Nickel-catalyzed Ullmann-type coupling reaction to prepare tetra-ortho-substituted biaryls

Article abstract of DOI:10.1055/s-2001-17488

A nickel-catalyzed Ullmann-type reaction on the coupling of bis-ortho-substituted arylhalides to prepare tetra-ortho-biaryls was brought about in moderate to high yields. Bu₄NI might function as an efficient bridging ligand to accelerate the formation of dinickel-center intermediate, which subsequently eliminates to desired coupling product.

Full text of DOI:10.1055/s-2001-17488

LETTER
1527
Nickel-catalyzed Ullmann-type Coupling Reaction to Prepare Tetra-ortho-
substituted Biaryls
P
reparationof Te
a
tra-ortho-s
n
ubstitute
d
Biaryls Hong, Rob Hoen,1 Jing Zhang,2 Guo-qiang Lin*
Shanghai Institute of Organic Chemistry, CAS, 354 Fenglin Road, Shanghai 200032, P. R. China
E-mail: lingq@pub.sioc.ac.cn
Received 26 July 2001
report the nickel-catalyzed Ullmann-type reaction of bis-
ortho-substituted arylhalides in the presence of Bu4NI. To
our knowledge, this is the first example of a catalytic nick-
el-mediated Ullmann-type reaction to prepare tetra-ortho-
Abstract: A nickel-catalyzed Ullmann-type reaction on the cou-
pling of bis-ortho-substituted arylhalides to prepare tetra-ortho-bi-
aryls was brought about in moderate to high yields. Bu4NI might
function as an efficient bridging ligand to accelerate the formation
of dinickel-center intermediate, which subsequently eliminates to substituted biaryls.
desired coupling product.
To establish an efficient protocol for coupling of bis-
Key words: nickel, Ullmann-type reaction, tetra-ortho-substituted
ortho-substituted arylhalides, we first tested the effect of
Bu4NI9 in the coupling reaction of arylbromide 1a and
aryliodide 1b (Table 1). The ratio of cp/rp reversed from
36: 64 to 65: 35 in favor of the formation of the coupling
product (cp, 2a) (entry 1 vs 2) when 0.6 equiv of Bu4NI
was present in the reaction mixture. An increase of Bu4NI
from 0.6 equiv to 2 equiv caused an elevation in the ratio
of cp/rp (entry 3 vs 2). Although the iodide ion was spec-
ulated as a ligand which could coordinate to the nickel
center,7k the yield of 2a dropped when the amount of PPh3
was decreased from 0.4 equiv to 0.2 equiv (entry 4 vs 3).
This implies that PPh3 is a stronger ligand than the iodide
ion. Interestingly, 0.1 equiv of Bu4NI was effective
enough to obtain 2a in moderate yield (entry 5). It was
proposed8 that hydride from NaH might coordinate to the
nickel center to form nickel-hydride which would elimi-
nate to give reductive product (rp). Here it was also found
that the ratio of cp/rp was slightly increased by using only
3.0 equiv of NaH (entry 6 vs 5). Zinc functions as a
promoter8,10 (entry 6 vs 7). 0.2 equiv of nickel catalyst was
necessary for coupling of arylbromide 1a (entry 8 vs 7).
Although previously7 it has been proposed that the halo-
gen-exchanged reaction would be the initial step when
Bu4NI was added into the reaction mixture, the very low
solubility of Bu4NI in nonpolar solvents11 (such as ben-
zene, toluene) implies that this process might be very dif-
ficult. In entries 10 and 11, the ratio of cp/rp of aryliodide
1b was considerably increased in the presence of Bu4NI.
biaryls, bridging ligand
Biaryls are common structure motifs in natural products
and are the core for many of the most effective chiral
ligands.3 The synthesis of this class of compound has been
effected by a number of useful methods4 (Scheme 1), al-
beit mostly using Cu-mediated methodology. Pioneering
work by Semmelhack5 has shown that nickel-promoted
Ullmann-type reaction was an efficient method for pre-
paring biaryls bearing some sensitive functional groups.
But, unfortunately, the combination of sterically hindered
substrates to give products with four ortho substituents
could not be accomplished using a nickel catalyst sys-
tem.5,6
Many works indicated7 that polar solvents facilitate the
solvation of nickel(II) complexes formed in the oxidative
addition steps and thus promote the coupling process, and
meanwhile the aryl radicals generated in the reaction tend
to abstract hydrogen from the conventionally reported po-
lar solvents (such as THF and DMF) and thus result in hy-
drogenolysis product of the aryl halides. It is therefore
often hard to offer satisfactory yield while running such
reaction in a polar solvent. Recently, we accomplished the
coupling of arylhalides in toluene, using an in situ gener-
ated nickel catalyst.8 Toluene was found to considerably
retard the dehalogenated process of the substrate. Here we
R1
R1 R3
R3
R1
R3
Reductive
elimination
Transmetallation/
Oxidative addition
M1X
M2
M1
+
R2
R2 R4
R4
R2
R4
M1 = Pd, Ni
M2 = ZnX, MgX,SnR3
B(OR')2, etc.
Ortho-substituted Biaryls
X = Br, I, OTf
Scheme 1 Transition metal-catalyzed coupling reaction to prepare biaryls
Therefore, iodide might play a significant role in the ac-
celeration of the coupling as a bridging ligand as suggest-
ed in previously.9a,12
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1527,1530,ftx,en;Y16201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1528
R. Hong et al.
LETTER
Table 1 Effect of Bu4NI in Nickel-catalyzed Ullmann-type Reaction on Substrate 1a (X = Br) or 1b (X = I)a
CHO
MeO
OMe
NiCl2(PPh3)2/Zn
OMe
MeO
MeO
CHO
NaH/additive/toluene
90oC
OMe
OHC
X
1a/b X = Br/I
Entry
2a
NaH (equiv) Bu4NI (equiv) Reaction time Yield (%)b
NiCl2(PPh3)2 PPh3 (equiv) Zn (equiv)
(equiv)
Ratio (cp : rp)c
(h)
12
6
(isolated)
95 (27)
93
1
2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.2
0.2
0.1
0.4
0.4
0.4
0.2
0.4
0.4
0.4
0.2
0.4
0.4
0.2
3
3
3
3
3
3
1
3
3
3
3
6
6
6
6
6
3
3
3
3
3
3
36: 64
65: 35
80: 20
56: 44
65: 35
70: 30
63: 37
32: 68
67: 33
84: 16
83: 17
0.6
2
3
4.5
94 (70)
95
4
2
5
3
5
0.1
0.1
0.1
0.1
96
6
3
>95
7
12
7
85
8
>95
9d
10d
11d
4
>95 (53)
>95 (73)
>95 (75)
0.1
0.1
1e
1e
a All of the reactions were performed at 90-95 °C in toluene (0.2 M).
b The total yields of coupling product (cp) and reductive product (rp) were determined by HPLC (in parenthesis they are the isolated yields of
coupling product 2a).
c The ratios of coupling product (cp) to reductive product (rp) were determined by HPLC.
d The substrate is aryliodides (1b).
e The reaction was ready in 1 hour (determined by TLC).
A proposed mechanism8 is shown in Scheme 2. It was ob- mechanism7c or the elimination of a nickel-hydride com-
served that ratio of cp/rp at initial time was lower than that plex.8,13 However, the latter complex TS1 would form a
at the end of the reaction. Initial formation of mononickel di-arylnickel complex after ligand transfer and this would
complex OA might lead to coordination by the iodide ion lead to coupling product (CP) by elimination.
as bridging ligand to form di-nickel complex TS1 as
shown in Scheme 2. The former would favor the forma-
tion of the reductive product (RP) through a radical
With the optimized set of conditions (Table 1, entry 6 and
entry 11) a range of arylhalides 1c-l were examined
(Table 2). Most yields of coupling products were dramat-
14
R2
R2
elimination
(X = H)
NiXL2
OA
R1
R1
RP
[I-]
R1
R2 R2
L
R2
I
I
Ni
Ni
L
R2
TS1
R1 R1
R1
CP
RP: reductive product; OA: oxidative addition;
TS1: dinickel-center intermediate; CP: coupling product
Scheme 2 Proposed Mechanism for the Effect of Bu4NI in the Nickel-catalyzed Ullmann-type Coupling Reaction
Synlett 2001, No. 10, 1527–1530 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparation of Tetra-ortho-substituted Biaryls
1529
Table 2 Nickel-Bu4NI system catalyzed Ullmann-type reaction to
ically increased in the presence of Bu4NI. For example,
the isolated yield for the coupling of 1d was 77%, while it
was only 44% in the absence of Bu4NI (entry 4). The cou-
pling product of 1c/1d (entries 3 and 4) is a key interme-
diate for the synthesis of natural product, schizandrin.15 In
the presence of 0.5 equiv of Bu4NI, the coupling yields of
1k and 1l were increased to 72% and 45%, respectively
(entries 11 and 12). The latter coupling product 2l had
been previously synthesized through a multi-step pro-
cess.14i We have developed a mild and efficient method
for preparing this compound. For the coupling of 1g,14
some Cu-mediated methods 14d,f had previously been car-
ried out in moderate yields under harsh conditions, how-
ever, the coupling product 2g was afforded in 97% yield
under our conditions (entry 7). The presence of a methyl
ester functionality on one of the ortho-positions gave low-
er yields than an aldehyde group on the same position (en-
try 8 vs 1, entry 9 vs 2). This is probably caused by the
greater bulkiness and the electronic effect of the methyl
ester group. The rate of coupling of 1j was very fast, how-
ever, it necessitated 30 mol% of catalyst (Method C,
Table 2) because of the decomposition of the catalyst (en-
try 10).
prepare 2,2’,6,6’-substituted Biarylsa (continued)
R1
R1 R1
Method A-C
R4
X
R4
R4
R3
R2
R3
R2 R2
R3
2a-l
1a-l
Entry Substrate
Meth- Time Yield%b
Yield%c
58
od
(h)
(isol.)
6
7
8
9
A
5
94 (89)
Br
CHO
CHO
O
O
1f
B
A
B
1.5
8
>99 (97) 91
I
O
O
1g
33 (23)
68 (60)
3
Br
COOMe
MeO
MeO
1h
Table 2 Nickel-Bu4NI system catalyzed Ullmann-type reaction to
1
29
prepare 2,2’,6,6’-substituted Biarylsa
I
COOMe
MeO
MeO
R1
R1 R1
Method A-C
R4
X
R4
R4
1i
10
11
C
A
1
4
80 (71)
83 (72)
30
52
I
R3
R2
R3
R2 R2
R3
OMe
OMe
MeO
2a-l
1a-l
Entry Substrate
Meth- Time Yield%b Yield%c
1j
od
(h)
(isol.)
Br
1
A
3
70 (62)
27
51
30
44
CHO
Br
MeO
1k
Br
OMe
1a
12
A
7
55 (45)
18
CHO
2
3
4
B
A
B
1
6
2
83 (75)
78 (71)
82 (77)
CHO
I
MeO
1l
OMe
1b
a Unless indicated, all of the reactions were performed with Zn (3
equiv), NaH (3 equiv), Bu4NI (0.1 equiv) at 90 °C in toluene (0.2 M)
(in parenthesis are the isolated yields of coupling product). Method A:
NiCl2(PPh3)2 (0.2 equiv)/PPh3 (0.4equiv). Method B: NiCl2(PPh3)2
(0.1 equiv)/PPh3 (0.2 equiv). Method C: NiCl2(PPh3)2 (0.3 equiv)/
PPh3 (0.6 equiv). The typical procedure is given in Ref. 16.
b Determined by 300 MHz 1H NMR spectra.
MeO
MeO
CHO
Br
OMe
1c
MeO
MeO
CHO
I
c The isolated yields of coupling product were obtained without
Bu4NI.
OMe
1d
COOMe
I
5
B
1.5
93 (85)
65
In conclusion, this method represents a novel, efficient
and mild synthesis of tetra-ortho-substituted biaryls
through a nickel-catalyzed Ullmann-type coupling reac-
tion using Bu4NI as an additive. Iodide might act as a
Me
1e
Synlett 2001, No. 10, 1527–1530 ISSN 0936-5214 © Thieme Stuttgart · New York

1530
R. Hong et al.
LETTER
(8) Lin, G.-Q.; Hong, R. J. Org. Chem. 2001, 66, 2877.
(9) Some references on iodide ions: (a) Iyoda, M.; Otsuka, H.;
Sato, K.; Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63,
80. (b) Takagi, K.; Hayama, N.; Inokawa, S. Chem. Lett.
1979, 917. (c) Chao, C. S.; Cheng, C. H.; Chang, C. T. J.
Org. Chem. 1983, 48, 4904.
(10) Amatore, C.; Jutand, A. Acta Chem. Scand. 1990, 44, 755.
(11) Vernon, A. A.; Luder, W. F.; Giella, M. J. Am. Chem. Soc.
1941, 63, 862.
(12) Other opinion was that added halide ions exert a powerful
catalytic effect on the rate of oxidative addition of the
carbon-halide bond to a more reactive metal complex, see:
Forster, D. J. Am. Chem. Soc. 1975, 97, 951. Our
bridging ligand to favor the formation of a diarylnickel
complex and sequentially eliminate to give the desired bi-
aryls. To our knowledge, it is the first example of a nickel-
catalyzed reaction to obtain this kind of highly hindered
biaryls. This reaction is synthetically useful as well as
mechanistically intriguing.
Acknowledgement
We acknowledge the financial assistance by the NSFC (079201)
and the Major Basic Research Development Program (G2000
077506). We also thank Dr. Hong-feng Luo and Mr. Ke-ming Xia
for 1H NMR and HPLC performances, respectively.
unpublished results indicated that this interpretation might
be reasonable for an SN2 mechanism (nucleophilic addition
on the arylhalides) rather than ion-pair or three-center two-
electron process during the oxidative addition..
References and Notes
(13) Lourak, M.; Vanderesse, R.; Fort, Y.; Caubere, P. J. Org.
Chem. 1989, 54, 4840.
(1) Current address: Department of Chemistry, University of
Groningen, The Netherlands.
(14) (a) Chapman, R. F.; Swan, G. A. J. Chem. Soc. 1970, 865.
(b) Omote, Y.; Fujinuma, Y.; Sugiyama, N. Bull. Chem. Soc.
Jpn. 1971, 44, 572. (c) Brown, E.; Robin, J.-P.; Dhal, R.
Tetrahedron 1982, 38, 2569. (d) Ziegler, F. E.; Chliwner, I.;
Fowler, K. W.; Kanfer, S. J.; Kuo, S. J.; Sinha, N. D. J. Am.
Chem. Soc. 1980, 102, 790. (e) Kanoh, S.; Muramoto, H.;
Kobayashi, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jap.
1987, 60, 3659. (f) Gies, A.-E.; Pfeffer, M. J. Org. Chem.
1999, 64, 3650. (g) Lindsten, G.; Wennerström, O.;
Isaksson, R. J. Org. Chem. 1987, 52, 547. (h) Hassan, J.;
Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M.
(2) Current address: School of Pharmacy, West China
University Of Medical Science, Chendu, P. R. China.
(3) (a) Bringmann, G.; Walter, R.; Weirich, R.Angew. Chem.,
Int. Ed. Engl. 1990, 29, 977. (b) Noyori, R.; Takaya, H. Acc.
Chem. Res. 1990, 23, 345.
(4) (a) Fanta, P. E. Synthesis 1974, 9. (b) Meyers, A. I. J.
Heterocycl. Chem. 1998, 35, 991. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263. (d) Lipshutz, B. H.; Kayser, F.;
Liu, Z.-P.Angew. Chem., Int. Ed. Eng. 1994, 33, 1842.
(e) Ziegler, F. E.; Schwartz, J. A. J. Org. Chem. 1978, 43,
985.
(5) Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.;
Mendelson, L. E.; Ryono, L. S.; Smith, J. G.; Stauffer, R. D.
J. Am. Chem. Soc. 1981, 103, 6460 and references therein.
(6) Knight, D. W. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 482 and references therein.
(7) (a) Clark, F. R. S.; Norman, R. O. C.; Thomas, C. B. J.
Chem. Soc., Perkin Trans.1 1975, 121. (b) Zembayashi, M.;
Tamao, K.; Yoshida, J.; Kumada, M. Tetrahedron Lett.
1977, 18, 4089. (c) Tsou, T. T.; Kochi, J. K. J. Am. Chem.
Soc. 1979, 101, 6319. (d) Tsou, T. T.; Kochi, J. K. J. Am.
Chem. Soc. 1979, 101, 7574. (e) Uchiyama, M.; Suzuki, T.;
Yamakazi, Y. Chem. Lett. 1983, 1165. (f) Torii, S.;
Tamaka, H.; Morisaki, K. Tetrahedron Lett. 1985, 26, 1655.
(g) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627 and
references therein. (h) Iyoda, M.; Otsuka, H.; Sato, K.;
Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80 and
references therein. (i) Miura, M.; Hashimoto, H.; Itoh, K.;
Nomura, M. Chem. Lett. 1990, 459. (j) Jutand, A.; Negri,
S.; Mosleh, A. J. Chem. Soc., Chem. Commun. 1992, 1729.
(k) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org.
Chem. 1995, 60, 176. (l) Hennings, D. D.; Iwama, T.;
Rawal, V. H. Org. Lett. 1999, 1, 1205.
Tetrahedron 1998, 54, 13793. (i) Dubois, F.; Gingras, M.
Tetrahedron Lett. 1998, 39, 5039.
(15) Warshawsky, A. M.; Meyers, A. I. J. Am. Chem. Soc. 1990,
112, 8090.
(16) Typical procedure (Method B): A 20 mL schlenk flask was
charged with NiCl2(PPh3)2 (0.1 mmol), PPh3 (0.2 mmol), Zn
dust (3.0 mmol), NaH (3.0 mmol, oil-free), Bu4NI (0.1
mmol) and arylhalide 1g (276 mg, 1.0 mmol), sealed with a
rubber septum, evacuated and filled with argon several times
(vacuum line). Freshly distilled toluene (5 mL) was added
via a syringe. The mixture was stirred at 90 °C for 1.5 h, then
cooled and quenched by 5% HCl(aq). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
three times. The combined organic layers were washed with
5% NaHCO3(aq), brine and dried over Na2SO4. Upon
removal of the solvent, the corresponding biaryl 2g was
obtained as a white solid (144 mg, 0.483 mmol) in 97% yield
after flash chromatography on silica gel (EtOAc-PE, 1: 3).
1H NMR spectral data of 2g is in agreement with published
data (ref. 12d and 12f). Other coupling products (2a, c-l) are
in agreement with results reported in literature (ref.12).
Synlett 2001, No. 10, 1527–1530 ISSN 0936-5214 © Thieme Stuttgart · New York