Sequential reaction of arynes via insertion into the π-bond of amides and trapping reaction with dialkylzincs

Article abstract of DOI:10.1021/ol100387h

Figure presented The sequential transformation of arynes into ortho-disubstituted arenes is achieved by a one-pot procedure using formamides and dialkylzincs. This reaction proceeded via a route involving the trapping reaction of the formal [2 + 2] cycloaddition adducts or quinone methides generated by the insertion of arynes into the C=O bond of amides.

Full text of DOI:10.1021/ol100387h

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1956-1959
Sequential Reaction of Arynes via
Insertion into the π-Bond of Amides
and Trapping Reaction with Dialkylzincs
Eito Yoshioka, Shigeru Kohtani, and Hideto Miyabe*
School of Pharmacy, Hyogo UniVersity of Health Sciences, Minatojima, Chuo-ku,
Kobe 650-8530, Japan
miyabe@huhs.ac.jp
Received February 15, 2010
ABSTRACT
The sequential transformation of arynes into ortho-disubstituted arenes is achieved by a one-pot procedure using formamides and dialkylzincs.
This reaction proceeded via a route involving the trapping reaction of the formal [2 + 2] cycloaddition adducts or quinone methides generated
by the insertion of arynes into the CdO bond of amides.
Arynes are highly strained and kinetically unstable interme-
diates that have received much attention as powerful elec-
trophiles in organic chemistry.1,2 In particular, the introduc-
tion of o-(trimethylsilyl)aryl triflates as mild aryne precursors
led to growing activity in this field,3 resulting in the
development of new aryne-based reactions for preparing
complex ortho-disubstituted arenes.4-10 In most cases, arynes
have been utilized in transition-metal-catalyzed reactions
involving cross-coupling processes.4,5 Recently, much effort
has been directed toward the transition-metal-free reactions,
which comprise the initial addition of nucleophiles to arynes
and the subsequent trapping step with electrophiles.6-8
(5) For selected examples of coupling reactions, see: (a) Yoshikawa,
E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173. (b) Jeganmohan,
M.; Cheng, C.-H. Org. Lett. 2004, 6, 2821. (c) Henderson, J. L.; Edwards,
A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006, 128, 7426. (d) Liu, Z.;
Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535. (e) Jayanth, T. T.;
Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46, 5921. (f) Xie, C.; Zhang,
Y.; Yang, Y. Chem. Commun. 2008, 4810. (g) Jeganmohan, M.; Bhuv-
aneswari, S.; Cheng, C.-H. Angew. Chem., Int. Ed. 2009, 48, 391. (h)
Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572.
For transition-metal-catalyzed insertion into the σ-bond, see: (i) Yoshida,
H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2003,
125, 6638. (j) Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem.,
Int. Ed. 2004, 43, 5052.
(1) For reviews, see: (a) Kessar, S. V. In ComprehensiVe Organic
Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol.
4, pp 483-515. (b) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901.
(c) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (d) Wenk, H. H.;
Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (e) Pen˜a,
D.; Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006, 45, 3579
.
(2) For some recent studies, see: (a) Dockendorff, C.; Sahli, S.; Olsen,
M.; Mihau, L.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028. (b) Asao,
N.; Sato, K. Org. Lett. 2006, 8, 5361. (c) Soorukram, D.; Qu, T.; Barrett,
A. G. M. Org. Lett. 2008, 10, 3833. (d) Ganta, A.; Snowden, T. S. Org.
Lett. 2008, 10, 5103. (e) Akai, S.; Ikawa, T.; Takayanagi, S.; Morikawa,
Y.; Mohri, S.; Tsubakiyama, M.; Egi, M.; Wada, Y.; Kita, Y. Angew. Chem.,
Int. Ed. 2008, 47, 7673. (f) Cant, A. A.; Bertrand, G. H. V.; Henderson,
(6) For some reactions of arynes with nucleophile followed by electro-
phile, see :(a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 3935. (b) Zhao, J.; Larock, R. C. Org. Lett. 2005,
7, 4273. (c) Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71,
4689. (d) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem.
Soc. 2006, 128, 11040. (e) Yoshida, H.; Morishita, T.; Fukushima, H.;
Ohshita, J.; Kunai, A. Org. Lett. 2007, 9, 3367. (f) Okuma, K.; Nojima,
A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009, 11, 169. (g) Cant, A. A.;
Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.; Greaney, M. F. Angew.
Chem., Int. Ed. 2009, 48, 5199. For some reactions involving the
nucleophilic addition and subsequent protonation, see: (h) Liu, Z.; Larock,
R. C. Org. Lett. 2004, 6, 99. (i) Jeganmohan, M.; Cheng, C.-H. Chem.
Commun. 2006, 2454. (j) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71,
4689. (k) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029. (l) Sha,
F.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458.
J. L.; Roberts, L.; Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199
.
(3) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(4) For selected examples of [2 + 2 + 2] cycloaddition, see: (a) Pen˜a,
D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew. Chem., Int.
Ed. 1998, 37, 2659. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am.
Chem. Soc. 1999, 121, 5827. (c) Sato, Y.; Tamura, T.; Mori, M. Angew.
Chem., Int. Ed. 2004, 43, 2436. (d) Qiu, Z.; Xie, Z. Angew. Chem., Int. Ed.
2009, 48, 5729. (e) Saito, N.; Shiotani, K.; Kinbara, A.; Sato, Y. Chem.
Commun. 2009, 4284
.
10.1021/ol100387h  2010 American Chemical Society
Published on Web 04/02/2010

[2 + 2] cycloaddition adducts, generated by the insertion of
arynes into the CdO bond, with organometallic reagents.
In this paper, we describe the sequential reaction involving
the insertion into the carbonyl group of amides and the
subsequent trapping process of the intermediates with di-
alkylzincs. In general, the [2 + 2] adducts containing
heteroatoms are considerably unstable due to strain energy.
Thus, the success of this sequential transformation reflects
the overall difference in the strain energy of arynes and the
four-membered intermediates.11e,f
Table 1. Reaction of Aryne Precursor 1 with DMFa
Figure 1. Insertion of arynes into the CdO bond of amides.
When nucleophile and electrophile belong to the same
molecule, however, most useful reactions are restricted to
insertion into the σ-bond (X-Y)7 and [2 + 3] cycloaddition8
(Figure 1). Little success was achieved in the insertion into
the π-bond (XdY) classified as [2 + 2] cycloaddition,9,10
except for Suzuki’s study on the insertion into the CdC bond
giving stable benzocyclobutenes.11 Thus, the insertion of
arynes into the carbon-heteroatom double bond is a chal-
lenging task. As the only example of the synthetically useful
insertion into the π-bond of carbonyl compounds, the 2:1
coupling reaction of arynes and aldehydes was recently
developed by Yoshida, Kunai, and others.12 Therefore, there
have been no reports on the trapping reaction of the formal
entry reagent (3.0 equiv) DMF (equiv) solvent yieldb (%)
1
2
3
4
5
TBAF·3H2O
TBAF
TBAF
TBAF
TBAF
3.0
3.0
3.0
3.0
3.0
CH3CN 31c
CH3CN 56
THF
46
CH2Cl2 43
CH3OH no reaction
CH3CN 70
6
TBAF
10
7
8
9
10
TBAF
CsF
TBAHF2
TBAT
DMF
DMF
DMF
DMF
84
72
67
31
a Reactions were carried out at rt for 3 h. b Isolated yield. c The starting
material 1 was recovered in 31% yield.
(7) For selected examples of insertion into the σ-bond, see: (a) Yoshida,
H.; Terayama, T.; Ohshita, J.; Kunai, A. Chem. Commun. 2004, 1980. (b)
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340. (c)
Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2005,
46, 6729. (d) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc.
2006, 128, 11752. (e) Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3965. (f)
Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem. Commun. 2007,
2405. (g) Zhang, T.; Huang, X.; Xue, J.; Sun, S. Tetrahedron Lett. 2009,
50, 1290. (h) Stoltz, B. M.; Ebner, D.; Tambar, U. K.; Storgaard, M.; Ide,
N. D. J. A. Org. Synth. 2009, 86, 161.
As a preliminary experiment, we selected amides as a
carbonyl compound10 and first probed the utility of N,N-
dimethylformamide (DMF) without organometallic reagents
(Table 1). 3-Methoxy-2-(trimethylsilyl)phenyl triflate 1 was
employed as an aryne precursor, since the electronic effect of
polarized aryne having an electron-donating group was expected
to show excellent reactivity and regioselectivity toward the
CdO bond. All reactions of triflate 1 with DMF were evaluated
at room temperature for 3 h in the presence of several fluoride
ion sources. Initially, we allowed triflate 1 to react with 3 equiv
of DMF and 3 equiv of TBAF·3H2O in CH3CN. The desired
salicylaldehyde derivative 2 was obtained in 31% yield,
accompanied by 31% yield of the recovered starting material 1
(entry 1). The presence of water influenced the chemical
efficiency; thus, improvement in the chemical yield was
observed by changing TBAF·3H2O into anhydrous TBAF (entry
2). In regard to the solvent effect, the replacement of CH3CN
with THF or CH2Cl2 led to a decrease in the chemical yields
and the reaction in MeOH did not proceed effectively (entries
3-5). Increasing the amount of DMF improved the chemical
yields (entry 6). The chemical yield was increased into 84%
when DMF was used as a solvent (entry 7). Next, the effect of
fluoride ion sources was studied (entries 8-10). The good
chemical yields were also observed when CsF or tetrabutylam-
monium bifluoride (TBAHF2) was employed, although the use
of tetrabutylammonium difluorotriphenylsilicate (TBAT) was
(8) For selected examples of [3 + 2] cycloaddition reactions of arynes,
see: (a) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (b)
Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C. J. Org.
Chem. 2008, 73, 219. (c) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.;
Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525. (d) Dai, M.; Wang, Z.;
Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613. (e) Huang, X.; Zhang,
T. Tetrahedron Lett. 2009, 50, 208.
(9) For reports on insertion into the π-bond, see: (a) Gompper, R.; Kutter,
E.; Seybold, G. Chem. Ber. 1968, 101, 2340. (b) Heaney, H.; Jablonski,
J. M.; McCarty, C. T. J. Chem. Soc., Perkin Trans. 1 1972, 2903. (c)
Nakayama, J.; Yoshida, M.; Simamura, O. Chem. Lett. 1973, 451. (d)
Nakayama, J.; Midorikawa, H.; Yoshida, M. Bull. Chem. Soc. Jpn. 1975,
48, 1063. (e) Aly, A. A.; Mohamed, N. K. A. A.; Hassan, A. A.; Mourad,
A.-F. E. Tetrahedron 1999, 55, 1111. (f) Okuma, K.; Shiki, K.; Sonoda,
S.; Koga, Y.; Shioji, K.; Kitamura, T.; Fujiwara, Y.; Yokomori, Y. Bull.
Chem. Soc. Jpn. 2000, 73, 155. (g) Okuma, K.; Okada, A.; Koga, Y.;
Yokomori, Y. J. Am. Chem. Soc. 2001, 123, 7166.
(10) Yaroslavsky, S. Tetrahedron Lett. 1965, 6, 1503.
(11) (a) Hamura, T.; Ibusuki, Y.; Uekusa, H.; Matsumoto, T.; Suzuki,
K. J. Am. Chem. Soc. 2006, 128, 3534. (b) Hamura, T.; Ibusuki, Y.; Uekusa,
H.; Matsumoto, T.; Siegel, J. S.; Baldridge, K. K.; Suzuki, K. J. Am. Chem.
Soc. 2006, 128, 10032. (c) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki,
K. Angew. Chem., Int. Ed. 2006, 45, 6842. (d) Kraus, G. A.; Wu, T.
Tetrahedron 2010, 66, 569. For some examples of the reaction of
benzocyclobutenes, see: (e) Suzuki, T.; Hamura, T.; Suzuki, K. Angew.
Chem., Int. Ed. 2008, 47, 2248. (f) Feltenberger, J. B.; Hayashi, R.; Tang,
Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666.
(12) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai, A.
Org. Lett. 2004, 6, 4049.
Org. Lett., Vol. 12, No. 9, 2010
1957

less effective. It is also noteworthy that the high regioselectivity
was achieved due to the methoxy group and the formation of
regioisomer was not observed.
Table 2. Trapping Reaction Using Organometallic Reagentsa
Scheme 1. Reaction of Aryne Precursor 1 with DMA
a Reactions were carried out in DMF at rt. b Isolated yield. c The starting
material 1 was recovered in 16% yield. d A trace amount of 5a was obtained.
yield was obtained when CsF was employed as a fluoride ion
source (entry 2). Under the optimized conditions, Me2Zn and
Ph2Zn worked well, allowing facile incorporation of structural
variety (entries 3 and 4). In particular, the reaction using Ph2Zn
proceeded with excellent chemical efficiency to give the adduct
5c in 97% yield. In contrast, EtMgBr did not work (entry 5).
Dialkylzincs are known to be a radical initiator,15 and we also
studied the Et2Zn-induced radical reactions.16 To gain further
insight into the reaction mechanism, Et3B was tested as an ethyl
radical source under the similar reaction conditions (entry 6).
However, the addition of ethyl radical to the intermediate was
not observed as a major process; thus, the radical mechanism
would be excluded.
As a related study, in 1965, Yaroslavsky reported the
reaction of benzenediazonium chloride or benzenediazonium-
2-carboxylate with DMF giving low yields of salicylalde-
hyde.10 However, in general, the regiochemical course of
insertion into amides was limited to the insertion into the
N-C σ-bond, although the various reactions of arynes with
amides including sulfinamide, enamide, and urea have
recently been investigated.13 Therefore, the reaction of 1 was
next studied with the use of bulky N,N-dimethylacetamide
(DMA) as a solvent instead of DMF (Scheme 1). In marked
contrast to DMF, the competitive insertion into the N-C
bond of DMA was observed. In the presence of anhydrous
TBAF, treatment of 1 with DMA predominantly gave the
desired product 3 in 34% yield, accompanied by another
adduct 4 in 10% yield as a result of insertion into the N-C
σ-bond. Thus, the sterically less hindered formamides are
highly promising nucleophiles for the present reaction.14
With these results in mind, we next investigated the sequential
reaction involving the trapping process of an intermediate with
organometallic reagents (Table 2). The key issues of this
reaction are the sufficient nucleophilicity of carbonyl oxygen
atom toward arynes and the compatibility of carbonyl com-
pounds and organometallic reagents. Among several evaluated
reagents, dialkylzincs trapped an intermediate with high activity
to form the aminophenols 5a-c by a one-pot procedure. After
a solution of triflate 1 and anhydrous TBAF in DMF was stirred
at room temperature for 15 min, a solution of Et2Zn in hexane
(1.0 M) was added to the reaction mixture (entry 1). As
expected, the desired aminophenol 5a was obtained in 50%
yield after being stirred at room temperature for 12 h. Good
Figure 2. Reaction pathway.
Encouraged by the successful trapping reaction, we
calculated the stability of possible intermediates A-C (Figure
2).17 The calculation supports that the quinone methide E-
and Z-forms B and C would be thermodynamically the stable
intermediates. As a major reaction pathway, we assumed that
dialkylzincs added to not the four-membered intermediate
A but the intermediates B and C.
(13) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247. (b) Liu, Z.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112. (c) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 1558. (d) Allan, K. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2008, 130, 17270. (e) Pintori, D.; Greaney, M. F. Org. Lett.
2010, 12, 168.
(14) Reactions were tested by employing dimethyl carbonate and ethyl
formate instead of DMF as a carbonyl compound. However, the desired
ortho-disubstituted arenes were not obtained.
Further investigations using other formamides and aryne
precursors were performed (Scheme 2). At first, we allowed
1958
Org. Lett., Vol. 12, No. 9, 2010

The nucleophilicity of carbonyl oxygen atom of DMF toward
uncharged triple bond was sufficient to bring about insertion
of benzyne into the CdO bond to give the adduct 10 in 76%
yield. In contrast to triflate 1 having a methoxy group at
3-position, the use of triflate 11 having a methoxy group at
the 4-position led to a decrease in regioselectivity to give
the adducts 12a and 12b in a 5:4 ratio. In the case of triflate
13, the chemical yield of adduct 14 was decreased to 37%
because of the competitive formation of thia-Fries rearrange-
ment product 15.18
Scheme 2. Trapping Reaction Using Et2Zn
In summary, we have demonstrated that the sequential
transformation of arynes into ortho-disubstituted arenes is
achieved by one-pot procedure using formamides and di-
alkylzincs. This transformation proceeded smoothly via a
route involving the trapping reaction of quinone methide
intermediates, derived from the formal [2 + 2] cycloaddition
adducts, with dialkylzincs.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (C) (H.M.) and for
Young Scientists (B) (E.Y.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan and
Astellas Foundation for Research on Metabolic Disorders
(H.M.).
Supporting Information Available: Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra, and
calculation of intermediates. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL100387H
DMF-d7 to react with triflate 1 under similar reaction
conditions using CsF and Et2Zn. As expected, the deuterated
product 5a-d was isolated in 70% yield. The one-pot
procedure was improved for the reaction with 1-formylpi-
peridine 7 because this amide could not be used as a solvent.
The reaction of triflate 1 with 7 (10 equiv) was carried out
in CH3CN by using anhydrous TBAF to afford the desired
adduct 8 in 40%. To test the electronic effect around the
triple bond of arynes, the simple triflate 9 was next employed.
(15) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org.
Chem. 1999, 64, 9189. (b) Cougnon, F.; Feray, L.; Bazin, S.; Bertrand,
M. P. Tetrahedron. 2007, 63, 11959.
(16) (a) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J.
Org. Chem. 2000, 65, 176. (b) Miyabe, H.; Asada, R.; Takemoto, Y.
Tetrahedron. 2005, 61, 385.
(17) Details are provided in the Supporting Information. For this
calculation, the effect of Lewis acidic R2Zn was neglected.
(18) Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-
Jones, G. C.; Mun˜oz, M. P.; Shepperson, I. R. Angew. Chem., Int. Ed. 2008,
47, 5067.
Org. Lett., Vol. 12, No. 9, 2010
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