Pushing the limits of steric demand around a biaryl axis: Synthesis of tetra-ortho-substituted biaryl naphthalenes

Article abstract of DOI:10.1039/c0cc02170a

The synthesis of tetra-ortho-substituted biaryl naphthalenes, including examples bearing multiple ortho-isopropyl groups, has been developed via a catalytic rearrangement process.

Full text of DOI:10.1039/c0cc02170a

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Pushing the limits of steric demand around a biaryl axis:
synthesis of tetra-ortho-substituted biaryl naphthaleneswz
Adam C. Glass, Sam Klonoski, Lev N. Zakharovy and Shih-Yuan Liu*
Received 29th June 2010, Accepted 27th July 2010
DOI: 10.1039/c0cc02170a
The synthesis of tetra-ortho-substituted biaryl naphthalenes,
including examples bearing multiple ortho-isopropyl groups,
has been developed via a catalytic rearrangement process.
Substituted biaryls are important substructures of many
biologically active compounds,1 organic materials,2 and
ligands in metal catalysts.3 The development of methods for
the synthesis of biaryls has mostly been dominated by metal-
mediated coupling chemistry (i.e., cross-coupling,4 direct
arylation,5 and oxidative coupling6) due to its versatility.
Scheme 1 Ring-expansion rearrangement strategy for the synthesis
However, the assembly of highly substituted biaryls, in particular
tetra-ortho-substituted derivatives, has generally been challenging
for coupling-based strategies.7,8 This is arguably due to the
steric demand imposed by the coupling of two bis-ortho-
substituted biaryl precursors. Alternative approaches toward
the construction of tetra-ortho-substituted biaryls have
recently been developed that include annulation-based strategies,
e.g., Diels–Alder9 and [2+2+2] cycloadditions.10
of tetra-ortho-substituted biaryl naphthalenes.
cyclopropyl carbonyl compound 1 (Table 1) as a representa-
tive electrophile for our survey. As can be seen from Table 1,
the isolated yields of the addition products 2 are relatively
independent of the electronic nature (entries 1–5) as well as the
steric demand (entry 1 vs. entry 8, and entries 5–7) of the
nucleophiles. A consistent yield of B70% yield was observed.
Somewhat surprisingly, the highest isolated yield (81%) for
the generation of 2 resulted from the addition of the largest
nucleophile, 2,4,6-triisopropylphenyllithium (entry 7).
Despite the significant advances that have been made
to date, novel strategies for the generation of tetra-ortho-
substituted biaryls are still highly desired. We have been
pursuing a rearrangement-based approach for the synthesis
of substituted biaryl naphthalenes.11–13 Scheme 1 illustrates
our strategy in which the addition of an arene nucleophile
to the starting material A is followed by a ring-expansion
rearrangement to furnish the desired biaryl naphthalene C via
a cyclopropyl carbinol intermediate B. The distinguishing
feature of our approach is that the key C–C bond-forming
step is accomplished through a simple addition of a nucleophile
to a carbonyl.14 Given the strong thermodynamic driving force
for this nucleophilic addition,15 we envision that our method
could serve as a potential method for the construction of tetra-
ortho-substituted biaryl naphthalenes. In this communication,
we demonstrate that a range of tetra-ortho-substituted biaryl
naphthalenes can be produced via our method, including
a very hindered tetra-ortho-substituted biaryl naphthalene
bearing three isopropyl groups in the ortho positions.
This nucleophilic addition reaction is highly diastereoselective.
Only one single diastereomer was observed for each of the
1
products 2 (as analyzed by H NMR). We have structurally
characterized the adduct between
2 and 2-methoxy-1-
naphthyllithium, i.e., 2c, via single crystal X-ray crystallo-
graphy. The relative stereochemistry of the structure is consistent
with an approach of the nucleophile opposite the blocking
silylcyclopropane group (see Table 1). Interestingly, com-
pound 2c adopts a conformation in the solid state where the
carbinol proton H(1) engages in hydrogen bonding with the
oxygen O(2) of the methoxynaphthalene (O(2)–H(1) = 1.83(2) A,
sum of van der Waals radii = 2.72 A).16
Having established the synthesis of an array of rearrange-
ment precursors 2, we turned our attention to the catalytic
ring-expansion rearrangement. We determined that the
rearrangement of cyclopropyl carbinol 2a in the presence of
a catalytic amount of Lewis acid furnished the desired tetra-
ortho-substituted biaryl 3a, however as a 73 : 27 mixture with
its undesired tri-ortho-substituted isomer 4a (Table 2, entry 1).11
We discovered that the choice of solvent has a dramatic
influence on regioselectivity. When the reaction is performed
in toluene instead of 1,2-dichloroethane, the ratio of 3a to 4a
improves to 93 : 7 (Table 2, entry 2). Other solvents that we
screened did not improve the yield and/or the regioselectivity
significantly (Table 2, entries 3–8). Interestingly, a reversal of
regioselectivity was observed when acetonitrile was used as the
solvent (Table 2, entry 8). We also screened a number of
Lewis acids (Table 2, entries 9–12) and found europium triflate
(entry 2) to be the most efficient catalyst under our conditions.
We first investigated the feasibility of the nucleophilic
addition to starting material A (Step 1 in Scheme 1). We chose
Department of Chemistry, University of Oregon, Eugene, Oregon
97403, USA. E-mail: lsy@uoregon.edu; Fax: +1 (541) 346-0487;
Tel: +1 (541) 346-5573
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures, compound characterization data. CCDC 778408 and
CCDC 778409 contain the supplementary crystallographic data for
complex 2c and 7d, respectively. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc02170a
y Correspondence concerning X-ray crystallography should be
directed to Lev Zakharov (E-mail: lev@uoregon.edu).
c
286 Chem. Commun., 2011, 47, 286–288
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Table 1 Nucleophilic addition to 1
Table 3 Rearrangement of 2 under optimized conditions
Entry
Precursor
Nu
Yield %a
3 : 4b
Entry
Li–Nu
Product
Yield %a
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
71
43
63
55
79
78
93 : 7
>95 : 5
>95 : 5
>95 : 5
>95 : 5
>95 : 5
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
70
71
67
70
68
67
7
2g
86
>95 : 5
>95 : 5
8
2h
79
7
2g
2h
81
68
a
b
1
Isolated yield, average of two runs. Determined by H NMR.
8
which gave a 93 : 7 mixture of regioisomers, all other
substrates that we tested gave the tetra-ortho-substituted
isomer exclusively. Noteworthy is the rearrangement of 2g,
which produced a tetra-ortho-substituted biaryl bearing two
ortho-isopropyl groups in 86% yield.
a
Isolated yield, average of two runs.
Table 2 Optimization survey for the regioselective synthesis of 3a
Encouraged by these results, we sought to push the limits of
steric demand around the biaryl axis by replacing the a-methyl
group in 1 with an isopropyl group. The corresponding
precursor 5 (Scheme 2) can be synthesized in a few steps from
commercially available indanone.17 Scheme 2 shows that a
series of bis-ortho-substituted phenyllithium nucleophiles add
to the carbonyl electrophile 5 in modest yield.
Entry
Catalyst
Solvent
Yield %a
3a : 4ab
1
2
3
4
5
6
7
8
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Eu(OTf)3
Sm(OTf)3
Er(OTf)3
SnCl4
1,2-Dichloroethane
Toluene
THF
DMF
t-BuOH
PhCl
1,3-Dichlorobenzene
MeCN
Toluene
Toluene
Toluene
Toluene
68
78
54
29
42
53
52
15
76
79
31
29
73 : 27
93 : 7
92 : 8
76 : 24
82 : 18
96 : 4
We were very pleased to observe that intermediates 6a–6d
underwent catalytic ring opening rearrangement under our
optimized conditions to yield hindered tetra-ortho-substituted
biaryl naphthalenes. As can be seen from Table 4, the isolated
yields are independent of the steric demand around the biaryl
axis. ‘‘Nucleophiles’’ (Nu in Table 4) containing methoxy,
methyl, ethyl, and isopropyl groups in the 2,6-positions
rearrange to produce the desired biaryl in reasonable yield
(entries 1–4). We were also very pleased to see that the
93 : 7
25 : 75
85 : 15
81 : 19
40 : 60
35 : 65
9
10
11
12
BF3ꢀEt2O
a
GC yield (3a + 4a) vs. a calibrated internal standard, average of two
b
runs. Determined by GC.
With an optimized rearrangement protocol established, we
subjected the various rearrangement precursors 2 from Table 1
to these conditions to test the scope of our method. We were
pleased to see that a variety of substrates rearranged to furnish the
desired biaryl naphthalenes in moderate to good yields (Table 3).
With the exception of entry 1 (Nu = 2,6-dimethoxyphenyl),
Scheme 2 Nucleophilic addition to 5.
c
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Table 4 Rearrangement of 6 under optimized conditions
yield (over two steps) in 52% ee. Current efforts are geared
toward optimizing the efficiency of this asymmetric process
and developing a better understanding of its mechanism.
Support has been provided by the University of Oregon. This
material is based upon work supported by the National Science
Foundation under Grant No. DGE-0742540 (A.C.G.).
Entry
Precursor
Nu
Yield %a
7 : 8b
Notes and references
1
2
3
6a
6b
6c
63
73
73
>95 : 5
>95 : 5
>95 : 5
1 For examples, see: G. Bringmann and D. Menche, Acc. Chem.
Res., 2001, 34, 615–624.
2 For recent examples, see: (a) K. Takaishi, M. Kawamoto and
K. Tsubaki, Org. Lett., 2010, 12, 1832–1835; (b) Y. Ueno,
S. Komatsuzaki, K. Takasu, S. Kawai, Y. Kitamura and
Y. Kitade, Eur. J. Org. Chem., 2009, 4763–4769.
3 For an overview of biaryl phosphine, BINAP, and BINOL ligands
in catalysis applications, see: (a) D. S. Surry and S. L. Buchwald,
Angew. Chem., Int. Ed., 2008, 47, 6338–6361; (b) M. Berthod,
G. Mignani, G. Woodward and M. Lemaire, Chem. Rev., 2005,
105, 1801–1836; (c) J. M. Brunel, Chem. Rev., 2005, 105, 857–897.
4 For an overview, see: Modern Arylation Methods, ed.
L. Ackermann, Wiley-VCH, Weinheim, Germany, 2009.
5 For an overview, see: (a) D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174–238; (b) G. P. McGlacken and
L. M. Bateman, Chem. Soc. Rev., 2009, 38, 2447–2464.
6 For an overview, see: (a) M. C. Kozlowski, B. J. Morgan and
E. C. Linton, Chem. Soc. Rev., 2009, 38, 3193–3207;
(b) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540–548.
7 For recent successful examples, see: (a) M. G. Organ, S. Calimsiz,
M. Sayah, K. H. Hoi and A. J. Lough, Angew. Chem., Int. Ed., 2009,
48, 2383–2387; (b) L. Ackermann, H. K. Potukuchi, A. Althammer,
R. Born and P. Mayer, Org. Lett., 2010, 12, 1004–1007.
4
6d
76
>95 : 5
a
b
Isolated yield, average of two runs. Determined by H NMR.
1
undesired regioisomer 8 is not observed under our reaction
conditions. Noteworthy is the synthesis of 7d, which is a tetra-
ortho-substituted biaryl containing three ortho-isopropyl
substituents. To the best of our knowledge, it is the most sterically
encumbered biaryl naphthalene that has been synthesized to date.
We have structurally characterized 7d via single crystal X-ray
diffraction, thus unambiguously establishing its identity.
8 For pioneering work in the synthesis of tetra-ortho-substituted
biaryls via cross-coupling, see: (a) S. Miyano, S. Okada, T. Suzuki,
S. Handa and H. Hashimoto, Bull. Chem. Soc. Jpn., 1986, 59,
2044–2046; (b) C. Dai and G. C. Fu, J. Am. Chem. Soc., 2001, 123,
2719–2724; (c) A. F. Littke, L. Schwarz and G. C. Fu, J. Am.
Chem. Soc., 2002, 124, 6343–6348; (d) J. Yin, M. P. Rainka,
X. X. Zhang and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124,
1162–1163; (e) J. E. Milne and S. L. Buchwald, J. Am. Chem. Soc.,
2004, 126, 13028–13032.
In order to improve the utility of our synthetic method, we
attempted the rearrangement without isolating the cyclopropyl
carbinol intermediate (Compound B in Scheme 1). When 1 was
treated with organolithium reagents followed by catalytic ring
expansion rearrangement, we observed the formation of the
desired biaryl naphthalenes 9 in up to 65% yield over two steps
(Table 5). The undesired tri-ortho-substituted biaryl was not
observed under these conditions.
9 For leading references, see: (a) J. R. Perkins and R. G. Carter,
J. Am. Chem. Soc., 2008, 130, 3290–3291; (b) M. Hapke, A. Gutnov,
N. Weding, A. Spannenberg, C. Fischer, C. Benkhauser-Schunk and
¨
B. Heller, Eur. J. Org. Chem., 2010, 509–514.
10 For leading references, see: (a) K. Tanaka, Chem.–Asian J., 2009,
4, 508–518; (b) G. Nishida, K. Noguchi, M. Hirano and
K. Tanaka, Angew. Chem., Int. Ed., 2007, 46, 3951–3954.
11 A. C. Glass, B. B. Morris, L. N. Zakharov and S.-Y. Liu, Org.
Lett., 2008, 10, 4855–4857.
12 For a comprehensive review on the synthesis of substituted
naphthalenes, see: C. B. de Koning, A. L. Rousseau and W. A. L.
van Otterlo, Tetrahedron, 2003, 59, 7–36.
13 For leading referencesof biaryl naphthalene synthesis using
rearrangement-based methods, see: (a) Y. Nishii, T. Yoshida,
H. Asano, K. Wakasugi, J. Morita, Y. Aso, E. Yoshida,
J. Motoyoshiya, H. Aoyama and Y. Tanabe, J. Org. Chem.,
2005, 70, 2667–2678; (b) G. S. Viswanathan, M. Wang and
C.-J. Li, Angew. Chem., Int. Ed., 2002, 41, 2138–2141;
(c) T. Shibata, Y. Ueno and K. Kanda, Synlett, 2006, 411–414;
(d) T. Hamura, T. Suzuki, T. Matsumoto and K. Suzuki, Angew.
Chem., Int. Ed., 2006, 45, 6294–6296; (e) Z. B. Zhu, Y. Wei and
M. Shi, Chem.–Eur. J., 2009, 15, 7543–7548; (f) A. Padwa,
U. Chiacchio, D. J. Fairfax, J. M. Kassir, A. Litrico,
M. A. Semones and S. L. Xu, J. Org. Chem., 1993, 58,
6429–6437. To the best of our knowledge, there were no examples
of tetra-ortho-substituted biaryl naphthalenes in these reports.
14 M. Hatano, T. Miyamoto and K. Ishihara, Curr. Org. Chem.,
2007, 11, 127–157.
We have initiated preliminary studies toward an asymmetric
version of this process. To this end, we successfully isolated
optically pure 1 via semi-preparatory chiral HPLC. Treatment of
optically pure 1 with 2-methoxynaphthyllithium and subsequent
catalytic rearrangement with Eu(OTf)3 furnished the desired
tetra-ortho-substituted biaryl naphthalene 3c in 54% isolated
Table 5 Biaryl naphthalene synthesis without isolation of intermediates
Entry
1
Li–Nu
Product
Yield %a
9a
9b
61
65
15 For example, the enthalpy of the addition of MeMgBr to di-t-butyl
ketone has been determined to be ꢁ150 kJ molꢁ1, see: T. Holm, Acta
Chem. Scand., Ser. B, 1976, 30, 985–990.
2
a
16 A. Bondi, J. Phys. Chem., 1964, 68, 441–451.
17 See Supporting Information for details.
Isolated yield, average of two runs.
c
288 Chem. Commun., 2011, 47, 286–288
This journal is The Royal Society of Chemistry 2011