A multicomponent coupling reaction induced by insertion of arynes into the C=O bond of formamide

Article abstract of DOI:10.1002/anie.201102088

And aryne makes three: The three-component coupling of arynes, DMF, and active methylenes has provided an efficient method for the synthesis of 2H-chromene and coumarin derivatives (see scheme). The sequential multistep reactions are driven by the release of strain energy in the arynes and intermediates, and this finding was supported by thermodynamics. Copyright

Full text of DOI:10.1002/anie.201102088

Communications
DOI: 10.1002/anie.201102088
Aryne Chemistry
A Multicomponent Coupling Reaction Induced by Insertion of Arynes
=
into the C O Bond of Formamide**
Eito Yoshioka, Shigeru Kohtani, and Hideto Miyabe*
Aryne compounds are highly reactive intermediates that have
been widely used in organic synthesis.[1,2] In recent years,
studies on aryne-based reactions have achieved some re-
markable success, particularly in sequential reactions with a
nucleophile and an electrophile for the preparation of
complex ortho-disubstituted arene derivatives,[3–5] which are
difficult to synthesize by other methods. Most importantly,
these advances have shown that the insertion of aryne
compounds into various element–element s-bonds can be
achieved even under transition-metal-free conditions.[6,7] In
contrast, less is known about the corresponding p-bond
insertion,[8] except for the studies by Suzuki and co-workers
=
on the insertion into the C C bond to give stable benzocy-
clobutenes.[9] The synthetically useful insertion into the C O
=
bond was recently achieved by Yoshida et al.[10]
In general, the diversity observed in the reaction of arynes
[11]
=
Scheme 1. Insertion of aryne compounds into the C O bond of an
À
with amides is limited to N C s-bond insertion. Recently,
amide compounds. EWG=electron-withdrawing group.
our research group reported the efficient insertion into the
=
C O p-bond of sterically less-hindered formamide com-
pounds and the subsequent trapping process of the inter-
mediates with dialkylzinc reagents.[12,13] Herein, we report a
three-component coupling reaction leading to the cyclic
products 3 and 4 through the insertion into a p-bond of
N,N-dimethylformamide (DMF; Scheme 1). In this manner,
the active methylenes 1 were employed as a second nucleo-
phile for trapping the unstable intermediates A or B.
However, it is important to notice that the active methylenes
1 have an excellent reactivity toward aryne compounds. The
research groups of Stoltz[14] as well as Yoshida and Kunai[15]
Our experiments began with the investigation of three-
component coupling reaction of an aryne precursor 5, DMF,
and acetylacetone 6 (Table 1).[17] The competitive insertion of
the aryne compound into 6 to give the undesired product 8
was suppressed when DMF was employed as a solvent. In the
Table 1: Three-component coupling reaction using acetylacetone 6.[a]
À
independently reported that the insertion into the C C s-
bond of 1 leads to ortho-disubstituted arenes 2 and proceeds
with good chemical efficiency by use of b-keto ester and a-
cyanocarbonyl compounds, and so on.[16] Therefore, the key
requirement for the present cascade sequence is assumed to
be the control of two competitive insertions between DMF
and active methylenes 1 and the sufficient reactivity of active
methylenes toward intermediates A or B.
Entry
Reagent[b]
Acetylacetone 6 [equiv]
Yield [%][c]
7
8
1[d]
2[d]
3[d]
4[d]
5[d]
6[e]
7[f]
TBAF
TBAF
TBAF
CsF
TBAHF2
TBAF
TBAF
1.05
1.5
2.0
1.5
1.5
1.5
1.5
83
86
85
65
77
84
74
trace
3
3
6
[*] Dr. E. Yoshioka, Dr. S. Kohtani, Prof. H. Miyabe
School of Pharmacy
Hyogo University of Health Sciences
1-3-6, Minatojima, Chuo-ku, Kobe, 650-8530 (Japan)
Fax: (+81)78-304-2794
6
trace
E-mail: miyabe@huhs.ac.jp
4[g]
[**] This work was supported by a Grant-in-Aid for Scientific Research
(C; to H.M. and S.K.) and for Young Scientists (B; to E.Y.) from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan.
[a] Reactions were carried out in DMF at RT for 3 h. [b] 3.0 equivalents of
the fluoride ion source was employed. [c] Yield of isolated product.
[d] 0.1m solution of 5. [e] 0.033m solution of 5. [f] 0.33m solution of 5.
[g] A small amount of a different adduct was observed. Tf=trifluorome-
thanesulfonyl, TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102088.
6638
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Angew. Chem. Int. Ed. 2011, 50, 6638 –6642

presence of anhydrous TBAF (tetra-n-butylammonium fluo-
ride), treatment of triflate 5 with 6 in DMF predominantly
gave the desired 2H-chromene 7 (Table 1, entries 1–3). The
2H-chromene 7 was obtained in 86% yield by using
1.5 equivalents of 6 (Table 1, entry 2). The replacement of
anhydrous TBAF with CsF or tetrabutylammonium bifluor-
ide (TBAHF2) led to a decrease in the chemical yields
(Table 1, entries 4 and 5). The concentration of the reaction
was adjusted and 0.1m solution of 5 gave the best result
=
(Table 1, entries 2, 6, and 7). The insertion into the C O p-
Scheme 3. Reaction pathway.
bond proceeded with excellent regioselectivity without the
formation of regioisomers.[18,19]
Several aryne precursors were next examined (Scheme 2).
A good yield was obtained in the reaction of simple triflate 9
with 6. Having a substituent on the aryne compound had an
To gain further insight into the feasibility of a path b, the
reactions of salicylaldehyde derivatives 18–20 with 6 were
evaluated under similar reaction conditions (Scheme 4). The
Scheme 4. Reaction of salicylaldehyde derivatives with 6.
three-component coupling reaction using DMF was usually
performed over 3 hours (Table 1 and Scheme 2). Although
the prolonged reaction of 18 with 6 led to the formation of 7, a
significant amount of starting material was recovered after
3 hours. In the case of 19 and 20, sufficient conversion was not
observed even after 48 hours. These experimental outcomes
support our proposal that path a should be the major pathway.
Further investigations using several ketones 21–24 were
performed (Table 2). In the cases of 21 and 22 the reaction
rates were lower; thus, all reaction times were changed to
12 hours. Under the optimized reaction conditions, the bulky
1,3-diketone 21 bearing two phenyl groups showed good
reactivity (Table 2, entry 1). The acetone 22 having an a-CF3
group also acted as a nucleophile and trapped the unstable
intermediates to give the corresponding product 26 in 40%
yield (Table 2, entry 2), even though salicylaldehyde 18 was
also obtained by hydrolysis of the intermediates. The cyclic
1,3-diketones produced the tricyclic compounds, thereby
allowing facile incorporation of structural variety (Table 2,
entries 3 and 4). In particular, the three-component coupling
reaction with 23 proceeded with good chemical efficiency, and
produced 27 in 83% yield (Table 2, entry 3). In the case of
unsymmetrical diketone 24, tricyclic compound 28 was
obtained as the major regioisomer (Table 2, entry 4).
Scheme 2. Reaction of several aryne compounds with DMF and
acetylacetone 6.
impact on regioselectivity, with 4-methoxytriflate 11 leading
to regioisomers 12 and 13 in a 6:5 ratio (on the basis of
1H NMR analysis). This observation indicated the formation
of an aryne compound as an intermediate. Triflate 14 worked
well and afforded the 2H-chromene 15. This result indicates
that the nucleophilicity of the carbonyl oxygen atom of DMF
was sufficient to bring about insertion of an aryne compound
bearing two methoxy groups. In the case of triflate 16, the
three-component coupling product 17 was isolated in 66%
yield, and was accompanied by the competitive formation of
the thia-Fries rearrangement product in 9% yield.[20]
We consider that the electrophilicity of the four-mem-
bered intermediate A would be increased by strain energy.
Therefore, we propose a pathway involving the addition of an
enolate anion to unstable intermediates A or B and the
elimination of dimethylamine (path a in Scheme 3). However,
the route via salicylaldehyde C, generated by the hydrolysis of
A or B, cannot be excluded even under the careful anhydrous
reaction conditions (path b).
Next, we directed our attention to the investigation of b-
keto esters as a second nucleophile to trap the unstable
intermediates A or B (Table 3).[21] As expected, coumarin
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Table 2: Reaction of 5 and DMF with ketones 21–24.[a]
Entry Ketone (equiv)
Product (yield [%])[b]
1
21 (1.5)
25 (79)
2
3
4
22 (1.5)
23 (1.0)
24 (1.0)
26 (40)[c]
27 (83)
28 (56)
Scheme 5. Multicomponent coupling reaction.
[a] Reactions were carried out in DMF in the presence of anhydrous TBAF
(3.0 equiv) at RT for 12 h. [b] Yield of isolated product. [c] Salicylaldehyde
18 was obtained in 35% yield.
40 in 86% yield. Similarly, the reaction of 5 gave 41. This
À
transformation involves the formation of three C C and two
À
C O bonds. In comparison with a previously reported
method,[23] a favorable experimental feature of our method
is that the reaction proceeds under neutral conditions at room
temperature. Moreover, our method has enabled the new
four-component coupling reaction using two different 1,3-
diketones in a one-pot procedure, which readily gave the
xanthene derivative 42.
derivative 34 was synthesized in 77% yield by employing b-
keto ester 29 (Table 3, entry 1). b-Keto ester 30 bearing a
phenyl group worked well (Table 3, entry 2). A high chemical
Table 3: Reaction of 5 and DMF with esters 29–33.[a]
The multistep sequential reaction (Step A1 and Step A3)
is obviously driven by high reactivity related to the strain
energy of reactants (Scheme 6). The thermodynamic data,
obtained by an ab initio molecular orbital calculation, indi-
cate that Step A1 is remarkably exothermic (DH =
À177 kJmolÀ1) mainly as a result of the release of the strain
energy of aryne D.[24] This enthalpy change sufficiently
overcomes the entropy loss of the bimolecular coupling
(TDS = À71 kJmolÀ1). In total, the changes in Gibbs free
energy of all steps mean that this sequential reaction is
thermodynamically favorable (DG < 0 kJmolÀ1). On the
Entry
b-Keto ester (equiv)
Product (yield [%])[b]
1
29 (1.5)
34 (77)
2
3
4
5
30 (1.5)
31 (1.5)
32 (1.5)
33 (1.5)
35 (83)
36 (86)
37 (27)
+ 5 (40)
38 (56)
[a] Reactions were carried out in DMF at RT for 12 h. [b] Yield of isolated
product.
yield was also observed in the reaction using diethyl malonate
31 (Table 3, entry 3). The reaction of ester 32 having a nitro
group proceeded, albeit with a relatively lower yield (Table 3,
entry 4). Coumarin derivative 38 was isolated in 56% yield
even when b-keto ester 33, having a bulky adamantyl group,
was employed (Table 3, entry 5).
Our reaction was successfully applied to the convenient
synthesis of a neuropeptide Y Y5 receptor antagonist, which
was developed by Merck-Banyu researchers (Scheme 5).[22] In
the presence of anhydrous TBAF, treatment of triflate 9 with
dimedone 39 (2.5 equiv) in DMF gave the desired antagonist
Scheme 6. Change in Gibbs free energy, enthalpy, and entropy at
325.15 K.
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other hand, Step B1 (also see: path b in Scheme 3) from
salicylaldehyde 18 is not favored because of thermodynamic
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In conclusion, we have developed the multicomponent
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into DMF and subsequent trapping with active methylenes.
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Experimental Section
General Procedure for the reaction of triflates, DMF, and acetylace-
tone 6: Triflate (0.40 mmol) in DMF (1.0 mL) was added to a solution
of anhydrous TBAF (314 mg, 1.2 mmol), acetylacetone 6 (62 mL,
0.60 mmol) in DMF (3.0 mL) under argon at RT. After stirring at RT
for 3 h, silica gel (1.0 g) was added to the reaction mixture, and was
subsequently concentrated under reduced pressure. Purification of
the residue by flash column chromatography on silica gel (AcOEt/
hexanes = 1:8–1:0 with 2% CH2Cl2) afforded the corresponding
product.
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Received: March 24, 2011
Published online: May 27, 2011
Keywords: 2H-chromenes · arynes · coumarins ·
.
insertion reaction · synthetic methods
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in the Supporting Information.
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