A general and versatile method for C-C cross-coupling synthesis of conjugated enynes: One-pot sequence starting from carbonyl compounds

Article abstract of DOI:10.1002/anie.200504594

(Chemical Equation Presented) Ultimate coupling partners: Widely available enolizable aldehydes and ketones undergo Sonogashira cross-coupling with other carbonyl compounds to give conjugated enynes in a newly devised general method (see scheme; NfF = nonafluorobutane-1-sulfonyl fluoride). The synthetic protocol comprises at least four operating steps, which are carried out in one pot using common reagents, catalysts, and additives.

Full text of DOI:10.1002/anie.200504594

Angewandte
Chemie
Multistep One-Pot Syntheses
DOI: 10.1002/anie.200504594
A General and Versatile Method for CÀC Cross-
Coupling Synthesis of Conjugated Enynes: One-
Pot Sequence Starting from Carbonyl
Compounds**
Ilya M. Lyapkalo* and Michael A. K. Vogel
In light of the pivotal role of the carbonyl group in organic
[
1]
synthesis, new general transformations of the carbonyl
compounds are always of particular importance. This is why
the relatively recent discovery of transition-metal-catalyzed
reactions of alkenyl triflates, readily available from enolizable
carbonyl precursors, immediately found widespread applica-
[
2]
tion. Following this line of research, alkenyl 1,1,2,2,3,3,4,4,4-
nonafluorobutane-1-sulfonates (hereinafter referred to
alkenyl nonaflates) were introduced and advantageously
[
3]
employed as a useful alternative to the triflates in Heck,
Negishi, Stille, and Sonogashira coupling reactions.
[
4]
[5]
[6]
Routinely, the coupling protocols consist of two steps that
include O-sulfonylation of the starting carbonyl compounds,
followed by Pd-catalyzed CÀC cross-coupling of the isolated
alkenyl perfluoroalkanesulfonate leading to the desired
products. Alternatively, Reissig and co-workers established
that isolation and purification of the alkenyl nonaflates is not
necessary for the subsequent coupling reaction provided that
the nonaflates are generated from trimethylsilyl enol ethers
and the mild sulfonylating reagent nonafluorobutane-1-sul-
[
7]
fonyl fluoride (NfF) under catalysis by fluoride ion. This
resulted in the development of a general, one-pot trans-
formation of trimethylsilyl enol ethers into 1,3-dienes by in
situ generation of alkenyl nonaflates followed by Heck
[
8]
reactions. However, it requires an extra step to obtain the
requisite trimethylsilyl enolates from the ultimate precursors,
ketones or aldehydes. This requirement serves to highlight a
major challenge in the development of general and straight-
forward coupling methods, namely, the conversion of carbon-
[*] Dr. I. M. Lyapkalo
Institute of Chemical & Engineering Sciences
1
Pesek Road, Jurong Island, Singapore 627833 (Singapore)
Fax: (+65)6316-6184
E-mail: ilya_lyapkalo@ices.a-star.edu.sg
M. A. K. Vogel
Freie Universität Berlin
Institut für Chemie—Organische Chemie
Takustrasse 3, 14195 Berlin (Germany)
[
**] We thank Prof. H.-U. Reissig (Freie Universität Berlin, Germany) and
Prof. B. Cox (AstraZeneca, Macclesfield, UK) for useful discussions.
Financial support by the Agency for Science Technology and
Research (A*STAR Singapore) and by the Alexander von Humboldt
Foundation is most gratefully acknowledged. We are indebted to
Bayer AG for the generous donation of nonafluorobutane-1-sulfonyl
fluoride.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 4019 –4023
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4019

Communications
yl compounds to the alkenyl nonaflates, combined with the
these intermediates to give high yields of the desired products
subsequent CÀC cross-coupling step in a one-pot operation.
Here we report a novel general method for the synthesis
of conjugated enynes based on the Sonogashira reaction, with
both components originating from widely available carbonyl
compounds, whereby the generated alkenyl nonaflate and
4a–e (Table 1, entries 1–5).
The metal-free noncoordinating P base provided perfect
regioselectivity control in favor of the deprotonation at the
position most remote to the ring nitrogen of 1c leading
exclusively to the product 4d (Table 1, entry 4). However, the
1
[
14]
0
alkyne intermediates interact smoothly under Pd catalysis to
give the anticipated cross-coupling products in an one-pot
reaction sequence.
To achieve a clean conversion of the starting materials 1–3
to the mixture of a cyclic nonaflate and a terminal alkyne
Table 1: Reaction conditions and yields of the products 4 according to
Scheme 1.
Entry
Cyclic
ketone 1
Ketone 2 or
aldehyde 3
Reaction
conditions
Product 4
(Yield [%])
[
a]
(
Scheme 1), we needed to find a base that would not react
1
A, 17 h
2
3
4
5
1a
A, 24 h
A, 24 h
A, 24 h
Scheme 1. One-pot synthesis of the enynes 4 starting from cyclic
ketones 1 and methyl ketones 2 or aldehydes 3. a) NfF; b) base;
c) iPr NH (excess), Pd(OAc) (5 mol%), PPh (10 mol%), CuI
2
2
3
(
10 mol%), LiCl, 24 h at 258C, or 17 h at 45–478C, or 5–6 h at 608C.
with NfF but be strong enough to provide a-deprotonation of
the carbonyl substrates and effect E2elimination of NfOH
from the intermediate alkenyl nonaflates at ambient or
subambient temperatures. Since lithium amide bases are
1) B then
[
9]
2) A, 17 h
known to react with NfF readily, even at low temperature,
we turned our attention to metal-free nitrogen bases. After
[
10]
extensive experimentation,
no)tris(1-pyrrolidinyl)phosphorane
to as P base) and 1-(tert-butylimino)-1,1,3,3,3-pentakis(di-
we found that (tert-butylimi-
[
11]
(hereinafter referred
1
6
A, 24 h
5
5
[12]
methylamino)-1l ,3l -diphosphazene (P base ), commer-
2
cially available representatives of the family of phosphazene
bases, were particularly successful (Figure 1).
When combined with NfF in dry aprotic solvent, the P
bases effect clean and complete conversion of cyclic and
acyclic ketones to the cyclic nonaflate and the respective
alkyne intermediates which can be observed by H NMR
spectroscopy of the crude reaction mixtures. The one-pot
reaction sequence culminates in Sonogashira coupling of
1
then
2) A, 17 h
) A, 36 h
7
8
1
1
2
) B then
) A, 17 h
[
c,d]
3b
[
a] Nonaflation/elimination conditions: A (P base, NfF, DMF, 08Cto
1
2
58C), B (P base, NfF, THF, À788Cto 25 8C, 4.5 h); for the Sonogashira
2
coupling, see step c in Scheme 1. [b] >95:<5 selectivity in favor of the
kinetically controlled double-bond regioisomer shown. [c] The compo-
nent was added to the reaction mixture under the conditions 2 after the
1
complete conversion of the cyclic ketone 1 to the nonaflate ( H NMR
control) under the conditions (1). [d] Added at À108C. [e] 1.2:1 mixture
Figure 1. Phosphazene bases employed for generation of alkenyl nona-
flates and terminal alkynes from the carbonyl compounds 1–3.
of the tri- (4h) and tetrasubstituted CÀCdouble-bond regioisomers was
obtained under the conditions specified in the entry 7.
4
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Chemie
P base was not regioselective in the deprotonation of 1d with
1
regard to the a-methine and a-methylene positions (Table 1,
footnote [e]). Fortunately, the regioselectivity was dramati-
cally improved when the much stronger P base was employed
2
under the kinetically controlled conditions, resulting in the
enynes 4e and 4h bearing the less substituted double bonds
(
Table 1, entries 5 and 8).
Aldehydes proved to be a promising source of terminal
alkynes. In all cases, clean conversions were observed
entries 6–8 in Table 1, entry 3 in Table 2). Moreover, alde-
Scheme 2. One-pot synthesis of the acyclic enynes 6 employing
(
trimethylsilyl enolates 5. a) iPr NH (excess), Pd(OAc) (5 mol%), PPh
2
2
3
(10 mol%), CuI (10 mol%), LiCl, 17–24 h at 258C.
Table 2: Reaction conditions and yields of the products 6 according to
Scheme 2.
Entry Ketone 2
Reaction
TMS enolate 5 Product 6
addition of the trimethylsilyl enol ethers 5 to reaction
mixtures containing the appropriate excess of NfF after the
completion of the alkyne formation (Table 2), that is, when
free phosphazene bases were no longer present. Remarkably,
under these conditions the fluoride ion effects desilylation
and nonaflation of the trimethylsilyl enol ether moiety in a
highly selective manner, without appreciably affecting fragile
[
a]
or aldehyde 3 conditions
(Yield [%])
1
A, 17 h
[
18]
trimethylsilyl alcohol protection (Table 2, entries 2 and 3).
The subsequent Sonogashira coupling resulted in good yields
of the desired products 6a–c. Noteworthy, the product 6a is
produced with almost complete retention of the Z config-
uration of the double bond originating from the parent enol
[
19]
2
3
B
B
ether 5a.
In conclusion, the method represents a straightforward,
general, and versatile approach to highly diverse conjugated
enynes, starting from readily available carbonyl precursors.
Relatively low nucleophilicity, in combination with high
basicity, makes phosphazene bases compatible with NfF,
thereby permitting clean formation of alkenyl nonaflates
[
20]
under the “internal quench” conditions.
Furthermore,
neither phosphazene bases nor their salts impede the
bimetallic catalytic cycle of the subsequent Sonogashira
reaction. The operational simplicity of our one-pot protocol
and a wide selection of commercially available carbonyl
compounds permit a flexible, convergent approach towards a
variety of conjugated enynes. It should open up new and
interesting opportunities for the synthesis of target products
[
2
a] For the conversions to the alkynes: A (P base, NfF, DMF, 08Cto
1
58C), B (P base, NfF, THF, À788Cto 25 8C, 4.5 h); for the Sonogashira
2
coupling, see a) in Scheme 2. [b] Obtained and characterized as free
alcohols after the TMS deprotection.
[
21]
hydes are more acidic and react much faster than ketones,
which enables the highly selective reaction of the aldehyde
moiety in the presence of the unprotected keto group in the 6-
oxo-heptanal 3b (entries 7 and 8). To our knowledge, one-
containing conjugated enyne or enediyne fragments and
exhibiting very promising antibiotic, antitumor, and other
[
2d,22]
biological activities.
step formation of CÀC triple bond by elimination of H O
2
[
15,16]
from aldehydes is unprecedented.
Experimental Section
Acyclic nonaflates are unsuccessful as cross-coupling
components when generated directly from carbonyl com-
pounds using phosphazene bases, because of their ease of
Typical procedure for the one-pot synthesis of enynes: Synthesis of 4a
[
23]
(entry 1, Table 1): Predried LiCl (0.127 g, 3.00 mmol) was placed
into a reaction flask equipped with a three-way tap and a magnetic
stirrer coated with teflon, and was heated to ca. 250–3008C with a
heat gun under high vacuum for a few minutes. After the LiCl had
cooled down under an atmosphere of dry argon, DMF (2mL), N-
ethoxycarbonyl tropinone (1a) (0.395 g, 2.00 mmol), 2-fluoroaceto-
phenone (2a) (0.345 g, 2.50 mmol), and NfF (1.495 g, 4.95 mmol)
were added successively. The reaction mixture was cooled down to
[
17]
elimination to give alkynes. However, a modification of the
protocol made it possible to obtain cross-coupling products
from the combination of both acyclic carbonyl precursors. We
realized that the highly reactive soluble fluoride sources
+
À
phosphazenium fluorides [Pbase]H F , generated during the
course of the alkyne formation from the compounds 2 and 3,
could be used to selectively produce the appropriate (acyclic)
108C under vigorous stirring, and P base (2.406 g, 7.70 mmol) was
1
added dropwise within 2–3 min. After completion of the nonaflation
and elimination steps (17 h at RT, H NMR monitoring), iPr NH
[
7b]
1
nonaflate (Scheme 2). Thus, the nonaflates required for the
2
coupling products 6 were routinely generated in situ by simple
(3 mL) was added, followed by solid PPh (0.052g, 0.20 mmol), CuI
3
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4021

Communications
(
0.038 g, 0.20 mmol), and Pd(OAc) (0.022 g, 0.10 mmol) (all together
[9] The reaction results in the anticipated nonafluorobutane-1-
sulfonamides: I. M. Lyapkalo, H.-U. Reissig, A. Schaefer, A.
Wagner, Helv. Chim. Acta 2002, 85, 4206 – 4215.
[10] Trialkylamines are not basic enough to promote the nonaflation,
whereas DBU gives low conversions as a result of the side
reaction with NfF. The results will be reported in a subsequent
full account.
2
in one lot), and the reaction mixture was stirred at 608C for 5.5 h. It
was then subjected to aqueous workup (benzene/water; in other cases
usually tBuOMe/water or hexane/water), the two-phase mixture was
filtrated carefully through a pad of celite and the aqueous phase re-
extracted with benzene. The combined organic layers were dried
(
Na SO ), the solvent was then removed under vacuum, and the
2 4
residue was subjected to column chromatography (silica gel, gradient
elution (1. hexane, 2. benzene/hexane 1:4, 3. benzene/hexane 1:1,
[11] R. Schwesinger, J. Willaredt, H. Schlemper, M. Keller, D.
Schmitt, H. Fritz, Chem. Ber. 1994, 127, 2435 – 2454. It has the
4
. benzene) to give pure 4a (0.579 g, 97% yield) as a yellow oil.
highest basicity (pK = 28.35 in MeCN) of the commercially
a
1
H NMR (C D , 500 MHz, 758C): d = 1.05 (t, J = 7.1 Hz, 3H, Me),
available P bases.
6
6
1
1
1
1
7
1
.29–1.36 (brm, 1H), 1.55 (ddd, J = 11.8, 9.0, 2.8 Hz, 1H), 1.64 (mc,
H), 1.77 (ddddd, J = 12.5, 12.5, 8.0, 2.8, 1.7 Hz, 1H), 1.83 (brd, J =
[12] a) Commercially available as a 2m solution in THF (pK = 33.49
a
in MeCN); b) According to the primary classification given by
Schwesinger, the subscript designates the number of P atoms in
7 Hz, 1H), 2.99 (brd, J = 17 Hz, 1H) (all CH ), 4.06 (dq, J = 10.8,
2
.1 Hz, 1H), 4.09 (dq, J = 10.8, 7.1 Hz, 1H) (both OCH ), 4.29 (brs,
2
the molecule. For the synthesis and properties of P or higher
2
H, CHN), 4.37 (brs, 1H, CHN), 6.29 (ddd, J = 5.3, 1.9, 1.8 Hz, 1H,
order phosphazene bases, see: R. Schwesinger, H. Schlemper, C.
Hasenfratz, J. Willaredt, T. Dambacher, T. Breuer, C. Ottaway,
M. Fletschinger, J. Boele, H. Fritz, D. Putzas, H. W. Rotter, F. G.
Bordwell, A. V. Satish, G. Z. Ji, E. M. Peters, K. Peters, H. G.
von Schnering, L. Walz, Liebigs Ann. 1996, 1055 – 1082and
references therein.
CH=C), 6.68 (td, J = 7.6, 1.3 Hz, 1H), 6.74 (ddd, J = 9.5, 8.3, 1.3 Hz,
1
H), 6.78–6.73 (m, 1H), 7.25 ppm (td, J = 7.4, 1.8 Hz, 1H) (all CHAr);
C (C D , 125.8 MHz, 758C): d = 14.8 (q, Me), 29.9, 34.5, 38.2 (all brt,
6 6
1
3
CH ), 52.4, 53.7 (both d, CHN), 61.0 (t, OCH ), 82.8 (s, C=C), 95.0 (d,
2
2
3
2
J13C,19 = 3.2Hz, C =C), 112.8 (d, J13C,19 = 15.7 Hz, CAr), 115.7 (dd,
J13C,19 = 21.0 Hz), 124.1 (dd, J13C,19 = 3.8 Hz), 129.9 (dd, J13C,19
F
F
2
3
3
=
F
F
F
[13] S. Chang, S. H. Yang, P. H. Lee, Tetrahedron Lett. 2001, 42,
4833 – 4836.
[14] T. Imahori, Y. Kondo, J. Am. Chem. Soc. 2003, 125, 8082– 8083.
4
7
1
.9 Hz), 133.6 (dd, J
39.7 (brd, C=CH), 154.4 (s, C=O), 163.2ppm (d, J13C,19 = 251.6 Hz,
13C,19
= 1.3 Hz) (all CHAr), 118.6 (brs, C=CH),
F
1
F
À1
C-F); IR (film): n˜ = 3060–3035 cm (=C-H), 2980–2835 (C-H), 2210
[
[
[
[
15] For the relevant multistep methods known to date, see a) M.
(
C=C), 1700 (C=O), 1620–1490 (C=C); MS (EI, 80 eV): m/z (%) =
Shibasaki, Y. Torisawa, S. Ikegami, Tetrahedron Lett. 1982, 23,
+ + +
3
00 (M +1, 21), 299 (M , 100), 271 ([M ÀC H ], 37), 270
2
4
4607 – 4610; b) L. A. Paquette, S. Hormuth, C. J. Lovely, J. Org.
+
+
(
(
(
[M ÀC H ],
91),
242
([M ÀC H ÀCO],
45),
226
2
5
2
5
Chem. 1995, 60, 4813 – 4821; c) T. Matsuura, S. Yamamura, Y.
Terada, Tetrahedron Lett. 2000, 41, 2189 – 2192.
+
+
[M ÀC H ÀCO ], 28), 198 ([M ÀCO EtÀC H ], 85), 183
2
5
2
2
2
4
+
+
[M ÀCO EtÀC H ÀNH], 10), 29 (C H , 44); C,H,N analysis (%):
2
2
4
2
5
16] Preliminary investigations show that the nonaflation/elimination
protocol is applicable to a wide range of carbonyl compounds,
leading to terminal or internal alkynes or allenes, depending on
the stereoelectronic effects of the substituents in the carbonyl
substrate. The results will be reported in due course.
calcd for C H FNO (299.4): C 72.22, H 6.06, N 4.68; found C 71.91,
1
8
18
2
H 5.95, N 4.64.
Received: December 27, 2005
Published online: May 9, 2006
17] In our attempts to generate the nonaflates from isopropyl methyl
ketone or benzyl methyl ketone using P base (1 equiv) and NfF
2
Keywords: CÀCcoupling · cross-coupling · enynes ·
under the kinetic conditions, we could detect only mixtures of
the alkyne and the starting material, which clearly indicates that
nonaflation is the rate-determining step.
.
homogeneous catalysis · phosphazene bases
1
18] H NMR analyses of the reaction mixtures towards the end of
3
the final coupling step indicated that the Me SiO group at sp -
3
hybridized carbon centers of the coupling products remained
intact, which should warrant the stability of the most frequently
used alcohol silyl protecting groups, such as tBuMe Si, tBuPh Si,
[
1] “The chemistry of carbonyl compounds is virtually the backbone
of synthetic organic chemistry”: J. D. Roberts, M. C. Caserio,
Basic Principles of Organic Chemistry, Benjamin, New York,
2
2
or Et Si, under our reaction conditions.
3
[
19] Trimethylsilyl enolate 5a was obtained as an 8:92 E/Z mixture by
1965, p. 426.
silylation of the freshly distilled pentanal with Me SiCl/NaI/
[
2] a) W. J. Scott, J. E. McMurry, Acc. Chem. Res. 1988, 21, 47 – 54;
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3
iPr NEt in MeCN at À458C to 58C. The pure Z isomer was then
2
isolated by preparative HPLC (68% yield).
[
[
20] E. J. Corey, A. W. Gross, Tetrahedron Lett. 1984, 25, 495 – 498.
21] The antimycotic agent terbinafine (Lamisil) manufactured by
Novartis Pharmaceuticals is perhaps most prominent example of
a widely applied drug bearing an eneyne structural motif; for
other interesting bioactive compounds, see: a) L. Garlaschelli, E.
Magistrali, G. Vidari, O. Zuffardi, Tetrahedron Lett. 1995, 36,
5633 – 5636; b) H.-J. Zhang, K. Sydara, G. T. Tan, C. Ma, B.
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[
3] a) K. Voigt, P. von Zezschwitz, K. Rosauer, A. Lansky, A.
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1
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5, 2103 – 2112.
5
[
[
5] A. Wada, Y. Ieki, M. Ito, Synlett 2002, 1061 – 1064.
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4
0, 5337 – 5340.
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40, 274 – 277, and references therein; b) I. M. Lyapkalo, M.
Tetrahedron 1996, 52, 6453 – 6518, and references therein.
[
[23] Since Pd(OAc)
our method, LiCl was considered as an additive for in situ
generation of [Pd(PPh Cl ] from Pd(OAc) and PPh at the
outset of the cross-coupling step. [Pd(PPh Cl ] is one of the
2
was used as a uniform source of catalytic Pd in
3
Webel, H.-U. Reissig, Eur. J. Org. Chem. 2002, 1015 – 1025.
8] a) M. Webel, H.-U. Reissig, Synlett 1997, 1141 – 1142; b) I. M.
Lyapkalo, M. Webel, H.-U. Reissig, Eur. J. Org. Chem. 2002,
3
)
2
2
2
3
[
3
)
2
2
most frequently used precatalysts for the Sonogashira reaction
of alkenyl sulfonates: a) S. W. Scheuplein, K. Harms, R.
Brueckner, J. Suffert, Chem. Ber. 1992, 125, 271 – 278; b) L.
3646 – 3658; c) I. M. Lyapkalo, J. Hogermeier, H.-U. Reissig,
Tetrahedron 2004, 60, 7721 – 7729.
4
022 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 4019 –4023

Angewandte
Chemie
Castedo, A. Mourino, L. A. Sarandeses, Tetrahedron Lett. 1986,
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2
L. A. Sarandeses, Tetrahedron Lett. 1988, 29, 1203 – 1206; d) M.
Moniatte, M. Eckhardt, K. Birckmann, R. Brueckner, J. Suffert,
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However, we did not carry out a specific study on the LiCl effect.
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