A Convenient Preparation Method for Benzophenone Imine Catalyzed by Tetrabutylammonium Fluoride

Article abstract of DOI:10.1021/acs.oprd.9b00226

Benzophenone imine is a useful ammonia equivalent in the Buchwald-Hartwig amination and an important intermediate for the synthesis of N-protected primary amines. However, the conventional synthesis of benzophenone imine requires stoichiometric amounts of metal reagents or high-pressure conditions. Herein we report a facile method for preparing benzophenone imine to enhance its potential utility. The reaction is performed by mixing commercially available benzophenone and bis(trimethylsilyl)amine in the presence of a catalytic amount of tetrabutylammonium fluoride at ambient temperature and pressure and can be readily applied to a multigram-scale synthesis even in a standard academic laboratory setup. Preliminary mechanistic studies and the application of the reaction to one-pot benzophenone imine synthesis/Buchwald-Hartwig amination are also reported.

Full text of DOI:10.1021/acs.oprd.9b00226

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
A Convenient Preparation Method for Benzophenone Imine
Catalyzed by Tetrabutylammonium Fluoride
Yuta Kondo, Kazuhiro Morisaki,† Yoshinobu Hirazawa, Hiroyuki Morimoto,* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
S
* Supporting Information
Scheme 1. Approaches for Synthesizing Benzophenone
Imine
ABSTRACT: Benzophenone imine is a useful ammonia
equivalent in the Buchwald−Hartwig amination and an
important intermediate for the synthesis of N-protected
primary amines. However, the conventional synthesis of
benzophenone imine requires stoichiometric amounts of
metal reagents or high-pressure conditions. Herein we
report a facile method for preparing benzophenone imine
to enhance its potential utility. The reaction is performed
by mixing commercially available benzophenone and
bis(trimethylsilyl)amine in the presence of a catalytic
amount of tetrabutylammonium fluoride at ambient
temperature and pressure and can be readily applied to
a multigram-scale synthesis even in a standard academic
laboratory setup. Preliminary mechanistic studies and the
application of the reaction to one-pot benzophenone
imine synthesis/Buchwald−Hartwig amination are also
reported.
KEYWORDS: tetrabutylammonium fluoride,
benzophenone imine, Buchwald−Hartwig amination,
one-pot synthesis
INTRODUCTION
■
Benzophenone imine, one of the most frequently used N-
unsubstituted ketimines, is a well-established ammonia
equivalent in Buchwald−Hartwig amination reactions.1−3 It
is also an important synthetic intermediate, especially for the
synthesis of glycine Schiff base, one of the most well-known
starting materials for the synthesis of non-natural amino acid
derivatives4 and related N-substituted ketimine derivatives.5
Benzophenone imine was also recently applied as a substrate
for catalytic C−H functionalization reactions.6 Therefore, an
efficient method for preparing benzophenone imine is
important for the synthesis of nitrogen-containing compounds.
Conventional preparation methods for benzophenone imine,
however, have several drawbacks that limit their potential
utility. For example, the addition of phenylmagnesium halides
to benzonitrile, one of the most practical methods for
preparing benzophenone imine, requires the use of air- and
moisture-sensitive Grignard reagents and generates stoichio-
metric amounts of metal waste (Scheme 1, eq a).7
Benzophenone imine is also accessible from benzophenone
and excess ammonia, but this reaction requires the use of
stoichiometric amounts of titanium chloride or a high-pressure
apparatus (Scheme 1, eqs b and c).8 Although the recent
development of synthetic methodologies allows for the
synthesis of benzophenone imine in a catalytic manner
(Scheme 1, eqs d and e),9 the azide starting material is not
readily applicable for large-scale synthesis, and benzhydryl-
amine is generally obtained by reductive amination of the
parent benzophenone. Therefore, a much simpler and more
convenient method for synthesizing benzophenone imine is
highly desirable.
To overcome these limitations, and in accordance with our
recent interest in the chemistry of N-unsubstituted ketimines,10
we were interested in the transformation of benzophenone to
benzophenone imine using bis(trimethylsilyl)amine as a
nitrogen source and tetrabutylammonium fluoride (TBAF) as
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00226
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
a catalyst (Scheme 1, eq f). Although TBAF is a known catalyst
for the synthesis of N-sulfenyl imines from carbonyl
compounds and bis(trimethylsilyl)sulfenamides,11 the method
has not been applied to the synthesis of other imines, including
benzophenone imine. We envisaged that benzophenone imine
could be prepared from benzophenone if the parent bis-
(trimethylsilyl)amine could function as the nitrogen source.
Herein we report our efforts to realize the reaction.
Benzophenone and bis(trimethylsilyl)amine react in the
presence of a catalytic amount of commercially available
TBAF in THF to give benzophenone imine in good yield at
ambient temperature and pressure, and the reaction can be
readily applied to multigram-scale synthesis even in a simple
academic laboratory setup. Preliminary mechanistic studies of
the reaction and its application to one-pot benzophenone
imine synthesis/Buchwald−Hartwig amination are also
reported.
fluoride anion is important, several other tetrabutylammonium
salts were examined, but none afforded 3 (entries 10−13).
Finally, extending the reaction time of TBAF to 6 h afforded 3
in 97% isolated yield (entry 14).
We next applied the optimized reaction conditions to a
large-scale synthesis of 3. The reaction proceeded on a 10
mmol scale, and the crude mixture was purified by silica gel
column chromatography to give 3 in 97% yield (Scheme 2, eq
a). Furthermore, the reaction proceeded smoothly on a 60
mmol scale in a 100 mL flask to give 10 g of 3 after extraction
and distillation (Scheme 2, eq b).
Scheme 2. Large-Scale Syntheses of Benzophenone Imine
RESULTS AND DISCUSSION
■
We initially examined the catalyst to test whether bis-
(trimethylsilyl)amine (2) could be used as a nitrogen source
to transform benzophenone (1) to benzophenone imine (3)
(Table 1). First, we evaluated several metal fluorides to find a
a
Table 1. Catalyst Screening
To clarify the reaction pathway, we obtained preliminary
mechanistic information. 1H NMR analysis of the crude
mixture revealed that hexamethyldisiloxane was generated in
the reaction mixture (Scheme 3, eq a), suggesting that the
trimethylsilyl group in 2 acts as an oxygen scavenger. The
reaction also proceeded in the presence of catalytic amounts of
tetrabutylammonium chloride and potassium trimethylsilano-
late (Scheme 3, eq b), while the same reaction did not proceed
in the absence of tetrabutylammonium chloride. These results
suggested that tetrabutylammonium trimethylsilanolate12 is
one of the active species in the catalytic cycle. In addition, the
presence of small amounts of water in the TBAF solution is
important to promote the reaction effectively, as the addition
of desiccants retarded the reaction to some extent (Scheme 3,
eq c).
On the basis of both the above experimental information
and earlier studies in the literature,11c,13 we propose a possible
reaction mechanism (Scheme 4). First, TBAF reacts with 2 in
the presence of water to give tetrabutylammonium trimethylsi-
lanolate I, which adds to 2 to give hexamethyldisiloxane and
nucleophilic bis(trimethylsilyl)amide II. Next, the addition of
II to 1 gives intermediate III, for which intramolecular
migration of the trimethylsilyl group from the nitrogen atom to
the oxygen atom gives intermediate IV. Finally, elimination of
trimethylsilanolate from IV produces 3 and the starting
tetrabutylammonium trimethylsilanolate I, closing the catalytic
cycle.
b
b
entry
catalyst
NaF
KF
3 (%)
n.d.
n.d.
n.d.
n.d.
87
77
4
7
n.d.
n.d.
n.d.
n.d.
n.d.
1 (%)
1
2
3
4
5
6
7
8
9
>99
>99
>99
>99
13
23
96
93
>99
>99
>99
>99
>99
n.d.
CsF
AgF
TBAF
c
TBAF·xH2O
TMAF
TBAT
DAST
TBACl
10
11
12
13
TBAOAc
d
TBAOH
TBAH2F3
e
c
f
14
TBAF
>99 (97 )
a
The reactions were performed using 1 (1.0 mmol), 2 (2.0 equiv),
and catalyst (10 mol %) in THF (0.10 mL) at room temperature for 2
h. Abbreviations: n.d. = not detected; TMAF = tetramethylammo-
nium fluoride; TBAT = tetrabutylammonium difluorotriphenylsili-
b
cate; DAST = diethylaminosulfur trifluoride. Determined by 1H
c
NMR analysis of the crude mixtures. Commercially available TBAF
solution (1.0 M in THF including <10% water) was used.
Commercially available TBAOH solution (10% in MeOH) was
used. The reaction was performed for 6 h. Isolated yield.
d
e
f
suitable countercation for the fluoride ion, but none provided
the desired product 3 (entries 1−4). On the other hand, TBAF
and its hydrate provided 3 in good yields (entries 5 and 6),
while related fluoride sources such as TMAF and TBAT
provided 3 with lower efficiencies (entries 7 and 8) and DAST
provided no 3 at all (entry 9). To determine whether the
Finally, we applied our synthetic method for benzophenone
imine to a one-pot Buchwald−Hartwig amination (Scheme
5).2b The expected cross-coupling reactions proceeded in a
one-pot manner without isolation of 3, and the desired cross-
coupling products 4a and 4b were obtained in high yields.
These results demonstrated the potential applicability of our
B
DOI: 10.1021/acs.oprd.9b00226
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 3. Preliminary Mechanistic Information
Scheme 4. Possible Reaction Mechanism
Scheme 5. One-Pot Catalytic Benzophenone Imine
Synthesis and Buchwald−Hartwig Amination
the present reaction conditions are still limited to benzophe-
none imine itself and further investigation of the reaction
conditions is necessary to expand the substrate scope,14
benzophenone imine is the most frequently used nitrogen
source among the class of products. Therefore, we hope that
this work will contribute to the future development of cross-
coupling reactions and related synthesis of nitrogen-containing
compounds.
method for Buchwald−Hartwig amination and related cross-
coupling reactions.
EXPERIMENTAL SECTION
■
CONCLUSIONS
General. All of the reactions were performed in flame-dried
or oven-dried glassware under an argon atmosphere unless
otherwise noted. Reagents, catalysts, and solvents were
obtained from commercial sources and used as received unless
otherwise stated. Flash silica gel column chromatography was
performed with Kanto Chemical silica gel 60N (spherical
neutral, particle size 40−50 μm). NMR spectra were acquired
on 500 MHz Bruker Avance III spectrometers. 1H and
13C{1H} NMR chemical shifts are reported in parts per million
and referenced to tetramethylsilane or residual solvent peaks as
■
We have developed a convenient method for the preparation of
benzophenone imine. The reaction is performed by simply
mixing commercially available benzophenone and bis-
(trimethylsilyl)amine as reagents in the presence of a catalytic
amount of tetrabutylammonium fluoride at ambient temper-
ature and pressure and can be readily applied for multigram-
scale synthesis even in a standard academic laboratory setup. A
preliminary mechanistic study of the reaction and its
application to one-pot benzophenone imine synthesis/
Buchwald−Hartwig amination were also realized. Although
1
internal standards (tetramethylsilane at 0 ppm for H and
C
DOI: 10.1021/acs.oprd.9b00226
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
CDCl3 at 77.0 ppm for 13C{1H}). Coupling constants are
reported in hertz. The following abbreviations are used: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad.
Benzophenone (1) was purchased from FUJIFILM Wako
Pure Chemical Corporation. 1,1,1,3,3,3-Hexamethyldisilazane
(2) was purchased from Tokyo Chemical Industry Co., Ltd.
and dried over 4 Å molecular sieves before use. TBAF solution
(1.0 M in THF including <10% water) was purchased from
Tokyo Chemical Industry Co., Ltd. and used as received.
Toluene (dehydrated, H2O < 10 ppm) was purchased from
Kanto Chemical Co. and kept in a glovebox. Tetrahydrofuran
was dried over 4 Å molecular sieves before use.
General Procedure for Catalyst Screening (Table 1). A
4 mL vial with a Teflon-lined screw cap equipped with a
magnetic stir bar was dried under vacuum using a heat gun and
refilled with argon. To the vial were added benzophenone (1)
(1.0 mmol), 1,1,1,3,3,3-hexamethyldisilazane (2) (2.0 mmol,
2.0 equiv), catalyst (0.10 mmol, 10 mol %), and THF (0.10
mL). The vial was stirred at room temperature (25 °C) for 2 h,
and the yield of benzophenone imine (3) was determined by
1H NMR analysis of the crude mixture.
reduced pressure. The residue in the flask was concentrated
under vacuum at room temperature to remove hexamethyldi-
siloxane and excess 2 and then heated to 110 °C (bath
temperature) under vacuum to remove tributylamine gen-
erated from tetrabutylammonium fluoride. The remaining
residue was further purified by vacuum distillation at 150 °C
(bath temperature) to give 3 as a yellow oil (bp 108−110 °C,
1
10.1 g, 93% yield, >99% purity based on H NMR analysis).
Preliminary Mechanistic Information 1: Intermediacy
of Tetrabutylammonium Trimethylsilanolate (Scheme
3, Eq b). A 4 mL vial with a Teflon-lined screw cap equipped
with a magnetic stir bar was dried under vacuum using a heat
gun and refilled with argon. To the vial were added 1 (182 mg,
1.0 mmol), tetrabutylammonium chloride (27.8 mg, 0.10
mmol, 10 mol %), potassium trimethylsilanolate (12.8 mg, 0.10
mmol, 10 mol %), and THF (0.10 mL). The mixture was
stirred at room temperature for 30 min before addition of 2
(0.42 mL, 2.0 mmol, 2.0 equiv). The resulting mixture was
further stirred at room temperature (25 °C) for 2 h, and the
1
yield of 3 was determined by H NMR analysis of the crude
mixture.
The above reaction was also performed in the absence of
tetrabutylammonium chloride, and the product 3 was not
Isolation of the Product (Entry 14). A 4 mL vial with a
Teflon-lined screw cap equipped with a magnetic stir bar was
dried under vacuum using a heat gun and refilled with argon.
To the vial were added 1 (182 mg, 1.0 mmol), 2 (0.42 mL, 2.0
mmol, 2.0 equiv), and tetrabutylammonium fluoride (1.0 M in
tetrahydrofuran) (0.10 mL, 0.10 mmol, 10 mol %). The vial
was stirred at room temperature (25 °C) for 6 h. After the
1
detected by H NMR analysis of the crude mixture.
Preliminary Mechanistic Information 2: Addition of
Desiccants (Scheme 3, Eq c). A 4 mL vial with a Teflon-
lined screw cap equipped with a magnetic stir bar was charged
with desiccant (100 mg/mmol), and the vial was dried under
vacuum using a heat gun and refilled with argon. To the vial
were added 1 (182 mg, 1.0 mmol), 2 (0.42 mL, 2.0 mmol, 2.0
equiv), and tetrabutylammonium fluoride (1.0 M in tetrahy-
drofuran) (0.10 mL, 0.10 mmol, 10 mol %). The vial was
stirred at room temperature (25 °C) for 6 h, and the yield of 3
1
consumption of 1 was confirmed by H NMR analysis, the
crude mixture was directly purified by flash silica gel column
chromatography using 9:1 hexane/Et3N as the eluent to give 3
as an orange oil (177 mg, 97% yield).
Benzophenone Imine (3).15 1H NMR (500 MHz, CDCl3):
δ 9.72 (br s, 1H), 7.58 (br s, 4H), 7.49−7.46 (m, 2H), 7.44−
7.41 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 177.60,
139.87, 137.89, 129.99, 129.58, 128.76, 127.86 (overlapped),
127.14.
1
was determined by H NMR analysis of the crude mixture.
General Procedure for One-Pot Catalytic Benzophe-
none Imine Synthesis and Buchwald−Hartwig Amina-
tion (Scheme 5). A 20 mL Schlenk tube equipped with a
magnetic stir bar was dried under vacuum using a heat gun and
refilled with argon. To the flask were added 1 (182 mg, 1.0
mmol), 2 (0.42 mL, 2.0 mmol, 2.0 equiv), and tetrabuty-
lammonium fluoride (1.0 M in tetrahydrofuran) (0.10 mL,
0.10 mmol, 10 mol %). The tube was stirred at room
temperature (25 °C) for 6 h. After the consumption of 1 was
Procedure for 10 mmol Scale Synthesis (Scheme 2,
Eq a). A 25 mL flask equipped with a magnetic stir bar was
dried under vacuum using a heat gun and refilled with argon.
To the flask were added 1 (1.82 g, 10 mmol), 2 (4.2 mL, 20
mmol, 2.0 equiv), and tetrabutylammonium fluoride (1.0 M in
tetrahydrofuran) (1.0 mL, 1.0 mmol, 10 mol %). The flask was
stirred at room temperature for 6 h. After the consumption of
1
confirmed by H NMR analysis, Pd(OAc)2 (2.25 mg, 0.010
mmol, 1.0 mol %), DPPF (8.32 mg, 0.015 mmol, 1.5 mol %),
NaOtBu (115 mg, 1.2 mmol, 1.2 equiv), toluene (5.0 mL, 0.20
M), and aryl bromide (1.2 mmol, 1.2 equiv) were added to the
reaction mixture under an argon atmosphere. The mixture was
further stirred at 100 °C for 6 h. After the consumption of 3
1
1 was confirmed by H NMR analysis, the crude mixture was
concentrated under vacuum to remove hexamethyldisiloxane
and excess 2. The residue was purified by flash silica gel
column chromatography using 9:1 hexane/Et3N as the eluent
to give 3 as an orange oil (1.76 g, 97% yield, >99% purity based
1
was confirmed by H NMR analysis, the crude mixture was
1
directly purified by flash silica gel column chromatography to
give the cross-coupling product 4.
on H NMR analysis).
Procedure for 60 mmol Scale Synthesis (Scheme 2,
Eq b). A 100 mL flask equipped with a magnetic stir bar was
dried under vacuum using a heat gun and refilled with argon.
To the flask were added 1 (10.9 g, 60 mmol), 2 (25.2 mL, 120
mmol, 2.0 equiv), and tetrabutylammonium fluoride (1.0 M in
tetrahydrofuran) (6.0 mL, 6.0 mmol, 10 mol %). The flask was
stirred at room temperature for 6 h. After the consumption of
1 was confirmed by 1H NMR analysis (>99% conversion based
on 1H NMR analysis of the crude mixture), the crude mixture
was quenched with H2O (100 mL) and extracted with Et2O
(60 mL × 2). The combined organic layer was dried over
Na2SO4, filtered in a 100 mL flask, and evaporated under
N-(4-Methoxyphenyl)-1,1-diphenylmethanimine (4a)2f
(Scheme 5). The reaction was performed according to the
general procedure with 4-bromoanisole (160 μL, 1.2 mmol),
and the crude mixture was directly purified by flash silica gel
column chromatography using 20:1 to 10:1 hexane/EtOAc
with 1% NEt3 as the eluent to give N-(4-methoxyphenyl)-1,1-
diphenylmethanimine (4a) as a yellow oil (268 mg, 93%
1
yield). H NMR (500 MHz, CDCl3): δ 7.74−7.71 (m, 2H),
7.46−7.43 (m, 1H), 7.40−7.37 (m, 2H), 7.31−7.27 (m, 3H),
7.13−7.11 (m, 2H), 6.70−6.66 (m, 4H), 3.72 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 167.77, 155.83, 144.33, 140.02,
D
DOI: 10.1021/acs.oprd.9b00226
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Communication
Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116,
12564−12649.
136.60, 130.48, 129.55, 129.17, 128.45, 128.13, 128.00, 122.56,
113.72, 55.28.
4-((Diphenylmethylene)amino)benzonitrile (4b)2f
(Scheme 5). The reaction was performed according to the
general procedure with 4-bromobenzonitrile (218 mg, 1.2
mmol), and the crude mixture was directly purified by flash
silica gel column chromatography using 20:1 hexane/EtOAc
with 1% NEt3 as the eluent to give 4-((diphenylmethylene)-
amino)benzonitrile (4b) as a pale-yellow solid (261 mg, 93%
(2) For selected examples using benzophenone imine as an ammonia
equivalent in Buchwald−Hartwig amination, see: (a) Wolfe, J. P.;
Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. An Ammonia
Equivalent for the Palladium-Catalyzed Amination of Aryl Halides
and Triflates. Tetrahedron Lett. 1997, 38, 6367−6370. (b) Mann, G.;
́
Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. Palladium-Catalyzed
C−N(sp2) Bond Formation: N-Arylation of Aromatic and Unsatu-
rated Nitrogen and the Reductive Elimination Chemistry of Palladium
Azolyl and Methyleneamido Complexes. J. Am. Chem. Soc. 1998, 120,
827−828. (c) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P.
Amination Reactions of Aryl Halides with Nitrogen-Containing
Reagents Mediated by Palladium/Imidazolium Salt Systems. J. Org.
Chem. 2001, 66, 7729−7737. (d) Kampmann, S. S.; Skelton, B. W.;
Wild, D. A.; Koutsantonis, G. A.; Stewart, S. G. An Air-Stable
Nickel(0) Phosphite Precatalyst for Primary Alkylamine C−N Cross-
Coupling Reactions. Eur. J. Org. Chem. 2015, 2015, 5995−6004.
(e) Peacock, D. M.; Roos, C. B.; Hartwig, J. F. Palladium-Catalyzed
Cross Coupling of Secondary and Tertiary Alkyl Bromides with a
Nitrogen Nucleophile. ACS Cent. Sci. 2016, 2, 647−652. (f) Power, D.
J.; Jones, K. D.; Kampmann, S. S.; Flematti, G. R.; Stewart, S. G.
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1
yield). H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz,
2H), 7.51 (t, J = 7.0 Hz, 1H), 7.43 (dt, J = 8.5, 2.0 Hz, 4H),
7.33−7.28 (m, 3H), 7.09 (d, J = 7.0 Hz, 2H), 6.77 (dt, J = 8.5,
2.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 169.44, 155.44,
138.53, 135.20, 132.71, 131.39, 129.50, 129.17, 129.17, 128.30,
128.13, 121.33, 119.25, 106.14.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00226.
■
S
NMR spectra of products and reaction mixtures (PDF)
(3) For reviews of the use of other ammonia surrogates and
ammonia itself in Buchwald−Hartwig amination reactions, see:
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amination of aryl halides with ammonia. Chem. Soc. Rev. 2010, 39,
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Organometallic Reactions of Ammonia. Angew. Chem., Int. Ed.
2011, 50, 86−95. (c) Schranck, J.; Tlili, A. Transition-Metal-
Catalyzed Monoarylation of Ammonia. ACS Catal. 2018, 8, 405−
418. (d) Lavoie, C. M.; Stradiotto, M. Bisphosphines: A Prominent
Ancillary Ligand Class for Application in Nickel-Catalyzed C−N
Cross-Coupling. ACS Catal. 2018, 8, 7228−7250. For selected
examples, see: (e) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.;
Putman, D. G. Allyl amines as ammonia equivalents in the preparation
of anilines and heteroarylamines. Tetrahedron Lett. 1998, 39, 1313−
1316. (f) Lee, S.; Jørgensen, M.; Hartwig, J. F. Palladium-Catalyzed
Synthesis of Arylamines from Aryl Halides and Lithium Bis-
(trimethylsilyl)amide as an Ammonia Equivalent. Org. Lett. 2001, 3,
2729−2732. (g) Huang, X.; Buchwald, S. L. New Ammonia
Equivalents for the Pd-Catalyzed Amination of Aryl Halides. Org.
Lett. 2001, 3, 3417−3419. (h) Lee, D.-Y.; Hartwig, J. F. Zinc
Trimethylsilylamide as a Mild Ammonia Equivalent and Base for the
Amination of Aryl Halides and Triflates. Org. Lett. 2005, 7, 1169−
1172. (i) Shen, Q.; Hartwig, J. F. Palladium-Catalyzed Coupling of
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2006, 128, 10028−10029. (j) Surry, D. S.; Buchwald, S. L. Selective
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: ohshima@phar.kyushu-u.ac.jp.
*E-mail: hmorimot@phar.kyushu-u.ac.jp.
ORCID
■
Hiroyuki Morimoto: 0000-0003-4172-2598
Takashi Ohshima: 0000-0001-9817-6984
Present Address
†K.M.: Institute for Chemical Research, Kyoto University,
Kyoto 611-0011, Japan.
Notes
The authors declare the following competing financial
interest(s): a part of the work in this article has been filed in
a patent application.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (JSPS KAKENHI Grant
JP15H05846 in Middle Molecular Strategy to T.O.) and
Grants-in-Aid for Scientific Research (B) (JSPS KAKENHI
Grant JP17H03972 to T.O.) and (C) (JSPS KAKENHI Grant
JP18K06581 to H.M.) from JSPS and Basis for Supporting
Innovative Drug Discovery and Life Science Research
(BINDS) (Grant JP18am0101091) from AMED. Y.K. and
K.M. thank JSPS for Research Fellowships for Young
Scientists. Y.K. is grateful for the support from the Academic
Challenge Program 2018 of Kyushu University.
̈
Enthaler, S.; Schaffner, B.; Dumrath, A.; Spannenberg, A.; Neumann,
̈
H.; Borner, A.; Beller, M. A General Palladium-Catalyzed Amination
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yield based on NMR analysis, respectively), and further screening of
conditions is required.
́
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G
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