Direct asymmetrie catalytic thienylaluminum addition to ketones: A concise approach to the synthesis of (S)-tiemonium iodide

Article abstract of DOI:10.1021/ol901193q

A direct asymmetric addition of a (2-thienyl)aluminum reagent to ketones catalyzed by a titanium catalyst of (S)-BINOL to afford chiral tertiary 2-thienyl alcohols is reported. The catalytic system works excellently for aromatic ketones and for 1-acetylcyclohexene, furnishing products in excellent enantioselectivities of up to 97% ee. However, the additions to dialkyl ketones afford products in low enantioselectivities of 8-17% ee. Importantly, a concise 3-step synthesis of (S)-tiemonium iodide with an 84% yield is demonstrated.

Full text of DOI:10.1021/ol901193q

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3386-3389
Direct Asymmetric Catalytic
Thienylaluminum Addition to Ketones: A
Concise Approach to the Synthesis of
(S)-Tiemonium Iodide
Deepak B. Biradar,† Shuangliu Zhou,†,‡ and Han-Mou Gau*,†
Department of Chemistry, National Chung Hsing UniVersity, Taichung 402, Taiwan,
and Anhui Key Laboratory of Molecule-based Materials, College of Chemistry and
Materials Science, Anhui Normal UniVersity, Wuhu, Anhui 241000, China
hmgau@dragon.nchu.edu.tw
Received June 1, 2009
ABSTRACT
A direct asymmetric addition of a (2-thienyl)aluminum reagent to ketones catalyzed by a titanium catalyst of (S)-BINOL to afford chiral tertiary
2-thienyl alcohols is reported. The catalytic system works excellently for aromatic ketones and for 1-acetylcyclohexene, furnishing products
in excellent enantioselectivities of up to 97% ee. However, the additions to dialkyl ketones afford products in low enantioselectivities of
8-17% ee. Importantly, a concise 3-step synthesis of (S)-tiemonium iodide with an 84% yield is demonstrated.
Catalytic asymmetric synthesis of chiral alcohols is of
great importance for the syntheses of enantiomerically pure
natural products and pharmaceuticals,1 and the addition
of carbon-based nucleophiles to organic carbonyls con-
stitutes the most straightforward strategy.2 However, fewer
catalysts have been established for additions to ketones.3
In addition to organozinc reagents, organoaluminum
compounds were proven to be excellent reagents for
asymmetric addition reactions, but in limited cases.4
Recently, there has been increasing interest in asymmetric
† National Chung Hsing University.
(4) (a) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc.
1997, 119, 4080. (b) Pagenkopf, B. L.; Carreira, E. M. Tetrahedron Lett.
1998, 39, 9593.
‡ Anhui Normal University.
(1) Garc´ıa, C.; Martin, V. Curr. Org. Chem. 2006, 10, 1849.
(2) (a) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757. (b) Ramo´n, D. J.;
Yus, M. Chem. ReV. 2006, 106, 2126.
(5) (a) You, J.-S.; Hsieh, S.-H.; Gau, H.-M. Chem. Commun. 2001, 1546.
(b) Kwak, Y.-S.; Corey, E. J. Org. Lett. 2004, 6, 3385. (c) d’Augustin, M.;
Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376. (d) Biswas,
K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew. Chem., Int. Ed. 2005,
44, 2232. (e) Wu, K.-H.; Gau, H.-M. J. Am. Chem. Soc. 2006, 128, 14808.
(f) Chen, C.-A.; Wu, K.-H.; Gau, H.-M. Angew. Chem., Int. Ed. 2007, 46,
5373. (g) Siewert, J.; Sandmann, R.; Zezschwitz, P. Angew. Chem., Int.
Ed. 2007, 46, 7122. (h) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown,
M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446. (i) Wu, K.-H.;
Chuang, D.-W.; Chen, C.-A.; Gau, H.-M. Chem. Commun. 2008, 2343. (j)
Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew. Chem., Int. Ed. 2008,
47, 8211. (k) Chen, C.-A.; Wu, K.-H.; Gau, H.-M. AdV. Synth. Catal. 2008,
350, 1626. (l) Hsieh, S.-H.; Chen, C.-A.; Chuang, D.-W.; Yang, M.-C.;
Yang, H.-T.; Gau, H.-M. Chirality 2008, 20, 924. (m) Biradar, D. B.; Gau,
H.-M. Org. Lett. 2009, 11, 499. (n) Zhou, S.; Wu, K.-H.; Chen, C.-A.;
Gau, H.-M. J. Org. Chem. 2009, 74, 3500.
(3) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239. (c) Garc´ıa, C.;
LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (d)
Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895. (e) Prieto, O.; Ramo´n,
D. J.; Yus, M. Tetrahedron: Asymmetry 2003, 14, 1955. (f) Garc´ıa, C.;
Walsh, P. J. Org. Lett. 2003, 5, 3641. (g) Ramo´n, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2004, 43, 284. (h) Li, H.; Walsh, P. J. J. Am. Chem. Soc.
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10.1021/ol901193q CCC: $40.75
Published on Web 07/09/2009
 2009 American Chemical Society

catalysis with organoaluminum nucleophiles because of
their greater reactivities.5
Tertiary thienyl alcohols are well-known for their
biological activity as well as key substructures in bioactive
compounds and pharmaceuticals such as tiemonium iodide
(a)6 and compounds b7 and c8 (Figure 1). Tiemonium
Table 1. Optimizations of Asymmetric 2-Thienyl Additions to
2′-Acetonaphthone Catalyzed by in Situ-Formed (S)-BINOL/
Ti(OiPr)4 Systemsa
Al reagent Ti(OiPr)4
temp convn
(°C)
ee
(%)c
entry
(equiv)
(equiv)
solvent
(%)b
1
2
3
4
5
6
7
8
2
3
3
3
3
2
2
2
2
THF
rt
99
99
99
68
67
94
99
99
65
73
77
85
88
92
92
85
2
THF
0-rt
1.5
1.5
1.5
1.5
1.7
1.9
THF
0-rt
THF
0
0
0
0
0
THF
toluene
toluene
toluene
Figure 1. Bioactive compounds or drugs containing 2-thienyl
alcohols.
a 2′-Acetonaphthone, 0.50 mmol; equivalents of Al reagent and Ti(OiPr)4
b
1
are relative to 2′-acetonaphthone. Conversions were based on H NMR
spectra. c Enantioselectivities were determined by HPLC.
iodide is sold as an anticholinergic/spasmolytic drug, and
compound b is an antiallergic/antiasthmatic drug. Com-
pound c shows a bioactivity against chronic obstructive
pulmonary disease. Despite the importance of tertiary
thienyl alcohols, their syntheses were reported in only a
few papers via additions of organometallic reagents to
thienylketones.9 Recently, the optically active thienyl aryl
methanols were obtained in good yields and high enan-
tioselectivities through additions of thienylboronic acid
to aldehydes in the presence of ZnEt2 and 20 mol % chiral
Schiff-base amino alcohol ligands.10 To continue our
efforts in developing organoaluminum reagents for asym-
metric catalysis, we report herein the first catalytic
asymmetric thienylaluminum additions to ketones cata-
lyzed by in situ-prepared Ti(OiPr)4 complexes of (S)-
BINOL and the application of the resulting tertiary alcohol
to the preparation of enantiomerically pure tiemonium
iodide.
In this study, the 2-thienylaluminum reagent, Al(2-
thienyl)3(THF),11 was prepared and addition reactions were
optimized on 2′-acetonaphthone (1n) in the presence of
Ti(OiPr)4 and a catalytic amount of 10 mol % (S)-BINOL.
The results are summarized in Table 1. The reaction
condition of 1.7 equiv of Al(2-thienyl)3(THF) and 2 equiv
of Ti(OiPr)4 at 0 °C in toluene was found to furnish
product 2n in the best 99% conversion and the best
enantioselectivity of 92% ee (entry 7).
used for 2-thienyl additions to 3-bromo-1-phenylpropan-1-
one (1q), affording both enantiomeric products of (S)-2q and
(R)-2q in 94% and 93% ee (entries 17 and 18), respectively.
The above results reveal minimal effects of types of
substituent and substituted positions on the aromatic group
in terms of stereoselectivities. For the conjugated enone of
1-acetylcyclohexene, the reaction gave tertiary alcohol 2r
exclusively in high yield with a high enantioselectivity of
91% ee (entry19).
However, the 2-thienyl addition to R-tetralone under the
optimized conditions gave 2s in a moderate 61% ee with an
excellent 92% yield (entry 20). The aliphatic ketones were
also examined, and the reactions afforded the products in
high yields but with low enantioselectivities of 8-17% ee
(entries 21-23). The addition to 2′-methoxyacetophenone
afforded the product 2e in high yield due to the chelate effect
of the substrate, which facilitates the coordination of 2′-
methoxyacetophenone to the active metal center. However,
small differentiations of both directions accessing the metal
center lowered the enantioselectivity.
To demonstrate the synthesis of chiral tiemonium iodide,
we initially carried out the 2-thienyl addition to the aromatic
ketone 1w containing the morpholine moiety. 1w was
prepared in 63% yield from reactions of morpholine hydro-
chloride, paraformaldehyde, and acetophenone in refluxing
ethanol.12 However, the reaction did not take place at all
even with the use of 5 equiv of Al(2-thienyl)3(THF) (entry
24). Fortunately, chiral tiemonium iodide could be prepared
from 3-bromo-1-phenylpropan-1-one (1q) (Scheme 1). 2-Thie-
nyl additions to 1q catalyzed by a titanium catalyst of (S)-
or (R)-BINOL furnished 2q in excellent yields and enanti-
oselectivities. Treatment of 2q with morpholine produced
3q in high yields and similar enantioselectivities to those of
Having established the optimized conditions, we then
examined the catalytic reactions with functionalized ketones
and the results are shown in Table 2. For aromatic ketones
with either an electron-withdrawing or an electron-donating
substituent at 2′-, 3′-, or 4′-positions, 2-thienyl additions
afforded tertiary alcohols in excellent enantioselectivities of
90% ee or greater except for substrates of 2′-methoxyac-
etophenone and R-bromo-2′-acetonaphthone which afforded
the products in 45% and 80% ee (entries 5 and 16). The
catalytic systems of both (S)- and (R)-BINOL ligands were
(6) (a) Duchene-Marullaz, P.; Jovanovic, D.; Busch, N.; Vacher, J. Arch.
Int. Pharmacodyn. Ther. 1963, 141, 465. (b) Roland, Y. M. U.S. 3145204,
1964.
(7) Richard, F.; Piwinski, J. J. U.S. 5679692, 1997.
(8) Belmonte, K. E.; Busch-Petersen, J.; Laine, D.; Palovich, M. R. WO
2005009362, 2005.
Org. Lett., Vol. 11, No. 15, 2009
3387

Table 2. Asymmetric 2-Thienyl Additions to Ketones Catalyzed by in Situ-Formed (S)-BINOL/Ti(OiPr)4 Systemsa
a Ketone/(2-C4H3S)3Al(THF)/Ti(OiPr)4 ) 0.50/0.85/1.0 mmol. b Isolated yields. c Enantioselectivities were determined by HPLC. d (R)-BINOL was used.
e NR: no reaction.
2q. 3q obtained from the catalytic system of (S)-BINOL
reacted with methyl iodide to furnish tiemonium iodide (4q),
which was subjected for an X-ray diffraction study. The
crystal data confirmed an S-confiuration for 4q (Figure 2).13
This three-step synthesis produced (S)-tiemonium iodide ((S)-
4q) in an overall yield of 84%.
(9) (a) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006,
128, 9998. (b) Schneider, U.; Kobayashi, S. Angew. Chem., Int., Ed. 2007,
46, 5909. (c) Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9,
4535.
(11) Rahbarnoohi, H.; Kumar, R.; Heeg, M. J.; Oliver, J. P. Organo-
metallics 1994, 13, 3300.
(12) (a) Moriarty, R. M.; Prakash, O.; Thachet, C. T.; Musallam, H. A.
Heterocycles 1985, 23, 633. (b) Sumita, K.; Koumori, M.; Ohno, S. Chem.
Pharm. Bull. 1994, 42, 1676.
(10) Liu, X. D.; Qiu, L.; Hong, L.; Yan, W. J.; Wang, R. Tetrahedron:
Asymmetry 2009, 20, 616.
3388
Org. Lett., Vol. 11, No. 15, 2009

Scheme 1. Asymmetric Synthesis of (S)-Tiemonium Iodide
In summary, we have developed the first asymmetric
catalytic 2-thienylaluminum additions to varieties of ketones.
The catalytic system worked excellently for aromatic ketones
having either an electron-donating or an electron-withdrawing
substituent on the aromatic ring and for 1-acetylcyclohexene
with excellent enantioselectivities of up to 97% ee. In
contrast, the additions of 2-thienyl to aliphatic ketones
produced corresponding tertiary alcohols in low enantiose-
lectivities of 8-17% ee. Importantly, a concise synthesis of
Figure 2. Molecular structure of (S)-tiemonium iodide. Hydrogen
atoms are omitted for clarity.
(S)-tiemonium iodide in 3 steps with an overall 84% yield
was also demonstrated.
Acknowledgment. Financial support under grant no. NSC
96-2113-M-005-007-MY3 from the National Science Council
of Taiwan is appreciated.
Supporting Information Available: Experimental and
characterization data for all compounds and cif file for (S)-
tiemonium iodide. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) Crystal data for (S)-tiemonium iodide: C18H24INO2S, M ) 445.34,
monoclinic, space group P21, T ) 100 (2) K, a ) 10.8791(2) Å, b ) 9.4754
(2) Å, c ) 18.4279(4) Å, ꢀ ) 99.751(2)°, V ) 1872.17(7) Å3, Z ) 4,
absorption coefficient ) 1.831 cm-1, total reflections collected 16307, unique
reflections collected 7336 (Rint ) 0.0265), goodness-of-fit indicator ) 0.929,
R1 ) 0.0232, wR2 ) 0.0469. Absolute structure parameter ) -0.016(11).
OL901193Q
Org. Lett., Vol. 11, No. 15, 2009
3389