Effect of oxygen substituents on the regioselectivity of the Pd-assisted biaryl coupling reaction of benzanilides

Article abstract of DOI:10.1016/j.tetlet.2005.06.167

This study investigated the effect of oxygen substituents in the benzoyl part of N-(2-iodophenyl)benzamide on the coupling position in its Pd-assisted biaryl coupling reaction. Benzamide with methylenedioxy and acyloxy groups yielded the ortho-product for

Full text of DOI:10.1016/j.tetlet.2005.06.167

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6091–6094
Effect of oxygen substituents on the regioselectivity
of the Pd-assisted biaryl coupling reaction
of benzanilides
Takashi Harayama,* Yuko Kawata, Chie Nagura, Tomonori Sato, Taeko Miyagoe,
Hitoshi Abe and Yasuo Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Received 9June 2005; revised 30 June 2005; accepted 30 June 2005
Available online 20 July 2005
Abstract—This study investigated the effect of oxygen substituents in the benzoyl part of N-(2-iodophenyl)benzamide on the cou-
pling position in its Pd-assisted biaryl coupling reaction. Benzamide with methylenedioxy and acyloxy groups yielded the ortho-
product formed predominantly by connection to a more hindered carbon. The mechanism is discussed from the perspectives of both
steric and coordinated effects.
Ó 2005 Elsevier Ltd. All rights reserved.
Intramolecular aryl–aryl coupling reactions involving a
palladium reagent have been used to synthesize many
condensed aromatic compounds.1 Recently, we reported
the synthesis of condensed heteroaromatic compounds
using biaryl coupling reactions with palladium
reagents2,3 and the syntheses of naphthobenzazepines
and pyrrolophenanthridine alkaloids by regioselective
C–H bond activation using the intramolecular coordina-
tion of the amine to Pd.4
substituents on the phenyl ring in the palladation of
Schiff bases (A). They found that the bulkiness of the
methoxy group at C3 and an ethylenedioxy group
at C3 and C4 hindered direct metallation by PdII at the
C2 (ortho) position to give the cyclopalladation product
at the C6 (para) position; they further found that the
methylenedioxy group did not impede palladation of
the phenyl ring at the C2 (ortho) position to selectively
produce the ortho-product.8 Moreover, Dyke et al.
reported that the cyclopalladation of benzylamine (B)
possessing a methoxy or methylenedioxy group occurred
at the C6 (para) position,9 in contrast to the results of
Vila et al. mentioned above. Therefore, we investigated
the influence of oxygen substituents on coupling posi-
tion in the Pd-assisted reaction of N-(2-iodophenyl)benz-
amides (1).10
Examining the synthesis of trisphaeridine, we found that
the coupling reaction of N-(2-iodophenyl)benzamide
(1a) possessing a methylenedioxy group with Pd(OAc)2
and PPh3 in the presence of Na2CO3 in DMF produced
the ortho-product (2a), which was formed by connection
to a more hindered carbon and the para-product (3a) in
a 4 to 1 ratio.2c By contrast, Cai et al. reported that the
biaryl coupling reaction of N-(2-bromophenyl)-3,4-
methylenedioxybenzamide (1, R1+R2 = –OCH2O–,
R3 = H) catalyzed by Pd(OAc)2 in the absence of phos-
phine ligand in DMA exclusively gave the para-product
crinasiadine (3, R1+R2 = –OCH2O–, R3 = H) with a
48.5% yield.5,6 Vila et al. investigated the influence of
The results of the coupling reactions using methods A
[Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and K2CO3
(200 mol %)], B2d,e [Pd(OAc)2 (100 mol %), DPPP
(100 mol %), n-Bu3P (100 mol %), and Ag2CO3
(200 mol %)], and C [Pd(OAc)2 (10 mol %), (o-tol)3P
(20 mol %), and K2CO3 (200 mol %)] in DMF under
reflux are summarized in Table 1 (Scheme 1).
First, the reactions of 1 using Method A were exam-
ined. The coupling reactions of 1a and 1b possessing
a methylenedioxy group gave the ortho-products 2a
*
Corresponding author. Tel./fax: +81 862517963; e-mail: harayama@
pharm.okayama-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.167

6092
T. Harayama et al. / Tetrahedron Letters 46 (2005) 6091–6094
Table 1. Results of biaryl coupling reactions of benzanilides (1) in
(see run 15). The reaction of 1g possessing a phenol
group gave 2g and 3g in almost equal amounts (see
run 18), although Rawal et al. reported that the
coupling reaction of iodocarbamate (4a) possessing a
phenol group using HerrmannÕs palladacycle catalyst11
and Cs2CO3 in DMA exclusively gave a 76% yield of
the ortho-product (5a);12 the reaction of the bromo
ether (4b) with Pd(PPh3)4 and t-BuOK in DMA pre-
dominantly provided the ortho-product (5b) in an
87% yield.12
DMF under refluxa
Run
Substrate
Method
Yield (%)
Ratiob
2+3
2:3
1
2
1a
1b
A
B
698.5:1
Quant
9.2:1
3
4
5
A
B
C
Quant
84
96
7.5:1
11.5:1
5.6:1
6
7
8
1c
1d
1e
1f
A
B
C
Quant
Quant
Quant
2.9:1
3.8:1
2.0:1
The regioselectivity of the coupling reaction involving
two possible positions, C2 (ortho) and C6 (para), can
be discussed based on steric and electronic effects.
The difference in the regioselectivity of methoxy and
methylenedioxy groups reflects the steric bulkiness of
the methoxy group8 and the fact that the lone pair
of electrons in the methylenedioxy oxygen atom is more
electronegative than that in the methoxy oxygen atom
because of reduced resonance of the p-electron on the
benzene ring compared with those of other oxygen
groups.13 Therefore, the lone pair of electrons in the
methylenedioxy oxygen atom would coordinate to
the PdII on the square-planer complex more tightly to
produce the ortho-product predominantly via the inter-
mediate (C).
9
10
11
A
B
C
86
85
Quant
0.9:1
1.1:1
0.4:1
12
13
14
A
B
C
93
98
Quant
1.0:1
1.3:1
0.6:1
15
16
17
A
B
C
96
Quant
Quant
1.2:1
1.3:1
0.4:1
18
19B
20
1g
1h
1i
A
c
791.0:1
83
Quant
1.4:1
1.2:1
C
21
22
23
A
B
C
76
Quant
96
7.0:1
8.3:1
2.9:1
Acetate (1h) gave the ortho-product (2g) selectively via
connection to a more hindered carbon and subsequent
alkaline hydrolysis14 (see run 21), whereas the ester
(1k) provided the para-product (3k) selectively for steric
reasons (see run 29).
24
25
26
A
B
C
Quant
83
97
16.5:1
14.6:1
4.0:1
27
28
1j
A
B
70
68
4.3:1
6.3:1
Benzoate (1i) produced the ortho-product (2i) with bet-
ter selectivity, while monochloroacetate (1j) produced
2j with less selectivity than 1h (see runs 24 and 27).
These results are attributable to the coordinating ability
of carbonyl oxygen to PdII, such that the ortho-product
(2) was produced selectively via the coordinated inter-
mediate (D).
29
30
31
1k
A
B
C
78
Quant
81
0.3:1
0.4:1
0.1:1
a All reactions were carried out in DMF under Ar atmosphere and
reflux for 15–30 min. Method [Pd(OAc)2 (10 mol %), PPh3
(20 mol %), and K2CO3 (200 mol %)]. Method [Pd(OAc)2
A
B
(100 mol %), DPPP (100 mol %), n-Bu3P (100 mol %), and Ag2CO3
(200 mol %)]. Mehtod C [Pd(OAc)2 (10 mol %), (o-tol)3P (20 mol %),
and K2CO3 (200 mol %)].
All of the reactions using our new method (Method
B),2d except run 25, yielded the ortho-product (2)
as the major product; this product was more steri-
cally hindered than the para-product (3), in compari-
son with Method A. This indicates that a bidentate
ligand (DPPP) is sterically smaller than two mono-
dentate ligands (PPh3) on a square-planar inter-
mediate2d,f and suggests that the bulkiness of the
ligand affects the regioselectivity. Therefore, reac-
tions were carried out using Method C with (o-tol)3P,
which has a larger cone angle and is bulkier than
PPh3,15 as the ligand. Table 1 summarizes the results
using Method C. The general decrease in ortho-products
(2) from the coupling reaction at the sterically hindered
position indicates that ligand bulkiness influences
regioselectivity.16,17
b Determined by HPLC and NMR analysis.
c K2CO3 (200 mol %) as a base in place of Ag2CO3, because If was
gradually decomposed by using Ag2CO3.
and 2b as the major products; these products were
formed by connection to a more hindered carbon (see
runs 1 and 3). By contrast, the reaction of benzamides
(1d and e) possessing methoxy group(s) under the same
reaction conditions gave the corresponding coupling
products (2 and 3) in a ratio of 0.9–1.0 to 1, showing
nearly equal selectivity (see runs 9and 12). The reac-
tion of compounds with an ethylenedioxy group gave
2c and 3c in a ratio of 2.9to 1, which was an inter-
mediate value between 1b possessing a methylenedioxy
group and 1d and e possessing a methoxy group(s) (see
run 6). Interestingly, even 1f possessing a bulky tert-
butoxy group yielded 2f and 3f in a ratio of 1.2 to 1
In conclusion, the ratio of 2 to 3 was influenced by the
coordinating ability of substituent(s) to the PdII complex
and by the steric relationship between the substituent(s)
and the phosphine ligand.

T. Harayama et al. / Tetrahedron Letters 46 (2005) 6091–6094
6093
R2
R1
R2
R1
R2
R1
OH
I
N
N
N
R3
R3
X
R3
O
O
O
Y
1
3
2
4a : X=I, Y=NCO2CH3
4b : X=Br, Y=O
a : R1 + R2 = -OCH2O-, R3 = CH2OCH3
b : R1 + R2 = -OCH2O-, R3 = CH3
c : R1 + R2 = -OCH2CH2 O-, R3 = CH3
d : R1 = R2 = OCH3 , R3 = CH3
HO
e : R1 = H, R2 = OCH3, R3 = CH3
f : R1 = H, R2 = OBut, R3 = CH3
g : R1 = H, R2 = OH, R3 = CH3
Y
h : R1 = H, R2 = OAc, R3 = CH3
5a : Y=NCO2CH3
5b : Y= O
i : R1 = H, R2 = OCOC6H5, R3 = CH3
j : R1 = H, R2 = OCOCH2Cl, R3 = CH3
k : R1 = H, R2 = COOCH3, R3 = CH3
R
R
R
C=O
O
R1O
R2O
4
3
R
R
Pd
Pd
N
2
2
6
6
N
R'
CH3
CH3
O
N
N
O
C
R'
R'
D
R1 + R2 = CH2
R1 = R2 = CH3
A
B
Scheme 1.
Y. Heterocycles 2004, 62, 803–806; (j) Abe, H.; Takeda, S.;
Fujita, T.; Nishioka, K.; Takeuchi, Y.; Harayama, T.
Tetrahedron Lett. 2004, 45, 2327–2329; (k) Harayama, T.;
Hori, A.; Serban, G.; Morikami, Y.; Matsumoto, T.; Abe,
H.; Takeuchi, Y. Tetrahedron 2004, 60, 10645–10649; (l)
Nishioka, H.; Shoujiguchi, Y.; Abe, H.; Takeuchi, Y.;
Harayama, T. Heterocycles 2004, 64, 463–466; (m) Abe,
H.; Nishioka, K.; Takeda, S.; Arai, M.; Takeuchi, Y.;
Harayama, T. Tetrahedron Lett. 2005, 46, 3197–3200.
3. Harayama, T. Heterocycles 2005, 65, 697–713.
4. (a) Harayama, T.; Sato, T.; Hori, A.; Abe, H.; Takeuchi,
Y. Synlett 2003, 1141–1144; (b) Harayama, T.; Sato, T.;
Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2004, 1446–
1456; (c) Harayama, T.; Hori, A.; Abe, H.; Takeuchi, Y.
Heterocycles 2003, 60, 2429–2434; (d) Harayama, T.;
Hori, A.; Abe, H.; Takeuchi, Y. Tetrahedron 2004, 60,
1611–1616.
Acknowledgements
The authors are indebted to the SC-NMR Laboratory
of Okayama University for the NMR experiments.
References and notes
1. (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley
& Sons: New York, 2004, pp 176–201; (b) Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000; (c) Dyker, G. Chem. Ber. 1997,
130, 1567–1578; (d) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469;
(e) Miura, M.; Nomura, M. Topics in Current Chemistry
´
2002, 219, 212–241; (f) Echavarren, A. M.; Gomez-Lor,
´
´
B.; Gonzalez, J.; de Frutos, O. Synlett 2003, 585–597.
2. (a) Harayama, T.; Shibaike, K. Heterocycles 1998, 49,
191–195; (b) Harayama, T.; Akiyama, T.; Akamatsu, H.;
Kawano, K.; Abe, H.; Takeuchi, Y. Synthesis 2001, 444–
450; (c) Harayama, T.; Akamatsu, H.; Okamura, K.;
Miyagoe, T.; Akiyama, T.; Abe, H.; Takeuchi, Y. J.
Chem. Soc., Perkin Trans. 1 2001, 523–528; (d) Harayama,
T.; Akiyama, T.; Nakano, Y.; Nishioka, H.; Abe, H.;
Takeuchi, Y. Chem. Pharm. Bull. 2002, 50, 519–522; (e)
Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.;
Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis
2002, 237–241; (f) Harayama, T.; Hori, A.; Nakano, Y.;
Akiyama, T.; Abe, H.; Takeuchi, Y. Heterocycles 2002,
58, 159–164; (g) Harayama, T.; Sato, T.; Nakano, Y.; Abe,
H.; Takeuchi, Y. Heterocycles 2003, 59, 293–301; (h)
Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.;
Takeuchi, Y. Synlett 2003, 847–848; (i) Harayama, T.;
Morikami, Y.; Hori, A.; Nishioka, H.; Abe, H.; Takeuchi,
5. Shao, H. W.; Cai, J. C. Chinese Chem. Lett. 1997, 8, 493–
496.
6. Since phosphine ligand is generally required for the Heck-
type reaction of bromoarene, the reaction conditions were
somewhat unusual.7a,b The exclusive para-selectivity by
Cai et al. might be attributable to the presence of NH-
amide, because a species of leaving group do not affect
significantly the regioselectivity.7c,d
7. (a) Heck, R. F. In Organic Reactions; Dauben, W. G., Ed.;
John Wiley & Sons: New York, 1982; Vol. 27, pp 345–390;
(b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7;
(c) Reaction of 3,4-methylenenedioxy-N-(2-bromo-1-
naphthyl)-N-methylbenzamide under Method C produced
the ortho- and para-products in a ratio of 5.1 to 1; (d)
Hennings, D. D.; Iwasa, S.; Rawal, V. H. Tetrahedron
Lett. 1997, 38, 6379–6382.
8. (a) Vila, J. M.; Suarez, A.; Pereira, M. T.; Gayoso, E.;
Gayoso, M. Polyhedron 1987, 6, 1003–1007; (b) Teijido,

6094
T. Harayama et al. / Tetrahedron Letters 46 (2005) 6091–6094
´
´
B.; Fernandez, A.; Lopez-Torres, M.; Castro-Juiz, S.;
12. Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem.
1997, 62, 2–3.
´
´
Suarez, A.; Ortigueira, J. M.; Vila, J. M.; Fernandez, J. J.
J. Organomet. Chem. 2000, 598, 71–79.
9. Barr, N.; Dyke, S. J. Organomet. Chem. 1983, 243, 223–
232.
13. Buckley, T. F., III; Rapoport, H. J. Am. Chem. Soc. 1980,
102, 3056–3062.
14. The ratio was determined by the HPLC method after
alkaline hydrolysis because the coupling products always
contained some of the hydrolyzed products (2g and 3g).
15. Tolmann, C. A. Chem. Rev. 1977, 77, 313–348.
16. (a) Reactions using bulky biphenyl phosphine ligand gave
para-products in ratios exceeding 20 to 1. Campeau, L.-C.;
Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186–9187; (b) Hennessy, E. J.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 12084–12085.
17. Interestingly, the reaction of 1f using Pd(OAc)2, K2CO3,
and no phosphine ligand produced 2f and 3f in a ratio of
0.35 to 1 with a total yield of 97% and with selectivity
similar to that of Method C.
10. Benzamides (1b and d) were prepared in high yield via
amidation of the appropriate benzoyl chloride and 2-
iodoaniline, followed by N-methylation. Benzamides (1c, e,
h and k) were prepared from the corresponding substituted
benzoyl chloride and 2-iodo-N-methylaniline in 80–90%
yield. Benzamide (1g) was synthesized by alkaline hydro-
lysis of 1h, and the other benzamides (1f, i and j) were
synthesized by etherification of 1g with isobutene, and by
benzoylation and chloroacetylation of 1g, in good yield.
¨
11. Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.
P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1844–1848.