Aryl aldehydes as traceless dielectrophiles in bifunctional titanocene-catalyzed propargylic C-X activations

Article abstract of DOI:10.1021/ol202401n

The titanocene-catalyzed construction of all-carbon substituted tertiary centers directly from aromatic aldehydes is described. The starting aldehyde behaves as a traceless functionality in the formation of multiple carbon-carbon bonds through consecutive

Full text of DOI:10.1021/ol202401n

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5680–5683
Aryl Aldehydes as Traceless Dielectrophiles
in Bifunctional Titanocene-Catalyzed
Propargylic CÀX Activations
Catherine A. Campos, Joseph B. Gianino, David M. Pinkerton, and
Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame,
Indiana 46556, United States
bashfeld@nd.edu
Received September 5, 2011
ABSTRACT
The titanocene-catalyzed construction of all-carbon substituted tertiary centers directly from aromatic aldehydes is described. The starting
aldehyde behaves as a traceless functionality in the formation of multiple carbonÀcarbon bonds through consecutive carbonÀheteroatom bond
activations. The sequential addition of a metal acetylide and a second carbon nucleophile to the dielectrophilic aldehyde enables the construction
of symmetrical and unsymmetrical 1,4-diynes in good yields.
Aldehydes are one of the most widely recognized elec-
trophilic functional groups in organic synthesis. However,
their use as a traceless functional handle for multiple CÀC
bond formations is generally limited to sequential, acid-
mediated FriedelÀCrafts-type arylations1 and Michael
additions to in situ generated Knoevenagel condensation
products.2 The synthetic utility of this ubiquitous func-
tional group would be greatly expanded if construction
of an all-carbon substituted tertiary center could be
achieved through sequential, direct nucleophilic substitu-
tions of a dielectrophilic aldehyde. Contrary to conventional
carbonyl reactivity, conditions that render an aldehyde
dielectrophilic ultimately generate a tertiary, all-alkyl sub-
stituted carbon center through two distinct nucleophilic
additions in a one-pot procedure. Based on our previous
work with titanocene-catalyzed CÀC bond formations,3
we reasoned that the redox and oxophilic properties of
titanocene4 could be harnessed to facilitate the initial
addition of a carbon-based nucleophile and activate the
resulting alkoxide for a second CÀC bond formation.
These sequential CÀX/CÀO bond activations lead to a
net double alkylation that rapidly installs two functional
handles.
Based on the documented ability of titanocene to reduce
propargyl alcohol derivatives,5 we chose to begin our
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r
10.1021/ol202401n
Published on Web 09/29/2011
2011 American Chemical Society

studies by examining metal acetylides as the first nucleo-
philic component in our dialkylation sequence. We envi-
sioned that a multifunctional catalyst could be used to
directly assemble an all-carbon substituted tertiary center
via the controlled addition of an acetylide and a second
carbon nucleophile to an aromatic aldehyde (eq 1).6 This
cascade design would greatly enhance synthetic efficiency7
by streamlining the CÀC bond-forming process.8 Herein,
we report the implementation of this concept toward the
successful construction of symmetrical and unsymmetrical
1,4-diynes directly from dielectrophilic aldehydes.
(Table 1, entry 1).13 However, replacement of TMSCl with
Ac2O increased the yield of 3a to 65% yield (entry 2).14 The
addition of Ac2O is likely facilitating propargylic CÀO
activation.
In light of our previous finding that phosphine additives
dramatically affect titanocene-catalyzed CÀC bond for-
mations, we examined this phenomenon in the formation
of 1,4-diynes.3 Gratifyingly, the addition of (4-MeO-
C6H4)3P (20 mol %) effectively increased the yield of 3a
to 83% (entries 3). A similar effect was observed with
benzaldehyde (1b) wherein the addition of phosphine
increased the yield of 1,4-diyne 3b from 20% to 66%
(entries 4 and 5).15 Upon further investigation, we discove-
red that the yield of 1,4-diyne 3 was highly dependent on
the nature and amount of phosphine employed. Tributyl-
phosphine and triphenylphosphite gave <5% of 3b
(entries 6 and 7), and electron-rich aryl phosphines failed
Although the metal-catalyzed addition of acetylides to
aldehydes is well established,9 introduction of two acety-
lenes to yield 1,4-diynes, a synthetically versatile subunit
that allows access to polyunsaturated fatty acids, leuko-
trienes, and prostaglandins10 is less precedented.11,12
Therefore, we began our studies by examining the addition
of two alkynes to a dielectrophilic aldehyde as a means of
assembling this architectural motif. Treatment of aldehyde
1a and iodoalkyne 2a with Cp2TiCl2 (5 mol %), Zn(0), and
TMSCl in CH2Cl2 provided diyne 3a in only 12% yield
Table 1. Optimized 1,4-Diyne Formationa
entry
X
additive
R
Y mol % yield (%)b
1
2
OMe (1a) Ac2O
OMe (1a) Ac2O
OMe (1a) Ac2O
no phosphine
no phosphine
4-MeO-C6H4
no phosphine
4-MeO-C6H4
n-Bu
À
12 (3a)
65 (3a)
83 (3a)
20 (3b)
66 (3b)
0 (3b)
(6) For recent reviews, see: (a) Felpin, F.-X.; Fouquet, E. Chem-
€
Reactions; Springer: Berlin, 2006.
À
SusChem 2008, 1, 718. (b) Muller, T. J. J. Metal Catalyzed Cascade
3
20
À
4
H (1b)
H (1b)
H (1b)
H (1b)
H (1b)
H (1b)
H (1b)
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
(7) For reviews on tandem reactions, see: (a) Ambrosini, L. M.;
Lambert, T. H. ChemCatChem 2010, 2, 1373. (b) Wender, P. A.; Verma,
V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40. (c) Trost,
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5
20
20
20
6
7
OPh
<5 (3b)
34c (3b)
58c (3b)
80 (3b)
8
2,4,6-MeO-C6H4 20
9
4-MeO-C6H4
4-MeO-C6H4
10
40
10
a Reaction conditions: 1 (0.40 mmol), 2a (0.96 mmol), Cp2TiCl2
(2.0 mol %), Zn (0.84 mmol), TMSCl or Ac2O (0.80 mmol), and
phosphine at 0.1 M for 2 h at rt. b Isolated yields. c Yields determined
by 500 MHz 1H NMR.
(10) (a) Lim, Y. J.; Lee, C.-O.; Hong, J.; Kim, D.-k.; Im, K. S.; Jung,
J. H. J. Nat. Prod. 2001, 64, 1565. (b) Chill, L.; Miroz, A.; Kashman, Y.
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E. R. H.; Lowe, B. E.; Lowe, G. J. Chem. Soc. C 1966, 129.
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J. S.; Reddy, B. V. S.; Chandrakanth, D.; Prashant, B. Chem. Lett. 2008,
37, 954. (b) Yadav, J. S.; Reddy, B. V.; Thrimurtulu, N.; Reddy, N.;
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R. J. Organomet. Chem. 2003, 670, 151.
to improve the yield of 3b (entry 8). These results indicate
that the relative size and basicity of added phosphine
profoundly affects the amount of 1,4-diyne obtained.
Lowering the amount of (4-MeO-C6H4)3P from 20 to
10 mol % led to a modest decrease in the yield of 3b
(entry 9). However, increasing the amount of (4-MeO-
C6H4)3P to 40 mol % provided 3b in an improved 80%
yield (entry 10). Interestingly, when the amount of phos-
phine exceeded 40 mol %, little improvement was observed.
Withoptimizedconditions in hand, we examineda series
of aldehydes in the formation of symmetrical 1,4-diynes
(Table 2). In general, electron-rich benzaldehyde deriva-
tives provided 1,4-diynes in good toexcellent yields(entries
ꢀ
ꢀ
(12) (a) Tejedor, D.; Lopez-Tosco, S.; Gonzalez-Platas, J.; Garcıa-
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Tetrahedron 2000, 56, 9927.
(15) The remaining material was recovered as unreacted benzalde-
hyde.
Org. Lett., Vol. 13, No. 20, 2011
5681

1À5). The bis-alkynylation reaction appears insensitive to
ortho substitution and iodoalkyne substitution (entries 1
and 4). Aliphatic iodoalkynes are tolerated, as exemplified
by the conversion of propargyl ether 2e and n-butyl
iodoalkyne 2f to 1,4-diynes 3g and 3h respectively
(entries 5 and 6). Silylacetylene 2g also provided the
corresponding symmetrical 1,4-diyne 3i, although in di-
minished yield (entry 7). The presence of an aryl halide in
aldehydes 1d and 1e did not hinder 1,4-diyne formation
(entries 8 and 9). Likewise, ester-substituted aldehyde 1f
gave diyne 3l (entry 10). However, the more electron-
deficient p-CF3 and p-NO2 substituted benzaldehyde deri-
vatives showed negligible overall reactivity. Analogous
reactions with heteroaromatic aldehydes proceeded in
excellent yield as exemplified by the reaction of thiophene
1g to yield 1,4-diyne 3m (entry 11).
Table 3. Synthesis of Unsymmetrical 1,4-Diynesa
entry
Ar
R1
R2 product yield (%)b
1
2
3
4
5
6
7
2-Me-C6H4 (1c) 2-Me-C6H4 (2h) 2a
4a
4b
4c
4d
4e
4f
52
56
50
57
53
55
50
1c
1c
1c
4-Cl-C6H4 (2b)
2a
4-F3C-C6H4 (2d) 2a
2d
2c
2c
4-MeO-C6H4 (1a) Ph (2a)
4-Cl-C6H4 (1d)
4-MeO-C6H4 (2c) 2a
2b 2a
1d
4g
a Same as those in Table 1 with the exception that the second
alkynyliodide and Ac2O were added after formation of the intermediate
propargylic alkoxide was observed. b Isolated yields.
Table 2. Synthesis of Symmetrical 1,4-Diynesa
arose as a result of the initial acetylide addition to the
aldehyde. Specifically, sequential treatment of aldehyde 1c
with iodoalkyne 2a followed by propargyl acetate 2i
provided diyne 4h in good yield, while leaving the primary
propargylic acetate intact (eq 2). The observed chemo-
selectivity would indicate that the propargylic CÀX acti-
vation event is governed by the electronic influence of the
aromatic aldehyde and not primarily dictated by the steric
environment around the resulting alkoxide derivative.
entry
Ar
R
product yield (%)b
1
2
3
4
5
6
7
8
9
2-Me-C6H4 (1c)
4-MeO-C6H4 (1a)
4-MeO-C6H4 (1a)
2-Me-C6H4 (1c)
4-MeO-C6H4 (1a)
4-MeO-C6H4 (1a)
4-MeO-C6H4 (1a)
4-Cl-C6H4 (1d)
4-F-C6H4 (1e)
Ph (2a)
3c
3d
3e
3f
93
88
59
76
60
56
25
96
80
50
92
4-Cl-C6H4 (2b)
4-MeO-C6H4 (2c)
4-F3C-C6H4 (2d)
CH2OEt (2e)
nBu (2f)
Si(iPr)3 (2g)
Ph (2a)
3g
3h
3i
3j
Ph (2a)
3k
3l
10 4-MeO2C-C6H4 (1f) Ph (2a)
11 2-thiophene (1g) Ph (2a)
3m
While examining the Ti-catalyzed formation of unsym-
metrical 1,4-diynes, we observed two instances where 1,5-
diyne 5 was generated as a significant byproduct of the
reaction (eq 3).5a,16,17 Treatment of aldehyde 1b with
iodoalkyne 2a followed by 2d in the presence of PtBu3
yielded 1,5-diyne 5a in 38% as a 1:1 mixture of meso and dl
diastereomers. Likewise, the addition of iodoalkyne 2e
to aldehyde 1c provided a 1:1 diastereomeric mixture of
1,5-diyne 5b in 20% yield.18 Postulating that the 1,4-
and 1,5-diynes arise from a configurationally unstable
propargyltitanocene intermediate, treatment of enan-
tiomerically enriched acetate 619 with iodoalkyne 2c,
a Same conditions as those in Table 1. b Isolated yields.
Efforts to apply this protocol directly to the concurrent
addition of two different alkyne components resulted in
statistical mixtures of symmetrical and unsymmetrical 1,4-
diynes. After extensive optimization, it was discovered that
the symmetrical products could be relegated to trace
amounts (<10%) if the second alkyne component was
added after alkoxide formation and followed by the slow
addition of Ac2O over 11 h (Table 3). Additionally, switch-
t
ing from (4-MeO-C6H4)3P to Bu3P provided slightly
better yields of the unsymmetrical 1,4-diynes. In general,
electron-rich and -poor aryl substituents on the alde-
hyde and iodoalkyne components gave diynes 4 in good
yields. To the best of our knowledge, this represents the
first example of an unsymmetrical 1,4-diyne synthesis
using a one-pot, three-component, intermolecular cou-
pling strategy.
(16) 1,5-Diynes were typically observed in e5% yield during 1,4-
diyne synthesis.
(17) (a) Melikyan, G. G.; Spencer, R.; Rowe, A. Organometallics
2010, 29, 3556. (b) Meilkyan, G. G.; Combs, R. C.; Lamirand, J.; Khan,
M.; Nicholas, K. M. Tetrahedron Lett. 1994, 35, 363.
(18) The remaining material consisted of a complex mixture contain-
ing allenes, unreacted starting material, and unidentified coupling
products.
(19) Acetate 11 was synthesized by the following procedure:
(a) Tyrrell, E.; Hunie Tesfa, K.; Mann, A.; Singh, K. Synthesis 2007,
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The formation of the second carbonÀcarbon bond
proved chemoselective for the alkoxide derivative that
5682
Org. Lett., Vol. 13, No. 20, 2011

Cp2TiCl2, Zn(0), tBu3P, and Ac2O generated 1,4-diyne 4f
with complete loss of optical activity (eq 4). The combina-
tion of these results supports a mechanism involving the
reduction of an intermediate propargylic acetate by low
valent titanocene in the construction of 1,4-diynes.5b,20,21
the zinc or titanocene acetylide derivative of 2, both of
which are possible under the reaction conditions. Finally,
reduction of the resulting Ti(IV) complex by zinc dust
completes the catalytic cycle. Although the exact role of
phosphine is the subject of current investigation, we
hypothesize that it may stabilize low valent titanocene
complexes generated while also increasing the reactivity
of organozinc intermediates through an unusual PÀZn
ligation.22
Scheme 1. Proposed Catalytic Cycle for 1,4-Diyne Formation
In an effort to gain further mechanistic insight into the
titanocene-catalyzed synthesis of 1,4-diynes, the conver-
sion of aldehyde 1b to diyne 3b was examined. The need for
Cp2TiCl2 and Zn(0) was confirmed by the observation that
omission of either reagent led to recovered aldehyde 1b
after 2 h at rt. Although the presence of Zn(0) and
phosphine in the absence of Cp2TiCl2 provided the inter-
mediate propargylic alcohol after extended periods of time
(>24 h), the presence of Cp2TiCl2 has an obvious impact
on alkoxide formation. Substitution of Cp2TiCl2 for
BF3•OEt2 failed to provide either the propargylic alcohol
or diyne 3b, indicating that titanium is likely not merely
acting as a Lewis acid in the second alkynylation event.
Our composite results point to a synergistic effect of
catalytic Cp2TiCl2, zinc dust, and phosphine in both
formation of the initial propargyl alcohol derivative and
acetate displacement in the generation of 1,4-diynes.
While the details of the initial metal acetylide addition
are as yet unknown, a possible mechanism for the second
CÀC bond-forming event begins with the reduction of
acetate 7 by Cp2TiIIICl to yield propargyl radical 8
(Scheme 1).5a A second single electron transfer provides
propargyltitanocene 9, which undergoes coupling with a
second equivalent of alkynyliodide 2. Alternatively, the
introduction of the second alkyne equivalent may involve
In summary, we have developed a unique three-compo-
nent coupling reaction to access 1,4-diynes in a remarkably
mild and efficient process that relies on the multifunctional
capabilities of titanocene. The use of commercially avail-
able and inexpensive Cp2TiCl2 makes this process at-
tractive from a practical standpoint in comparison to
alternative methods. Mechanistic studies and efforts to-
ward expanding the scope of dielectrophilic aldehydes
using various carbon nucleophiles are underway. The
results of these, and subsequent studies, will be reported
in due course.
Acknowledgment. The authors would like to thank the
Universityof Notre Damefor financialsupport, and Profs.
Richard E. Taylor and Bradley D. Smith of the University
of Notre Dame for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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