Enantioselective Conjugate Additions of “Difficult” Ketones to Nitrodienynes and Tandem Annulations

Article abstract of DOI:10.1002/adsc.201600849

The first enantioselective conjugate additions of problematic aromatic ketones and acetone to nitrodienynes have been achieved by employing a chiral multifunctional primary amine catalyst recently developed by us. The reactions took place in a 1,4-manner. Furthermore, by utilizing the resulting chiral functionalized 1,3-enynes as a starting point, we have developed unprecedented p-toluenesulfonic acid-catalyzed tandem annulations, which allow the efficient and selective construction of various synthetically useful cyclic 1,5-diketones (R=Ar) and dienones (R=Me). (Figure presented.).

Full text of DOI:10.1002/adsc.201600849

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DOI: 10.1002/adsc.201600849
Enantioselective Conjugate Additions of “Difficult” Ketones to
Nitrodienynes and Tandem Annulations
Teng Liu,+a Mingxin Zhou,+a Tengrui Yuan,a Binbin Fu,a Xinran Wang,a
Fangzhi Peng,a,* and Zhihui Shaoa,*
a
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and
Technology, Yunnan University, Kunming 650091, Peopleꢀs Republic of China
E-mail: pengfangzhi@ynu.edu.cn or zhihui_shao@hotmail.com
+
T. Liu and M. Zhou contributed equally to this work.
Received: August 1, 2016; Revised: October 25, 2016; Published online: && &&, 0000
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday.
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600849.
Abstract: The first enantioselective conjugate addi- acid-catalyzed tandem annulations, which allow the
tions of problematic aromatic ketones and acetone efficient and selective construction of various syn-
to nitrodienynes have been achieved by employing thetically useful cyclic 1,5-diketones (R=Ar) and di-
a chiral multifunctional primary amine catalyst re- enones (R=Me).
cently developed by us. The reactions took place in
a 1,4-manner. Furthermore, by utilizing the resulting
chiral functionalized 1,3-enynes as a starting point, Keywords: acetone; aromatic ketones; conjugate ad-
we have developed unprecedented p-toluenesulfonic dition; nitrodienynes; tandem annulations
Introduction
both aromatic ketones and acetone to nitroolefins
with excellent enantioselectivities (up to 99% ee).[6a,7]
Conjugate addition is one of the most important tools To additionally demonstrate the significance and gen-
for the construction of C–C bonds.[1] In this context, erality of this class of chiral primary amine catalysts,
the direct conjugate addition of carbonyl compounds we became interested in the more “difficult” transfor-
to nitroolefins has received much attention, as the re- mations – regioselective and enantioselective conju-
sulting adducts, g-nitrocarbonyl compounds, are val- gate addition of aromatic ketones to polyconjugated
uable building blocks in organic synthesis.[2] Hence, nitrodienynes and the reaction between acetone and
considerable effort has been devoted to the develop- nitrodienynes. Such previously unreported processes,
ment of asymmetric catalysts for such processes. In if successful, would provide an efficient access to 1,3-
sharp contrast to the high enantioselectivities ob- enynes, which are important structural motifs found
tained with cyclic ketones, especially cyclohexa- in many natural products and drugs,[8] and are versa-
nones,[3] aromatic ketones and acetone still remain tile building blocks for organic synthesis.[9]
two of the most problematic substrates for the nitro-
In recent years, the conjugate addition of polycon-
Michael addition. To date, only a few catalysts have jugated substrates has received increasing attention.[10]
been reported for the conjugate addition of either ar- Recently, we introduced nitrodienynes as a new class
omatic ketones[4] or acetone[5] with enantiomeric ex- of polyconjugated substrates,[11] and reported the
cesses of >90%. Moreover, it is noteworthy that enantioselective nickel-catalyzed conjugate addition
there are few catalysts with broad substrate scope of 1,3-dicarbonyl compounds to nitrodienynes.[11]
that can catalyze the asymmetric conjugate addition Later, we developed the enantioselective conjugate
of both aromatic ketones and acetone to nitroolefins addition of acetaldehyde to nitrodienynes catalyzed
with high enantioselectivities.[6] Recently, we designed by a chiral secondary amine.[12] The obtained 1,3-
and synthesized a new class of chiral primary amine enynes have been demonstrated to be useful inter-
catalysts bearing multiple hydrogen-bonding donors mediates for the enantioselective synthesis of Amaryl-
which efficiently catalyzed the conjugate addition of lidaceae alkaloids such as (+)-a-lycorane and (+)-ly-
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corine.[13] Encouraged by these successes, we decided Results and Discussion
to significantly expand the scope of the conjugate ad-
dition reactions of nitrodienynes by using both aro- Initially, the model reaction between aromatic ketone
matic ketones and acetone as more challenging react- 1a and nitrodienyne 2a was explored in the presence
ing partners.
of our chiral primary amine catalysts in DCM at
As part of our interest in developing new catalytic room temperature. To our delight, these newly devel-
asymmetric reactions involving conjugated alkynes,[14] oped primary amine catalysts prompted the model re-
herein we report the first enantioselective conjugate action (Table 1). Among these catalysts, 4a provided
addition of problematic aromatic ketones and acetone the best results (75% yield and 97% ee) (entry 1). Its
to polyconjugated nitrodienynes catalyzed by a chiral diastereoisomer 4b afforded 54% yield and 91% ee
multifunctional primary amine catalyst recently devel- (entry 2).The presence of acid additives was crucial
oped by us. These processes provide novel and useful for the reaction to occur. Without an acid additive,
1,3-enynes bearing a g-nitro ketone motif in good the reaction became sluggish (entry 7). Among the
yields with high enantioselectivities. Furthermore, by acid additives examined, 4-MeOC6H4CO2H was
utilizing the resulting chiral 1,3-enynes as a new start- found to be the best. Solvents had varied effects on
ing point, we have developed unprecedented Brøn- the yield but little influence on the enantioselectivity
ACHTUNGTRENNUNGsted acid-catalyzed tandem annulations, which allow (entries 9–14). DCM was found to be the optimal sol-
the efficient and selective construction of various syn- vent. When the reaction took place at an elevated
thetically useful cyclic 1,5-diketones (R=Ar) and di- temperature (408C), the product 3a was obtained in
enones (R=Me).
53% yield and 93% ee (entry 8). Thus, under the opti-
mized reaction conditions, 1,4-addition product 3a
with a propargylic stereocenter was obtained in 75%
yield with 97% ee. Notably, either the 1,6- or 1,8-addi-
tion product was not detected in any case.
Table 1. Optimization of the reaction conditions for the enantioselective conjugate addition of 1a to 2a.[a]
Entry
4
Additive
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-NO2C6H4CO2H
PhCO2H
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
75
54
56
60
60
50
trace
53
68
62
58
60
55
42
97
91
96
96
95
92
ND
93
96
96
95
96
91
92
7
–
8[d]
9
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
4-MeOC6H4CO2H
10
11
12
13
14
toluene
m-xylene
ether
EtOAc
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.1 mmol), 4 (0.015 mmol), additive (0.015 mmol), and solvent (0.3 mL) at room
temperature.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
At 408C.
[b]
[c]
[d]
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Table 2. Enantioselective conjugate addition of aromatic ke-
Table 3. Enantioselective conjugate addition of acetone to
tones to nitrodienynes.[a]
nitrodienynes.[a]
Entry
R
Yield [%][b]
ee [%][c]
En-
try
Ar
R
Yield
[%][b]
ee
1
2
3
4
5
6
7
8
Ph
5a, 90
5b, 88
5c, 83
5d, 88
5e, 86
5f, 85
5g, 81
5h, 84
91
90
82
90
93
87
91
80
[%][c]
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
1,3-benzodioxole
4-Cl-C6H4
2-thienyl
Me
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a, 75
3b, 76
3c, 70
3d, 72
3e, 79
3f, 82
3g, 64
3h, 73
3i, 64
3j, 69
3k, 70
3l, 72
3m, 69
3n, 78
97
97
94
95
96
96
83
91
96
97
96
96
97
98
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
1,3-benzodioxole
4-Cl-C6H4
2-thienyl
Me
Ph
Ph
Ph
Ph
Ph
Ph
[a]
Reaction conditions: acetone (1.0 mmol), 2 (0.1 mmol),
4a (0.015 mmol), 4-MeOC6H4CO2H (0.015 mmol), and
DCM (0.3 mL) at room temperature.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
9
4-Me-C6H4
4-MeO-C6H4
4-NO2-C6H4
3-NO2-C6H4
4-CF3-C6H4
4-Br-C6H4
10
11
12
13
14
[b]
[c]
g-nitro ketone 6 in 92% yield [Eq. (1)], thus demon-
strating an efficient route to products equivalent to
the direct conjugate addition of aromatic ketones to
alkyl-substituted nitroolefins via two effective atom-
economic catalytic addition processes.[15] The (S) con-
figuration was established by comparison of the opti-
cal rotation of 6 with the previously reported value of
this compound.[16]
[a]
Reaction conditions: 1 (0.3 mmol), 2 (0.1 mmol), 4a
(0.015 mmol), 4-MeOC6H4CO2H (0.015 mmol), and
DCM (0.3 mL) at room temperature.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
[b]
[c]
Under the optimized reaction conditions, the scope
of the conjugate addition reaction of aromatic ke-
tones to nitrodienynes was examined (Table 2). The
reaction has a broad substrate scope with respect to
both aromatic ketones and nitrodienynes. Various ar-
omatic- and heteroaromatic-substituted nitrodienynes
underwent smoothly the conjugate addition reaction
with aromatic ketones (entries 1–7). Notably, an
alkyl-substituted nitrodienyne was also a suitable sub-
To further demonstrate the utility of our Michael
strate for the conjugate reaction (entry 8). With adducts, tandem annulations were then investigated.
regard to aromatic ketones, it appears that the posi- Treatment of 1,4-adducts 3 of aromatic ketones with
tion and the electronic property of the substituent on H2O in the presence of p-toluenesulfonic acid (p-
the aromatic ring are well tolerated by the conjugate TSA) (20 mol%) in toluene at 1108C produced 1,5-di-
addition reaction (entries 9–14).
ketones 7 bearing three contiguous stereocenters in
The present catalyst systems were also suitable for good yields with excellent diastereoselectivities (>
the enantioselective conjugate addition of acetone to 20:1) without loss of enantioselectivities (Table 4).[17]
nitrodienynes (Table 3). Various functionalized 1,3- 1,5-Diketones exhibit various bioactivities including
enynes 5 were obtained in good yields with high enan- antitumor and antidiabetic.[18] They are also useful in-
tioselectivities.
termediates for the preparation of heterocyclic com-
The 1,4-adducts obtained through the present pro- pounds such as substituted pyridines and quino-
tocols are versatile building blocks because they con- lines.[19] Thus, the development of a new and efficient
tain three functional groups: an enyne, a ketone, and method to prepare 1,5-diketones is of great value.
a nitro group. For example, Pd/C-catalyzed chemose- The present catalytic tandem reaction, which involved
lective hydrogenation of 1,3-enyne 3h gave saturated regioselective hydration of 1,3-enynes (in situ genera-
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Table 4. Tandem hydration/intramolecular Michael cycliza-
Table 5. Tandem hydration/intramolecular aldol cyclization:
tion: synthesis of 1,5-diketones.[a]
synthesis of dienones.[a]
En-
try
Ar
R
Yield
[%][b]
ee
Entry
R
Yield [%][b]
ee [%][c]
[%][c]
1
2
3
4
5
6
7
Ph
8a, 92
8b, 95
8c, 90
8d, 96
8e, 93
8f, 96
8g, 90
94
88
85
89
92
89
94
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7a, 88
7b, 86
7c, 85
7d, 85
7e, 81
7f, 92
7g, 80
7h, 91
7i, 90
7j, 88
7k, 93
7l, 92
7m, 91
97
96
95
96
95
94
93
98
96
96
96
97
88
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
1,3-benzodioxole
4-Cl-C6H4
2-thienyl
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
1,3-benzodioxole
4-Cl-C6H4
Me
Ph
Ph
Ph
Ph
Ph
Ph
[a]
4-Me-C6H4
4-MeO-C6H4
4-NO2-C6H4
3-NO2-C6H4
4-CF3-C6H4
4-Br-C6H4
The reaction was performed with 5 (0.1 mmol), p-TSA
(0.02 mmol) and H2O (4.0 equiv.) in toluene (0.5 mL)
under reflux for 1–2 h.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
9
10
11
12
13
[b]
[c]
[a]
The reaction was performed with 3 (0.1 mmol), p-TSA
(0.02 mmol) and H2O (4.0 equiv.) in toluene (0.5 mL)
under reflux for 5–8 h.
Yield of isolated product.
Determined by HPLC on a chiral stationary phase.
thetically useful enantioenriched cyclic dienones 8
rather than 1,5-diketones 8’ (Table 5). It is noteworthy
that due to the vinylogous reactivity, cyclic dienones
have been demonstrated as a useful class of com-
pounds, for example, in enantioselective transition
metal-catalyzed and organocatalyzed reactions.[20]
The exclusive formation of 8 suggested that this
[b]
[c]
tion of enones) followed by intramolecular Michael
cyclization, provides a new and attractive alternative tandem annulation reaction proceeded through hydra-
for the preparation of these synthetically useful com- tion of 1,3-enynes followed by intramolecular aldol
pounds.
cyclization instead of Michael cyclization. A possible
Interestingly, when the 1,4-adducts 5 of acetone reaction mechanism is proposed in Scheme 1. The p-
were subjected to the same reaction conditions, a dis- TSA was proposed to play multiple roles in the
tinct annulation reaction took place, providing syn- tandem reactions: (i) catalyzing the regioselective hy-
Scheme 1. Proposed reaction mechanism for the tandem reaction of 5.
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23.9 mg (75%); yellow oil; [a]2D0: + 50.4 (c 1.0 CHCl3);
1H NMR (400 MHz, CDCl3): d=7.92 (d, J=7.6 Hz, 2H),
7.57–7.53 (m, 1H), 7.46–7.42 (m, 2H), 7.29–7.27 (m, 3H),
7.23–7.21 (m, 2H), 6.82 (d, J=16.4 Hz, 1H), 6.01 (d, J=
16.0 Hz, 1H), 4.66 (dd, J=12.4 Hz, J=5.6 Hz, 1H), 4.56
(dd, J=12.0 Hz, J=6.8 Hz, 1H), 3.99 (t, J=6.4 Hz, 1H),
3.38 (d, J=6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
196.2, 142.2, 136.1, 136.0, 133.8, 128.8, 128.8, 128.7, 128.2,
126.3, 107.2, 87.9, 83.4, 77.5, 40.4, 27.0; HR-MS: m/z=
342.1100, calcd. for C20H17NO3Na [M+Na]+: 342.1102;
HPLC (Chiralcel AD-H, 2-propanol/n-hexane=30/70, flow
dration of alkynes to in situ generate a,b-unsaturated
enones; (ii) promoting the subsequent either Michael
or aldol cyclization. The formation of dienones 8
rather than 1,5-diketones 8’ suggested that the intra-
molecular aldol cyclization of 10’ is faster than the
corresponding Michael cyclization of 10.
Conclusions
rate 0.95 mLminÀ1, l=254 nm):
tmajor =12.9 min, tminor =
In summary, we have developed two more “difficult”
conjugate addition reactions – the conjugate addition
of aryl ketones to our newly designed polyconjugated
nitrodienynes and the reaction between acetone and
nitrodienynes. These two transformations were effi-
ciently catalyzed by a common chiral primary amine
organocatalyst recently developed by us. The reac-
tions took place in 1,4-manner. The processes provid-
ed new and synthetically useful 1,3-enynes bearing
a g-nitro ketone motif in good yields with high enan-
tioselectivities. Furthermore, by utilizing the resulting
chiral functionalized 1,3-enynes as a unique starting
point, we have developed unprecedented p-TSA-cata-
lyzed tandem annulations, which provided a new,
rapid and selective method to various synthetically
valuable 1,5-diketones (R=Ar) and dienones (R=
Me), respectively.
14.9 min.
General Procedure for the Enantioselective
Conjugate Addition of Acetone to Nitrodienynes
To a solution of acetone (1.0 mmol) and nitrodienyne 2
(0.1 mmol) in DCM (0.3 mL) was added catalyst 4a
(15 mol%) and 4-MeOC6H4CO2H (15 mol%). The resulting
solution was stirred at room temperature until the reaction
was complete (monitored by TLC). The crude product was
purified by flash silica gel chromatography (petroleum
ether/ethyl acetate as eluents).
Characterization of a representative compound – (S,E)-4-
(nitromethyl)-8-phenyloct-7-en-5-yn-2-one
(5a):
yield:
23.1 mg (90%); yellow oil; [a]2D0: +118.5 (c 1.0 CHCl3);
1H NMR (400 MHz, CDCl3): d=7.29–7.19 (m, 5H), 6.83 (d,
J=16.4 Hz, 1H), 6.00 (d, J=16.4, 1H), 4.56–4.50 (m, 1H),
4.49–4.44 (m, 1H), 3.78–3.72 (m, 1H), 2.80 (d, J=7.2 Hz,
2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): d=204.7,
142.2, 135.9, 128.8, 128.7, 128.6, 126.3, 107.1, 87.6, 83.3, 77.3,
44.9, 30.2, 26.7; HR-MS: m/z=280.0944, calcd. for
C15H15NO3Na [M+Na]+: 280.0948; HPLC (Chiralcel AD-H,
2-propanol/n-hexane=30/70, flow rate 0.9 mLminÀ1, l=
254 nm): tmajor =10.7 min, tminor =11.7 min.
Experimental Section
General Methods
1H NMR and 13C NMR spectra were recorded on
a 400 MHz spectrophotometer. Chemical shifts (d) are ex-
pressed in ppm, and J values are given in Hz. The enantio-
meric excess was determined by HPLC using Chiralpak
AD-H, Chiralcel OD-H and Chiralcel OJ-H columns with
n-hexane and 2-propanol as eluents. High resolution mass
spectrometry (HR-MS) was recorded on a VG Auto Spec-
3000 spectrometer. Optical rotations were measured on
a JASCO DIP-370 polarimeter. All chemicals and solvents
were used as received without further purification unless
otherwise stated. Column chromatography was performed
on silica gel (230–400 mesh).
General Procedure for the Tandem Hydration/
Michael Cyclization
To a solution of 3 (0.1 mmol) in toluene (0.5 mL) was added
p-TSA (20 mol%) and H2O (4.0 equiv.). The resulting solu-
tion was stirred under reflux until the reaction was complete
(monitored by TLC). The crude product was purified by
flash silica gel chromatography (petroleum ether/ethyl ace-
tate as eluents).
Characterization of
a
representative compound
–
(3S,4S,5R)-4-benzoyl-3-(nitromethyl)-5-phenylcyclohexa-
none (7a): yield: 29.6 mg (88%); colourless oil; [a]2D0: À2.4 (c
1.0 CHCl3); 1H NMR (400 MHz, CDCl3): d=7.75 (d, J=
7.6 Hz, 2H), 7.52 (t, J=7.2 Hz, 1H), 7.40 (t, J=7.6 Hz, 2H),
7.13–7.11 (m, 3H), 6.82–6.80 (m, 2H), 4.53 (dd, J=12.0 Hz,
J=4.8 Hz, 1H), 4.42 (dd, J=12.0 Hz, J=5.6 Hz, 1H), 4.13–
4.10 (m, 1H), 3.74–3.70 (m, 1H), 3.16–3.10 (m, 2H), 2.98–
2.92 (m, 1H), 2.76–2.71 (m, 1H), 2.47–2.41 (m, 1H);
13C NMR (100 MHz, CDCl3): d=208.0, 199.9, 138.8, 136.6,
133.7, 129.0, 128.5, 128.2, 127.9, 127.7, 77.8, 47.6, 44.2, 42.4,
41.9, 34.0; HR-MS: m/z=336.1241, calcd. for C20H18NO4
[MÀH]+: 336.1240; HPLC (Chiralcel AD-H, 2-propanol/n-
General Procedure for the Enantioselective
Conjugate Addition of Aromatic Ketones to
Nitrodienynes
To a solution of aromatic ketone 1 (0.3 mmol) and nitrodie-
nyne 2 (0.1 mmol) in DCM (0.3 mL) was added catalyst 4a
(15 mol%) and 4-MeOC6H4CO2H (15 mol%). The resulting
solution was stirred at room temperature until the reaction
was complete (monitored by TLC). The crude product was
purified by flash silica gel chromatography (petroleum
ether/ethyl acetate as eluents).
Characterization of a representative compound – (S,E)-3-
(nitromethyl)-1,7-diphenylhept-6-en-4-yn-1-one (3a): yield:
hexane=20/80, flow rate 0.9 mLminÀ1, l=254 nm): tminor
10.0 min, tmajor =12.6 min.
=
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General Procedure for the Tandem Hydration/Aldol
Cyclization
To a solution of 5 (0.1 mmol) in toluene (0.5 mL) was added
p-TSA (20 mol%) and H2O (4.0 equiv.). The resulting solu-
tion was stirred under reflux until the reaction was complete
(monitored by TLC). The crude product was purified by
flash silica gel chromatography (petroleum ether/ethyl ace-
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Characterization of a representative compound – (R,E)-5-
(nitromethyl)-3-styrylcyclohex-2-enone (8a): yield: 28.0 mg
(93%); yellow solid; [a]2D0: À34.0 (c 1.0 CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.47–7.43 (m, 2H), 7.34–7.30 (m,
3H), 6.99–6.92 (m, 1H), 6.88–6.82 (m, 1H), 6.09–6.08 (m,
1H), 4.46–4.42 (m, 2H), 2.98 (m, 1H), 2.87–2.82 (m, 1H),
2.60–2.55 (m, 1H), 2.42–2.34 (m, 1H), 2.31–2.21 (m, 1H);
13C NMR (100 MHz, CDCl3): d=196.4, 154.3, 136.2, 135.6,
129.5, 129.0, 128.3, 127.7, 127.4, 79.3, 40.5, 33.4, 28.4; HR-
MS: m/z=257.1049, calcd. for C15H15NO3 [M]+: 257.1052;
HPLC (Chiralcel OD-H, 2-propanol/n-hexane=25/75, flow
rate 0.9 mLminÀ1, l=254 nm): tminor =34.526 min, tmajor
40.329 min.
=
Acknowledgements
We gratefully acknowledge financial support from the NSFC
(21372193, 21362040, 21672184), the Program for Chang-
jiang Scholars and Innovative Research Team in University
(IRT13095), the Doctoral Fund of Ministry of Education of
China (20135301110002), and the Government of Yunnan
Province (2013FA026).
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8 Enantioselective Conjugate Additions of “Difficult”
Ketones to Nitrodienynes and Tandem Annulations
Adv. Synth. Catal. 2016, 358, 1 – 8
Teng Liu, Mingxin Zhou, Tengrui Yuan, Binbin Fu,
Xinran Wang, Fangzhi Peng,* Zhihui Shao*
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