Rapid 1,4-alkynylation of acyclic enones using K[F3BC≡CR]

Article abstract of DOI:10.1055/s-0028-1087481

Conjugate alkynylation of acyclic enones using sp-hybridised potassium organotrifluoroborates in the presence of BF₃·OEt₂ is rapidly attained. The simplicity of the processes is suitable for the preparation of small compound librarie

Full text of DOI:10.1055/s-0028-1087481

LETTER
51
Rapid 1,4-Alkynylation of Acyclic Enones Using K[F3BC≡CR]
1
, 4-Alkynylati
e
on of
A
cyc
r
lic
E
non
r
es uccio Bertolini, Simon Woodward*
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
E-mail: simon.woodward@nottingham.ac.uk
Received 12 September 2008
F
F
BF3
R
Abstract: Conjugate alkynylation of acyclic enones using sp-hy-
bridised potassium organotrifluoroborates in the presence of
BF3·OEt2 is rapidly attained. The simplicity of the processes is suit-
able for the preparation of small compound libraries.
B
R
+
BF3
+
KBF4
K
Key words: conjugated alkynylation, enones, potassium organotri-
fluoroborates
Equation 1
straction from 1 by admixture of BF3⋅OEt2, driven by the
formation of stable KBF4 (Equation 1).14
Since their introduction to organic chemistry, aryl boronic
acids1 [ArB(OH)2] and more latterly vinyltri-
fluoroborates2 [F3BCR=CR2]– have become mainstay sp2-
C nucleophiles. Their air-stability, long shelflife, func-
tional group tolerance, and widespread commercial avail-
ability (over 2500 examples3) allow practical storage of
C-nucleophile compound libraries. While good routes ex-
ist to sp-hybridised K[F3BC≡CR] 14 exist, fewer applica-
tions of these closely related air-stable, nonhygroscopic
compounds have been reported.4,5
The reaction of alkynyltrifluoroborate 1a with enone 2a
served as an optimization model (Table 1).
Table 1 Alkynylation of Enone 2a with Potassium Organotrifluoro-
borate 1a under Different Reaction Conditions
O
O
C5H11
BF3K
(1a)
BF3⋅OEt2
solvent (2.0 mL)
2a
4aa
C5H11
Recently, in connection with another project, we needed
access to a library of compounds resulting from 1,4-alky-
nylation of enones.6 While recent advances have been
made in this demanding reaction, allowing direct use of
alkynes alone, these are presently limited to the use of ei-
ther specialist Michael acceptors7 or specific alkynes.8 For
the main part, catalytic 1,4-additions of alkyne nucleo-
philes to enones 2 (whether asymmetric or not) have re-
quired in situ prepared derivatives of Cu,9 Zn,10 or Al.11
We were attracted to the reports of Chong12 and Suzuki13
who used (1-alkynyl)diisopropoxyboranes 3 in Lewis
acid promoted reactions (Scheme 1).
(0.2 mmol)
Entry Solvent Nucleophile BF3·OEt2 Conditions
Yield
(equiv)
(equiv)
(%)a
1b
2
THF
2.0
1.5
r.t., 18 h
23
toluene 2.0
CH2Cl2 1.5
CH2Cl2 2.0
CH2Cl2 2.0
CH2Cl2 2.0
1.5
70 °C, 45 min 13
3c
4
1.1
r.t., 50 min
0 °C, 40 min
r.t., 35 min
r.t., 5 min
47
56
74
70
1.5
5
1.5
6
2.0
R3
B(Oi-Pr)2
R1
O
a GC yields.
O
3
b Conversion: 58%.
c Conversion: 97%.
R2
R1
R2
Lewis acid
promoter
R3
2
4
Scheme 1
Both polar and nonpolar solvents (entries 1 and 2) were
ineffective for the reaction. Dichloromethane proved to be
the optimal solvent (entries 3–6) presumably because the
trifluoroborates of type 1 have marginal solubility in it
while KBF4 does not. The highest yields were attained in
reactions where there were slight excesses of both the nu-
cleophile 1 and the BF3·OEt2 promoter in procedures car-
ried out at ambient temperature (entries 5 and 6). Under
these conditions enormous rate accelerations, compared
to the chemistry of Suzuki13 are attained. For example, the
published equivalent of entry 6 carried out using the boron
ester 3 takes 120 hours to complete, that is, over 1400
times slower. We propose that the rate enhancement in the
Despite the success of Scheme 1, use of 3 has a number of
limitations: it is very sensitive to hydrolysis and its reac-
tions can be very slow (up to 120 h). We speculated that
increasing the Lewis acidity of the boron component
would lead to a dramatic rate promotion in the 1,4-addi-
tion. One simple route to attaining this goal is fluoride ab-
SYNLETT 2009, No. 1, pp 0051–0054
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087481; Art ID: D32608ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

52
F. Bertolini, S. Woodward
LETTER
R3
R1
present system is due to two factors: (i) increased boron
Lewis acidity in transition state A (Figure 1); and (ii) an
ability to operate at higher reaction mixture concentra-
tions (0.1 M vs. 0.005 M).
F
O
B
F
R1
H
A
To define the full scope of new reaction conditions syn-
thesis of a small library of 1,4-alkynylation products was
carried out (Table 2).
Figure 1
a
Table 2 Results of the Alkynylation of Acyclic Enones with Potassium Organotrifluoroborates in the Presence of BF3·OEt2
Entry
Enone
Potassium organotrifluoroborate
Time (min)
Product
Yield (%)b
70
O
O
1
2a
2a
1b
30
4ab
4ac
Ph
BF3K
Ph
O
O
2
1c
40
57
BF3K
O
O
Ph
3
4
2b
2b
1a
1b
30
25
4ba
4bb
75
87
C5H11
BF3K
Ph
Ph
Ph
Ph
Ph
C5H11
O
O
O
O
O
O
Ph
Ph
Ph
BF3K
BF3K
BF3K
BF3K
BF3K
Ph
Ph
Ph
5
6
7
8
2b
2c
2c
2d
1c
1b
1c
1b
40
25
30
30
4bc
4cb
4cc
4db
77
65
54
55
Ph
Ph
O
O
Ph
Ph
Ph
Ph
Ph
Ph
O
O
Ph
H7C3
H7C3
Ph
Synlett 2009, No. 1, 51–54 © Thieme Stuttgart · New York

LETTER
1,4-Alkynylation of Acyclic Enones
53
Table 2 Results of the Alkynylation of Acyclic Enones with Potassium Organotrifluoroborates in the Presence of BF3·OEt2a (continued)
Entry
9c
Enone
Potassium organotrifluoroborate
Time (min)
30
Product
Yield (%)b
O
O
O
O
2e
2f
2f
1a
4ea
4fa
4fb
40
C5H11
C5H11
Ph
BF3K
H11C5
H11C5
C5H11
C5H11
Ph
O
O
10
11
1a
1b
150
240
57
48
BF3K
H13C6
H13C6
BF3K
H13C6
H13C6
a All reactions were performed in accordance with the general procedure (see experimental section).
b Isolated yields.
c Conversion = 75%.
relatively few K[F3BCCR] are commercially available, this
situation is changing rapidly.
In all cases high or complete conversions were attained
rapidly to afford single-component reaction mixtures
from which the products of type 4 were easily isolated.
Aryl-substituted enones15 afforded the highest yields. In
the cases of dialkyl-substituted enones (e.g., entry 9) the
mass balance was accounted for by noneluting oligomeric
byproducts which were easily separated by filtration
through silica.16 Attempts to suppress oligomerisation in
the case of entry 9 by changing the reaction concentration
in the range 0.2–0.06 M did not change the isolated yield
of addition product.
(5) (a) Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron
Lett. 2004, 45, 729. (b) Ochiai, M.; Miyamoto, K.; Yokota,
Y.; Suefuji, T.; Shiro, M. Angew. Chem. Int. Ed. 2005, 44,
75. (c) Vieira, A. S.; Ferreira, F. P.; Fiorante, F. P.;
Guadagnin, F. C.; Stefani, H. A. Tetrahedron 2008, 64,
3306.
(6) For a recent review on 1,4-alkynylations of enones, see:
Shinji, F.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall,
D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635.
(7) (a) Knöpfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
125, 6054. (b) Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682.
(c) Chang, S.; Na, Y.; Choi, E.; Kim, S. Org. Lett. 2001, 3,
2089.
In summary we have found improved experimental condi-
tions for in situ generation of F2BC≡CR and its addition to
enones. The reaction is technically simple and uses an in-
definitely stable acetylene anion equivalent in the form of
K[F3BC≡CR].
(8) Nishimura, T.; Guo, X. X.; Uchiyama, N.; Katoh, T.;
Hayashi, T. J. Am. Chem. Soc. 2008, 130, 1576.
(9) Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson, T. J. Org.
Chem. 1997, 62, 182.
(10) Kim, S.; Lee, J. M. Tetrahedron Lett. 1990, 31, 7627.
(11) Kwak, Y. S.; Corey, E. J. Org. Lett. 2004, 6, 3385.
(12) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244.
(13) Fujishima, H.; Takada, E.; Hara, S.; Suzuki, A. Chem. Lett.
1992, 658.
Acknowledgment
F.B. is a 2008 Rotarian Fellow. S.W. is grateful for input and sup-
port from the COST D40 ‘Innovative Catalysis’ programme and
EPSRC for funding (EP/F033478/1).
(14) The nucleophile described in Equation 1 has been recently
used by Tehrani and co-workers for the alkynylation of two
imines. However, the corresponding products were obtained
only in poor yields (17–31%). See: Stas, S.; Tehrani, K. A.;
Laus, G. Tetrahedron 2008, 64, 3457.
References and Notes
(1) For a recent review, see: Hall, D. G. In Boronic Acids -
Preparation, Applications in Organic Synthesis and
Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005,
1–99.
(2) (a) Darses, S.; Michaud, G.; Genet, J.-P. Tetrahedron Lett.
1998, 39, 5045. (b) Molander, G. A.; Rivero, M. R. Org.
Lett. 2002, 4, 107.
(15) a,b-Unsaturated esters were unreactive under the present
conditions.
(16) Typical Procedure for the Conjugated Alkynylation of
Acyclic Enones (Entry 4, Table 2)
Under an argon atmosphere, BF3·OEt2 (0.45 mmol, 63.9
mg), was added at r.t. to a stirred suspension of potassium
organotrifluoroborate 1b (0.6 mmol, 124.8 mg) in CH2Cl2
(3.0 mL). To the resulting mixture was added a solution of
enone 2b (0.3 mmol, 62.6 mg), and the reaction was allowed
to react for 25 min at r.t. The reaction was then quenched
with brine (2.0 mL) and then diluted with CH2Cl2 (6 mL).
(3) Based on a survey of the SciFinder Scholar (ACS), CAPLUS
and MEDLINE databases, September 2008.
(4) (a) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem.
1999, 1875. (b) Molander, G. A.; Katona, B. W.;
Machrouhi, F. J. Org. Chem. 2002, 67, 8416; while presently
Synlett 2009, No. 1, 51–54 © Thieme Stuttgart · New York

54
F. Bertolini, S. Woodward
LETTER
Evaporation of the dried (MgSO4) organic solution afforded
a crude reaction mixture which was purified by silica gel
column chromatography eluting with light petroleum–Et2O
(9:1) to give pure 1,3,5-triphenylpent-4-yn-1-one (4bb;
87%) as a white solid, mp 89–90 °C. IR (CHCl3): n = 3009,
1687, 1601, 1491, 1449, 1351, 1239 cm–1. 1H NMR (400
MHz, CDCl3): d = 3.47 (dd, 1 H, J1 = 16.4 Hz, J2 = 6.0 Hz),
3.71 (dd, 1 H, J1 = 16.4 Hz, J2 = 8.0 Hz), 4.66–4.73 (m, 1 H),
7.28–7.32 (m, 4 H), 7.38–7.43 (m, 4 H), 7.48–7.52 (m, 2 H),
7.57–7.61 (m, 3 H), 7.98–8.04 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 33.8, 47.3, 83.4, 90.8, 123.4, 127.1,
127.6, 127.9, 128.2, 128.7, 128.8, 131.7, 133.3, 136.9,
141.3, 197.15. ESI-MS (+): m/z = 333.12 [M + Na]+.
5-Methyl-7-phenylhept-6-yn-3-one (4ab, Entry 1, Table
2)
Yield 70%. Yellow liquid. IR (CHCl3): n = 3011, 2979,
2937, 1713, 1599, 1489, 1459, 1410, 1359, 1239, 1116 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12 (t, 3 H, J = 7.2 Hz),
1.30 (d, 3 H, J = 7.2 Hz), 2.48–2.55 (m, 2 H), 2.58 (dd, 1 H,
J1 = 16.4 Hz, J2 = 7.2 Hz), 2.76 (dd, 1 H, J1 = 16.4 Hz,
J2 = 6.8 Hz), 3.19–3.26 (m, 1 H), 7.27–7.32 (m, 3 H), 7.37–
7.41 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 7.7, 21.0,
22.4, 36.7, 49.1, 80.9, 93.2, 123.6, 127.4, 128.2, 131.6,
209.4. ESI-MS (+): m/z = 223.11 [M + Na]+.
5,8-Dimethylnon-8-en-6-yn-3-one (4ac, Entry 2, Table 2)
Yield 57%; pale yellow liquid. 1H NMR (400 MHz, CDCl3):
d = 1.09 (t, 3 H, J = 7.2 Hz), 1.22 (d, 3 H, J = 6.8 Hz), 1.89
(s, 3 H), 2.41–2.53 (m, 3 H), 2.69 (dd, 1 H, J1 = 16.0 Hz,
J2 = 7.2 Hz), 3.08–3.14 (m, 1 H), 5.15–5.20 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 7.7, 20.9, 22.3, 23.8, 36.6,
49.1, 82.1, 92.2, 120.8, 127.0, 209.4.
1,3-Diphenyldec-4-yn-1-one (4ba, Entry 3, Table 2)
Yield 75%; colorless oil. IR (CHCl3): n = 3008, 2933, 2861,
1686, 1600, 1494, 1449, 1351, 1255, 1181, 1024, 977 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, 3 H, J = 6.0 Hz),
1.22–1.39 (m, 4 H), 1.41–1.50 (m, 2 H), 2.19 (dt, 2 H,
J1 = 7.2 Hz, J2 = 2.4 Hz), 3.30 (dd, 1 H, J1 = 16.4 Hz,
J2 = 7.2 Hz), 3.57 (dd, 1 H, J1 = 16.4 Hz, J2 = 8.0 Hz), 4.40–
4.46 (m, 1 H), 7.23–7.30 (m, 1 H), 7.32–7.38 (m, 2 H), 7.43–
7.51 (m, 4 H), 7.54–7.61 (m, 1 H), 7.95–8.00 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 18.8, 22.2, 28.6,
31.1, 33.4, 47.7, 81.0, 83.7, 126.9, 127.5, 128.2, 128.3,
128.6, 133.1, 137.0, 142.0, 197.6. ESI-MS (+): m/z = 327.17
[M + Na]+.
1H NMR (400 MHz, CDCl3): d = 2.21 (s, 3 H), 2.93 (dd, 1 H,
J1 = 16.4 Hz, J2 = 6.0 Hz), 3.11 (dd, 1 H, J1 = 16.4 Hz,
J2 = 8.0 Hz), 4.44–4.48 (m, 1 H), 7.22–7.50 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 30.7, 33.6, 51.9, 83.3,
90.4, 123.3, 127.2, 127.5, 128.0, 128.3, 128.8, 131.7, 141.0,
205.8. ESI-MS (+): m/z = 271.10 [M + Na]+.
7-Methyl-4-phenyloct-7-en-5-yn-2-one (4cc, Entry 7,
Table 2)
Yield 54%; pale yellow liquid. IR (CHCl3): n = 3011, 1715,
1602, 1494, 1453, 1359, 1240, 1160, 900 cm–1. 1H NMR
(400 MHz, CDCl3): d = 1.91 (s, 3 H), 2.18 (s, 3 H), 2.85 (dd,
1 H, J1 = 16.4 Hz, J2 = 6.4 Hz), 3.01 (dd, 1 H, J1 = 16.4 Hz,
J2 = 8.0 Hz), 4.33 (dd, 1 H, J1 = 8.0 Hz, J2 = 6.4 Hz), 5.21–
5.28 (m, 2 H), 7.25–7.43 (m, 5 H). 13C NMR (100 MHz,
CDCl3): d = 23.7, 30.7, 33.5, 52.0, 84.5, 89.3, 121.3, 126.8,
127.1, 127.4, 128.7, 141.0, 205.8. ESI-MS (+): m/z = 235.11
[M + Na]+.
4-(Phenylethynyl)heptan-2-one (4db, Entry 8, Table 2)
Yield 55%; light yellow liquid.IR (CHCl3): n = 3010, 2961,
2933, 2874, 1713, 1600, 1490, 1442, 1362, 1239, 1163, 909
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.98 (t, 3 H, J = 6.0
Hz), 1.45–1.62 (m, 4 H), 2.25 (s, 3 H), 2.62 (dd, 1 H,
J1 = 16.4 Hz, J2 = 6.4 Hz), 2.78 (dd, 1 H, J1 = 16.4 Hz,
J2 = 7.6 Hz), 3.09–3.15 (m, 1 H), 7.28–7.31 (m, 3 H), 7.39–
7.42 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 13.9, 20.5,
27.6, 30.6, 37.0, 49.0, 81.9, 92.0, 123.6, 127.7, 128.2, 131.6,
207.0. ESI-MS (+): m/z = 237.12 [M + Na]+.
4-Pentylundec-5-yn-2-one (4ea, Entry 9, Table 2)
Yield 40% (conversion 75%); colorless liquid. IR (CHCl3):
n = 3007, 2958, 2932, 2860, 1713, 1602, 1466, 1361, 1239,
1163 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.82–0.93 (m,
6 H), 1.18–1.55 (m, 14 H), 2.15 (dt, 2 H, J1 = 6.8 Hz, J2 = 2.4
Hz), 2.20 (s, 3 H), 2.48 (dd, 1 H, J1 = 16.0 Hz, J2 = 6.0 Hz),
2.61 (dd, 1 H, J1 = 16.0 Hz, J2 = 8.0 Hz), 2.78–2.90 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.0 (2 C), 18.7, 22.2,
22.6, 26.9, 27.5, 28.7, 30.6, 31.0, 31.5, 35.2, 49.5, 81.9, 82.1,
207.4.
4-Hexylundec-5-yn-2-one (4fa, Entry 10, Table 2)
Yield 57%; pale yellow liquid. IR (CHCl3): n = 3010, 2958,
2931, 2859, 1713, 1602, 1466, 1361, 1239, 1162 cm–1. 1H
NMR (400 MHz, CDCl3): d = 0.81–0.92 (m, 6 H), 1.21–1.52
(m, 16 H), 2.15 (dt, 2 H, J1 = 7.2 Hz, J2 = 2.0 Hz), 2.20 (s, 3
H), 2.48 (dd, 1 H, J1 = 15.6 Hz, J2 = 6.4 Hz), 2.61 (dd, 1 H,
J1 = 15.6 Hz, J2 = 8.0 Hz), 2.78–2.87 (m, 1 H). 13C NMR
(100 MHz, CDCl3): d = 14.0, 14.1, 18.7, 22.2, 22.6, 27.2,
27.5, 28.8, 29.0, 30.6, 31.0, 31.8, 35.2, 49.5, 81.9, 82.1,
207.5. ESI-MS (+): m/z = 273.21 [M + Na]+.
6-Methyl-1,3-diphenylhept-6-en-4-yn-1-one (4bc, Entry
5, Table 2)
Yield 77%; solid; mp 44–46 °C. IR (CHCl3): n = 3009, 1687,
1600, 1494, 1450, 1351, 1255, 1023, 976, 900 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.86 (m, 3 H), 3.38 (dd, 1
H, J1 = 16.4 Hz, J2 = 6.4 Hz), 3.61 (dd, 1 H, J1 = 16.4 Hz,
J2 = 7.6 Hz), 4.57 (dd, 1 H, J1 = 7.6 Hz, J2 = 6.4 Hz), 5.17–
5.23 (m, 2 H), 7.24–7.30 (m, 1 H), 7.33–7.39 (m, 2 H), 7.44–
7.51 (m, 4 H), 7.57–7.62 (m, 1 H), 7.94–8.01 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 23.6, 33.6, 47.3, 84.6,
89.7, 121.2, 126.9, 127.1, 127.6, 128.2, 128.6, 128.7, 133.2,
136.9, 141.3, 197.2. ESI-MS (+): m/z = 297.12 [M + Na]+.
4,6-Diphenylhex-5-yn-2-one (4cb, Entry 6, Table 2)
Yield 65%; pale yellow liquid. IR (CHCl3): n = 3011, 1717,
1601, 1491, 1453, 1405, 1360, 1240, 1160, 1070, 1027 cm–1.
4-(Phenylethynyl)decan-2-one (4fb, Entry 11, Table 2)
Yield 48%; light yellow liquid. IR (CHCl3): 3011, 2930,
2858, 1714, 1601, 1490, 1466, 1362, 1161, 913 cm–1. 1H
NMR (400 MHz, CDCl3): d = 0.86–0.94 (m, 3 H), 1.25–1.41
(m, 6 H), 1.43–1.62 (m, 4 H), 2.20 (s, 3 H), 2.62 (dd, 1 H,
J1 = 16.4 Hz, J2 = 6.4 Hz), 2.78 (dd, 1 H, J1 = 16.4 Hz,
J2 = 7.6 Hz), 3.06–3.13 (m, 1 H), 7.28–7.33 (m, 3 H), 7.39–
7.43 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 14.1, 22.7,
27.3, 27.9, 29.0, 30.6, 31.8, 34.9, 49.0, 81.9, 92.1, 123.7,
127.7, 128.2, 131.6, 206.9. ESI-MS (+): m/z = 279.17 [M +
Na]+.
Synlett 2009, No. 1, 51–54 © Thieme Stuttgart · New York

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