Ortho lithiation-in situ borylation of substituted morpholine benzamides

Article abstract of DOI:10.1016/j.tet.2017.02.002

Morpholine amides are cheap and safe alternative to Weinreb amides as acylating agents of organometallic species. Herein, the in-situ lithiation/borylation of 18 ortho- meta- and para-substituted morpholine benzamides has been investigated. 10 of the 18 substrates provided the desired boronic esters as the major isomer (>90% regioselectivity) in crude isolated yields ranging from 68 to 93%. The synthetic usability of such building blocks was subsequently illustrated via the synthesis of a kinase inhibitor.

Full text of DOI:10.1016/j.tet.2017.02.002

Accepted Manuscript
Ortho lithiation-in situ borylation of substituted morpholine benzamides
Anna Cederbalk, Morten Lýsen, Jan Kehler, Jesper L. Kristensen
PII:
S0040-4020(17)30127-8
10.1016/j.tet.2017.02.002
TET 28443
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 August 2016
Revised Date: 19 January 2017
Accepted Date: 2 February 2017
Please cite this article as: Cederbalk A, Lýsen M, Kehler J, Kristensen JL, Ortho lithiation-in situ
borylation of substituted morpholine benzamides, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.002.
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Ortho lithiation-in situ borylation of
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Anna Cederbalk, Morten Lysén, Jan Kehler, Jesper L. Kristensen

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Tetrahedron
journal homepage: www.elsevier.com
Ortho lithiation-in situ borylation of substituted morpholine benzamides
Anna Cederbalka, Morten Lýsenb, Jan Kehlerb and Jesper L. Kristensena,*
a
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark.
b
Process Development and Department of Discovery Chemistry/DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Morpholine amides are cheap and safe alternative to Weinreb amides as acylating agents of
organometallic species. Herein, the in-situ lithiation/borylation of 18 ortho- meta- and para-
substituted morpholine benzamides has been investigated. 10 of the 18 substrates provided the
desired boronic esters as the major isomer (>90% regioselectivity) in crude isolated yields
ranging from 68-93%. The synthetic usability of such building blocks was subsequently
illustrated via the synthesis of a kinase inhibitor.
Available online
Keywords:
Lithiation
2009 Elsevier Ltd. All rights reserved
.
In-situ trapping
Borylation
Selectivty
Cross coupling
1. Introduction
intermediate is rapidly removed from the equilibrium. We
previously reported the synthesis of aryl boronic ester derivatives
via lithiation of benzonitriles and ethyl benzoate – substrates one
would not usually consider as candidates for DoM-chemistry.14
Herein we wish to report the extension of this approach to the in
situ borylation of morpholino benzamides – an alternative to
Weinreb amides.
Aryl boronic acids (ArB(OH)2) are invaluable tools in organic
synthesis, from coupling partners in the Suzuki-Miyaura reaction
to C-O, C-N, C-S bond formations.1 The current state of the art
in the synthesis of ArB(OH)2 derivatives includes reaction of
organometallic intermediates with trialkyl borates,2 coupling of
organo halides with bis-boronic esters3 or acids4 and by C-H
activation.5,6
When synthesizing 1,2-substituted aryls, Directed ortho
Metallation (DoM)7 can provide access to 2-substituted
ArB(OH)2. This is usually done in a stepwise sequence: 1)
formation of the lithiated species by addition of a strong alkyl
lithium base; 2) addition of a trialkyl borate, which after aqueous
work-up provide the ArB(OH)2. If the desired substrate contains
any functional groups that can be attacked by the alkyl lithium
base, this approach is not viable.
To address this shortcoming, a variant of the DoM has been
developed which relies on the in-situ trapping of lithiated
intermediates.8-9 One method is to treat the substrate with a
mixture of a non-nucleophilic base and an electrophile that is
compatible with that base. Metalation with a sterically hindered
metal amide, e.g. lithium diisopropyl amide (LDA) or Lithium
2,2,6,6-tetramethylpiperidide (LTMP),10 in combination with
triisopropylborate or TMSCl have proven effective for this
purpose.11-13 Even though these bases may not be sufficiently
strong to fully deprotonate the substrate, an equilibrium of the
substrate and the lithiated intermediate is established and in-situ
trapping leads to high conversion rates since the lithiated
a1) LDA or LTMP, B(OiPr)3, THF, -78°C to rt. 2) Acetic acid,
Neopentylglycol, rt. Ratios determined from 1H-NMR spectra of crude
products.
Scheme 1. Initial investigations on the in-situ trapping.
Weinreb amides are popular acylation reagents of
organometallic intermediates due to their high reactivity and the
fact that they give access to the corresponding ketones without
the formation of tertiary alcohols resulting from over-addition.15
Morpholine amides have similar synthetic utility with the added
advantage of being safer to handle and available at considerable

2
Tetrahedron
ACCEPTED MANUSCRIPT
lower cost.16 We set out to investigate the applicability of
Table 1. In situ borylation of morpholine amides.
Weinreb and morpholine amides as substrates for in-situ
borylation as this would give access to very versatile building
blocks.
2. Results and Discussion
Initial treatment of Weinreb amide 1a with either LDA or
LTMP in combination with B(OiPr)3 led to recovery of starting
material with no detectable amounts of the desired aryl boronic
ester (Scheme 1). Switching to the more sterically hindered
Weinreb analogue 1b led to the exclusive formation of a
rearranged product 2b as previously observed by Genêt.17
Product ratio (NMR)
Crude
Yield
-
Purity
(NMR)
-
SM
R
3
4
5
3a
3b
3c
3d
3e
3f
OMe
CF3
F
100
0
0
-
-
-
-
-
-
95
84
90
Subjecting morpholine amide 1c to the same reaction afforded
a mixture of starting material and the desired boronic ester 2c.
With LDA as base, approximately 10% of the amide 2d resulting
from the nucleophillic attack of LDA was also formed, whereas
this side reaction was not observed with LTMP. Encouraged by
this result we decided to investigate the scope of the in-situ
borylation with LTMP/B(OiPr)3 with para, ortho and meta
substituted morpholine benzamides. We intentionally included
substrates where the substituents were expected to compete with
the morpholine amide functionality with respect to their ability to
direct the site of lithiation on the aromatic ring. All morpholine
benzamides discussed below except ortho substituted cyano
morpholine amide 3f, were synthesized from the corresponding
acid chlorides, see supporting information for details.
73
27
-
59
95
Cl
100
100
100
78
93
Br
-
90
90
CN
-
80
84
Product ratio (NMR)
Crude
Purity
SM
R
6
30
1
7
-
8
70
1
Yield
95b
68
-
(NMR)
The data for the ortho, meta and para-substituted substrates
are summarized in Table 1. The crude yields listed in the table
refer to material obtained after aqueous work-up and purity is
determined from integration of the signal in the aromatic region
6a
6b
6c
6d
6e
6f
OMe
95b
90
-
CF3
F
92
90
-
5
5
Cl
-
100
Complex mixture
50 50
72
-
80
-
1
1
of the H-NMR spectra (copies of all crude H-NMR spectra are
included in the supporting information). Boronic acids are often
taken on in the next step directly, but we chose to isolate the
crude mixture as the corresponding neopentyl boronic esters in
order to facilitate the interpretation of the NMR-spectra.
Attempts to purify the boronic ester via chromatography failed
presumably due to hydrolysis of the boronic ester moiety.
Br
CN
-
67
80
Subjecting morpholine benzamides (3a-f, 6a-f and 9a-f) to the
same conditions as in Scheme 1 afforded a mixture of the desired
boronic esters and their regioisomers. In 10 out of 18 instances
the crude material was 80-95% pure - sufficient for further
manipulations without purification, as one would typically do
with ArB(OH)2. In general, the morpholine amides substituent
out-performed the other substituents giving ortho substituted
boronic esters as the major product. It is important to keep in
mind that the ratios between the isomeric boronic ester does not
necessary reflect the ratio between the lithiated intermediates as
the reactivity of these towards the B(OiPr)3 may not be the same.
Product ratio (NMR)
Crude
Yield
78
Purity
(NMR)
85
SM
R
9
-
10
93
11
7
9a
9b
9c
9d
9e
9f
OMe
CF3
F
-
100
43
-
68
90
43
-
14
5
-
-
Cl
95
86
95
Br
-
100
84
-
93
85
CN
-
16
63
80
In situ borylation of ortho OMe-substituted benzamide 3a did
not afford boronic esters 7 and 8, only recovery of starting
material was afforded. Para substituted benzamide afforded
boronic ester 10a in high yield and regioselectivity. Similarly,
meta-substituted benzamide 6a gave the corresponding boronic
ester in high regioselectivity 8a together with 30% of unreacted
starting material.
a
See experimental section for details. Crude yields refer to isolated yield of
crude material after aqueous work-up and purity is determined from
integration of the signal in the aromatic region of the H-NMR spectra. The
1
crude yield and purity of 4b was determined in the following in the following
way: crude yield is the mass recovery and purity was determined by 1H-
b
NMR. Isolated as a mixture of 6a and 8a in 95% yield based on recovered
starting material.
The CF3-substituted benzamides resulted in boronic esters 4b,
7b and 10b in high yield and purity. In accordance with our
F-substituted morpholine benzamides 6c and 9c all gave low
conversion to the corresponding boronic esters. Deuterium
incorporation experiments were performed by treatment with
LTMP at -78 °C. Full deuterium incorporation after 5 minutes
was observed for 6c while subjecting 9c to the same conditions
led to self condensation. These results indicate that the poor
observation
with
meta
substituted
trifluoromethyl
benzonitriles,14b the addition of the boronic ester does not occur
between the substituents, but rather para to the trifluoromethyl
substituent. This phenomenon was also observed by Schlosser.11

3
yields are due to deborylation of the corresponding boronic ester
or low reactivity of the lithiated intermediate, rather than
insufficient deprotonation.
ACCEPTED MANUSCRIPT
The Cl-substituted substrates all performed well giving a
single isomeric boronic ester as the major product, whereas the
results from the Br-substituted derivatives were highly dependent
on the position of the Br-atom on the ring. The ortho- and para-
substituted derivatives 3e and 9e provided high yields and
purities of the desired compounds, whereas 6e lead to a complex
mixture with intense colouring – presumably via the formation of
benzynes resulting from LiBr-elimination of the lithiated
intermediate. CN-substituted morpholine amides 3f and 9f
resulted in boronic esters in high regioselectivity ortho to the
morpholine amide substituent in agreement with the fact that
amides are stronger directing groups than nitriles12 whereas 6f
provided a 1:1 mixture of 7f and 8f.
In some instances, the crude product contained up to 10% of
an impurity containing vinyligous signals in the 1H-NMR
spectrum. We suggest that these are the result of lithiation of the
morpholin-ring followed by ring opening - a phenomenon
initially reported by Trapani.19 To investigate this, 9b was treated
with LTMP at -78 °C for 1.5 hours and subsequently quenched
with acetic acid at that temperature which led to the self-
condensed product 12 in 48% isolated yield (Scheme 2). Letting
the reaction mixture reach RT before quenching with acetic acid
gave a similar self-condensed product (13) in 47% yield - in
which the morpholine ring also was cleaved. The NMR signals
from the vinylogous amine in 13 are in good agreement with
impurities observed in some of the crude products in table 1.
Scheme 3. Assignment of 4c, 5c, 6a/14a and 9a/14 based on
HMBC and HSQC-spectra
To demonstrate the synthetic utility of the morpholine amide
boronic esters, a possible p38 MAP kinase inhibitor13 was
synthesized starting from 4d (Scheme 3). The crude mixture of
4d was subjected to Suzuki conditions to yield 15 using
Pd(dppf)Cl2 as catalyst. Subsequent condensation with 4-lithio-
N,N-dimethylaniline afforded benzophenone 16 in 85% isolated
yield without any trace of the corresponding tertiary alcohol.
Buchwald-Hartwig coupling with o-toluidine afforded 17.
Similarly, 3e and 3f were subjected to the Suzuki conditions
affording 18 and 19 in 55% and 68% yield, respectively.
Scheme 2. Self-condesation of 9b.
The relative position of the boronic ester groups was assigned
by HMBC and HSQC spectra. The assignment for 3c and 4c is
given as an example in Scheme 3. A correlation between H3-
CC=O and H5-CC=O is seen for regioisomer 3c whereas a
correlation between H6-CC=O is seen for isomer 4c. In some
cases a definite assignment could not be made based on this
approach. Thus, 6a and 9a was oxidized with H2O2 to the
corresponding phenols 14a and 14b. The relative coupling
pattern between H3, H4 and H5 in 14a substantiated the assigned
structure for 6a and for 14b a correlation was seen between
H3/H6 and the carbonyl carbon. For boronic ester 3f the correct
regioisomer was determined by conversion to the cross-coupled
product 19 (Scheme 4). The configuration of these products were
unambiguously assigned from HMBC and HSQC spectra.
a) Pd(dppf)Cl2 K2CO3 2M, 4-iodoanisole, PhMe, H2O, 100 °C, 46%. b) 4-
bromo-N,N- dimethylaniline, n-BuLi, THF, -78 °C to RT, 85%. c) o-
toluidine, Pd(OAc)2, X-Phos, NaOt-Bu, t-BuOH, Toluene, MW 160 °C, 95%
Scheme 4. Selective and sequential functionalisation of 4d.
3. Conclusion
In conclusion, we have detailed the first examples of ortho
lithiation of morpholine benzamides. The lithiation/in-situ
borylation of 18 different morpholine benzamides substituted
with OMe, CF3, F, Cl, Br and CN in the ortho, meta and para
position was investigated. CF3 and Cl substituted morpholine
amides performed the best, affording the boronic esters as a
single isomer in high yield and purity whereas the result from the
other substituents was found to rely heavily on which
regioisomer that was employed, as 10 of the 18 investigated
substrates provided the desired aryl boronic ester. The synthetic
utility of one these aryl boronic esters was subsequently
demonstrated in a three step synthesis.

4
Tetrahedron
morpholino(3-(trifluoromethyl)phenyl)methanone (6b)25:
4. Experimental section
ACCEPTED MANUSCRIPT
(900 mg, 66 %) as colorless solid. 1H NMR (400 MHz,
General procedure for morpholine amides:
Chloroform-d) δ 7.71-7.69 (m, 2H), 7.65–7.50 (m, 2H), 3.74 (bs,
6H), 3.44 (bs, 2H).
To the carboxylic acid (4.98 mmol), PhMe (25 mL) was added
followed by SOCl2 (1.1 mL, 14.92 mmol). The suspension was
heated to reflux for 2 hours before the solvent was removed
under reduced pressure. The mixture was dissolved in dry DCM
(10 mL) before K2CO3 (1.5 g, 10.85 mmol) was added and
morpholine amine (1.5 mL) was added drop wise at 0 °C. The
cooling bath was removed after 30 minutes and stirring was
continued at rt overnight. The mixture was filtered, the solvent
evaporated and the crude material was purified by column
chromatography.
(3-fluorophenyl)(morpholino)methanone (6c)26:
1
(1.24 g, 83 %) H NMR (400 MHz, Chloroform-d) δ 7.38 –
7.27 (m, 1H), 7.15 – 6.97 (m, 3H), 3.65 (bs, 6H), 3.38 (bs, 2H).
13C NMR (101 MHz, Chloroform-d) δ 168.9, 162.5 (d, J = 248.4
Hz), 137.4 (d, J = 6.6 Hz), 130.4 (d, J = 8.1 Hz), 122.7 (d, J = 3.2
Hz), 116.9 (d, J = 21.0 Hz), 114.4 (d, J = 22.8 Hz), 66.8.
(3-chlorophenyl)(morpholino)methanone (6d)26:
1
(2-methoxyphenyl)(morpholino)methanone (3a)21:
(1.42 g, 52 %) H NMR (400 MHz, Chloroform-d) δ 7.43 –
7.31 (m, 3H), 7.30 – 7.23 (m, 1H), 3.71 (bs, 7H), 3.44 (bs, 2H).
13C NMR (101 MHz, Chloroform-d) δ 168.8, 137.1, 134.7, 130.0,
130.0, 127.3, 125.2, 66.8.
1
(1.24 g, 85 %) H NMR (400 MHz, Chloroform-d) δ 7.40 –
7.29 (m, 1H), 7.25 – 7.20 (m, 1H), 7.01 – 7.95 (m, 1H), 6.92 –
6.87 (m, 1H), 3.83 – 3.73 (m, 4H), 3.61 – 3.54 (m, 1H), 3.27 –
3.17 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 168.0,
155.4, 130.7, 128.2, 125.4, 121.2, 111.1, 67.1, 67.0, 55.7, 47.4,
42.3.
(3-bromophenyl)(morpholino)methanone (6e)27:
General procedure but starting from the double amount of
starting material (1.2g, 89 %)1H NMR (400 MHz, Chloroform-d)
δ 7.57 – 7.54 (m, 2H), 7.36 – 7.22 (m, 2H), 3.71 (bs, 6H), 3.44
(bs, 2H). 13C NMR (101 MHz, Chloroform-d) δ 168.7, 137.3,
133.0, 130.2, 130.2, 125.6, 122.7, 66.8.
morpholino(2-(trifluoromethyl)phenyl)methanone (3b):
(1.10 g, 81 %)1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J
= 7.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H)), 7.52 (t, J = 7.6 Hz, 1H),
7.33 (d, J = 7.5 Hz, 1H), 3.93 – 3.82 (m, 1H), 3.78 – 3.74 (m,
2H), 3.59 – 3.54 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ
167.6, 134.6 (d, J = 2.4 Hz), 132.4, 129.4, 127.4, 126.9 (q, J =
4.5 Hz), 123.6 (d, J = 274.0 Hz), 66.7, 66.4, 47.6, 42.3.
3-(morpholine-4-carbonyl)benzonitrile (6f)28:
(1.20 g, 82 %) 1H NMR (600 MHz, Chloroform-d) δ 7.75 –
7.65 (m, 2H), 7.64 – 7.62 (m, 1H), 7.56 – 7.53 (m, 1H), 3.76 (bs,
4H), 3.64 (bs, 2H), 3.40 (bs, 2H). 13C NMR (151 MHz,
Chloroform-d) δ 168.0, 136.7, 133.4, 131.5, 130.9, 129.7, 118.0,
113.2, 66.8, 48.3, 42.8.
(2-fluorophenyl)(morpholino)methanone (3c)22:
General procedure but starting from the double amount of
starting material (1.36 g, 45 %) as pale white crystals.1H NMR
(600 MHz, Chloroform-d) δ 7.42 - 7.38 (m, 2H), 7.21 (t, J = 7.5
Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 3.87 – 3.79 (m, 2H), 3.78 –
3.76 (m, 2H), 3.65 – 3.63 (m, 2H), 3.34 (s, 2H). 13C NMR (151
MHz, Chloroform-d) δ 165.4, 158.2 (d, J = 247.7 Hz), 131.7 (d, J
= 8.0 Hz), 129.4 (d, J = 3.7 Hz), 124.9 (d, J = 3.3 Hz), 123.8 (d, J
= 17.7 Hz), 115.9 (d, J = 21.4 Hz), 67.0 (d, J = 15.2 Hz), 47.6,
42.61.
(4-methoxyphenyl)(morpholino)methanone (9a)22:
1
(660 mg, 46 %) as a pale yellow oil. H NMR (400 MHz,
Chloroform-d) δ 7.38 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz,
2H), 3.82 (s, 3H), 3.78 – 3.47 (m, 8H). 13C NMR (101 MHz,
Chloroform-d) δ 160.9, 129.2, 127.4, 113.8, 66.9, 55.4.
morpholino(4-(trifluoromethyl)phenyl)methanone (9b)29:
General procedure but starting from the double amount of
starting material.(1.57 g, 58 %) 1H NMR (400 MHz, Chloroform-
d) δ 7.69 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 3.78 (s,
4H), 3.63 (s, 2H), 3.40 (s, 2H). 13C NMR (101 MHz,
Chloroform-d) δ 169.0, 139.0 (d, J = 1.4 Hz), 131.91 (q, J = 32.8
Hz), 127.6, 125.8 (q, J = 3.8 Hz), 125.1, 122.4, 119.7, 66.9.
(2-chlorophenyl)(morpholino)methanone (3d)22:
(1.00 g, 69 %) 1H NMR (400 MHz, Chloroform-d) δ 7.42 –
7.37 (m, 1H), 7.36 – 7.27 (m, 3H), 3.95 – 3.82 (m, 1H), 3.80 –
3.75 (m, 3H), 3.72 – 3.67 (m, 1H), 3.61 – 3.56 (m, 1H), 3.32 –
3.26 (m, 1H), 3.23 – 3.17 (m, 1H). 13C NMR (101 MHz,
Chloroform-d) δ 167.1, 135.5, 130.5, 130.5, 129.8, 128.0, 127.4,
67.0, 66.9, 47.3, 42.2.
(4-fluorophenyl)(morpholino)methanone (9c)29:
(1.04 g, 70 %)1H NMR (600 MHz, Chloroform-d) δ 7.42 (dd,
J = 8.4, 5.4 Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 3.70-3.60 (m, 8 H).
13C NMR (151 MHz, Chloroform-d) δ 169.7, 164.5, 162.8, 131.4,
129.6 (d, J = 8.4 Hz), 115.8 (d, J = 21.9 Hz), 67.0. 1H NMR (600
MHz, Chloroform-d) δ 7.42 (dd, J = 8.4, 5.4 Hz, 2H), 7.10 (t, J =
8.5 Hz, 2H), 3.70-3.60 (m, 8 H).
(4-chlorophenyl)(morpholino)methanone (9d)26: General
procedure but starting from the double amount of starting
material.
(2-bromophenyl)(morpholino)methanone (3e)23:
1
(0.767 g, 57 %) H NMR (600 MHz, Chloroform-d) δ 7.63 –
7.54 (m, 1H), 7.36 (td, J = 7.5, 1.1 Hz, 1H), 7.27 – 7.20 (m, 2H),
3.93 – 3.84 (m, 1H), 3.83 – 3.69 (m, 5H), 3.58 (ddd, J = 11.5,
6.3, 3.2 Hz, 1H), 3.28 (ddd, J = 13.5, 6.3, 3.2 Hz, 1H), 3.19 (ddd,
J = 13.4, 6.8, 3.2 Hz, 1H). 13C NMR (151 MHz, Chloroform-d) δ
167.9, 137.7, 133.0, 130.6, 127.9, 127.9, 119.3, 66.9, 66.8, 47.3,
42.2.
(3-methoxyphenyl)(morpholino)methanone (6a)24:
(1.46 g, 50 %) as colorless needles.1H NMR (400 MHz,
Chloroform-d) δ 7.38 (q, J = 8.5 Hz, 1H), 3.59 (d, J = 82.9 Hz,
3H).13C NMR (101 MHz, Chloroform-d) δ 169.4, 136.2, 133.7,
128.9, 128.7, 66.9.
(1.201 g, 83 %)1H NMR (400 MHz, Chloroform-d) δ 7.31
(td, J = 7.6, 1.3 Hz, 1H), 6.98 – 6.86 (m, 3H), 3.82 (s, 3H), 3.70
(bs, 6H), 3.46 (bs, 2H). 13C NMR (101 MHz, Chloroform-d) δ
170.3, 159.9, 136.8, 129.8, 119.2, 115.8, 112.7, 67.1, 55.5.
(4-bromophenyl)(morpholino)methanone (9e)29:
(1.00 g, 76 %) as colorless needles.1H NMR (400 MHz,
Chloroform-d) δ 7.57 – 7.51 (m, 2H), 7.32 – 7.26 (m, 2H), 3.68

5
1
(s, 6H), 3.49 - 3.44 (m, 2H). 13C NMR (101 MHz, Chloroform-d)
δ 169.4, 134.1, 131.8, 128.8, 124.3, 66.8.
4-(morpholine-4-carbonyl)benzonitrile (9f)23: (1.15g, 78 %)
1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.3 Hz, 2H),
7.42 (d, J = 8.1 Hz, 2H), 3.66 (s, 4H), 3.53 (s, 2H), 3.28 (s, 2H).
13C NMR (101 MHz, Chloroform-d) δ 168.4, 139.8, 132.6, 127.9,
118.1, 113.9, 113.9, 66.9.
Isolated as beige solid in 90 % yield and in 90 % purity. H
ACCEPTED MANUSCRIPT
NMR (400 MHz, DMSO-d6) δ 7.75 – 7.63 (m, 2H), 7.31 (t, J =
7.7 Hz, 1H), 3.73 (s, 4H), 3.66 (dt, J = 5.4, 2.7 Hz, 2H), 3.59 (dd,
J = 5.8, 3.6 Hz, 2H), 3.54 (t, J = 5.0 Hz, 2H), 3.04 (qt, J = 13.3,
4.5 Hz, 2H), 0.96 (s, 5H). 13C NMR (101 MHz, DMSO-d6) δ
167.3, 142.3, 134.2, 133.4, 129.5, 119.0, 71.6, 65.7, 65.5, 60.0,
46.4, 41.1, 31.4, 21.2.
3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-(morpholine-4-
General procedure for the in situ trapping:
carbonyl)benzonitrile (4f): Isolated in 80 % yield and in 94 %
1
purity. H NMR (600 MHz, Chloroform-d) δ 8.03 (dd, J = 7.6,
In a 5 mL dried microvial with a septum, under N2, 2,2,6,6-
tetramethylpiperidine (1.2 mmol) was dissolved in dry THF (2.5
mL) and cooled to -10°C before n-BuLi (1.2 mmol) was added
over 2 min under N2. The mixture was stirred for 15 min. before
cooling to -78°C. At -78°C B(OiPr)3 (1.4 mmol) was added over
2 min. and stirred for 15 min. at -78°C before the morpholine
amide (1.0 mmol) dissolved in dry THF (1.5 mL) was added drop
wise over 7 min. The reaction was left in the dry ice bath
overnight slowly reaching room temperature. The reaction was
quenched with glacial acetic acid (1.4 mmol) followed by
addition of 2,2-dimethyl-1,3-propandiol (1.5 mmol). The mixture
was stirred for 3 h. at room temperature, then transferred to a
separating funnel with CH2Cl2 (7 mL) and washed with aqueous
KH2PO4 (10 W/V%) (4 x 6 mL). The combined water phase was
back extracted twice with CH2Cl2 (10 mL) and the combined
organic phase was dried over MgSO4 and the solvent was
evaporated to give the crude arylboronic ester.
1.3 Hz, 1H), 7.70 (dd, J = 7.8, 1.3 Hz, 1H), 7.44 (t, J = 7.7 Hz,
1H), 3.82 – 3.80 (m, 4H), 3.74 (s, 4H), 3.66 – 3.64 (m, 2H), 3.20
– 3.19 (m, 2H), 1.01 (s, 6H). 13C NMR (151 MHz, Chloroform-d)
δ 167.8, 145.5, 139.2, 134.4, 128.3, 117.2, 109.6, 72.6, 66.5,
66.3, 47.3, 42.1, 32.0, 21.9.
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-
(trifluoromethyl)phenyl)(morpholino)methanone (7b) :
Isolated in 80 % yield and in 94 % purity as a beige solid. 1H
NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 7.8 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 3.76-3.71 (m, 8H),z 3.57 (s,
2H), 3.18 (s, 2H), 1.01 (s, 6H). 13C NMR (101 MHz,
Chloroform-d) δ 170.7, 142.5, 135.5, 132.5 (q, J = 32.6 Hz),
125.1, 124.7 (q, J = 3.7 Hz), 122.4, 122.3 (q, J = 3.8 Hz), 72.6,
66.5 (d, J = 25.4 Hz), 45.0 (d, J = 555.6 Hz), 31.9, 21.9.
(3-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-
yl)phenyl)(morpholino)methanone (8d) :
(trifluoromethyl)phenyl)(morpholino)methanone (4b):
Isolated in 72 % yield and in 80 % purity. 1H NMR (600
MHz, Chloroform-d) δ 7.34 (dd, J = 8.0, 1.0 Hz, 1H), 7.24 (t, J =
7.9 Hz, 1H), 7.11 (dd, J = 7.6, 1.0 Hz, 1H), 3.75 (s, 4H), 3.68 –
3.60 (m, 6H), 3.42 – 3.36 (m, 2H) 1.08 (s, 6H). 13C NMR (151
MHz, Chloroform-d) δ 170.9, 141.3, 138.3, 130.0, 129.7, 123.8,
72.6, 68.1, 66.9, 32.0, 25.7, 22.2.
1
Isolated in 84 % yield and 90 % purity as a beige solid. H
NMR (600 MHz, Chloroform-d) δ 8.02 (d, J = 7.5 Hz, 1H), 7.71
(d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 3.94 – 3.90 (m, 1H),
3.82 – 3.67 (m, 7H), 3.65 – 3.51 (m, 3H), 1.02 (s, 6H). 13C NMR
(151 MHz, Chloroform-d) δ 168.5, 138.8, 132.4, 128.4 (q, J = 4.9
Hz), 128.1, 126.3 (q, J = 31.0 Hz), 124.0 (q, J = 274.3 Hz), 72.7,
66.5, 65.9, 47.4, 40.8, 32.0, 22.0. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C17H21BF3NO4 394.1408; Found 394,1410.
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-
methoxyphenyl)(morpholino)methanone (10a):
Isolated in 78 % yield and in 85 % purity as a 93:7 mixture of
10a and 11a. 1H NMR (600 MHz, Chloroform-d) δ 7.30 (d, J =
2.7 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.92 (dd, J = 8.3, 2.7 Hz,
1H), 3.81 (s, 3H), 3.72 (s, 4H), 3.68 – 3.48 (m, 6H), 3.28 – 3.17
(m, 2H), 1.00 (s, 6H). 13C NMR (151 MHz, Chloroform-d) δ
172.2, 159.3, 134.2, 132.4, 127.2, 119.1, 116.5, 72.6, 72.5, 67.0,
66.7, 60.5, 55.4, 31.9, 22.0.
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-
fluorophenyl)(morpholino)methanone (4c):
Isolated in 59 % yield and 95 % purity as an inseperable
1
mixture of 4c and 3c. 4c: H NMR (600 MHz, Chloroform-d) δ
7.57 (dd, J = 7.5, 1.1 Hz, 1H), 7.31 (ddd, J = 8.3, 7.4, 5.3 Hz,
1H), 7.11-7.08 (m, 1H), 3.78-3.77 (m, 2H), 3.72 (s, 4H), 3.59-
3.58 (m, 2H), 3.22 – 3.21 (m, 2H), 0.99 (s, 6H). 13C NMR (101
MHz, Chloroform-d) δ 166.6, 157.9 (d, J = 246.1 Hz), 130.6 (d, J
= 3.2 Hz), 129.9 (d, J = 7.4 Hz), 124.2 (d, J = 3.4 Hz), 117.7 (d, J
= 21.6 Hz), 72.5, 66.7, 66.6, 47.3, 42.1, 31.9, 22.0. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C16H21BFNO4 344.1440; Found
344.1441.
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-
(trifluoromethyl)phenyl)(morpholino)methanone (10b) :
Isolated in 68 % yield and 90% purity.1H NMR (400 MHz,
Chloroform-d) δ 8.10 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.31 (d, J
= 7.9 Hz, 1H), 3.77 (bs, 3H), 3.76 (bs, 5H), 3.57 (t, J = 4.8 Hz,
2H), 3.17 (t, J = 4.8 Hz, 2H), 1.03 (s, 6H). 13C NMR (101 MHz,
Chloroform-d) δ 170.8, 145.3, 131.9 (q, J = 3.7 Hz), 130.3 (d, J =
32.3 Hz), 127.4 (q, J = 3.7 Hz), 126.0, 125.4, 122.7, 72.6, 66.7,
66.4, 47.6, 42.1, 33.0, 22.0.
(2-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-
yl)phenyl)(morpholino)methanone (4d):
Isolated in 78 % yield and 93 % purity as a pale yellow
solid.1H NMR (400 MHz, Chloroform-d) δ 7.71 (dd, J = 7.4, 1.2
Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H),
3.80 – 3.66 (m, 8H), 3.61 (t, J = 4.9 Hz, 2H), 3.20-3.15 (m, 2H),
0.99 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 168.1, 140.3,
133.4, 131.5, 130.2, 129.2, 72.5, 66.6, 66.5, 46.9, 41.7, 31.9,
21.9. HRMS (ESI-TOF) m/z: [M + 1] Calcd for C16H21BClNO4
338.1325; Found 338.1325.
(4-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-
yl)phenyl)(morpholino)methanone (10d) :
1
Isolated in 86 % yield and in 95 % purity. H NMR (600
MHz, Chloroform-d) δ 7.77 (d, J = 3.0 Hz, 1H), 7.42 – 7.33 (m,
1H), 7.11 (dt, J = 8.0, 2.5 Hz, 1H), 3.83 – 3.63 (m, 8H), 3.57 –
3.43 (m, 2H), 3.17 (s, 2H), 1.05 – 0.97 (m, 6H).13C NMR (101
MHz, Chloroform-d) δ 171.1, 140.1, 134.9, 134.5, 130.6, 127.1,
72.5, 68.0, 66.7, 66.5, 47.7, 42.2, 31.9, 25.7, 21.9.1H NMR (400
MHz, Chloroform-d) δ 7.69 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0
Hz, 2H), 3.78 (bs, 4H), 3.63 (bs, 2H), 3.40 (bs, 2H).
(2-bromo-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-
yl)phenyl)(morpholino)methanone (4e):

6
Tetrahedron
(4-bromo-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-
funnel with CH2Cl2 (7 mL) and washed with aqueous KH2PO4
ACCEPTED MANUSCRIPT
yl)phenyl)(morpholino)methanone (10e) :
(10 W/V%) (4 x 6 mL). The combined water phase was back
extracted twice with CH2Cl2 (10 mL) and the combined organic
phase was dried over MgSO4 and the solvent was evaporated.
Purification by column chromatography (eluent 35:65
Isolated in 93 % yield and in 85 % purity as a yellow oil and
the only detectable regioisomer.
1H NMR (600 MHz,
Chloroform-d) δ 7.94 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.1, 2.2
Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 3.83 – 3.65 (m, 16H), 3.66 –
3.50 (m, 3H), 3.29 – 3.12 (m, 4H), 1.00 (s, 6H). 13C NMR (151
MHz, Chloroform-d) δ 171.1, 140.6, 137.8, 133.5, 127.3, 122.8,
72.5, 66.7, 66.4, 47.7, 42.1, 31.9, z21.9. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C16H21BBrNO4 404.0639; Found 404.0640.
EtOAc/nHeptane)
afforded
(2-(morpholine-4-carbonyl)-5-
(trifluoromethyl)phenyl)(4-(trifluoromethyl)phenyl)methanone
(13) (103 mg, 48 %) as a pale solid. 1H NMR (600 MHz,
Chloroform-d) δ 7.94 – 7.84 (m, 1H), 7.81 (d, J = 1.7 Hz, 0H),
7.77 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.9 Hz, 0H), 6.46 (dd, J =
15.4, 9.1 Hz, 0H), 4.69 (dd, J = 15.5, 1.7 Hz, 0H), 4.37 (dd, J =
9.2, 1.7 Hz, 0H), 3.92 (t, J = 5.4 Hz, 1H), 3.85 (d, J = 5.3 Hz,
1H). 13C NMR (151 MHz, Chloroform-d) δ 194.1, 169.3, 139.8
(d, J = 255.0 Hz), 135.2 (q, J = 32.9 Hz), 134.0, 131.7 (q, J =
33.7 Hz), 130.5, 129.1, 128.9 (q, J = 3.7 Hz), 127.2 (q, J = 3.7
Hz), 125.9 (q, J = 3.7 Hz), 124.3 (d, J = 58.6 Hz), 122.4 (d, J =
58.6 Hz), 120.6 (d, J = 58.5 Hz), 96.7, 59.7, 45.4. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C20H15F6NO3 454.0848; Found
454.0847.
3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-(morpholine-4-
carbonyl)benzonitrile (10f):
1
Isolated in 83 % yield and 80 % purity. H NMR (400 MHz,
Chloroform-d) δ 8.11 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 7.9, 1.7
Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 3.75 (bs, 8H), 3.56 (t, J = 4.8
Hz, 3H), 3.14 (t, J = 4.8 Hz, 2H), 1.01 (s, 7H). 13C NMR (101
MHz, Chloroform-d) δ 170.1, 145.9, 138.9, 133.9, 126.3, 118.4,
112.3, 72.6, 66.5, 66.3, 47.5, 42.1, 31.9, 21.9.
(2-hydroxy-4-methoxyphenyl)(morpholino)methanone
(14a)30:
(2-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl)(4-
(trifluoromethyl)phenyl)methanone (12):
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-
In a 5 mL dried microvial with a septum, under N2, 2,2,6,6-
tetramethylpiperidine (0.6 mmol) was dissolved in dry THF (1.25
mL) and cooled to -10°C before n-BuLi (0.6 mmol) was added
over 2 min under N2. The mixture was stirred for 15 min. before
cooling to -78°C and stirring for an additional 15 min. Then, (2-
(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-
methoxyphenyl)(morpholino)methanone (292 mg, 0.876 mmol)
was dissolved in THF (3 mL), H2O2 (89 mg, 2.63 mmol)
followed by NaOH (43 mg, 0.54 mmol) were added at RT. After
stirring at the same T for 16 h. NaOH (70 mg, 1.75 mmol) was
added and stirred for another 2 h. Evaporation of the water phase
and purification by column chromatography (eluent 90:10
EtOAc/EtOH) afforded 14a (103 mg, 0.434 mmol, 50 %) as an
off white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H),
6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 6.71 (dd,
J = 7.7, 1.5 Hz, 1H), 3.82 (s, 3H), 3.56 (bs, 6H), 3.33 (bs, 2H).
(trifluoromethyl)phenyl)(morpholino)methanone (10b)
(0.5
mmol) dissolved in dry THF (0.75 mL) was added drop wise
over 7 min. The temperature was maintained for 2 h. before
qunching the reaction by the addition of glacial acetic acid (0.7
mmol) and transferring the solution to a separating funnel with
CH2Cl2 (5 mL) and washed with aqueous KH2PO4 (10 W/V%) (4
x 5 mL). The combined water phase was back extracted twice
with CH2Cl2 (5 mL) and the combined organic phase was dried
over MgSO4 and the solvent was evaporated. Purification by
column chromatography (eluent 35:65 EtOAc/nHeptane)
(2-hydroxy-4-methoxyphenyl)(morpholino)methanone
(14b)31:
(2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-
methoxyphenyl)(morpholino)methanone (180.4 mg, 0.542 mmol)
was dissolved in THF (3 mL), H2O2 (105 µL 1.08 mmol)
followed by NaOH (43 mg, 0.54 mmol) were added at RT. After
stirring at the same T for 2 H H2O (2 mL) and DCM (5 mL) were
added. Water phase was extracted with DCM (4 x 5 mL), the
combined organic layer was dried by adding MgSO4 and was
evaporated to dry-ness in vacuo. Purification by column
chromatography afforded 14 (74 mg, 0.311 mmol, 57 %) as off
white powder. 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s,
1H), 7.15 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 2.6 Hz, 1H), 6.39 (dd,
J = 8.8, 2.6 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 8H). 13C NMR (151
MHz, Chloroform-d) δ 171.6, 163.5, 162.3, 129.8, 108.7, 106.2,
102.1, 55.5, 46.6. [M + Na]+ Calcd for C12H15NO4 260.0893
Found; 260.0894.
afforded
(2-(morpholine-4-carbonyl)-5-
(trifluoromethyl)phenyl)(4-(trifluoromethyl)phenyl)methanone
(12) a pale solid (50.4 mg, 47 %).1H NMR (600 MHz,
Chloroform-d) δ 7.92 (d, J = 8.1 Hz, 2H), 7.86 (dd, J = 8.0, 1.7
Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.74 (s, 1H), 7.56 (d, J = 7.9
Hz, 1H), 3.75 – 3.72 (m, 4H), 3.67 – 3.66 (m, 2H), 3.37 – 3.35
(m, 2H). 13C NMR (151 MHz, Chloroform-d) δ 194.3, 167.9,
140.9, 139.0, 137.8, 135.2 (q, J = 32.8 Hz), 131.3 (q, J = 33.5
Hz), 130.6, 128.3 (q, J = 3.6 Hz), 128.0, 126.4 (q, J = 3.7 Hz),
125.9 (q, J = 3.8 Hz), 124.3 (d, J = 50.1 Hz), 122.5 (d, J = 50.1
Hz), 120.7 (d, J = 50.0 Hz), 66.6, 66.5, 48.0, 42.4. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C20H15F6NO3 454.0848; Found
454.0847.
(5-chloro-4'-methoxy-[1,1'-biphenyl]-2-
yl)(morpholino)methanone (15):
N-(2-hydroxyethyl)-4-(trifluoromethyl)-2-(4-
(trifluoromethyl)benzoyl)-N-vinylbenzamide (13):
In
a 5 mL microvial, (4-chloro-2-(5,5-dimethyl-1,3,2-
In a 5 mL dried microvial with a septum, under N2, 2,2,6,6-
tetramethylpiperidine (1.2 mmol) was dissolved in dry THF (2.5
mL) and cooled to -10°C before n-BuLi (1.2 mmol) was added
over 2 min under N2. The mixture was stirred for 15 min., cooled
to -78°C and stirred for an additional 15 min. before (2-(5,5-
dimethyl-1,3,2-dioxaborinan-2-yl)-4-
(trifluoromethyl)phenyl)(morpholino)methanone (10b) (1 mmol)
dissolved in dry THF (1.5 mL) was added drop wise over 7 min.
The reaction was left in the dry ice bath overnight slowly
reaching room temperature. The reaction was quenched with
glacial acetic acid (1.4 mmol) then transferred to a separating
dioxaborinan-2-yl)phenyl)(morpholino)methanone (10d) (100
mg, 0.296 mmol) was dissolved in PhMe (1.48 mL) and EtOH
(0.74 mL). K2CO3 (2 M, 0.592 mmol, 0.3 mL), 4-bromoanisole
(0.355 mmol, 45 µL) and Pd(PPh3)4 (7.6 mg, 5 mol%) were
added and the mixture was evacuated and filled with N2 three
times, capped and heated to 130 °C for 30 min. in a Biotage
IniatorTM microwave system. Solvent was evaporated and
purification by column chromatography (eluent: 35:75
EtOAC/nHeptane) afforded 15 (45 mg, 0.136 mmol, 46 %) as
pale orange powder. 1H NMR (300 MHz, Chloroform-d): δ 7.39 -
7.33 (m, 5H), 6.96 - 6.91 (m, 2H), 3.84 (s, 3H), 3.52 - 3.44 (m,

7
1H), 3.32 - 3.22 (m, 2H), 2.95 (ddd, J = 13.3, 7.5, 3.1 Hz, 1H),
2.69 (ddd, J = 13.5, 5.4, 2.9 Hz, 1H), 2.56 (ddd, J = 11.0, 7.6, 2.9
Hz, 1H). 13C NMR (75 MHz, Chloroform-d) δ 168.9, 159.7,
139.7, 135.1, 132.7, 130.5, 129.6, 129.0, 128.8, 127.3, 114.0,
66.1, 65.9, 55.3, 46.7, 41.8.
8.25 (m, 2H), 7.88 – 7.82 (m, 1H), 7.68 (dd, J = 6.9, 2.3 Hz,
ACCEPTED MANUSCRIPT
1H), 7.64 – 7.59 (m, 1H), 7.41 – 7.34 (m, 2H), 3.72 – 3.65 (m,
2H), 3.64 – 3.58 (m, 1H), 3.53 – 3.44 (m, 1H), 3.40 – 3.36 (m,
1H), 3.25 – 3.17 (m, 2H), 2.97 – 2.88 (m, 1H). 13C NMR (101
MHz, Chloroform-d) δ 166.5, 148.3, 140.6, 138.7, 136.6, 135.1,
133.2, 130.7, 129.77, 128.9, 123.4, 123.3, 120.6, 66.5, 66.4, 46.7,
41.7. [M + Na]+ Calcd for C17H15BrN2O4 413,0107; Found
413,0107.
(5-Chloro-4'-methoxy-biphenyl-2-yl)-(4-dimethylamino-
phenyl)-methanone (16):
In a 100 mL flame dried Schlenk flask under N2, 4-bromo-
N,N-dimethylaniline (5.25 mmol, 1.05 g) was dissolved in dry
THF (20 mL) and cooled to -78°C before n-BuLi (1.6 M in
hexanes, 5.25mmol, 3.28 mL) was added. After stirring for 10
min. at -78°C (5-Chloro-4'-methoxy-biphenyl-2-yl)-morpholin-4-
yl-methanone (59a) dissolved in THF (5 mL) was added over 1
min. The reaction was matured for 20 min. before the ice bath
was removed allowing the reaction to reach room temperature. At
room temperature the reaction was quenched with acetic acid
(50%) (10 mL) and stirred for 10 min. Extraction with EtOAc (3
x 15 mL), drying (MgSO4), evaporating on celite, and
purification by flash chromatography gave the title compound as
2-(morpholine-4-carbonyl)-3'-nitro-[1,1'-biphenyl]-3-
carbonitrile (19):
3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-(morpholine-4-
carbonyl)benzonitrile (212 mg, 0.65 mmol) and 1-iodo-3-
nitrobenzene (193 mg, 0.776 mmol) were dissolved in DMF (5
mL). Mixture was degassed, filled with N2 and K2CO3 (2 M, 0.65
mL, 1.29 mmol) was added. Pd(dppf)Cl2 (53 mg, 10 mol %) was
added and the mixture was again degassed, filled with N2 and
heated to 100 °C. After stirring at the same T for 2 H. solvent
was evaporated and purification by column chromatography
(eluent: 40:60 EtOAC/nHeptane) afforded 19 (149 mg, 0.44
mmol, 68 %) as a off white powder. 1H NMR (600 MHz,
Chloroform-d) δ 8.30 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.26 (t, J =
2.0 Hz, 1H), 7.85 – 7.83 (m, 1H), 7.80 (dd, J = 7.7, 1.3 Hz, 1H),
7.70 – 7.69 (m, 1H), 7.67 – 7.63 (m 2H), 3.80 – 3.77 (m, 1H),
3.74 – 3.70 (m, 1H), 3.64 – 3.60 (m, 1H), 3.53 – 3.50 (m, 1H),
3.49 – 3.45 (m, 1H), 3.25 – 3.18 (m, 2H), 2.98 – 2.93 (m, 1H).
13C NMR (151 MHz, Chloroform-d) δ 165.1, 148.5, 139.6, 138.9,
137.9, 134.9, 134.2, 133.0, 130.2, 130.1, 123.7, 123.3, 116.6,
111.4, 66.4, 66.3, 47.0, 42.1. HRMS (ESI-TOF) m/z: [M + Na]+
C18H15N3O4 360.0954; Found 360.0953.
1
a yellow solid (1.12 g, 85%). Mp. 124-126°C (EtOAc/PE). H
NMR (300 MHz, CDCl3): δ 7.52 (d, J = 8.9 Hz, 2H), 7.40-7.39
(m, 1H), 7.31-7.30 (m, 2H), 7.21 (d, J = 8.9 Hz, 2H), 6.74 (d, J =
8.7 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 3.72 (s, 3H), 3.00 (s, 6H).
13C NMR (75 MHz, Chloroform-d) δ 195.3, 158.9, 153.1, 141.6,
138.0, 134.8, 132.1, 131.4, 129.6, 129.5, 129.4, 126.2, 124.5,
113.6, 110.2, 55.0, 39.9.
(4-Dimethylamino-phenyl)-(4'-methoxy-5-o-tolylamino-
biphenyl-2-yl)-methanone (17):
A 5 mL vial for septum capping was charged with (5-chloro-
4'-methoxy-biphenyl-2-yl)-(4-dimethylamino-phenyl)-methanone
(16) (1 mmol, 365 mg), o-toluidine (1.1 mmol, 118 mg), Nat-
OBu (1.4 mmol, 135 mg), Pd(OAc)2 (2%, 0.02 mmol, 4.5 mg),
and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-
Phos) (4%, 0.04 mmol, 19 mg). Toluene/t-BuOH 5:1 (3mL) was
added, the vial was capped and the reaction was heated in a
Biotage IniatorTM microwave system for 15 min. at 160°C.
After cooling, the reaction was poured into aqueous sat. NH4Cl
(10 mL), extracted with EtOAc (3 x 10 mL), dried (MgSO4),
evaporated on celite and purified by flash chromatography to
give the title compound as a yellow solid (418 mg, 95%). Mp.
Supplementary Material
Supplementary data (copies of NMR-spectra) associated with this
article can be found in the online version, at XXX.
Acknowledgments
Julie Møller Andreasen and Helle Gammelgaard Knudsen are
gratefully acknowledged for preliminary investigations.
References and notes
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95-97 °C. H NMR (300 MHz, Chloroform-d) δ 7.69-7.64 (m,
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1
pale white powder. H NMR (600 MHz, Chloroform-d) δ 8.28 –

8
Tetrahedron
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