New C=C bond formation via nonstoichiometric titanium(IV) halide mediated vicinal difunctionalization of α,β-unsaturated acyclic ketones

Article abstract of DOI:10.1021/ol9904040

(equation presented) X = Cl: 92%, ZIE > 99/1 X = Br: 85%, ZIE = 9/1 Highly stereoselective vicinal difuctionalization of α/β-unsaturated ketones for the synthesis of multifunctionalized trisubstituted alkenes is described. The new reaction employs titaniu

Full text of DOI:10.1021/ol9904040

ORGANIC
LETTERS
2000
Vol. 2, No. 5
617-620
New CdC Bond Formation via
Nonstoichiometric Titanium(IV) Halide
Mediated Vicinal Difunctionalization of
r,â-Unsaturated Acyclic Ketones
Guigen Li,* Joe Gao, Han-Xun Wei, and Mason Enright
Department of Chemistry and Biochemistry, Texas Tech UniVersity,
Lubbock, Texas 79409-1061
qeggl@ttu.edu
Received December 20, 1999
ABSTRACT
Highly stereoselective vicinal difuctionalization of r,â-unsaturated ketones for the synthesis of multifunctionalized trisubstituted alkenes is
described. The new reaction employs titanium(IV) halides (0.5 equiv) as promoters and inexpensive commercial chemicals as starting materials.
The reaction can be performed at room temperature in a convenient vial without the protection of inert gases. Good to excellent yields and
high Z/E stereoselectivity have been realized in most cases presented (16 examples).
The application of the Baylis-Hillman reaction to carbon-
carbon single bond formation has become increasingly
important in modern organic chemistry.1 However, the
utilization of a Baylis-Hillman-type procedure in forming
carbon-carbon double bonds has not been well documented
so far.2 This process can result in (halomethyl)acrylates and
2-(halomethyl)vinyl ketones, which are versatile building
blocks for organic synthesis.3 To date, the synthesis of these
important molecules has been done by treating Baylis-
Hillman adducts with various halogen reagents such as NBS/
Me2S, hydrogen halides and CuBr2/SiO2, etc.3 During our
study of Baylis-Hillman-type processes,4 we found these
compounds can be readily generated by using a one-pot
tandem difunctionalization of R,â-unsaturated ketones medi-
ated by a nonstoichiometric amount of titanium(IV) halides
(TiX4, X ) Cl, Br) or the combination of TiX4/(n-Bu)4NI5
Scheme 1
(1) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219. (b) Brzezinski, L. J.; Rafel, S.; Leahy,
J. M. J. Am. Chem. Soc. 1997, 119, 4317. For recent reviews, see: (c)
Ciganek, E. Org. React. 1997, 51, 201. (d) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001.
(2) During the preparation of this manuscript, a paper has appeared that
mentions two examples of similar CdC formation by using different
conditions (Z/E selectivity, 46/54 and 34/66; yield, 51% and 57%): Uehira,
S.; Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett. 1999, 1, 1383.
(3) (a) Buchholz, R.; Hoffmann, H. M. R. HelV. Chim. Acta 1991, 74,
1213. (b) Xu, L.-X. Kundig, E. P. HelV. Chim. Acta 1994, 77, 1480. (c)
Basavaiah, D.; Hyma, R. S.; Padmaja, K.; Krishnamacharyulu, M.
Tetrahedron 1999, 55, 6971 and references therein.
10.1021/ol9904040 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

acceptors. Excellent Z/E selectivity was realized for most
cases, only in cases 2 and 5 were the minor E isomers
observed with the Z/E selectivity of 9:1 and 6:1, respectively,
when TiBr4 was employed as the promoter. Only 0.5 equiv
of TiCl4 or TiBr4 is needed for the complete conversion,
which reveals that two halogen atoms of each TiX4 molecule
participated in halogen transformations. The reaction did not
proceed to completion with less than 0.5 equiv of TiX4 even
in prolonged period (>30 h). However, a stoichiometric
amount of TiCl4 or TiBr4 can drive the reaction to completion
within 5 h with yields and Z/E selectivity similar to those of
Table 1.
Scheme 2
in highly stereoselective fashions. In this communication,
we present our preliminary research results about this
reaction, which is represented in Scheme 1, with the results
collected in Tables 1 and 2.
This one-pot, three-component reaction was performed
simply by mixing aldehyde, R,â-unsaturated ketone, and TiX4
in dichloromethane solution at room temperature. The
reaction went to completion in 24 h and gave good to
excellent yields (Table 1). Both TiCl4 and TiBr4 worked very
well as promoters in this new process in which the latter
was inferior to the former with regard to controlling Z/E
stereoselectivity. As indicated in Table 1, both aromatic and
aliphatic aldehydes can be utilized as the electrophilic
Dichloromethane appears to be the best solvent for the
present reaction system. The effort to improve Z/E selectivity
for cases 2 and 5 by using other solvents, such as toluene,
THF, and acetonitrile, was unsuccessful. The anticipated
products were obtained with good yields by using the above
solvents, but a stoichiometric amount of titanium halides
turned out to be necessary. A variety of conditions including
the use of various solvents/cosolvents will be studied so that
Table 1. Results of TiX4-Mediated New CdC Bond Formation7a,8
a Purified yields by column chromatography. b Two isomers were observed by crude 1H NMR determination, Z/E ) 9:1 and 6:1 for 2 and 5, respectively.
c Baylis-Hillman adduct was isolated in 10% yield.
618
Org. Lett., Vol. 2, No. 5, 2000

acrylates and similar derivatives can be employed as the
substrates, which has not been successful under the present
conditions.
at the same time. This mechanistic hypothesis can be
supported by the observation of aldol (minor) and Baylis-
Hillman adducts (major) for entry 4 by quenching the
reaction at 0 °C within 2 h. It can also be supported by our
recent research results on the similar reaction promoted by
TiCl4 in which R,â-unsaturated cycloketones and N-acyl
benzoxalinone were employed as Micheal-type acceptors.4a
This reaction predominantly yielded Baylis-Hillman olefins
with R,â-unsaturated cycloketones as the substrate, whereas
â-halogenated aldol adducts became the major products when
R,â-unsaturated N-acyl benzoxalinone was employed as the
substrate (Scheme 5). Interestingly, these N-acyl benzoxali-
The stereochemical assignment was carried out by con-
verting one of the products (entry 1) to an authentic sample,
which was synthesized by a literature procedure.3c In this
procedure, the Baylis-Hillman adduct was treated with
hydrogen chloride at room temperature for a few minutes to
afford (3Z)-3-(chloromethyl)-4-phenylbut-3-en-2-one (Scheme
1
3). The Z/E geometric selectivity was determined by H
Scheme 3
Scheme 5
none derived products could not undergo the dehydration
reaction under the present conditions.
NMR analysis in which the singlet peak of the â-CH2 protons
of the Z-isomer shifts to farther upfield as compared with
that of E-isomer.
It seems reasonable to suggest that the reaction proceeds
through the formation of aldol and Baylis-Hillman inter-
mediates and the subsequent reactions involving these
intermediates. As shown in Scheme 4, these intermediates
After we succeeded in the above TiCl4- and TiBr4-
mediated difunctionalization reaction, we then tried to
incorporate an iodine moiety onto (Z)-2-(halomethyl)vinyl
ketones by taking advantage of the TiX4/(n-Bu)4NI combina-
tion.2 Surprisingly, the products obtained by using this
combination were not what we anticipated (Scheme 6). The
resulting products were essentially identical to those gener-
ated from solely pure TiBr4- or TiCl4-promoted process. The
reaction went to completion in 24 h at room temperature to
afford the relevant chloro or bromo products. Good yields
and excellent stereoselectivity were obtained with further
reduced loading of titanium halides [TiX4/(n-Bu)4NI ) 0.26
Scheme 4
(6) Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
1, pp 139-172. (b) Reetz, M. T. Organotitanium Reagents in Organic
Synthesis; Springer-Verlag: Berlin, 1986.
(7) (a) Typical Procedure (Entry 1, Table 1). Into a dry vial was added
freshly distilled dichloromethane (1.5 mL), benzaldehyde (0.1 mL, 1.0
mmol), and methyl vinyl ketone (0.10 mL, 1.2 mmol). The reaction mixture
was stirred at room temperature and then loaded with titanium tetrachloride
(0.5 mL, 1 M solution in dichloromethane, 0.5 mmol). The resulting solution
in the capped vial was stirred at the same temperature for 24 h without
argon protection. The reaction was finally quenched by dropwise addition
of saturated aqueous NaHCO3 solution (5 mL). The phases were separated,
and the aqueous phase was extracted with dichloromethane (3 × 10 mL).
The combined organic layers were dried over anhydrous sodium sulfate
and concentrated to dryness. Purification by flash chromatography (EtOAc/
hexane, 1/8, v/v) provided 1 (184 mg, 92%) as light yellow solid. (b)
Typical Procedure (Entry 1, Table 2). To a stirred mixture of benzalde-
hyde (0.10 mL, 1.0 mmol), methyl vinyl ketone (0.10 mL, 1.2 mmol), and
(n-Bu)4NI (96 mg, 0.26 mmol) in dichloromethane (1.5 mL) was added
0.26 mL of a 1 M TiCl4 (0.26 mmol) solution in dichloromethane. The
reaction mixture was stirred at room temperature for 24 h and then quenched
by dropwise addition of saturated aqueous NaHCO3 solution (5 mL). The
product was isolated by extraction with dichloromethane (3 × 10 mL), dried
over anhydrous sodium sulfate, and concentrated to dryness. Purification
by flash chromatography (EtOAc/hexane, 1/8, v/v) provided 1 (135 mg,
69%).
are initially generated from the reactions of aldehydes with
titanium enolates derived from the TiCl4-mediated R,â-
unsaturated additions.6 Routes a and b of Scheme 4, involving
â-elimination and SN2′ reactions, respectively, could proceed
(4) (a) Li, G.; Wei, H.-X.; Caputo, T. D. Tetrahedron Lett. 2000, 41, 1.
(b) Li, G.; Wei, H.-X.; Whittlesey, B.; Batrice, N. N. J. Org. Chem. 1999,
64, 1061. (c) Wei, H.-X.; Hook, J. D.; Fitzgerald, K. A.; Li, G.
Tetrahedron: Asymmetry 1999, 10, 661.
(5) For the TiCl4/(n-Bu)4NI combination, see: (a) Taniguchi, M.; Hino,
T.; Kishi, Y. Tetrahedron Lett. 1986, 39, 4767. (b) Yachi, K.; Maeda, K.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1997, 38, 5161.
Org. Lett., Vol. 2, No. 5, 2000
619

of R,â-unsaturated acyclic ketones for the stereoselective
synthesis of mutifunctionalized (Z)-keto allyl bromides,
chlorides, and the relevant diene derivatives. The reaction
can be carried out at room temperature without the need for
inert atmosphere to give good to excellent yields and
complete Z/E stereoselectivity. This new method has the
advantage of the Baylis-Hillman reaction by using inex-
pensive and readily available starting materials.
Scheme 6
equiv each] (Table 2), which is in contrast to the former
system where the reaction could not proceed to completion
with less than 0.5 equiv of TiX4. Less than 5% of iodinated
products were observed for all cases shown in Table 2. These
results suggest that four chlorine ions per TiCl4 molecule
instead of the iodine anion of (n-Bu)4NI were all consumed
during the reaction process. At this stage, it is not clear why
the affinity of R,â-unsaturated ketones for chlorine ion is
superior to that for the iodine counterpart under the present
conditions.
Acknowledgment. Generous support from the Robert A.
Welch Foundation (grant D-1361) and the South Plains
Foundation are gratefully acknowledged. We thank the
National Science Foundation (CHE-9808436) and Texas
Tech University for purchasing the 500 MHz NMR. We
thank Mr. David W. Purkiss for his assistance in NMR
spectroscopic analysis.
In summary, we have demonstrated a new nonstoichio-
metric TiCl4- and TiBr4-mediated vicinal difuctionalization
Supporting Information Available: 1H and 13C NMR
spectra for all pure products. These materials are available
free of charge via the Internet at http://pubs.acs.org.
Table 2. Results of TiX4/(n-Bu)4NI-Mediated CdC Bond
Formation7b
OL9904040
(8) 1H NMR Data, Table 1 (200 MHz, CDCl3). 1: δ 7.70 (s, 1H),
7.62-7.40 (m, 5H), 4.44 (s, 2H), 2.50 (s, 3H). 2: δ 7.65-7.58 (m, 3H),
4.44 (s, 0.2H), 4.35 (s, 1.8H), 2.50 (s, 3H). 3: δ 8.26 (s, 1H), 7.95-7.74
(m, 4H), 7.60-7.52 (m, 3H), 4.39 (s, 2H), 2.62 (s, 3H). 4: δ 8.35-8.30
(d, 2H, J ) 8.8), 7.75-7.70 (d, 2H, J ) 8.8), 7.72-7.68 (d, 1H J ) 5.4),
4.39 (s, 2H), 2.95-2.84 (q, 2H, J ) 14.4, 7.2), 1.26-1.18 (t, 3H, J ) 7.2);
5 δ 8.30-8.24 (q, 1H, J ) 8.2, 1.2), 8.02 (s, 1H), 7.80-7.63 (m, 3H), 4.21
(s, 1H), 2.55 (s, 3H). 6: δ 7.78-7.68 (q, 4H), 4.39 (s, 1H), 2.53 (s, 3H).
7: δ 7.65 (s, 1H), 7.62-7.57 (d, 2H, J ) 8.8), 7.01-6.97 (d, 2H, J ) 8.8),
4.49 (s, 2H), 3.86 (s, 3H), 2.48 (s, 3H). 8: δ 6.89-6.81 (t, 1H, J ) 7.4),
4.31 (s, 2H), 2.45-2.33 (q, 2H, J ) 7.4, 14.8), 2.35 (s, 3H), 1.42-1.18
(m, 14H), 0.92-0.85 (t, 3H, J ) 6.4). 9: δ 8.05-8.01 (d, 1H, J ) 8.0),
7.79-7.45 (m, 4H), 7.42-7.36 (d, 1H, J ) 11.0), 7.24-7.10 (q, 1H, J )
14.8, 11.0), 4.53 (s, 2H), 2.89-2.77 (q, 2H, J ) 14.4, 7.2), 1.23-1.14 (t,
3H, J ) 7.2). 10: δ 8.06-8.01 (q, 1H, J ) 8.2, 1.2), 7.81-7.49 (m, 4H),
7.42-7.35 (d, 1H, J ) 11.2), 7.24-7.10 (q, 1H, J ) 13.2, 11.2), 4.51 (s,
2H), 2.47 (s, 3H). 13C NMR Data, Table 1 (125 MHz, CDCl3). 1: δ 197.3,
143.6, 136.9, 134.0, 129.8, 129.5, 128.8, 37.5, 25.8. 2: δ 197.1, 142.7,
137.1, 134.1, 129.0, 129.6, 128.8, 37.4, 25.1. 3: δ 197.1, 141.4, 138.9,
133.3, 131.1, 131.1, 130.0, 128.8, 126.8, 126.7, 126.4, 125.4, 123.9, 38.0,
26.2. 4: δ 199.4, 148.0, 140.6, 139.2, 138.9, 130.1, 124.0, 37.1, 31.2, 8.2.
5: δ 196.7, 147.0, 140.3, 137.7, 134.1, 130.5, 130.2, 125.2, 37.0, 26.0. 6
δ 197.0, 141.4, 138.8, 137.6, 129.6, 125.9, 125.8, 125.8, 37.0, 25.0. 7: δ
197.3, 161.0, 143.8, 134.9, 131.9, 126.5, 114.4, 55.3, 37.9, 25.7. 8: δ 196.8,
149.1, 138.2, 35.5, 31.8, 29.4, 29.4, 29.3, 29.2, 28.4, 25.4, 22.6, 14.0. 9:
δ 199.2, 148.0, 140.6, 136.9, 136.8, 133.4, 131.3, 129.6, 128.6, 127.6, 124.6,
35.7, 30.6, 8.2. 10 δ 196.6, 148.1, 141.9, 137.6, 137.2, 133.5, 131.4, 129.8,
128.7, 127.6, 125.0, 35.4, 25.6.
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