One-pot, modular approach to functionalized ketones via nucleophilic addition/Buchwald-Hartwig amination strategy

Article abstract of DOI:10.1039/c8cc08444k

A general one-pot procedure for the 1,2-addition of organolithium reagents to amides followed by the Buchwald-Hartwig amination with in situ released lithium amides is presented. In this work amides are used as masked ketones, revealed by the addition of organolithium reagents which generates a lithium amide, suitable for subsequent Buchwald-Hartwig coupling in the presence of a palladium catalyst. This methodology allows for rapid, efficient and atom economic synthesis of aminoarylketones in good yields.

Full text of DOI:10.1039/c8cc08444k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C8CC08444K
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One-Pot, Modular Approach to Functionalized Ketones via
Nucleophilic Addition/Buchwald-Hartwig Amination Strategy†
a
a
a
Jorn de Jong‡ , Dorus Heijnen‡ , Hugo Helbert‡ , Ben L. Feringa*a
Received 00th January 20xx,
Accepted 00th January 20xx
A general one-pot procedure for the 1,2-addition of organolithium reagents to amides followed by the Buchwald-Hartwig
amination with in-situ released lithium amides is presented. In this work amides are used as masked ketones, revealed by
the addition of organolithium reagents which generates a lithium amide, suitable for subsequent Buchwald-Hartwig coupling
in the presence of a palladium catalyst. This methodology allows for rapid, efficient and atom economic synthesis of
aminoarylketones in good yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
The palladium catalysed amination of aromatic bromides was Furthermore they are being employed as photoinitator and
discovered in 1983 and has since proven to be one of the most have found use in medicinal chemistry, for instance as kinase
important and versatile transformation in organic synthesis. inhibitors18.
Pioneered by Migita1 and co-workers, the groups of Buchwald
and Hartwig among others developed the method towards its
Scheme 1 Lithium hemiaminal as a versatile building block
current status of privileged transformation in organic
Base
Buchwald-Hartwig
amination :
HN
+
chemistry2–6, with widespread applications in areas ranging
from materials science to medicinal chemistry6,7. Traditionally
cross-coupling reactions to form a C-N bond require the use of
additional base to achieve a full catalytic cycle. Stoichiometric
amounts of tert-butanolate salts or cesium carbonate are often
used for this purpose, though the use of lithium amide as base
has also been reported to be a valuable substitute in Buchwald-
Hartwig couplings8. Alternatively, LiHMDS is chosen for its non-
nucleophilic properties. Few reports describe aminations where
lithium amides are directly playing the role of coupling
partners9,10. Our group recently disclosed a one pot procedure
for the 1,2-addition of organolithium reagents to (Weinreb)
amides, followed by alpha-arylation, which required no
additional base11,12 (scheme 1a). Optimizing the alpha-arylation
step, the product arising from the competing Buchwald-Hartwig
coupling was sometimes observed as a minor side product. We
envisioned this amination process to be a very useful
transformation. In the present study we take advantage of the
nucleophilic properties of organolithium reagents by
performing a 1,2-addition to an amide yielding a masked
ketone13–16. Collapse of the tetrahedral intermediate generates
in-situ a lithium amide17 allowing direct Buchwald-Hartwig
amination without the need for additional base (scheme 1b).
This approach gives rapid access to a variety of amino
substituted benzophenones which are widely used, among
others, in cosmetics due to their UV protecting properties.
N
Cl
Pd. cat
X = H, R = n-Bu
O
Me2NLi as base (in situ released)
With  proton
Ar
a)
Pd cat., ArBr
3
Li
O
Alpha arylation
O
N
Up to >95 selectivity
R-Li
N
R
X
X
2
1
Masked ketone
O
This work
b)
R
No  proton
N
Me2NLi as coupling partner
No additional base
4
X = Cl, Br
Pd cat.
Amination
The
competition
between
alpha-deprotonation
or
transmetallation to palladium could be avoided by the use of
organolithium reagents lacking alpha hydrogen atoms.
Therefore the lithium amide resulting from the 1,2-addition of
an organolithium reagent to amide 1 - after dissociation of the
tetrahedral intermediate 2 - is only available for Buchwald-
Hartwig amination type reaction. In order to determine the
optimal conditions for the reaction a ligand screening was
performed and the results are shown in table 1. XPhos
palladacycle G2 (entry 2) proved to be the most efficient
catalyst in toluene at 80ºC. Other well established catalysts for
Buchwald-Hartwig amination based on mono and bidentate
phosphine ligands19,20 (entries 3-6) or the use of palladacycle G1
(entry 1) were found to be less or not active in our case.
a. Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands
‡ J. de Jong, D. Heijnen and H. Helbert contributed equally to this work
† Electronic Supplementary Information (ESI) available : General, experimental
procedures and characterisation of compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Catalyst optimisationa
These solvents are reported as environmenViteawlArtficrlieeOnndlinlye
alternatives to THF. Whereas 2-MeTHF gave lower conversion
(entry 11), CPME proved to be a valuable substitute (entry 16).
DOI: 10.1039/C8CC08444K
O
O
1) PhLi
Ph
N
Scheme 2 Variation of amidesa
2) Pd. cat
N
Cl
5k
O
1
O
1) PhLi, THF, 0°C
Ph
NR2
Entry
Catalyst
Solvent (Temp)
Conversionb
R2N
O
Cl
2) 5% Pd2(dba)3/SPhos
Reflux, 1h
5a-m
O
1
2
3
SPhos Pd G1
XPhos Pd G2
Toluene (80oC)
Toluene (80oC)
Toluene (80oC)
Toluene (80oC)
Toluene (80oC)
Toluene (80oC)
THF (reflux)
42
83
29
0
O
O
Ph
Ph
Ph
N
Pd2(dba)3/Josiphos
Pd2(dba)3/DTBPF
Pd2(dba)3/QPhos
Pd2(dba)3/SPhos
XPhos Pd G2
Ph
O
N
N
N
4
5
6
7
49
69
95
94
95
87
62
93
84
0
5e, 80%b
5c, 71%
5b, 66%
5a, 75%
O
O
Ph
Ph
Ph
8
9
SPhos Pd G1
Pd2(dba)3/SPhos
PEPPSI-iPr
THF (reflux)
THF (reflux)
THF (reflux)
2-MeTHF (60oC)
1,4-dioxane (60oC)
MTBE (reflux)
Hexane (60oC)
Et2O (reflux)
CPME
N
N
N
N
10
11
12
13
14
15
16
O
5g, 72%b
5h, 87%b,c
5f, 85%b
Pd2(dba)3/SPhos
Pd2(dba)3/SPhos
Pd2(dba)3/SPhos
Pd2(dba)3/SPhos
Pd2(dba)3/SPhos
Pd2(dba)3/SPhos
O
O
O
Ph
Ph
Ph
N
5i, 23%b,c
MeO
N
N
<5
95
5j, 85%
5k, 56%
iPr
.t-BuOMe
O
O
H2
N
Ph
Ph
Cl
iPr
iPr
Cl
Pd
NH2
OMe
P
Pd
P
P
N
P
N
MeO
Fe
5m, 38%b
5l, 38%
Josiphos
SPhos Pd G1
aYields refer to isolated yields after column chromatography, for an overview of
unsuccessful attempts see ESI. bPhLi added dropwise and reaction mixture stirred for 1
h before addition of the catalyst. cAfter addition of the catalyst the reaction mixture was
heated at reflux overnight.
XPhos Pd G2
tBu
tBu
tBu
tBu
P
P
P
Fe
Ph
Fe
Ph
Ph
tBu
MeO
OMe
Ph
P
tBu
Ph
QPhos
DTBPF
SPhos
4-Bromo-N,N-dimethylbenzamide was also a suitable substrate
for this reaction but aryl chlorides were preferred as they
generate less waste, are generally cheaper and more widely
available. Moreover by using aryl chlorides instead of aryl
bromides we drastically decrease the risk of having undesired
lithium-halogen exchange taking place24.
aReaction were carried on a 0.2 mmol scale, organolithium reagent was added
dropwise and the mixture was stirred 15 min at 0ºC followed by the addition of Pd
catalyst (5% loading) and stirred for additional 1 h at the indicated temperature.
bConversion determined by GC-MS. CPME = Cyclopentyl methyl ether.
Conversion towards the desired product was increased with the
catalyst XPhos Pd G2 in THF at reflux (entry 7). Using Pd-
PEPPSI21,22 (entry 10) in this solvent didn’t improve the
conversion, but Pd2(dba)3/SPhos (entry 9) and SPhos
palladacycle G1 (entry 8) gave comparable conversion.
Pd2(dba)3/SPhos was preferred to palladacycles (G1, G2) as it is
a cheaper catalyst. The influence of solvents was also tested,
identifying THF at reflux (entry 9) as the solvent of choice for
this reaction. Ethereal solvents show good conversion (entries
11 – 13) whilst the reaction doesn’t proceed in hexane (entry
14). Low conversion was observed when the reaction was
performed in Et2O at reflux (entry 15) indicating that elevated
temperature was required for the coupling step. 1,4-Dioxane
(entry 12) also proved to be efficient and can be considered as
an alternative if higher temperatures are required. Finally 2-
MeTHF and cyclopentyl mether ether (CPME)23 were tested.
With the optimal conditions in hand (table 1, entry 9), a range
of amides was tested leading to
a
variety of
aminobenzophenones represented in scheme 2. The scope
includes both meta (5a) and para chlorobenzamides (5b-5j).
Cyclic (5c-5g) as well as acyclic (5a,5b) amines were coupled in
excellent
methylpiperazine
yields.
Interestingly,
(5g), indolines
morpholine
(5f),
and
(5j-5l)
tetrahydroisoquinoline (5m) moieties were also successfully
coupled in good yields providing a motif widely used in
medicinal chemistry25,26
. Notably methylbenzylamine and
dibenzylamine were also efficient coupling partners affording
protected amines (5h, 5i) that can be further converted, after
debenzylation, into free amines or mono-methylated amines.
Methodologies to directly synthesize free anilines have been
reported27–29 but they usually require large excess of ammonia,
2 | J. Name., 2012, 00, 1-3
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high pressure or long reaction time with the problem of
selectivity for the primary amine versus secondary and tertiary chlorophenyl)(morpholino)methanone
amines. The methodology presented here can be considered as
COMMUNICATION
Figure 1: 7Li (A) and 1H (B) -NMR analysis of the reaction with (4-
View Article Online
DOI: 10.1039/C8CC08444K
A - 7Li-NMR
Li
N
an attractive alternative to target primary and secondary
arylamines.
5)
Morpholine + PhLi
5
4
3
2
1
O
O
Scheme 3 Variation of lithium reagentsa
N
+ PhLi + Pd2(dba)3/SPhos
66oC for 1h
4)
Cl
O
Li
Cl
O
Li
O
O
O
O
O
O
3)
N
+ PhLi, 66oC for 1h
O
N
1) RLi, THF, 0°C
Ph
R
N
Cl
Cl
Cl
2) 5% Pd2(dba)3/SPhos
Reflux, 1h
Li
O
N
Cl
N
2)
N
+ PhLi
1
5n-u
Ph
O
Cl
O
O
O
Li
CF3
1)
PhLi
Me2N
O
Me2N
Me2N
5n, 87%
5o, 54%
5p, 49%
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
-0.1
-0.2
-0.3
-0.4
O
O
f1 (ppm)
O
O
B - 1H-NMR
S
O
Me2N
N
Me2N
7)
Me2N
7
N
5r, 50%
O
5q, 41%
5s, 58%
5f
O
O
OMOM
O
6)
6
5
4
3
2
1
Cl
5)
4)
Morpholine + PhLi
5f-StM
Me2N
Me2N
5t, 27%
5u, 26%
+ PhLi
aYields refer to isolated yields after column chromatography.
+ Pd2(dba)3/SPhos
66oC 1h
+ PhLi, 66oC 1h
3) 5f-StM
The scope of aryl lithium nucleophiles was investigated and the
results are given in scheme 3. Not only phenyllithium could be
coupled (5n) but a diversity of aryllithium reagents, easily
prepared via Li-halogen exchange or deprotonation, were
found to be suitable reagents in this reaction. Aryllithium
bearing ether, amine or electron withdrawing functionalities
were successfully coupled (5o-5q). Heterocyclic lithium
2) 5f-StM
+ PhLi
O
N
O
Cl
5f-StM
7.90 7.85 7.80 7.75 7.70 7.65 7.60 7.55 7.50 7.45 7.40 7.35 7.30 7.25 7.20 7.15 7.10 7.05 7.00 6.95 6.90 6.85 6.80 6.75 6.70 6.65
f1 (ppm)
Conditions : 0.1 mmol in 0.7mL of THF-d8 at 25ºC with LiCl in D2O as internal standard.
reagents such as 2-thienyllithium or 2-furyllithium were suitable Hypothesized structure of lithium species between brackets.
coupling partners and provided the desired products 5r and 5s.
This hypothesis is also supported by 1H-NMR (full spectrum
available in the supporting information) were no lithium
morpholin-4-ide (B-5) nor 4-chlorobenzophenone (B-6) can be
detected. The in-situ formed intermediate (B-2) was then
heated at reflux for 1h but remain unaffected (B-3) and no
product of 1,2-elimination was observed (comparison with B-6),
showing the stability of this intermediate under our reaction
conditions. When Pd2(dba)3/SPhos was added to the
intermediate and the solution was heated at reflux for 1h, the
Though lower yields were obtained when using more sterically
hindered coupling partners the desired products were
successfully isolated (5t, 5u).
Small amounts of tertiary alcohol, arising from premature
collapse of the tetrahedral intermediate were observed for
most entries. It is the decreased reactivity in the second step
however, that caused the lower yields for some of the
substrates, providing (after hydrolysis) the bromo-ketone
intermediate as a final product.
1
Previous reports already described the equilibrium between the
intermediate 2 and products resulting from the 1,2-elimination
desired product 5f was selectively formed as confirmed by H-
NMR (spectrum B-4 and B-7), resulting also in a sharp signal in
7Li-NMR at 0.60 ppm, corresponding to the LiCl (spectrum A-4)
released. These experiments point toward the existence of a
stable tetrahedral lithium hemiaminal intermediate 2 and a
slow in-situ release of lithium amide which is directly consumed
in the amination reaction.
Finally, the versatility of this approach was demonstrated with
the rapid and efficient synthesis of an isoform-specific
phosphoinositide 3-kinase inhibitors32. The herein described
protocol drastically improves the yield compare to the
previously reported synthesis and combines the formation of
the C-N bond with a 1,2-addition in a one-pot procedure,
of R2NLi being in favour of the tetrahedral intermediate 230,31
.
7Li and 1H-NMR analysis was performed to investigate the
formation and stability of intermediate 2 under our reaction
conditions (Figure 1). As expected, when 1 eq. of PhLi (spectrum
A-1) was added to (4-chlorophenyl)(morpholino)methanone 5f-
StM, a single signal at 0.92 ppm was observed (spectrum A-2).
This intermediate has a different chemical shifts compared to
signals of lithium morpholin-4-ide at 0.87 ppm (spectrum A-5),
indicating that the equilibrium is completely shifted towards the
intermediate 2 (Scheme 1).
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leading to ketone 7 (a comparison of the two synthetic routes is
available in the supporting information). The environmental
friendly character of this transformation should also be
highlighted as it exhibits a high reaction mass efficiency33 (RME)
of 79% and produces only a light waste product LiCl with low
toxicity.
7
8
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9
10
Scheme 4 Application in the synthesis of a kinase inhibitor (AMA37)
11
12
OR
O
1) PhLi
O
O
2) Pd2(dba)3/SPhos
N
N
13
14
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O
Atom economy = 87%
RME = 79%
Cl
6
O
91%
BBr3
74%
8 : R = H : AMA37
7 : R = Me
15
16
17
In conclusion, a one-pot procedure toward the synthesis of
amine aryl ketones has been developed, enabling Buchwald-
Hartwig amination with in-situ generated lithium amides.
Starting from easily accessible amides and organolithium
reagents, this strategy allows for fast and efficient modular
functionalization with high atom economy generating only LiCl
as stoichiometric waste. A diversity of aryllithium nucleophiles
and amide coupling partners has been combined following this
strategy and the applicability of the methodology was
illustrated with the efficient synthesis of a selective kinase
inhibitor.
18
19
20
21
Conflicts of interest
There are no conflicts to declare.
22
23
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Acknowledgements
This work was supported financially by the European Research
Council (Advanced Investigator Grant, No. 227897 to B.L.F.); The
Netherlands Organization for Scientific Research (NWO− CW);
funding from the Ministry of Education, Culture, and Science
(Gravitation program 024.001.035); The Royal Netherlands
Academy of Arts and Sciences (KNAW); and NRSC-Catalysis are
gratefully acknowledged.
25
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DOI: 10.1039/C8CC08444K
A one-pot procedure for 1,2-addition of organolithium reagents to amides followed by Buchwald-
Hartwig amination with in-situ released lithium amides is presented.