A novel titanium tetrachloride-induced rearrangement of an enantiopure 4-naphthyldioxolane. The possible role of titanium in the umpolung of tosyloxy and chlorine

Article abstract of DOI:10.1016/j.tetlet.2009.08.107

The rearrangement of (2′S,4′R,5′S)-2-(2′,5′-dimethyl-1′,3′-dioxolan-4′-yl)-4,5,7-trimethoxynaphthalen-1-yl 4″-methylbenzenesulfonate with titanium(IV) chloride affords (1R,3S,4R)-10-chloro-6,7,9-trimethoxy-1,3-dimethyl-3,4-dihydro-4-hydroxynaphtho[1,2-c]p

Full text of DOI:10.1016/j.tetlet.2009.08.107

Tetrahedron Letters 50 (2009) 6361–6363
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A novel titanium tetrachloride-induced rearrangement of an enantiopure
4-naphthyldioxolane. The possible role of titanium in the umpolung
of tosyloxy and chlorine
*
Robin G. F. Giles , Joshua D. McManus
Department of Chemistry, Murdoch University, Murdoch, WA 6150, Australia
a r t i c l e i n f o
a b s t r a c t
The rearrangement of (20S,40R,50S)-2-(20,50-dimethyl-10,30-dioxolan-40-yl)-4,5,7-trimethoxynaphthalen-1-
yl 400-methylbenzenesulfonate with titanium(IV) chloride affords (1R,3S,4R)-10-chloro-6,7,9-trimethoxy-
1,3-dimethyl-3,4-dihydro-4-hydroxynaphtho[1,2-c]pyran in good yield. This transformation is
characterized by two unusual aromatic substitution reactions in that, in one, tosyloxy is lost and, in
the other, aromatic chlorination occurs with titanium(IV) chloride as the source of chlorine.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 22 April 2009
Revised 28 May 2009
Accepted 28 August 2009
Available online 2 September 2009
We report on the rearrangement of the enantiopure 4-naphthyl-
dioxolane 1 using titanium tetrachloride at ꢀ65 °C to provide the
naphtho[1,2-c]pyran 2, a transformation involving, prima facie,
two remarkable electrophilic aromatic substitution reactions.
These are an ipso electrophilic substitution reaction in which the
electrophile departing from one of the aromatic rings is the tos-
yloxonium ion (TsO+) and, furthermore, chlorination of the alterna-
tive, highly electron-rich aromatic ring occurs with chloride from
titanium tetrachloride. We propose a mechanism in which the re-
agent, titanium tetrachloride, facilitates the complementary umpo-
lung of chlorine and tosyloxy. The yield for this multistep process is
42%, or 65% based on consumed dioxolane 1 and recovered diol 3.
The structure, including stereochemistry, of the product naph-
thopyran 2 follows unambiguously from high-resolution mass
spectroscopic, nuclear magnetic resonance and chemical data that
will be reported in a subsequent full paper, together with the ready
synthesis of the enantiopure dioxolane 1 and details of its transfor-
mation into the product 2. In particular, the aromatic region of the
1H NMR spectrum shows two one-proton singlets while strongly
supportive evidence is provided by entirely consistent correlations
in a NOESY spectrum.
In view of the unusual nature of the conversion of dioxolane 1
into naphthopyran 2, in which two molar equivalents1 of titanium
tetrachloride were used, two possible mechanisms are illustrated
in Scheme 1. The stereochemistry at C-4 and C-5 in dioxolane 1
is transferred unaltered2 to C-4 and C-3, respectively, in the naph-
thopyran 2, although it is premature to speculate on the factors
controlling the orientation of the product C-1 methyl group. While
initial coordination of titanium tetrachloride can occur to either O-
1 or O-3 of the dioxolane ring1 only the latter, giving the prelimin-
ary intermediate 4, leads to an allowed 6-enolendo-endo-trig3 ring-
closure.1 Consequent cleavage of the C-2/O-3 dioxolane bond and
coordination of titanium to both oxygens would require the con-
formation depicted at the vicinal carbons in the derived oxonium
ion 5. Intramolecular electrophilic aromatic substitution by this
oxonium ion could occur either ortho- or para- to the activating
methoxy substituent and the former option would require only
the simple loss of a proton to form the corresponding linear naph-
thopyran. The well-known preference,4 however, for naphthalenes
MeO
OMe
MeO
OMe
OH
O
2
MeO
MeO
4
3
4
5
1
TsO
Cl
O
O
2
1
MeO
OMe
OH
MeO
TsO
to undergo
larly at low temperatures, leads exclusively, in this case, to ipso
substitution to afford the -complex 6.
The simplest mechanism for the transformation of this
a-, rather than b-, electrophilic substitution, particu-
OH
3
r
r
-com-
plex 6 into the product 2 would be through regioselective nucleo-
philic attack by chloride at C-10 of the alternative resonance
* Corresponding author. Tel.: +61 8 9386 5634; fax: +61 8 9386 6016.
E-mail address: robcal@aapt.net.au (R.G.F. Giles).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.107

6362
R. G. F. Giles, J. D. McManus / Tetrahedron Letters 50 (2009) 6361–6363
Cl4
Ti
_
MeO
OMe
_
O
TiCl4
O
O
MeO
+
TsO
+
TsO
O
O
5
4
Ar
MeO
OMe
O
Cl
Ti 4
_
+
S
O
O
O
6
5
8
O
a'
OTiCl4
10
MeO
TsO
Cl
O
O
a
a'
7
6
_
TsO
_
O
Ar
Cl
S
O
O
Cl3
Ti
Cl
O
O
O
O
_
TsO
Ti
Cl
H
_
+
O
O
a'
O
O
Cl
Cl
O
O
a
a'
8
9
O
O
_
1. H+
O
e
OH
e'
2. Work-up,
with
Cl
e'
conformational
inversion
O
2
Scheme 1.
contributor 7 of this complex with the loss of tosylate as shown in
Scheme 1. This suggestion, however, raises several questions
including, first, why chloride attacks with complete regioselectivi-
naphtho[1,2-c]pyran 8,4,5 particularly at low temperatures, to af-
ford the observed product 2. In an alternative mechanism the
negatively charged titanium in
r-complex 6 then completes the
ty at C-10 rather than also at C-8 (through the third related
plex of 6) and most particularly at C-5 of the -complex 6, to afford
the 5-chloro-isomer of product 2. It would be reasonably assumed
that, of these three related resonance contributors to the -com-
plex, 6, giving the 5-chloro-isomer of product 2, would be the pre-
ferred contributor as it does not involve disruption of the
aromaticity of the second aromatic ring4 as do both the other res-
onance contributors, while C-10 is likely to be the most crowded
site for nucleophilic attack. Nonetheless it is recognized that the
alternative resonance contributors such as 7 are highly conjugated.
Second, chloride would be attacking an electron-rich naphthalene,
r
-com-
first electrophilic substitution by facilitating the removal of tosyl-
oxy from the ring-system, as shown in 6, to yield the angular
naphthopyran 8. Also, the two meta-disposed methoxy groups
on the highly electron-rich terminal aromatic ring combine to
achieve electrophilic aromatic substitution of this ring by bond-
ing to one of the chlorine atoms on titanium, as shown in struc-
ture 8, and the electron pair attaching this chlorine to titanium
then transfers to the metal. Tosylate can also leave this interme-
r
r
diate complex 8 to furnish
r-complex 9. Loss of a proton from 9
and hydrolytic work-up removes the coordinating capacity of
titanium and the pyran half-chair undergoes conformational
inversion6 in order to allow all three substituents on the hetero-
cyclic ring to assume the (pseudo)equatorial orientations
observed in the product 2.
albeit as the derived
r-complex.
On the other hand, C-10 would be the predicted site for elec-
trophilic chlorination of the naphthalenic aromatic system of the

R. G. F. Giles, J. D. McManus / Tetrahedron Letters 50 (2009) 6361–6363
6363
We have previously published two papers7,8 reporting several
References and notes
examples of the low-temperature, titanium tetrachloride-induced
isomerisations of naphthyldioxolanes into angular naphtho[1,2-
c]pyrans as the sole products. These examples were very differ-
ent, however, from the present example since in the first7 the
1. Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1 1996,
2241.
2. Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1 1997,
3361.
3. Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939.
4. (a) Fieser, L. F.; Fieser, M. Advanced Organic Chemistry; Reinhold: New York,
1961. Chapter 11; (b) Field, L. D.; Sternhell, S.; Wilton, H. V. J. Chem. Educ. 1999,
76, 1246 and references cited therein.
a
-position ortho- to the dioxolane in each case was unsubstituted,
thereby allowing unfettered
-substitution. In the second paper8
this -position was occupied by a bromine atom that prevented,
a
a
5. For example: (a) Giles, R. G. F.; Green, I. R.; Knight, L. S.; Lee Son, V. R.; Mitchell,
P. K.; Yorke, S. C. J. Chem. Soc., Perkin Trans. 1 1994, 853; (b) Chorn, T. A.; Giles, R.
G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. K.; Yorke, S. C. J. Chem. Soc., Perkin Trans.
1 1984, 1339 and elsewhere.
until it was removed, the high-yield formation of angular
products.
6. Aggarwal, R.; Birkbeck, A. A.; de Koning, C. B.; Giles, R. G. F.; Green, I. R.; Li, S.-H.;
Oosthuizen, F. J. Tetrahedron Lett. 2003, 44, 4535.
Supplementary data
7. Giles, R. G. F.; Green, I. R.; Knight, L. S.; Lee Son, V. R.; Yorke, S. C. J. Chem. Soc.,
Perkin Trans. 1 1994, 865.
8. Giles, R. G. F.; Gruchlik, Y. ARKIVOC 2004, x, 134.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.107.