Titanocene-catalyzed metallation of propargylic acetates in homopropargyl alcohol synthesis

Article abstract of DOI:10.1016/j.tetlet.2014.07.029

The titanium-catalyzed metallation and subsequent carbonyl addition of propargylic acetates enable the direct formation of homopropargylic alcohols in good yields. The corresponding products were obtained as single regioisomers without the corresponding a

Full text of DOI:10.1016/j.tetlet.2014.07.029

Tetrahedron Letters 55 (2014) 5025–5028
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Tetrahedron Letters
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Titanocene-catalyzed metallation of propargylic acetates
in homopropargyl alcohol synthesis
⇑
Jennifer L. Meloche, Peter T. Vednor, Joseph B. Gianino, Allen G. Oliver, Brandon L. Ashfeld
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46637, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The titanium-catalyzed metallation and subsequent carbonyl addition of propargylic acetates enable the
direct formation of homopropargylic alcohols in good yields. The corresponding products were obtained
as single regioisomers without the corresponding allene adducts observed.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 April 2014
Revised 1 July 2014
Accepted 3 July 2014
Available online 17 July 2014
Keywords:
Titanocene-catalyzed
Propargylic acetates
Homopropargyl alcohols
Metallation/carbonyl addition
Despite the growing number of uses for homopropargyl alco-
hols in
-Lewis acid mediated rearrangements,1 the addition of
p
propargylic or allenic organometallics to carbonyls has received
less attention than the closely related allylation.2 The use of main
group organometallics3 often yields regioisomeric mixtures of
homopropargylic and allenic alcohols, and the metallation condi-
tions are typically incompatible with sensitive functionality.4 In
contrast, the in situ formation of propargyl zinc,3d,5 chromium,6 zir-
conium,7 and titanium8 complexes can avoid issues of chemoselec-
tivity, while regioselectivity is highly dependent on the
substitution pattern of the propargylic substrate.8f,9 Herein, we
have developed a complementary protocol that allows for the mild
generation of a propargyl organometallic, that proceeds with a
high degree of regioselectivity in the carbonyl addition event
(Fig. 1a). Our protocol utilizes a combination of catalytic titanocene
and stoichiometric zinc dust to facilitate the metallation of readily
prepared propargylic acetates.2a,h,10
Figure 1. Propargyl metal addition to aldehydes.
Inspired by our previous work on titanocene-catalyzed cata-
lyzed metallations and multicomponent couplings,2a,h,13,14 we
sought to establish the use of propargylic acetate 1a as a viable
organometallic precursor in the synthesis of alcohol 3a (Table 1).
In general, we discovered that Zn dust (2 equiv) was superior to
both Mg turnings and Mn powder as the terminal reductant, and
that the amount of titanocene proved crucial to achieving a good
yield of 3a. For example, while 5 mol % Cp2TiCl2 and Zn dust in
CH2Cl2 gave homopropargylic alcohol 3a in 12% yield, increasing
the catalyst loading to 10 mol % showed a dramatic increase in
yield to 57% (entries 1 and 2). Ultimately, 20 mol % of Cp2TiCl2
led to 69% yield of 3a (entry 4). While too much catalyst proved
detrimental, titanocene was necessary to achieve any product for-
mation as the absence of the catalyst led to complete recovery of
starting material even after prolonged reaction times (>48 h, entry
We were encouraged by reports from Ding11 and Cuerva12 illus-
trating the stoichiometric titanation of propargylic acetates and
titanocene-catalyzed carbonyl addition of propargyl halides,
respectively, to explore the titanocene-catalyzed metallation-
carbonyl addition sequence involving propargylic acetates and
aldehydes. We speculated that catalytic Cp2TiCl2 and zinc dust
would facilitate the direct metallation of propargylic acetates 1
in the presence of aldehyde 2 to regioselectivity generate the
desired alcohol adduct 3 (Fig. 1b).13
⇑
Corresponding author.
E-mail address: bashfeld@nd.edu (B.L. Ashfeld).
http://dx.doi.org/10.1016/j.tetlet.2014.07.029
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5026
J. L. Meloche et al. / Tetrahedron Letters 55 (2014) 5025–5028
Table 1
Table 2
Optimization of reaction conditionsa
Carbonyl electrophile structural variabilitya
Entry
1
2
3
Yieldb,c (%)
Entry
Cp2TiCl2 (mol %)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
12c
57
69
52c
—
10
20
25
0
20
20
74
dr = 1:1
21
—
THF
a
40
dr = 1:1
Reaction conditions: 1a (0.19 mmol), 2a (0.38 mmol), Cp2TiCl2, and Zn
2
(0.38 mmol), rt, 48 h.
b
Isolated yields with an anti/syn = 1:1 determined by either 500 MHz 1H NMR or
HPLC, see Supporting information for details.
c
Yields determined by 500 MHz 1H NMR.
55
dr = 1.2:1
3
4
5
6). In each experiment depicted in Table 1, alcohol 3a was obtained
as a 1:1 mixture of anti/syn diastereomers across a broad spectrum
of reaction temperatures (0 °C–80 °C).
With optimized conditions in hand, we turned our attention
toward evaluating the structural variability of aldehyde 2 in the
formation of alcohol 3. In general, good yields of the corresponding
homopropargyl alcohols were obtained upon treatment of propar-
gyl acetate 1a and a variety of aldehydes 2 with Cp2TiCl2 (20 mol %)
and Zn dust (Table 1). Aryl aldehydes 2b and 2c gave decent yields
of alcohols 3b and 3c (entries 1 and 2). It should be noted that
electron rich aryl aldehydes proceeded in lower yields than the
more electron deficient counterparts (e.g., p-MeOC6H4CHO–25%).
48
dr = 1.6:1
60
dr = 2:1
53
dr = 8:1
a,b-Unsaturated aldehyde 2d underwent exclusive 1,2-addition
6
to provide the corresponding allylic alcohol 3d in 55% yield (entry
3). Aliphatic aldehydes also proved viable in providing the
corresponding alcohols in decent yields along with improved dia-
stereoselectivities. Phenyl acetaldehyde (2e) and hexanal (2f) gave
alcohols 3e and 3f in good yields and 1.6:1 and 2:1 dr, respectively,
(entries 4 and 5). In contrast, carbocycle-substituted aldehydes, 2g
and 2h underwent propargylation to give homopropargylic alco-
hols 3g and 3h in good yields and further improved diastereoselec-
tivities (entries 6 and 7). Diastereomeric ratios are not enhanced
when performed at lower temperatures, and inferior yields were
observed. While ketones proved viable, the corresponding alcohols
were formed in diminished yields. For example, acetophenone (2i)
yielded alcohol 3i in 30% yield and with a dr = 1.2:1 (entry 8).
We next turned our attention toward evaluating the functional
group flexibility on propargyl acetate 1 in the coupling to aldehyde
2a (Table 3). In contrast to the stoichiometric Cp2TiII-mediated
propargylation,11c aliphatic substrates were unreactive under this
catalytic protocol. Neutral acetate 1b and acetates 1c and 1d
bearing electron rich aryl groups at R2 gave alcohols 4a, 4b, and
4c in comparable yields (entries 2 and 3). However, acetates with
strong electron-withdrawing aryl groups at R2 (e.g., p-O2N-C6H4,
p-Cl-C6H4, p-MeO2C-C6H4) gave only trace quantities (<5%) of the
expected product. Allyl acetate 1e was sufficiently activated to
facilitate metallation to give alcohol 4d in 35% yield (entry 4).
Electron rich aryl substitution on the alkyne in acetate 1f gave
alcohol 4e in modest yield, while the corresponding electron poor
aryl derivatives failed to undergo metallation (entry 5). Alkyl sub-
stitution on the alkyne proved beneficial, providing alcohols 4f in
49% yield and 4g in 60% yield (entry 6 and 7). In general, the
metallation event proved highly dependent on the propargylic
C–O bond strength given the mild reductants Cp2TiCl2 (cat.) and
Zn dust employed.
68
dr = 2.4:1
7
8
30
dr = 1.2:1
a
Reaction conditions: 1 (0.19 mmol), 2 (0.38 mmol), Cp2TiCl2 (20 mol %), and Zn
(0.38 mmol) in CH2Cl2 (0.25 M), rt, 48 h.
b
Isolated yields.
Ratios determined by either 500 MHz 1H NMR or HPLC, see Supporting infor-
c
mation for details.
In previous studies we reported that the addition of
substoichiometric titanocene facilitated the formation of
organozinc reagents directly from the corresponding halides.2a,13
While allylic acetates proved unreactive, our subsequent work on
a titanocene-catalyzed multicomponent coupling for the construc-
tion of tertiary all-carbon centers yielded evidence to suggest the
intermediacy of a propargylic metal species.14 To gain a better
understanding we examined in more detail the conversions of 1a
and 2a to alcohol 3a. The absence of Cp2TiCl2 or Zn dust resulted
in near quantitative recovery of the starting acetate 1a. Using a
stoichiometric amount of Cp2TiCl or Cp2TiCl2 without Zn dust also
gave ꢀ5% of the homopropargyl alcohol 3a. These results suggest
that neither titanocene nor Zn0 are capable of independently
facilitating both the metallation and carbonyl addition steps.
Additionally, replacing Cp2TiCl2 with BF3ÅOEt2 failed to provide

J. L. Meloche et al. / Tetrahedron Letters 55 (2014) 5025–5028
5027
Table 3
Propargylic acetate functional group tolerancea
Entry
1
1
4
Yieldb (%)
20
Scheme 1. Stereochemical consequence.
benzoate 6 as a fine, white solid (Eq. 1). Recrystallization and
X-ray crystallography confirmed that the anti stereoisomer
depicted was indeed the major product. While not definitive, it is
reasonable to assume that the major diastereomers in Table 2 also
bear an anti orientation.
2
27
O
H
Ar
H
3
4
26
35
OH
O
ArCOCl, DMAP, Et3N
64%
(1)
H
Ph
Ar = p-Br-C6H4
Ph
Me
Me
3h
6
major diastereomer
x-ray crystal structure
ð1Þ
Similar to a proposal by Yamamoto and coworkers, the C–C
bond forming event likely proceeds through one of two possible
closed transition states (Fig. 2).9c Formation of the anti diastereo-
mer via TS1 should be favored over TS2 due to the minimization
of eclipsing interactions between Ar and R on the allenyl metal
complex and aldehyde, respectively. Given the increased acidity
of the tertiary proton at the newly formed propargylic/benzylic
center, we speculated that the diastereoselectivity observed
resulted from epimerization of the tertiary center during the reac-
tion. However, when a single diastereomer of 3a was subjected to
the reaction conditions, no epimerization was observed, which
would indicate that the diastereomeric ratios are due to a kinetic
preference for TS1.
5
25
6c
49
60
7
a
Reaction conditions: 1 (0.19 mmol), 2 (0.38 mmol), Cp2TiCl2 (20 mol %),and Zn
(0.38 mmol) in CH2Cl2 (0.25 M), rt, 48 h.
b
Isolated yields with an anti/syn = 1:1.
c
Anti/syn = 1.7:1 determined by 500 MHz 1H NMR.
homopropargylic alcohol 3a suggesting that titanocene is likely not
acting as a Lewis acid, and that both titanocene and zinc are
involved in the metallation event.2a,14d,15
Figure 2. Rationalization of diastereoselectivity.
Further mechanistic insight was obtained by evaluating the ste-
reochemical outcome of the metallation/carbonyl addition events.
Addition of enantioenriched acetate (+)-1a16 to aldehyde 2a gave
homopropargyl alcohol ( )-3a as a racemic mixture in 1:1 diastere-
oselectivity indicating the intermediacy of the configurationally
unstable propargyl organometallic species (Scheme 1).11b,14d,17
Additionally, treatment of racemic acetate 1a using the chiral
titanocene catalyst 5 failed to provide the corresponding alcohol
3a with any appreciable enantioinduction or diastereoselectivity.
The relative configuration of the major diastereomer obtained
in the carbonyl additions depicted in Table 2 was determined by
X-ray crystallography. Isolation of the major 3h diastereomer
followed by acylation with p-bromobenzoyl chloride yielded
The requirement that both titanocene and zinc be present to
provide the reactivity observed indicates a synergistic effect in
the formation of an allenyl organometallic necessary to produce
the observed propargylic alcohol. One possible mechanism that is
consistent with our previous work on titanocene-catalyzed metal-
lations,13 involves an initial reductive transmetallation from a mix-
ture of propargylic/allenyl titanocene species to give an allenyl
zinc(II) organozinc5a that undergoes carbonyl addition through a
closed transition state. The propargylation event then occurs regi-
oselectivity with anti stereoselectivity that appears dependent on
aldehyde steric approach control.18 However, an alternative mech-
anism that includes Cp2(Cl)Ti–R as the intermediate involved in the
C–C bond formation cannot be ruled out.8f,9c

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J. L. Meloche et al. / Tetrahedron Letters 55 (2014) 5025–5028
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Acknowledgments
We thank the Walther Cancer Foundation and the University of
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Supplementary data (experimental procedures and compound
characterizations) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
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