Catalytic amide base system generatedin situfor 1,3-diene formation from allylbenzenes and carbonyls

Article abstract of DOI:10.1039/d0ob02007a

The amide base generatedin situfrom tetramethylammonium fluoride and N(TMS)₃catalyzes the synthesis of 1,3-diene from an allylbenzene and carbonyl compound. The system is applicable to the transformations of a variety of allylbenzenes with functional groups (halogen, methyl, phenyl, methoxy, dimethylamino, ester, and amide moieties). Acyclic and cyclic diaryl ketones, pivalophenone, pivalaldehyde, and isobutyrophenone are used as coupling partners. The role oftransβ-methyl stilbenes in product formation is also elucidated.

Full text of DOI:10.1039/d0ob02007a

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Catalytic amide base system generated in situ for
1,3-diene formation from allylbenzenes and
carbonyls†
Cite this: DOI: 10.1039/d0ob02007a
Received 30th September 2020,
Accepted 27th October 2020
Masanori Shigeno, * Akihisa Kajima, Kunihito Nakaji, Kanako Nozawa-Kumada
and Yoshinori Kondo*
DOI: 10.1039/d0ob02007a
rsc.li/obc
The amide base generated in situ from tetramethylammonium for the limited substrate scope and functional group tolerance
fluoride and N(TMS)3 catalyzes the synthesis of 1,3-diene from an posed by conventional reactions using strong Brønsted bases
allylbenzene and carbonyl compound. The system is applicable to such as n-BuLi, sec-BuLi, Grignard reagents, and NaNH2.12
the transformations of a variety of allylbenzenes with functional Schneider et al. revealed that a catalytic amount of NaHMDS
groups (halogen, methyl, phenyl, methoxy, dimethylamino, ester, promotes the deprotonative coupling of allylbenzenes with
and amide moieties). Acyclic and cyclic diaryl ketones, pivalophe- aldimines (Fig. 1, iii), while Walsh et al. reported that LiHMDS
none, pivalaldehyde, and isobutyrophenone are used as coupling is an appropriate base for the Pd-catalyzed arylations of allyl-
partners. The role of trans β-methyl stilbenes in product formation benzenes (Fig. 1, iv). However, to date, deprotonative reactions
is also elucidated.
The establishment of the synthetic methodologies of 1,3-
dienes has gained considerable attention among organic che-
mists owing to the presence of these molecules in biologically
active compounds and natural products and their use as syn-
thetically potent modules in organic synthesis (Diels–Alder
reaction and hydrofunctionalization).1 Wittig, Horner–
Wadsworth–Emmons, Julia–Kocienski, and Peterson olefina-
tions are traditional and reliable protocols for the synthesis of
1,3-dienes, in which functionalized allylic substrates, such as
allylphosphonium salts, allyl phosphonates, allyl sulfones, and
allyl silanes are employed for the coupling reactions with
carbonyls.1–4 Non-functionalized allylbenzenes are easily avail-
able and thus, their direct conversion to 1,3-dienes is attrac-
tive. However, such examples are still limited. For example,
Gong et al. reported that in the presence of Pd and Cr catalysts
combined with benzoquinone, the coupling reactions of allyl-
benzenes with α-diazo esters afford the 1,3-dienoates (Fig. 1,
i).5 Jiang et al. reported that Pd catalyzes the allylic C–H olefi-
nations of allylbenzenes with sulfoxonium ylides to form 1,3-
dienones (Fig. 1, ii).6 Recently, deprotonative functionaliza-
tions of allylbenzenes have been studied using catalytic and
stoichiometric amounts of hexamethyldisilazide bases (HMDS
= hexamethyldisilazide; Fig. 1b).7–11 These bases compensate
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aoba, Sendai, 980-8578, Japan.
E-mail: masanori.shigeno.e5@tohoku.ac.jp, yoshinori.kondo.a7@tohoku.ac.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 1,3-Diene syntheses of allylbenzenes and deprotonative functio-
d0ob02007a
nalizations related to this study.
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using HMDS-amide base have not been applied to the syn-
thesis of 1,3-dienes.13
We have previously studied the deprotonative functionaliza-
tions of C–H pronucleophiles using HMDS-amide base gener-
ated in situ from a catalytic amount of fluoride salt and a stoi-
chiometric amount of aminosilane.14,15 In addition to the reac-
tions of heteroarenes, acetates, and terminal alkynes used as a
pronucleophile, stilbene formation of methyl(hetero)arenes
with carbonyl compounds was recently achieved (Fig. 1, v).14e
In this study, we established that the system is effective for the
deprotonative coupling of allylbenzenes with carbonyls to
afford 1,3-dienes (Fig. 1, vi). The reaction proceeds at nearby
ambient temperature and displays a high functional group tol-
erance (methyl, phenyl, halogen, methoxy, dimethylamino,
1,3-benzodioxole, ester, and amide moieties) in allylbenzenes.
Carbonyl electrophiles such as acyclic and cyclic diaryl ketones
(xanthone, thioxanthone, fluorenone, and suberenone), pivalo-
phenone, pivalaldehyde, and isobutyrophenone were employed
in the reaction. The system was also applied to the conversions
of trans-β-methylstilenes.
Initially, the 1,3-diene formation process was examined
using allylbenzene 1a and benzophenone 2a as model sub-
strates (Table 1). The effects of fluoride and alkoxide salts were
investigated in N,N-dimethylformamide (DMF). The results
revealed that tetramethylammonium fluoride (TMAF) was the
most effective, affording 3aa in 90% yield (entries 1–7).
Solvents other than DMF were also tested (entries 8–12): 1,3-
dimethyl-2-imidazolidinone (DMI) afforded the product in
73% yield, while N,N-dimethylacetamide (DMA), dimethyl sulf-
oxide (DMSO), tetrahydrofuran (THF), and toluene were
ineffective. The use of N(TMS)3 (3 equiv.) resulted in the for-
mation of 3aa in 90% isolated yield (entry 13).16
Fig. 2 Scope of allyl(hetero)arenes 1 for the 1,3-diene formation with
2a. Reactions were conducted at 0.2 mmol scale. Isolated yields. E/Z
ratios were determined by 1H-NMR analysis of the isolated product. a 2a
(1.1 equiv.) was used. b Product was isolated after treatment with HCl.
c Reaction was conducted with TMAF (30 mol%) in DMI.
With the optimized conditions in hand, the scope of the
allylbenzene pronucleophiles was next surveyed (Fig. 2). The
halogen atoms (F, Cl, and Br) on the phenyl group were well-
tolerated to afford the coupling products 3ba–3ea in high
yields. Allylbenzenes 1f and 1g, which bear methyl groups at
the ortho- and para-positions, respectively, afforded the pro-
ducts in 81% and 62% respective yields, while phenyl-substi-
tuted 1h afforded 3ha in 85% yield. The reactions of substrates
comprising electron-donating methoxy and dimethylamino
substituents also proceeded smoothly to afford the products in
87% and 86% yields, respectively.17 Safrole 1k underwent the
reaction to yield the product 3ka in 96% yield. The electrophi-
lic ester and amide moieties were compatible with the reac-
tions to provide the desired products 3la and 3ma.
2-Allylbenzothiophene 1n and 2-allyl-1-methylindole 1o were
suitable and furnished the corresponding products in 94%
and 88% yields, respectively. 1-Octene and 1,4-pentadiene were
also tested in the reactions, however, no desired products were
formed (results not shown).
Table 1 Optimization of 1,3-diene formation of 1a with 2a a
Entry
Fluoride or alkoxide source
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
KF
RbF
CsF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMI
DMA
DMSO
THF
Toluene
DMF
0
0
48
61
NaOMe
NaO-t-Bu
KO-t-Bu
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
56
81
90 (88)c
73
22
0
0
9
The proposed 1,3-diene formation of 1a was next performed
with a variety of carbonyl compounds (Fig. 3). Thus, diaryl
ketones 2b–2d possessing F, Cl, and methoxy substituents
were subjected to the reaction, providing the respective 1,3-
dienes in 79%, 71%, and 92% yields, respectively. When
xanthone 2e and thioxanthone 2f were used as the electro-
phile, the desired products 3ae and 3af were produced in the
10
11
12
13
0
99 (90)c−e
a Reactions were conducted at 0.2 mmol scale. b Yields were deter-
mined by 1H-NMR analysis. c Yield in parentheses denotes the isolated
yield. d N(TMS)3 (3 equiv.) was used. e E/Z ratio was determined to be
>30 : 1 by 1H-NMR analysis of the isolated product.
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Fig. 4 Proposed mechanism of the present 1,3-diene formation.
The proposed mechanism for the 1,3-diene formation
Fig. 3 Scope of carbonyl compounds 2. Reactions were conducted at
0.2 mmol scale. Isolated yields. E/Z ratios were determined by 1H-NMR process is portrayed in Fig. 4. Amide base A, which is initially
analysis of the isolated product. a Products were isolated after treatment
generated from TMAF and N(TMS)3, induces the deprotonation
with HCl. b TMAF (30 mol%) was used. c DMI was used as a solvent.
of 1 to afford allyl anion B.15a Next, B reacts with 2 to form alk-
d Reaction was conducted at 40 °C. eRatios of major isomer/minor
oxide C, which subsequently produces silyl ether D with the
concomitant formation of A. The conversion of D to 3 is
assisted by A and/or siloxide E.22
isomers were determined by 1H-NMR analysis of the isolated product.
f Reaction was conducted at 60 °C.
respective yields of 81% and 97%. 9-Fluorenone 2g and diben-
zosuberenone 2h also reacted with 1a to afford 3ag and 3ah,
respectively. Subsequently, tert-butyl phenyl ketone 2i was
applied to the reaction and the 1,3-diene 3ai was furnished in
67% yield.18 Pivaladehyde 2j was also used in the reaction to
form 3aj in 67% yield. As enolizable carbonyl compounds, iso-
butyrophenone 2k and isobutyraldehyde 2l were tested; the
former gave the target product in 73% yield, while the latter
gave neither 1,3-diene nor silyl ether product.† 19
Conclusions
In summary, we demonstrated that the catalytic amide system
using TMAF and N(TMS)3 can be employed for the preparation
of 1,3-dienes from allylbenzenes and carbonyls. The current
system displayed a broad substrate scope for both reactants.
β-Methyl stilbenes were also found to be relevant as a
pronucleophile.
We further examined the reactions of trans β-methyl stil-
benes 4, which are less reactive than the corresponding allyl
arenes (Scheme 1).20 Fortunately, the reactions of 4a and 4b
with carbonyls proceeded smoothly to afford the products in
88% and 98% yields, respectively.21
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by JSPS KAKENHI Grant
Number 19H03346 (YK), JSPS KAKENHI Grant Number
19K06967 (MS), the Environment Research and Technology
Development Fund (JPMEERF20202R02) of the Environmental
Restoration and Conservation Agency of Japan (MS), The
Uehara Memorial Foundation (MS), Grand for Basic Science
Research Projects from The Sumitomo Foundation (MS),
Yamaguchi Educational and Scholarship Foundation (MS),
NIPPON SHOKUBAI Award in Synthetic Organic Chemistry,
Japan (MS), and also the Platform Project for Supporting Drug
Discovery and Life Science Research funded by Japan Agency
Scheme 1 Reactions of trans β-methyl stilbenes 4. Reactions were con-
ducted at 0.2 mmol scale. Isolated yields. E/Z ratios were determined by
1H-NMR analysis of the isolated product.
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for Medical Research and Development (AMED) (MS, KNK,
and YK).
7 R. E. Mulvey and S. D. Robertson, Angew. Chem., Int. Ed.,
2013, 52, 11470.
8 W. Bao, H. Kossen and U. Schneider, J. Am. Chem. Soc.,
2017, 139, 4362.
9 N. Hussain, G. Frensch, J. Zhang and P. J. Walsh, Angew.
Chem., Int. Ed., 2014, 53, 3693.
Notes and references
1 (a) M. B. Smith and J. March, March’s Advanced Organic 10 For other examples of deprotonative functionalizations
Chemistry, John Wiley & Sons, Inc., New York, 6th edn,
2007; (b) E. J. Corey, Angew. Chem., Int. Ed., 2002, 41, 1650;
(c) J. F. Hartwig, Organotransition Metal Chemistry. From
Bonding to Catalysis, University Science Books, Sausalito,
2010.
2 (a) The Chemistry of Dienes and Polyenes, ed. Z. Rappoport,
Wiley, Chichester, U.K., 1997; (b) B. E. Maryanoff and
A. B. Reitz, Chem. Rev., 1989, 89, 863; (c) D. J. Ager, Org.
React., 1990, 38, 1; (d) D.-J. Dong, H.-H. Li and S.-K. Tian,
J. Am. Chem. Soc., 2010, 132, 5018; (e) T. Borg, P. Tuzina
and P. Somfai, J. Org. Chem., 2011, 76, 8070; (f) F. Billard,
R. Robiette and J. Pospisil, J. Org. Chem., 2012, 77, 6358;
(g) R. Zhou, C. Wang, H. Song and Z. He, Org. Lett., 2010,
12, 976.
using HMDS-amide bases, see: (a) H. Suzuki, R. Igarashi,
Y. Yamashita and S. Kobayashi, Angew. Chem., Int. Ed.,
2017, 56, 4520; (b) Y. Yamashita and S. Kobayashi, Chem. –
Eur. J., 2018, 24, 10; (c) Z. Wang, Z. Zheng, X. Xu, J. Mao
and P. J. Walsh, Nat. Commun., 2018, 9, 3365; (d) S.-C. Sha,
S. Tcyrulnikov, M. Li, B. Hu, Y. Fu, M. C. Kozlowski and
P. J. Walsh, J. Am. Chem. Soc., 2018, 140, 12415; (e) G. Liu,
P. J. Walsh and J. Mao, Org. Lett., 2019, 21, 8514;
(f) D.-D. Zhai, X.-Y. Zhang, Y.-F. Liu, L. Zheng and
B.-T. Guan, Angew. Chem., Int. Ed., 2018, 57, 1650;
(g) Y.-F. Liu, D.-D. Zhai, X.-Y. Zhang and B.-T. Guan, Angew.
Chem., Int. Ed., 2018, 57, 8245; (h) Y.-F. Liu, L. Zheng,
D.-D. Zhai, X.-Y. Zhang and B.-T. Guan, Org. Lett., 2019, 21,
5351; (i) M. Bhanuchandra, H. Yorimitsu and A. Osuka,
Org. Lett., 2016, 18, 384; ( j) W. Clegg, G. C. Forbes,
A. R. Kennedy, R. E. Mulvey and S. T. Liddle, Chem.
Commun., 2003, 406.
3 As alternative methodologies, transition metal catalysis are
used for coupling unsaturated carbon-carbon bond units to
provide 1,3-dienes, which include cross-coupling of alkenyl
(pseudo)halides, ene-yne coupling, and cross-metathesis. 11 Recently, Mita, Sato, and coworkers reported that cobalt-
For reviews, see: (a) M. De Paolis, I. Chataigner and
J. Maddaluno, Top. Curr. Chem., 2012, 327, 87;
(b) E.-I. Negishi, Z. Huang, G. Wang, S. Mohan, C. Wang
and H. Hattori, Acc. Chem. Res., 2008, 41, 1474 Also see the
recent reports: (c) V. T. Nguyen, H. T. Dang, H. H. Pham,
catalyzed coupling reactions of allylbenzenes with CO2 and
carbonyls proceeds in the presence of AlMe3, see:
(a) K. Michigami, T. Mita and Y. Sato, J. Am. Chem. Soc.,
2017, 139, 6094; (b) T. Mita, S. Hanagata, K. Michigami and
Y. Sato, Org. Lett., 2017, 19, 5876.
V. D. Nguyen, C. Flores-Hansen, H. D. Arman and 12 (a) G. Fraenkel, X. Chen, J. Gallucci and Y. L. Ren, J. Am.
O. V. Larionov, J. Am. Chem. Soc., 2018, 140, 8434;
(d) J. H. Delcamp, P. E. Gormisky and M. C. White, J. Am.
Chem. Soc., 2013, 135, 8460; (e) E. M. Stang and
M. C. White, J. Am. Chem. Soc., 2011, 133, 14892; (f) Y. Al-
Jawaheri and M. C. Kimber, Org. Lett., 2016, 18, 3502;
(g) A. L. Hansen, J.-P. Ebran, M. Ahlquist, P.-O. Norrby and
T. Skrydstrup, Angew. Chem., Int. Ed., 2006, 45, 3349;
(h) C. Zheng, D. Wang and S. S. Stahl, J. Am. Chem. Soc.,
Chem. Soc., 2008, 130, 4140; (b) C. Fiorelli, L. Maini,
G. Martelli, D. Savoia and C. Zazzetta, Tetrahedron, 2002,
58, 8679; (c) J. Tanaka, M. Nojima and S. Kusabayashi,
J. Am. Chem. Soc., 1987, 109, 3391; (d) S. Lamothe, K. Cook
and T. Chan, Can. J. Chem., 1992, 70, 1733; (e) J. Terao,
Y. Jin, K. Torii and N. Kambe, Tetrahedron, 2004, 60, 1301;
(f) T. W. Campbell and W. G. Young, J. Am. Chem. Soc.,
1947, 69, 3066.
2012, 134, 16496; (i) X.-H. Hu, J. Zhang, X.-F. Yang, Y.-H. Xu 13 Allylbenzene-Cr(CO)3 complexes were reported to couple
and T.-P. Loh, J. Am. Chem. Soc., 2015, 137, 3169;
( j) A. M. Olivares and D. J. Weix, J. Am. Chem. Soc., 2018,
140, 2446; (k) M. Liu, P. Yang, M. K. Karunananda,
Y. Wang, P. Liu and K. M. Engle, J. Am. Chem. Soc., 2018,
with carbonyls to afford 1,3-diene-Cr(CO)3 derivatives by
using KO-t-Bu, see: D. Gentric, J.-Y. Le Bihan,
M.-C. Senechal-Tocquer, D. Senechal and B. Caro,
Tetrahedron Lett., 1986, 27, 3849.
140, 5805; (l) G. A. Molander and L. A. Felix, J. Org. Chem., 14 (a) K. Inamoto, H. Okawa, H. Taneda, M. Sato, Y. Hirono,
2005, 70, 3950.
M. Yonemoto, S. Kikkawa and Y. Kondo, Chem. Commun.,
2012, 48, 9771; (b) K. Inamoto, H. Okawa, S. Kikkawa and
Y. Kondo, Tetrahedron, 2014, 70, 7917; (c) H. Taneda,
K. Inamoto and Y. Kondo, Chem. Commun., 2014, 50, 6523;
(d) M. Shigeno, Y. Fujii, A. Kajima, K. Nozawa-Kumada and
Y. Kondo, Org. Process Res. Dev., 2019, 23, 443;
(e) M. Shigeno, K. Nakaji, K. Nozawa-Kumada and
Y. Kondo, Org. Lett., 2019, 21, 2588; (f) M. Shigeno,
T. Okawa, M. Imamatsu, K. Nozawa-Kumada and Y. Kondo,
Chem. – Eur. J., 2019, 25, 10294; (g) M. Shigeno, K. Nakaji,
A. Kajima, K. Nozawa-Kumada and Y. Kondo, Chem. Pharm.
4 Hodgson and coworkers reported the 1,3-diene synthesis
starting from alkenyllithium and epoxide in the presence
of
lithium
2,2,6,6-tetramethylpiperidide,
see:
D. M. Hodgson, M. J. Fleming and S. J. Stanway, J. Org.
Chem., 2007, 72, 4763.
5 P.-S. Wang, H.-C. Lin, X.-L. Zhou and L.-Z. Gong, Org. Lett.,
2014, 16, 3332.
6 (a) C. Li, M. Li, W. Zhong, Y. Jin, J. Li, W. Wu and H. Jiang,
Org. Lett., 2019, 21, 872 Also see: (b) Y. Ping, S. Zhang,
T. Chang and J. Wang, J. Org. Chem., 2019, 84, 8275.
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Bull., 2019, 67, 1179 Also see: (h) M. Shigeno, Y. Kai,
T. Yamada, K. Hayashi, K. Nozawa-Kumada, C. Denneval
and Y. Kondo, Asian J. Org. Chem., 2018, 7, 2082.
a silyl ether (corresponding to D in Fig. 4) and/or an
alcohol. Thus, acid treatment was performed to
convert the mixture to the target 1,3-dienes, 3ja, 3ag, and
3ah.
15 For related studies reported by other groups, see:
(a) S. Large, N. Roques and B. R. Langlois, J. Org. Chem., 18 The stereochemistries of 3ai and 3ak were confirmed by
2000, 65, 8848; (b) M. Hu, B. Gao, C. Ni, L. Zhang and NOE spectroscopic experiments.
J. Hu, J. Fluorine Chem., 2013, 155, 52 Also see: 19 Also when benzaldehyde was employed, neither 1,3-diene
(c) S. Okusu, K. Hirano, E. Tokunaga and N. Shibata, nor silyl ether was formed.
ChemistryOpen, 2015, 4, 581; (d) B. Gao, Y. Zhao, M. Hu, 20 trans β-Methyl stilbenes were often obtained as a byproduct
C. Ni and J. Hu, Chem. – Eur. J., 2014, 20, 7803; (e) B. Teng,
W. Chen, S. Dong, C. W. Kee, D. A. Gandamana, L. Zong
and C.-H. Tan, J. Am. Chem. Soc., 2016, 138, 9935.
in the functionalizations of allylbenzenes, and not used for
the reactions, see the ref. 8 and 11.
21 For comparison with the catalytic amide base generated
in situ, stoichiometric amounts of NaHMDS and KHMDS
were examined in the reaction of 1a and 2a, which
gave the coupling products, but as mixtures of 1,3-diene
3aa and alcohol (Scheme S1†). The reagents were also
used in the reactions of less reactive substrate 4b with 2e,
which resulted in the low-yield product formations
(Scheme S2†). The results show that the current catalytic
amide base system is more effective for the 1,3-diene
formation.
16 In the general procedure of this study, after quenching the
reaction with H2O, the mixture was stirred at room temp-
erature for 1 h, analogously to the procedure of our pre-
vious report of stilbene synthesis14e (see ESI†). However, it
was confirmed that, even when the stirring after the
quench was conducted at 0 °C for 5 min, 3aa, 3da, and 3ea
were obtained in good yields of 97%, 80%, and 87%,
respectively, which are comparable with those shown in
Table 1 (entry 13) and Fig. 2.
17 In the reactions of 1j (Fig. 2), 2g (Fig. 3), and 2h (Fig. 3), a 22 Similar elimination step was noted in our previous studies,
significant amount of coupling products were obtained as
see ref. 14c.
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