Relay redox and Lewis acid catalysis in the titanocene- catalyzed multicomponent assembly of 1,5-enynes

Article abstract of DOI:10.1002/adsc.201300359

Herein we describe a direct, multicomponent assembly of 1,5-enynes. The titanocene-catalyzed coupling of an aryl aldehyde, iodoalkyne, and allylsilane enables the convergent and rapid synthesis of this versatile architectural motif in good to excellent yields. Copyright

Full text of DOI:10.1002/adsc.201300359

COMMUNICATIONS
DOI: 10.1002/adsc.201300359
Relay Redox and Lewis Acid Catalysis in the Titanocene-
Catalyzed Multicomponent Assembly of 1,5-Enynes
Antonio J. Lepore,a David M. Pinkerton,a and Brandon L. Ashfelda,*
a
Department of Chemistry and Biochemistry, Mike and Josie Harper Cancer Research Institute, University of Notre
Dame, Notre Dame, Indiana 46556, USA
Fax : (+1)-574-631-6652; phone: (+1)-574-631-1727; e-mail: bashfeld@nd.edu
Received: April 27, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300359.
Abstract: Herein we describe a direct, multicompo-
nent assembly of 1,5-enynes. The titanocene-cata-
lyzed coupling of an aryl aldehyde, iodoalkyne, and
allylsilane enables the convergent and rapid synthe-
sis of this versatile architectural motif in good to ex-
cellent yields.
premise that redox- and Lewis acid-relay catalysis can
À
facilitate two mechanistically distinct consecutive C
C bond formations.[4] Therefore, we surmised that the
addition of an acetylide equivalent 2 and allylation re-
agent 3 to an electron deficient aldehyde 1 in a titano-
cene-catalyzed relay cascade sequence would result in
a convergent assembly of 1,5-enynes (Scheme 1, b).
To test our hypothesis that a bifunctional titano-
Keywords: allylation; 1,5-enynes; propargylation;
relay catalysis
À
À
cene catalyst would facilitate consecutive C X/C O
bond activations to form an all-carbon tertiary center,
we speculated that the allyl metal reagent derived
from allyl bromide[5] and Cp2TiCl2/Zn(0) would par-
ticipate in the three-component coupling.[6] Thus, we
Recently, 1,5-enynes have emerged as a synthetically began by treating aldehyde 1a, iodoalkyne 2a, and
versatile intermediate for the construction of highly allyl bromide (3a) with Cp2TiCl2 (2 mol%), zinc dust,
substituted and strained carbocyclic frameworks.[1] and Ac2O to yield enyne 4a in 12% yield [Eq. (1)].
Unfortunately, strategies for assembling this valuable
building block typically rely on the sequential con-
À
struction of each s-C C bond through a series of al-
kylation events (Scheme 1, a).[2] In contrast, recent
developments in relay catalysis for the formation of
À
multiple C C bonds in a single operation has led to
new strategies for the rapid assembly of increasingly
complex molecular architectures.[3] Our recent work
on the development of bifunctional titanocene-cata-
lyzed multicomponent couplings is based on the Interestingly, the low yield of 4a was not a result of
poor substrate reactivity. Rather, the major by-prod-
ucts from this reaction corresponded to propargylic
homodimerization of the initial carbonyl addition
adduct (1,5-diyne) and bisalkynylation of 1a (1,4-
diyne), indicating an efficient initial acetylide addition
but an indiscriminate propargylic alkylation.[4a] Antici-
À
pating a more efficient C C bond formation by using
a nucleophilic allyl derivative directly, we replaced 3a
with allylsilane (3b) which resulted in the formation
of enyne 4a in 90% yield.[7] Importantly, this modifi-
cation led to the production of less than 10% 1,5-
diyne.
Unfortunately, when these conditions were applied
Scheme 1. Synthetic approaches toward 1,5-enynes.
to the titanocene-catalyzed multicomponent coupling
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Antonio J. Lepore et al.
Table 2. Aldehyde and iodoalkyne variability.[a]
COMMUNICATIONS
with aldehyde 1b, poor aldehyde conversion was ob-
served (Table 1, entry 1). Attempts to promote the
formation of 4b through longer reaction times and
elevated temperatures led to an intractable mixture of
products. Based on our previous work, we speculated
that the addition of (4-MeOC6H4)3P would promote
the metallation of 2a and subsequent propargylic alk-
oxide formation.[4a,8] However, we quickly discovered
that the amount of phosphine drastically influenced
product distribution with respect to 1,5-enyne 4b, in-
termediate propargylic acetate 5, and formation of
1,5-diyne 6. While the addition of 10 mol% (4-
MeOC6H4)3P improved the conversion of 1b, a 60:40
product distribution of 4b/6 was observed (entry 2).
Increasing the amount of phosphine to 20 mol% fur-
ther enhanced in the ratio of 4b/6, while 40 mol% ef-
fectively eliminated competitive formation of the un-
desired 1,5-diyne (entries 3 and 4). Interestingly, the
addition of >40 mol% of phosphine inhibited the
propargylic allylation event, effectively arresting the
relay reaction at acetate 5 (entry 5). With our opti-
mized conditions in hand (entry 4), we focused our at-
tention on the structural variability of the components
involved in the formation of 1,5-enynes.
Treatment of various aldehydes 1 and iodoalkynes
2 in the titanocene-catalyzed multicomponent cou-
pling with allylsilane (3b) provided the corresponding
1,5-enynes in good to excellent yields (Table 2). Elec-
tron-deficient aryl-substituted iodoalkynes gave excel-
lent yields (80–90%) of enynes 4c–e. The TIPS-substi-
tuted iodoalkyne, useful as an acetylene equivalent,[9]
provided enyne 4f in 80% yield. The reaction proved
[a]
Conditions: 1 (0.4 mmol), 2 (0.8 mmol), 3b (0.8 mmol),
Cp2TiCl2 (2 mol%), Zn dust (0.8 mmol), (4-MeOC6H4)3P
(40 mol%), Ac2O (0.48 mmol) in CH2Cl2 (0.1M).
Table 1. Product distribution based on phosphine concentra-
tion.[a]
tolerant of aliphatic iodoalkynes as exemplified by
the formation of enynes 4g and 4h in 83% and 54%
yield, respectively. The stability of the primary prop-
argylic acetate in 4h when compared to the in situ
generated secondary propargylic acetate highlights
the chemoselectivity of this process. Considering the
growing interest in biologically active natural prod-
ucts bearing 1,3-diynes,[10] it is noteworthy that the
corresponding iodo-1,3-diyne proceeded to give 1,5-
enyne 4i in 70% yield. The titanocene-catalyzed mul-
ticomponent coupling also tolerated a variety of dif-
ferent aryl aldehyde components. Benzaldehyde and
p-toluealdehyde independently underwent coupling
with 2a and 3b in 66% and 82% yield, respectively. In
general, electron-rich aryl aldehydes provided the cor-
responding 1,5-enynes in better yields than electron-
deficient substrates, as illustrated by enynes 4l and
4m. Coupling of heteroaryl substrates also proceeded
smoothly, as illustrated by the conversion of 2-formy-
lindole and 2-formylthiophene to 1,5-enynes 4n and
4o, respectively.
Entry
X (mol%)
4b/5/6[b]
Conversion [%][b]
1
2
3
4
5
–
100/0/0
60/0/40
94/0/6
100/0/0
0/100/0
33
100
100
10
20
40
80
100 (86)[c]
100
[a]
Conditions: 1b (0.4 mmol), 2a (0.8 mmol), 3b (0.8 mmol),
Cp2TiCl2 (2 mol%), Zn dust (0.8 mmol), (4-MeOC6H4)3P,
Ac2O (0.48 mmol).
Determined by 400 MHz H NMR analysis.
Isolated yield.
[b]
[c]
1
2
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Relay Redox and Lewis Acid Catalysis in the Titanocene-Catalyzed Multicomponent Assembly
To evaluate allylsilane compatibility, we examined the formation of bicycleACTHNUGRTENUNG[3.1.0]hexene 9 in near quan-
the multicomponent coupling of aldehyde 1b and io- titative yield as a single diastereomer [Eq. (2)].[1a,g]
doalkyne 2a with a series of functionalized silanes 7
(Table 3). In general, good yields of the corresponding
1,5-enynes 8 resulting from allylation in an SE2’ fash-
ion were obtained for a structurally diverse assort-
ment of allylsilanes. CyclohexylACTHNUTRGNEUNG(allyl)silane 7a and
methallylsilane 7b underwent a facile coupling to
yield enynes 8a and 8b in excellent yield (entries 1
and 2). The functionalized trans-1,4-disilyl-2-butene
7c coupled with 1b and 2a in 92% yield without pro-
tiodesilylation of the resulting homoallylic silyl group
(entry 3). Allyl silanes 7d and 7e provided the corre-
sponding 1,5-enynes 8d and 8e bearing a second allyl-
ic leaving group for subsequent allylic substitution in
good yields (entries 4 and 5).[11] It is worth mentioning
that additional allylic substitution of enynes 8d and 8e
under the reaction conditions was not observed.
The versatility of 1,5-enynes as synthetic building
blocks is highlighted by the variety of ring systems
that are readily accessible through the proximal
alkene-alkyne functionality. Cyclization of enyne 4a
with catalytic AuClACHTNUGTRNEUGN(PPh3) and AgSbF6 led directly to
Likewise, cyclobutene 10 is readily prepared by treat-
ment of enyne 4g with Grubbs II catalyst (10 mol%)
in 56% yield [Eq. (3)].[1d,f] Highly substituted biaryl
iodobenzene derivative 11 is also easily prepared in
77% yield by treating 1,5-enyne 8b with NIS [Eq.
(4)].[1c] The secondary transformations described in
Eqs. (2)–(4) highlight the synthetic utility of this prac-
tical architectural motif that is assembled with a high
degree of convergency using the titanocene-catalyzed
multicomponent coupling described herein.
Table 3. Evaluation of the allylsilane component.[a]
Entry Allylsilane
Product
Yield [%][b]
88
Our composite results indicate the involvement of
Cp2TiCl2, zinc dust, and phosphine in both formation
of the initial propargyl alcohol derivative and subse-
quent propargylic substitution event. Based on our
previous work in 1,4-diyne[4a] and diarylethynylmeth-
1[c]
AHCTUNGTRENNUNG
ane[4b] synthesis, a potential mechanism (Scheme 2)
for the 3-component assembly of 1,5-enynes involves
initial titanocene-catalyzed reductive transmetallation
of iodoalkyne 2a in the presence of zinc dust and
phosphine, followed by addition to aldehyde 1a.[5a,12]
Acylation of propargylic alkoxide 12 with Ac2O facili-
2
96
92
43
3[c]
4
5
45
[a]
Conditions: same as in Table 2.
Isolated yields.
Obtained as a 1:1 mixture of diastereomers.
[b]
[c]
Scheme 2. Proposed mechanism.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Antonio J. Lepore et al.
COMMUNICATIONS
tates propargylic activation by either Cp2Ti(IV)X2 or Experimental Section
Zn(II)X2 salts resulting in the addition of allylsilane
3b. Based on the 1:1 diastereoselectivity observed in Representative Procedure for the Titanocene-
À
the addition of crotylsilane derivatives, the second C
C bond forming event likely proceeds via an open toward 1,5-Enynes
Catalyzed Multicomponent Coupling Approach
transition state 13 with propargylic carbocationic-like
An 8-mL screw-cap vial, equipped with a magnetic stir bar,
character.[2b,f,h]
was charged with Cp2TiCl2 (2.0 mg, 8.0 mmol) and zinc dust
(52.3 mg, 0.8 mmol) then purged with argon for 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 aldehyde
Perhaps most intriguing was the effect the phos-
phine concentration had on the reaction outcome.
While our empirical observations point to a beneficial
effect in the initial iodoalkyne metallation and car-
bonyl addition steps, higher concentrations of phos-
phine proved detrimental in the subsequent propar-
gylic allylation. This is consistent with our earlier find-
ings that phosphine additives promote iodoalkyne
1
(0.4 mmol) and iodoalkyne 2 (0.8 mmol) in CH2Cl2
(1.0 mL) was added dropwise and stirred at room tempera-
ture until full consumption of aldehyde 1 was observed by
TLC (~2 h). The reaction mixture was then cooled to 08C
metal-halogen exchange and addition to the alde-
[8]
À
hydes through an unusual Zn P ligation. However,
and
a solution of allylsilane 3 (0.8 mmol) in CH2Cl2
excessive amounts of phosphine may lead to Lewis
acid saturation, thereby hindering propargylic ioniza-
tion. While speculative at this stage, the exact role of
phosphine in titanocene-catalyzed C C bond forma-
tions is the subject of current investigations.
(0.75 mL) was added followed by Ac2O (45.0 mg,
0.44 mmol) in one portion. After consumption of the prop-
argyl acetate intermediate had been observed by TLC (~
6 h), the reaction mixture was then diluted with hexanes
(4 mL), filtered through a short plug of neutral 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 to give the
target 1,5-enyne 4.
À
Given the redox capabilities of Cp2TiACTHNUTRGNEU(GN III)Cl and
the formation of 1,5-diyne 6 during our initial optimi-
zation, an alternative mechanism that involves reduc-
tion of the intermediate propargylic acetate through
sequential single-electron transfers to yield a propar-
gylic titanocene complex cannot be ruled out. Subse-
quent alkylation involving a transmetallation from sil-
icon and reductive elimination would ultimately pro-
vide enyne 4a. However, given the oxophilicity of the
Acknowledgements
The authors thank the University of Notre Dame for financial
metal complexes present,[13] and the comparable reac- support of this work.
tivity of allylsilanes under Lewis acidic conditions,
a catalytic relay of redox and Lewis acid mediated
bond formations by an adaptable catalyst system ap-
pears most plausible.
References
In summary, we have developed a titanocene-cata-
lyzed multicomponent coupling resulting in a conver-
gent assembly of 1,5-enynes from readily available al-
dehydes, allylsilanes, and iodoalkynes. Through con-
secutive C X/C O bond activations, two new C C
bonds are generated in a single operation using alde-
hydes as a traceless, dielectrophilic functionality. The
resulting 1,5-enynes are versatile building blocks in
the construction of cyclobutenes, [3.1.0] bicycles, and
highly substituted iodobenzenes. Additional mecha-
nistic studies to elucidate the role of phosphine, and
the application of this method in total synthesis are
currently being pursued, and will be reported in due
course.
[1] a) A. Buzas, F. Gagosz, J. Am. Chem. Soc. 2006, 128,
12614–12615; b) Y. Chen, D. M. Ho, C. Lee, J. Am.
Chem. Soc. 2005, 127, 12184–12185; c) B. Crone, S. F.
Kirsch, K.-D. Umland, Angew. Chem. 2010, 122, 4765–
4768; Angew. Chem. Int. Ed. 2010, 49, 4661–4664; d) O.
Debleds, J.-M. Campagne, J. Am. Chem. Soc. 2008, 130,
1562–1563; e) K. Fiukamizu, Y. Miyake, Y. Nishibaya-
shi, Angew. Chem. 2009, 121, 2572–2575; Angew.
Chem. Int. Ed. 2009, 48, 2534–2537; f) T. J. A. Graham,
E. E. Gray, J. M. Burgess, B. C. Goess, J. Org. Chem.
2010, 75, 226–228; g) M. R. Luzung, J. P. Markham,
F. D. Toste, J. Am. Chem. Soc. 2004, 126, 10858–10859;
h) M. Nishida, N. Adachi, K. Onozuka, H. Matsumura,
M. Mori, J. Org. Chem. 1998, 63, 9158–9159.
À
À
À
[2] a) M. J. Ardolino, J. P. Morken, J. Am. Chem. Soc.
2012, 134, 8770–8773; b) M. Georgy, V. Boucard, J.-M.
Campagne, J. Am. Chem. Soc. 2005, 127, 14180–14181;
c) S. Hara, Y. Satoh, A. Suzuki, Chem. Lett. 2010, 11,
1289–1290; d) G. W. Kabalka, M.-L. Yao, S. Borella, J.
Am.
Chem.
Soc.
2006,
128,
11320–11321;
e) G. G. K. S. N. Kumar, K. K. Laali, Org. Biomol.
Chem. 2012, 10, 7347–7355; f) R. Sanz, A. Martꢁnez,
J. M. ꢂlvarez-Gutꢁerrez, F. Rodrꢁguez, Eur. J. Org.
4
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Relay Redox and Lewis Acid Catalysis in the Titanocene-Catalyzed Multicomponent Assembly
Chem. 2006, 2006, 1383–1386; g) J. S. Yadav, B. V. S.
Reddy, T. S. Rao, K. V. R. Rao, Tetrahedron Lett. 2008,
49, 614–618; h) Z.-p. Zhan, J.-l. Yu, H.-j. Liu, Y.-y. Cui,
R.-f. Yang, W.-z. Yang, J.-p. Li, J. Org. Chem. 2006, 71,
8298–8301; i) G. W. Kabalka, S. Borella, M.-L. Yao,
Synthesis 2008, 325–329; j) R. Sanz, A. Martꢁnez, D.
Miguel, J. ꢂlvarez-Gutiꢃrrez, F. Rodrꢁguez, Synthesis
2007, 3252–3256.
[7] L. H. Sommer, L. J. Tyler, F. C. Whitmore, J. Am.
Chem. Soc. 1948, 70, 2872–2874.
[8] E. E. Wilson, A. G. Oliver, R. P. Hughes, B. L. Ashfeld,
Organometallics 2011, 30, 5214–5221.
[9] I. V. Escamilla, L. F. R. Ramos, J. S. N. Escalera,
A. A. L. Hernꢄndez, J. Mex. Chem. Soc. 2011, 55, 133–
136.
[10] B. M. Trost, V. S. Chan, D. Yamamoto, J. Am. Chem.
Soc. 2010, 132, 5186–5192.
[11] a) I. S. Kim, M.-Y. Ngai, M. J. Krische, J. Am. Chem.
Soc. 2008, 130, 6340–6341; b) R. M. Magid, J. G. Welch,
J. Am. Chem. Soc. 1968, 90, 5211–5217; c) B. M. Trost,
J. W. Herndon, J. Am. Chem. Soc. 1984, 106, 6835–
6837.
[12] a) Y. Dang, H. J. Geise, J. Organomet. Chem. 1991, 405,
1–39; b) R. E. Estꢃvez, J. Justicia, B. Bazdi, N. Fuentes,
M. Paradas, D. Choquesillo-Lazarte, J. M. Garcꢁa-Ruiz,
R. Robles, A. Gansꢅuer, J. M. Cuerva, J. E. Oltra,
Chem. Eur. J. 2009, 15, 2774–2791; c) A. Gansꢅuer, M.
Behlendorf, D. von Laufenberg, A. Fleckhaus, C. Kube,
D. V. Sadasivam, R. A. Flowers, Angew. Chem. 2012,
124, 4819–4823; Angew. Chem. Int. Ed. 2012, 51, 4739–
4742; d) A. Gansꢅuer, H. Bluhm, M. Pierobon, J. Am.
Chem. Soc. 1998, 120, 12849–12859; e) J. Justicia, I.
Sancho-Sanz, E. ꢂlvarez-Manzaneda, J. E. Oltra, J. M.
Cuerva, Adv. Synth. Catal. 2009, 351, 2295–2300; f) J. E.
McMurry, Acc. Chem. Res. 2012, 45, 281–286; g) F.
Yang, G. Zhao, Y. Ding, Z. Zhao, Y. Zheng, Tetrahe-
dron Lett. 2002, 43, 1289–1293.
[3] a) L. M. Ambrosini, T. H. Lambert, ChemCatChem
2010, 2, 1373–1380; b) H. M. L. Davies, E. J. Sorensen,
Chem. Soc. Rev. 2009, 38, 2981–2982; c) F.-X. Felpin, E.
Fouquet, ChemSusChem 2008, 1, 718–724; d) L.-Q. Lu,
J.-R. Chen, W.-J. Xiao, Acc. Chem. Res. 2012, 45, 1278–
1293; e) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev.
2009, 38, 2993–3009; f) K. C. Nicolaou, D. J. Edmonds,
P. G. Bulger, Angew. Chem. 2006, 118, 7292–7344;
Angew. Chem. Int. Ed. 2006, 45, 7134–7186; g) P. J. Par-
sons, C. S. Penkett, A. J. Shell, Chem. Rev. 1996, 96,
195–206; h) D. B. Ramachary, S. Jain, Org. Biomol.
Chem. 2011, 9, 1277–1300; i) L. F. Tietze, Chem. Rev.
1996, 96, 115–136; j) L. F. Tietze, U. Beifuss, Angew.
Chem. 1993, 105, 137–170; Angew. Chem. Int. Ed. Engl.
1993, 32, 131–163.
[4] a) C. A. Campos, J. B. Gianino, D. M. Pinkerton, B. L.
Ashfeld, Org. Lett. 2011, 13, 5680–5683; b) J. B. Giani-
no, B. L. Ashfeld, J. Am. Chem. Soc. 2012, 134, 18217–
18220.
[5] a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–
2794; b) H. Tanaka, S. Yamashita, Y. Ikemoto, S. Torii,
Tetrahedron Lett. 1988, 29, 1721–1724.
[13] a) Z. Liu, L. Liu, Z. Shafiq, Y.-C. Wu, D. Wang, Y.-J.
Chen, Synthesis 2007, 1961–1969; b) A. Netz, K. Pol-
born, T. J. J. Mꢆller, J. Am. Chem. Soc. 2001, 123, 3441–
3453; c) P. Rubenbauer, E. Herdtweck, T. Strassner, T.
Bach, Angew. Chem. 2008, 120, 10260–10263; Angew.
Chem. Int. Ed. 2008, 47, 10106–10109.
[6] a) L. M. Fleury, B. L. Ashfeld, Org. Lett. 2009, 11,
5670–5673; b) L. M. Fleury, B. L. Ashfeld, Tetrahedron
Lett. 2010, 51, 2427–2430; c) L. M. Fleury, A. D. Kosal,
J. T. Masters, B. L. Ashfeld, J. Org. Chem. 2013, 78,
253–269; d) A. D. Kosal, B. L. Ashfeld, Org. Lett. 2010,
12, 44–47.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
6 Relay Redox and Lewis Acid Catalysis in the Titanocene-
Catalyzed Multicomponent Assembly of 1,5-Enynes
Adv. Synth. Catal. 2013, 355, 1 – 6
Antonio J. Lepore, David M. Pinkerton,
Brandon L. Ashfeld*
6
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!