Trimethylsilyl trifluoromethanesulfonate- accelerated addition of catalytically generated zinc acetylides to aldehydes

Full text of DOI:10.1021/jo900102w

we planned to employ (eq 1).5 Interestingly, we found that
replacement of TMSOTf with TMSCl prevented acetylene
silylation from occurring.
Trimethylsilyl Trifluoromethanesulfonate-
Accelerated Addition of Catalytically Generated
Zinc Acetylides to Aldehydes
C. Wade Downey,* Brian D. Mahoney, and
Vincent R. Lipari
Gottwald Center for the Sciences, UniVersity of Richmond,
Accordingly, we began our investigation by studying the
addition of phenylacetylene to benzaldehyde in the presence of
ZnBr2, i-Pr2NEt, and TMSCl in CH2Cl2 (Table 1, entry
1).Because ample precedent demonstrates that zinc acetylide
Richmond, Virginia 23173
wdowney@richmond.edu
ReceiVed January 15, 2009
TABLE 1. Reaction Optimization
entry
R
X
solvent
temp
conv (%)b
1
2
3
4
5
6
7
Ph
Ph
4-anisyl
Ph
Ph
Ph
Ph
Ph
Ph
4-anisyl
Cl
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
toluene
Et2O
Et2O
Et2O
Et2O
rt
rt
rt
rt
rt
rt
rt
0 °C
rt
rt
<5
93
65
72
<5
61
78
73
89
88
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
In the presence of TMSOTf, a wide variety of terminal acetyl-
enes add rapidly and efficiently to aldehydes via a catalytically
generated zinc acetylide. In the absence of TMSOTf, no reaction
is observed under otherwise identical conditions.
8
9c
10c
Metal-catalyzed addition of terminal acetylenes to aldehydes1
remains an active area of research because of the synthetic utility
of the propargyl alcohol products.2 Zinc catalysis in particular
has been a fruitful field, as popularized by the development of
an enantioselective system by Careirra and co-workers.3 The
frequent requirement for elevated temperatures in these
reactions1c,d,3 and our own continued interest in silylation-
induced reactivity4 attracted us to the possibility that trimeth-
ylsilyl trifluoromethanesulfonate (TMSOTf) might accelerate
these reactions. Herein, we report the results of our efforts in
this area, which demonstrate that TMSOTf remains active as a
silylating agent and/or Lewis acid even in the presence of a
carbanion nucleophile.
a Standard reaction conditions: phenylacetylene (0.5 mmol), ZnBr2 (0.1
mmol), i-Pr2NEt (0.75 mmol), RCHO (1.0 mmol), TMSX (0.55 mmol),
b
1
solvent (3 mL), 1 h. Conversion determined by H NMR spectroscopy of
the unpurified reaction mixture. c Modified stoichiometry for i-Pr2NEt and
TMSOTf: i-Pr2NEt (1.0 mmol), TMSOTf (0.6 mmol).
formation occurs under these conditions,6 we were disappointed
in the very low conversion observed. When TMSCl was replaced
with TMSOTf, however, acetylide silylation was suppressed in
favor of propargyl alcohol formation (entry 2). Unfortunately, side
reactions hampered generality with respect to aldehyde under these
conditions by reducing conversion to the desired product (entry
3).7 A simple change in medium to Et2O provided a more reliable
and general system (entry 7), and final adjustments in stoichiometry
resulted in our optimized reaction conditions (entries 9 and 10).
Our working hypothesis regarding the reaction mechanism
is outlined in Scheme 1.8 Formation of zinc acetylides by
treatment of a terminal alkyne with ZnBr2 and an amine base
is well documented.3,6 Subsequently, addition of the acetylide
to the aldehyde takes place, followed by silylation of the zinc
alkoxide by TMSOTf, to release the product and regenerate the
catalyst (Scheme 1A). In this reaction mechanism, TMSOTf
At the outset of these experiments, our primary concern was
that terminal silylation of the zinc acetylide might occur under
our reaction conditions. Indeed, Shaw and Rahaim have very
recently shown that zinc acetylides react with TMSOTf in
excellent yield under reaction conditions very similar to those
(1) For recent work, see the following. (a) Ti: Gao, G.; Wang, Q.; Yu, X.-
Q.; Xie, R.-G.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 122–125. (b) In: Sakai,
N.; Kanada, R.; Hirasawa, M.; Konokahara, T. Tetrahedron 2005, 61, 9298–
9304. (c) Ag: Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395–4398. (d) Cu: Asano,
Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901–3904. (e) Zn:
Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomasini, C. J. Org. Chem.
2005, 70, 5733–5736. For a Lewis base-catalyzed approach, see: (f) Lettan, R. B.;
Scheidt, K. A. Org. Lett. 2005, 7, 3227–3230.
(2) For the use of propargyl alcohols as building blocks in organic synthesis,
see: (a) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197–3199. (b)
Kabalka, G.; Wu, Z.; Ju, Y. Org. Lett. 2004, 6, 3929–3931. (c) Engel, D. A.;
Dudley, G. B. Org. Lett. 2006, 8, 4027–4029.
(5) Rahaim, R. J., Jr.; Shaw, J. T. J. Org. Chem. 2008, 73, 2912–2915.
(6) (a) Lee, K. Y.; Park, D. Y.; Kim, T. H.; Kim, J. N. Bull. Korean Chem.
Soc. 2005, 26, 1617–1619. (b) Leeuwenbergh, M. A.; Timmers, C. M.; van der
Marel, B. A.; van Boom, J. H.; Mallet, J.-M.; Sinay¨, P. G. Tetrahedron Lett.
1997, 38, 6251–6254.
(7) Cannizzaro reaction appears to be competitive with the desired reaction
for some substrates when CH2Cl2 is employed as solvent. For additions to
benzaldehyde and anisaldehyde, 1H NMR analysis of the unpurified reaction
mixtures revealed the presence of benzyl alcohol and p-methoxybenzayl alcohol,
respectively.
(3) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806–1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687–9688.
(4) (a) Downey, C. W.; Johnson, M. W. Tetrahedron Lett. 2007, 48, 3559–
3562. (b) Downey, C. W.; Johnson, M. W.; Tracy, K. J. J. Org. Chem. 2008,
73, 3299–3302.
(8) Although the catalyst is represented as ZnBr2 in these mechanistic
schemes, it may be in equilibrium with the equally active Zn(OTf)2 under these
reaction conditions.
2904 J. Org. Chem. 2009, 74, 2904–2906
10.1021/jo900102w CCC: $40.75 2009 American Chemical Society
Published on Web 03/04/2009

TABLE 2. Addition of Phenylacetylene to Various Aldehydesa
SCHEME 1. Proposed Mechanisms
serves to induce catalyst turnover. We are disinclined toward
this mechanism at present because no product is observed in
the absence of TMSOTf (vide infra), even with stoichiometric
quantities of ZnBr2. Alternatively, preactivation of the aldehyde
oxygen by the Lewis acidic TMSOTf would preclude the
necessity for subsequent silylation of an alkoxide species
(Scheme 1B). Furthermore, the ability of TMSOTf to activate
the aldehyde toward nucleophilic attack may explain the
remarkable rate acceleration observed. Indeed, this mechanism
is analogous to our mechanistic hypothesis regarding the
TMSOTf-induced one-pot enol silane formation-Mukaiyama
aldol reaction previously reported by our laboratory.4a
The control experiments illustrated below are in agreement with
both variations of the proposed mechanisms and serve to illustrate
the remarkable ability of TMSOTf to accelerate these reactions.
As shown in eq 2, no reaction occurs in the absence of TMSOTf
under otherwise optimized reaction conditions. Furthermore, we
have eliminated the possibility that TMSOTf acts merely as an
agent to transform ZnBr2 into Zn(OTf)2 by showing in eq 3 that
Zn(OTf)2 is also an ineffective catalyst in the absence of TMSOTf.9
We also considered the possibility that a silylated acetylide was
acting as the nucleophile in these reactions, in a manner somewhat
analogous to the Mukaiyama aldol reaction. In the event, however,
we confirmed that the independently synthesized and purified silyl
acetylide is inactive under our reaction conditions (eq 4). In
summary, these experiments show that TMSOTf is necessary for
reactivity but does not appear to react directly with either the
acetylide or the zinc catalyst.
a See Supporting Information for experimental procedures, which vary
by substrate. b Isolated yield after chromatography.
the scope of this reaction by performing a survey of various
aldehydes (Table 2). Aromatic aldehydes are exceptional
substrates for this reaction (entries 1-3), including electron-
rich aromatic and heteroaromatic electrophiles (entries 4 and
5). The electron-poor p-nitrobenzaldehyde, however, was ham-
pered by poor solubility in diethyl ether and also reacted poorly
(<50% yield) in CH2Cl2 (not shown). Bulky naphthyl-substituted
aldehydes (entries 6 and 7) and cinnamyl aldehydes (entries 8
and 9) are also excellent acceptors. Saturated aldehydes were
more problematic as a result of competing aldol and enol silane
formation reactions.10Nonetheless, portionwise addition of al-
dehyde, i-Pr2NEt, and TMSOTf allowed successful addition to
R-branched aliphatic aldehydes in high yield (entries 10 and
11). The representative unbranched propionaldehyde failed to
react efficiently (<50% conversion, not shown).
After the establishment of the aldehyde scope, we conducted
a survey of a range of terminal acetylenes in order to more fully
determine the reaction scope. The addition of various acetylenes
to the representative electrophile benzaldehyde is summarized
in Table 3. To our pleasure, both electron-rich and electron-
(9) When TMSOTf is present, Zn(OTf)2 reacts in a manner comparable to
that of ZnBr2.
After the determination of optimized reaction conditions and
preliminary verification of the reaction mechanism, we examined
(10) Aldehyde-derived enol silane was detectable by 1H NMR spectroscopy
of the unpurified reaction mixture.
J. Org. Chem. Vol. 74, No. 7, 2009 2905

TABLE 3. Addition of Various Acetylenes to Benzaldehydea
Because the aldehyde competitively converts to an enol silane
under these reaction conditions, we anticipated generally lower
yields. To our delight, however, aromatic-substituted alkynes
again reacted in outstanding yields (entries 1-4). Reactivity
with other alkynes did suffer somewhat (entries 5-7), but
moderate to good yields were still obtained for this challenging
substrate class.
In conclusion, TMSOTf remarkably accelerates the zinc-
catalyzed addition of terminal acetylenes to aldehydes, without
significant competing acetylene silylation. The TMSOTf may
induce catalyst turnover by silylation of the nascent zinc
alkoxide or may precomplex and activate the aldehyde elec-
trophile. The reaction scope includes both aromatic and aliphatic
acetylenes and aldehydes. We anticipate the extension of this
general strategy to other zinc-catalyzed alkyne addition reac-
tions, including stereoselective variants.
Experimental Section
Typical Procedure for TMSOTf-Accelerated Addition of
Terminal Acetylenes to Aldehydes. Synthesis of Product 1.2c
To an oven-dried round-bottomed flask under N2 atmosphere was
added ZnBr2 (104 mg, 0.398 mmol). The flask was charged with
Et2O (12 mL), and then phenylacetylene (220 µL, 205 mg, 2.00
mmol), diisopropylethylamine (700 µL, 519 mg, 4.01 mmol),
benzaldehyde (408 µL, 426 mg, 4.01 mmol), and TMSOTf (432
µL, 530 mg, 2.39 mmol) were added sequentially. The heteroge-
neous mixture was stirred for 1 h and then passed through a plug
of silica (1.0 cm × 3.0 cm) with Et2O. The mixture was
concentrated in vacuo and then dissolved in THF (6 mL). The
solution was stirred with 1.0 M HCl (3 mL) for 15 min, then diluted
in Et2O and washed with water (1×) and saturated NaHCO3 (1×).
The organic layer was diluted with hexanes (1:2 hexanes/Et2O) and
dried over Na2SO4. The solvent was removed in vacuo, and the
residue was purified by column chromatography (5-20% EtOAc/
hexanes) as a yellow oil (95% yield): IR (film) 3348, 1480, 1437,
1021, 955, 901, 750, 726, 683 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.65 (d, J ) 7.3 Hz, 2H), 7.53-7.49 (m, 2H), 7.44 (t, J ) 7.8
Hz, 2H), 7.40-7.32 (m, 4H) 5.73 (s, 1H), 2.28 (bs, 1H); 13C NMR
(125 MHz, CDCl3) δ 140.7, 131.8, 128.7, 128.6, 128.5, 128.3,
126.8, 122.5, 88.7, 86.7, 65.2; HRMS (ESI) exact mass calcd for
C15H12ONa [M + Na]+ 231.0780, found 231.0790.
a See Supporting Information for experimental procedures, which vary
by substrate. b Isolated yield after chromatography.
TABLE 4. Addition of Various Acetylenes to Isobutyraldehydea
Acknowledgment. We thank the Thomas F. Jeffress and Kate
Miller Jeffress Memorial Trust and Research Corporation for
funding. B.D.M. acknowledges the University of Richmond
College of Arts & Sciences for a Gottwald fellowship and the
University of Richmond Department of Chemistry for a Puryear-
Topham fellowship. We thank Dr. Timothy Smith for assistance
with mass spectral data.
a See Supporting Information for experimental procedures, which vary
by substrate. b Isolated yield after chromatography.
poor aromatic acetylenes reacted in exemplary yields (entries
1-4). Alkyl and trialkylsilyl acetylenes were also competent
substrates, demonstrating the wide scope of reactivity under
these conditions (entries 5 and 6). Ethyl propiolate also reacted
competently to provide good yield of the γ-hydroxy ynoate
product (entry 7).
Supporting Information Available: Experimental proce-
dures, compound characterization data, and spectra. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
We next targeted isobutyraldehyde for a survey of the addition
of the same acetylenes to an aliphatic substrate (Table 4).
JO900102W
2906 J. Org. Chem. Vol. 74, No. 7, 2009