Conjugate addition of a primary carbon radical to α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(00)00528-1

Triethylborane in the presence of trace oxygen was employed simultaneously as a radical initiator and carboxyl protecting group to promote the conjugate radical addition of 2-phenethyl iodide to α,β- unsaturated carboxylic acids in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00528-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3797–3800
Conjugate addition of a primary carbon radical to
α,β-unsaturated carboxylic acids
Baogen Wu, Bonnie A. Avery and Mitchell A. Avery
a
b
a,b,c,∗
a
Department of Medicinal Chemistry, University of Mississippi, PO Box 1848, University, Mississippi 38677-1848, USA
Department of Pharmaceutics, National Center for the Development of Natural Products, School of Pharmacy, University,
Mississippi 38677-1848, USA
b
c
Department of Chemistry, University of Mississippi, PO Box 1848, University, Mississippi 38677-1848, USA
Received 29 February 2000; revised 27 March 2000; accepted 30 March 2000
Abstract
Triethylborane in the presence of trace oxygen was employed simultaneously as a radical initiator and carboxyl
protecting group to promote the conjugate radical addition of 2-phenethyl iodide to α,β-unsaturated carboxylic
acids in good yields. © 2000 Elsevier Science Ltd. All rights reserved.
Over the last two decades, interest in free radical reactions in organic synthesis has greatly increased,
1
with many radical reaction types now providing useful synthetic strategies. Of various radical based
reactions, the 1,4-addition of carbon radicals to enones represents a well known subset. While the
synthetic applications of conjugate radical additions to α,β-unsaturated esters has also been studied,
little work has been reported in the area of direct conjugate radical addition to α,β-unsaturated carboxylic
2
3
acids. As part of ongoing efforts to develop direct methods for conjugate addition to eneoic acids, herein
we report the direct conjugate radical addition of phenethyl iodide to α,β-unsaturated acids enhanced by
triethylborane.
Employing routine conditions for effecting conjugate radical addition, a benzene solution of artemi-
sinic acid 1 containing a low concentration of tributyltin hydride was refluxed in the presence of AIBN
and 2-phenylethyl iodide. Under these conditions, the product 2 was formed in low yield (less than 5%)
4
(
Scheme 1). Triethylborane, which serves as one of several methods for the generation of radical species,
5
is an effective radical initiator for radical additions under mild conditions. When a small amount of
triethylborane was employed as a radical initiator in place of AIBN above, only starting material was
detected. However, with 1.2 mol equivalents of triethylborane, the reaction proceeded smoothly providing
2
in 72% yield as a mixture of diastereomers (R:S=2:1).
Table 1 shows some other examples of direct conjugate radical addition to α,β-unsaturated carboxylic
6
acids in the presence of triethylborane. When the reaction was performed under standard radical addition
∗
Corresponding author. Fax: 662-915-5638; e-mail: mavery@olemiss.edu (M. A. Avery)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00528-1
tetl 16807

3
798
Scheme 1.
conditions (Entries 1, 3 and 5, AIBN was used as an initiator), the yields were poor (less than 15% yield).
Substituents at the 2- or 3-position of the α,β-unsaturated acid gave comparable results (Entries 6, 7, 9
and 10), while the 2,3-disubstituted α,β-unsaturated carboxylic acid 3e gave a poor yield (Entry 8) of
conjugate addition product 4e. We noted that many of the yields were moderate after chromatography
despite a relatively clean TLC profile, while the isolated yield of product 2 starting from artemisinic acid
1
, a crystalline, nonvolatile acid with greater lipophilicity, was quite acceptable. Thus, purification of
a simple acid was studied in greater depth to estimate the loss due to conventional purification. Entry
gave 71% of 4a after flash chromatography on silica gel; however, careful quantitation of the crude
2
7
reaction product by HPLC methods revealed the yield to be 80%.
Table 1
Since alkyl radicals are generally nucleophilic, their addition to olefinic substrates would be enhanced
by electron-withdrawing substituents on the olefinic linkage.4,8 It has been reported that all acyloxy-
dialkylboranes are monomeric, or only very loosely self-associated in dilute solution, and generally
9
dimeric in the solid state. Therefore, when an α,β-unsaturated carboxylic acid (e.g. 1) is treated with
triethylborane, an acyloxydiethylborane (e.g. 5) should be formed leading to an expected decrease in the
electron density of its olefinic moiety and an increase in the radical addition rate to 5 leading to radical
6
(Scheme 2). It therefore seems possible that in the above reactions, triethylborane serves not only as a
radical initiator, but also to enhance the reactivity of the α,β-unsaturated carboxylic acid toward radical
addition. If the borate ester did not exert a beneficial influence in the addition step, one might expect the
silyl ester to undergo radical addition equally well. To gauge this, reaction of the diphenyl-tert-butylsilyl
3
(
DPS) ester of 1 (7) was studied with catalytic Et B and O , 1.7 equiv., PhCH CH I and 1.5 equiv. n-
3
2
2
2

3
799
Bu SnH (vide supra). While 8 was formed in modest yield in this case (40%), it was inferior to production
3
of 2 via the borate ester 5 (72%).
Scheme 2.
The secondary enhancing effect of preforming the borate ester might be to protect the n-Bu SnH from
3
reaction with the carboxyl group. In a separate experiment, 1 reacted slowly with n-Bu SnH to furnish a
3
stannyl carboxylate (NMR). Finally, the effect of the H-atom donor was briefly examined. In principle,
radical 6 could afford product 2 via a mechanism not involving n-Bu SnH. Reaction of 5, PhCH CH I
3
2
2
and varying amounts of Et B (catalytic O ) did not provide the product 2, indicating that a H-atom donor
3
2
was required in the reaction. If tris(trimethylsilyl)silane were used in place of tributylstannane in this
process, product 2 was formed, but in low yield (10%).
In summary, we have described a simple and efficient direct radical addition of a primary alkyl iodide
to α,β-unsaturated carboxylic acids enhanced by triethylborane. We have also found that the reaction
proceeded smoothly with a substituent in either the α- or β-position of the acid, while α,β-disubstituted
acid gave only poor yields of addition products.
Acknowledgements
This investigation received financial support from the UNDP/World Bank/WHO Special Programme
for Research and Training in Tropical Diseases (TDR), and from the NIAID. Special thanks go to Dr.
Richard Haynes for helpful discussions.
References
1
. For reviews, see: (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon–Carbon Bonds; Pergamon Press:
New York, 1986; (b) Curran, D. P. Synthesis 1988, 417–439; (c) Curran, D. P. Synthesis 1988, 489–513; (d) Jasperse, C.
P.; Curran, D. P.; Ferig, T. L. Chem. Rev. 1991, 91, 1237–1286; (e) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic Press: London, 1992; (f) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in
Organic Chemistry: John Wiley & Sons: New York, 1995; (g) Fallis, A. G.; Irina, M.; Brinza, I. M. Tetrahedron 1997, 53,
1
7 543–17 594; (h) Yet, L. Tetrahedron 1999, 55, 9349–9403.
2. (a) Vassen, R.; Runsing, J.; Shrf, H. D. Chem. Ber. 1986, 119, 3492–3497; (b) Adlington, R. M.; Baldwin, J. E.; Basak, A.;
Kozyrod, R. P. J. Chem. Soc., Chem. Commun. 1983, 944–945.
3
4
5
6
. Vroman, J. A.; Khan, I.; Avery, M. A. Tetrahedron Lett. 1997, 38, 6173–6176.
. For a review, see: Smadja, W. Synlett 1994, 1–26.
. Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1041–1044.
. General synthetic procedure: The acid (5 mmol) was added to a flame dried 250 mL two-necked round bottomed flask
under an atmosphere of Ar. Freshly distilled solvent (150 mL) was introduced, and a solution of triethylborane (6 mL, 1 M
in hexane, 1.2 equiv.) was added. The resulting mixture was stirred for 3 h at the indicated temperature shown in Table 1.

3
800
2
-Phenylethyl iodide (8.5 mmol, in 5 mL hexane) was added followed by the addition of a 0.1 mL solution of triethylborane
via a syringe containing a trace of oxygen. A solution of n-Bu SnH (2.2 g, 1.5 equiv. in 40 mL hexane) was then slowly
3
added via a syringe pump over a period of 10 h, and the reaction mixture was stirred for an additional 6 h. Following
evaporation of the solvent, the residue was dissolved in 10 mL of ether, and a 10 mL solution of saturated KF was added.
The mixture was stirred overnight, filtered and washed with ether. The ether solution was combined, concentrated to 20
mL, and stirred with 2N NaOH for 1 h. The layers were separated, and the aqueous layer was washed with ether (3×30
mL), and neutralized with 1N HCl. The aqueous layer was extracted with ether, and the combined ether extracts were
washed with brine and water, and then dried over MgSO
4
. Concentration and silica gel flash chromatography of the residue
gave the desired product. Known compounds had physical and spectroscopic properties in accord with literature reports,
−
1
and new compounds gave satisfactory analytical data. Compound 4c: IR (KBr) 3400–2500, 1707, 1603 1456 1077 cm
;
1
H NMR (CDCl
m), 1.23 (2H, m), 0.97 (3H, t, J=7.2 Hz); C NMR (CDCl
4.2, 14.1. Compound 4e: IR (KBr): 3400–2500, 1708, 1603, 1495, 1379 cm ; H NMR (CDCl
3H, m), 2.85 (1H, q, J=7.0 Hz), 2.59 (2H, t, J=8.2 Hz), 1.69 (1H, m), 1.53 (2H, m), 1.26 (2H, m), 0.95 (3H, q, J=7.02
3
): δ 7.27 (2H, m), 7.17 (3H, m), 2.61 (2H, t, J=8.4 Hz), 2.33 (2H, d, J=6.8 Hz), 1.87 (1H, m), 1.61 (2H,
13
3
) δ 179.8, 141.9, 128.2 (3C), 125.7 (2C), 45.2, 34.4, 33.8, 30.6,
1 1
−
2
3
): δ 7.27 (2H, m), 7.16
(
13
Hz); C NMR (CDCl
3
): δ 180.2, 142.2, 128.2 (3C), 125.2 (2C), 60.4, 35.4, 33.8, 30.7, 24.2, 20.9, 14.0. Compound 4g:
−1 1
IR (KBr) 3450–2500, 1699, 1601, 1346, 1250 cm ; H NMR (CDCl
3
): δ 8.14 (2H, m), 7.13–7.37 (7H, m), 3.10 (1H, m),
13
2
1
.90 (1H, m), 2.65–2.79 (3H, m), 2.05 (1H, t, J=8.2 Hz), 1.92 (1H, m); C NMR (CDCl
29.6 (2C), 128.5 (2C), 128.3 (2C), 126.2, 123.6 (2C), 45.9, 37.5, 33.2, 24.3.
3
): δ 180.5, 146.7, 146.4, 140.6,
7
. General analytical procedure: A Waters chromatography system (Waters, Milford, MA, USA) equipped with two 510
programmable pumps with a Rheodyne 7725I injector and a 486 tunable UV detector at 216 nm was used to quantitate
the compounds. The column selected was a Phenomenex 250×4.6 mm, reversed phase C-18 IBO-SIL silica column with
5
micron particle size (Phenomenex, Torrance, CA, USA). All injections were performed using a 20 µL loop and at a
flow rate of 1 mL/min. The chromatographic system was controlled using the 2010 Millennium chromatography (Waters,
Milford, MA, USA) manager software (version 2.10) loaded on a Digital Venturis computer (Digital, Maynard, MA, USA).
The mobile phase was prepared by mixing HPLC grade acetonitrile (Fisher Scientific, Fair Lawn, NJ, USA) and nanopure
water (Barnstead, Neuton, MA, USA) in a 70:30 ratio. The two solvents were premixed then filtered and degassed in a
water vacuum assembly for about 5 min. To a clean, dry 10 mL volumetric flask was added an accurately weighed sample
(approximately 40 mg) of the compound, which was then dissolved in 1 mL of acetonitrile and diluted to 10 mL with the
mobile phase to make a stock solution. Four calibration standards were prepared by diluting the stock solution with the
mobile phase. The calibration curve was generated by plotting the logarithm of area under the curve versus the logarithm
of concentration. Regression analysis was performed on the data points using the Cricket Graph software Version 1.3.2
(Cricket Graph, Malvern, PA, USA). The equation of the regression line was used to quantitate unknown control samples.
8
9
. Curran, D. P.; Qi, H.; Porter, N. A.; Su, Q.; Wu, W. Tetrahedron Lett. 1993, 34, 4489–4492; For Lewis acid enhanced
reactivity of α,β-unsaturated esters and amides, see: Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J. Org.
Chem. 1995, 60, 3576–3577. For the use of BEt
Chem. Soc., Chem. Commun. 1993, 429–430.
3
for intramolecular cyclization, see: Clive, D. J.; Postema, M. H. D. J.
. Yalpani, M.; Boese, R.; Seevogel, K.; Kster, R. J. Chem. Soc., Dalton Trans. 1993, 47–50.