Deaminative carbonylative coupling of alkylamines with styrenes under transition-metal-free conditions

Article abstract of DOI:10.1039/d0cc04062b

A transition-metal-free deaminative carbonylation of alkylamines with styrenes has been developed. The reaction shows good functional group compatibility and various α,β-unsaturated ketones were obtained in moderate to good yields. The alkyl radical generated from Katritzky salts via base-promoted C-N bond cleavage is one of the key intermediates in this reaction. This journal is

Full text of DOI:10.1039/d0cc04062b

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Deaminative Carbonylative Coupling of Alkylamines with Styrenes
under Transition-Metal-Free Conditions
Fengqian Zhao,a Chong-Liang Lia,b and Xiao-Feng Wu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A transition-metal-free deaminative carbonylation of alkylamines Lewis base as the promoter.8 Hong’s group developed a N-
with styrenes has been developed. The reaction shows good heterocyclic carbene -catalyzed de aminative radical -radical
functional group compatibility and various α, β-unsaturated coupling strate gy of Katritzky salts with aldehyde s.9 More
ketones were obtained in moderate to good yields. The alkyl recently, the re search group of Loh and Hu described a base -
radical generated from Katritzky salts via base-promoted C-N bond promote d deaminative vinylation of alkylamine s with alke nyl
cleavage is one of the key intermediates in this reaction.
boronic acids via Katritzky salts.10a Intere stingly, the se
transformations provided novel approache s to transform the
C-N bonds under metal- and photocatalyst -free conditions.
Transition-metal-catalyze d cross-coupling reactions are among
the most powerful methods in organic synthe sis and have
been achieve d in the construction of various C -C, C-N, C-O, and
C-S bonds in the past fe w decades.1 Given that some
transition-metal catalysts are expensive, se nsitive to air and
moisture, and special attention should be given to the metal
residues in the produced fine chemicals, the development of
transition-metal -free strategie s would offer economical
friendly and environmental benignly alternate s in organic
synthesis.
Alkylamine s are widely prese nt in natural products,
pharmaceuticals and materials.2 Derivatization of amino
groups is one of the most important transformations, and it is
also an attractive direction to modify the structure of relate d
biomolecule s.3 Compared to the be nzylic and allylic amine s,
which are used as an alkylating age nt via the cle avage of
C(sp3)-N bonds,4 alkylamines are rarely use d due to the
stronger C-N bonds. Recently, an at tractive strate gy, by
conve rting the alkylamines into Katritzky salts to activate the
C-N bonds, have been de velope d. The synthetic value of the
Katritzky salts have been demonstrate d by the achieve ments
in cross-coupling re actions (Sche me 1a).5 Metal- or photo-
catalysts were applied to initiate the single electron transfer
(SET) process.6-7 Re markably, in 2019, Shi, Li and co -workers
Scheme 1. Deaminative transformations of alkylamines through Katritzky salts.
reporte d
a
met al/light-free deaminative borylation of
On the other hand, as a conve nient and che ap C1 re source,
CO is an indispensable reage nt for carbonylation re actions.11
Numerous procedure s have bee n develope d and applied
based on acade mic or industrial inte rests. In 2019, Xiao, Lu and
co-workers report their achie veme nt on deaminative alkyl -
Heck-type re actions by photo -induced C-N bonds scission of
Katritzky salts. By performing the re action under CO pressure,
the carbonylative transformation version can be re alize d as
well and five example s of α, β-unsaturated ke tone s were
alkylamine s under mild conditions with catalytic amount of
a.Leibniz-Institut fꢀr Katalyse e. V. an der Universität Rostock, Albert-Einstein-
Straβe 29a, 18059 Rostock, Germany, E-mail: xiao-feng.wu@catalysis.de
b.Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018,
People’s Republic of China
Electronic Supplementary Information (ESI) available: [general information,
analytic data, NMR spectra]. See DOI: 10.1039/x0xx00000x
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obtained in good yields (Sche me 1b).12 Howe ver, transition- details). Subse que ntly, some additive s were added to the
View Article Online
DOI: 10.1039/D0CC04062B
metal- and/or photo-catalyst free de aminative carbonylation reaction syste m. It was found that LiOMe was be st for this
reactions of Katritzky salts have not bee n reported yet. transformation and give n a significant incre ase in the yield of
Considering our continual inte rests in the field of carbonylati ve the target product (Table 1, entries 5-13). Howe ver, only trace
transformations, and to develop methodologie s to ove rcome amount of the de sired product was dete cted in the absence of
the challenge s discussed, we herein report a transition metal - DBU (Table 1, entry 14). A slight decre ase in temperature was
free de aminative carbonylation reaction of alkylamine s with
styrenes toward the synthesize of α, β-unsaturated ketones.
bene ficial for this conversion (Table 1, entry 15). In addition,
by re ducing the concentration of 1a to 0.05 M, the yield was
increase d slightly as well (Table 1, entry 16). Finally, the
desire d product 3aa can be obtained in 76% yield by re acting
1.0 equivalent of Katritzky salt 1a with 2.0 e quivalents of 1,1 -
diphenylethylene 2a in the pre sence of 2.0 equivale nts of DBU
and 1.0 equivalent of LiOMe in THF (2.0 mL) unde r the CO (50
bar) at 80 °C for 15 h.
Table 1. Optimization of the reaction conditions.a
Table 2. Scope of styrenes for the deaminative carbonylation.
Entry
1
Base
DBU
DBN
TBD
Additive
/
T [°C]
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
Yield [%]b
54
53
54
1
2
/
3
/
4
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBN
DBU
DBU
/
/
5
Cs2CO3
KOH
58
55
41
64
50
66
68
59
40
2
6
7
K2HPO4
t-BuOK
t-BuONa
t-BuOLi
LiOMe
LiOH
8
9
10
11
12
13
14
15
16c
Li2CO3
LiOMe
LiOMe
LiOMe
DBU
70
76 (74)d
DBU
80
aReaction conditions: 1 a (0.1 mmo l), 2 a (0.2 mmol), b ase (0.2 mmol), add itive
(0.1 mmol), TH F (1.0 mL), CO (50 bar), 15 h. bDetermined by GC using
hexadecane as the intern al stand ard. cTHF (2.0 mL). d Isolated yield . DBU = 1,8-
Diazabicyclo [5.4.0]undec-7-ene. DBN = 1,5-Diazabicyclo[4.3.0]non-5-ene. TBD =
Reaction conditions: 1 a (0.1 mmol), 2 (0.2 mmo l, 2 .0 equiv), DBU (0.2 mmol, 2.0
equiv), LiOMe (0.1 mmol, 1.0 equiv), THF (2.0 mL), CO (50 bar), 80 °C, 15 h,
isolated yield. a 1 mmol scale.
1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimid ine.
Triethylenediamine.
DABCO
=
Under the optimized conditions, the substrate scope of this
transformation we re carried out. A variety of styrene s were
tested firstly and led to the corre sponding α, β-unsaturate d
ketone s in moderate to good yields in ge neral (Table 2). 2, 3 or
4-Alkyl and alkoxyl -substituted diaryl alkene s can all be
effectively transforme d in this reaction and gave the desire d
products in good to excellent yields (3aa-3af ). Whe n
substrates with strong electron -de ficient functional groups or
haloge n were used, the de sired products can be obtained in
good yields as well (3ag-3ak). Disubstitute d and
polysubstituted diaryl alkene s were also well-tole rate d (3al-
Our optimization studie s started with the cross-coupling of
cyclohe xyl -substitute d pyridinium salt 1a with 1,1 -
diphenylethylene 2a (Table 1). The desired product 3aa was
detected in 54% yield by GC with DBU as the base and THF as
the solve nt (Table 1, entry 1). Other base s, such as DBN and
TBD, gave similar results whe re as DABCO re sulted poor yield
(Table 1, entrie s 2-4). The amount of DBU w as examined as
well and no increase in the yield even with 4.0 equivalents of
DBU were used (see the Supporting Information for more
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3ao). Styrene with 1 -naphthyl, 2-naphthyl, thie nyl and pyridyl
substitutions at α-positions gave the corre sponding products
smoothly as well (3ap-3as). This novel strate gy can also be
extende d to internal diaryl alke nes, 69% yield of the desire d
product was provided when β-e ste r substituted diaryl alke ne
was use d (3at). Furthermore, α-methyl substituted arylalke ne
can also be used as the substrate and gave the targete d 3au in
43% yield. Howe ver, poor yield (< 30%) was obtaine d whe n
styrene or trans-1,2 -diphenylethe ne w as te sted in this
reaction. It is important to me ntion that, for the
unsymme trical diaryl alkene s, (Z) and (E)-stere oisome rs were
obtained as a mixture in almo st e qual amount (except 3ab,
3ak, 3aq, 3as and 3au). 2-Phe nyl -substitute d alkene s afford
the (E)-isome r as the major product (3ab : E/Z = 85:15; 3ak :
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DOI: 10.1039/D0CC04062B
E/Z
= 96:4) due to the steric hindrance. Howe ver, 1-(1 -
phenylvinyl)naphthale ne 2q gave e ven worse result on the
stereoselectivity (E/Z = 77:23).
Scheme 2. Mechanistic experiments.
Table 3. Scope of Katritzky salts for the deaminative carbonylation.
To gain some insight into the re action mechanism, se veral
control expe riments were performe d (Scheme 2). The re action
was inhibited in the pre sence of TEMPO under the standard
conditions, the adduct 4 of radical trapped by TEMPO was
detected by GC -MS while no de sired product could be
obtained (Sche me 2a). And when 2,6 -di -tert-butylphenol was
added to this re action, the product was only obtained in 40%
yield (Scheme 2b). The se results sugge st that a radical was
generate d in the re action. In addition, lack of DBU lead to no
adduct 4 obse rved whe reas it was detecte d in the abse nce of
LiOMe (Scheme 2c). These re sults indicate that DBU is the key
to promote the cleavage of C-N bond.
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol, 2.0 equiv), DBU (0.2 mmol,
2.0 equiv), LiOMe (0.1 mmol, 1.0 equiv), THF (2.0 mL), CO (50 bar), 80 °C, 15 h,
isolated yield.
Scheme 3. Proposed mechanism.
The n various Katritzky salts derived from alkyl amine s were
explore d (Table 3). Cyclic, chain and phenyl-containing amine
derivative s were transforme d into the desired products in
moderate to good yields (3ba-3ha). It is worth noting that
pharmaceutically relevant saturate d heterocyclic a mine was
also tolerated, the desire d product was obtained in good yield
(3ia). And free alcohol could undergo the transformation as
well, given the corresponding products smoothly (3ja-3ka).
On the basis of the mechanistic studies and
literature, 7,8,11,12 a possible mechanism is proposed (Sche me
3). Unde r the assistant of DBU, an alkyl radical 5 was forme d
from Katritzky salts 1 by the cle avage of C-N bonds firstly and
me anwhile produce a DBU· radical. Then, the alkyl radical 5
was captured by CO to give the acyl radical 6. Subse quently,
the addition of acyl radical 6 to alke nes 2 form a more stable
radical species 7, which was transforme d into
a cationic
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J. Name. , 2013, 00, 1-3 | 3
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interme diate 8 by the pre viously produced DBU· radical via a
SET pathway. Finally, the deprotonation of 8 afforded the
corresponding product 3.
6
For selected recent examples on metal-catalyzed
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Conclusions
In summary, a transition-metal -free de aminative carbonylation
of activated alkylamine s with styrene s via cleavage of C-N
bonds of Katritzky salts has been developed. In the absence of
transition metal catalyst or light irradiation, various α, β-
unsaturated ketone s we re obtained in moderate to good
yields. Versatile functional groups, such as alde hyde , haloge n,
alkoxy, thienyl, pyridyl, e ster, hydroxyl, we re tolerate d in this
reaction.
7
For selected recent examples on photore dox catalysis and
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Conflicts of interest
There are no conflicts to declare.
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bonds activation via Katritzky salts has been successful
developed. Various α, β-unsaturated ketone s were obtained
in moderate to good yields with alkylamines and styrenes as
the substrates.
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