Redox and Lewis acid relay catalysis: A titanocene/zinc catalytic platform in the development of multicomponent coupling reactions

Article abstract of DOI:10.1021/jo501890z

A titanocene-catalyzed multicomponent coupling is described herein. Using catalytic titanocene, phosphine, and zinc dust, zinc acetylides can be generated from the corresponding iodoalkynes to affect sequential nucleophilic additions to aromatic aldehydes. The intermediate propargylic alkoxides are trapped in situ with acetic anhydride, which are susceptible to a second nucleophilic displacement upon treatment with a variety of electron-rich species, including acetylides, allyl silanes, electron-rich aromatics, silyl enol ethers, and silyl ketene acetals. Additionally, employing cyclopropane carboxaldehydes led to ring-opened products resulting from iodine incorporation. Taken together, these results form the basis for a new mode of three-component coupling reactions, which allows for rapid access to value added products in a single synthetic operation.

Full text of DOI:10.1021/jo501890z

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Article
Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Cata-lytic
Platform in the Development of Multicomponent Coupling Reactions
Joseph B. Gianino, Catherine A. Campos, Antonio J Lepore, David M. Pinkerton, and Brandon L. Ashfeld
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501890z • Publication Date (Web): 03 Oct 2014
Downloaded from http://pubs.acs.org on October 6, 2014
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Page 1 of 36
The Journal of Organic Chemistry
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Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Catalyt-
ic Platform in the Development of Multicomponent Coupling Re-
actions
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Joseph B. Gianino, Catherine A. Campos, Antonio J. Lepore, 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
ABSTRACT: A titanocene-catalyzed multicomponent coupling is described herein. Using catalytic titanocene,
phosphine, and zinc dust, zinc acetylides can be generated from the corresponding iodoalkynes to affect sequen-
tial nucleophilic additions to aromatic aldehydes. The intermediate propargylic alkoxides are trapped in situ with
acetic anhydride, which are susceptible to a second nucleophilic displacement upon treatment with a variety of
electron rich species, including acetylides, allyl silanes, electron-rich aromatics, silyl enol ethers, and silyl ketene
acetals. Additionally, employing cyclopropane carboxaldehydes led to ring-opened products resulting from iodine
incorporation. Taken together, these results form the basis for a new mode of three-component coupling reac-
tions, which allows for rapid access to value added products in a single synthetic operation.
Introduction
The all-carbon tertiary center is a ubiquitous motif found throughout pharmaceutically and biologically im-
portant compounds (Figure 1).1 While a number of stepwise methods exist for the synthesis of tertiary carbon
centers, a catalytic, three-component assembly of all-carbon tertiary centers remains a formidable challenge to the
synthetic chemist.2 Surprisingly, there are few reported protocols for the unsymmetrical, geminal substitution of
two distinct coupling partners to a 2–carbon acceptor functionality.3 This type of synthetic assembly is generally
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limited to Friedel-Crafts type bisalkylations catalyzed by Lewis and Brønsted acids, which typically only provide
achiral tertiary centers.4 Van Vranken, Wang, and others have recently reported an elegant approach to this chal-
lenge in tertiary carbon construction by employing either a copper- or palladium-catalyzed carbene formation
followed by in situ sequential cross-coupling events.5 A key migratory insertion of the metal-stabilized carbene
efficiently incorporates the third alkyl substituent. While undoubtedly a tour de force in transition metal-catalyzed
cross-couplings, the light and heat sensitivity of diazo compounds,6 and the at times indiscriminate reactivity of
metal-stabilized carbenes,7 are limiting factors.
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OH
Me
HO
O
O
O
OH
O
Me
O
Me
O
O
OH
HO
O
MeO
OMe
OH
HO
HO2C
Me
OMe
podophyllotoxin (1)
antimitotic
ampelopsin D (2)
resveratrol derivative
okilactomycin (3)
anti-cancer antibiotic
Figure 1. Representative biologically active natural products.
In an effort to streamline tertiary carbon construction, we sought to develop a three-component coupling of
readily available feedstock materials under exceptionally mild conditions that would enable the assembly of ar-
chitecturally diverse frameworks. Speculating that aromatic aldehydes could serve as the acceptor of two distinct
nucleophilic components in a dielectrophilic fashion,8 we focused on the identification of a mixed metal catalyst
system to perform multiple mechanistically distinct synthetic transformations in a one-pot fashion. Specifically,
the addition of an acetylide anion to an electron deficient aldehyde results in an activated propargylic alkoxide
intermediate that under Lewis acidic conditions would undergo an SN2-like displacement in the presence of a
second carbon nucleophile.9 To achieve this design, we required a catalyst system that would facilitate the metal-
lation and subsequent carbonyl addition to aldehyde 4 via the C–X activation of alkynyl iodide 5, and then medi-
ate the C–O activation of the resulting alkoxide to form a second C–C bond (Figure 2). The incorporation of a
third component 6 ultimately provides the desired coupling adduct 8 bearing the targeted tertiary carbon assem-
blage.
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The Journal of Organic Chemistry
Van Vranken:
ONa
1
EtO2C
R1
CO2Et
CO2Et
Pd2(dba)3•CHCl3, PPh3
THF, 66 ˚C
2
3
4
5
6
7
8
9
EtO
I
TMS
TMS
N2
R1
Wang:
H
Ar2
NNHTs
+ Ar2–Br + R
Pd2(dba)3, XPhos, CuI
LiOtBu, PhMe, 90 ˚C
Ar1
Ar1
H
R
Nuc–Z
This work:
redox catalysis
6
10
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18
O
Nuc
Cp2TiLn (cat.)
ZnX2, PR3
X
Cp2TiCl2 (cat.)
Zn, PR3
H
I
X
R2
4
8
Redox or Lewis acid catalysis
R2
5
Figure 2. Recent approaches toward 3˚ carbon construction.
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The well-established redox and Lewis acidic properties of titanocene and zinc complexes,10 led us to initially
evaluated these inexpensive metals as catalysts to facilitate these mechanistically disparate reaction pathways.
Titanocene(III) chloride (Nugent’s reagent) has garnered substantial interest in the synthetic community as a sin-
gle electron transfer (SET) catalyst in recent years. It’s ability to mildly and chemoselectively affect SET pro-
cesses has allowed for a wide range of transformations, including pinacol couplings,11 Reformatsky reactions,12
Barbier reactions,12a,13 and reductive epoxide openings.14 Furthermore, the ability of titanocene to affect multiple
carbon–carbon bond formations has been elegantly demonstrated by Gansäuer, Oltra and Cuerva in radical-
cascade reactions, which have been applied to several natural products and interesting chemotypes.15 In our own
lab, we investigated the catalytic Barbier reaction catalyzed by titanocene and phosphine. We discovered that the
combination of Cp2TiCl2 and phosphine, in the presence of a reducing metal, had a synergistic effect on the gen-
eration of organometallic reagents from allylic and benzylic halides.13a,13b,13d In light of our previous work and
those of others, we hypothesized that a combination of Cp2TiCl2, phosphine, and zinc dust would result in the
mild generation of a metal-acetylide. Upon addition to an electrophilic aldehyde, the combination of TiIV and in
situ generated ZnII would initiate activation of the propargylic alkoxide intermediate for attack by either a second
acetylide equivalent,16 arene,17 allyl silane,18 or silyl enol ether19 to form the second C–C bond. Herein we de-
scribe our efforts and observations toward the development of a convergent and flexible multicomponent cou-
pling method for the assembly of these versatile molecular frameworks.
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Results and Discussion
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9
We began our study by examining a functionalized alkyne as both the second and third nucleophiles in this 3-
component coupling reaction. Recognizing that the initial challenge was going to be the catalytic metallation and
addition of an acetylide to an aldehyde,20 we focused on the coupling of two equivalents of alkyne 9 to aldehyde
4a (eq. 1). While Periasamy and coworkers demonstrated that titanium(IV) acetylides could be generated from
terminal acetylenes upon treatment with TiCl4 and Et3N,21 these conditions yielded only recovered starting mate-
rials. Expanding on our previous work in the area of Cp2TiCl2-catalyzed organozinc formations, we next explored
the metallation of 9 and its subsequent addition of aldehyde 4a using a combination of Cp2TiCl2 (5 mol%), Zn
dust, and a non-nucleophilic amine base.13a Unfortunately, neither diyne 11 or the intermediate propargylic alco-
hol (not shown) were observed, but rather migratory insertion of a Cp ligand from Cp2TiCl2 gave fulvene 10 in
≤5% yield and recovered 4a.22
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OTBS
CHO
9
TBSO
(1)
Cp2TiCl2 (5 mol%)
Zn, base, THF, Δ
base = Et3N or DBU
4a
MeO
H
Ar
OTBS
MeO
10 5%
11 not observed
Given the inefficient metallation of terminal alkyne 9, we next attempted acetylide formation from halo-
acetylenes utilizing a metal-halogen exchange process. While Shrihari and coworkers showed that the metallation
of iodoacetylenes could be effected with zinc dust in THF, refluxing conditions were required, which limited the
iodoalkyne and aldehyde functional group compatibility.23 To establish a more mild and general protocol, we
examined the use of Cp2TiCl2 as a Barbier-type redox metallation catalyst under milder conditions. Gratifyingly,
the addition of iodoacetylene 5a to aldehyde 4a in the presence of Cp2TiCl2 (2 mol%) and Zn dust in THF afford-
ed propargyl alcohol 12a in 50% yield along with only trace amounts of the desired 1,4-diyne 13a (Table 1, entry
1). Speculating that the reaction conditions were not sufficiently Lewis acidic to enable C–O bond activation of
the intermediate propargylic alkoxide, the in situ functionalization to a better leaving group should alleviate this
issue. Thus, the addition of TMSCl, which is known to promote catalyst turnover in Cp2TiCl2-catalyzed reac-
tions,11a-d,11f,11g,12-13,13c-f,14 gave 12a in 69% yield, but with no diyne formation (entry 2). However, utilizing CH2Cl2
in place of THF with the addition of TMSCl gave us our first glimpse of 1,4-diyne 13a albeit in 12% yield along
with alcohol 12a (entry 3). Employing Ac2O in place of TMSCl significantly improved the yield of 13a to 65%
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while enabling ≥95% conversion of the intermediate propargylic alcohol 12a (entry 4). We quickly learned that
the electronic nature of the aldehyde played a critical role in product distribution. For example, treatment of 4-
methylbenzaldehyde (4b) in CH2Cl2 or a mixed solvent system of CH2Cl2/THF (1:1) provided only alcohol 12b to
10% and 55% respectively (entries 5 and 6). Again, the addition of Ac2O led to formation of 1,4-diyne 13b albeit
in a mere 5% yield (entry 7).
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A close inspection of the conversion of 4a to 13a from the experiment in entry 4 revealed a significant quantity
of unreacted iodo alkyne 5a, leading us to conclude that acetylide formation was a problematic step in this multi-
component coupling. Employing aldehyde 4c bearing an electron withdrawing group failed to provide significant
quantities of alcohol 12c or diyne 13c, even in the presence of Ac2O (entries 8 and 9). Previously, we had shown
that the addition of phosphines had a marked impact on the titanocene-catalyzed metallation of allylic halides.13a
Based on this work, we initially examined what effect phosphine additives would have on the formation of 1,4-
diynes. Attempting the alkynylation of aldehyde 4c with 5a in CH2Cl2 with the addition of PtBu3 (40 mol%) im-
proved the yield of 12c to 66% yield (entry 10). Interestingly, the combination of Ac2O and the electron rich tri-
aryl phosphine P(4-MeO-C6H4)3 enabled full conversion of the intermediate alcohol to 1,4-diyne 13c in 33%
yield (entry 11). While the role of phosphine in the metallation of 5a and subsequent addition to aldehyde 4c is
unclear at present, it is conceivable that ligation to either zinc or low-valent titanocene may attenuate the reactivi-
ty of either metal en route to product formation.24 Further attempts at optimization by varying the time, tempera-
ture, and solvent failed to improve the yield of 13c. However, with these results in hand, we turned our attention
toward examining the phosphine in this three-component coupling.
Table 1. Titanocene-Catalyzed Acetylide Additiona
Ph
OH
CHO
I
Ph 5a
+
Cp2TiCl2 (2 mol%)
Zn, solvent, rt
additive
R
Ph
R
Ph
R
4a: R = OMe
4b: R = Me
4c: R = Cl
12a: R = OMe
12b: R = Me
12c: R = Cl
13a: R = OMe
13b: R = Me
13c: R = Cl
entry
1
4
additive
–
solvent
THF
yield of 12(%)
yield of 13(%)
≤5
4a
50
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2b
3b
4c
5
4a
4a
4a
4b
4b
4b
4c
4c
4c
TMSCl
THF
CH2Cl2
69
55
≤5
10
55
≤5
10
≤5
66
≤5
12
65
≤5
≤5
5
1
2
3
4
5
6
7
8
TMSCl
Ac2O
CH2Cl2
–
CH2Cl2
9
6d
7c
8
–
Ac2O
CH2Cl2/THF
CH2Cl2
10
11
12
13
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15
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–
CH2Cl2
≤5
11
≤5
9
Ac2O
CH2Cl2
CH2Cl2
10
PtBu3
Ac2O
11
4c
CH2Cl2
0
33
P(4-MeOC6H4)3
aReaction conditions: 4 (0.50 mmol), 5a (0.75 mmol), Cp2TiCl2 (5 mol%), and Zn (1.1 mmol) at 0.25 M for 2 h at rt. bTM-
SCl (0.75 mmol) was added to reaction. cAc2O (0.75 mmol) was added to reaction. dCH2Cl2/THF was used in a 1:1 ratio.
While halogenated solvents and the addition of Ac2O aided in conversion of the intermediate propargylic alco-
hol to 1,4-diyne, these conditions appeared to inhibit metallation of the iodoalkyne, except when in the presence
of phosphine. Therefore, we next surveyed a series of phosphorus reagents in an effort to optimize conversion of
both the starting aldehyde and intermediate propargylic alcohol to the desired 1,4-diyne (Table 2). In general, the
reaction appeared sensitive to both the electronic and steric properties of the added phosphines. Treatment of
aldehyde 4a with the more electron rich triaryl phosphine, P(4-MeO-C6H4)3 increased the yield of 1,4-diyne 13a
to 83% (entry 1). Should the reaction proceed through a propargylic cation, the p-MeO substituent of 4a would
likely assist in this conversion that may mask the generality of these reaction conditions. Thus, we chose to eval-
uate benzaldehyde (4d) and discovered that although in the absence of phosphine, 1,4-diyne 13d was formed, the
addition of P(4-MeO-C6H4)3 increased the yield from 20% to 66% (entries 2 and 3). Trialkyl phosphines and
phosphites effectively inhibited 1,4-diyne formation, whereas P(2-furyl)3 gave 13d in 26% yield (entries 4-7).
The addition of P(2,4,6-MeO-C6H4)3 improved the yield to 34%, but remained inferior to P(4-MeO-C6H4)3 (en-
tries 3 and 8). While using less P(4-MeO-C6H4)3 led to a similar decrease in yield, employing 40 mol% provided
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13d in 80% yield (entries 9 and 10). The addition of more than 40 mol% phosphine inhibited formation of 14d,
leading to decreased yields.
1
2
3
4
5
Table 2. Role of Phosphine in 1,4-Diyne Generationa
6
7
Ph
8
9
CHO
I
Ph 5a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
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30
31
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Cp2TiCl2 (2 mol%), Zn
Ac2O, PL3, CH2Cl2, rt
X
Ph
X
4a: R = OMe
4d: R = H
13a: R = OMe
13d: R = H
entry
4
PL3 (mol%)
yield of 13 (%)
1
2
4a
4d
4d
4d
4d
4d
4d
4d
4d
4d
P(4-MeO-C6H4)3 (20)
-
83
20
66
0
3
P(4-MeO-C6H4)3 (20)
PnBu3 (20)
4
5
P(PhO)3 (20)
<5
<5
26
34
58
80
6
P(MeO)3 (20)
7
P(2-furyl)3 (20)
P(2,4,6-MeO-C6H4)3 (20)
P(4-MeO-C6H4)3 (10)
P(4-MeO-C6H4)3 (40)
8
9
10
aReaction conditions: 4 (0.50 mmol), 5a (0.75 mmol), Cp2TiCl2 (5 mol%), Zn (1.1 mmol), and Ac2O (0.75 mmol) at 0.25
M for 2 h at rt.
To gain further insight into the mechanism of this three-component coupling, and to obtain a better understand-
ing of its strengths and limitations, a few key control experiments are worth noting. The presence of both
Cp2TiCl2 and Zn dust were crucial to 1,4-diyne formation as the absence of either component in the coupling of
aldehyde 4a and phenyl iodoacetylene 5a led to quantitative recovery of both the starting materials. While earlier
work has shown the compatibility of Mn powder and Mg turnings as stoichiometric reductants in the presence of
Cp2TiCl2,11-14 substituting Zn dust for either of these metals failed to provide the corresponding 1,4-diyne. Addi-
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tionally, the aromatic nature of aldehyde itself proved important for 1,4-diyne formation. When cyclohexane car-
boxaldehyde (14) was subjected to our optimized conditions, acetate 15 was obtained in quantitative yield with-
out subsequent conversion to 1,4-diyne 16 (eq. 2). Additionally, the initial acetylide addition proved chemoselec-
1
2
3
4
5
6
7
tive for aldehydes as both acetophenone and benzophenone were recovered unreacted.
8
9
Ph
10
11
12
13
14
15
16
17
18
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I
Ph 5a
Cp2TiCl2 (2 mol%), Zn
O
OAc
(2)
Ph
H
(p-MeOC6H4)3P, Ac2O
CH2Cl2, rt
Ph
14
15e ≥99%
16e not observed
Although our optimized conditions depicted in Table 2 proved effective for the assembly of symmetrical 1,4-
diynes, employing two different iodoalkynes yielded a nearly statistical mixture of symmetrical and unsymmet-
rical adducts. For example, the addition of iodoalkynes 5a and 5b to aldehyde 4a led to 1,4-diynes 13a, 13e, and
13g in a 3.3:1.4:1.0 ratio and 57% overall yield (eq. 3). Speculating that a sequential addition of the iodoacetylene
components would minimize formation of the symmetrical adducts, and in an effort to slow down the rate of the
second C–C bond formation, we examined the addition of 5a to electron deficient aldehyde 4c followed by addi-
tion of the slower metallating iodo alkyne 5c (eq. 4). Interestingly, the major product from this experiment was
determined to be the dimerized 1,5-diyne 17a. The formation of this 1,5-diyne is likely due to the propensity of
propargylic acetates to undergo metallation by Cp2TiCl2 in the presence of Zn, which in the absence of a second
iodoalkyne or suitable electrophile, would then couple to give the observed major product.25
R1
O
I
Ph 5a, I
Ar, 5b
(3)
R2
H
Cp2TiCl2 (2 mol%), (p-MeOC6H4)3P
Zn, Ac2O, CH2Cl2, rt
Ar = p-MeOC6H4
MeO
4a
MeO
57%
14a/14b/14c = 3.3:1.4:1.0
13a: R1 = R2 = Ph
13e: R1 = R2 = Ar
13f: R1 = Ph, R2 = Ar
Cl
nBu
O
I
Ph 5a, I
nBu, 5c
(4)
H
Cp2TiCl2 (2 mol%), (p-MeOC6H4)3P
Zn, Ac2O, CH2Cl2, rt
Cl
nBu
4c
17a
20%, dr =1:1
Cl
Ding and coworkers previously reported this homodimerization of activated propargylic acetates in the pres-
ence of Cp2TiCl2.26 Whether these 1,5-diynes result from a free-radical combination or polar substitution mecha-
nism, we hypothesized that by minimizing the effective concentration of the intermediate propargylic acetate
would be key to unsymmetrical 1,4-diyne formation. Thus, we examined the syringe pump addition of acetic
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anhydride upon alkoxide formation while in the presence of the second acetylene equivalent (Table 3). Treatment
of aldehyde 4c with iodide 5a with Cp2TiCl2 (2 mol%), (4-MeO-C6H4)3P (40 mol%), and Zn dust led to the ex-
pected propargylic alkoxide, as observed by TLC analysis, at which point iodide 5d was added followed by Ac2O
1
2
3
4
5
6
7
t
to give a primarily 1,5-diyne 17b (entry 1). Switching to the more Lewis basic Bu3P led to an increase in 1,4-
8
diyne formation, and the addition of Ac2O via syringe pump over 5 h further improved the yield of 13g to 17%
(entries 2 and 3). The ratio of 13g to 17b could be further improved by the addition of Ac2O over 11 h, whereas
longer addition times led to intractable mixtures of unidentified side products.
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51
52
53
54
55
56
57
58
59
60
Table 3. Optimization of Unsymmetrical 1,4-Diynes.a
Ph
Ar
O
Ar
5a, I
Ar, 5d
H
Cp2TiCl2 (2 mol%), PL3
Zn, Ac2O, CH2Cl2, rt
Ar = p-ClC6H4
Ar
Ar
Cl
Ar
17b, dr =1:1
Cl
13g
4c
entry
PL3
P(4-MeO-C6H4)3
PtBu3
Ac2O addition (h)
yield of 13g (%)b
yield of 17b (%)b
1
2
3
4
0
0
8
11
10
16
7
17
35
60
PtBu3
5
PtBu3
11
aReaction conditions: 4c (0.50 mmol), 5a (0.75 mmol), Cp2TiCl2 (5 mol%), Zn (1.1 mmol), and Ac2O (0.75
mmol) at 0.25 M for 2 h at rt. bYields determined by 500 MHz 1H NMR.
With a set of optimized conditions in hand, we turned our focus toward evaluating the scope of 1,4-diyne con-
struction (Table 4). In general, modest yields of the desired adducts were obtained with various aldehydes and
iodo alkynes. Aryl aldehydes bearing both electron donating and electron withdrawing substituents performed
admirably to provide the corresponding symmetrical 1,4-diynes 13c, 13h and 13i. Also, alkyl substituted acety-
lenes proved to be viable coupling partners, as illustrated by the formation of diyne 13i. The iodoalkyne compo-
nent proved equally tolerable to electronic differences, as illustrated by the formation of diynes 13j-m and 13f.
Importantly, the aldehyde component showed good steric and electronic tolerance. Substitution at the ortho posi-
tion did not hinder the carbonyl addition or benzylic substitution events (13j-l).
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Table 4. Synthesis of 1,4-Diynesa
1
2
3
4
5
6
7
R3
O
I
R2, I
R3
5
H
Cp2TiCl2 (2 mol%), tBu3P (40 mol%)
Zn, Ac2O, CH2Cl2, rt
R1
R1
R2
4
13
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EtO
Ph
Ph
Me
Ph
Ph MeO
Ph
Me
Cl
EtO
Me
13h 93%
13c 96%
13i 60%
13j 52%
Cl
CF3
OMe
OMe
Ph
Ph
Cl
Ph
Ph
Me
Me
MeO
13k 56%
13l 50%
13m 55%
13f 53%
aReaction conditions: 4 (0.21 mmol), 131 (0.25 mmol), 132 (0.25 mmol), Cp2TiCl2 (2 mol%) Zn (0.50 mmol), tBu3P (0.084
mmol) and Ac2O (0.50 mmol) at 0.10 M.
A distinct advantage to transition metal-catalyzed couplings is the exceptional chemoselectivity that these cata-
lyst exhibit for specific functional groups.27 Similarly, our titanocene-catalyzed three-component coupling proved
chemoselective for the aryl-propargylic acetate in the second C–C bond formation. To illustrate, the coupling of
aldehyde 4e with iodide 5a and the iodoalkyne 5e gave unsymmetrical 1,4-diyne 13n in 58% yield without for-
mation of adducts resulting from displacement of the primary propargylic acetate (eq. 5).
Ph
Me
O
OAc
5e
I
Ph 5a,
I
Me
(5)
H
Cp2TiCl2 (2 mol%), tBu3P (40 mol%)
Zn, Ac2O, CH2Cl2, rt
58%
OAc
4e
13n
A major driving force behind the design concept depicted in Figure 2 is the mechanistic flexibility of the
TiIV/Zn catalyst system to permit the incorporation of components bearing different modes of reactivity. To fur-
ther probe the mechanistic flexibility of this catalyst system, we chose to examine the addition of nucleophilic
silicon reagents (Table 5).18 Our hypothesis was that the addition of either an allyl silane or silyl enol ether would
prompt the catalyst system to proceed down a Lewis acid-mediated C–C bond formation for incorporation of the
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third component. Thus, treatment of aldehydes 4 with iodo alkyne 5 and various allyl silanes 18 (Z = CHR), pro-
vided the corresponding 1,5-enynes 19a-f in good to excellent yields. Aromatic, silyl and alkynyl iodoalkynes
were effectively integrated in the assembly of 19a and 19b, as well as substituted C1-C3-substituted allyl silanes
(19d-f). A variety of silyl enol ether derivatives proved competent nucleophilic components under the reaction
conditions, including those derived from acetophenone (19g-i), siloxy furan (19j), cyclohexanone (19k), and cy-
clohexane carboxaldehyde (19l) derivatives.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. 1,5-Enynes and β-Alkynyl Carbonylsa
R3
R3
O
TMS
Z
18
I
R2 5,
Z
H
R1
Cp2TiCl2, (p-MeOC6H4)3P
Zn, Ac2O, CH2Cl2, rt
Z = CH2 or O
R1
R2
4
19
Ph
TIPS
Me
19b 80%
Me
19c 70%
Cl
Ph
19a 86%
TMS
Me
Ph
Ph
Ph
Cl
Cl
Cl
19f 96%
19d 88%
19e 92%
O
O
O
Me
Ph
Ph
Ph
OAc
nBu
Me
S
Ph
19g 72%
19h 62%
19i 75%
O
O
CHO
O
Ph
19j 60%, dr =1:1
Ph
Ph
Me
MeO
19k 68%, dr =1:1
Me
19l 78%, dr =1:1
aReaction conditions: 6 (0.40 mmol), 13 (0.80 mmol), 17 (0.80 mmol) Cp2TiCl2 (2 mol%), Zn (0.80 mmol), (4-
MeOC6H4)3P (0.16 mmol), and Ac2O (0.48 mmol) at 0.10 M.
The reactivity observed in the incorporation of allyl and carbonyl components was also applicable to electron-
rich arenes as the second nucleophile to provide diarylethynyl methanes (Table 6).17 Anticipating a Friedel-
Crafts-like arylation of the intermediate propargylic acetate, we supplemented our optimized conditions with
Cs2CO3 and found that PtBu3 (80 mol%) 1,2-dichloroethane (DCE) provided better yields of the diarylethynyl
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methanes. Initially, we examined the acetylide addition to an aryl aldehyde bearing a pendant arene nucleophile
and discovered that the intramolecular arylation proved quite facile to give the tricyclic adduct 21a in 77% yield.
The intermolecular reaction likewise provided a good yield of 21b, as did the utilization of N,N-dimethyl aniline
in the formation of 21c. Additionally, heteroaromatics, in particular N-protected indole, was an excellent nucleo-
phile in the formation of 21d-h. Heteroaromatic aldehydes also proved effective substrates, producing heteroaryl
methanes 21c, 21g, and 23h. In contrast to the optimized procedures for the formation of unsymmetrical 1,4-
diynes, 1,5-enynes, and β-alkynyl carbonyls, the electron rich arene was added simultaneously with the iodoal-
kyne and aldehyde, without formation of the undesired symmetrical 1,4-diynes or 1,5-diyne dimers previously
observed.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Synthesis of Diarylethynyl Methanesa
O
Ar
I
R2 5, + Ar
H 20
H
R1
R1
Cp2TiCl2 (5 mol%), Zn, Ac2O
tBu3P (80 mol%), Cs2CO3
DCE, rt
R2
4
21
OMe
OMe
NMe2
MeN
OMe
Ph
OMe
Ph
Ph
Ph
MeO
Me
TsN
21a 77%
21b 77%
21c 68%
21d 90%
MeN
MeN
MeN
TsN
O
nBuMeO
MeO
BnO
Ph
S
Ph
21e 80%
21f 68%
21g 68%
21h 71%
t
aReaction conditions: 6 (0.21 mmol), 13 (0.63 mmol), 18 (0.42 mmol), Cp2TiCl2 (5 mol%) Zn (0.63 mmol), Bu3P (0.17
mmol) and Ac2O (0.50 mmol) at 0.10 M.
The formation of 1,5-diynes in our optimization of unsymmetrical 1,4-diyne construction was certainly intri-
guing, and prompted us to further probe the potential synthetic utility of intermediates arising from the SET re-
duction of propargylic acetates. Given the propensity of cyclopropylcarbinyl radicals to undergo ring expansion,28
we speculated that addition of the acetylide derived from 5a to cyclopropyl carboxaldehyde (22) in the presence
of Cp2TiCl2, Zn dust, and P(4-MeOC6H4)3 would provide either 1,4-diyne 24a following direct acetate substitu-
tion, or 1,3-enyne 24b upon ring expansion (Scheme 1). Surprisingly, neither 24a or 24b were obtained, but ra-
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ther iodine reincorporation to give iodo enyne 25 as the sole product in a 1.5:1 ratio of E/Z isomers was observed.
1
2
3
This rather intriguing conversion amounts to the formal insertion of a homoallyl fragment into the C–I bond of
4
5
5a.
6
Ph
7
8
9
24a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
expected diyne formation not observed
+
Ph
I Ph 5a
Cp2TiCl2 (2 mol%)
Ph
O
24b
H
(p-MeOC6H4)3P
Zn, Ac2O, CH2Cl2
Ph
Ph
I
22a
23
Exclusive Iodine Incorporation
Ph
25a 42%, E/Z =1.5:1
Scheme 1. Iodine incorporation in cyclopropane ring openings.
The synthetic utility of 1,3-enynes in transition metal-catalyzed processes is well established,29 and this archi-
tectural motif is quite prevalent in many biologically active compounds.30 Therefore, we sought to identify the
optimal set of reaction conditions for the formation of 25a (Table 7). While the yield of 25a showed a modest
improvement with 5 mol% of Cp2TiCl2, a more dramatic effect was observed with the amount of P(4-MeOC6H4)3
employed. In contrast to our three-component couplings described vide supra, the yield of 25a was inversely pro-
portional to the amount of phosphine added. The addition of 100 mol% of P(4-MeOC6H4)3 produced a mixture of
enyne 25a and propargylic acetate 26a in 27% and 63% yield, respectively (entry 1). Decreasing the amount of
phosphine to 60 mol% gave a 57% yield of 25a and 11% of recovered 26a (entry 2). The acetate underwent com-
plete conversion with 40 mol% phosphine, and the yield of 25a was improved to 69% by omitting P(4-
MeOC6H4)3 altogether (entries 3 and 4).
Table 7. Effect of Phosphine on Iodoenyne Formationa
I
Ph 5a
OAc
O
I
Cp2TiCl2 (10 mol%), Zn
+
H
P(4-MeO-C6H4)3 (X mol%)
Ac2O, CH2Cl2, rt
Ph
Ph
22a
25a
26a
entry
1c
mol% of phosphine
100
yield of 25a (%)b
yield of 26a (%)b
27
63
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2c
3
60
40
0
57
52
69
71
11
0
1
2
3
4
5
6
7
8
4
0
5d
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 28a (0.50 mmol), 13b (0.75 mmol), Cp2TiCl2 (10 mol%), Zn (1.1 mmol), and Ac2O (0.75 mmol) at
0.25 M for 2 h at rt. bProduct obtained as a 1.4:1 mixture of E/Z isomers. cYields determined by 500 MHz 1H NMR. d5 mol%
Cp2TiCl2 employed.
The formation of enyne 25 showed comparable tolerance to structural variability on the iodoalkyne component
in the ring-opening iodination reaction as was observed in the synthesis of unsymmetrical 1,4-diynes (Table 8).
Aryl iodoalkynes provided iodoenynes 25 in moderate to good yields with 2-methyl phenyl substituted alkyne
giving the corresponding enyne in 81% yield (entries 2-4). In contrast, aliphatic iodoalkyne 5c, furnished enyne
25e in 21% yield along with enol acetate 27 (eq. 6). It should be noted that for each combination of aldehyde and
iodoalkyne we have examined thus far, only a modest preference for the E-alkene isomer was observed.
Table 8. Iodoalkynes Functional Diversitya
O
I
I
R 5
H
Cp2TiCl2 (5 mol%), Zn
Ac2O, CH2Cl2, rt
R
22a
25
entry
R
product
yield (%)b
E/Zc
1:1
1
2
3
2-Me-C6H4
4-Cl-C6H4
4-CF3-C6H4
25b
25c
25d
81
43
69
1.3:1
1.5:1
aReaction conditions: 22a (0.50 mmol), 5 (0.75 mmol), Cp2TiCl2 (5 mol%), Zn (1.1 mmol), and Ac2O (0.75 mmol) at 0.25
M for 2 h at rt. bIsolated yields. cRatios determined by 500 MHz 1H NMR.
I
nBu 5c
O
I
I
Cp2TiCl2 (5 mol%), Zn
+
OAc
(6)
H
Ac2O, CH2Cl2, rt
nBu
22a
25e
21%, E/Z =1:1
27
41%, E/Z =1:1
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The addition to substituted cyclopropyl carboxaldehydes presents regioselectivity issues in the iodine incorpo-
ration step. Treatment of cyclohexane-substituted cyclopropyl carboxaldehyde 22b and iodoalkyne 5a to the op-
timized reaction conditions led to a E/Z mixtures of both regioisomers 28a and 28b in 66% total yield (eq. 7). As
we saw previously, there was a modest preference in each case for the E-alkene, and a 1.7:1 ratio of regioisomers
favoring incorporation of iodine at the more substituted cyclopropyl carbon. This result is consistent with a radi-
cal-radical annihilation wherein cyclopropane ring opening occurs to yield the more stable carbon-centered radi-
cal.28 However, a carbocation intermediate that is quenched by iodide, a β-carbon elimination pathway, or a re-
ductive coupling from an organotitanocene complex cannot be ruled out at this stage.31 Furthermore, the presence
of the alkene in α,β-unsaturated aldehyde 29 led to the expected, fully conjugated dienyne 30 in 44% yield and a
5:2:1 mixture of olefin isomers (eq. 7). The formation of enynes 25 and 28, and dienyne 30 support a mechanism
involving a reduction of an intermediate propargylic acetate or alkoxide following by strain-driven ring expansion
and subsequent iodine incorporation either through a radical, carbocation, or titanocene-bound intermediate.32
This rather unusual reactivity allows for the rapid assembly of an extended carbon-chain bearing multiple func-
tional handles, including a primary iodide, from readily accessible starting materials.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
I
28a
O
c-C6H11
Ph
I
Ph 5a
+
c-C6H11
(7)
(8)
c-C6H11
H
Cp2TiCl2 (5 mol%), Zn
Ac2O, CH2Cl2, rt
66% total yield
I
22b
28b
Ph
28a: 41%, E/Z = 3.8:1
28b: 25%, E/Z = 5:1
O
Ph
I
Ph 5a
H
Cp2TiCl2 (5 mol%), Zn
Ac2O, CH2Cl2, rt
44%
I
29
30
E,E/E,Z/Z,Z = 5:2:1
Seeking to expand on this ring opening approach toward 1,3-enynes, we next focused our attention on the addi-
tion of the metal acetylide derived from 5a to cyclobutyl carboxaldehyde 31 (eq. 9). While the reactivity of 31
was certainly less than when compared the to cyclopropyl analogs, a ring expansion followed by β-elimination
provided 1,2-disubstituted cyclopentene 32, albeit in only 20% yield (eq. 9). Unfortunately, attempts to improve
the yield of 32 proved problematic, and an intractable mixture of unidentifiable side product was the most com-
mon result. However, this initial proof of concept demonstrates the various mechanistic pathways that the inter-
mediate propargylic acetate may proceed down in the presence of low-valent titanocene.
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Ph
Ph
I
Ph 5a
Ph
(9)
1
CHO
Cp2TiCl2 (5 mol%), Zn, Ac2O
CH2Cl2, 50 ˚C
20%
2
3
31
32
4
5
6
7
8
The varied reactivity of each starting component and reagents, different oxidation states, and possible ligand
complexes lead to an unusually high number of potential mechanistic permutations en route to each product illus-
trated herein. However, based on our findings, and those presented in the literature, our working mechanistic
hypothesis involves initial metal acetylide generation that is catalyzed by Cp2TiIIICl arising from the in situ reduc-
tion of Cp2TiIVCl2 and Zn dust. The resulting acetylide undergoes addition to the starting aldehyde, which may be
enhanced by phosphine ligation, to provide an initial alkoxide, which is acylated by Ac2O. At this stage, either
Lewis acid-mediated ionization or SET reduction of the activated acetate precedes the second C–C bond for-
mation step, the nature of which is highly dependent on the nucleophile employed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion
In summary, this study serves to highlight the utility of titanocene catalysts to enable production of various
structurally interesting carbon-based subunits from relatively simple starting materials. The ability of titanocene
to mildly and effectively generate a range of organometallic intermediates can serve as an initial starting point for
the development of a diverse array of sequential cross-coupling events. The ability of a mixed metal system com-
prised of Cp2TiCl2 and Zn dust to behave in a redox or Lewis acidic fashion provides the adaptable reactivity
necessary to assemble components of varying structure to access diverse libraries important to pharmaceutical
drug design. This catalyst system effectively streamlines molecular assembly, and continued research in this area
of reaction development will likely continue to unveil new applications for many years to come.
EXPERIMENTAL SECTION
Solvents and reagents were ACS reagent grade and used without further purification unless noted below. Dime-
thylformamide (DMF), tetrahydrofuran (THF), dichloromethane (CH2Cl2) and diethyl ether (Et2O) were passed
through a column of molecular sieves and stored under argon. 1,2-Dichloroethane (DCE) was distilled, stored
over 4 Å molecular sieves, and degassed prior to use. Acetic anhydride (Ac2O) was distilled over CaH and zinc
dust was washed sequentially with 1.0 M aq. HCl, water, and Et2O prior to use. All reactions were carried out in
flame-dried glassware under an argon atmosphere unless otherwise specified. Aldehydes 4a-e and 22a were pur-
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chased and used without further purification. Alkynyl iodides 5a-e,33 alkyne 9,34 and aldehydes 22b,35 29,36 and
3137 were prepared according to literature procedures.
1
2
3
4
5
6
7
8
9
1H Nuclear magnetic resonance (NMR) spectra were obtained at either 300 or 500 MHz, and 13C{1H} NMR
spectra at 100, 125 or 150 MHz. Chemical shifts are reported in parts per million (ppm, δ), and referenced to re-
sidual solvent or tetramethylsilane (TMS). Coupling constants are reported in Hertz (Hz). Spectral splitting pat-
terns are designated as s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; comp, complex; app,
apparent; hom, higher order multiplet; and br, broad. Infrared (IR) spectra were obtained using an FT-IR using a
silicon (Si) crystal in an attenuated total reflectance (ATR) tower and reported as wavenumbers (cm-1). High and
Low resolution electrospray ionization (ESI) measurements were made with a TOF mass spectrometer. Analytical
thin layer chromatography (TLC) was performed using 250 micron 60 F254 silica gel plates, visualized with UV
light and stained with a p-anisaldehyde solution. Flash column chromatography was performed according to
Still’s procedure35b using 40-63 µm 60Å silica gel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Representative Acetylide Addition Procedure: A two-dram screw cap vial, equipped with a magnetic stir
bar, was charged with Cp2TiCl2 (2.5 mg, 0.01 mmol) and zinc dust (72 mg, 1.1 mmol) then purged with argon for
5 min. Dry, degassed solvent (0.50 mL) was added and the suspension stirred at room temperature until a
blue/green color persisted. A solution of aldehyde 4 (0.50 mmol) and iodophenylacetylene 13a (171 mg, 0.75
mmol) in the indicated solvent (1.5 mL) was then added and the reaction stirred at room temperature until full
consumption of aldehyde 6 was observed by TLC (~1 h). The reaction was then diluted with CH2Cl2 (2 mL), fil-
tered through a short plug of silica gel eluting with CH2Cl2 (50 mL), and the filtrate concentrated under reduced
pressure. The crude mixture was purified directly by flash chromatography eluting with the indicated solvent
mixture to give the corresponding propargyl alcohol 12.
1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (12a): Purification by flash chromatography eluting with hex-
1
anes/EtOAc (2:1) provided 82 mg (69%) of 12a as a yellow oil. H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 8.5
Hz, 2 H), 7.46-7.44 (m, 2 H), 7.30-7.29 (m, 3 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.62 (s, 1 H), 3.80 (s, 3 H); 13C{1H}
NMR (125 MHz) δ 133.2, 132.0, 128.8, 128.5, 128.4, 128.4, 122.7, 114.2, 89.1, 86.7, 65.0, 55.6; IR (neat) 3388,
3064, 2999, 2955, 2836, 2250, 1607, 1510, 1491, 1438, 1253, 1171; HRMS (ESI) Calcd for C16H14O2Na,
261.0886; Found, 261.0918.
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3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (12b): Purification by flash chromatography eluting with hexanes/EtOAc
(3:1) provided 61 mg (55%) of 12b as a yellow oil. Spectral data (1H NMR and 13C{1H} NMR) consistent with
literature values.38
1
2
3
4
5
6
7
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (12c): Purification by flash chromatography eluting with hex-
8
9
1
anes/EtOAc (3:1) provided 80 mg (66%) of 12c as a yellow oil. H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
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Hz, 2 H), 7.47-7.46 (m, 2 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.34-7.32 (m, 3 H), 5.67 (s, 1 H); 13C{1H} NMR (125
MHz) δ 139.3, 134.5, 132.0, 129.2, 129.2, 128.5, 128.3, 122.4, 88.4, 87.2, 64.6; IR (neat) 3312, 3056, 2926,
2857, 2228, 1599, 1520, 1488, 1408, 1266, 1192, 1092; HRMS (ESI) Calcd for C15H11ClONa, 265.0391; Found,
265.0430 .
Representative 1,4-Diyne Procedure: A vial, equipped with a magnetic stir bar, was charged with titanocene
dichloride (1.8 mg, 7.0 µmol) and zinc dust (50 mg, 0.77 mmol), and then purged with argon for 5 min. Dry, de-
gassed CH2Cl2 (0.25 mL) was added and the resulting gray slurry was stirred vigorously at 25 °C until it took on
a blue/green color. A solution of tri-tert-butylphosphine (30 mg, 0.15 mmol) in CH2Cl2 (0.25 mL) was added
slowly, followed by the dropwise addition of a solution of aldehyde 4 (0.37 mmol) and the first alkynyl iodide 5
(0.37 mmol) in CH2Cl2 (0.50 mL). The resulting mixture was stirred at 25 °C until TLC indicated full consump-
tion of the starting aldehyde (3-4 h), at which time the second alkynyl iodide 5 (0.55 mmol) was added neat and
in one portion via syringe. A solution of Ac2O (80 µL, 0.84 mmol) in CH2Cl2 (0.80 mL) was then added at the
indicated temperature over 11 h via syringe pump. Once the addition of Ac2O was complete, the resulting crude
mixture was diluted with CH2Cl2 (2.0 mL) and filtered through a plug of silica gel eluting with 100% Et2O. The
filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with the
indicated solvent system to yield the desired 1,4-diyne 13.
(3-(4-Methoxyphenyl)penta-1,4-diyne-1,5-diyl)dibenzene (13a): 1,4-diyne 13a was obtained in 83% yield
(0.26 mmol scale, 69 mg) after 2 h at 25 °C, eluting with 1:1, hexanes/CH2Cl2, as a clear, yellow oil. Spectral data
(1H NMR and 13C{1H} NMR) consistent with literature values.39
(3-(p-Tolyl)penta-1,4-diyne-1,5-diyl)dibenzene (13b): 1,4-diyne 13b was obtained in 5% yield (0.26 mmol
scale, 4 mg) after 2 h at 25 °C, eluting with 1:1, hexanes/CH2Cl2, as a clear, yellow oil. Spectral data (1H NMR
and 13C{1H} NMR) consistent with literature values.39
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(3-(4-Chlorophenyl)penta-1,4-diyne-1,5-diyl)dibenzene (13c): 1,4-diyne 13c was obtained in 96% yield
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(0.37 mmol scale, 120 mg) after 2 h at 25 ˚C, eluting with 10:1 hexanes/CH2Cl2, as a clear yellow oil. H NMR
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(500 MHz) δ 5.17 (s, 1 H), 7.30-7.33 (comp, 6 H), 7.36-7.38 (m, 2 H), 7.46-7.49 (comp, 4 H), 760-7.62 (m, 2 H);
13C{1H} (125 MHz) δ 29.8, 83.3, 86.2, 122.9, 128.5, 128.6, 128.9, 129.1, 132.0, 133.6, 136.6; IR (neat) 3081,
3057, 3033, 1598, 1488, 1442, 1404, 1293, 1092, 1016; HRMS (ESI) Calcd for C23H16Cl, 327.0935; Found,
327.0948.
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Penta-1,4-diyne-1,3,5-triyltribenzene (13d): 1,4-diyne 13d was obtained in 80% yield (0.26 mmol scale, 60
mg) after 2 h at 25 ˚C, eluting with 3:1, hexanes/CH2Cl2, as a clear, yellow oil. Spectral data (1H NMR and
13C{1H} NMR) consistent with literature values.37
4,4',4''-(Penta-1,4-diyne-1,3,5-triyl)tris(methoxybenzene) (13e): 1,4-diyne 13e was obtained in 58% yield
(0.37 mmol scale, 57 mg) after 8 h at 50 ˚C, eluting with 1:1, hexanes/CH2Cl2 to 4:1 CH2Cl2/hexanes, as a clear,
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orange oil. H NMR (500 MHz) δ 3.82 (s, 6 H), 3.83 (s, 3 H), 5.15 (s, 1 H), 6.83-6.86 (m, 4 H), 6.93-6.95 (m, 2
H), 7.42-7.44 (m, 4 H), 7.59- 7.60 (m, 2 H); 13C{1H} (125 MHz) δ 29.5, 55.4, 55.5, 82.5, 85.8, 114.0, 114.2,
115.4, 128.6, 130.7, 133.4, 159.1, 159.7; IR (neat) 3052, 3005, 2959, 2935, 2838, 1606, 1571, 1463, 1442, 1249,
1173, 1034; HRMS (ESI) Calcd for C26H23O3, 383.1642; Found, 383.1677.
4,4'-(5-Phenylpenta-1,4-diyne-1,3-diyl)bis(methoxybenzene) (13f): 1,4-diyne 13f was obtained in 53% yield
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(0.37 mmol scale, 69 mg) after 14 h at 25 ˚C, eluting with 4:1, hexanes/CH2Cl2, as a clear, orange oil. H NMR
(500 MHz) δ 3.82 (s, 3 H), 3.84 (s, 3 H), 5.16 (s, 1 H), 6.84-6.85 (m, 2 H), 6.93-6.95 (m, 2 H), 7.30-7.31 (comp, 3
H), 7.42-7.44 (m, 2 H), 7.47- 7.49 (comp, 2 H), 7.59-7.60 (m, 2 H); 13C{1H} (125 MHz) δ 29.5, 55.5, 55.6, 82.6,
82.7, 85.6, 87.3, 114.0, 114.3, 115.3, 123.3, 128.38, 128.41, 128.6, 130.5, 132.0, 133.4, 159.1, 159.7; IR (thin
film) 3055, 3004, 2958, 2935, 2837, 1602, 1509, 1462, 1291, 1250, 1174, 1071, 1032; HRMS (ESI) Calcd for
C25H21O2, 353.1536; Found, 353.1535.
4,4'-(5-Phenylpenta-1,4-diyne-1,3-diyl)bis(chlorobenzene) (13g): 1,4-diyne 13g was obtained in 50% yield
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(0.37 mmol scale, 66 mg) after 14 h at 25 ˚C, eluting with 20:1 hexanes/CH2Cl2 as a clear, yellow oil. H NMR
(500 MHz) δ 5.16 (s, 1 H), 7.28-7.32 (comp, 5 H), 7.36-7.41 (m, 4 H), 7.47-7.49 (comp, 2 H), 7.58-7.60 (m, 2 H);
13C{1H} (125 MHz) δ 29.8, 82.2, 83.5, 85.9, 87.3, 121.4, 122.8, 128.5, 128.7, 128.8, 128.9, 129.1, 132.0, 133.3,
133.7, 134.7, 136.5; IR (neat) 3057, 2925, 2852, 1594, 1487, 1443, 1401, 1373, 1294, 1243, 1092, 1046, 1015;
HRMS (ESI) Calcd for C23H15Cl2O, 377.0494; Found, 377.0466.
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(3-(o-Tolyl)penta-1,4-diyne-1,5-diyl)dibenzene (13h): 1,4-diyne 13h was obtained in 93% yield (0.37 mmol
scale, 104 mg) after 2 h at 25 ˚C, eluting with 100% hexanes, as a clear, yellow oil. Spectral data (1H NMR and
13C{1H} NMR) consistent with literature values.39
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1-(1,7-Diethoxyhepta-2,5-diyn-4-yl)-4-methoxybenzene (13i). 1,4-diyne 13i was obtained in 60% yield (0.37
mmol scale, 64 mg) after 3 h at 25 ˚C, eluting with 100% CH2Cl2, as a clear, colorless oil. 1H NMR (300 MHz) δ
1.22 (t, J = 7.0Hz, 6 H), 3.56 (q, J = 7.0 Hz, 4 H), 3.80 (s, 3 H), 4.18 (d, J = 2.0 Hz, 4 H), 4.78 (m, 1 H), 6.88 (d, J
= 9.0 Hz, 2 H), δ 7.42 (d, J = 9.0 Hz, 2 H); 13C{1H} NMR (75 MHz) δ 15.0, 28.2, 55.3, 58.2, 65.4, 78.5, 83.4,
114.0, 128.2, 129.6, 158.9; IR (neat) 2974, 2934, 2245, 2198, 1510, 1250, 1177, 1105; HRMS (ESI) Calcd for
C18H22O3Na, 309.1461; Found, 309.1483.
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2,2'-(5-Phenylpenta-1,4-diyne-1,3-diyl)bis(methylbenzene) (13j). 1,4-diyne 13j was obtained in 52% yield
(0.37 mmol scale, 72 mg) after 14 h at 25 ˚C, eluting with 20:1, hexanes/CH2Cl2, as a clear yellow oil. Product
was isolated as a mixture of 13j and the corresponding symmetrical diynes. The combined yield of the minor
symmetrical adducts (11%) was determined by integration of their benzylic protons at 5.30 ppm and 5.22 ppm in
the 1H NMR spectrum of the mixture. 1H NMR (500 MHz) δ 2.43 (s, 3 H), 2.56 (s, 3 H), 5.26 (s, 1 H), 7.09- 7.12
(comp, 1 H), 7.16-7.30 (comp, 8 H), 7.41-7.47 (comp, 3 H), 7.78-7.80 (m, 1 H); 13C{1H} (125 MHz) δ 19.6, 20.9,
28.5, 81.8, 82.5, 86.7, 90.5, 123.0, 123.3, 126.7, 125.6, 127.8, 127.9, 128.37, 128.39, 128.4, 129.6, 131.0, 131.9,
132.2, 136.0, 136.5, 140.6; IR (neat) 3057, 2923, 2853, 1655, 1592, 1489, 1443, 1399, 1293, 1176, 1092, 1015;
HRMS (ESI) Calcd for C25H21, 321.1638; Found, 321.1625.
1-(1-(4-Chlorophenyl)-5-phenylpenta-1,4-diyn-3-yl)-2-methylbenzene (13k). Reaction was performed in
1,2-dichloroethane. Mixture was stirred at 25 °C for 3 h and heated to 45 °C upon addition of Ac2O for 11 hr. 1,4-
diyne 13k was obtained in 56% yield (0.37 mmol scale, 70 mg) eluting with 15:1, hexanes/CH2Cl2, as a clear,
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orange oil. H NMR (500 MHz) δ 2.54 (s, 3 H), 5.21 (s, 1 H), 7.20-7.31 (comp, 8 H), 7.37-7.39 (m, 2 H), 7.45-
7.47 (comp, 2 H), 7.74-7.75 (m, 1 H); 13C{1H} (125 MHz) δ 19.5, 28.4, 81.50, 82.8, 86.2, 87.5, 121.7, 123.1,
126.7, 127.8, 128.0, 128.4, 128.5, 128.7, 131.0, 132.0, 133.2, 134.4, 136.0, 136.1; IR (neat) 3063, 3022, 2926,
1596, 1488, 1462, 1443, 1398, 1380, 1265, 1176, 1091, 1014; HRMS (ESI) Calcd for C24H18Cl, 341.1092;
Found, 341.1072.
1-Methyl-2-(1-phenyl-5-(4-(trifluoromethyl)phenyl)penta-1,4-diyn-3-yl)benzene (13l). Reaction was per-
formed in 1,2-dichloroethane. Mixture was stirred at 25 ˚C for 3 h and then heated to 45 ˚C upon addition of
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Ac2O over 11 h. 1,4-diyne 13l was obtained in 50% yield (0.37 mmol scale, 68 mg) eluting with 15:1, hex-
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anes/CH2Cl2, as a clear orange oil. H NMR (500 MHz) δ 2.55 (s, 3 H), 5.24 (s, 1 H), 7.22-7.31 (comp, 6 H),
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7.46-7.48 (m, 2 H), 7.55 (s, 4 H), 7.75 (d, J = 7, 1 H); 13C{1H} (125 MHz) δ 19.6, 28.4, 81.3, 83.0, 85.9, 89.2,
123.0, 125.3 (q, J = 3.6 Hz), 126.8, 127.8, 128.1, 218.4, 128.5, 131.1, 132.0, 132.2, 135.9, 136.0; IR (neat) 3062,
3023, 2928, 1735, 1677, 1615, 1490, 1461,1323, 1265, 1168, 1129, 1068, 1017; HRMS (ESI) Calcd for C25H18F3,
375.1355; Found, 375.1361.
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1-Chloro-4-(1-(4-methoxyphenyl)-5-phenylpenta-1,4-diyn-3-yl)benzene (13m). 1,4-diyne 13m was obtained
in 55% yield (0.37 mmol scale, 72 mg) after 2 h at 50 ˚C, eluting with 4:1, hexanes/CH2Cl2, as an orange solid.
1H NMR (500 MHz) δ 3.81 (s, 3 H), 5.16 (s, 1 H), 6.83-6.85 (m, 2 H), 7.30-7.32 (comp, 3 H), 7.36- 7.37 (m, 2
H), 7.40-7.42 (m, 2 H), 7.47-7.49 (comp, 2 H), 7.60-7.62 (m, 2 H); 13C{1H} (125 MHz) δ 29.8, 55.5, 83.19,
83.22, 86.5, 96.1, 114.1, 115.0, 123.0, 128.5, 128.6, 128.9, 129.0, 132.0, 133.4, 136.9, 159.9; IR (thin film) 3055,
2957, 2933, 2836, 1605, 1509, 1488, 1289, 1249, 1173, 1070, 1033, 1015; HRMS (ESI) Calcd for C24H18ClO,
357.1041; Found, 357.1031.
6-Phenyl-4-(o-tolyl)hexa-2,5-diyn-1-yl acetate (13n). 1,4-diyne 13n was obtained in 58% yield (0.37 mmol
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scale, 65 mg) after 14 h at 25 ˚C, eluting with 3:1, hexanes/CH2Cl2, as a clear yellow oil. H NMR (500 MHz) δ
2.08 (s, 3 H), 2.48 (s, 3 H), 4.73 (d, J = 2.5, Hz, 1 H), 5.05 (t, J = 2.0, Hz, 1 H), 7.18-7.33 (comp, 6 H), 7.41-7.45
(m, 2 H), 7.67-7.68 (m, 1 H); 13C{1H} (125 MHz) δ 19.5, 20.9, 27.8, 52.7, 76.4, 82.8, 83.9, 85.9, 123.0, 126.7,
127.8, 128.0, 128.4, 128.5, 131.0, 131.9, 135.7, 136.0, 170.4; IR (neat) 3067, 2942, 1747, 1597, 1489, 1450,
1376, 1271, 1226, 1051, 1028; HRMS (ESI) Calcd for C21H18O2Na, 325.1199; Found, 325.1212.
(±)-4,4'-Tetradeca-5,9-diyne-7,8-diyl)bis(chlorobenzene) (meso and dl). 1,5- diyne 17a wad obtained as a
1:1 mixture in 20% yield (0.18 mmol scale, 15 mg) after 12 h at 25 ˚C, eluting with 12:1, hexanes/CH2Cl2, as a
yellow solid. 1H NMR (500 MHz) δ 0.90 (t, J = 7, 6 H), 0.92 (t, J = 7, 6 H), 1.32-1.52 (m, 16 H), 2.17 (t, J = 7, 4
H), 2.21 (t, J = 7, 4 H), 3.86 (s, 2 H), 3.90 (s, 2 H), 7.08-7.10 (m, 4 H), 7.15-7.18 (m, 4 H), 7.19-7.23 (comp, 8
H); 13C{1H} (125 MHz) δ 13.9, 18.6, 18.7, 22.0, 22.1, 31.0, 31.1, 45.3, 45.4, 78.6, 79.2, 86.0, 86.3, 128.1, 130.2,
130.3, 133.1, 137.9, 138.0; IR (neat) 3051, 2959, 2932, 2872, 1594, 1490, 1464, 1407, 1378, 1329, 1265, 1091,
1015; HRMS (ESI) Calcd for C26H28Cl2, 410.1568; Found, 410.1579.
General procedure for the synthesis of 1,5-enynes. An 8 mL screw cap vial, equipped with a magnetic stir
bar, was charged with Cp2TiCl2 (2.0 mg, 8.0 µmol) and zinc dust (52.3 mg, 0.8 mmol) then purged with argon for
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10 min. The mixture was taken up in CH2Cl2 (0.25 mL) and the resulting suspension stirred at room temperature
until a blue/green color persisted. Tris(4-methoxyphenyl)phosphine (28.2 mg, 0.08 mmol) was then added in one
portion, and the mixture stirred for an additional 5 min. A solution of 4 (0.4 mmol) and 5 (0.8 mmol) in CH2Cl2
(1.0 mL) was added dropwise and stirred at room temperature until full consumption of 4 was observed by TLC
(~2 h). The reaction was then cooled to 0 ˚C and a solution of 18 (0.8 mmol) in CH2Cl2 (0.75 mL) was added
followed by Ac2O (45.0 mg, 0.44 mmol) in one portion. After consumption of the propargyl acetate intermediate
was observed by TLC (~6 h), the reaction was diluted with hexanes (4 mL), filtered through a short plug of neu-
tral alumina gel eluting with hexanes/CH2Cl2 4:1 (15 mL), and the filtrate concentrated under reduced pressure.
The resulting crude mixture was purified by flash chromatography eluting with the indicated solvent system to
give the target 1,5-enyne 19.
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1-Chloro-4-(1-phenylhex-5-en-1-yn-3-yl)benzene (19a). The multicomponent coupling was performed on a
0.4 mmol scale. Purification by filtration on neutral alumina gel eluting with hexane/CH2Cl2 (4:1) provided 92
mg (86%) of 19a as a pale, yellow oil. 1H NMR and 13C{1H} NMR spectra were consistent with literature re-
ported values.40
Triisopropyl(3-(o-tolyl)hex-5-en-1-yn-1-yl)silane (19b). The multicomponent coupling was performed on a
0.4 mmol scale. Purification by flash chromatography eluting with hexanes/CH2Cl2 (20:1) provided 105 mg
(80%) of 19b as a white paste. 1H NMR (500 MHz, CDCl3) δ 7.61 (m, 1 H), 7.25-7.20 (m, 1 H), 7.17-7.13 (m, 2
H) 6.01-5.93 (m, 1 H), 5.14-5.08 (m, 2 H), 2.50-2.45 (m, 2 H), 2.38 (s, 3 H), 1.12 (s, 9 H); 13C{1H} NMR (125
MHz) δ 139.9, 136.0, 135.0, 130.6, 128.0, 126.9, 126.4, 117.1, 110.0, 83.4, 41.9, 35.9, 18.9, 18.9, 11.6; IR (neat)
3075, 3018, 2941, 2863, 2168; HRMS (ESI) Calcd for C22H34Si, 349.2322; Found, 349.2354.
1-Methyl-2-(8-phenylocta-1-en-5,7-diyn-4-yl)benzene (19c). The multicomponent coupling was performed
on a 0.4 mmol scale. Purification by flash chromatography eluting with hexanes/CH2Cl2 (10:1) provided 81 mg
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(70%) of 19c as a pale yellow oil. H NMR (500 MHz, CDCl3) δ 7.53-7.50 (comp, 3 H), 7.38-7.31 (comp, 3 H),
7.27-7.24 (m, 1 H), 7.22-7.17 (m, 2 H), 5.94 (ddt, J = 17, 10, 7 Hz, 1 H), 5.19-5.13 (m, 2 H), 4.08-4.05 (m, 1 H)
2.63-2.51 (m, 2 H), 2.39 (s, 3 H); 13C{1H} NMR (125 MHz) δ 138.54, 135.20, 135.05, 132.70, 130.77, 129.12,
128.55, 127.73, 127.28, 126.65, 122.14, 117.67, 85.47, 76.26, 74.44, 67.57, 40.92, 35.36, 19.50; IR (neat) 3052,
2980, 2304, 2244; HRMS (ESI) Calcd for C21H18, 270.1409; Found, 270.1403.
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1-Chloro-4-(1-(cyclohex-2-en-1-yl)-3-phenylprop-2-yn-1-yl)benzene (19d). The multicomponent coupling
was preformed on a 0.4 mmol scale. Purification by flash chromatography eluting with hexanes/CH2Cl2 (20:1)
provided 108 mg (88%) of 19d (1:1 dr) as a pale, yellow oil. 1H NMR (500 MHz, CDCl3) Diastereomer A: δ
7.44-7.42 (m, 2 H), 7.35-7.29 (m, 7 H), 5.87 (d, J = 10.5, 1 H), 5.83-5.75 (m, 1 H), 3.77 (d, J = 7, 1 H), 2.54-2.50
(m, 1 H), 2.00-1.99 (comp, 2 H), 1.82-1.72 (comp, 2 H), 1.65-1.49 (comp, 2 H). Diastereomer B: 7.44-7.42 (m, 2
H), 7.35-7.29 (m, 7 H), 5.83-5.75 (m, 1 H), 5.50 (dd, J = 10.5, 2, 1 H), 3.77 (d, J = 7, 1 H), 2.54-2.50 (m, 1 H),
2.00-1.99 (comp, 2 H), 1.82-1.72 (comp, 2 H), 1.65-1.49 (comp, 2 H); 13C{1H} NMR (125 MHz) Diastereomer
A: 139.3, 132.8, 132.6, 129.9, 129.5, 129.1, 128.7, 128.4, 128.1, 123.8, 90.5, 84.5, 43.8, 42.7, 27.9, 25.5, 21.8;
Diastereomer B: δ 139.2, 132.7, 131.9, 129.8, 129.3, 129.0, 128.7, 128.6, 128.4, 123.8, 90.3, 84.5, 43.8, 42.5,
26.5, 25.4, 21.6; IR (neat) 2932, 2198; HRMS (ESI) Calcd for C21H19Cl, 306.1144; Found, 306.1175.
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(3-(4-Chlorophenyl)-5-phenyl-2-vinylpent-4-yn-1-yl)trimethylsilane (19e). The multicomponent coupling
was preformed on a 0.4 mmol scale. Purification by flash chromatography eluting with hexanes/CH2Cl2 (20:1)
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provided 130 mg of 19e (1:1 dr, 92%) as a pale, yellow oil. H NMR (500 MHz, CDCl3) Diastereomer A: δ
7.47-7.45 (m, 2 H), 7.31-7.30 (comp, 6 H), 7.28 (s, 1 H), 5.72-5.63 (m, 1 H), 5.03-4.99 (comp, 1 H), 4.95 (dd, J
= 10.5, 2.0 Hz, 1 H), 3.87 (d, J = 4.5 Hz, 1 H), 2.57-2.49 (comp, 1 H), 0.98-0.84 (m, 2 H) 0.02 (s, 9 H); Diastere-
omer B: δ 7.47-7.45 (m, 2 H), 7.31-7.30 (comp, 6 H), 7.28 (s, 1 H), 5.72-5.63 (m, 1 H), 5.03-4.99 (comp, 1 H),
4.77 (dd, J = 17.5, 1.5 Hz, 1 H), 3.83 (d, J = 5.5 Hz, 1 H), 2.57-2.49 (comp, 1 H), 0.80-0.73 (m, 2 H), –0.06 (s, 9
H); 13C{1H} NMR (125 MHz) Diastereomer A: δ 142.0, 139.0, 132.7, 131.9, 130.1, 128.5, 128.3, 126.0,
116.3, 89.8, 85.3, 47.7, 46.6, 21.3, –0.5; Diastereomer B: δ 140.4, 138.8, 132.6, 131.9, 130.0, 128.4, 128.3,
128.1, 123.8, 115.9, 89.4, 85.2, 47.7, 46.3, 18.4, –0.5; IR (neat) 3078, 2952, 2924; HRMS (ESI) Calcd for
C22H25ClSi, 352.1429; Found, 352.1414.
1-Chloro-4-(5-methyl-1-phenylhex-5-en-1-yn-3-yl)benzene (19f). The multicomponent coupling was pre-
formed on a 0.4 mmol scale. Purification by filtration on neutral alumina gel eluting with hexane/CH2Cl2 (4:1)
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provided 108 mg (96%) of 19f as a pale yellow oil. H NMR and 13C{1H} NMR spectra were consistent with
literature reported values.40
General Procedures for the synthesis of β-alkynyl ketones: A vial, equipped with a magnetic stir bar, was
charged with Cp2TiCl2 (2.0 mg, 8.0 µmol) and zinc dust (55 mg, 0.84 mmol) then purged with nitrogen for 5 min.
Dry, degassed CH2Cl2 (0.25 mL) was added and the resulting gray slurry was stirred vigorously at room tempera-
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ture until it took on a blue/green color. Tris(4-methoxyphenyl)phosphine (56 mg, 0.16 mmol) was then added in
one portion followed by the dropwise addition of a solution of aldehyde 4 (0.40 mmol) and alkynyl iodide 5 (0.48
mmol) in CH2Cl2 (1.0 mL). The resulting mixture was stirred at room temperature until TLC indicated full con-
sumption of the starting aldehyde (~2-4 h), then silyl enol ether 18 (0.48 mmol) was added in one portion via
syringe followed by a solution of Ac2O (40 µL, 0.44 mmol) in CH2Cl2 (0.75 mL) over 11 h via syringe pump.
Once the addition of Ac2O was complete, the resulting crude mixture was stirred at room temperature for 2 h,
then diluted with CH2Cl2 (2 mL), filtered through a short plug of silica gel eluting with 100% Et2O (55 mL). The
filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with the
indicated solvent system to yield β-alkynyl ketone 19.
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1-Phenyl-3-(o-tolyl)non-4-yn-1-one. Ketone 19g was isolated as a clear, yellow oil in 72% yield (0.5 mmol
scale, 110 mg) after 14 h at room temperature, eluting with 20:1 hexanes/EtOAc to EtOAc. 1H NMR (500 MHz,
CDCl3) δ 7.95-7.97 (m, 2 H), 7.53-7.58 (m, 2 H), 7.43-7.46 (m, 2 H), 7.13-7.22 (m, 3 H), 4.55 (ddt, J = 2, 4.5, 9.3
Hz, 1 H), 3.53 (dd, J = 9.5, 16.5 Hz, 1 H), 3.15 (dd, J = 4.5, 16.3 Hz, 1 H), 2.41 (s, 3 H), 2.12 (td, J = 2, 7 Hz Hz,
2 H), 1.27-1.42 (m, 4 H), 0.83 (s, 3 H); 13C{1H} NMR (125 MHz) δ 197.8, 140.2, 137.2, 135.2, 133.3, 130.8,
128.7, 128.4, 127.5, 127.0, 126.5, 83.2, 81.2, 46.1, 31.1, 30.1, 22.1, 19.4, 18.6, 13.8; IR (neat) 3066, 2956, 2930,
2871, 2363, 1688, 1597, 1458, 1449, 1350, 1253, 1202, 1038; HRMS (ESI) Calcd for C22H25O, 305.1900; Found,
305.1914.
6-Oxo-6-phenyl-4-(p-tolyl)hex-2-yn-1-yl acetate. Ketone 19h was isolated as a pale, yellow liquid in 62%
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yield (0.5 mmol scale, 99 mg) after 14 h at room temperature, eluting with 3:1 hexanes/CH2Cl2 to CH2Cl2. H
NMR (500 MHz, CDCl3) δ 7.91-7.93 (m, 2 H), 7.53-7.57 (m, 1 H), 7.42-7.46 (m, 2H), 7.30-7.32 (m, 2 H), 7.13
(appd, J = 8 Hz, 2 H), 4.66 (d, J = 2 Hz, 2 H), 4.41-4.45 (m, 1 H), 3.55 (dd, J = 7.5, 17 Hz, 1 H), 3.34 (dd, J =
6.5, 17 Hz, 1 H), 2.32 (s, 3 H), 2.05 (s, 3 H); 13C{1H} NMR (125 MHz) δ 197.0, 170.5, 137.8, 137.0, 136.8,
133.4, 129.6, 128.8, 128.3, 127.6, 88.6, 76.7, 52.9, 47.1, 32.7, 21.2, 21.0; IR (neat) 3055, 3024, 2922, 1747, 1691,
1596, 1512, 1448, 1358, 1225, 1147, 1024, 976; HRMS (ESI) Calcd for C21H21O3, 321.1485; Found, 321.1472.
1,5-Diphenyl-3-(thiophen-2-yl)pent-4-yn-1-one. Ketone 19i was isolated as an orange oil in 75% yield (0.4
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mmol scale, 93 mg) after 14 h at room temperature, eluting with 20:1 hexanes/EtOAc. H NMR (500 MHz,
CDCl3) δ 8.99-8.01 (m, 2 H), 7.57-7.60 (m, 1 H), 7.46 (app t, J = 8 Hz, 2 H), 7.39-7.42 (m, 2 H), 7.28-7.30 (m, 3
H), 7.21 (dd, J = 1.5, 5.3 Hz, 1 H), 7.13 (appdt, J = 1, 3.5 Hz, 1 H), 6.96 (dd , J = 3, 5 Hz, 1 H), 4.98 (appt, J = 7
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Hz, 1 H), 3.72 (dd, J = 7, 16.8 Hz, 1 H), 3.57 (dd, J = 7, 17 Hz, 1 H); 13C{1H} NMR (125 MHz) δ 196.8, 144.8,
136.8, 133.6, 131.8, 128.8, 128.4, 128.3, 128.2, 127.0, 125.1, 124.4, 123.2, 90.3, 83.1, 47.6, 29.1; IR (neat) 3061,
2904, 1767, 1680, 1596, 1580, 1489, 1446, 1404, 1350, 1219, 1180, 1070, 1003; HRMS (ESI) Calcd for
C21H17OS, 317.0995; Found, 317.0999.
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5-(3-Phenyl-1-(o-tolyl)prop-2-yn-1-yl)furan-2(5H)-one (19j). A two-dram screw cap vial, equipped with a
magnetic stir bar, was charged with Cp2TiCl2 (2.6 mg, 10.3 µmol) and zinc dust (40.0 mg, 0.165 mmol) then
purged with argon for 5 min. Dry, degassed CH2Cl2 (0.50 mL) was added and the suspension stirred at room tem-
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perature until a blue/green color persisted. A solution of Bu3P (16.0 mg, 0.082 mmol) in CH2Cl2 (0.25 mL) was
then added dropwise, and the mixture stirred for an additional 10 min. A solution of o-tolualdehyde (25 mg, 0.206
mmol), phenyliodoacetylene 5a (141 mg, 0.618 mmol) and (furan-2-yloxy)trimethylsilane (64 mg, 0.418 mmol)
in CH2Cl2 (0.75 mL) was then added and the reaction stirred at room temperature until full consumption of o-
tolualdehyde was observed by TLC (~1 h). A solution of Ac2O (46 mg, 0.453 mmol, 43 µL) in CH2Cl2 (0.5 mL)
was then added slowly over 11 h via syringe pump. The reaction was then diluted with CH2Cl2 (2 mL), filtered
through a short plug of silica gel eluting with CH2Cl2 (50 mL), and the filtrate concentrated under reduced pres-
sure. Purification by flash chromatography eluting with hexanes/EtOAc (2:1) provided 39 mg (66%) of 19j in a
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1:1 mixture of diastereomers as a yellow oil. H NMR (500 MHz, CDCl3) Isomer A: δ 7.61-7.59 (m, 1 H), 7.56-
7.54 (m, 1 H), 7.50-7.47 (m, 1 H), 7.45-7.40 (comp, 2 H), 7.32-7.16 (comp, 5 H), 6.27 (dd, J = 6.0, 2.0 Hz, 1 H),
5.36 (ddd, J = 5.5, 2.0, 2.0 Hz, 1 H), 4.61 (d, J = 6.5 Hz), 2.44 (s, 3 H) Isomer B: δ 7.61-7.59 (m, 1 H), 7.56-7.54
(m, 1 H), 7.50-7.47 (m, 1 H), 7.45-7.40 (comp, 2 H), 7.32-7.16 (comp, 5 H), 6.13 (dd, J = 6.0, 2.0 Hz, 1 H),5.19
(ddd, J = 6.5,1.5,1.5 Hz, 1 H), 4.56 (d, J = 5.5Hz), 2.41 (s, 3 H); 13C{1H} NMR (125 MHz) Isomer A: δ 172.6,
154.0, 136.0, 134.2, 131.9, 131.0, 128.6, 128.5, 128.3, 128.1, 126.7, 123.4, 122.8, 86.5, 85.5, 84.6, 39.3, 20.0
Isomer B: 172.5, 153.9, 136.0, 133.8, 131.9, 131.1, 128.6, 128.5, 128.2, 127.0, 126.5, 1234, 122.7, 85.9, 85.5,
84.6, 38.4, 19.7. IR (neat) 3103, 3020, 2938, 2877, 2230, 1788, 1659, 1588, 1490, 1275, 1152, 1032; HRMS
(ESI) Calcd for C20H16O2Na, 311.1043; Found, 311.1017.
2-(1-(4-Methoxyphenyl)hept-2-yn-1-yl)cyclohexanone. Ketone 19k was prepared as a 1:1 mixture of dia-
stereomers according to the general procedure to provide the product as a clear colorless liquid in 68% yield (0.4
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mmol scale, 81 mg) after 14 h at room temperature, eluting with 1:1 hexanes/CH2Cl2. H NMR (500 MHz,
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CDCl3) Isomer A: δ 7.25-7.29 (comp, 2 H), 6.81-6.88 (comp, 2 H), 4.35 (ddd, J = 2.3, 2.3, 4.5 Hz, 1 H), 3.78 (s, 3
H), 2.66-2.71 (m, 1 H), 2.40-2.47 (comp, 2 H), 2.21 (td, J = 1, 7 Hz, 2 H), 1.20-2.07 (comp, 10 H), 0.91 (t, J = 7
Hz, 3 H) Isomer B: δ 7.25-7.29 (comp, 2 H), 6.81-6.88 (comp, 2 H), 4.09 (ddd, J = 2.3, 2.3, 7 Hz, 1 H), 3.78 (s, 3
H), 2.40-2.47 (comp, 1 H), 2.19-2.35 (comp, 2 H), 2.17 (td, J = 1, 7 Hz, 2 H), 1.20-2.07 (comp, 10 H), 0.89 (t, J =
7 Hz, 3 H); 13C{1H} NMR (125 MHz) Isomer A: δ 158.5, 133.4, 129.9, 113.8, 84.8, 81.7, 57.8, 55.4, 42.2, 35.9,
31.3, 30.8, 27.9, 24.9, 22.2, 18.7, 13.8 Isomer B: δ 158.4, 132.0, 129.1, 113.6, 82.7, 79.4, 57.2, 55.3, 42.1, 35.9,
31.2, 29.0, 27.4, 24.6, 22.1, 18.6, 13.8; IR (neat) 2935, 2868, 1712, 1602, 1512, 1462, 1301, 1252, 1176, 1124,
1032; HRMS (ESI) Calcd for C20H27O2, 299.2006; Found, 299.2017.
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1-(3-Phenyl-1-(p-tolyl)prop-2-yn-1-yl)cyclohexanecarbaldehyde. Ketone 19l was prepared according to the
general procedure with the addition of Ac2O performed at 0 ̊C to provide the product as a clear colorless oil in
78% yield (0.5 mmol scale, 124 mg) as a 1:1 mixture of diastereomers after 14 h at room temperature, eluting
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with 3:1 hexanes/CH2Cl2 to CH2Cl2. H NMR (500 MHz, CDCl3) δ 9.68 (s, 1 H), 7.43-7.45 (m, 2 H), 7.29-7.31
(m, 3 H), 7.17-7.19 (m, 2 H), 7.11-7.13 (m, 2 H), 3.89 (s, 1 H), 2.33 (s, 3 H), 2.12-2.18 (m, 1 H), 2.04-2.07 (m, 1
H), 1.45-1.68 (comp, H), 1.07-1.30 (comp, H); 13C{1H} NMR (125 MHz) δ 207.3, 137.4, 133.7, 131.9, 129.5,
129.1, 128.5, 128.3, 123.5, 88.4, 85.6, 53.2, 46.0, 29.8, 29.8, 25.6, 23.0, 22.9, 21.3; IR (neat) 2933, 2857, 1698,
1602, 1512, 1490, 1451, 1415, 1285, 1242, 1178, 1023; HRMS (ESI) Calcd for C23H24ONa 339.1719; Found,
339.1740.
General procedure for the synthesis of diarylethynylmethanes. A two-dram screw cap vial, equipped with
a magnetic stir bar, was charged with Cp2TiCl2 (2.6 mg, 10.3 µmol) and zinc dust (40.0 mg, 0.165 mmol) then
purged with argon for 5 min. Dry, degassed DCE (0.50 mL) was added and the suspension stirred at room tem-
t
perature until a blue/green color persisted. A solution of Bu3P (33.0 mg, 0.165 mmol) in DCE (0.25 mL) was
then added dropwise, and the mixture stirred for an additional 10 min. A solution of aldehyde (0.206 mmol), io-
doacetylene 5 (0.618 mmol) and arene 20 (0.418 mmol) in DCE (0.75 mL) was then added and the reaction
stirred at room temperature until full consumption of aldehyde 4 was observed by TLC (~1 h). Cs2CO3 (67.0 mg,
0.206 mmol) was then added in one portion followed by the slow addition of Ac2O (46 mg, 0.453 mmol, 43 µL)
in DCE (0.5 mL) over 11 h via syringe pump. The reaction was then diluted with CH2Cl2 (2 mL), filtered through
a short plug of silica gel eluting with CH2Cl2 (50 mL), and the filtrate concentrated under reduced pressure. The
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crude mixture was purified directly by flash chromatography eluting with the indicated solvent mixture to give
diarylethynyl methane 21.
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2,4-Dimethoxy-5-(phenylethynyl)-10,11-dihydro-5H-dibenzo[a,d][7]annulene (21a). Purification by flash
chromatography eluting with hexanes/CH2Cl2 (1:1) provided 56 mg (77%) of 21a as a white solid. 1H NMR (500
MHz, CDCl3) δ 7.34-7.29 (m, 3 H), 7.22-7.10 (m, 6 H), 6.33-6.32 (m, 2 H), 5.81 (s, 1 H), 4.02-3.96 (m, 1 H),
3.84 (s, 3 H), 3.81-3.75 (m, 4 H), 2.95-2.82 (m, 2 H); 13C{1H} NMR (125 MHz) δ 159.5, 157.1, 142.8, 140.1,
138.7, 131.7, 130.8, 130.6, 128.2, 127.7, 127.5, 126.3, 124.2, 120.1, 106.6, 96.6, 92.2, 82.1, 56.2, 55.4, 33.5,
32.8, 32.5; IR (neat) 3058, 2963, 2906, 2360, 2335, 2194, 1747, 1605, 1594, 1204, 1145; HRMS (ESI) Calcd for
C25H22O2 354.1620; Found, 354.1607; m.p. = 109-111 ˚C.
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2,4-Dimethoxy-1-(3-phenyl-1-(o-tolyl)prop-2-yn-1-yl)benzene (21b). Purification by flash chromatography
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eluting with hexanes/EtOAc (10:1) provided 50 mg (77%) of 21b as a clear, yellow oil. H NMR (500 MHz)
δ7.46-7.45 (m, 1 H), 7.43-7.41 (m, 2 H), 7.33 (d, J = 6.0 Hz, 1 H), 7.26-7.24 (comp, 3 H), 7.18-7.12 (comp, 3 H),
6.48-6.44 (m, 2 H), 5.64 (s, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.35 (s, 3 H); 13C{1H} (125 MHz) δ 160.1, 157.5,
140.0, 136.1, 131.9, 130.5, 129.9, 128.3, 128.2, 127.8, 126.8, 126.1, 124.1, 122.1, 104.4, 98.8, 91.1, 83.4, 55.8,
55.5, 33.5, 19.6 ; IR (neat) 3071, 3014, 2936, 2835, 2247, 2220, 1672, 1611, 1502, 1418, 1378, 1334, 1293, 1208,
1156, 1115, 1036; HRMS (ESI) Calcd for C24H23O2 343.1693; Found, 343.1692.
N,N-Dimethyl-4-(3-phenyl-1-(1-tosyl-1H-indol-3-yl)prop-2-yn-1-yl)aniline (21c). Purification by flash
chromatography eluting with hexanes/CH2Cl2 (1:1) provided 71 mg (68%) of 21c as a clear, orange oil. 1H NMR
(500 MHz, CDCl3) δ 7.96-7.94 (m, 1 H), 7.75 (dd, J = 8.0, 2.0 Hz, 2 H), 7.51-7.49 (m, 2 H), 7.44-7.42 (m, 2 H),
7.30-7.24 (m, 5 H), 7.20 (dd, J = 8.5, 1.0 Hz, 2 H), 7.16-7.13 (m, 2 H), 6.67 (d, 8.5 Hz, 2 H), 5.23 (s, 1 H), 2.92
(s, 6 H), 2.33 (s, 3 H); 13C{1H} NMR (125 MHz) δ 150.0, 145.1, 136.0, 135.5, 132.0, 130.1, 129.8, 128.8, 128.5,
128.2, 127.4, 127.1, 124.9, 124.4, 124.3, 123.7, 123.4, 120.8, 114.0, 112.9, 89.8, 83.9, 53.7, 40.9, 34.7.
3-(1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl)-1-methyl-1H-indole (21d). Purification by flash chroma-
tography eluting with hexanes/CH2Cl2 (1:1) provided 65 mg (90%) of 21d as a yellow solid. 1H NMR (500 MHz,
CDCl3) δ 7.60 (dt, J = 7.5, 1.0 Hz, 1 H), 7.46-7.43 (m, 4 H), 7.29-7.26 (m, 4 H), 7.75-7.04 (m, 1 H), 6.95 (d, J =
0.5 Hz, 1 H), 6.87-6.85 (m, 2 H), 5.41 (s, 1 H), 3.78 (s, 3 H), 3.73 (s, 3 H); 13C{1H} NMR (125 MHz) δ 158.7,
137.7, 133.9, 132.0, 129.2, 128.4, 128.0, 127.4, 126.7, 124.1, 122.0, 120.0, 119.3, 115.9, 114.1, 110.0, 91.2, 83.3,
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55.6, 34.9, 33.0; IR (neat) 3051, 2935, 2836, 2302, 1609, 1265, 738; HRMS (ESI) Calcd for C25H22NO 352.1696;
Found, 352.1670; m.p. = 120-121 ˚C.
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CDCl3) δ 7.54 (dt, J = 8.0, 0.5 Hz, 1 H), 7.38-7.35 (m, 2 H), 7.26-7.24 (m, 1 H), 7.20-7.16 (m, 1 H), 7.04-7.01
(m, 1 H), 6.87 (d, J = 1.0 Hz, 1 H) 6.84-6.81 (m, 2 H), 5.16 (s, 1 H), 3.76 (s, 3 H), 3.70 (s, 3 H), 2.25 (dt, J = 7.0,
2.5, 2 H), 1.56-1.50 (m, 2 H), 1.46-1.39 (m, 2 H), 0.91 (t, 7.0 Hz, 3 H); 13C{1H} NMR (125 MHz) δ 158.4, 137.6,
134.6, 128.9, 127.2, 126.7, 121.8, 120.0, 119.0, 116.6, 113.9, 109.4, 83.2, 81.3, 55.4, 34.2, 32.9, 31.4, 22.3, 18.9,
13.9; IR (neat) 3052, 2959, 2934, 2873, 2305, 1609, 1509, 1265, 1033; HRMS (ESI) Calcd for C23H26NO
332.2009; Found, 332.2012.
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3-(4-(Benzyloxy)-1-(4-methoxyphenyl)but-2-yn-1-yl)-1-methyl-1H-indole (21f). Purification by flash chro-
matography eluting with hexanes/CH2Cl2 (1:1) provided 43 mg (53%) of 21f as a yellow oil. 1H NMR (500 MHz,
CDCl3) δ 7.55-7.53 (m, 1 H), 7.40-7.38 (m, 2 H), 7.34-7.26 (m, 6 H), 7.23-7.19 (m, 1 H), 7.07-7.03 (m, 1 H),
6.92 (s, 1 H), 6.87-6.84 (m, 2 H), 5.27 (br s, 1 H), 4.61 (s, 2 H), 4.28 (d, J = 2.0 Hz, 2 H), 3.79 (s, 3 H), 3.74 (s, 3
H); 13C{1H} NMR (125 MHz) δ 158.6, 137.8, 137.7, 133.6, 129.0, 128.6, 128.4, 128.0, 127.4, 126.5, 122.0,
119.8, 115.6, 114.0, 109.5, 88.2, 78.8, 71.5, 58.0, 55.5, 34.3, 32.9; IR (neat) 3057, 3029, 2932, 2851, 1610, 1509,
1469, 1249; HRMS (ESI) Calcd for C27H25NO2Na 418.1778; Found, 418.1789.
3-(1-(Furan-2-yl)-3-phenylprop-2-yn-1-yl)-1-methyl-1H-indole (21g). Purification by flash chromatography
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eluting with hexanes/CH2Cl2 (3:1) provided 44 mg (68%) of 21g as a dark yellow oil. H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 8.0 Hz, 1 H), 7.52-7.50 (m, 2 H), 7.39 (t, J = 1.5 Hz, 1 H), 7.34-7.31 (m, 4 H), 7.29-7.25
(m, 1 H), 7.16-7.13 (m, 2 H), 6.36-6.34 (m, 2 H), 5.58 (s, 1 H), 3.78 (s, 3 H); 13C{1H} NMR (125 MHz) δ 154.0,
142.0, 137.5, 132.0, 128.4, 128.2, 127.4, 126.6, 123.6, 122.0, 119.8, 119.4, 112.3, 110.5, 109.6, 106.4, 88.0, 82.6,
33.0, 29.8; IR (neat) 3116, 3053, 2930, 2879, 2824, 1598, 1614, 1488, 1010; HRMS (ESI) Calcd for C22H17NO
312.1383; Found, 312.1355.
1-Methyl-3-(3-phenyl-1-(thiophen-2-yl)prop-2-yn-1-yl)-1H-indole (21h). Purification by flash chromatog-
1
raphy eluting with hexanes/CH2Cl2 (2:1) provided 48 mg (71%) of 21h as a yellow solid. H NMR (500 MHz,
CDCl3) δ 7.68-7.66 (m, 1 H), 7.48-7.46 (m, 2 H), 7.30-7.28 (m, 4 H), 7.22 (dt, J = 6.0, 1.0 Hz, 1 H), 7.16 (dd, J =
5.0, 1.5 Hz, 1 H), 7.11-7.08 (m, 3 H), 6.92 (dd, J = 5.0, 3.5 Hz, 1 H), 5.71 (s, 1 H), 3.75 (s, 3 H); 13C{1H} NMR
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Page 29 of 36
The Journal of Organic Chemistry
(125 MHz) δ 146.1, 137.6, 131.9, 128.4, 128.2, 127.3, 126.7, 126.4, 125.1, 124.5, 123.6, 122.1, 119.8, 119.4,
115.0, 109.6, 90.1, 83.0, 33.0, 31.0; IR (neat) 3054, 2932, 2824, 1698, 1614, 1579, 1488, 1472; m.p. = 118-121
˚C (decomposed).
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General procedure for the synthesis of iodoenynes. A vial, equipped with a magnetic stir bar, was charged
with Cp2TiCl2 (6.2 mg, 25 µmol) and zinc dust (69 mg, 1.05 mmol) then purged with nitrogen for 5 min. Dry,
degassed CH2Cl2 (1.0 mL) was added and the resulting gray slurry was stirred vigorously at room temperature
until it took on a blue/green color. A solution of aldehyde 22a, 22b, or 29 (0.50 mmol) and alkynyl iodide 5 (0.75
mmol) and Ac2O (70 µL, 0.75 mmol) in CH2Cl2 (1.0 mL) was then added dropwise. The resulting mixture was
stirred at room temperature until TLC indicated full consumption of the starting aldehyde (~2-4 h). The crude
mixture was then diluted with CH2Cl2 (2 mL) and filtered through a plug of silica eluting with 100% Et2O (55
mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting
with the indicated solvent system to yield the desired iodoenyne 25, 28, or 30.
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(E)-(6-Iodohex-3-en-1-yn-1-yl)benzene, (Z)-(6-iodohex-3-en-1-yn-1-yl)benzene (25a). The reaction was
performed on 0.5 mmol scale. Purification by flash chromatography eluting with 100% hexanes provided 99 mg
1
(71%) of 25a as a clear, yellow oil. H NMR (500 MHz, CDCl3) δ (E)-isomer: 7.44-7.52 (comp, 2 H), 7.30-7.37
(comp, 3 H), 6.16 (dt, J = 7, 15.5 Hz, 2 H), 5.80-5.83 (m, 1 H), 3.20 (t, J = 7 Hz, 2 H), 2.76 (app qd, J = 1.5, 7 Hz,
2 H), (Z)-isomer: 7.44-7.52 (comp, 2 H), 7.30-7.37 (comp, 3 H), 5.97 (dt, J = 7, 10.5 Hz, 1 H), 5.85-5.87 (m, 1
H), 3.26 (t, J = 7 Hz, 2 H), 2.98-3.03 (m, 2 H); 13C{1H} NMR (125 MHz) δ 142.1, 141.4, 132.3, 131.7, 128.5,
128.5, 128.5, 128.4, 123.4, 123.4, 112.4, 111.7, 94.9, 89.6, 87.7, 85.8, 37.2, 34.3, 3.9, 3.7; IR (neat) 3079, 3059,
3027, 2958, 2926, 2202, 2123, 1669, 1597, 1572, 1489, 1441, 1423, 1368, 1299, 1279, 1217, 1171, 1103, 1069;
HRMS (ESI) Calcd for C12H11I, 281.9906; Found, 281.9921.
(E)-1-(6-Iodohex-3-en-1-yn-1-yl)-2-methylbenzene,
(Z)-1-(6-iodohex-3-en-1-yn-1-yl)-2-methylbenzene
(25b). The reaction was performed on 0.5 mmol scale. Purification by flash chromatography eluting with hexanes
provided 121 mg (81%) of 25b as a clear, yellow oil. 1H NMR (500 MHz, CDCl3) δ (E)-isomer: 7.39-7.40 (m, 1
H), 7.11-7.25 (comp, 3 H), 6.14 (dt, J = 7, 15.5 Hz, 1 H), 5.84 (dt, J = 1.5, 16 Hz, 1 H), 3.19 (t, J = 7 Hz, 2 H),
2.75 (app qd, J = 1.5, 7 Hz, 2 H), 2.43 (s, 3 H); (Z)-isomer: 7.41-7.42 (m, 1 H), 7.11-7.25 (comp, 3 H), 5.95 (dt, J
= 7, 11 Hz, 1 H), 5.87-5.90 (m, 1 H), 3.24 (t, J = 7 Hz, 2 H), 3.00 (app q, J = 7 Hz, 2 H), 2.46 (s, 3 H); 13C{1H}
NMR (125 MHz, CDCl3) δ (E)-isomer: 141.7, 140.2, 132.0, 129.6, 128.4, 125.7, 123.1, 112.6, 91.6, 88.5, 37.3,
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