Direct β-acylation of 2-arylidene-1,3-indandiones with acyl chlorides catalyzed by organophosphanes

Article abstract of DOI:10.1039/c3cc45201h

We have developed an organophosphane-catalyzed direct β-acylation of a series of conjugated systems bearing ketone, amide and ester functionalities using acyl chlorides as trapping reagents. A wide variety of highly functional ketone derivatives were gene

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Direct β-Acylation of 2-Arylidene-1,3-indandiones with Acyl Chlorides
Catalyzed by Organophosphanes †
Chia-Jui Lee,a Chia-Ning Sheu, a Cheng-Che Tsai, a Zong-Ze Wu, a and Wenwei Lin*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
organophosphane as the organocatalyst.
We have developed an organophosphane-catalyzed direct β-
acylation on a series of conjugated systems bearing ketone,
amide and ester funcitonalities using acyl chlorides as
trapping reagents. A wide variety of highly functional ketone
50
10 derivatives were generated efficiently in very mild condition
with high yields according to our protocol. Our adducts can
even be utilized as important building blocks for the synthesis
of functional tri/tetracyclic pyridazine derivatives.
55
60
The exploration of direct transformation of C-H bonds of
15 electron-deficient alkenes into C-C bonds attracts chemists much
attention because it is considered as a very challenging task and
has many benefits in organic synthesis.1 A lot of efforts have
been taken to develop efficient methods for generation of C-C
bonds (sp2-sp2 or sp2-sp3) using organometallic reagents2,3a or
20 even utilizing transition-metal catalyzed coupling reactions2,3b,3c
with potential electrophiles. Among all the developed protocols,
organozinc reagents turned out to be the most practical one with
high functional-group tolerance such as ketone or aldehyde
functionalities.3a However, the activation of nucleophiles as
25 organometallic species (path a) or electrophiles with an iodo- or
bromo- substitution (path b) is normally required, which may
further limit the substrate scope when sensitive functional groups
are present (equation 1, Scheme 1).2-3 Recently, direct oxidative
acylation of aryl-substituted olefins4, arenes5, or heteroarenes6
30 with aromatic aldehydes was demonstrated as an interesting
approach to install ketone functionality. However the extension
or study of this similar concept with electrophilic alkenes is still
unrevealed and difficult probably due to the electron-deficient
properties of olefins. The Morita-Baylis-Hillman reaction, which
35 is one of the most powerful methods for C-C bond formation, has
many important applications in synthetic chemistry (equation 2).7-
Scheme 1 Functionalization of electrophilic alkenes.
65
70
Scheme 2 β-Acylation of electrophilic alkenes 6-10: synthesis of 1-5.
At first, 2-(4-bromobenzylidene)-1,3-indandione (6a) and
75 benzoyl chloride (11a, 1.2 equiv) were selected as testing
substrates with different nucleophilic organocatalysts in the
presence of Et3N (1.3 equiv) in THF (Table 1). 1,4-
Diazabicyclo[2.2.0]octane
(DABCO)
and
1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), which are commonly
80 used as nucleophilic catalysts, failed to catalyze our designed
reaction (entries 1 and 2). We then turned our attention to use
organophosphanes as catalysts. Triphenylphosphine also failed to
promote the reaction even in 20 mol% catalytic loading (entry 3).
When an organophosphane (15 mol%) with stronger
85 nucleophilicity, such as Bu3P, Et3P, or iBu3P, was employed as
the catalyst, the expected adduct 1aa was provided within 1 h in
40%, 85%, or 78% yield, respectively (entries 4-6). However, a
bulky trialkyl organophosphane, such as Cy3P, did not
successfully catalyze the reaction (entry 7). To our delight,
90 MePPh2 (10 mol%) showed a very high catalytic ability for our
expected reaction, and the desired adduct 1aa was provided in
98% yield within 1 h (entries 9-10). Surprisingly, only the
corresponding phosphorus zwitterion 12a instead of 1aa was
afforded when 1.2 equiv of Bu3P was used (entry 11 vs entry 4).
95 This phenomenon was not observed in case of MePPh2 (1.2
equiv), and the reaction of 6a and 11a in the presence of Et3N
proceeded smoothly at room temperature within 1 h to furnish
1aa in 95% yield (entry 12).10
9
It allows direct functionalization on α-position of α,β-
unsaturated ketones or esters with different electrophiles such as
aldehydes and imines, thus making synthesis shorter and more
40 efficient.7-9 To our surprise, it is still impossible to directly install
an acyl group at β-position of an electrophilic olefin with the
retention of its original functionalities. Herein, we report the
preparation of highly conjugated ketone derivatives 1-5 starting
from α,β-unsaturated ketone, ester, or amide derivatives 6-10 and
45 acyl chlorides 11 catalyzed by organophosphane in the presence
of Et3N via direct β-acylation (Scheme 2). To the best of our
knowledge, it is the first time to directly install a ketone
functionality at β-position of electrophilic olefins using an
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O
O
O
O
O
MePPh2 (10 mol%)
R2COCl 11 (1.2 equiv)
R2
Table 1 Optimization of reaction conditions for the synthesis of 1aa a
H
O
R1
O
O
R1
Cat.
(15 mol%)
Et3N (1.3 equiv)
THF, RT
H
Ph
PhCOCl (11a, 1.2 equiv)
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DOI:110.1039/C3CC45201H
6
Et3N (1.3 equiv)
THF, RT
O
O
Entry
R1
R2
Time (h)
1 (%)b
Br
Br
6a
1aa
1
p-BrPh 6a
Ph 11a
o-ClPh 11b
m-ClPh 11c
p-ClPh 11d
o-BrPh 11e
p-BrPh 11f
p-MeOPh 11g
2-Furyl 11h
2-Thienyl 11i
iPr 11j
2
1aa, 98
Entry
Cat.
Time (h)
Yield of 1aa (%)b
2
6a
1
1ab, 97
1ac, 98
1c
2c
3c
4
DABCO
DBU
1 (24)d
1 (24)d
1 (24)d
No reaction
No reaction
No reaction
40
3
6a
0.5
0.5
0.5
0.5
7.5
3
4
6a
1ad, 93
1ae, 97
Ph3P
5
6a
Bu3P
1
6
6a
1af, 97
5
Et3P
1
85
7
8c
6a
1ag, 97
1ah, 71 (90)d
6
iBu3P
Cy3P
1 (2)d
78 (87)e
No reaction
75 (90)e
99
6a
7
1
9
6a
5
1ai, 87
8
EtPPh2
MePPh2
MePPh2
Bu3P
1 (2)d
10e
11e
12e
13
6a
1
1aj, 79
9
1
6a
cHexyl 11k
Nonanyl 11l
CF3f 11m
11a
1
1ak, 79
1al, 57
10f
11h
12h
1
98g
0i
1 (12)d
6a
0.5
10 min
1
6a
1am, 80
1ba, 92g
1ca, 75 (90)d
1da, 97
1ea, 97
MePPh2
1
95
aReactions were performed with 6a (0.3 mmol) in anhydrous THF (1.5 mL) under
nitrogen. bDetermined by 1H NMR analysis of the crude reaction mixture using
Ph3CH as an internal standard. c20 mol% of catalyst was used. dThe reaction time
14
15
16
17
18
19
20
21c
22c
23c
24c
25
Ph 6b
m-NO2Ph 6c
p-NO2Ph 6d
p-CHOPh 6e
p-CF3Ph 6f
p-CNPh 6g
m-FPh 6h
p-MePh 6i
p-MeOPh 6j
2-Furyl 6k
2-Thienyl 6l
3-Pyridinyl 6m
11a
3
1
f
11a
5 was prolonged to 2, 12 or 24 h. eThe NMR yield was investigated within 2 h. 10
mol% of MePPh2 was used. gIsolated yield. h1.2 equivalent of Bu3P or MePPh2 was
used. iOnly the corresponding phosphorus zwitterion 12a (98% yield) resulting from
6a and Bu3P was obtained.
11a
0.5
1
11a
1fa, 97
11a
0.5
1
1ga, 99
The broad reaction scope of our optimized protocol for
10 substrates 6 with 11 is demonstrated in Table 2. It shows that,
under our catalytic reaction condition (10 mol% of MePPh2),
direct β-acylation of 6 with various acyl chlorides 11 was realized
successfully (Table 2). The reaction of 6a and aryl-substituted
acyl chlorides 11a-f (1.2 equiv) in the presence of MePPh2 (10
15 mol%) and Et3N (1.3 equiv) took place efficiently at room
temperature (0.5 to 2 h), leading to the corresponding acylated
adduct 1aa-1af in excellent yields (entries 1-6). An aryl-
subsitituted acyl chloride with an electron-donating group, such
as 11g, is less reactive than 11a-f towards 6a according to the
20 same protocol, providing the expected adduct 1ag in 97% yield
(7.5 h; entry 7). Heteroaryl-substituted acyl chlorides, such as
11h and 11i, also worked nicely with 6a within 3 or 5 h to furnish
the corresponding products 1ah and 1ai in good yields (entries 8
and 9). It is necessary to increase the catalyst loading of MePPh2
25 (50 mol%) when alkyl-substituted acyl chlorides such as 11j, 11k,
and 11l were employed, and the corresponding adducts 1aj, 1ak
and 1al were afforded in good to high yields within 0.5 or 1 h
(entries 10-12). Interestingly, trifluoroacetic anhydride (11m) was
very reactive towards 6a in the presence of 10 mol% of MePPh2
30 and Et3N (1.3 equiv), and the reaction proceeded successfully and
efficiently to give the corresponding adduct 1am (80%, 10 min;
entry 13). Not only a wide range of acyl chlorides 11a-m can be
applied with 6a, but also other different β-aryl or β-heteroaryl
substituted Michael acceptors 6b-m can be utilized successfully
35 according to the same protocol (entries 14-25). All the
corresponding acylated adducts 1ba-1ha starting from 6b-h were
generated within 0.5 to 3 h in good to excellent yields, and
remarkably an aldehyde funcitonality can be tolerated
successfully in case of 1ea (entries 14-20). When less reactive
40 substrates, such as 6i-l, were treated with 11a, 15 mol% MePPh2
was necessary to efficiently promote our designed reactions
(entries 21-24).
11a
1ha, 91
1ia, 99
11a
2
11a
3
1ja, 94
11a
7
1ka, 33 (71)d
1la, 53 (92)d
1ma, 94
11a
7
11a
1
aReactions were performed with 6 (0.3 mmol) in anhydrous THF (1.5 mL) under
45 nitrogen. bIsolated yield. c15 mol% of MePPh2 was used. dRecovered yield. e50
mol% of MePPh2 was used. fTrifluoroacetic anhydride (TFAA) was used. gThe
structure of 1ba was determined by X-ray analysis.11
Fluorinated organic compounds are important substrates, and
therefore many related studies as well as development of new
50 synthetic methods are growing up rapidly.12 After our careful
optimization of reaction conditions, EtPPh2 was the best catalyst
for the reactions of 6 and TFAA, and all the corresponding
adducts 1 with the trifluoroacetyl group were provided very
efficiently in good to excellent yields (Scheme 3).
55
60 Scheme 3 Direct β-installation of the trifluoroacetyl group of 6.
Furthermore, our developed protocol allowed direct double β-
acylation of 6. A three-component reaction of 6a (2.1 equiv) and
11n (0.3 mmol) in the presence of MePPh2 (30 mol%) and Et3N
(2.2 equiv) underwent smoothly within 7 h at room temperature,
65 furnishing a complex molecule 1an in 74% yield (Scheme 4).
70
75 Scheme 4 Synthesis of 1an via a three-component reaction.
Table 2 Organocatalytic synthesis of 1 via direct β-acylation.a
2
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According to experimental results10 (Tables 1-2, Schemes 3-4),
a plausible reaction mechanism was proposed (Scheme 5). First,
react with hydrazine hydrate for a double condensation reaction.
The reactions proceeded smoothly within 10 min at ambient
temperature, and the resulting pyridazinDesOI1: 610w.10eVr3ei9e/woCbA3trCatCiicn4le5eOd2n0l1iinnHe
the Michael addition of organophosphane (R3P) towards 6 took
place, giving rise to the corresponding zwitterion 12. The 60 moderate to high yield (Scheme 7). Other adducts such as 1aa
5
intermediate 12 was acylated with an acyl chloride 11, leading to
the formation of 13. Then deprotonation of 13 by Et3N happened,
and the resulting ylide 14 underwent an intramolecular 1,2-
addition reaction towards the ester group followed by elimination
of enolate and then regeneration of R3P, affording the
and 3a were also employed to provide 1711 and 1811 within 1.5 h
to 2 h in high yields. It is worth mentioning that pyridazines
constitute important structural motif representing many
biologically active compounds.14
In conclusion, we have demonstrated a novel strategy for the
metal-free, catalytic direct β-acylation on the simple conjugated
65
10 corresponding acylated product 1.
systems via organophosphanes.
A diverse range of α,β-
unsaturated ketone, ester or amide derivatives have been
successfully applied, which provided an array of corresponding
70 β-acylated products in good to excellent yields. With this
interesting result, we developed very convenient two-step
synthesis for the drug potential materials, pyridazines. Further
extensions of this work are currently underway in our laboratories.
The authors thank the National Science Council of the Republic of
75 China (NSC 101-2113-M-003-001-MY3) and National Taiwan Normal
University (NTNU 100-D-06) for financial support.
15
Scheme 5 Plausible reaction mechanism for formation of 6.
Notes and references
20
Remarkably, our synthetic protocol can be applied in the
preparation of β-acylated adducts 2-5 successfully in our
preliminary studies (Scheme 6). After careful optimization (see
ESI), Bu3P was chosen as the organocatalyst (10 or 20 mol%).
Aryl and cyclohexyl acyl chlorides 11 were reacted efficiently
a Department of Chemsitry, National Taiwan Normal University, 88, Sec.
4, Tingchow Road, Taipei 11677, Taiwan, R.O.C. Fax: (+886)
80 229324249; E-mail: wenweilin@ntnu.edu.tw
† Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/b000000x/
25 with 3-arylidene oxindoles 7a-b to afford the corresponding
products 2a-d in 56-94% yields (0.5-3.5 h). Acenaphthyl derived
arylidene analogue 8a also worked very well according to our
protocol to provide 3a in 80% yield (50 min). Interestingly,
acenaphthyl alkylidene containing an ester group 8b was well
30 tolerated too, affording the product 3b in 71% yield (0.5 h). The
substrate scope was further extended by using 2-indanone or 2-
coumaranone derived arylidene (9 or 10) to furnish the
corresponding product 4 or 5, respectively (71% or 83%; 3 h). It
is interesting that, in the case of 10, both geometrical isomers of
35 the products (Z)-5a (67%) and (E)-5a (16%) were obtained.
1
2
3
For the selected examples using quinone derivatives as substrates : (a) E. M.
Beccalli, G. Broggini, M. Martinelli and S. Sottocornola, Chem. Rev. 2007, 107,
5318; (b) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M. Del Bel
and P. S. Baran, J. Am. Chem. Soc. 2011, 133, 3292.
(a) P. Knochel in Handbook of Functionalized Organometallics, Wiley-VCH,
New York, 2005; (b) C. C. C. J. Seechurn, C. M. O. Kitching, T. J. Colacot and
V. Snieckus, Angew. Chem., Int. Ed. 2012, 51, 5062; (c) R. Jana, T. P. Pathak
and M. S. Sigman, Chem. Rev. 2011, 111, 1417.
85
90
95
(a) C. Sämann, M. A. Schade, S. Yamada and Knochel, P. Angew. Chem., Int.
Ed. 2013, DOI: 10.1002/anie.201302058; (b) A. M. Echavarren, M. Perez, A.
M. Castano and J. M. Cuerva, J. Org. Chem. 1994, 59, 4179; (c) A. Capperucci,
A. Degl'Innocenti, P. Dondoli, T. Nocentini, G. Reginato and A. Ricci,
Tetrahedron 2001, 57, 6267; for a reported example (FG = CO2Me, R2 = PhCO;
12% yield) via a palladium-catalyzed reaction (Heck type) starting from an
electrophilic alkene (FG
= CO2Me), PhCOCl, and Et3N, see: (d) C.-M.
Andersson and A. Hallberg, J. Org. Chem. 1988, 53, 4257.
J. Wang, C. Liu, J. Yuan and A. Lei, Angew. Chem., Int. Ed. 2013, 52, 2256.
Z. Shi and F. Glorius, Chem. Sci. 2013, 4, 829
4
100 5
6
7
K. Matcha and A. P. Antonchick, Angew. Chem., Int. Ed. 2013, 52, 2082.
(a) Y. Wei and M. Shi, Chem. Rev. 2013, DOI: 10.1021/cr300192h; (b) D.
Basavaiah and G. Veeraraghavaiah, Chem. Soc. Rev. 2012, 41, 68; for acylation
of alcohol: (c) C. E. Müller, P. R. Schreiner, Angew. Chem. Int. Ed. 2011, 50,
6012.
40
105
8
V. Declerck, J. Martinez and F. Lamaty, Chem. Rev. 2009, 109, 1.
Z. Shi, P. Yu, T.-P. Loh and G. Zhong, Angew. Chem., Int. Ed. 2012, 51, 7825.
9
45 Scheme 6 Synthesis of 2-5 via direct β-acylation (see ESI).
10 More detailed information about mechanism studies including controlled
experiments was provided in the ESI.
N
O
N
O
O
cat. EtPPh2
TFAA
CF3
H
R
CF
3 NH2NH2 H2O
110 11 The structures of 1ba, 2a, 3a, 4, 5, 17 and 18 were confirmed by X-ray analysis
(CCDC 935870, 935871, 935872, 935873, 937197, 935874, and 935875).
12 For selected examples, see: (a) M. Schlosser, Angew. Chem., Int. Ed. 2006, 45,
5432; (b) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320.
MeOH
RT, 10 min
R
Et3N, THF
RT, 10 min
R
O
O
O
(Scheme 3)
16
6
1
N
50
N
N
N
O
16a (R = p-BrC6H4): 78%
N
Ph
N
O
Ph
16b (R = p-NO2C6H4): 76%
16c (R = p-CNC6H4): 75%
16d (R = p-CF3C6H4): 81%
16e (R = m-FC6H4): 67%
16f (R = m-NO2C6H4): 79%
CF3
115 13 (a) T.-T. Kao, S.-e. Syu, Y.-W. Jhang and W. Lin, Org. Lett. 2010, 12, 3066; (b)
K.-W. Chen, S.-e. Syu, Y.-J. Jang and W. Lin, Org. Biomol. Chem. 2011, 9,
2098.
R
NO2
Br
17: 95% (1.5 h)
18: 82% (2 h)
Scheme 7 A two-step synthesis of heterocycles 16-18.
14 (a) J. Reniers, C. Meinguet, L. Moineaux, B. Masereel, S. P. Vincent, R.
Frederick and J. Wouters, Eur. J. Med. Chem. 2011, 46, 6104; (b) R. Frédérick,
55
Next, the utility of the products 1 for further derivatization is
demonstrated. In this direction the products 1 were allowed to
120
W. Dumont, F. Ooms, L. Aschenbach, C. J. Van der Schyf, N. Castagnoli, J.
Wouters and A. Krief, J. Med. Chem. 2006, 49, 3743.
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