Convenient palladium-catalyzed preparation of primary anilines using a fluorous benzophenone imine reagent

Article abstract of DOI:10.1055/s-2004-820011

A novel fluoroalkyl benzophenone imine reagent (f-BPI) serves as a convenient ammonia surrogate for the palladium-catalyzed Buchwald-Hartwig amination of aryl halides. The highly fluorinated imine moiety acts as a handle for rapid purification of intermediates using fluorous chromatographic techniques, and is removed in a subsequent stage by acid hydrolysis to provide the corresponding primary anilines.

Full text of DOI:10.1055/s-2004-820011

LETTER
841
Convenient Palladium-Catalyzed Preparation of Primary Anilines Using a
Fluorous Benzophenone Imine Reagent
Preparation of
Pr
h
A
nilin
r
es Using
i
Fluoro
s
us Benzo
t
phenon
o
e
Imine pher L. Cioffi, Michael L. Berlin,1 R. Jason Herr*
Medicinal Chemistry Department, Albany Molecular Research, Inc., P.O. Box 15098, Albany, NY 12212-5098, USA
E-mail: rjason.herr@albmolecular.com
Received 23 December 2003
A discussion with the scientists at Fluorous Technologies,
Inc. (FTI) led to the preparation of a fluorous version of
benzophenone imine for evaluation in comparison to
Buchwald’s published method.3a As a result, FTI prepared
Abstract: A novel fluoroalkyl benzophenone imine reagent (f-BPI)
serves as a convenient ammonia surrogate for the palladium-catal-
yzed Buchwald–Hartwig amination of aryl halides. The highly
fluorinated imine moiety acts as a handle for rapid purification of
intermediates using fluorous chromatographic techniques, and is the reagent 4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hepta-
removed in a subsequent stage by acid hydrolysis to provide the
corresponding primary anilines.
decafluorodecyl)benzophenone imine (f-BPI, 2) which
we subjected to Buchwald’s palladium-catalyzed cross
Key words: amination, arylation, cross-coupling, palladium-catal-
yzed, fluorous
coupling reaction conditions with some of the same aryl
halides 1a–i to provide a series of N-arylimine adducts 3
(Scheme 1). In this way we could compare a few yields
directly with the original3a method. Following the cross-
The last half-decade has seen tremendous advances in the coupling reaction, the crude mixtures were purified by
development of useful and practical methods for palladi- quick filtration through a plug of FluoroFlash silica gel
um-catalyzed amination of aryl halides and triflates.2 Ear- (also referred to as a ‘fluorous solid phase extraction’ or
ly on in the course of these discoveries, however, it had ‘fluorous SPE’)5 to provide the purified N-arylimine prod-
become plain that alternative protocols were required for ucts 3a–i, as shown in Table 1.6 A slight excess of aryl
the direct generation of primary anilines, as ammonia was substrate 1 to imine 2 was used to ensure efficient purifi-
found not to participate. As a result, several methods have cation by the fluorous solid phase purification technique.
appeared in which various ammonia surrogates were In all cases the reactions were observed to achieve 100%
found to undergo palladium-catalyzed coupling reactions conversion of the imine 2.
with aryl halides to provide N-aryl amines.3 One of the
first methods developed by the Buchwald group utilized
To accomplish the fluorous SPE purification, the reaction
mixture solvent was removed under reduced pressure and
benzophenone imine as the ammonia equivalent in a
the residue was dissolved in a minimal amount of THF
cross-coupling reaction with aryl halides and triflates, to
and applied to a plug of fluorous silica gel. The support
was first flushed with a MeOH–water mixture (4:1) to re-
move the excess 1, by-products, catalysts and inorganic
salts. After discarding this fluorophobic organic wash, the
provide the corresponding N-aryl benzophenone imines.3a
These adducts were then subjected to various deprotection
conditions to unmask the amine functionality, either in a
separate step or during the workup of the amination reac-
plug was then flushed with a fluorophilic solvent (either
tion, to provide primary anilines. In these cases, the inter-
MeOH or THF). This second wash was collected and the
mediate N-aryl imines were found to crystallize directly
solvent was removed to provide the N-aryl products 3a–i
following the aqueous workup, followed by chromatogra-
in good purity (>95% as determined by 1H and 13C NMR
phy after the hydrolysis step to provide clean material. In
analyses).
our experience we have found that larger molecules have
Hydrolysis of the imine moiety of N-arylimines 3a–i with
not crystallized directly, leading to the necessity of purifi-
aqueous HCl in THF at room temperature was achieved in
cation at one or both stages of the transformation. How-
a separate step. In most cases the hydrolyses were com-
ever, with the advent of convenient fluorous techniques
plete within fifteen minutes, after which the reaction mix-
tures were treated with macroporous triethylammonium
methylpolystyrene carbonate (MP-carbonate) resin7 and
stirred for an additional five minutes. The basified con-
tents were then loaded directly onto a FluoroFlash car-
tridge for a second fluorous separation to provide pure
aniline products 4a–i in good overall yields, as shown in
Table 1. This time the fluorous solid phase was flushed
with a MeOH–water mixture (4:1) to provide the anilines
4 as free bases in good purity (>95% as determined by 1H
and 13C NMR analyses). The second wash of the fluorous
silica gel with a fluorophilic mobile phase (MeOH or
for the rapid purification of organic compounds,4 we
decided to investigate the possibility of combining a
fluorine-containing tag into our ammonia surrogate. In
this way, a fluorous handle would add to the value of
Buchwald’s amination procedure by taking additional
advantage of the efficient purification method.
SYNLETT 2004, No. 5, pp 0841–0845
0
2.
0
4.
2
0
0
4
Advanced online publication: 24.02.2004
DOI: 10.1055/s-2004-820011; Art ID: S11303ST
© Georg Thieme Verlag Stuttgart · New York

842
C. L. Cioffi et al.
LETTER
1. 2, Pd2dba3, BINAP
t-BuONa, PhCH3, 80 ºC
R
R
2. Fluorous SPE
(see Table 1)
X
N
1a–i
(CF2)7CF3
3a–i
X = Br, I, OTf
(CF2)7CF3
1. 2 N HCl, THF, r.t.
R
2. MP-carbonate resin;
Fluorous SPE
NH2
O
4a–i
(organic phase)
5
(see Table 1)
(fluorous phase)
(CF2)7CF3
NH
2 (f-BPI)
Scheme 1 General method for preparation of primary anilines 4 using f-BPI reagent 2.
THF) then provided pure recovered fluorous benzophe- the two-step yield of 97% of 4a from 1a reported by
none 5, which was usually observed at >60% recovery for Buchwald. We were therefore pleased to conclude that the
the two-step process.17
fluorous tag imparts no adverse effects to the coupling
reaction efficiency, so that f-BPI can be used as a general
reagent to provide primary anilines (electron-rich and -de-
ficient) and amino heterocycles without complication.
Examination of the results shows that these coupling and
hydrolysis reactions are comparable to yields of the anal-
ogous reactions with benzophenone imine as reported by
the Buchwald group.3a For example the cross-coupling of In conclusion, novel (now commercially available) hepta-
1-bromo-4-tert-butylbenzene (1d) with f-BPI to provide decafluorodecyl benzophenone imine reagent 2 (f-BPI)
3d was achieved in 95% yield (entry 4), which compares serves as a convenient ammonia equivalent in the palladi-
favorably to the 90% yield achieved by Buchwald’s group um-catalyzed Buchwald–Hartwig amination of aryl ha-
for the analogous preparation of the adduct with ben- lides and triflates. The highly fluorinated imine protecting
zophenone imine itself. Hydrolysis of 3d to provide 4- group acts as a handle for rapid purification of non-crys-
tert-butylaniline (4b) was achieved in 97% yield (entry 4), talline intermediates using fluorous chromatographic
which is similar to the throughput realized for Buchwald’s techniques, and is removed in a subsequent stage by
equivalent benzophenone imine cleavage (84% yield). treatment with aqueous acid in THF to provide the pure
Similarly, the coupling of 4-bromobenzonitrile (1a) to f- corresponding primary anilines.
BPI was achieved in 86% yield, and hydrolyzed to 4-ami-
nobenzonitrile (4a) in 95% yield (entry 1). The overall
yield of the two-step procedure (82%) is comparable to
Table 1 Amination of Aryl Halides and Triflates 1 with f-BPI 2 and Subsequent Hydrolysis to Primary Anilines 4
Entry
1
Aryl Substrate 1
NC
N-Aryl Imine 3
Yielda (%)
Aniline 4
NC
Yielda,b (%)
NC
NH2
Br
86
958,9
1a
4a
N
(CF2)7CF3
3a
O2N
O2N
O2N
Br
NH2
2
79
918,10
1b
4b
N
(CF2)7CF3
3b
Synlett 2004, No. 5, 841–845 © Thieme Stuttgart · New York

LETTER
Preparation of Primary Anilines Using Fluorous Benzophenone Imine
843
Table 1 Amination of Aryl Halides and Triflates 1 with f-BPI 2 and Subsequent Hydrolysis to Primary Anilines 4 (continued)
Entry
3
Aryl Substrate 1
N-Aryl Imine 3
Yielda (%)
Aniline 4
Yielda,b (%)
O
O
O
H3C
H3C
H3C
79
908,11
978,12
638,13
888,14
90
Br
NH2
N
(CF2)7CF3
1c
4c
3c
4
5
6
7
8
9
95
94
65
65
97
93
Br
NH2
N
(CF2)7CF3
1d
4d
3d
3d
H3CO
NH2
H3CO
Br
5e
4e
H3CO
N
(CF2)7CF3
(CF2)7CF3
(CF2)7CF3
3e
H3C
I
H3C
NH2
1f
4f
H3C
3f
N
O2N
O2N
O2N
OTf
NH2
1g
4b
N
3b
S
S
S
Br
Br
NH2
9215
1h
4h
N
(CF2)7CF3
3h
N
N
NH2
968,16
1i
4i
N
N
(CF2)7CF3
3i
a Isolated yields after fluorous solid phase extraction (chromatography).
b Superscripted numbers are literature references for the known compounds.
All non-aqueous reactions were performed under a dry atmosphere
of nitrogen unless otherwise specified. Commercial grade reagents
and anhydrous solvents were used as received from vendors and no
attempts were made to purify or dry these components further. Re-
moval of solvents under reduced pressure was accomplished with a
Buchi rotary evaporator at approximately 28 mm Hg pressure using
a Teflon-linked KNF vacuum pump. TLC was performed using 1’’
× 3’’ AnalTech No. 02521 silica gel plates with fluorescent indica-
tor. Visualization of TLC plates was made by observation with ei-
ther short wave UV light. Solid phase extractions were carried out
using FluoroFlashTM silica gel or pre-packed 10 g FluoroFlashTM
silica gel columns, purchased from Fluorous Technologies, Inc. 1H
and 13C NMR spectra were obtained on a 300 MHz NMR spectro-
meter and are reported in ppm d values, using TMS as an internal
reference. Melting points are uncorrected. API Mass spectroscopic
analyses were performed using atmospheric pressure chemical
ionization (APCI).
Synlett 2004, No. 5, 841–845 © Thieme Stuttgart · New York

844
C. L. Cioffi et al.
LETTER
N-Aryl Imines 3a–i; General Procedure
To an oven-dried round-bottom flask charged with tris(dibenz-
1H NMR (300 MHz, CDCl3): d = 7.79 (m, 1 H), 7.71 (m, 1 H), 7.36
(m, 3 H), 7.24 (m, 2 H), 7.15 (m, 2 H), 7.06 (m, 1 H), 6.53 (m, 1 H),
6.51 (m, 1 H), 2.93 (m, 2 H), 2.41 (m, 2 H).
ylidene)dipalladium(0) [Pd2(dba)3,
1
mol%], racemic-2,2¢-
bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP, 3 mol%), sodium
tert-butoxide (1.4 mmol) and anhyd toluene (2 mL) at r.t. under ni-
trogen were added aryl halide or triflate 1 (1.1 mmol) and the fluor-
ous benzophenone imine reagent 2 (f-BPI, 1.0 mmol) and the
mixture was heated at 80 ºC. When the conversion was judged as
complete (by TLC analysis), the mixture was cooled to r.t. and the
solvent was removed under reduced pressure. The residue was dis-
solved in THF (1 mL) and placed onto a column containing Fluo-
roFlashTM silica gel (5 g), which was pre-treated with a MeOH–
water mixture (4:1, 20 mL). The column was initially flushed with
a MeOH–water mixture (4:1, 30 mL, fluorophobic fraction) to re-
move non-fluorous organic components, followed by elution with
either MeOH or THF (30 mL, fluorophilic fraction). The collected
fluorophilic fraction was concentrated under reduced pressure to
provide the desired imine adducts 3 in >95% purity in all cases. Fi-
13C NMR (300 MHz, CDCl3): d = 23.76, 26.21, 28.99, 67.53,
107.80. 112.74, 113.00, 123.86, 123.96, 124.02, 124.08, 127.98,
128.04, 128.21, 128.70, 128.98, 129.34, 129.46, 130.50.
APCI MS: m/z = 709 [C27H16F17NS + H]+.
Anilines 4a–i; General Procedure
To a solution of the imine adduct 3 in THF (0.3 M solution) at r.t.
was added aqueous 2.0 M HCl solution (approximately 5% by vol-
ume with THF). When the conversion was judged as complete (by
TLC analysis), the mixture was made alkaline by addition of MP-
carbonate resin (150 mg). The mixture was then placed directly onto
a cartridge of FluoroFlashTM silica gel (5 g), which was pretreated
with a MeOH–water mixture (4:1, 20 mL). The column was initially
flushed with a MeOH–water mixture (30 mL, fluorophobic frac-
tion) to collect the organic product, followed by elution with MeOH
or THF (30 mL, fluorophilic fraction) to collect the fluorous ben-
zophenone byproduct. The fluorophobic fraction was concentrated
under reduced pressure to provide the desired aniline free bases 4 in
>95% purity in all cases. The fluorophilic fraction was concentrated
under reduced pressure to provide recovered fluorous benzophe-
none 5. Final products were characterized by APCI MS, 1H NMR
and 13C NMR spectroscopy. The reaction conditions were not opti-
mized, and selected examples are shown.
1
nal products were characterized by APCI MS, H NMR and 13C
NMR spectroscopy. The reaction conditions were not optimized,
and selected examples are shown.
4-({[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorode-
cyl)phenyl]phenylmethylene}amino)benzonitrile (3a)
From 4-bromobenzonitrile (1a, 64 mg, 0.35 mmol); light yellow
gum (200 mg, 86%).
1H NMR (300 MHz, CDCl3): d = 7.80 (m, 2 H), 7.71 (m, 1 H), 7.36
(m, 3 H), 7.24 (m, 2 H), 7.15 (m, 2 H), 7.06 (m, 1 H), 6.55 (m, 2 H),
2.93 (m, 2 H), 2.41 (m, 2 H).
13C NMR (300 MHz, CDCl3): d = 26.77, 33.03, 106.71, 119.59,
121.73, 128.64, 129.57, 130.31, 131.01, 131.76, 133.14, 155.81,
169.39.
4-Aminobenzonitrile (4a)8,9
From 4-{[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-
decyl)phenyl]phenylmethylene}-amino)benzonitrile (3a, 130 mg,
0.18 mmol); yellow oil (20 mg, 95%); mp 84–87 ºC (Lit9a mp 86–
87 ºC).
APCI MS: m/z = 728 [C30H17F17N2 + H]+.
1H NMR (300 MHz, CDCl3): d = 7.42 (d, J = 8.57 Hz, 2 H), 6.65 (d,
J = 8.61 Hz, 2 H), 4.10 (br s, 2 H).
1-[4-({[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluoro-
decyl)phenyl]phenylmethylene}amino)phenyl]ethanone (3c)
From 4¢-bromoacetophenone (1c, 70 mg, 0.35 mmol); yellow gum
(190 mg, 79%).
1H NMR (300 MHz, CDCl3): d = 7.81 (m, 2 H), 7.75 (m, 1 H), 7.40
(m, 3 H), 7.30 (m, 2 H), 7.15 (m, 2 H), 7.06 (m, 1 H), 6.60 (m, 2 H),
2.93 (m, 2 H), 2.53 (s, 3 H), 2.41 (m, 2 H).
13C NMR (300 MHz, CDCl3): d = 26.63, 32.99, 120.97, 127.70,
128.61, 129.67, 130.31, 131.02, 132.62, 132.75, 156.26, 168.72,
197.51.
13C NMR (300 MHz, CDCl3): d = 112.71, 125.66, 151.83.
APCI MS: m/z = 154 [C7H6N2 + H]+.
4¢-Aminoacetophenone (4c)8,11
From 1-[4-({[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecaflu-
orodecyl)phenyl]phenylmethylene}-amino)phenyl]ethanone (3c,
160 mg, 0.22 mmol); white solid (26 mg, 90%); mp 100–102 ºC
(Lit11a mp 104–105 ºC).
1H NMR (300 MHz, CDCl3): d = 7.83 (d, J = 2.48 Hz, 2 H), 6.66 (d,
J = 2.52 Hz, 2 H), 4.11 (br s, 2 H), 2.50 (s, 3 H).
13C NMR (300 MHz, CDCl3): d = 31.97, 34.33, 115.37, 126.46,
141.22, 144.25.
APCI MS: m/z = 136 [C8H9NO + H]+.
APCI MS: m/z = 745 [C31H20F17NO + H]+.
{[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorode-
cyl)phenyl]phenylmethylene}-m-tolylamine (3f)
From 3-iodotoluene (1f, 84 mg, 0.35 mmol); light yellow gum (84
mg, 65%).
1H NMR (300 MHz, CDCl3): d = 7.79 (m, 2 H), 7.71 (m, 1 H), 7.57
(m, 2 H), 7.48 (m, 3 H), 7.33 (m, 1 H), 7.26 (m, 3 H), 7.09 (m, 1 H),
2.98 (m, 2 H), 2.36 (m, 2 H), 2.21 (s, 3 H).
13C NMR (300 MHz, CDCl3): d = 24.26, 26.23, 29.52, 33.12, 68.37,
118.58, 122.54, 124.69, 128.49, 128.62, 128.86, 128.91, 128.99,
129.27, 130.03, 130.17, 130.51, 130.70, 130.79, 131.41.
m-Toluidine (4f)8,14
From {[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorode-
cyl)phenyl]phenylmethylene}-m-tolylamine (3f, 140 mg, 0.20
mmol); yellow oil (18 mg, 88%).
1H NMR (300 MHz, CDCl3): d = 7.03 (m, 1 H), 6.56 (m, 1 H), 6.44
(m, 1 H), 3.49 (br s, 2 H), 2.22 (s, 3 H).
13C NMR (300 MHz, CDCl3): d = 22.46, 113.33, 116.99, 120.42,
130.20, 140.20, 147.55.
APCI MS: m/z = 107 [C7H9N + H]+.
APCI MS: m/z = 717 [C30H20F17N + H]+.
{[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorode-
cyl)phenyl]phenylmethylene}thiophen-3-ylamine (3h)
From 3-bromothiophene (1h, 62 mg, 0.35 mmol); light yellow gum
(220 mg, 97%).
2-Aminothiophene (4h)15
From {[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorode-
cyl)phenyl]phenylmethylene}-thiophen-3-ylamine (3h, 200 mg,
0.28 mmol); white solid (26 mg, 92%); mp 140–145 ºC (Lit15a mp
146 ºC ).
Synlett 2004, No. 5, 841–845 © Thieme Stuttgart · New York

LETTER
Preparation of Primary Anilines Using Fluorous Benzophenone Imine
845
1H NMR (300 MHz, CDCl3): d = 7.10 (m, 1 H), 6.58 (m, 1 H), 6.10
(m, 1 H), 3.61 (br s, 2 H).
(www.biotage.com). Pre-packaged cartridges are
compatible with many MPLC systems.
(7) (a) Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L.
Tetrahedron Lett. 1997, 38, 7959. (b) Aberler, N. S.;
Ganesan, A.; Lambert, J. N.; Saubern, S.; Smith, R.
13C NMR (300 MHz, CDCl3): d = 99.95, 121.15,125.20, 145.19.
APCI MS: m/z = 100 [C4H5NS + H]+.
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1 1999, 1251. (d) Available from Argonaut Technologies,
Inc. (www.argotech.com).
Acknowledgment
The authors wish to acknowledge and thank Dr. Marvin S. Yu of
Fluorous Technologies, Inc. (FTI) for the preparation of compound
2, Drs. John E. Reilly and Larry Yet of Albany Molecular Research,
Inc. (AMRI) for helpful suggestions and Dr. Dmytro (Dima) O.
Tymoshenko of AMRI for advice on the use of MP-carbonate resin.
(8) The obtained physical data was identical to material
obtained from a commercial vendor.
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(6) We used either a slurry-packed plug of commercially
available FluoroFlash fluorous silica gel or pre-packed
FluoroFlash cartridges available from both Fluorous
Technologies, Inc. (www.fluorous.com) and Biotage, Inc.
Synlett 2004, No. 5, 841–845 © Thieme Stuttgart · New York