New synthesis of vaulted biaryl ligands via the Snieckus phenol synthesis

Article abstract of DOI:10.1021/ol047852e

(Chemical Equation Presented) In an effort to develop a synthesis of the VAPOL ligand that avoids the use of a chromium carbene complex, a route was examined that involved the annulation of a naphthalene carboxamide via the method of Snieckus. The latter

Full text of DOI:10.1021/ol047852e

ORGANIC
LETTERS
2005
Vol. 7, No. 3
367-369
New Synthesis of Vaulted Biaryl
Ligands via the Snieckus Phenol
Synthesis
Su Yu, Constantinos Rabalakos, William D. Mitchell, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@cem.msu.edu
Received October 18, 2004
ABSTRACT
In an effort to develop a synthesis of the VAPOL ligand that avoids the use of a chromium carbene complex, a route was examined that
involved the annulation of a naphthalene carboxamide via the method of Snieckus. The latter derivatives could be converted in a two-step
sequence to 2-phenyl-4-phenanthrols in 60−72% overall yields. The utility of this method for the synthesis of VAPOL derivatives is demonstrated
in the synthesis of (S)-7,7 -dimethyl-VAPOL.
′
The VAPOL ligand is a bis-3,3′-(4-phenanthrol) that has been
developed as a member of the vaulted biaryl family of chiral
ligands for applications in catalytic asymmetric synthesis.1
Successful chiral catalysts that have been derived from
VAPOL include aluminum derivatives as catalysts for Diels-
Alder reactions,2 a zirconium derivative for imino-aldol
reactions,3 and boron derivatives for catalytic asymmetric
aziridination reactions.4 The latter is particularly general over
a wide range of substrates and as a result is a valuable method
for the synthesis of chiral aziridines and, thus in turn, chiral
amines.
The penultimate step in the current synthesis of the
VAPOL ligand is the oxidative coupling of the phenanthrol
2 to give the 3,3′-bisphenanthrol carbon skeleton, and the
final step is its resolution (Scheme 1).5 The synthesis begins
with 1-bromonaphthalene and provides racemic VAPOL in
four steps in 40% overall yield.1 The key step in the synthesis
is the benzannulation of the 1-naphthylcarbene complex 4
with phenylacetylene, which in the presence of acetic
anhydride gives the substituted phenanthrol 3, which is
reduced in high yield to the phenanthrol 2 with aluminum
trichloride and ethanethiol. This reaction can be scaled-up
to include a reaction of 250 g of carbene complex 4 with
phenylacetylene with conveniently sized glassware (3 L). The
cost of chromium carbonyl ($3/g) is not an issue on a small
scale, but for large-scale synthesis of the ligand it could
become prohibitive. In addition, we envisioned that there
would be a need for a synthesis that would allow for access
(1) Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.;
Rob, A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold,
A. L. J. Am. Chem. Soc. 1996, 118, 3392.
(2) (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993,
115, 3814. (b) Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 3321. (c)
Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119,
10551.
(3) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed.
2001, 40, 2271.
(4) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 6403.
(b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518. (c)
Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675.
(5) See ref 1 and: Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu,
C.; Wulff, W. D. Org. Lett. 2003, 5, 1813.
10.1021/ol047852e CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/08/2005

Naphthalene carboxylic acids 12a and 12b were converted
to the corresponding acid chlorides and then reacted with
diisopropylamine under Schotten-Baumann conditions to
give amides 13a and 13b in good yield (Scheme 3). As was
Scheme 1
Scheme 3
to derivatives of VAPOL that did not require starting with
1-naphthyl bromides.
Some time ago, Sibi, Dankwardt, and Snieckus reported
a synthesis of naphthols from benzene carboxamides.6 This
annulation is a two-step process that involves directed
metalation with an alkyllithium and then subsequent alky-
lation with allyl bromide to give the ortho-substituted
benzamide 7 (Scheme 2). The key step in their phenol
found by Sibi, Dankwardt, and Snieckus for benzene
carboxamides, the ortho-lithiated amides derived from 13
6
could not be directly alkylated with an allylic bromide. In
accord with the procedure developed by Sibi, Dankwardt,
and Snieckus, if the ortho-lithiated species is trans-metalated
by the addition of freshly prepared magnesium bromide
etherate, the resulting organomagnesium can be alkylated
with allylic halides in good yields in THF. Due to the poor
solubility of the amide 13a, an attempt to perform this
reaction in ether led to no reaction. The ortho-metalation is
best done at -78 °C: if it is done at 0 °C, the yield of 17a
decreases to 47%. Also, it was found that ortho-metalation
of the diethylamide corresponding to 13a gave a lower yield
of 17a.8 In contrast to the procedure of Sibi, Dankwardt,
and Snieckus,6 we found that 13a could be ortho-metalated
without TMEDA8 and that optimal yield could be achieved
with 1 equiv of the electrophile. It was found, however, that
3 equiv of magnesium bromide etherate was required for
Scheme 2
synthesis was realized with the discovery that the allyl group
could be metalated with strong bases such as methyllithium
and lithium diisopropylamide with subsequent intramolecular
addition of the resulting carbanion to the amide function and,
after ketone formation, tautomerization to a naphthol.
Although other examples of this process are known,7 this
method has not yet been extended to 1-naphthyl carboxa-
mides nor to 2-substituted allyl halides. If this were possible,
then a direct approach to the synthesis of 4-phenanthrols
would result as outlined in Scheme 2 (9 from 11).
(7) (a) Luche, J. L.; Einhorn, C.; Einhorn, J.; Sinisterra-Gago, J. V.
Tetrahedron Lett. 1990, 31, 4125. (b) Wang, X.; Snieckus, V. Tetrahedron
Lett. 1991, 32, 4879. (c) Clive, D. L. J.; Khodabocus, A.; Vernon, P. G.;
Angoh, A. G.; Bordeleau, L.; Middleton, D. S.; Lowe, C.; Kellner, D. J.
Chem. Soc., Perkin Trans. 1 1991, 1433. (d) Cambie, R. C.; Hill, J. H. M.;
Rutledge, P. S.; Stevenson, R. J.; Woodgate, P. D. J. Organomet. Chem.
1994, 474, 31. (e) Samanta, S. S.; Ghosh, S. C.; De, A. J. Chem. Soc.,
Perkin Trans. 1 1997, 2683. (f) Khatib, S.; Bouzoubaa, M.; Coudert, G.
Tetrahedron Lett. 1998, 39, 989. (g) Hattori, T.; Takeda, A.; Suzuki, K.;
Koike, N.; Koshiishi, E.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1998,
3661. (h) Fu, J.-M.; Snieckus, V. Can. J. Chem. 2000, 78, 905. (i)
Namsa-aid, A.; Ruchirawat, S. Org. Lett. 2002, 4, 2633. (j) Kamila, S.;
Mukherjee, C.; Mondal, S. S.; De, A. Tetrahedron 2003, 59, 1339.
(8) Bowles, P.; Clayden, J.; Helliwell, McCarthy, C.; Tomkinson, M.;
Westlund, N. J. Chem. Soc., Perkin Trans. 1 1997, 2607.
(6) Sibi, M. P.; Dankwardt, J. W.; Snieckus, V. J. Org. Chem. 1986, 51,
271.
368
Org. Lett., Vol. 7, No. 3, 2005

optimum yield. The requisite allylic halide, R-bromometh-
ylstyrene 15, is prepared by the bromination of R-methyl-
styrene.9 This bromination with NBS produces an 81:19
mixture of the allylic bromide 15 and the vinyl bromide 16
that is used directly in the alkylation process since the vinyl
bromide 16 is unreactive under these conditions.
performed on a 10 g scale to give 17a in 60% yield after
purification by silica gel chromatography, which is lower
than that obtained on a 1 g scale (80%).
This new strategy for the synthesis of vaulted biaryl
ligands was applied to the preparation of 7,7′-dimeth-
ylVAPOL (Scheme 4). The oxidative dimerization of the
The base-induced intramolecular cyclizations of the amide
17a and 17b were successful with methyllithium and gave
high yields of the phenanthrols 2a and 2b as long as the
reaction mixture was warmed to room temperature (Table
1). If the reaction temperature was brought from -78 to -20
°C before quench, no product was observed, and if the
quench occurred at -5 °C, then only a 51% yield of 2a was
observed. The reaction could also be run in ether rather than
THF. Although the amide 17a is not completely soluble in
ether and a slurry was obtained, a good yield of 2a could
nonetheless be obtained (85%). Methylmagnesium bromide
could also be used as the base; however, to effect efficient
closure, the solution needed to be brought to reflux. Interest-
ingly, the use of LDA as a base led to the cleavage of the
allyl group and the isolation of the amide 13a in 60% yield
(Table 1). This type of process was not observed by Sibi et
al.6 They found that LDA also gave cyclization products with
benzene carboxamides that had been ortho-alkylated with
simple allyl bromide.
Scheme 4
Table 1. Ring-Closure of O-Allylamide 17
4-phenanthrol 2b was accomplished by melting 2b in an
Erlenmeyer flask and then maintaining the temperature of
the flask at 185 °C for 20 h in the presence of air. The
product is then extracted from the dark solid mixture and
purified by silica gel chromatography to give racemic 7,7′-
dimethylVAPOL 18 in 67% yield. Optically pure VAPOL
can be obtained either by resolution1 or by deracemization.5
The latter is more convenient for the preparation of small
quantities of ligands for screening purposes. Thus, the
deracemization of 18 was accomplished by the in situ
generation of a Cu(II)-(-)-sparteine complex by the ultra-
sonic treatment of CuCl with (-)-sparteine in the presence
of air and then the exposure of this copper complex to
racemic 18 under an inert atmosphere. After 24 h, the ligand
was purified by chromatography on silica gel to give 7,7′-
dimethylVAPOL 18 as the (S)-enantiomer in 99.1% ee with
a 78% recovery. The efficacy of this ligand in asymmetric
catalysis will be reported independently.
time yield of yield of
substrate
base
MeLi
temp
(h)
2 (%)
13 (%)
17a
17a
17a
17a
17b
-78 to 25 °C
-78 to 25 °C
-78 to 25 °C
25 to 68 °C
15
15
20
15
15
90
LDA
60
a
s-BuLi
MeMgBr
MeLi
80
80
-78 to 25 °C
a A 60% yield of 13a was isolated.
The two step conversion of the amide 13a to the phen-
anthrol 2a was also examined in a one-pot process. After
the allyl bromide 15 was added to the metalated amide and
warmed to room temperature, the reaction mixture was
recooled to -78 °C and treated with 6 equiv of methyllithium
(to compensate for the extra 2 equiv of MgBr2-etherate).
This led to the isolation of 2a in a reasonable 60% yield;
however, it contained a few small impuritites and was
difficult to purify. While this synthesis has not been carried
out on a molar scale, the alkylation of amide 13a was
Acknowledgment. This work was supported by a grant
from the National Institutes of Health (GM 63019).
Supporting Information Available: Synthetic procedures
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Reed, S. F. J. Org. Chem. 1965, 3258.
OL047852E
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