back-
bone. These ligands and their C-2-unsubstituted ana-
logs 5–7 were evaluated in palladium-catalyzed ami-
nation reactions of a variety of (hetero)aryl bromides
and chlorides with diverse amines including sterically
hindered anilines and alkyl amines. In particular,
ligand 6 (BI-DIME) proved to be highly efficient in
the amination reaction of a wide variety of challeng-
ing substrates.
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