A brand-new Pd-mediated generation of benzyne and its [2+2+2] cycloaddition: δ-carbon elimination and concomitant decarboxylation

Article abstract of DOI:10.1016/j.tetlet.2008.09.017

We found a brand-new method for the generation of aryne from methyl 2-bromobenzoates via the Pd-mediated concomitant δ-carbon elimination and decarboxylation. The generated arynes underwent Pd-mediated [2+2+2] cycloaddition to give triphenylenes.

Full text of DOI:10.1016/j.tetlet.2008.09.017

Tetrahedron Letters 49 (2008) 6569–6572
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A brand-new Pd-mediated generation of benzyne and its [2+2+2] cycloaddition:
d-carbon elimination and concomitant decarboxylation
*
Hoo Sook Kim, Saravanan Gowrisankar, Eun Sun Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We found a brand-new method for the generation of aryne from methyl 2-bromobenzoates via the
Pd-mediated concomitant d-carbon elimination and decarboxylation. The generated arynes underwent
Pd-mediated [2+2+2] cycloaddition to give triphenylenes.
Received 19 August 2008
Revised 3 September 2008
Accepted 5 September 2008
Available online 8 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arynes
Palladium
d-Carbon elimination
Decarboxylation
Triphenylene
Recently, we published the synthesis of cyclopropane-fused
dihydrobenzofuran derivatives under Pd-mediated Heck type reac-
tion conditions of 2-bromophenol-attached Baylis–Hillman
adducts (Scheme 1).1 In the reaction, Pd-mediated activation of
C(sp3)–H bond occurred, and the resulting cyclopropane-fused
compound 2 was produced in moderate yield.1 3-Benzylidene-
2,3-dihydrobenzofuran (3) was also isolated together in the reac-
tion, albeit in low yield.1 The mechanism for the formation of com-
panying simultaneous decarboxylation has not been reported, to
the best of our knowledge.
Recently, Pd-catalyzed [2+2+2] cycloadditions of arynes for the
preparation of polycyclic aromatic hydrocarbons (PAHs) have been
developed and studied extensively.3,4 The corresponding o-tri-
methylsilylaryl triflates were used as adequate aryne precur-
sors,3–5 which generate arynes by the action of CsF (Kobayashi
method).5 Cyclotrimerization reactions of arynes were carried out
directly from the o-trimethylsilylaryl triflates, the precursor of
arynes, in the presence of CsF/Pd(0) at rt.3–5
pound
3 could be thought as d-carbon elimination and
concomitant elimination of CO2 as in Scheme 1. Palladium-medi-
ated transformations involving b-carbon elimination are well
reported in the literature,2 however, d-carbon elimination accom-
During the course of our studies,1 we imagined the possibility of
generation of benzyne from methyl 2-bromobenzoate (4a) via
COOMe
Pd(0)
Ph
Ph
COOMe
H
+
O
Ref. 1
O
O
1
2 (77%)
3 (low yield)
Br
Me
O
BrPd
O
Ph
δ-Carbon elimination and
concomitant decarboxylation
O
Scheme 1.
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J. N. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.017

6570
H. S. Kim et al. / Tetrahedron Letters 49 (2008) 6569–6572
O
O
CH3
CH3
[2+2+2]
Pd(0)
- CH3PdBr
- CO2
O
O
Pd
Br
Br
(II)
5a
(I)
4a
- CO2
- Pd(0)
O
O
O
K
H
- KBr
Pd(0)
O
O
O
Pd
L
(IV)
K2CO3
Pd
Br
(III)
Br
L
4b
Scheme 2. Postulated reaction mechanism.
Table 1
Optimization of conditions for the conversion of 4a–5a
Entry
Conditionsa
Time (min)
Yield(%)
1
2
3
4
5
Pd(OAc)2 (10 mol%), K2CO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 110°C
Pd(OAc)2 (5 mol%), PPh3 (0.1 equiv),K2 CO3 (2.0 equiv), TBAB ( 1.0 equiv), DMF, 110°C
Pd(OAc)2 (5 mol%), PPh3 (0.1 equiv),K2 CO3 (2.0 equiv), D MF, 110°C
90
60
240
210
180
52
45
23
19
18
Pd(OAc)2 (5 mol%), PPh3 (0.1 equiv),K2 CO3 (2.0 equiv),TBAB (1.0 equiv),KI (2.0 equiv),DMF,110°C
Pd(OAc)2 (5 mol%), PPh3 (0.1 equiv),K2 CO (2.0 equiv),TPAI (1.0 equiv),DMF,110
°C
3
6
7
Pd(OAc)2 (5 mol%), PPh3 (0.1 equiv) ,K2 CO3 (2.0 equiv) ,T BAC (1.0 equiv), DMF, 110 °C6
0
57b
9
Pd(OAc)2 (10mol%) , PPh3 (0.1 equiv),K2 CO3 (2.0 equiv),KF(1.0 equiv),DMF,110°C
180
a
Dimerized compound 6a was isolated in 8%. Compound 6a was also observed in other entries in variable amounts.
TBAB is tetrabutylammonium bromide; TPAI is tetrapropylammonium iodide; TBAC is tetrabutylammonium chloride.
b
Table 2
Relative reactivity of various 2-halobenzoic acid derivatives
R
Pd(OAc)2 (5 mol%), PPh3 (10 mol%)
R
X
K2CO3 (2.0 equiv), TBAC (1.0 equiv)
DMF, 110 oC
R
4
5a
6
Entry
1a
Substrate
COOMe
Time(min)
60
4 (%)
5a (%)
6 (%)
nd
nd
nd
15
nd
nd
57
27
44
nd
21
25
6a (8)
Br
COOH
4a
2
30
nd
Br
COOMe
4b
3a
4
50
6a (20)
nd
I
4c
COOMe
120
120
30
Cl
COOEt
4d
5a
6b (30)
nd
Br
COOallyl
4e
6
Br
4f
a
Variable amounts of reduction product, methyl benzoate or ethyl benzoate, were observed.

H. S. Kim et al. / Tetrahedron Letters 49 (2008) 6569–6572
6571
OMe
OMe
MeO
COOMe
same
conditions
MeO
MeO
MeO
COOMe
Br
MeO
COOMe
+
+
120 min
MeOOC
6c (18%)
OMe
4g
7g (5%)
5g'
5g (42%)
OMe
OMe
Br
same
conditions
COOMe
COOMe
MeOOC
+
+
COOMe
60 min
4h
5h (41%)
6d (trace)
7h (31%)
5h'
COOMe
+
COOMe
same
conditions
COOMe
COOMe
Br
COOMe
+
MeOOC
90 min
MeOOC
MeOOC
MeOOC
MeOOC
6e (24%)
4i
7i (30%)
5i (0%)
COOMe
Scheme 3.
d-carbon elimination2 and concomitant elimination of CO2. The
in situ generated benzyne intermediate must be converted into tri-
phenylene 5a via the well-known Pd-mediated [2+2+2] cycloaddi-
tion mechanism.3 Our strategy and the proposed mechanism are
shown in Scheme 2, with 4a as an example: (i) oxidative addition
of aryl bromide 4a to Pd(0) generates the intermediate (I), (ii)
simultaneous d-carbon elimination and decarboxylation to pro-
duce benzyne (II), and the final (iii) Pd-mediated [2+2+2] cyclo-
addition of benzyne to give triphenylene (5a).
Initially, we examined the reaction of methyl 2-bromobenzoate
(4a) in the presence of Pd(OAc)2/K2CO3/TBAB in DMF at 110 °C,1
and obtained triphenylene (5a) in 52% isolated yield to our de-
light.3a,6 Trials for the optimization of reaction conditions are sum-
marized in Table 1. The use of TBAB (entries 1 and 2) or TBAC
(entry 6) showed better yields of 5a than the cases involving the
use of TBAB/KI (entry 4), TPAI (entry 5), or KF (entry 7). Among
the examined conditions, the combination of Pd(OAc)2/PPh3/
K2CO3/TBAC was found to be the best (entry 6). Under this opti-
mized conditions, compound 5a was obtained in 57% isolated yield
together with aryl–aryl coupling product 6a (8%, Table 2).7
As a next examination, we studied the relative reactivity of var-
ious 2-halobenzoic acid derivatives 4b–f, and the results are sum-
marized in Table 2. The reaction of 2-bromobenzoic acid (4b)
produced 5a in low yield (27%). In this case, oxapalladacycle inter-
mediate (IV)8 could be the plausible intermediate (vide supra,
Scheme 2).9 As expected, methyl 2-iodobenzoate (4c) afforded
moderate yield of 5a (44%), however, the yield of 6a was increased
to 20%. Chloro derivative 4d was almost un-reactive and severe
decomposition was observed. Ethyl ester 4e and allyl ester 4f
showed lower yields than the corresponding methyl ester 4a. The
smallest methyl group might be eliminated more readily during
the d-carbon elimination stage than the bigger ethyl group (entry
1 vs entry 5). For the allyl ester 4f, the mechanism might be differ-
The generation of aryne and the following [2+2+2] cycloaddi-
tion reaction were examined with related substrates 4g–i as shown
in Scheme 3. From the reaction of 4g, triphenylene derivative 5g
was obtained in 42% yield together with dimeric compound 6c
(18%) and reduction compound 7g (5%). Trace amount of regioiso-
meric 5g0 (<5%) was observed in the 1H NMR spectrum of 5g as in
the previous reports of similar compounds.3a,c,10 Naphthalene
derivative 4h produced 5h in moderate yield (41%) also. Regioiso-
meric triphenylene 5h0 was also found (<5%) in the 1H NMR spec-
trum of 5h.3c In the reaction, we could not isolate 6d in appreciable
amount instead reduction compound 7h was isolated in 31% yield.
The reaction of dimethyl 2-bromoterephthalate (4i) did not pro-
duce triphenylene 5i in appreciable amount, instead we isolated
dimer 6e (24%) and reduction compound 7i (30%), unfortunately.
From the results, the generation of arynes from 2-halobenzoates
seemed general in part, but sometimes substrate-dependent and
needed to be studied more.
In summary, we found a brand-new method for the generation
of aryne from methyl 2-bromobenzoates via the Pd-mediated con-
comitant d-carbon elimination and decarboxylation. Further stud-
ies on the reaction mechanism and the synthetic applicability are
actively underway.
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2007-
313-C00417). Spectroscopic data were obtained from the Korea
Basic Science Institute, Gwangju branch.
References and notes
1. Kim, H. S.; Gowrisankar, S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49,
3858–3861.
2. For the reactions involving b-carbon elimination, see: (a) Nishimura, T.;
Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org. Chem. 2004, 69, 5342–5347; (b)
Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125,
8862–8869; (c) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S. Org. Lett. 2003,
ent from the proposed one: formation of
p-allyl palladium inter-
mediate and conversion into the palladacyclic intermediate (IV)
in Scheme 2 and the generation of CO2 and benzyne could be
regarded as the more plausible mechanism.

6572
H. S. Kim et al. / Tetrahedron Letters 49 (2008) 6569–6572
5, 2997–2999; (d) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S.
(138 mg, 1.0 mmol), and TBAC (139 mg, 0.5 mmol) in DMF (2.0 mL) was heated
to 110 °C for 60 min. After the usual aqueous workup and column
chromatographic purification process (hexanes/ether, 10:1), triphenylene 5a
(22 mg, 57%) and dimer 6a (5 mg, 8%) were isolated. All the spectroscopic data
of 5a and 6a were identical with that reported.3a,c,7
Tetrahedron Lett. 2002, 43, 3037–3039; (e) Nishimura, T.; Ohe, K.; Uemura, S. J.
Am. Chem. Soc. 1999, 121, 2645–2646; (f) Nishimura, T.; Uemura, S. J. Am. Chem.
Soc. 1999, 121, 11010–11011; (g) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.;
Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407–10408; (h) Terao, Y.; Wakui, H.;
Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 5236–
5243; (i) Wakui, H.; Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2004, 126, 8658–8659; (j) Zhang, Y.; Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008,
130, 2900–2901; (k) Nishimura, T.; Uemura, S. Synlett 2004, 201–216.
3. For the Pd-mediated cyclotrimerization reactions of arynes, see: (a) Pena, D.;
Escudero, S.; Perez, D.; Guitian, E.; Castedo, L. Angew. Chem., Int. Ed. 1998, 37,
2659–2661; (b) Iglesias, B.; Cobas, A.; Perez, D.; Guitian, E.; Vollhardt, K. P. C.
Org. Lett. 2004, 6, 3557–3560; (c) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. Org.
Lett. 1999, 1, 1555–1557; (d) Pena, D.; Cobas, A.; Perez, D.; Guitian, E.; Castedo,
L. Org. Lett. 2000, 2, 1629–1632; (e) Pena, D.; Perez, D.; Guitian, E. Chem. Rec.
2007, 7, 326–333; (f) Romero, C.; Pena, D.; Perez, D.; Guitian, E. Chem. Eur. J.
2006, 12, 5677–5684.
4. For the other Pd-catalyzed reactions of arynes, see: (a) Zhang, X.; Larock, R. C.
Org. Lett. 2005, 7, 3973–3976; (b) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72,
223–232; (c) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron
Lett. 1999, 40, 7533–7535; (d) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int.
Ed 2000, 39, 173–175; (e) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J.
Am. Chem. Soc. 2000, 122, 7280–7286.
5. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214.
6. Typical procedure for the synthesis of compound 5a: A stirred mixture of 4a
(108 mg, 0.5 mmol), Pd(OAc)2 (6 mg, 5 mol %), PPh3 (13 mg, 10 mol %), K2CO3
7. Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem. 2006, 71, 1284–1287 and
further references cited therein.
8. For the synthesis of oxapalladacycles and their structures, see: (a) Fernandez-
Rivas, C.; Cardenas, D. J.; Martin-Matute, B.; Monge, A.; Gutierrez-Puebla, E.;
Echavarren, A. M. Organometallics 2001, 20, 2998–3006; (b) Lee, S. H.; Lee, K. H.;
Lee, J. S.; Jung, J. D.; Shim, J. S. J. Mol. Catal. A 1997, 115, 241–246; (c) Maehara,
A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159–1162; (d) Mei,
T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215–
5219.
9. The formation of (IV) from (I) by direct elimination of CH3Br (Scheme 2) would
also be possible. For this type of reductive cleavage process involving
decarboxylation, see: Harayama, H.; Kuroki, T.; Kimura, M.; Tanaka, S.;
Tamaru, Y. Angew. Chem., Int. Ed. 1997, 36, 2352–2354.
10. Compound 5g: Yellow solid, mp 126–128 °C; IR (film) 1614, 1495,
1217 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 3.988 (s, 3H), 3.990 (s, 3H), 4.00
;
(s, 3H), 7.17 (dd, J = 8.5 Hz and 2.5 Hz, 1H), 7.22–7.25 (m, 2H), 7.89–7.92 (m,
3H), 8.38–8.45 (m, 3H); 13C NMR (CDCl3, 125 MHz) d 55.41, 55.45, 55.47,
105.28, 106.11, 106.12, 114.85, 115.41, 115.61, 122.92, 123.89, 124.28,
124.35, 124.39, 125.00, 129.74, 130.22, 131.32, 158.01, 158.23, 158.78;
ESIMS m/z 319 (M++1). Anal. Calcd for C21H18O3: C, 79.22; H, 5.70. Found: C,
79.03; H, 5.87.