Synthesis of chromans via Pd-catalyzed alkene carboetherification reactions

Article abstract of DOI:10.1039/c1cc15880e

A new method for the construction of 2-substituted and 2,2-disubstituted chromans via Pd-catalyzed carboetherification reactions between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols is described. These reactions effect formation of a C-O bond and a C-C bond to afford the chroman products in good yield, and also provide stereoselective access to tricyclic chroman derivatives.

Full text of DOI:10.1039/c1cc15880e

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Synthesis of chromans via Pd-catalyzed alkene carboetherification
reactionswz
Amanda F. Ward, Yan Xu and John P. Wolfe*
Received 22nd September 2011, Accepted 11th November 2011
DOI: 10.1039/c1cc15880e
A new method for the construction of 2-substituted and
2,2-disubstituted chromans via Pd-catalyzed carboetherification
reactions between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols
is described. These reactions effect formation of a C–O bond and a
C–C bond to afford the chroman products in good yield, and also
provide stereoselective access to tricyclic chroman derivatives.
Chromans and other benzo-fused oxygen heterocycles are displayed
in a number of biologically active natural products,1 including
a-tocopherol2a and polyalthidin.2b In addition, 2-benzylchroman
derivatives such as englitazone (1, antidiabetic activity)3a and
molecules with general structure 2 (b-secretase inhibitory
activities)3b have been explored as pharmaceutical leads (Fig. 1).
Over the past several years we have developed a new
Scheme 1 Palladium-catalyzed carboetherification reactions of alcohols
approach to the construction of substituted tetrahydrofurans
via palladium-catalyzed carboetherification reactions between
aryl or alkenyl halides and alcohols bearing pendant alkenes.4–6
For example, treatment of alcohol 3 with 4-bromobiphenyl,
NaOtBu, and a catalyst composed of Pd2(dba)3/Dpe-Phos
provided 4 in 70% yield with >20 : 1 dr (Scheme 1). We
envisioned that this method could provide a concise and
convergent approach to benzofurans or chromans7,8 from
simple starting materials (phenols bearing pendant alkenes).9
However, although the Pd-catalyzed carboetherification reactions
were quite effective for the generation of tetrahydrofurans, our
efforts to employ Pd-catalyzed carboetherification reactions for
the synthesis of 6-membered heterocycles (e.g. tetrahydropyrans)
failed to afford satisfactory results.10 In addition, the scope of our
vs. phenols.
carboetherification method appeared to be limited to aliphatic
alcohol substrates, as efforts to couple 2-allylphenol 5 with
bromobenzene failed to generate the desired substituted
benzofuran product.11 Instead, the formation of 2-(prop-1-
en-1-yl)phenol 6 via double bond isomerization was observed.
We have previously illustrated that the mechanism of
Pd-catalyzed carboetherification reactions, such as those shown
in Scheme 1, involves suprafacial insertion of the substrate
alkene into the Pd–O bond of an intermediate palladium
alkoxide complex.4,5a Recent mechanistic studies conducted
by our group and others have shown that the rate of alkene
insertion into Pd-heteroatom bonds is highly dependent on the
nucleophilicity of the heteroatom, and the insertion likely
occurs from an intermediate Pd-complex that bears a single
phosphine ligand.12 These results suggest that two factors may
be responsible for the poor reactivity of phenols such as 5 in
Pd/Dpe-Phos-catalyzed carboetherifications: (a) the relatively
low nucleophilicity of phenols as compared to aliphatic alcohols;
and (b) use of the chelating bis-phosphine Dpe-Phos, which may
disfavor generation of the reactive monophosphine intermediate.
These factors apparently slow the catalytic reaction to the point
that alkene isomerization of 5 to 6 occurs more rapidly than the
desired transformation.
Fig. 1 Biologically active 2-benzylchroman derivatives.
University of Michigan, Department of Chemistry, 930 N. University
Ave., Ann Arbor, MI 48109-1055, USA. E-mail: jpwolfe@umich.edu;
Tel: +1 734-763-3432
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for all new compounds reported in the
text. See DOI: 10.1039/c1cc15880e
The hypothesis outlined above suggests that use of catalysts
bearing monodentate phosphine ligands may provide improved
results in carboetherification reactions of phenol derivatives, as
these ligands could potentially facilitate the key alkene insertion
step. In addition, we also anticipated that the conversion of
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 609–611 609

Table 1 Optimization of ligand for the coupling of 7 with bromobenzenea
Table 2 Pd-catalyzed carboetherification reactions of phenols
bearing pendant alkenesa
Entry
1
Ligand
Yieldb (%)
84 (75)
2
3
4
5
76
31
12
47
30
6
a
Conditions: 1.0 equiv. 7, 2.0 equiv. PhBr, 2.0 equiv. NaOtBu,
b
2 mol% Pd2(dba)3, 4 mol% ligand, toluene (0.25 M), 110 1C. Yield
were determined by 1H NMR analysis of crude reaction mixtures using
phenanthrene as an internal standard. The yield in parentheses is an
isolated yield of the pure product.
2-(but-3-en-1-yl)phenol (7) to chroman 8 (Table 1) may be
more straightforward than the analogous transformation of
2-allylphenol (5) to a benzofuran derivative, as 7 should be
much less prone to base-mediated alkene isomerization than 5.
Thus, we elected to initially examine the coupling of 7 with
bromobenzene using the biaryl monophosphine ligand S-Phos.
We had previously found that this ligand provided good
results in other challenging carboetherification reactions,5e
and we were gratified to discover that these conditions
afforded the desired product 8 in 86% isolated yield. A quick
survey of related biaryl phosphines did not lead to any further
improvement in yield (entries 2–5), and Dpe-Phos produced 8
in only 30% yield (entry 6).
In order to examine the scope of the phenol carboetherification
reactions, a number of substrates with different substitution
patterns were synthesized and subjected to the optimized reaction
conditions. As shown in Table 2, substrates 7, 9, and 10 were
converted to 2-substituted- or 2,2-disubstituted chromans in
moderate to good yield (entries 1–9). In addition, cyclopentane-
and cyclohexane-derived substrates 11–12 were transformed
into tricyclic products 22–24 with high diastereoselectivity
(entries 10–12). However, stereocontrol was poor in the reaction
of 13 with 4-bromo-tert-butylbenzene (2: 1 dr), and a significant
amount (ca. 25%) of an inseparable unidentified low molecular
a
Conditions: 1.0 equiv. phenol substrate, 2.0 equiv. R-Br, 2.0 equiv.
NaOtBu, 2 mol% Pd2(dba)3, 4 mol% S-Phos, toluene (0.25 M),
b
c
110 1C. Isolated yield (average of two experiments). The two
inseparable stereoisomeric products were isolated in 63% yield and
ca. 75% purity. The remaining 25% of the mixture was primarily
composed of an unidentified low molecular weight side product that
appears to be derived from the phenol substrate.
weight side product was also formed (entry 13). In addition,
substrates bearing internal alkenes failed to undergo the
c
610 Chem. Commun., 2012, 48, 609–611
This journal is The Royal Society of Chemistry 2012

desired transformation; no reaction was observed at temperatures
up to 140 1C. Although these new reaction conditions were
generally effective for the preparation of chromans, efforts to
transform 5 into substituted benzofuran 26 were still only
modestly successful; the desired product was generated in 37%
yield (entry 14).
J. Org. Chem., 2005, 70, 3099; (e) A. F. Ward and J. P. Wolfe, Org.
Lett., 2009, 11, 2209.
6 For recent, complementary alkene difunctionalization reactions of
unsaturated alcohols that generate disubstituted tetrahydrofurans
with formation of both a C–C and a C–O bond, see: (a) P. Fries,
D. Halter, A. Kleinschek and J. Hartung, J. Am. Chem. Soc., 2011,
133, 3906; (b) Z. Chen and J. R. Falck, Angew. Chem., Int. Ed.,
2011, 50, 6626; (c) G. Zhang, L. Cui, Y. Wang and L. Zhang,
J. Am. Chem. Soc., 2010, 132, 1474; (d) S. Protti, D. Dondi,
M. Fagnoni and A. Albini, Eur. J. Org. Chem., 2008, 2240;
(e) X. Yang, X. Fang, X. Yang, M. Zhao, Y. Han, Y. Shen and
F. Wu, Tetrahedron, 2008, 64, 2259.
7 For recent reviews on the synthesis of chromans, see: (a) ref. 1;
(b) Y. Tang, J. Oppenheimer, Z. Song, L. You, X. Zhang and
R. P. Hsung, Tetrahedron, 2006, 62, 10785; (c) S. B. Ferreira, F. de
C. da Silva, A. C. Pinto, D. T. G. Gonzaga and V. F. Ferreira,
J. Heterocycl. Chem., 2009, 46, 1080; (d) Y.-L. Shi and M. Shi, Org.
Biomol. Chem., 2007, 5, 1499.
8 For selected recent syntheses of chroman derivatives, see:
(a) D. Enders, X. Yang, C. Wang, G. Raabe and J. Runsik,
Chem.–Asian. J., 2011, 6, 2255; (b) Z. Xin, Y. Zhang, H. Tao,
J. Xue and Y. Li, Synlett, 2011, 1579; (c) G. Hernandez-Torres,
M. C. Carreno, A. Urbano and F. Colobert, Eur. J. Org. Chem.,
2011, 3864; (d) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An,
Q.-Q. Yang, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed.,
2010, 49, 8379; (e) M. Leibeling, D. C. Koester, M. Pawliczek,
S. C. Schild and D. B. Werz, Nat. Chem. Biol., 2010, 6, 199.
9 Two other Pd-catalyzed alkene carboetherification methods have
successfully been employed for synthesis of benzofurans or
chromans from phenols bearing pendant alkenes. However, these
A range of different electrophiles were examined in the
carboetherification reactions of 7, 9, and 10. As shown in
Table 2, aryl halides bearing chloride, fluoride, methoxy and
diaryl ketone functionality were successfully converted to the
desired products. Alkenyl halides were also effective coupling
partners in these reactions (entries 6–7), and the coupling of 9
with the heteroaryl halide 3-bromopyridine also proceeded
smoothly (entry 4). However, the scope of carboetherification
reactions involving 11 and 12 was not as broad, and the use of
aryl halides that were relatively electron rich or electron
deficient led to poor reactivity or low yields.
In conclusion, we have developed a new method for
the construction of 2-substituted chroman derivatives via
Pd-catalyzed carboetherification reactions. These transformations
employ simple substrates, and provide access to a number of
different derivatives in a straightforward manner. In addition these
are the first examples of Pd-catalyzed alkene carboetherification
reactions between aryl bromides and alkenyl phenols, and are
also rare cases in which six-membered oxygen heterocycles
are generated via 1,2-alkene carboheterofunctionalization
processes. Future studies will be directed towards the development
of catalysts for enantioselective variants of these transformations.
transformations appear to be limited to alkenes bearing
a
substituent on the internal carbon atom. For Pd-catalyzed oxyalky-
nylation reactions between unsaturated phenols and hypervalent
iodoalkyne reagents, see: (a) S. Nicolai, S. Erard, D. F. Gonzalez
and J. Waser, Org. Lett., 2010, 12, 384. For Pd-catalyzed domino
Wacker/Heck reactions between unsaturated phenols and a,b-
unsaturated esters or ketones, see: (b) L. F. Tietze, D. A. Spiegel,
F. Stecker, J. Major, C. Raith and C. Große, Chem.–Eur. J., 2008,
14, 8956; (c) L. F. Tietze, J. Zinngrebe, D. A. Spiegel and
F. Stecker, Heterocycles, 2007, 74, 473; (d) L. F. Tietze,
F. Stecker, J. Zinngrebe and K. M. Sommer, Chem.–Eur. J.,
2006, 12, 8770; (e) L. F. Tietze, K. M. Sommer, J. Zinngrebe
and F. Stecker, Angew. Chem., Int. Ed., 2005, 44, 257.
Notes and references
1 H. C. Shen, Tetrahedron, 2009, 65, 3931.
2 (a) J.-M. Zingg and A. Azzi, Curr. Med. Chem., 2004, 11, 1113 and
references cited therein; (b) M. C. Zafra-Polo, M. C. Gonzalez,
J. R. Tormo, E. Estornell and D. Cortes, J. Nat. Prod., 1996,
59, 913.
3 (a) F. J. Urban and B. S. Moore, J. Heterocycl. Chem., 1992,
29, 431 and references cited therein; (b) K. W. Hunt, J. P. Rizzi and
A. Cook, PCT Int. Appl., WO 2011072064A1, 2011.
4 For reviews, see: (a) J. P. Wolfe, Eur. J. Org. Chem., 2007, 571;
(b) J. P. Wolfe, Synlett, 2008, 2913.
5 (a) M. B. Hay and J. P. Wolfe, J. Am. Chem. Soc., 2005,
127, 16468; (b) J. P. Wolfe and M. A. Rossi, J. Am. Chem. Soc.,
2004, 126, 1620; (c) M. B. Hay and J. P. Wolfe, Tetrahedron Lett.,
2006, 47, 2793; (d) M. B. Hay, A. R. Hardin and J. P. Wolfe,
10 Only a single example of a Pd-catalyzed alkene difunctionalization
reaction that generates a tetrahydropyran product has been
reported. See ref. 6c.
11 M. B. Hay, A. F. Ward, J. P. Wolfe, unpublished results.
12 (a) J. D. Neukom, N. S. Perch and J. P. Wolfe, Organometallics,
2011, 30, 1269; (b) J. D. Neukom, N. S. Perch and J. P. Wolfe,
J. Am. Chem. Soc., 2010, 132, 6276; (c) P. S. Hanley, D. Markovic
and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 6302;
(d) P. S. Hanley and J. F. Hartwig, J. Am. Chem. Soc., 2011,
133, 15661.
c
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Chem. Commun., 2012, 48, 609–611 611