Base-promoted addition of DMA with 1,1-diarylethylenes: Application to a total synthesis of (-)-sacidumlignan B

Article abstract of DOI:10.1039/d0ob00376j

A base-promoted addition of DMA (N,N-dimethylacetamide) to 1,1-diarylethylenes has been developed, and it provides a new strategy for the synthesis of N,N-dimethyl-4,4-diarylbutanamides from 1,1-diarylethylenes at room temperature. This method allows us to achieve the goal of synthesizing (-)-sacidumlignan B, and provides simple operation and broad substrate scope by avoiding the use of transition metal catalysts.

Full text of DOI:10.1039/d0ob00376j

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DOI: 10.1039/D0OB00376J
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Base-Promoted Addition of DMA with 1,1-diarylethylenes:
Application to a Total Synthesis of (-)-Sacidumlignan B
Zhen-Biao Luo,a Ya-Wen Wang b and Yu Peng *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A base-promoted addition of DMA (N,N-dimethylacetamide) to 1,1-
diarylethylenes has been developed, which provides a new strategy
for the synthesis of N,N-dimethyl-4,4-diarylbutanamides from 1,1-
diarylethylenes at room temperature. This method allows us to
achieve the goal of synthesizing (-)-sacidumlignan B, and provides a
simple operation and broad substrate scope by avoiding the use of
transition metal catalysts.
The plant Sarcostemma acidum (Roxb.) is distributed in the
coastal areas of Hainan Province, China, which has been used to
treat chronic cough and postnatal hypogalactia by local
residents.1 In 2005, Yue and co-workers reported that four new
lignans, namely, sacidumlignans A−D had been separated from
the plant Sarcostemma acidum and their structures and relative
configuration were proposed by 2D NMR experiments.2 The
sacidumlignans A−C possess naphthalene and di- and tetra-
hydronaphthalene backbone, furthermore, the sacidumlignan
D is a rearranged tetrahydrofuran lignan (Figure 1). Ramana
group reported the synthesis of sacidumlignans A, B and D.3
Moreover, the sacidumlignan A and (±)-sacidumlignan D have
been synthesized in our group.4 In continuation, we were
interested in developing a more efficient synthesis route for (-)-
sacidumlignan B. It is not difficult to find (-)-sacidumlignan B
with dihydronaphthalene skeleton can be synthesized by
intramolecular Friedel-Crafts reaction using diarylbutyr-
aldehyde, which can be synthesized by functional group
conversion utilizing diarylbutanamides. As we know, amides are
not only important tools for extending alkyl chains, but also can
be easily converted into carbonyl compounds, so we hope to
develop an approach to synthesize them to achieve the goal of
Figure 1 Structures of sacidumlignans A−D.
synthesizing (-)-sacidumlignan B. Generally, amides are
prepared from carboxylic acid by reaction with DMF and
thionyl chloride. However, Pines group developed potassium
tert-butoxide catalyzed addition of N-methyl-2-pyrrolidinone
and N-methyl-2-piperidone with olefins to synthesize lactams.5
Furthermore, with the continuous development and
innovation of addition,6 more and more pioneers have applied
new methods to synthesize amides (Scheme 1).7 Lee group
reported rhodium-catalyzed oxygenative addition of terminal
alkynes, providing amides.8 Kobayashi and co-workers have
done a lot of excellent works on the catalytic addition of
carbonyl compounds with alkenes, and they recently reported
catalytic alkylation reactions of weakly acidic carbonyl and
related pronucleophiles in the presence of potassium
hexamethyl-disilazide (KHMDS) and 18-crown-6 ether.9 These
a. State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
E-mail: pengyu@lzu.edu.cn
b.
Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of
GansuProvince and College of Chemistry and Chemical Engineering, Lanzhou
University,Lanzhou 730000, China.
†Electronic Supplementary Information (ESI) available: See DOI:
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10.1039/x0xx00000x
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Table 2 Substrate scope of alkenes
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DOI: 10.1039/D0OB00376J
Scheme 1 Strategies for the synthesis of amides from alkenes
work greatly inspired us to develop a method for the synthesis
of N,N-dimethyl-4,4-diarylbutanamides via a base-promoted
addition of DMA (N,N-dimethylacetamide) to 1,1-diarylethyl-
enes, which makes the experimental operation easier and
allows for gram scale of amides, and makes the reaction more
practical in organic synthesis.
Table 1. Optimization of the reaction conditions.
Entry
1
2
Base
Solvent
THF
THF
t/h
8
8
8
8
8
8
8
8
3
8
8
3
3
8
3
8
2
2
Yield/%
0
T/℃
-45
-15
0
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
NaHMDS (2.0 eq)
KOH (2.0 eq)
0
3
THF
0
Reactions were performed with the alkenes (1.0 mmol) and
NaHMDS (1.5 eq.) in DMA [0.5 M] at room temperature for 3.0 h.
4
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
5
Toluene
Benzene
DMF
0
6
0
Sodium bis(trimethylsilyl)amide (NaHMDS) is a base
commonly used in organic synthesis, DMA is a widely used
organic solvent, both of them are easy to be obtained, so we
wanted to use these two reagents to achieve our method. We
hypothesized that the addition of DMA to 1,1-diarylethylenes
was allowed to proceed under an argon atmosphere by using
NaHMDS as base (Scheme 1). In order to find a suitable reaction
7
23
35
73
5
8
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
9
10
11
12
13
14
15
16
17
18
tBuOK (2.0 eq)
LiHMDS (2.0 eq)
KHMDS (2.0 eq)
-
15
40
64
0
NaHMDS (1.5 eq)
NaHMDS (1.0 eq)
NaHMDS (3.0 eq)
NaHMDS (4.0 eq)
74
56
65
49
The reaction was conducted in solvent [0.5 M]. eq = equivalent. KOH
= Potassium hydroxide. THF = Hydrofuran. NaHMDS = Sodium
bis(trimethylsilyl)amide. LiHMDS = Lithium bis(trimethylsilyl)amide.
KHMDS
= Potassium bis(trimethylsilyl)amide. DMA = N, N-
Dimethylacetamide. DMF = N, N-Dimethylformamide. tBuOK =
Potassium butoxide. DMSO = Dimethyl sulfoxide.
Scheme 2 Versatile transformations of the amide 2o
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Scheme 3 Total synthesis of (-)-sacidumlignan B (3j)
temperature, we initially investigated 1,1-diphenylethylene and 10−13). A control experiment showed that the reaction did not
DMA (4.0 eq.) as test substrates, the reaction was conducted in occur without a base (Table 1, entry 14). Moreover, we
THF at −45°C in the presence of NaHMDS with 2 equivalents, examined the amount of NaHMDS, and found that 1.5
disappointingly, 1,1-diphenylethylene was not consumed (Table equivalents of NaHMDS as the base effectively promoted the
1, entry 1). After increasing the temperature, the results did not reaction smoothly (Table 1, entries 15−18). On the other hand,
change (Table 1, entries 2, 3). Small amount of substrate was we noticed that the commercially available NaHMDS was
exhausted, but the desired amide was not obtained at room dissolved in THF, while the amount of DMA was too low, the
temperature (Table 1, entry 4). Considering that solvent had an substrate was difficult to completely react, and the amount of
effect on the reaction, we tried to experiment with toluene and DMA was too high, which brought great trouble for
benzene, but failed to afford the corresponding product (Table experimental operation. After screening, we found that
1, entries 5, 6). To our delight, we used DMF as solvent and substrate concentration of 0.5 M was a better choice. The
successfully obtained N,N-dimethyl-4,4-diphenylbutanamide substrate scope of 1,1-diarylethylenes was examined under the
(2a) with poor yield (Table 1, entry 7). Although the yield was optimized conditions, as listed in Table 2. We found 1,1-
still low, it was improved under the conditions of DMSO, which diarylethylenes with various alkyl- and alkoxy- substituents on
indicated that solvent had huge impact on the reaction (Table the aromatic ring gave good yields of the amides (2a−2h), and
1, entry 8). Delightfully, the yield dramatically increased to 73% substrates bearing electron-withdrawing groups gave medium
in DMA, while the reaction time was greatly shortened at room yields (2i, 2j, 2k). Excitingly, 1,1-diphenylethylene with CF3-
temperature, which proved DMA was better solvent (Table 1, groups was employed, the desired adduct (2l) was obtained
entry 9). Screening of different bases indicated that KOH, successfully, and heterocyclic substrates gave the
LiHMDS and KHMDS were also capable of promoting the corresponding amides (2m, 2n) in moderate yields. Pleasingly,
addition, but NaHMDS gave better yield (Table 1, entries we provided gram scale (5.12 g) of the amide (2o) under our
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This work was supported by the National Natural Science
DOI: 10.1039/D0OB00376J
Foundation of China (Nos. 21772078), as well as State Key
Laboratory of Applied Organic Chemistry, Lanzhou University.
standard conditions in 71% yield, which greatly reflected the
potential utility of the method. On the basis of previous
literature reports, the possible mechanism seems to indicate
that the reaction is a base-promoted nucleophilic addition of
DMA to 1,1-diarylethenes.10
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Notes and references
To illustrate the synthetic potentiality of the addition process,
the amide (2o) was employed to prepare a series of functional
molecules (Scheme 2). The selective reduction of 2o using L-
selectride as the reductant afforded 3 in a moderate yield.11
Amidic hydrolysis of 2o with KOH, followed by acidification of
hydrochloric acid gave the corresponding carboxylic acid (3c).12
Synthesis (-)-sacidumlignan B (3j) is our goal, and then we
applied this addition to the synthesis of (-)-sacidumlignan B (3j)
to test our method (Scheme 3). We prepared the arylbromide
(3a) using the method from our previous work published.4
Treatment with n-butyllithium, the arylbromide underwent
Lithium-bromine exchange to give the aryllithium species,
which was treated sequentially with acetyl chloride to afford
tertiary alcohol. It was then dehydrated under acidic conditions
to give the 1,1-diarylethylene (3b). By our standard reaction
conditions, the addition of DMA to 1,1-diarylethenes proceeded
smoothly to give the amide (2o) in 71% yield. Treatment of the
amide with KOH, followed by acidification of hydrochloric acid
provided the carboxylic acid (3c). The acid with pivaloyl chloride
and triethylamine reacted to give the mixed anhydride.
Subsequently, the mixed anhydride with (R)-4-Phenyl-2-
oxazolidinone provided the oxazolidinone (3d).13 Next, the
oxazolidinone (3d) was deprotonated with LDA and selenated
with PhSeBr, followed by oxidative elimination with mCPBA to
furnish 3e. Conjugate addition of MeMgBr to the ,-
unsaturated imide (3e) produced 1,4-adducts (3f) (dr > 98: 2) in
the presence of CuBr•SMe2. Treatment of 3f with NaHMDS,
followed by methylation of the sodium enolate obtained the
oxazolidinone (3g) (dr = 94: 6).14 Exposure of the oxazolidinone
to LiOH and H2O2 provided the acid, then, the alcohol (3h) was
afforded by reduction of the acid with LiAlH4.15 The hydroxy
group of the alcohol was oxidized with Dess-Martin periodinane
to give the aldehyde (3i). Finally, hydrogenation of 3i with Pd/C
and H2 afforded the phenol, which was converted into (-)-
Sacidumlignan B (3j) under acidic conditions.
1
State Administration of Traditional Chinese Medicine. Chinese
Herb (Zhonghua Bencao), Shanghai Science and Technology
Press, Shanghai, 1999, 6, 383.
L.-S. Gan, S.-P. Yang, C.-Q. Fan and J.-M. Yue, J. Nat. Prod.
2005, 68, 221.
(a) S. K. Pandey and C. V. Ramana, J. Org. Chem. 2011, 76,
2315; (b) J. K. Rout and C. V. Ramana, J. Org. Chem. 2012, 77,
1566.
J. Zhang, C. Yan, Y. Peng, Z. Luo, X. Xu and Y. Wang, Org.
Biomol. Chem. 2013, 11, 2498.
2
3
4
5
6
H. Pines, S. V. Kannan and J. Simonik, J. Org. Chem. 1971, 36,
2311.
(a) Y. Nakao, T. Yukawa, Y. Hirata, S. Oda, J. Satoh and T.
Hiyama, J. Am. Chem. Soc. 2006, 128, 7116; (b) C. Chatalova-
Sazepin, Q. Wang, G. M. Sammis and J. Zhu, Angew. Chem. Int.
Ed. 2015, 54, 5443; (c) T. M. Ha, C. Chatalova-Sazepin, Q.
Wang and J. Zhu, Angew. Chem. Int. Ed. 2016, 55, 9249; (d) M.
Ohashi, K. Nakatani, H. Maeda and K. Mizuno, Org. Lett. 2008,
10, 2741; (e) H. Yi, X. Zhang, C. Qin, Z. Liao, J. Liu and A. Lei,
Adv. Synth. Catal. 2014, 356, 2873.
(a) M. Zhang, J. Xie and C. Zhu, Nature Commun. 2018, 9,
3517; (b) G. Wang, R. Shang, W. Cheng and Y. Fu, Org. Lett.
2015, 17, 4830; (c) K. Tanaka, Y. Shibata, T. Suda, Y. Hagiwara
and M. Hirano, Org. Lett. 2007, 9, 1215; (d) M. Ohashi, K.
Nakatani, H. Maeda and K. Mizuno, Org. Lett. 2008, 10, 2741;
(e) B. M. Trost, Angew. Chem. Int. Ed. 1995, 34, 259; (f) A. Ts.
Malkhasyan, E. M. Nazaryan, S. M. Mirakyan and G. T.
Martirosyan, Zhurnal Organicheskoi Khimii, 1980, 16, 2566.
I. Kim and C. Lee, Angew. Chem. Int. Ed. 2013, 52, 10023.
(a) Y. Yamashita, H. Suzuki and S. Kobayashi, Org. Biomol.
Chem. 2012, 10, 5750; (b) H. Suzuki, I. Sato, Y. Yamashita and
S. Kobayashi, J. Am. Chem. Soc. 2015, 137, 4336; (c) Y.
Yamashita, I. Sato, H. Suzuki and S. Kobayashi, Chem. Asian. J.
2015, 10, 2143; (d) I. Sato, H. Suzuki, Y. Yamashita and S.
Kobayashi, Org. Chem. Front. 2016, 3, 1241; (e) Y. Yamashita,
R. Igarashi, H. Suzuki and S. Kobayashi, Synlett. 2017, 28, 1287;
(f) Y. Yamashita and S. Kobayashi, Chem. Eur. J. 2018, 24, 10;
(g) Y. Yamashita, R. Igarashi, H. Suzuki and S. Kobayashi, Org.
Biomol. Chem. 2018, 16, 5969.
7
8
9
10 (a) B. A. Trofimov, E. Y. Schmidt, I. A. Ushakov, N. V. Zorina, E.
V. Skital’tseva, N. I. Protsuk and A. I. Mikhaleva, Chem. Eur. J.
2010, 16, 8516; (b) B. A. Trofimov, E. Y. Schmidt, N. V. Zorina,
E. V. Ivanova and I. A. Ushakov, J. Org. Chem. 2012, 77, 6880;
(c) B. A. Trofimov, E. Y. Schmidt, N. V. Zorina, E. V. Ivanova, I.
A. Ushakov and A. I. Mikhaleva, Adv. Synth. Catal. 2012, 354,
1813; (d) R. K. Saunthwal, M. Patel and A. K. Verma, J. Org.
Chem. 2016, 81, 6563.
11 C. L. Bailey, A. Y. Joh, Z. Q. Hurley, C. L. Anderson and B.
Singaram, J. Org. Chem. 2016, 81, 3619.
12 (a) K. Kitamoto, M. Sampei, Y. Nakayama, T. Sato and N. Chida,
Org. Lett. 2010, 12, 5756; (b) K. Kitamoto, Y. Nakayama, M.
Sampei, M. Ichiki, N. Furuya, T. Sato and N. Chida, Eur. J. Org.
Chem. 2012, 22, 4217.
In summary, we have reported an efficient and economical
method for addition of DMA to 1,1-diarylethylenes in the
absence of transition metal catalysts, and the addition
proceeded smoothly to synthesize N,N-dimethyl-4,4-
diarylbutanamides in good yields by using NaHMDS as a base in
DMA under mild conditions. Amides are versatile intermediates
for synthetic organic chemistry, we have used the approach to
get the goal of synthesizing (-)-sacidumlignan B, which shows
the practicability of our method.
13 C. H. V. A. Sasikala, P. R. Padi, V. Sunkara, P. Ramayya, P. K.
Dubey, V. B. R. Uppala and C. Praveen, Org. Process Res. Dev.
2009, 13, 907.
14 S. Nakamura, F. Kikuchi and S. Hashimoto, Tetrahedron
Asymmetry, 2008, 19, 1059.
Conflicts of interest
There are no conflicts to declare.
15 F. Yokokawa, T. Asano, T. Okino, W. H. Gerwick and T. Shioiri,
Tetrahedron, 2004, 60, 6859.
Acknowledgements
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