Functionalizations of [6]- and [7]Helicenes at Their Most Sterically Hindered Positions

Article abstract of DOI:10.1021/jo035057t

Although the reactions of enol ethers of aryl methyl ketones with benzoquinone make it easy to prepare nonracemic helicenes that are substituted by hydroxyl groups at their 1,ω-positions, the hydroxyl groups fail to facilitate the introduction of electrop

Full text of DOI:10.1021/jo035057t

F u n ction a liza tion s of [6]- a n d [7]Helicen es a t Th eir Most Ster ica lly
Hin d er ed P osition s
Kamil Paruch,†,| Libor Vyklicky´,† David Zhigang Wang,† Thomas J . Katz,*,†
Christopher Incarvito,‡, Lev Zakharov,‡,§ and Arnold L. Rheingold‡,§
Department of Chemistry, Columbia University, New York, New York 10027, Department of Chemistry
and Biochemistry, University of CaliforniasSan Diego, La J olla, California 92093-0358, and Department
of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
tjk1@columbia.edu
Received J uly 22, 2003
Although the reactions of enol ethers of aryl methyl ketones with benzoquinone make it easy to
prepare nonracemic helicenes that are substituted by hydroxyl groups at their 1,ω-positions, the
hydroxyl groups fail to facilitate the introduction of electrophiles ortho to them. However, ethers
of [6]- and [7]helicenols prepared in this way, seemingly because of the activation by the alkoxyl
groups at the 6-positions, combine with electrophilic reagents to introduce bromines and acyl groups
exactly into these positions. Moreover, these bromine and acyl groups can be transformed into
other functional groups (including phosphine oxides and acetylenes), the ether functions adjacent
to these functional groups can then be removed, and the phenols can be oxidized to quinone-acetals.
An alternative way to introduce functional groups next to the phenols is to rearrange their phosphate
esters. Two reactions that differentiate the ends of the helicenes are also described.
In tr od u ction
selective complexing agents,9 as chiral auxiliaries,10 as
inducers of enantioselectivity,11 or as fluoresence sen-
sors.12 These examples usually have substituents in
positions 1,2 and 15,16 of a [6]helicene skeleton, positions
1,2 and 17,18 of a [7]helicene skeleton, or positions 1,2
and ω,(ω-1) of a general helicene.
Helicenes, examples of which are [6]- and [7]helicenes,
structures 1 and 2, are chiral, conjugated molecules
whose derivatives in enantiomerically pure form have
been used as building blocks for helical conjugated
polymers,1 helical ligands,2 and structures that exhibit
unusual chiro-optical,3 electro-optical,4 and fluorescense5
properties or act as catalysts for enantioselective trans-
formations,6,7 as chiral derivatizing agents,8 as enantio-
† Columbia University.
‡ University of Delaware.
§ University of CaliforniasSan Diego (current address).
| Current Address: Schering-Plough Research Institute, 2015 Gal-
loping Hill Rd., Kenilworth, NJ 07033.
Current Address: Department of Chemistry, Yale University, New
Haven, CT 06520.
* Corresponding author.
The way helicenes substituted at positions 1 and 2
were prepared originally was by photocyclizing appro-
priately substituted diarylethenes.13 [6]- and [7]Helicenes
bearing OMe,10b,13b,14 Br,9a,11a,13a,15 CHO,13a CO2R,13a,16
CN,11a,13a and Me13a,17 were synthesized in this way.
However, this photochemical route has significant defi-
(1) (a) Sudhakar, A.; Katz, T. J .; Yang, B.-W. J . Am. Chem. Soc.
1986, 108, 2790. (b) Katz, T. J .; Sudhakar, A.; Teasley, M. F.; Gilbert,
A. M.; Geiger, W. E.; Robben, M. P.; Wuensch, M.; Ward, M. D. J . Am.
Chem. Soc. 1993, 115, 3182. (c) Gilbert, A. M.; Katz, T. J .; Geiger, W.
E.; Robben, M. P.; Rheingold, A. L. J . Am. Chem. Soc. 1993, 115, 3199.
(d) Dai, Y.; Katz, T. J . J . Org. Chem. 1997, 62, 1274. (e) Fox, J . M.;
Lin, D.; Itagaki, Y.; Fujita, T. J . Org. Chem. 1998, 63, 2031.
(2) Fox, J . M.; Katz, T. J . J . Org. Chem. 1999, 64, 302.
(3) (a) Nuckolls, C.; Katz, T. J .; Katz, G.; Collings, P. J .; Castellanos,
L. J . Am. Chem. Soc. 1999, 121, 79 and references therein. (b) Busson,
B.; Kauranen, M.; Nuckolls, C.; Katz, T. J .; Persoons, A. Phys. Rev.
Lett. 2000, 84, 79. (c) Verbiest, T.; Sioncke, S.; Persoons, A.; Vyklicky´,
L.; Katz, T. J . Angew. Chem., Int. Ed. 2002, 41, 3882.
(4) Nuckolls, C.; Shao, R.; J ang, W.-G.; Clark, N. A.; Walba, D. M.;
Katz, T. J . Chem. Mater. 2002, 14, 773.
(8) Weix, D. J .; Dreher, S. D.; Katz, T. J . J . Am. Chem. Soc. 2000,
122, 10027.
(9) (a) Yamamoto, K.; Ikeda, T.; Kitsuki, T.; Okamoto, Y.; Chika-
matsu, H.; Nakazaki, M. J . Chem. Soc., Perkin Trans. 1 1990, 271. (b)
Okubo, H.; Nakano, D.; Anzai, S.; Yamaguchi, M. J . Org. Chem. 2001,
66, 557. (c) Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett. 2000,
2, 3169.
(5) Phillips, K. E. S.; Katz, T. J .; J ockusch, S.; Lovinger, A. J .; Turro,
N. J . J . Am. Chem. Soc. 2001, 123, 11 899.
(6) (a) Reetz, M. T.; Beutenmu¨ller, E. W.; Goddard, R. Tetrahedron
Lett. 1997, 38, 3211. (b) Okubo, H.; Yamaguchi, M.; Kabuto, C. J . Org.
Chem. 1998, 63, 9500. (c) Dreher, S. D.; Katz, T. J .; Lam, K.-C.;
Rheingold, A. L. J . Org. Chem. 2000, 65, 815.
(7) Interestingly, even unfunctionalized helicenes can be used as
asymmetric catalysts. Sato, I.; Yamashima, R.; Kadowaki, K.; Yama-
moto, J .; Shibata, T.; Soai, K. Angew Chem., Int. Ed. 2001, 40, 1096.
(10) (a) Ben Hassine, B.; Gorsane, M.; Geerts-Evrard, F.; Pecher,
J .; Martin, R. H.; Castelet, D. Bull. Soc. Chim. Belg. 1986, 95, 547. (b)
Ben Hassine, B.; Gorsane, M.; Pecher, J .; Martin, R. H. Bull. Soc. Chim.
Belg. 1985, 94, 597. (c) Ben Hassine, B.; Gorsane, M.; Pecher, J .;
Martin, R. H. Bull. Soc. Chim. Belg. 1987, 96, 801.
(11) (a) Ben Hassine, B.; Gorsane, M.; Pecher, J .; Martin, R. H. Bull.
Soc. Chim. Belg. 1986, 95, 557. (b) Ben Hassine, B.; Gorsane, M.;
Pecher, J .; Martin, R. H. Bull. Soc. Chim. Belg. 1985, 94, 759.
(12) Reetz, M. T.; Sostmann, S. Tetrahedron 2001, 57, 2515.
10.1021/jo035057t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/03/2003
J . Org. Chem. 2003, 68, 8539-8544
8539

Paruch et al.
ciencies. It requires high dilution, which seriously limits
the amount of the material that can be prepared, and it
does not tolerate some groups (notably NO2 and NH2).13a
Among more recently developed methods to synthesize
functionalized helicenes,18 the Diels-Alder reaction of
enol ethers of bis(aryl methyl ketones) with 1,4-benzo-
quinone has been used to prepare substantial amounts
of helicenebisquinones.19 In both the photochemical and
Diels-Alder methods, the functional groups are usually
introduced before the main aromatic backbone is con-
structed. Functionalization of unsubstituted 1- or 2-posi-
tions after the main skeleton has been built is rare.
Examples are the addition of nucleophiles, amines,19a,20
and bromide1d to 6,11-dialkoxy[6]helicene-1,4,13,16-bis-
quinone, which regioselectively give, after oxidation, the
bisquinone’s 2,15-dibromo- and 2,15-diamino-derivatives.
In this paper, we describe how electrophiles can be
introduced with high regioselectivity onto methoxylated
[6]- and [7]helicenes that have been made by the Diels-
Alder-based route. Bromination, formylation, and acetyl-
ation substitute positions 2 and 15 in the former and the
analogous positions, 2 and 17, in the latter. The methoxyl
groups adjacent to the acetyl groups can then be cleaved
selectively by the action of BBr3. The resulting helical
salicylaldehydes and helical o-hydroxyacetophenones are
similar to helical salicylaldehydes previously used to
synthesize helical conjugated ladder polymers.1d The
functional groups introduced are transformed into others.
The regioselectivities of the transformations are con-
firmed by X-ray analysis.
prepare.19d,21 The reasons are that the Russig-Laatsch
reaction specifically alkylates those hydroxyl groups of
[6]- and [7]helicenebishydroquinones19d,21 that are at the
peripheries, leaving the other hydroxyl groups of the
hydroquinones at the 1- and ω-positions, and that these
helicenols are especially easy to resolve.3a,22 The absolute
stereochemistries of 3 and 4 are also known.19d,22 The
isomers that are dextrorotatory at the wavelength of the
sodium D-line have the P configuration. Although it
would seem that hydroxyl groups at the 1- and ω-posi-
tions could be used as handles to install additional
functionality at the 2- and 15-positions of the [6]helicene
and the 2- and 17-positions of the [7]helicene, attempts
to brominate 3 and 4 regioselectively1d gave complex
mixtures. Attempts to rearrange their diacetates by the
Fries procedure, using AlCl3 or Sc(OTf)3, to formylate the
diols by the Duff procedure (hexamethylenetetramine
and TFA),23 or to hydroxymethylate the diols by the use
of paraformaldehyde and either HCl alone or HCl in
AcOH led only to decomposition products. Instead of
introducing formyl groups next to the hydroxyl groups,
both POCl3 in DMF and the Arnold-Vilsmeier reagent24
in DMF gave mixtures whose main components (up to
40%) were the products that have formyl groups next to
only one of the hydroxyl groups and in place of the
hydrogen of the other hydroxyl group. But as shown in
Scheme 1, the 2- and (ω-1)-positions could successfully
be functionalized in 3a and 4a , the ethers formed when
3 and 4 are methylated.
Resu lts
Optically active dihydroxyhelicenes 3 and 4 were used
for the studies because they are particularly easy to
(13) (a) Mallory, F. B.; Mallory, C. W. Organic Reactions; Wiley:
New York, 1984; Vol. 30, p 1. (b) Liu, L.; Yang, B.; Katz, T. J .;
Poindexter, M. K. J . Org. Chem. 1991, 56, 3769. (c) Hopf, H. Classics
in Hydrocarbon Chemistry; Wiley-VCH: Weinheim, Germany, 2000;
Chapter 12, Section 12.1.
(14) (a) Yang, B.; Liu, L.; Katz, T. J .; Liberko, C. A.; Miller, L. L. J .
Am. Chem. Soc. 1991, 113, 8993. (b) Brown, J . M.; Field, I. P.;
Sidebottom, P. J . Tetrahedron Lett. 1981, 22, 4867. (c) Furche, F.;
Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.; Vo¨gtle, F.;
Grimme, S. J . Am. Chem. Soc. 2000, 122, 1717.
(15) Terfort, A.; Go¨rls, H.; Brunner, H. Synthesis 1997, 79.
(16) (a) Owens, L.; Thilgen, C.; Diederich, F.; Knobler, C. B. Helv.
Chim. Acta 1993, 76, 2757. (b) Wachsmann, C.; Weber, E.; Czugler,
M.; Seichter, W. Eur. J . Org. Chem. 2003, 2863.
(17) Sato, M.; Yamamoto, K.; Sonobe, H.; Yano, K.; Matsubara, H.;
Fujita, H.; Sugimoto, T.; Yamamoto, K. J . Chem. Soc., Perkin Trans.
2 1998, 1909.
(18) (a) Teply´, F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.;
Vyskocˇil, Sˇ.; Fiedler, P. J . Org. Chem. 2003, 68, 5193. (b) Stara´, I. G.;
Stary´, I.; Kollrovicˇ, A.; Teply´, F.; Sˇaman, D.; Fiedler, P. Collect. Czech.
Chem. Commun. 2003, 68, 917. (c) Sooksimuang, T.; Mandal, B. K. J .
Org. Chem. 2003, 68, 652. (d) Real, M.; Sestelo, J . P.; Sarandeses, L.
A. Tetrahedron Lett. 2002, 43, 9111. (e) Ogawa, Y.; Ueno, T.; Karikomi,
M.; Seki, K.; Haga, K. Uyehara, T. Tetrahedron Lett. 2002, 43, 7827.
(f) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem.-Eur. J . 2003,
9, 1412. (g) Field, J . E.; Hill, T. J .; Venkataraman, D. J . Org. Chem.
2003, 68, 6071. (h) For a list of recent non-photochemical preparations
of helicenes, see ref 5 in: Teply´, F.; Stara´, I. G.; Stara´, I.; Kollrovicˇ,
A.; Sˇaman, D.; Rul´ısˇek, L.; Fiedler, P. J . Am. Chem. Soc. 2002, 124,
9175.
Bromination of 3a and 4a with 2 equiv of NBS in 2:1
CH3CN-CH2Cl2 gave dibromohelicenes 3b and 4b in
25
high yields without detectable traces of regioisomers.
(NBS (1 equiv) gave 3b or 4b, along with the monobro-
minated products and starting materials 3a or 4a , in ca.
1:2:1 ratios.) Similarly, the benzyl ethers of 3 and of 4
gave the corresponding dibromo derivatives in 93% and
96% yields (see below), but the yields of the dibromo
derivatives obtained from other ethers and esters were
lower.26 Formylation of 3a and 4a in DMF at 25-80 °C
with (chloromethylene)dimethylammonium chloride (the
Arnold reagent)23 gave only monoformylated helicenes 3c
and 4c. No diformylated helicenes were obtained. More-
over, even for monoformylation to succeed with 3a , the
temperature had to be raised to 50 °C. However, when
the reagent was DMF plus POCl3 and the temperature
was 50-70 °C, the diformylations succeeded, and the
(21) Dreher, S. D.; Paruch, K.; Katz, T. J . J . Org. Chem. 2000, 65,
806.
(19) (a) Katz, T. J .; Liu, L.; Willmore, N. D.; Fox, J . M.; Rheingold,
A. L.; Shi, S.; Nuckolls, C.; Rickman, B. H. J . Am. Chem. Soc. 1997,
119, 10054. (b) Fox, J . M.; Goldberg, N. R.; Katz, T. J . J . Org. Chem.
1998, 63, 7456. (c) Dreher, S. D.; Weix, D. J .; Katz, T. J . J . Org. Chem.
1999, 64, 3671. (d) Paruch, K.; Katz, T. J .; Incarvito, C.; Lam, K.-C.;
Rhatigan, B.; Rheingold, A. L. J . Org. Chem. 2000, 65, 7602. (e) Paruch,
K.; Vyklicky´, L.; Katz, T. J .; Incarvito, C. D.; Rheingold, A. L. J . Org.
Chem. 2000, 65, 8774.
(22) Thongpanchang, T.; Paruch, K.; Katz, T. J .; Rheingold, A. L.;
Lam, K.-C.; Liable-Sands, L. J . Org. Chem. 2000, 65, 1850 and
references therein.
(23) Smith, W. E. J . Org. Chem. 1972, 37, 3972.
(24) J utz, C. Adv. Org. Chem. 1976, 9, 225.
(25) Carren˜o, M. C.; Garcia Ruano, J . L.; Sanz, G.; Toledo, M. A.;
Urbano, A. J . Org. Chem. 1995, 60, 5328.
(26) The bis-TMS and bismethoxymethyl ethers of 2 gave yields of
10% and <10%, while the bispivalate of 2 gave a 28% yield.
(20) Fox, J . M.; Katz, T. J . J . Org. Chem. 1999, 64, 302.
8540 J . Org. Chem., Vol. 68, No. 22, 2003

Functionalizations of [6]- amd [7]Helicenes
SCHEME 1a
a
Reaction conditions and yields. (a) t-BuOK, THF, then MeI (yields: 3a , 91%; 4a , 91%). (b) NBS, CH3CN, CH2Cl2, 25 °C, 1 h (yields:
3b, 93%; 4b, 87%). (c) ClCHdNMe2Cl, DMF, and(CH2Cl)2 (for 3c) or CH2Cl2 (for 4c) (yields: 3c, 59%; 4c, 60%). (d) DMF, POCl3, CH2Cl2,
50-70 °C (yields: 3d , 61%; 4d , 87%). (e) AcCl, AlCl3, CH2Cl2, 0 °C (yields: 3e, 80%; 4e, 53%); or Ac2O, AlCl3, CH2Cl2, 0 °C (yield: 4e,
63%). (f) AlCl3, AcCl, CH2Cl2, 25 °C (yields: 3f, 83%; 4f, 80%). (g) (i) BuLi; (ii) Ph2P(O)Cl, -78 °C, 4 h (yields: 3g, 51%; 4g, 67%). (h) BuLi,
THF, -78 °C, then DMF (yields: 3c, 35%, and 3d , 59%; 4c, 54%, and 4d , 21%). (i) BuLi, THF, -78 °C, then N-methoxy-N-methylacetamide
(yields: 3e, 37%, and 3f, 17%; 4e, 24%, and 4f, 9%).
SCHEME 2a
bisaldehydes 3d and 4d could be obtained in 61% and
87% yields. The structure of 4d was confirmed by X-ray
diffraction analysis.
Acetyl groups could also be introduced. Friedel-Crafts
acetylation with AlCl3 and AcCl in CH2Cl2 converts 3a
and 4a at 0 °C into monoacetylated helicenes 3e and 4e
and at 25 °C into the diacetylated products 3f and 4f. A
slightly better yield of 4e (63% instead of 53%) was
obtained when Ac2O was used instead of AcCl. The
regioselectivities of bromination, formylation, and acetyl-
ation are all the same. This was shown by the dibromi-
nated helicenes 3b and 4b when treated with BuLi and
then DMF, giving the diformylated helicenes 3d and 4d .
Monoformylated 3c and 4c were side products of these
transformations. Similar transformations of 3b and 4b
with N-methoxy-N-methylacetamide27 gave, respectively,
mixtures of 3e plus 3f and 4e plus 4f.
a
+
Reaction conditions and yields. (a) (i) ClCH2PPh3 Cl-, LiN-
Other functional groups could be placed in the 2- and
(ω-1)-positions by transforming those introduced ini-
tially. One functional group introduced in this way was
the ethynyl group, which was studied because ethynyl
functions at positions 2 and 15 made it possible to convert
a [6]helicene into a helical oligomer and a helical cyclo-
phane.28 Initial attempts to convert monoaldehyde 4c into
its 1,1-dibromoethylene derivative by the action of CBr4
(Si(CH3)3)2, THF; (ii) MeLi, THF (yields over the two steps: 3i,
72%; 3k , 56%; 4i, 76%; 4k , 53%). (b) PCl3, PCl5, PhH (yields: 3h ,
56%; 4h , 64%; 3j, 56%; 4j, 43%). (c) LDA, THF, -78 °C to +25 °C
(yields: 3i, 82%; 4i, 80%; 3k , 97%; 4k , 74%).
(ca. 30% for the two steps). Treatment of bisaldehyde 3d
with dimethyl-1-diazo-2-oxopropylphosphonate, as de-
scribed by Bestmann et al.,30 also produced the corre-
sponding bisalkyne 3k in very poor yield (traces according
to TLC). However, 3k , as well as alkynes 3i, 4i, and 4k ,
could be obtained in moderate to good yields (Scheme 2,
paths a) by treating the aldehydes with (chloromethyl)-
triphenylphosphonium chloride plus lithium bis(trimeth-
29
and PPh3 were indeed successful, but attempts to
convert this derivative into alkyne 4i gave only low yields
(27) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Oster, T. A.; Harris, T. M. Tetrahedron Lett. 1983, 24, 1851.
(28) Fox, J . M.; Lin, D.; Itagaki, Y.; Fujita, T. J . Org. Chem. 1998,
63, 2031.
(29) (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J . Am. Chem. Soc.
1962, 84, 1745. (b) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972,
13, 3769.
(30) Mu¨ller, S.; Liepold, B.; Roth, G. J .; Bestmann, H. J . Synlett
1996, 521.
J . Org. Chem, Vol. 68, No. 22, 2003 8541

Paruch et al.
SCHEME 3a
Attempts were also made to cleave the methoxy groups
adjacent to the phosphine oxide functions in 3g and 4g
by means of BBr3 (without Bu4NI), but the yields were
less than 15%. However, the goal of preparing 7f and 8f
could be achieved by making use of the selectivity with
which benzyl ethers are cleaved. Thus (Scheme 4) de-
benzylation by hydrogen in the presence of 10% pal-
ladium on carbon reduces 7b in ethyl acetate to 7c in a
yield of 81% and 8b in ethyl acetate to 8c in a yield of
85%. It is also interesting that further reaction can be
used to give 7d and 8d . The hydrogen pressure is
increased from 2.5 to 4 atm, and the reaction time is
extended from 30 min to 6-10 h. The consequence is that
7d and 8d , molecules that are selectively functionalized
at one end, can be obtained easily and in good yields.
The benzyl groups could also be removed from the
ether functions of phosphine oxides 7e and 8e (them-
selves prepared in the same way as the methyl ethers
3g and 4g in Scheme 1), but not, as above, by means of
hydrogen, but rather by means of ammonium formate
and palladium on carbon.40 Dihydroxybisphosphines 7g
and 8g could then be prepared in excellent yields by
removing the oxides from the phosphorus atoms of the
resulting 7f and 8f with HSiCl3 plus Bu3N,41 and they
were found to be fairly stable to oxidation. 1H NMR
analysis indicated that after its solution in CDCl3 had
been open to the air for 24 h, the extent to which 8g had
oxidized to the monophosphine oxide was 20%. The pure
solid did not oxidize appreciably during a period of 3 days.
A strategically different way to selectively functionalize
helicenes at the 1,ω- and 2,(ω-1)-positions made use of
1,3 migrations (Scheme 5).42 Upon treatment with LDA,
diethyl phosphates 9 and 10 rearrange cleanly, regiospe-
cifically, and in good yields to 11 and 12.
a
Reaction conditions and yields. (a) BBr3, tetrabutylammonium
iodide, CH2Cl2, -78 °C to 25 °C (yields: 5c, 37%; 6c, 66%; 5d ,
58%; 6d , 47%). (b) BBr3, CH2Cl2, -78 °C to 25 °C (yields: 5f, 89%;
6f, 75%).
ylsilyl)amide27 and by treating the resulting mixtures of
isomeric vinyl chlorides31 with MeLi.
As shown in Scheme 2, the ethynyl-substituted heli-
cenes 3i, 3k , 4i, and 4k can also be prepared by
dehydrohalogenating the vinyl chlorides, formed by
treating the corresponding acetyl derivatives (3e, 3f, 4e,
and 4f) with PCl3 and then PCl5 (Scheme 2, paths b and
c).32,33 The structure of 4i was demonstrated by X-ray
diffraction analysis.
Other functional group transformations could be used
to introduce phosphorus-containing functions next to the
oxygens at positions 1 and ω. Thus, combining 3b and
4b with BuLi followed by ClP(O)Ph2 (or alternatively, and
in similar yields, with ClPPh2 followed by H2O2) gave 3g
and 4g, respectively, accompanied by minor amounts of
monophosphine oxides.
To install reactive sites at the 1,ω-positions, in addition
to those at the 2- and (ω-1)-positions, one approach was
to regioselectively cleave the 1,ω-methoxy groups of 3f
and 4f. Treatments with AlCl3 in CH2Cl2 returned the
starting materials, and those with BCl3 gave complex
34
Also studied was whether functionalized helicenes
could be prepared by transforming the 1,ω-diols in the
molecules synthesized here into other functional groups,
in particular into quinone-acetals. Indeed, as Scheme 6
shows, PhI(O2CCF3)2 oxidizes 7c, giving 13 in 58% yield,
and 8c, giving 14 in 55% yield.43 The major byproducts
are the bromohelicene quinones, probably formed by
hydrolysis of the acetals. However, while this IIII reagent
fails to oxidize 5f and 6f to the corresponding quinone-
acetals, 15 and 16, Tl(NO3)3‚3H2O in HC(OMe)3 solvent
does, in yields of 97% and 94%.44
35
mixtures. However, the action of BBr3 in CH2Cl2 achieved
the desired result (Scheme 3).36 For the procedure to
succeed with the aldehyde derivatives 3c, 3d , 4c, and
4d , tetrabutylammonium iodide had to be added to the
reaction mixture.37 (Otherwise the starting materials
were returned.)38 The salicylaldehydes 5c, 5d , 6c, and
6d were then obtained in 37-66% yields. That structures
6c, 5f, and 6f were assigned correctly was verified by
X-ray diffraction analysis. For the analysis of compound
6f, a highly disordered cocrystallized molecule of ethyl
acetate was treated as a diffuse contribution by the
SQUEEZE method.39 The X-ray data corrected by
SQUEEZE showed 200 electrons per unit cell, close to
the required value of 192 electrons per unit cell.
Discu ssion
Electrophilic bromination, formylation, and acetylation
introduce substituents exclusively at positions 2 and 15
of 3 and at the corresponding positions of 4 (2 and 17),
even though these positions are more sterically hindered
than those on the peripheries of the rings. This regiose-
lectivity, which probably is a consequence of the electron-
donating effect of the alkoxy groups at positions 6,45 is
(31) The isomers were not separated.
(32) This procedure, developed for electron-rich aromatic compounds,
is that of: Evans, K. L.; Prince, P.; Huang, E. T.; Boss, K. R.; Gandour,
R. D. Tetrahedron Lett. 1990, 47, 6753.
(33) For an example of a procedure used previously, see: Buckle,
D. R.; Rockell, C. J . M. J . Chem. Soc., Perkin Trans. 1 1985, 2443.
(34) Parker, K. A.; Petraitis, J . J . Tetrahedron Lett. 1981, 22, 397.
(35) Miyaura, N. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 1, p 648.
(36) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett.
1981, 22, 899.
(37) For a similar method, using BBr3, NaI, and 15-crown-5, see:
Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981, 22, 4239.
(38) Other reagents (BeCl2, LiCl, PhSeNa, PhCH2SeNa, Ph2PLi, and
PhSNa) also either failed or gave complex mixtures.
(39) Van der Sluis, P.; Spek, A. L. Acta Crystallogr., Sect. A 1990,
A46, 194.
(40) Martinborough, E.; Denti, T. M.; Castero, P. P.; Wyman, T. B.;
Knobler, C. B.; Diederich, F. Helv. Chim. Acta. 1995, 78, 1037.
(41) Wang, Y.; Xin, L.; Ding, K. Tetrahedron. Lett. 2001, 43, 159.
(42) Dhawan, B.; Redmore, D. J . Org. Chem. 1991, 56, 833.
(43) Tamura, Y.; Yakura, T.; Haruta, J .; Kita, Y. J . Org. Chem. 1987,
52, 3928.
(44) (a) McKillop, A.; Perry, D. H.; Edwards, M.; Antus, S.; Farkas,
L.; Nogradi, M.; Taylor, E. C. J . Org. Chem. 1976, 41, 282. (b) Horie,
T.; Yamada, T.; Kawamura, Y.; Tsukayama, M.; Kuramoto, M. J . Org.
Chem. 1992, 57, 1038.
8542 J . Org. Chem., Vol. 68, No. 22, 2003

Functionalizations of [6]- amd [7]Helicenes
SCHEME 4a
a
Reaction conditions and yields. (a) NaH, DMF, then PHCH2Br, 10 h (yields: 7a , 85%; 8a , 82%). (b) NBS, CH3CN, CH2Cl2, 25 °C, 1
h (yields: 7b, 93%; 8b, 96%). (c) HCO2NH4, 10% Pd/C, THF, MeOH, 8-10 h (yields: 7f, 83%; 8f, 85%). (d) For 7c: 10% Pd/C, P(H2) ) 4
atm, EtOAc, 5 h (yield: 81%); for 8c: 10% Pd/C, P(H2) ) 2.5 atm, EtOAc, 30 min (yield: 85%). (e) 10% Pd/C, P(H2) ) 4 atm, EtOAc, 10
h for 7d (yield: 57%) and 6 h for 8d (yield: 64%). (f) BuLi, THF, -78°C, 40 min, then ClP(O)Ph2, -78 °C to +25 °C, 10 h (yields: 7e, 71%;
8e, 62%). (g) HSiCl3, Bu3N, toluene, reflux, 20 h (yields: 7g, 95%, 8g, 91%).
5 and 8.46 However, there is no doubt about the re-
giospecificities, for the X-ray analyses of 4d , 4i, 5f, 6c,
and 6f prove the structures of the acetylation and
formylation products, as well as those of the products of
the ether cleavages. Moreover, since the products of the
brominations were converted into those of formylation
and acetylation, all three electrophilic substitutions are
regioselective in the same sense. The transformations in
Scheme 6 provide a novel way for a functional group (the
carbonyl group) that differs from other functional groups
in the molecule to be introduced specifically at the 1- and
ω-positions.
SCHEME 5a
The ability to functionalize helicenes inside the helical
structures is important because helicenes functionalized
in this way display the useful properties enumerated in
the Introduction. Moreover it is these positions that
should be, and experimentally seem to be, most sensitive
to the chirality of the helicene ring system. Thus, a series
of experiments showed both that principle and why
camphanoyloxy groups at the 1- and ω-positions of
helicenes, but not on their peripheries, allow such
molecules to be resolved.19d,21,22
a
Reaction conditions and yields. (a) NaH, THF, 30 min, then
ClP(O)(OEt)2, 25 °C, 8 h (yields: 9, 87%; 10, 91%). (b) LDA, THF,
-55 °C to +25 °C, 4 h (yields: 11, 100%; 12, 98%).
SCHEME 6a
Noteworthy is that only three steps are required to
convert 3 into 5c (in 20% yield), into 5d (in 25% yield),
or into 5f (in 67% yield) and 4 into 6c (in 36% yield),
into 6d (in 37% yield), or into 6f (in 55% yield). The
precursors, nonracemic 3 and 4, are themselves prepared
from racemic helicenebisquinones in three steps and in
ca. 70-72% yields.19d,21 In contrast, the synthesis of the
only analogue of these compounds (a [6]helicene with
salicylaldehyde rings at both ends) required eight steps
a
Reaction conditions and yields. (a) PhI(O2CCF3)2, K2CO3,
(45) Similar effects are seen in Friedel-Crafts acylations of 1,2,4,5,8-
pentamethoxynaphthalene ((a) de Koning, C. B.; Giles, R. G. F.;
Engelhardt, L. M.; White, A. L. J . Chem. Soc., Perkin Trans. 1 1988,
3209) and of 2-methoxynaphthalene ((b) Girdler, R. B.; Gore, P. H.;
Hoskins, J . A. J . Chem. Soc. (C) 1966, 181. (c) Pivsa-Art, S.; Okuro,
K.; Miura, M.; Murata, S.; Nomura, M. J . Chem. Soc., Perkin Trans.
1 1994, 1703. (d) Kobayashi, S.; Komoto, I. Tetrahedron 2000, 556,
6463).
CH3CN, CH3OH, 25 °C, 20 min (yields: 13, 58%; 14, 55%). (b)
Tl(NO3)3‚3H2O, HC(OCH3)3, CH3OH, CH2Cl2, -30 °C to -10°C, 1
h (yields: 15, 97%; 16, 94%).
unlike that found in the reactions of unsubstituted [6]-
helicene. In the latter, bromination takes place at posi-
tions 5 and 12 and acetylation and nitration at positions
(46) op den Brouw, P. M.; Laarhoven, W. H. Recl.: J . R. Neth. Chem.
Soc. 1978, 97, 265.
J . Org. Chem, Vol. 68, No. 22, 2003 8543

Paruch et al.
from a racemic helicenebisquinone,1d,19a the overall yield
was only 12%, and the method was not extended to [7]-
helicene derivatives. The conversions of 3 into 7b and 4
into 8b also require only three steps, and the latter
transformation has given 14 g at a time with ease. These
substances are useful because the bromine substituents
can easily be transformed into other functionalities and
the ether functions subsequently removed, again easily.
The preparations of 11 and 12 are even shorter; only two
steps are required from 3 and 4, and the overall yields
are excellent. The quantitative yields of the [6]- and [7]-
helicenes in the base-promoted 1,3-migrations are nota-
bly large when compared to the yields (ca. 39-95%) in
similar reactions of benzene and naphthalene deriva-
tives.42,47
Also significant are that 3a and 4a can be monoformyl-
ated and monoacetylated selectively, not just diformyl-
ated and diacetylated, and that one of the two bromine
groups in 7b and 8b can be removed selectively. These
are significant because the reaction of benzoquinone with
the enol ethers of bisdiacetylaromatics constructs four
rings at a time, providing helicenes very efficiently, but
the helicenes it gives are identically substituted at their
two ends. For the two ends to be differentiated, there are
only two ways to proceed. One is to carry out a synthesis
that does not take advantage of geminate constructions.6c
The other is to differentiate the two ends after the
helicene’s ring system is prepared. What is remarkable
about the acylation experiments described above is that
electrophilic substitution can be controlled adequately by
a substituent deactivating a ring five or six away. While
such control cannot be achieved in brominations (at least
not in the experiments with N-bromosuccinamide de-
scribed above), it can be, as Scheme 1 shows, in reactions
that introduce acyl substituents, formyl groups (paths c
and d), and acetyl groups (paths e and f). And while the
brominations could not be controlled to introduce only
one bromine per molecule, Scheme 4 shows that it was
possible to remove selectively one of the two that were
introduced.
Con clu sion
Nonracemic dihydroxyhelicenes 3 and 4, which are
conveniently prepared on a large scale, can serve as
precursors of helicenes that are substituted by a variety
of fuctional groups at positions 1,2 and 15,16 of [6]-
helicene and the corresponding 1,2- and 17,18-positions
of [7]helicene, despite the steric hindrance at these
positions. Moreover, it is possible to introduce acyl or
bromine groups selectively at either one or both of the 2-
and 15-positions of the [6]helicene and at the correspond-
ing 2- and 18-positions of the [7]helicene. The monosub-
stitutions make it possible to synthesize well-function-
alized helicenes efficiently by a process that builds both
ends simultaneously and yet allows the ends to be
differentiated.
Ack n ow led gm en t. This material is based upon
work supported by the National Science Foundation
under Grant No. 00-94723. We thank Dr. Alfred Bader
for a Bader Fellowship to L.V. and Sean Masterson for
laboratory assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails; 1H, 13C NMR, IR, CD, and UV spectra for compounds
1
3a -3k , 4a -4k , 5c, 5d , 5f, 6c, 6d , and 6f; H, 13C NMR, and
IR spectra for compounds 7a -g, 8a -g, 9, and 11-16; and
X-ray diffraction data for (()-4d , (M)-(-)-4i, (()-5f, (()-6c, and
(()-6f. This material is available free of charge via the Internet
at http://pubs.acs.org.
(47) Dhawan, B.; Redmore, D. J . Org. Chem. 1984, 49, 4018.
J O035057T
8544 J . Org. Chem., Vol. 68, No. 22, 2003