Ti-catalyzed reformatsky-type coupling between α-halo ketones and aldehydes

Article abstract of DOI:10.1021/jo702189k

(Chemical Equation Presented) We describe the first Ti-catalyzed Reformatsky-type coupling between α-halo ketones and aldehydes. The reaction affords β-hydroxy ketones under mild, neutral conditions compatible with ketones and other electrophiles. The cat

Full text of DOI:10.1021/jo702189k

(CF3CO)2O as scavenger, which gives moderate yields of
â-hydroxy esters.6 Here we extend the Ti-based procedure to
the Reformatsky-type coupling between R-halo ketones and
aldehydes to obtain â-hydroxy ketones (aldol-like products)
under neutral conditions. The reaction is catalyzed by substo-
ichiometric proportions of the titanium complex, using Mn dust
as stoichiometric reductant and a combination of Me3SiCl and
2,4,6-collidine, developed in our laboratory, as titanocene-
regenerating agent.7
Ti-Catalyzed Reformatsky-Type Coupling
between r-Halo Ketones and Aldehydes
Rosa E. Este´vez, Miguel Paradas, Alba Milla´n,
Tania Jime´nez, Rafael Robles,* Juan M. Cuerva,* and
J. Enrique Oltra*
Department of Organic Chemistry, UniVersity of Granada,
Faculty of Sciences, Campus FuentenueVa s/n,
E-18071 Granada, Spain
Because Mn dust (unlike Zn) does not promote Reformatsky
reactions,5,6,8 we chose this metal to generate Cp2TiCl for our
experiments to avoid Zn-derived competing processes, which
might generate misleading observations.5,6,9 Thus, on the basis
of our own experience with Ti-catalyzed reactions,10 we
anticipated the catalytic cycle depicted in Scheme 1.
joltra@ugr.es; jmcuerVa@ugr.es; rrobles@ugr.es
ReceiVed October 9, 2007
According to our hypothesis, an R-halo ketone such as 1
would react with 2 equiv of Cp2TiIIICl to give a titanium(IV)
enolate such as 2, releasing 1 equiv of Cp2TiIVCl2 (Scheme 1).
Enolate 2 could subsequently react with an aldehyde (3) to give
adduct 4. Titanocene-regenerating agent 5, presumably derived
from the Me3SiCl/collidine mixture used,7a would generate Cp2-
TiCl2 from 4, releasing 6, which after the final acidic quenching
would give the desired â-hydroxy ketone 7. Eventually the Mn
present in the medium would reduce Cp2TiIVCl2 to Cp2TiIIICl,
thus closing the catalytic cycle.
We describe the first Ti-catalyzed Reformatsky-type coupling
between R-halo ketones and aldehydes. The reaction affords
â-hydroxy ketones under mild, neutral conditions compatible
with ketones and other electrophiles. The catalytic cycle
possibly proceeds via bis(cyclopentadienyl)titanium enolates.
(4) Bis(cyclopentadienyl)titanium(III) chloride (Nugent’s reagent) can
be generated in situ by stirring commercial Cp2TiCl2 with Zn or Mn dust
in THF, where it exists as an equilibrium mixture of the monomer Cp2TiCl
and the dinuclear species (Cp2TiCl)2; see: (a) RajanBabu, T. V.; Nugent,
W. A. J. Am. Chem. Soc. 1994, 116, 986-997. (b) Enemærke, R. J.; Larsen,
J.; Skrydstrup, T.; Daasbjerg, K. J. Am. Chem. Soc. 2004, 126, 7853-
7864. (c) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.; Mu¨ck-
Lichtenfeld, C.; Gansa¨uer, A.; Barchuck, A.; Keller, F. Angew. Chem., Int.
Ed. 2006, 45, 2041-2044. (d) Gansa¨uer, A.; Barchuk, A.; Keller, F.;
Schmitt, M.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C.; Daasbjerg,
K.; Svith, H. J. Am. Chem. Soc. 2007, 129, 1359-1371. For the sake of
clarity, we represent this complex as Cp2TiCl.
As long ago as 1887, Reformatsky reported the coupling
between ethyl R-haloacetates and aldehydes or ketones promoted
by zinc dust, thus establishing the basis of the Reformatsky
reaction.1 Currently, the Reformatsky reaction is considered in
a broad sense as being the process that results from the insertion
of a metal into a carbon-halogen bond activated by a carbonyl-,
carbonyl-derived, or carbonyl-related group in a vicinal (or
vinylogous) position, followed by coupling of the enolate thus
formed with aldehydes, ketones, or other kinds of electrophile.2a
In recent years, the Reformatsky reaction has been the subject
of renewed interest, due largely to the replacement of hetero-
geneous zinc dust by homogeneous metals and metal derivatives,
which have helped to improve the poor stereochemical control
of the classic Reformatsky reaction and facilitated the develop-
ment of metal-catalyzed versions of the process, among other
advantages.2,3 In this context, Little and co-workers introduced
the use of Cp2TiCl, a mild, homogeneous, single-electron-
transfer reagent4 to promote the Reformatsky-type reaction
between R-halo esters and aldehydes.5 This method proceeds
at room temperature under mild conditions and affords good
yields (78-95%) of â-hydroxy esters but requires stoichiometric
proportions of Cp2TiCl. Subsequently, Cozzi and co-workers
developed a titanium-catalyzed version of the process, using
(5) Parrish, J. D.; Shelton, D. R.; Little, R. D. Org. Lett. 2003, 5, 3615-
3617.
(6) Sgreccia, L.; Bandini, M.; Morganti, S.; Quintavalla, A.; Umani-
Ronchi, A.; Cozzi, P. G. J. Organomet. Chem. 2007, 692, 3191-3197.
(7) For the Me3SiCl/2,4,6-collidine combination as titanocene-regenerat-
ing agent, see: (a) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E.
Org. Lett. 2003, 5, 1935-1938. For pioneering work on collidine
hydrochloride and other pyridine hydrochloride derivatives, see: (b)
Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
12849-12859.
(8) In fact, after 6 h of stirring decanal (8) with 9 (2 equiv), Mn dust (8
equiv), 2,4,6-collidine (8 equiv), and Me3SiCl (4 equiv) in the absence of
Ti, an 81% yield of 8 was recovered unchanged and only a trace of coupling
product 10 was detected. Comparison of this result with that presented in
entry 1 of Table 1 (80% yield of 10 after the same reaction time) indicated
that under our conditions the potential Reformatsky reaction promoted by
Mn/Me3SiCl would be substantially slower than the Ti-catalyzed process.
(9) It may be presumed that not only Cp2TiCl but also Zn plays an
important role in Zn/Cp2TiCl2-promoted Reformatsky reactions; see: (a)
Ding, Y.; Zhao, Z.; Zhou, C. Tetrahedron 1997, 53, 2899-2906. (b) Chen,
L.; Zhao, G.; Ding, Y. Tetrahedron Lett. 2003, 44, 2611-2614.
(10) (a) Rosales, A.; Oller-Lo´pez, J. L.; Justicia, J.; Gansa¨uer, A.; Oltra,
J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628-2629. (b) Justicia, J.;
Rosales, A.; Bun˜uel, E. Oller-Lo´pez, J. L.; Valdivia, M.; Ha¨ıdour, A.; Oltra,
J. E.; Barrero, A. F.; Ca´rdenas, D. J.; Cuerva, J. M. Chem. Eur. J. 2004,
10, 1778-1788. (c) Justicia, J.; Oltra, J. E.; Cuerva, J. M. J. Org. Chem.
2004, 69, 5803-5806. (d) Justicia, J.; Oller-Lo´pez, J. L.; Campan˜a, A. G.;
Oltra, J. E.; Cuerva, J. M.; Bun˜uel, E.; Ca´rdenas, D. J. J. Am. Chem. Soc.
2005, 127, 14911-14921. (e) Este´vez, R. E.; Oller-Lo´pez, J. L.; Robles,
R.; Melgarejo, C. R.; Gansa¨uer, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
2006, 8, 5433-5436.
(1) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210-1212.
(2) For a recent review, see: (a) Ocampo, R.; Dolbier, W. R., Jr.
Tetrahedron 2004, 60, 9325-9374. For recent reports on Reformatsky-
type reactions catalyzed by SmI2, [ClMn(salen)], low-valent Fe, and CoI,
see: (b) Lannou, M. I.; He´lion, F.; Namy, J. L. Tetrahedron 2003, 59,
10551-10565. (c) Orsini, F.; Lucci, E. M. Tetrahedron Lett. 2005, 46,
1909-1911. (d) Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951-
2954. (e) Durandetti, M.; Pe´richon, J. Synthesis 2006, 1542-1548. (f)
Lombardo, M.; Gualandi, A.; Pasi, F.; Trombini, C. AdV. Synth. Catal. 2007,
349, 465-468.
(3) Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568-2571.
10.1021/jo702189k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/12/2008
1616
J. Org. Chem. 2008, 73, 1616-1619

TABLE 1. Ti-Catalyzed Coupling between Chloroacetone (9) and
Aliphatic Aldehydes 8, 11, 13, 15, 17, 19, and 21
SCHEME 1. Anticipated Cycle for the Ti-Catalyzed
Reformatsky-Type Coupling between r-Halo Ketones and
Aldehydes
To check our hypothesis, we treated decanal (8) with
chloroacetone (9) (2 equiv), a substoichiometric proportion of
Cp2TiCl2 (0.2 equiv), Mn dust (8 equiv), 2,4,6-collidine (8
equiv),11 and Me3SiCl (4 equiv) in THF at rt. Thus, after 6 h of
stirring we obtained an 80% yield (isolated product) of
4-hydroxytridecan-2-one (10) (Table 1). No formation of the
corresponding conjugated alkenone (dehydration product) was
detected under the mild conditions employed. This preliminary
result in support of our hypothesis prompted us to study the
Ti-catalyzed Reformatsky-type coupling between 9 and other
aliphatic aldehydes (11, 13, 15, 17, 19, and 21) under the same
conditions (Table 1). Thus, we obtained the expected â-hydroxy
ketones (12, 14, 16, 18, 20, and 22) in yields (isolated products)
ranging from a moderate 58% to a good 92%. Ti-catalyzed
coupling between 9 and 13 gave a 7/3 mixture of Cram/anti-
Cram addition products, showing moderate diastereofacial
selectivity. Moreover, the Ti-catalyzed coupling of 9 with
carbohydrate derivative 21 gave a 9/1 mixture of 1′R and 1′S
epimers of 22. In contrast, the Ti-catalyzed coupling between
9 and citronellal (15), the stereogenic center of which is farther
than in 13, showed no stereoselection. Neither was stereose-
lection observed for the Ti-catalyzed coupling of 9 with the
glyceraldehyde derivative 19.
a Mixture of 4R*,5R* and 4S*,5R* diastereomers12 in a ratio of
7/3. b 1/1 mixture of stereoisomers. c Mixture of 1′R and 1′S epimers12 in
a ratio of 9/1.
In contrast to the results described above for aliphatic
aldehydes, aromatic aldehydes were not suitable substrates for
our reaction, it being well-known that they are prone to undergo
pinacolization reactions in the presence of Cp2TiCl.16 In fact,
when we treated a mixture of benzaldehyde and chloroacetone
under our conditions we did not detect any formation of
4-hydroxy-4-phenylbutan-2-one. Furthermore, other substrates,
such as ketones (2-decanone, acetophenone), esters (ethyl
benzoate, ethyl acetoacetate), and nitriles (benzyl cyanide),
proved to be inert under our conditions. These observations
Subsequently, we studied the Ti-catalyzed coupling between
decanal (8) and different R-halo ketones (23, 25, 26, 28, 30,
31, and 33) (Table 2).
In this way, we obtained â-hydroxy ketones 24, 27, 29, 32,
and 34 in yields (isolated products) ranging from an acceptable
61% to a high 94% (Table 2). It should be noted that chloro
(23 an 28) and bromo ketones (25 and 30) gave similar results,
suggesting that the nature of the halide atom is irrelevant for
our process, at least as far as chlorides and bromides are
concerned. Moreover, Ti-catalyzed coupling between 2-chlo-
rocyclohexanone (33) and 8 gave mainly the 2R*,1′R* stere-
oisomer of 34.14 This stereoselectivity is similar to that
reported for bis(cyclopentadienyl)titanium enolates.15 Never-
theless, we observed no stereoselection for the Ti-catalyzed
coupling of acyclic halo ketones 28, 30, and 31 with decanal
(8) (Table 2).
(13) Stereochemical assignments were made by comparing NMR data
with those previously described for the closely related 2-(1-hydroxybutyl)-
cyclohexanone; see: Le Roux, C.; Gaspard-Iloughmane, H.; Dubac, J.; Jaud,
J.; Vignaux, P. J. Org. Chem. 1993, 58, 1835-1839.
(14) Stereoselectivity increased until a 8/1 ratio of 2R*,1′R* and 2S*,1′R*
diastereomers when we carried out the reaction at -20 °C using 1.1 equiv
of Cp2TiCl.
(15) Murphy, P. J.; Procter, G.; Russell, A. T. Tetrahedron Lett. 1987,
28, 2037-2040.
(11) 2,4,6-Collidine can be recovered at the end of the experiment by
simple acid-base extraction; see ref 7b.
(12) Stereochemical assignments were made by comparing NMR data
with those previously described. For product 14, see: (a) Heathcock, C.
H.; Flippin, L. E. J. Am. Chem. Soc. 1983, 105, 1667-1668. For product
22, see: (b) Izquierdo, I.; Plaza, M. T.; Robles, R.; Mota, A.; Franco, F.
Tetrahedron: Asymmetry 2001, 12, 2749-2754.
(16) (a) Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987, 28, 5717-5718.
(b) Gansa¨uer, A. Chem. Commun. 1997, 457-458. (c) Gansa¨uer, A.; Bauer,
D. J. Org. Chem. 1998, 63, 2070-2071. (d) Hirao, T.; Hatano, B.; Asahara,
M.; Muguruma, Y.; Ogawa, A. Tetrahedron Lett. 1998, 39, 5247-5248.
(e) Dunlap, M. S.; Nicholas, K. M. J. Organomet. Chem. 2001, 630, 125-
131.
J. Org. Chem, Vol. 73, No. 4, 2008 1617

TABLE 2. Ti-Catalyzed Coupling between Decanal (8) and r-Halo
Ketones 23, 25, 26, 28, 30, 31, and 33
General Procedure for Ti-Catalyzed Couplings between
R-Halo Ketones and Aldehydes. Strictly deoxygenated THF (20
mL) was added to a mixture of commercial Cp2TiCl2 (0.2 mmol)
and Mn dust (8 mmol) under an Ar atmosphere, and the suspension
was stirred until it turned lime green (about 15 min). Subsequently,
a solution of aldehyde (1 mmol), R-halo ketone (2 mmol), and 2,4,6-
collidine (8 mmol) in THF (2 mL) and Me3SiCl (4 mmol) were
added, and the mixture was stirred for 6 h. A saturated solution of
KHSO4 (40 mL) was then added, and the mixture was extracted
with EtOAc. The organic layer was washed with brine and dried
(Na2SO4) and the solvent removed. The residue was submitted to
flash chromatography (hexane/EtOAc), and isolated products were
characterized by spectroscopic techniques. When water was used
instead of the KHSO4 solution, a â-trimethylsilanyloxy ketone was
obtained (see product 36 in the Supporting Information).
Ti-Catalyzed Chemospecific Coupling of Chloroacetone with
Decanal in the Presence of 2-Decanone. Strictly deoxygenated
THF (20 mL) was added to a mixture of commercial Cp2TiCl2 (31
mg, 0.13 mmol) and Mn dust (282 mg, 3.84 mmol) under an Ar
atmosphere, and the suspension was stirred until it turned lime
green. Subsequently, a solution of decanal (100 mg, 0.64 mmol),
2-decanone (100 mg, 0.64 mmol), and chloroacetone (118 mg, 1.28
mmol) in THF (2 mL) followed by 2,4,6-collidine (542 mg, 4.48
mmol) and Me3SiCl (278 mg, 2.56 mmol) were added, and the
mixture was stirred for 6 h. A saturated solution of KHSO4 (40
mL) was then added, and the mixture was extracted with EtOAc.
The organic layer was washed with brine and dried (Na2SO4) and
the solvent removed. The residue was submitted to flash chroma-
tography (hexane/EtOAc 4/1) giving â-hydroxy ketone 10 (101 mg,
81%) and 2-decanone (95 mg, 95%).
1
a 1/1 mixture of stereoisomers. b Mixture of 2R*,1′R* and 2S*,1′R*
Compound 10: colorless oil; H NMR (300 MHz, CDCl3) δ
diastereomers in a 4/1 ratio.13
4.10-3.95 (m, 1H), 2.60 (dd, J ) 13.2, 6.0 Hz, 1H), 2.50 (dd, J )
13.2, 2.1 Hz, 1H), 2.15 (s, 3H), 1.60-1.20 (m, 16H), 0.85 (t, J )
5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ 210.3 (C), 67.7
(CH), 50.1 (CH2), 36.6 (CH2), 32.1 (CH2), 31.0 (CH3), 29.8 (CH2),
29.7 (CH2), 29.5 (CH2), 25.6 (CH2), 22.9 (CH2), 14.3 (CH3), (one
SCHEME 2. Discrimination between Aldehyde 8 and Ketone
35 by the Ti-Catalyzed Coupling with r-Halo Ketone 9
carbon signal was not observed); IR (film) 3391, 1637 cm-1
;
FABHRMS calcd for C13H26O2Na m/z 237.1830, found m/z
237.1832.
1
Compound 16: colorless oil; 1:1 mixture of stereoisomers; H
NMR (400 MHz, CDCl3) δ 5.05 (t, J ) 7.2 Hz, 1H), 4.16-4.04
(m, 1H), 3.00 (brs, 1H, OH), 2.62-2.42 (m, 2H), 2.14 (s, 3H),
2.00-1.86 (m, 2H), 1.64 (s, 3H), 1.56 (s, 3H), 1.40-1.00 (m, 5H),
0.87 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ
210.1 (C), 131.3 (C), 124.9 (CH), 124.8 (CH), 65.9 (CH), 65.4
(CH), 50.9 (CH2), 50.4 (CH2), 44.0 (CH2), 43.9 (CH2), 37.0 (CH2),
36.8 (CH2), 30.9 (CH3), 29.2 (CH), 28.8 (CH), 25.8 (CH3), 25.6
(CH2), 25.5 (CH3), 20.2 (CH3), 19.2 (CH3), 17.8 (CH3), 17.8 (CH2)
(some carbon signals were not observed); IR (film) 3426, 1636
cm-1; FABHRMS calcd for C13H24O2Na m/z 235.1674, found m/z
235.1673.
suggested that our procedure might be chemospecific for
aldehydes. Thus, when we treated an equimolar mixture of
decanal (8) (1 equiv) and 2-decanone (35) (1 equiv) with
chloroacetone (9) (2 equivs) and a substoichiometric proportion
of Cp2TiCl (0.2 equiv) we obtained an 81% yield of â-hydroxy
ketone 10, recovered 2-decanone unchanged, and (consequently)
did not detect 4-hydroxy-4-methyldodecan-2-one (Scheme 2).
This discrimination between an aldehyde and a ketone is
noteworthy, especially because this has not been reported for
Reformatsky-type reactions catalyzed by other metals.2b-f
In conclusion, we describe here the first Ti-catalyzed Refor-
matsky-type coupling between R-halo ketones and aldehydes.
The reaction affords medium-to-high yields of â-hydroxy
ketones at room temperature under mild, neutral conditions
compatible with ketones and other electrophiles. Stereochemical
evidence supports the idea that the catalytic cycle proceeds via
bis(cyclopentadienyl)titanium enolates. At the moment we are
undertaking a more thorough investigation into this reaction
mechanism and trying to develop an enantioselective version
of the process.
1
Compound 20: colorless oil; 1:1 mixture of stereoisomers; H
NMR (400 MHz, CDCl3) δ 4.12-4.08 (m, 1.5H, isomer a), 4.01
(t, J ) 8.0 Hz, 0.5H, isomer a), 3.98-3.90 (m, 1.5H, isomer b),
3.84 (dd, J ) 8, 6 Hz, 0.5H, isomer b), 3.14 (brs, 0.5H, OH, isomer
a), 2.84 (dd, J ) 17.4, 2.0 Hz, 0.5H, isomer a), 2.75 (brs, 0.5H,
OH, isomer b), 2.70 (dd, J ) 17.4, 8.2 Hz, 0.5H, isomer b), 2.60
(dd, J ) 17.4, 8.2 Hz, 0.5H, isomer a), 2.57 (dd, J ) 17.4, 3.0 Hz,
0.5H, isomer b), 2.20 (s, 3H), 1.44 (s, 1.5H, isomer a), 1.39 (s,
1.5H, isomer b), 1.35 (s, 1.5H, isomer a), 1.33 (s, 1.5H, isomer b);
13C NMR (100 MHz, CDCl3; DEPT) δ 209.8 (C), 208.2(C), 109.7
(C), 109.6 (C), 77.8 (CH), 77.6 (CH), 69.2 (CH), 67.9 (CH), 67.1
(CH2), 65.7 (CH2), 46.6 (CH2), 46.4 (CH2), 31.0 (CH3), 30.9 (CH3),
26.8 (CH3), 26.5 (CH3), 25.3 (CH3), 25.2 (CH3); IR (film) 3428,
Experimental Section
(17) Shulman, H.; Markarov, C.; Ogawa, A. K.; Romesberg, F.; Keinan,
E. J. Am. Chem. Soc. 2000, 122, 10743-10753.
(18) Tang, Z.; Yang, Z.; Chen, X.; Cun, L.; Mi, A.; Jing, Y.; Gong, L.
J. Am. Chem. Soc. 2005, 127, 9285-9289.
The following known compounds were isolated as pure samples
and their NMR spectra matched those reported: 12,17 14,12a 18,18
and 22.12b
1618 J. Org. Chem., Vol. 73, No. 4, 2008

1
1637 cm-1; FABHRMS calcd for C9H16O4Na m/z 211.0946, found
m/z 211.0946.
Compound 32: colorless oil; 1:1 mixture of stereoisomers; H
NMR (400 MHz, CDCl3) δ 7.98-7.90 (m, 2H), 7.50-7.44 (m,
1H), 7.42-7.18 (m, 7H), 4.57 (d, J ) 8.5 Hz, 0.5H, isomer a),
4.54 (d, J ) 5.4 Hz, 0.5H, isomer b), 4.38-4.28 (m, 1H), 2.90
(brs, 1H, OH) 1.42-1.16 (m, 16H), 0.87 (t, J ) 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3; DEPT) δ 201.2 (C), 201.0 (C), 137.0
(C), 136.7 (C), 136.5 (C), 135.2 (C), 133.4 (CH), 133.3 (CH), 129.8
(CH), 129.2 (CH), 129.1 (CH), 129.1 (CH), 129.0 (CH), 128.8 (CH),
128.7 (CH), 127.8 (CH), 127.7 (CH), 73.8 (CH), 72.6 (CH), 60.9
(CH), 58.8 (CH), 34.8 (CH2), 33.8 (CH2), 32.0 (CH2), 29.8 (CH2),
29.7 (CH2), 29.7 (CH2), 29.6 (CH2), 29.4 (CH2), 26.1 (CH2), 25.7
(CH2), 22.8 (CH2), 14.3 (CH3) (some carbon signals were not
observed); IR (film) 3430, 1637 cm-1; FABHRMS calcd for
C24H32O2Na m/z 375.2300, found m/z 375.2298.
Compound 24: white solid; mp 97-98 °C; 1H NMR (400 MHz,
CDCl3) δ 7.94 (d, J ) 8.5 Hz, 2H), 7.56 (t, J ) 8.5 Hz, 1H), 7.45
(t, J ) 8.5 Hz, 2H), 4.20 (m, 1H), 3.29 (brs, 1H, OH), 3.14 (dd, J
) 17.6, 2.8 Hz, 1H), 3.03 (dd, J ) 17.6, 8.8 Hz, 1H), 1.62-1.25
(m, 16H), 0.87 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3;
DEPT) δ 201.0 (C), 136.8 (C), 133.5 (CH), 128.7 (CH), 128.1 (CH),
67.8 (CH), 45.1 (CH2), 36.6 (CH2), 31.9 (CH2), 29.6 (CH2), 29.4
(CH2), 29.3 (CH2), 25.6 (CH2), 22.7 (CH2), 14.2 (CH3) (one carbon
signal was not observed); IR (KBr) 3378, 1679 cm-1; FABHRMS
calcd for C18H28O2Na m/z 299.1987, found m/z 299.1987.
1
Compound 27: colorless oil; H NMR (500 MHz, CDCl3) δ
3.94-3.88 (m, 1H), 3.12 (brs, 1H, OH), 2.60 (dd, J ) 17.8, 2.4
Hz, 1H), 2.45 (dd, J ) 17.8, 9.1 Hz, 1H), 1.48-1.16 (m, 16H),
1.06 (s, 9H), 0.80 (t, J ) 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3;
DEPT) δ 218.0 (C), 68.0 (CH), 44.5 (C), 43.2 (CH2), 36.6 (CH2),
32.0 (CH2), 29.8 (CH2), 29.5 (CH2), 26.4 (CH3), 25.7 (CH2), 22.8
(CH2), 14.2 (CH3), (two carbon signals were not observed); IR
(film) 3433, 1638 cm-1; FABHRMS calcd for C16H32O2Na m/z
279.2300, found m/z 279.2301.
Compound 34:19 colorless oil; mixture of syn/anti stereoisomers;
1H NMR (400 MHz, CDCl3) δ 4.15 (m, 0.5H, syn isomer), 3.72
(m, 0.5H, anti isomer), 3.41 (d, J ) 4.0, 0.5H, OH, anti isomer),
2.45-1.21 (m, 25H), 0.83 (t, J ) 6.0 Hz, 3H); IR (film) 3464,
1701 cm-1
.
Acknowledgment. We thank the Spanish MEC (project
CTQ2005-08402/BQU, grant to R.E.E.) and the “Junta de
Andaluc´ıa” (group FQM339, grant to M.P.) for financial support.
We also thank our English colleague Dr. J. Trout for revising
our English text.
Compound 29: colorless oil; roughly 1:1 mixture of syn/anti
1
stereoisomers; H NMR (400 MHz, CDCl3) δ 3.90 (m, 0.5H, syn
isomer), 3.64 (m, 0.5H, anti isomer), 2.85-2.70 (m, 1H, OH), 2.58
(quint, J ) 7.3 Hz, 0.5H, anti isomer), 2.53 (dq, J ) 7.3, 3.3 Hz,
0.5H, syn isomer), 2.23 (s, 3H), 1.53-1.16 (m, 14H), 1.10 (d, J )
7.3, 1.5H, syn isomer), 1.08 (d, J ) 7.3 Hz, 1.5H, anti isomer),
0.85 (t, J ) 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ
213.9 (C), 213.8 (C), 76.8 (CH), 70.1 (CH), 52.3 (CH), 51.0 (CH),
34.6 (CH2), 34.1 (CH2), 31.9 (CH2), 29.7 (CH3), 29.6 (CH2), 29.5
(CH2), 29.4 (CH2), 29.3 (CH2), 29.1 (CH3), 26.0 (CH2), 25.5 (CH2),
22.6 (CH2), 14.0 (CH3), 13.7 (CH3), 10.2 (CH3) (some carbon
Supporting Information Available: Reformatsky-type reactions
promoted by stoichiometric proportions of Cp2TiCl. Copies of NMR
spectra for all products reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO702189K
signals were not observed); IR (film) 3414, 1698, 1635 cm-1
;
FABHRMS calcd for C14H28O2Na m/z 251.1987, found m/z
251.1988.
(19) Findlay, J. A.; Desai, D. N.; Macaulay, J. B. Can. J. Chem. 1981,
59, 3303-3304.
J. Org. Chem, Vol. 73, No. 4, 2008 1619