Pd-PEPPSI-IPentCl-Catalyzed Amination Using Aminotriphenylsilane as an Ammonia Surrogate

Article abstract of DOI:10.1002/ejoc.201601565

Coupling of Ph₃SiNH₂ with aryl halides by using Pd-PEPPSI-IPent^Cl {dichloro(3-chloropyridyl)[4,5-dichloro-1,3-bis(2,6-dipent-3-ylphenyl)imidazol-2-ylidene]palladium(II)} yields triphenylsilyl-protected anilines. These trip

Full text of DOI:10.1002/ejoc.201601565

DOI: 10.1002/ejoc.201601565
Communication
Palladium-Catalyzed Amination
Pd-PEPPSI-IPentCl-Catalyzed Amination Using
Aminotriphenylsilane as an Ammonia Surrogate
Christopher Lombardi,[a] David Mitchell,[b] Michael J. Rodriguez,[b] and
Michael G. Organ*[a,c]
Abstract: Coupling of Ph3SiNH2 with aryl halides by using Pd- ilines can be isolated, alkylated without over-alkylation, and the
PEPPSI-IPentCl {dichloro(3-chloropyridyl)[4,5-dichloro-1,3-bis(2,6- protecting group can be removed under mild acidic conditions
dipent-3-ylphenyl)imidazol-2-ylidene]palladium(II)} yields tri- or in the presence of fluoride to afford the secondary aniline
phenylsilyl-protected anilines. These triphenylsilyl protected an- product.
Introduction
alkylation before removing the silyl group, thereby mitigating
over-alkylation concerns (Scheme 1).[16–29]
In the past decade, the Pd-catalyzed coupling of primary alkyl-
amines and ammonia with aryl halides and pseudo halides has
been well developed.[1–8] Prior to the advent of catalysts for
the direct amination with ammonia, a wide variety of ammonia
equivalents were developed to obtain primary arylamines from
aryl halides. The ammonia equivalents are first coupled to an
aryl halide and the masking removed to yield the primary aryl-
amine. Reagents that have been successfully used as ammonia
equivalents include: tert-butyl sulfinamide,[9] allylamine,[10]
benzophenone imine,[11,12] lithium bis(trimethylsilyl)amide
(LiHMDS),[13] zinc bis(trimethylsilyl)amide (ZnHMDS),[14] and
aminotriphenylsilane.[15]
Scheme 1. Amination, alkylation, and silyl group removal.
Results & Discussions
While ammonia equivalents require additional synthetic op-
erations compared to direct amination with ammonia, there are
several advantages to their use. Ammonia equivalents are easier
to handle than ammonia, they are not required in large excess,
they do not readily undergo a second undesired coupling that
plagues ammonia, and they are typically coupled under milder
conditions than ammonia.
Aminotriphenylsilane was first disclosed by Buchwald's
group in 2001 as a substitute for LiHMDS, which is too sterically
demanding to couple with ortho-substituted aryl halides.[15] We
envisaged that instead of immediately cleaving the silyl group
off to yield the primary arylamine, the product could undergo
The coupling of 1 with aryl chlorides was first attempted with
a variety of bases commonly employed in Buchwald–Hartwig
amination (Table 1). Pd-PEPPSI-IPentCl was selected as catalyst
because it is known to be highly efficient for the amination
and sulfination of sterically encumbered substrates.[30–33] While
NaOtBu gave conversion to product, the triphenylsilyl group of
the reactant or product was slowly removed resulting in large
amounts of 4-tert-butyl aniline and diarylamine. The bulkier
iPr3SiNH2 was coupled successfully, but it also gave the same
undesired products as 1. LiHMDS was the most effective base
for this reaction, likely because 1 is deprotonated prior to coor-
dination to palladium.[15]
Reaction conditions were then optimized for the use of
LiHMDS (Table 2). The reaction with 3, which is slightly deacti-
vated (i.e., the ring is electron-rich), went to completion in tolu-
ene at 100 °C. If the precatalyst was first activated with di-n-
butylmagnesium the coupling was found to proceed well at
room temperature (entry 1, Table 2).
[a] Department of Chemistry, York University,
4700 Keele Street, Toronto, Ontario M3J 1P3, Canada
[b] Lilly Research Laboratories, A Division of Eli Lilly and Company,
Indianapolis, IN 46285, USA
LiHMDS prohibits the use of many aryl chlorides with base-
sensitive functional groups. Hartwig and Lee reported ZnHMDS
as
ZnHMDS, formed in situ by the addition of ZnCl2 to LiHMDS,
suppressed base-mediated decomposition of methyl p-chloro-
benzoate (entries 4–7, Table 2). In order to aid the dissolution
[c] Centre for Catalysis Research and Innovation (CCRI) and Department of
Chemistry, University of Ottawa,
a
functional group-tolerant substitute for LiHMDS.[14]
Ottawa, Ontario K1N 6N5, Canada
E-mail: organ@uottawa.ca
http://mysite.science.uottawa.ca/organ/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601565.
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Communication
Table 1. Optimization of the reaction conditions for the coupling of 4-tert-
Table 3. Amination reactions with Ph3SiNH2 and aryl halides.
butylchlorobenzene with aminotriphenylsilane.[a]
Entry
2 [mol-%]
Base (equiv.)
Temp. [°C]
Conversion [%]
1
2
3
4
1
1
3
1
1
1
3
3
Cs2CO3 (3.0)
Cs2CO3 (3.0)
K3PO4 (1.2)
NaBHT (1.2)
NaOtBu (1.2)
NaOtBu (1.2)
NaOtBu (1.2)
LiHMDS (1.2)
80
0
0
0
< 5
< 5
10[c]
45[d]
100
100
100
90
5[b]
6
30
100
100
100
7
8
[a] Aryl-Cl (0.1
M
), conversion determined by 1H NMR spectroscopy of the
crude reaction mixture. [b] The precatalyst was first activated by stirring with
LiOiPr at 95 °C for 5 min. [c] 40 % of 3 was converted to bis[4-(tert-butyl)-
[a] Aryl-Cl (0.625
M), toluene, room temp. [b] 0.55 equiv. ZnCl2, 65 °C, 1:1
phenyl]amine. [d] 35 % of
phenyl]amine.
3
was converted to bis[4-(tert-butyl)-
toluene/THF. [c] Silylated product could not be isolated. [d] 3 mol-% Pd-PEP-
PSI-IHeptCl (see the Supporting Information for structure). [e] Toluene, 100 °C.
Table 2. Optimization of the reaction conditions with ZnHMDS for base-sensi-
tive substrates.[a]
Alkylation of 4 was attempted with 1-bromooctane (Table 4)
and no conversion was observed with potassium or cesium
carbonate in refluxing dichloromethane or acetonitrile. The use
of dimethylformamide (DMF) as solvent at elevated tempera-
tures resulted in partial desilylation of the reactant and subse-
quent over-alkylation of the unprotected aniline, which high-
lights the need for the silyl group. Deprotonation of the starting
silylamine was then examined to generate a better nucleophile.
Deprotonation with NaH caused partial loss of the silyl group
before alkylation was complete, whereas deprotonation with
LiHMDS at room temperature followed by addition of 1-bromo-
octane gave 60 % conversion to product.
Entry
R
Solvent
ZnCl2
[equiv.] [°C]
Temp.
Conversion
[%]
1
2
3
4
5
6
7
–C(CH3)3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
toluene
toluene
toluene
THF
DME
DME
–
–
r.t.
r.t.
r.t.
r.t.
r.t.
80
60
100
0
0
45
50
65
65
0.6
0.6
0.6
0.6
0.6
Table 4. Optimizing of alkylation reaction conditions by using 1-bromooctane
as substrate.[a]
1:1 THF/ toluene
[a] 4-tert-Butylchlorobenzene (0.625
M
); conversion determined by 1H NMR
spectroscopy of the crude reaction mixture.
of ZnCl2 the use of ethereal solvents were necessary. Dimeth-
oxyethane (DME) or a 1:1 mixture of toluene and THF pro-
ceeded equally well, but the co-solvent system was chosen for
convenience, because precatalyst activation works well in tolu-
ene, and both LiHMDS and ZnCl2 are commercially available as
THF solutions.
Having established two procedures for the coupling of 1, a
variety of sterically and electronically diverse aryl halides were
examined (Table 3). Hindered 2,6-dimethylchlorobenzene re-
acted well in the absence of ZnCl2 to provide 10. Substrates
bearing nitrile (5, 6), nitro (7), and ester (8) substituents were
coupled successfully, although column chromatography of the
silylated 4-nitroaniline resulted in hydrolysis, and hence, 4-
nitroaniline was isolated. In order to minimize hydrolysis on sil-
ica gel, triethylamine (1 %) was added to the eluent. Although
Entry Base
Solvent
Temp. [°C]
Conversion [%]
1
2
3
4
5
6
7
8
Cs2CO3
CH2Cl2
MeCN
MeCN
DMF
DMF
THF
40
0
0
0
0
K2CO3
Cs2CO3
K2CO3
Cs2CO3
NaH
reflux
reflux
120
120
60
0
< 5
0
LiHMDS
LiHMDS
Et2O
THF
r.t.
r.t.
60[a]
[a] Conversion determined by 1H NMR spectroscopy of the crude reaction
mixture.
By using LiHMDS to deprotonate the silylated amine, primary
the products all hydrolyze readily in dilute acid, they are bench (12–14, 17, 18), allylic (15), and benzylic (16) bromides, iodides,
stable with no loss of the triphenylsilyl group from 4 or 8 after and tosylates were successfully alkylated (Table 5). Isolation of
one year of storage in a vial in air.
17 shows that alkylation of sterically hindered aryl halides is
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Communication
General Procedure for Amination of Aryl Halides with Aminotri-
phenylsilane, LiHMDS, and ZnCl2: An oven-dried argon-filled vial
(A, V = 8 mL) containing a Teflon-coated magnetic stir bar was
possible and that the triphenylsilyl group is not lost during the
alkylation. Compound 18, which contains an electron-with-
drawing and base-sensitive ester group, was also alkylated in
high yield.
charged with LiHMDS in THF (1.0 M, 0.275 mL, 0.275 mmol), 0.5
M
ZnCl2 in THF (0.275 mL, 0.138 mmol), and THF (1.45 mL) with a
syringe and the resultant solution was stirred for 20 min. A separate
oven-dried argon filled vial (B, V = 8 mL) containing a Teflon-coated
magnetic stir bar was charged with Pd-PEPPSI-IPentCl (6.5 mg, 3 mol-
%). The vial was sealed with a Teflon-coated screw cap and back-
filled with argon (3 ×). Toluene (2 mL) and nBu2Mg in heptanes
(1.0 M, 15 μL, 6 mol-%) were added with a syringe and the solution
was stirred for 10 min. An oven-dried argon-filled vial (C, V = 8 mL)
containing a Teflon-coated magnetic stir bar was charged with
aminotriphenylsilane (75.7 mg, 0.275 mmol) and the aryl halide
(0.25 mmol, 1 equiv.). The vial was sealed with a Teflon-coated
screw cap and backfilled with argon (3 ×). The contents of vial B
were transferred with a syringe to vial C. The contents in vial A were
then transferred to vial C with a syringe. Vial C was then placed in
a pre-heated oil bath at 65 °C and was stirred for 24 h. The reaction
mixture was then cooled to r.t., diluted with CH2Cl2, filtered through
a plug of silica with ethyl acetate containing 1 % triethylamine, and
the filtrate concentrated in vacuo. The crude product was purified
with a flash chromatography on silica gel by using an eluent con-
taining 1 % triethylamine to yield the desired product.
Table 5. Alkylation of triphenylsilyl-protected anilines with alkyl bromides,
iodides, or tosylates.
[a] Product isolated without silyl group removal.
General Alkylation Procedure: An oven-dried argon-filled vial (V =
8 mL) containing a Teflon-coated magnetic stir bar was charged
with the silylated amine (1 equiv.). The vial was sealed with a Teflon-
coated screw cap and backfilled with argon three times. THF was
Removal of the triphenylsilyl group from the amine can be
accomplished by addition of HCl (1
M) or a slight excess of
then added with a syringe to dilute the silylated amine to 1.0
M.
tetrabutylammnonium fluoride (TBAF) to the reaction mixture.
Acid-catalyzed desilylation was faster (5 to 10 min) and simpler
than the desilylation with TBAF, which can require up to 2 h to
reach completion.
LiHMDS in THF (1.0 , 1.1 equiv.) and the electrophile (1.2 equiv.)
M
were then added with a syringe and the reaction progress was
monitored by TLC. When the reaction was judged complete, either
aqueous HCl (5 equiv., 1.0 M) or TBAF in THF (5 equiv., 1.0 M) were
added and the resultant mixture was stirred until complete removal
of the triphenylsilyl group was confirmed by TLC analysis. The reac-
Conclusion
tion mixture was then diluted with diethyl ether, 0.1
M NaOH was
added, and the layers were separated. The combined organic layers
were dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel to yield the desired product.
Aminotriphenylsilane is a convenient ammonia equivalent that
can be coupled by using Pd-PEPPSI-IPentCl and LiHMDS. Addi-
tion of ZnCl2 expands the substrate scope to include base-sen-
sitive substrates. The silyl-protected products are useful inter-
mediates for selective N-alkylation, which can then be easily
deprotected by acid or with fluoride.
Acknowledgments
This work was supported by the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) in the form of a CRD
grant and by the Eli Lilly Research Award Program (LRAP). C. L.
wishes to acknowledge the NSERC for a post-graduate scholar-
ship.
Experimental Section
General Procedure for the Amination of Aryl Halides with
Aminotriphenylsilane and LiHMDS: In a glovebox, a vial (V =
8 mL) containing a Teflon-coated magnetic stir bar was charged
with LiHMDS (44.9 mg, 0.275 mmol), sealed, and removed from
the glovebox. The vial was then charged with aminotriphenylsilane
(75.7 mg, 0.275 mmol), Pd-PEPPSI-IPentCl (6.5 mg, 3 mol-%), and the
aryl halide (if solid, 0.25 mmol, 1 equiv.). The vial was sealed with a
Teflon-coated screw cap and backfilled with argon (3 ×). The aryl
halide (if liquid, 0.25 mmol, 1 equiv.) and toluene (4 mL) were then
added with a syringe. The vial was then placed in a pre-heated oil
bath at the given temperature and the reaction was stirred for 24 h.
The mixture was then cooled to room temp., diluted with CH2Cl2,
filtered through a plug of silica with ethyl acetate containing 1 %
triethylamine, and the filtrate concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel by using
an eluent containing 1 % triethylamine to yield the desired product.
Keywords: Ammonia equivalent · N-Alkylation · Amination ·
N-heterocyclic carbene · Cross-coupling · Palladium
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Received: December 7, 2016
Published Online: ■
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Communication
Palladium-Catalyzed Amination
C. Lombardi, D. Mitchell,
M. J. Rodriguez, M. G. Organ* ....... 1–5
Pd-PEPPSI-IPentCl-Catalyzed Amin-
ation Using Aminotriphenylsilane as
an Ammonia Surrogate
Triphenylsilyl-protected anilines were 2-ylidene]palladium(II)}. The silylated
obtained from the cross-coupling of products were then alkylated without
aminotriphenylsilane with aryl halides over-alkylation, yielding the secondary
in the presence of Pd-PEPPSI-IPentCl amines after hydrolysis under mild
{dichloro(3-chloropyridyl)[4,5-dichloro- acidic conditions.
1,3-bis(2,6-dipent-3-ylphenyl)imidazol-
DOI: 10.1002/ejoc.201601565
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