Michael Additions Catalyzed by a β-Diketiminate-Supported Aluminum Complex

Article abstract of DOI:10.1021/acs.joc.8b00434

A β-diketiminate-supported aluminum bistriflate complex (^DipLAl(OTf)₂·Na[BAr^Cl₄]; ^DipL = CH(CMe)₂(N-C₆H₃-ⁱPr₂)₂; Tf = O₂SCF

Full text of DOI:10.1021/acs.joc.8b00434

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Michael additions catalyzed by a #-diketiminate-supported aluminum complex
Zhizhou Liu, and Dragoslav Vidovic
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00434 • Publication Date (Web): 13 Apr 2018
Downloaded from http://pubs.acs.org on April 13, 2018
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The Journal of Organic Chemistry
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Michael additions catalyzed by a -diketiminate-supported alumi-
num complex
Zhizhou Liua, Dragoslav Vidovićb,*
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aDepartment of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
bSchool of Chemistry, Monash University, 3800 Australia.
*Corresponding author. E-mail: drasko.vidovic@monash.edu
Supporting Information Placeholder
yields, while the latter transformations suffering from poor product
ABSTRACT: A -diketiminate-supported aluminum bistriflate
selectivity.8,9
complex (DipLAl(OTf)2Na[BArCl4]; DipL = CH(CMe)2(N-C6H3-
iPr2)2; Tf = O2SCF3; ArCl = 3,5-Cl2-C6H3), has been identified as an
efficient Lewis acid catalyst for Michael additions involving nu-
merous electron rich (hetero)aromatic substrates and several α,β-
unsaturated carbonyl compounds. In a vast majority of the at-
tempted Michael reactions our catalytic system was significantly
superior over the currently used methods for the same transfor-
mations in terms of reaction times and temperatures, catalyst load-
ings, isolated product yields and/or selectivity.
In our recent work, we have reported that well-defined and well-
characterized Al-based complexes could serve as quite reactive
Lewis acid catalysts for various Diels-Alder transformations.10,11 In
particular, -diketiminate-supported aluminum bis(triflate) com-
pound DipLAl(OTf)2
(
DipL = CH(CMe)2(N-C6H3-iPr2)2; Tf =
O2SCF3), when combined with Na[BArCl4] (ArCl = 3,5-Cl2-C6H3),
was a very active catalyst for a wide variety of these cycloadditions
(1, Figure 1).10 Additionally, we have shown that the activity of 1
was solely due to its Lewis acid properties and that this complex
did not act as sources of a Brønsted acid.10 Herein, we report that
C-C bond formation is arguably the most important process in
the field of organic chemistry.1 Numerous synthetic protocols were
developed that describe the formation of both single and double C-
C bonds for which efforts several prominent chemists received No-
bel prizes.2 Among this vast research field, Michael reactions or
Michael additions are considered as one of the most effective and
efficient processes for C-C bond formations due to versatility, high
functional group tolerance and quantitative atom economy.3 It is,
then, not surprising that these transformations (including hetero-
atom Michael additions) have been extensively used, for example,
in various aspects of synthetic chemistry as well as material and
biomedical sciences.4
Scheme 1. Comparative reaction conditions for Michael ad-
ditions involving N,N-dimethylaniline and either ethyl-4-
oxo-2-butenoate or 3-buten-2-one as catalyzed by trityl cat-
ion (Franzén), gold-based complex (Bertrand), tris(pen-
tafluorophenyl)borane (Werner) and our -diketiminate-
stabilized aluminum complex 1.
Michael reactions are manifested by the addition of a C-H frag-
ment (also known as a Michael donor) across an alkene moiety
(also known as a Michael acceptor) resulting in the net formation
of C-C and C-H bonds. In a vast number of Michael reactions, the
donor (usually a compound that contains a C(sp3)-H fragment and
neighboring electron withdrawing group(s) such as acyl and cyano)
is activated by a base followed by a nucleophilic attack on the ac-
ceptor (usually an ,-unsaturated carbonyl compound). Com-
pounds bearing C(sp2)-H fragments have also being used as nucle-
ophiles in Lewis acid- and iminium-catalyzed electrophilic aro-
matic substitutions/conjugate additions but these transformations
were limited to exclusively heteroaromatic substrates such as in-
doles and 4-hydroxy substituted coumarin-like compounds.5,6 In re-
cent years, groups of Franzén,7 Bertrand8 and Werner9 showed that
electron rich aromatic compounds (e.g. N,N-dimethylaniline)
could act as Michael donors for Lewis-acid catalyzed Michael ad-
ditions (Scheme 1). However, trityl-catalyzed additions were lim-
ited only to a very activated Michael acceptor (i.e. ethyl-4-oxo-2-
butenoate) and sometimes required prolonged reaction times (72
h).7 Additionally, gold- and borane-catalyzed reactions were per-
formed under extensive (24 h) heating (≥ 120 and 80C, respec-
tively), with the former system generating only moderate product
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system 1 is capable of catalyzing Michael additions between a di-
Table 1. Michael addition of N,N-dimethylanaline (2a)
verse range of electron rich (hetero)arenes and several dienophiles
exhibiting, in a vast majority of cases, dramatic improvements with
respect to the catalyst loading, reaction times and/or temperature as
well as product yields and selectivity in comparison to the pub-
lished methods for the same transformations.8,9
1
2
3
4
5
6
7
8
After establishing that complex 1 was a very active Lewis acid
catalyst for numerous Diels-Alder cycloadditions,10 we aimed to
extend its activity to Michael reactions. Our initial examination
showed that hydroarylation between methyl vinyl ketone (2a) and
N,N-dimethylanaline (3a), using a 1:1 mole ratio, proceeded within
1 h at room temperature using 2.5 mol% of 1 to give the target
product 4a in 87 % yield (entry 1, Table1). This was a quite signif-
icant result considering that substantially harsher reaction condi-
tions (i.e. elevated temperatures to 80 or 120C), higher catalyst
loadings (5 mol%) and noticeably longer reaction times (24 h) were
needed for the same transformation using gold-8 and borane-based9
catalysts. (Scheme 1). With this encouraging observation in hand,
we optimized this particular reaction with respect to the reactant
ration (entries 2 and 3) and the catalyst loading (entry 4). Our best
results were obtained using a 2:1 mole ratio of the aniline to the
dienophile and 2.5 mol% of 1 at room temperature for 1h. These
initial experiments immediately hinted that 1 was a fairly superior
catalyst in comparison to the gold- and borane-based compounds
(Scheme 1) because, as mentioned, the target transformation cata-
lyzed by the competitive systems not only required twice as much
the catalyst loading but was also left for considerably longer reac-
tion times (24 h) at significantly higher reaction temperatures (80
or 120C) to form the desired product.8,9 In fact, remarkable activ-
ity of 1 was also evident from the fact that lowering the reaction
temperature to 0C had no observable impact on the reaction rate
or the isolated yield of 4a (entry 5, Table 1). It should be empha-
sized that the absence of catalytic system 1 (entry 6) did not result
in any detectable formation of the desired product 4a as observed
by 1H NMR spectroscopy. The catalytic system’s individual com-
ponents (entries 7 and 8) also showed no activity with respect to
the investigated transformation. Lastly, as there is a growing con-
cern that the presence of hidden Brønsted acids might interfere or
completely be responsible for the observed product formations,10-
12 we also examined the target reaction in the presence of a soluble
and methyl vinyl ketone (3a).a
#
Catalyst
Catalyst
2a:3a temp
(C)
yield
(%)b
9
loading (%)
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1
2.5
2.5
2.5
1.5
2.5
-
1:1
1:2
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
25
25
25
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0
87
43
> 99
57
> 99
0
1
2
1
3
1
4
1
5
1
6
None
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25
7
DipLAl(OTf)2
2.5
2.5
1
0
8
Na[BArCl
]
0
4
9
tBuCl/AgOTf
0
10c
2.5
> 99
1
aStandard reaction conditions: 2a (1.0-2.0 mmol), 3a (1.0-2.0
mmol), cat., CD2Cl2, 0 or 25C for 1h, unless otherwise noted.
bDetermined by 1H NMR spectroscopy using 1,3,5-trime-
toxybenzene as standard. cIn the presence of 2,6-tBu2-pyridine
(0.025 mmol i.e. 1:1 mol equiv with respect to 1).
Having optimized the reaction conditions, we aimed to expand
the substrate scope using a diverse range of electron rich aromatic
and heteroaromatic reactants (Scheme 2). Unsurprisingly, apart
from 4-bromo-N,N-dimethylaniline (4l),9 all other target products
(4a-4o) were obtained in moderate to excellent yields. The use of
N,N-diethylaniline (2b), N,N-dibenzylaniline (2c) and their cyclic
analogue (2d) generated the corresponding products (4b-4d) in ex-
cellent yields. The formation of morpholine- and cyano-containing
products (4e and 4f) were sluggish with the established reaction
conditions but the yields (92 and 61%, respectively) were dramati-
cally improved with the use of 5 mol% of 1 and after allowing the
reaction to proceed for 12 and 24 h, respectively (Scheme 2). It
should be noted that the yield of 61% for the formation of 4f was
still twice as high as the value of 30% reported by Werner et al. for
the same transformation even though this particular transformation
was performed at room temperature instead of 80C required when
the borane-containing system was used.9 Similarly, excellent iso-
lated yields of 92 and 95%, respectively, were obtained for 4g and
4h representing a dramatic improvement over the yields of 39 and
57%, respectively, observed when these particular reactions were
catalyzed by B(C6F5)3 at 80 and 130C, respectively.9
t
source of triflic acid (HOTf), generated by mixing BuCl (tBu =
tert-butyl) and AgOTf (entry 9), and by addition of 2,6-tBu2-pyri-
dine in the reaction mixture containing 1 (entry 10).12e Triflic acid
was not an adequate catalyst for the investigated reaction while the
presence of a bulky base had no influence on the reaction rate or
the isolated yield of 4a. These control experiments are consistent
with system 1 acting as a Lewis acid and not a source of a Brønsted
acid.
Substitution at a meta position of N,N-dimethylaniline (2i-2k)
did not prevent the formation of the target products but the isolated
yields for 4j and 4k were moderate (67 and 69%, respectively) even
after the reaction was allowed to run for 24 h (Scheme 2). However,
excellent product yields for 4j (96%) and 4k (96%) were generated
once the catalyst loading was increased to 5 mol%. It is also note-
worthy that only the desired product was obtained when 3-meth-
oxy-N,N-dimethylaniline (2j) was used as Michael donor which
was not the case with the B(C6F5)3 catalyzed reaction that yielded a
mixture of two products.7 The use of the borane similarly generated
two products when N-methylindole (2n) was reacted with 3a,9
Figure 1. General structure for complex 1.
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in most cases, requiring much shorter reaction time (1 vs 24 h) un-
Scheme 2. Substrate scope of electron-rich aromatic and
heteroaromatic compounds 2 with methyl vinyl ketone
(3a).a
der ambient reaction conditions as well as using 50% less of the
1
catalyst loading.8,9
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4
5
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8
9
Our next aim was to investigate the scope of the Michael accep-
tor and the main results are summarized in Scheme 3. Ethyl vinyl
ketone (3b) and (E)-1,4-diphenylbut-2-ene-1,4-dione (3c) were
quite adequate substrates when reacted with N,N-dimethylanaline
producing excellent isolated yields of 4p (94%) and 4q (98%), re-
spectively, under standard reaction conditions. Even though it re-
quired a larger excess of the aniline (4 equiv with respect to the
dienophile), prolonged reaction times (24 h) as well as 5 mol% of
1, the reaction involving chalcone (3d) resulted in an excellent iso-
lated yield of 4r (90%) at ambient temperature, which was signifi-
cantly better than the product yield of 62% obtained by a gold-
based catalytic system at 135C.8 It should be also mentioned that
Werner et al. did not report the use of 3d in this particular transfor-
mation. Furthermore, a few aldehydes were also successfully con-
verted to their respective products 4s-4u, albeit in moderate yields
(30-66%), but the formation of the last product required the reac-
tion mixture to be heated to 60C. It is noteworthy that in the reac-
tion mixture involving acrolein and methacrolein (yielding 4s and
4t, respectively) significant amounts of unidentified side-products
were detected, even after the reaction temperature was lowered to
0C. This observation might suggest that our system is not as com-
patible with ,-unsaturated aldehydes as it is with the ketone an-
alogues because, as indicated, there were no observable side prod-
ucts when 3a-3d were used as Michael acceptors.
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Scheme 3. Substrate scope of various Michael acceptors.a
aStandard reaction conditions: 2 (2.0 mmol), 3a (1.0 mmol), 1
(0.025 mmol), CD2Cl2 (1.5 mL), 25C for 1h, unless otherwise
noted. Isolated yields are reported. b24 h. c5 mol% (0.050 mmol) of
1. d12 h. e2 h.
aReaction conditions: 2a (2.0 mmol), 3 (1.0 mmol), 1 (0.025
mmol), CH2Cl2 (1.0 mL) at 25C unless otherwise noted. b1h. c12h.
d2a (4.0 mmol). e5 mol% (0.050 mmol) of 1. f24 h. g60C.
while our catalytic system exhibited perfect selectivity control pro-
ducing only 4n in excellent yields (93%). Extensive (24 h) heating
(80C) might have been the main cause for the selectivity issues
with these borane catalyzed reactions as the same reaction cata-
lyzed by 1 were completed at room temperature within 1h.
In conclusion, Na[BArCl4]-activated -diketiminate-supported
aluminum bistriflate complex 1 showed exceptional activity re-
garding Michael addition between a wide range of electron-rich ar-
omatic/heteroaromatic substrates and several dienophiles. In a vast
majority of cases the reaction conditions, such as catalyst loadings,
reaction time and/or temperature, were significantly favorable
when 1 was used in comparison to the use of the gold- and borane-
based catalysts.8,9 Also, for a vast majority of explored Michael ad-
ditions considerably better isolated product yields were generated
with 1 than with the competitive catalytic systems. Lastly, a perfect
selectivity control was achieved using 1 for the preparation of 4j
and 4n (i.e. only the desired products were obtained), which was
not the case with the use of B(C6F5)3 that yielded a mixture of two
products.9
Furthermore, increasing the catalyst loading to 5 mol% and ex-
tending the reaction time to 2h was needed to generate 4m in ex-
cellent yields (94%). Lastly, reaction time of 12 h was required to
obtain excellent product yields (94%) between 2-methylfuran (2o)
and 3a. It should be emphasized that all reactions summarized in
Scheme 2 that generated excellent reaction yields (> 90%) exhib-
ited complete conversion (> 99%) of 3a to only the desired prod-
ucts. Therefore, our catalytic system 1 showed superior overall ac-
tivity in comparison to gold- and borane-based catalysts as it gen-
erated higher product yields under perfect selectivity control while,
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m/z: [M + H]+ Calcd for C14H20NO2 234.1494; Found C14H20NO2
EXPERIMENTAL SECTION.
234.1502.
1
2
3
4
5
6
7
8
General Considerations: All manipulations were carried out
using standard Schlenk techniques and a dry-box. CDCl3 and
CD2Cl2 were distilled over CaH2. Catalytic system 1 has been pre-
pared and used according to a published report.10 All other chemi-
cals were purchased from commercial sources and used without
further purification. NMR spectra were received using Bruker AV
300 or JEOL ECA400 SL spectrometers. Mass spectrometry was
performed by Waters Q-Tof Premier Micromass instrument, using
the electrospray ionization (ESI) mode.
3-(methyl(4-(3-oxobutyl)phenyl)amino)propanenitrile (4f): 140
mg, 61%. 1H NMR (300 MHz, CDCl3) δ 7.08 (d, J = 4.8 Hz, 2H),
6.85 (d, J = 4.8 Hz, 2H), 3.69(t, J = 5.52 Hz, 2H), 2.98 (s, 3H), 2.82
- 2.80 (m, 2H), 2.79 - 2.68 (m, 2H), 2.56 (t, J = 5.52 Hz, 2H), 2.13
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.4, 146.1, 130.2, 129.4,
118.6, 113.0, 49.2, 45.5, 38.8, 30.1, 28.8, 15.2. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H19N2O 231.1497; Found 231.1495.
4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butan-2-one (4g): 200
mg, 92%. 1H NMR (300 MHz, CDCl3) δ 6.87 (d, J = 6.2 Hz, 1H),
6.78 (m, 1H), 6.53 (d, J = 6.2 Hz, 1H), 3.19 - 3.16 (m, 2H), 2.85 (s,
3H), 2.75 - 2.70 (m, 6H), 2.13 (s, 3H), 1.98-1.95 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 208.7, 145.3, 128.9, 128.5, 126.7, 123.1, 111.3,
51.4, 45.8. 39.3, 30.1, 28.9, 27.8, 22.6. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H20NO 218.1545; Found 218.1544.
9
General Procedures - Coupling reaction of aromatic and hetro-
aromatic compounds with α, β-unsaturated carbonyl-containing
compounds: 1 (formed by mixing its components DipLal(OTf)2 (19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
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42
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44
45
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48
49
50
51
52
53
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mg, 0.025 mmol, 2.5 mol%) and NaBArCl (16 mg, 0.025 mmol,
4
2.5 mol%) was dissolved dissolved in 1.5 mL CD2Cl2 in a J. Young
NMR tube. Subsequently 1 equiv of the α,β-unsaturated carbonyl-
containing compounds (1.0 mmol) and 2 equiv of the aromatic or
hetro-aromatic compounds (2.0 mmol) were added. The reaction
mixture was left for the time indicated in Table 1 and Scheme 2 - 3
in the main text. After reaction completion, the corresponding prod-
ucts were purified by flash column chromatography on silica gel
using hexane/ethyl acetate mixtures. The formation of 4a and 4n
was also achieved by reacting 1.0g (8.2 mmol) of 2a and 1.07 g
(8.2 mmol) of 2n, respectively, with 0.29g (4.1 mmol) of 3a in the
presence of 78 mg (0.10 mmol) of DipLal(OTf)2 and 66 mg (0.10
mmol) of NaBArCl4 in about 10 ml of CH2Cl2 for 1h at room tem-
perature. These products were also isolated by the established pro-
cedure.
4-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)butan-
2-one (4h): 231 mg, 95%. H NMR (300 MHz, CDCl3) δ 6.61 (s,
2H), 3.11 - 3.07 (m, 4H), 2.75 - 2.70 (m, 8H), 2.15 (s, 3H), 2.00 -
1.92 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 208.6, 141.3, 128.1,
126.7, 121.8, 50.1, 45.8, 30.0, 28.9, 27.5, 22.2. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C16H22NO 244.1701; Found 244.1699.
1
4-(4-(dimethylamino)-2-methylphenyl)butan-2-one (4i): 195 mg,
1
95%. H NMR (300 MHz, CDCl3) δ 7.00 - 6.97 (m, 1H), 6.56 -
6.53 (m, 2H), 2.90 (s, 6H), 2.80 - 2.77 (m, 2H), 2.68 - 2.66 (m, 2H),
2.28 (s, 3H), 2.14 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.6,
149.4, 136.4, 129.3, 127.3, 114.9, 110.8, 44.5, 40.8, 30.0, 26.3,
19.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H20NO
206.1545; Found 206.1548.
Characterization of the synthesized compounds:
4-(4-(dimethylamino)phenyl)butan-2-one (4a): 185 mg, 97% (for
4-(4-(dimethylamino)-2-methoxyphenyl)butan-2-one (4j): 222 mg,
the NMR scale reaction) and 760 mg, 97% (for the gram scale re-
1
96%. H NMR (300 MHz, CDCl3) δ 6.98 - 6.95 (m, 1H), 6.26 -
1
action). H NMR (300 MHz, CDCl3) δ 7.06 (d, J = 8.6 Hz, 2H),
6.24 (m, 2H), 3.82 (s, 3H), 2.92 (s, 6H), 2.70 - 2.75 (m, 2H), 2.73 -
2.67 (m, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 209.3,
158.1, 150.8, 130.2, 117.5, 104.8, 96.5, 55.0, 44.3, 40.9, 29.9, 24.3.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H20NO2 222.1494;
Found 222.1499.
6.70 (d, J = 8.6 Hz, 2H), 2.91 (s, 6H), 2.88 - 2.77 (m, 2H), 2.76 -
2.65 (m, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.7,
149.2, 129.0, 128.9, 113.2, 45.7, 41.0, 30.2, 28.9. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C12H18NO 192.1388; Found
192.1382.
4-(4-(diethylamino)phenyl)butan-2-one (4b): 215 mg, 98%. 1H
NMR (300 MHz, CDCl3) δ 7.04 (d, J = 6.8 Hz, 2H), 6.64 (d, J =
6.8 Hz, 2H), 3.35 (q, J = 5.6 Hz, 4H), 2.81 - 2.77 (m, 2H), 2.76 -
2.65 (m, 2H), 2.14(s, 3H), 1.16 (t, J = 5.6 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ 208.7, 146.3, 129.0, 127.6, 112.2, 45.7, 44.4, 30.1,
28.8, 12.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H22NO
220.1701; Found 220.1721.
4-(2-bromo-4-(dimethylamino)phenyl)butan-2-one (4k): 259 mg,
96%. 1H NMR (300 MHz, CDCl3) δ 7.07 (d, J = 8.5 Hz, 1H), 6.87
(d, J = 2.6 Hz, 1H), 6.60 (dd, J = 8.5, 2.7 Hz, 1H), 2.92 (m, 8H),
2.73 (m, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.2,
150.1, 130.6, 127.3, 124.9, 116.3, 111.9, 44.0, 40.5, 30.0, 29.3.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H17NOBr 270.0494;
Found 270.0506.
4-(4-(dimethylamino)naphthalen-1-yl)butan-2-one (4m): 227 mg,
1
4-(4-(dibenzylamino)phenyl)butan-2-one (4c): 336 mg, 98%. H
1
94%. H NMR (300 MHz, CDCl3) δ 8.31 - 8.29 (m, 1H), 7.96 -
NMR (300 MHz, CDCl3) δ 7.40 - 7.23 (m, 10H), 6.99 (m, 2H), 6.67
(m, 2H), 4.62 (s, 4H), 2.91 (s, 6H), 2.80 - 2.76 (m, 2H), 2.75 - 2.65
(m, 2H), 2.12 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.6, 147.7,
138.1, 129.0, 128.9, 128.7, 126.9, 126.7, 112.7, 54.4, 45.6, 30.1,
28.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26NO
344.2014; Found 344.2012.
7.94 (m, 1H), 7.51 -7.49 (m, 2H), 7.25 - 7.23 (m, 1H), 7.01 (d, J =
5.9 Hz, 1H), 3.31 - 3.27 (m, 2H), 2.90 m,8H), 2.16 (s, 3H).13C
NMR (75 MHz, CDCl3) δ 208.3, 149.9, 132.7, 131.5, 129.3, 125.9,
125.0, 124.9, 123.9, 113.8, 45.4, 44.6, 30.1, 26.6. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C16H20NO 242.1545; Found
242.1544.
1
4-(4-(pyrrolidin-1-yl)phenyl)butan-2-one (4d): 204 mg, 94%. H
4-(1-methyl-1H-indol-3-yl)butan-2-one (4n): 187 mg, 93% (for the
NMR scale reaction) and 780 mg, 95% (for the gram scale reac-
tion). 1H NMR (300 MHz, CDCl3) δ 7.65 - 7.62 (m, 1H), 7.33-7.21
(m, 2H), 7.17 - 7.16 (m, 1H), 6.88 (s, 1H), 3.76 (s, 3H), 3.10 - 3.07
(m, 2H), 2.89 - 2.86 (m, 2H), 2.18 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 208.8, 137.0, 127.5, 126.4, 121.6, 118.7, 118.7, 113.6,
109.2, 44.3, 32.5, 30.0, 19.2. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C13H16NO 202.1232; Found 202.1225.
4-(5-methylfuran-2-yl)butan-2-one (4o):143 mg, 94%. 1H NMR
(300 MHz, CDCl3) δ 5.85 - 5.82 (m, 2H), 2.85 - 2.83 (m, 2H), 2.77
- 2.75 (m, 2H), 2.23 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 207.5, 152.7, 150.6, 105.9, 105.8, 42.0, 29.9, 22.3, 13.5.
NMR (300 MHz, CDCl3) δ 7.05 (d, J = 6.51 Hz, 2H), 6.51 (d, J =
6.51 Hz, 2H), 3.39 - 3.23 (m, 4H), 2.80 - 2.78 (m, 2H), 2.72 - 2.70
(m, 2H), 2.13 (s, 3H), 2.00 - 1.97 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ 208.7, 146.7, 129.0, 127.5, 111.8, 47.8, 45.9, 30.2, 29.0,
25.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H21NO
218.1545; Found 218.1548.
4-(4-morpholinophenyl)butan-2-one (4e): 214 mg, 92%. 1H NMR
(300 MHz, CDCl3) δ 7.10 - 7.08 (m, 2H), 6.85 - 6.83 (m, 2H), 3.83
- 3.86 (m, 4H), 3.12 - 3.10 (m, 4H), 2.84 - 2.80 (m, 2H), 2.73 - 2.69
(m, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 208.3, 149.7,
132.6, 129.0, 116.0, 67.0, 49.7, 45.4, 30.2, 28.9. HRMS (ESI-TOF)
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HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H13O2 153.0916;
Found 153.0916.
REFERENCES
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3
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8
(1) See, for example: Brown, W. H.; Foote, C. S.; Iverson, B. L.; Anslyn,
E. V. Carbon-carbon bond formation and synthesis (Ch 24.). In Organic
Chemistry, 5th edition, Brooks/Cole Cengage Learning, 2009.
1
1-(4-(dimethylamino)phenyl)pentan-3-one (4p): 193 mg, 94%. H
NMR (300 MHz, CDCl3) δ 7.07 (d, J = 6.5 Hz, 2H), 6.70 (d, J =
6.5 Hz, 2H), 2.91 (s, 6H), 2.81 - 2.77 (m, 2H), 2.70 - 2.65 (m, 2H),
2.41 (q, J = 5.5 Hz, 2H), 2.41 (t, J = 5.5 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 211.3, 149.2, 129.2, 128.9, 113.1, 44.4, 40.9, 36.2,
29.0, 7.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H20NO
206.1545; Found 206.1550.
(2) (a) Grubbs, R. H. Olefin-metathesis catalysts for the preparation of
molecules and materials (Nobel Lecture). Angew. Chem. Int. Ed. 2006, 45,
3760-3765. (b) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. From
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Natriummalonsaureather zu den Athern ungesättigter Säuren. J. Prakt.
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Reaction. Eur. J. Org. Chem. 2010, 2009-2016.
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R. N.; Antunes, O. A. C. Asymmetric Michael addition of chiral imines to
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thesis of Aspidosperma and Hunteria alkaloids. Tetrahedron: Asymmetry
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tors:ꢀ Ability to Form Interpolyelectrolyte Complexes and to Mediate Trans-
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Dewitt, D. M.; Hammond, P. T.; Lynn, D. M. Construction of Hydrolyti-
cally-Degradable Thin Films via Layer-by-Layer Deposition of Degradable
Polyelectrolytes J. Am. Chem. Soc. 2002, 124, 13992-13993. (d) Akinc, A.;
Lynn, D. M.; Anderson, D. G.; Langer, R. Parallel Synthesis and Biophys-
ical Characterization of a Degradable Polymer Library for Gene Delivery J.
Am. Chem. Soc. 2003, 125, 5316-5323. (e) Vernon, B.; Tirelli, N.; Bachi,
T.; Haldimann, D.; Hubbell, J. A. Water‐borne, in situ crosslinked bio-
materials from phase‐segregated precursors. J. Biomed. Mater. Res., Part A
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Caruso, V. Novel poly(amido-amine)-based hydrogels as scaffolds for
tissue engineering. Macromol. Biosci. 2005, 5, 613-622.
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Sabitha, G. InCl3-Catalysed Conjugate Addition of Indoles with Electron-
Deficient Olefins. Synthesis 2001, 2165-2169. (b) Bandini, M.; Cozzi, P.
G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. Sequential
One-Pot InBr3-Catalyzed 1,4- then 1,2-Nucleophilic Addition to Enones. J.
Org. Chem. 2002, 67, 3700-3704. (c) Ji, S.-J.; Wang, S.-Y. Ultrasound-ac-
celerated Michael Addition of Indole to α,β-Unsaturated Ketones Catalyzed
by Ceric Ammonium Nitrate (CAN). Synlett 2003, 2074-2076. (d) Shi, M.;
Cui, S.-C.; Li, Q.-J. Zirconium triflate-catalyzed reactions of indole, 1-me-
thylindole, and pyrrole with α,β-unsaturated ketone. Tetrahedron 2004, 60,
6679-6684. (e) Zhan, Z.-P.; Yang, R.-F.; Lang, K. Samarium triiodide-cat-
alyzed conjugate addition of indoles with electron-deficient olefins. Tetra-
hedron Lett. 2005, 46, 3859-3862. (f) Austn, J. F.; MacMillian, D. W. C.
Enantioselective Organocatalytic Indole Alkylations. Design of a New and
Highly Effective Chiral Amine for Iminium Catalysis. J. Am. Chem. Soc.
2002, 124, 1172-1173. (g) Paras, N. A.; MacMillian, D. W. C. New Strate-
gies in Organic Catalysis:ꢀ The First Enantioselective Organocatalytic
Friedel−Crafts Alkylation. J. Am. Chem. Soc. 2001, 123, 4370-4371. (h)
Fadeev, A. A.; Uchuskin, M. G.; Trushkov, I. V.; Makarov, A. S. Copper(II)
bromide-catalyzed conjugate addition of furans to α,β-unsaturated carbonyl
compounds. Chem. Heterocycl. Compd. 2017, 53, 1286-1293.
(6) See, for example: (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Or-
ganocatalytic Asymmetric Michael Reaction of Cyclic 1,3‐Dicarbonyl
Compounds and α,β‐Unsaturated Ketones—A Highly Atom‐Economic
Catalytic One‐Step Formation of Optically Active Warfarin Anticoagulant.
Angew. Chem., Int. Ed. 2003, 42, 4955-4957. (b) Kim, H.; Yen, C.; Preston,
P.; Chin, J. Substrate-Directed Stereoselectivity in Vicinal Diamine-Cata-
lyzed Synthesis of Warfarin. Org. Lett. 2006, 8, 5239-5242. (c) Erkkilä, A.;
Majander, I.; Pihko, P. M. Iminium Catalysis Chem. Rev. 2007, 107, 5416-
5470.
2-(4-(dimethylamino)phenyl)-1,4-diphenylbutane-1,4-dione (4q):
350 mg, 98%. 1H NMR (300 MHz, CDCl3) δ 8.05 - 7.98 (m, 4H),
7.57 - 7.39 (m, 6H), 7.32 - 7.19 (m, 2H), 6.68 - 6.64 (m, 2H), 5.25
- 5.20 (m, 1H), 4.23 (dd, J = 18.0, 9.9 Hz, 1H), 3.30 (dd, J = 18.0,
3.6Hz, 1H), 2.90 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 199.2,
198.5, 149.7, 136.7, 136.6, 133.1, 132.6, 128.9, 128.5, 128.4,
128.1, 125.8, 113.0, 47.7, 43.8, 40.4. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C24H24NO2 358.1807; Found 358.1806.
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3-(4-(dimethylamino)phenyl)-1,3-diphenylpropan-1-one (4r): 296
mg, 90%. 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 4.2 Hz, 2H),
7.53 - 7.52 (m, 1H), 7.45 - 7.41 (m, 2H), 7.26 - 7.24 (m, 4H), 7.15
- 7.13 (m, 3H), 6.67 (d, J = 5.1 Hz, 2H), 4.75 (t, J = 4.2 Hz, 1H),
3.71 (d, J = 4.2 Hz, 2H), 2.89 (s, 6H). 13C NMR (75 MHz, CDCl3)
δ 198.5, 149.2, 144.9, 137.2, 132.9, 132.2, 128.5, 128.4, 128.1,
127.7, 126.1, 112.8, 45.1, 45.0, 40.7. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C23H24NO 330.1858; Found 330.1847.
3-(4-(dimethylamino)phenyl)propanal (4s): 117 mg, 66%. 1H
NMR (300 MHz, CDCl3) δ 9.82 (t, J = 1.5 Hz, 1H), 7.10 - 7.06 (m,
2H), 6.71 - 6.69 (m, 2H), 2.92 (s, 6H), 2.92 - 2.85 (m, 2H), 2.75 -
2.69 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 202.3, 149.4, 128.9,
128.2, 113.1, 45.7, 40.8, 27.3. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H16NO178.1232; Found 178.1224.
3-(4-(dimethylamino)phenyl)-2-methylpropanal (4t): 82 mg, 43%.
1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 7.05 - 7.02 (m, 2H),
6.71 - 6.67 (m, 2H), 3.01 - 2.92 (m, 7H), 2.65 - 2.50 (m, 2H), 1.08
- 1.06 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 204.9, 149.3, 129.6,
126.5, 112.8, 48.3, 40.7, 35.8, 13.1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C12H18NO 192.1388; Found 192.1384.
3-(4-(dimethylamino)phenyl)propanal (4u): 75 mg, 30%. 1H NMR
(300 MHz, CDCl3) δ 9.78 (m, 1H), 7.30 - 7.23 (m, 5H), 7.10 - 7.08
(m, 2H), 6.68 - 6.61 (m, 2H), 4.59 (t, J = 7.8 Hz, 1H), 3.12 - 3.08
(m, 2H), 3.07 - 2.90 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 201.8,
149.4, 144.0, 131.0, 128.7, 128.4, 127.7, 126.4, 112.8, 49.6, 44.3,
40.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H20NO
254.1545; Found 254.1546.
ASSOCIATED CONTENT
Supporting Information
Copies of multinuclear NMR spectra. The Supporting Information
is available free of charge on the ACS Publications website.
Conflicts of Interest
Authors declare no competing financial interests.
AUTHOR INFORMATION
(7) Bah, J.; Franzén, J. Carbocations as Lewis Acid Catalysts in Diels–
Alder and Michael Addition Reactions. Chem. Eur. J. 2014, 20, 1066.
(8) (a) Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G. Gold-Catalyzed
Hydroarylation of Alkenes with Dialkylanilines. J. Am. Chem. Soc. 2014,
136, 13594-13597. (b) The exact mechanism for hydroarylation of enones
as reported by Bertrand and co-workers (ref. 8a) is not discussed so it is
assumed that the gold complex was acting as a Lewis acid to activate vari-
ous enones.
Corresponding Author
*Email: drasko.vidovic@monash.edu
ACKNOWLEDGMENT
We thank Monash University (DV) and South University of Sci-
ence and Technology of China (ZL) for the financial support.
(9) Li, W.; Werner, T. B(C6F5)3-Catalyzed Michael Reactions: Aromatic
C–H as Nucleophiles Org. Lett. 2017, 19, 2568-2571.
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(10) Liu, Z.; Lee, J. H. Q.; Ganguly, R.; Vidović, D. A Well‐Defined
Aluminum‐Based Lewis Acid as an Effective Catalyst for Diels–Alder
Transformations Chem. Eur. J. 2015, 21, 11344-11348.
(11) Liu, Z.; Ganguly, R.; Vidović, D. Pursuing the active species in an
aluminium-based Lewis acid system for catalytic Diels-Alder cycloaddi-
tions. Dalton Trans. 2017, 46, 753-759.
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