Synthesis of medium-ring and iodinated biaryl compounds by organocuprate oxidation

Article abstract of DOI:10.1002/anie.200462642

(Chemical Equation Presented) A biaryl banquet! Biphenyls with four ortho substituents, heteroaromatic compounds, iodinated biaryls, and medium rings containing biaryls are all readily synthesized by organocuprate oxidation. The utility of this new methodology is illustrated by the efficient synthesis of the medium-ring core of sanguiin H-5 (see scheme).

Full text of DOI:10.1002/anie.200462642

Communications
À
C C Coupling
number of reactions.[9] New methodology that can overcome
these caveats will allow efficient access to largely unexploited
classes of biaryls.
Synthesis of Medium-Ring and Iodinated Biaryl
Compounds by Organocuprate Oxidation**
Oxidation of organocuprates allows the formation of both
intermolecular[10] and intramolecular[11] biaryl bonds; how-
ever, extreme reaction conditions and poor functional-group
tolerance means that this reaction is not seen as being widely
useful. We have endeavored to change this opinion. Herein,
we report the optimization of organocuprate oxidation, which
involves the design and utilization of a new oxidant, the
exploitation the iodine–magnesium exchange procedure
developed by Knochel and co-workers,[12] and the cross-
coupling of different aryl units by an intramolecular process.
The utility of the new methodology is illustrated by the
efficient synthesis of the biaryl-containing medium-ring core
of sanguiin H-5.
David S. Surry, Xianbin Su, David J. Fox,
Vilius Franckevicius, Simon J. F. Macdonald, and
David R. Spring*
The importance of the biaryl motif is illustrated by its
presence in an extensive range of natural products, pharma-
ceuticals, agrochemicals, dyes, and chiral catalysts. A variety
of reactions are available to construct biaryls,[1] mostly
through palladium-,[2,3] nickel-,[4] or copper-mediated pro-
cesses.[5] Unfortunately, only a limited number of these
methods is suitable for the synthesis of medium-ring com-
pounds,[6] sterically hindered systems, and iodinated biaryls
(Scheme 1). Biaryl-containing medium-ring compounds are
Initial optimization studies revealed that a range of
copper(i) salts could be used in the organocuprate oxidation
reaction (Table 1), with the copper(i) bromide/dimethyl
Table 1: Substoichiometric amounts of dinitroarenes, such as 3, could
be used as effective oxidants.
Entry
1
Oxidant
Oxidant [equiv]
1
Yield [%]
68
Scheme 1. Biaryl-containing medium-ring compounds, sterically hin-
dered biaryls, and iodinated biaryls are all difficult synthetic targets
using existing methodology.
2
3
4
5
3
3
0.2
0.1
0.2
1
62
31
12
60
difficult to synthesize because of their associated torsional,
transannular, and large angle strain; nevertheless, there are
thousands of potent bioactive natural products that contain
this motif, such as the ellagitannin class of natural products, of
which sanguiin H-5 is one of over 500 members.[7] In addition,
the synthesis of biaryls that contain four ortho substituents is
often challenging, and palladium-catalyzed reactions that
accomplish this goal have only recently been developed.[8]
Moreover, iodinated biaryls are powerful synthetic inter-
mediates, yet they are only formed by a relatively small
CuCl2
CuCl2
6
1.5
57
sulfide complex proving the most convenient.[13] In contrast,
the choice of oxidant was crucial to the success of the reaction.
Initially, meta-dinitrobenzene[14] was the most successful
oxidant examined,[15] but it was difficult to obtain the pure
product free of oxidant-derived by-products. Therefore, the
new oxidant 3 was synthesized, which could be completely
removed by an aqueous acid wash during the work up or by
passage through silica gel.[16] Under the reaction conditions
employed, molecular oxygen as the oxidant caused significant
formation of phenols, whilst none were detected when 3 was
employed. Interestingly, as few as 0.2 equivalents of 3 (with
respect to the aryl magnesium species formed) may be used
without significant depreciation of yield (Table 1, entries 1
and 2). Further lowering of the quantity of dinitroarene to
0.1 equivalents, drastically decreased the yield of isolated
product (entry 3). This “substoichiometric” effect was not
observed for the inorganic, single-electron oxidant CuCl2
(entries 4 and 5). A likely explanation of these findings is
that the dinitroarene 3 can accept more than one electron
during the oxidation process.[17] Support for this hypothesis
[*] D. S. Surry, X. Su, Dr. D. J. Fox, V. Franckevicius, Dr. D. R. Spring
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB21EW (UK)
Fax: (+44)1223-336362
E-mail: drspring@ch.cam.ac.uk
Dr. S. J. F. Macdonald
GlaxoSmithKline
Centre for Excellence in Drug Discovery
Stevenage, SG12NY (UK)
[**] We gratefully acknowledge financial support from the EPSRC and
GSK (D.S.S.), Cambridge Trusts (X.S.), Pfizer UK (V.F.), and the
BBSRC. We would also like to acknowledge the EPSRC National
Mass Spectrometry Service Centre, Swansea, UK, for providing
mass-spectrometric analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462642
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Angewandte
Chemie
Table 3: Intramolecular biaryl formation using the optimized organo-
cuprate oxidation methodology.[a]
comes from the fact that the radical anion of meta-dinitro-
benzene (available by reduction of meta-dinitrobenzene with
one equivalent of potassium) may itself be used to perform
the oxidation (entry 6).[18]
Entry Substrate (1)
Product (2)
Yield [%]
The optimized methodology can be used for the prepa-
ration of a wide range of functionalized biaryls (Table 2). The
i
82
Table 2: Intermolecular biaryl formation by using the optimized organo-
cuprate oxidation methodology.[a]
Entry
Substrate (1)
Product (2)
Yield [%]
88
j
70
85
a
b
c
75
82
k
[a] Conditions: a) 1 (1 mmol), iPrMgCl (2 equiv), THF (3 mL), À208C,
10 min; b) CuBr·SMe2 (1 equiv); c) 3 (1 equiv) in THF (3 mL).
d
e
67
72
The success of this cyclization allows cross-coupling of
different aryl units (Scheme 2). Two different aryl units can be
f
66
75
53
g
h
Scheme 2. Formal cross-coupling of aryl units by intramolecular biaryl
formation followed by selective aminolysis: a) 2-iodobenzoyl chloride,
Et3N, DMAP, DMA, À208C, 6 h; b) 2,5-diiodobenzoyl chloride, Et3N,
DMAP, DMA, À208C, 6 h, 90%; c) iPrMgCl (2 equiv), THF, À208C;
d) CuBr·SMe2 (1 equiv); e) 3 (1 equiv), 79% from 1 l; f) 4-methoxyben-
zylamine, 1,4-dioxane, 608C, 6 h, 84%. DMAP=4-(dimethylamino)pyri-
dine, DMA=N,N-dimethylacetamide.
[a] Conditions: a) 1 (1 mmol), iPrMgCl (1 equiv), THF (3 mL), À208C,
10 min; b) CuBr·SMe2 (0.5 equiv); c) 3 (1 equiv) in THF (3 mL).
reaction does not seem to be significantly influenced by steric
interactions, thus allowing the synthesis of a biaryl bond with
multiple ortho substituents (2a and 2b). Iodinated aromatic
heterocycles are also suitable substrates, which makes the
synthesis of the corresponding dimer 2c possible.[19] The
iodine–magnesium exchange can be performed in the pres-
ence of an aryl bromide,[20] which allows the formation of
brominated biaryls (2d). Furthermore, the ability to regiose-
lectively perform a single iodine–magnesium exchange on
multiply iodinated substrates permits the synthesis of iodi-
nated biaryls 2e–h, which are often extremely difficult to form
directly by other methods because of oligomerization.
The reaction is equally successful when performed intra-
molecularly (Table 3) so that strained medium-ring com-
pounds with 10- and 11-membered rings (2i,j and 2k,
respectively) can be constructed without the need for high-
dilution conditions (approximately 0.3m in THF).
tethered with 2-hydroxybenzyl alcohol to give 1l,[21] which can
be readily cyclized in 79% yield by using our methodology.
The 11-membered ring product readily undergoes aminolysis
with concomitant loss of the tether to give 4 directly, thus,
allowing an overall cross-coupling of two aryl iodides. This
procedure could be readily exploited for the generation of a
library of functionalized biaryls derivatives, which could then
be further modified.
Most importantly, this methodology was used to form 2m,
a model for the highly strained medium-ring core of
sanguiin H-5 in 67% yield and with complete diastereoselec-
tivity (Scheme 3).[22] This significant result represents a high-
yielding synthesis of bisester biaryl-containing medium rings
that can be applied to the preparation of the ellagitannin
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Communications
[1] J. Hassan, M. Sꢂvignon, C. Gozzi, E. Sculz, M. Lemaire, Chem.
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[2] For the palladium-catalyzed dimerization of aryl halides, see:
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[3] For palladium-catalyzed cross-coupling reactions, see: a) T. N.
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[4] a) R. Hong, R. Hoen, J. Zhang, G. Lin, Synlett 2001, 1527;
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[5] a) P. E. Fanta, Synthesis 1974, 9; for a recent application, see:
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[6] a) Oxidative coupling, for example: B. Kramer, A. Averhoff,
S. R. Waldvogel, Angew. Chem. 2002, 114, 3103; Angew. Chem.
Int. Ed. 2002, 41, 2981; b) Ullmann-type coupling, for example:
S. Zhang, D. Zhang, L. S. Liebeskind, J. Org. Chem. 1997, 62,
2312; c) radical coupling: H. Tanaka, M. Doi, H. Shimizu, H.
Etoh, Heterocycles 1999, 51, 2415; d) reductive coupling: S.
Miyake, A. Sasaki, T. Ohta, K. Shudo, Tetrahedron Lett. 1985, 26,
5815.
Scheme 3. Synthesis of 2m, a model for the highly strained, medium-
ring core of sanguiin H-5.
family of natural products. The success of this reaction in
forming biaryl bonds in hindered systems and strained rings
may be because the two aryl moieties that eventually bond in
the intermediate organocuprate are a considerable distance
apart. The C-Cu-C bond angle is approximately 1808 and the
[23]
À
C Cu bond is somewhat long at 1.9 ꢀ, thereby reducing
unfavorable interactions.
In summary, we report a new functional-group-tolerant
methodology for the synthesis of sterically hindered biaryls,
including highly strained medium-ring-containing biaryls,
which are key structural units within the ellagitannin family
of natural products. The methodology can also be used to
cross-couple different aryl units by use of a tether. We are
currently working towards exploiting this methodology in the
synthesis of ellagitannin natural products.
[7] K. Khanbabaee, T. van Ree, Synthesis 2001, 1585.
[8] a) W. Su, S. Urgaonkar, P. M. McLaughlin, J. G. Verkade, J. Am.
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e) C. Dai, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 2719.
[9] a) Direct iodination: P. C. Anelli, M. Brochetta, C. Maffezzoni,
P. Paoli, P. Rossi, F. Uggeri, M. Visigalli, Perkin Trans. 1 2001,
1175; b) from a diazonium salt: B. Ghebremariam, S. Matile,
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coupling: D. Mirk, A. Willner, R. Frꢃlich, S. R. Waldvogel, Adv.
Synth. Catal. 2004, 346, 675, and references therein.
[10] a) For the first detailed studies, see: G. M. Whitesides, J.
SanFilippo, Jr., C. P. Casey, E. P. Panek, J. Am. Chem. Soc.
1967, 89, 5302; b) for an example of their use as an aggregation
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1974, 39, 400; c) for the oxidation of organocuprates under
“kinetic” conditions, see: B. H. Lipshutz, K. Siegmann, E.
Garcia, F. Kayser, J. Am. Chem. Soc. 1993, 115, 9276, and
references therein; e) for a recent application in crystal engi-
neering, see: Y. Morita, T. Murata, S. Yamada, M. Tadokoro, A.
Ichimura, K. Nakasuji, J. Chem. Soc. Perkin Trans. 1 2002, 2598.
[11] a) B. H. Lipshutz, F. Kayser, Z.-P. Liu, Angew. Chem. 1994, 106,
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Commun. 2000, 2329.
Experimental Section
General procedure for the biaryl bond-forming reaction: Titrated
iPrMgCl (1 mmol, 2.0m solution in THF) was added to a solution of
an aryl iodide (1 mmol) in THF (3 mL) at À208C. The reaction
mixture was then stirred for 10 min at À208C and then transferred by
cannula onto freshly recrystallized, solid CuBr·SMe2 (0.5 mmol).
After stirring the reaction mixture for 30 s, a solution of 3 (1 mmol) in
THF (3 mL) was added and the resulting solution was warmed to
ambient temperature. The reaction mixture was then filtered through
a plug of silica by using a mixture of hexane and EtOAc (1:1) as the
eluant. The filtrate was concentrated under reduced pressure and the
residue purified by flash column chromatography on silica gel.
3: 3,5-Dinitrobenzoic acid (21.2 g, 0.1 mol) was dissolved in
thionyl chloride (100 mL), heated at reflux for 10 h, and then cooled
to ambient temperature. Excess thionyl chloride was removed under
reduced pressure and by azeotropic distillation with toluene. The
residue was dissolved in CHCl3 (200 mL) and added dropwise to a
stirred slurry of 1-methylpiperazine (12.0 g, 0.12 mol) and K2CO3
(14 g, 0.1 mol) in CHCl3 (200 mL) at 08C. The reaction mixture was
warmed to ambient temperature over 1 h, washed with water (4 ꢁ
400 mL), dried over K2CO3, filtered, and the solvent removed under
reduced pressure. The residue was recrystallized from hexane as
yellow needles (20.4 g, 70%); m.p. 138–1418C; IR (film): n˜ = 1633,
1531, 1435, 1339, 1295, 1277, 1133, 995, 917, 908, 720, 681 cmÀ1
;
1H NMR (500 MHz; [D6]DMSO; 1208C): d = 8.87 (t, J = 2.0 Hz, 1H),
8.56 (d, J = 2.0 Hz, 2H), 3.54 (br, 4H), 2.42 (t, J = 5.0 Hz, 4H),
2.27 ppm (3H, s); 13C NMR (125 MHz; [D6]DMSO; 1208C): d
= 165.5, 149.1, 139.8, 127.6, 119.4, 54.7, 45.7 ppm; HRMS (ESI)
[MH]+ m/z = 295.1042, [C12H15N4O5]+ calcd m/z = 295.1043.
Received: November 17, 2004
Published online: February 9, 2005
[12] A. E. Jensen, W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P.
Knochel, Synthesis 2002, 565, and references therein.
[13] CuCN, CuSCN, and CuI gave comparable but lower yields.
[14] S. H. Bertz, C. P. Gibson, J. Am. Chem. Soc. 1986, 108, 8286.
[15] Other oxidants, such as FeCl3, [Fe(acac)3] (acac = acetylace-
tone), CuCl2, LiCuCl3, CrCl2, LiNO3, CeSO4, 2,3-dichloro-5,6-
À
Keywords: biaryls · C C coupling · medium-ring compounds ·
organocuprates · oxidation
.
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Chemie
dicyano-1,4-benzoquinone (DDQ), and potassium nitrosodisul-
fonate (Fremyꢄs salt), gave unsatisfactory yields.
[16] This compound is readily synthesized in high yield on a large
scale from commercially available starting materials (see the
Supporting Information) and can be stored indefinitely at room
temperature.
[17] The dianion of dinitrobenzene has been studied electrochemi-
cally; for an example see: H. Wang, V. D. Parker, Acta Chem.
Scand. 1994, 48, 933.
[18] An alternative possibility is that the biphenyl product can itself
act as a single-electron oxidant; however, this possibility was
ruled out as biphenyl did not act as an oxidant in control
reactions.
[19] It has recently been found that this dimerization proceeds in only
moderate yield in a palladium-catalyzed system, see: C. F.
Nising, U. K. Schmid, M. Nieger, S. Brꢅse, J. Org. Chem. 2004,
69, 6830.
[20] The halogen–metal exchange has recently been extended to
allow the formation of aryl magnesium compounds from the
corresponding aryl bromides: A. Krasovskiy, P. Knochel, Angew.
Chem. 2004, 116, 3396; Angew. Chem. Int. Ed. 2004, 43, 3333.
Our preliminary investigations suggest that Grignard reagents
formed in this way may also be used to form organocuprates,
which may be successfully oxidized under our conditions.
[21] a) M. Takahashi, T. Ogiku, K. Okamura, T. Da-te, H. Ohmizu, K.
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[22] The axial configuration of 2m was assigned by comparison to
literature data: G. Capozzi, C. Ciampi, G. Delogu, S. Menichetti,
C. Nativi, J. Org. Chem. 2001, 66, 8787.
[23] G. van Koten, S. L. James, J. T. B. H. Jastrzebski in Comprehen-
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Stone, G. Wilkinson, J. L. Wardell), Pergamon, Oxford, 1995,
chap. 2.
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