A practical, two-step synthesis of 2-substituted 1,3-butadienes

Full text of DOI:10.1021/jo802737x

SCHEME 1. Two-Step Diene Synthesis
A Practical, Two-Step Synthesis of 2-Substituted
1,3-Butadienes
Sushmita Sen, Swapnil Singh, and Scott McN. Sieburth*
Department of Chemistry, Temple UniVersity, 1901 North
13th Street, Philadelphia, PennsylVania 19122
TABLE 1. Cuprate Addition to 1,4-Dibromo-2-butene 1,
Dehydrohalogenation of 3, and Isolation of 4 as Diels-Alder Adduct
5a
scott.sieburth@temple.edu
ReceiVed December 16, 2008
R)
3 (%)
4 (%)
5 (%)
R ) PhCH2
n-C6H13
i-Bu
i-Pr
c-C6H11
3a (70)c
3b (74)
3c (75)
3d (79)
3e (72)
5a (62)
5b (51)
5c (67)
5d (72)
5e (71)
4c (52)
4d (30-77)d
A two-step procedure for preparing 2-alkyl-1,3-butadienes
is described. Cuprate addition to commercially available 1,4-
dibromo-2-butene yields 3-alkyl-4-bromo-1-butene, a product
of SN2′ substitution. Dehydrohalogenation gives 2-alkyl-1,3-
butadienes.
a Isolated yields. b reactions utilized 1.3 equiv of Grignard reagent in
diethyl ether at 0 °C; 3-50% CuI relative to the amount of Grignard
reagent used. c Product contaminated with dibenzyl; ratio determined by
1H NMR. d See Table 2 for details.
One of the fundamental building blocks of organic chemistry
is the 1,3-diene.1 Butadienes substituted at C-2 are a pivotal
component of our new method for constructing optically active
3-alkyl-4-silyl-1-butenes, but few 2-alkyl-1,3-butadienes are
commercially available.2 A broad set of methods have been
described for preparation of substituted 1,3-dienes;3,4 however,
a review of these procedures with a goal of generating simple
2-substituted derivatives in multigram quantities found them to
be neither simple nor amenable to scaleup, and this led us to
consider alternative procedures that would allow routine syn-
thesis of these compounds. We report here our investigation of
a two-step conversion of 1,4-dibromo-2-butene 1, Scheme 1.
Bromination of 1,3-butadiene and distillation of the product
yields the crystalline trans-1,4-dibromo-3-butene 1,5 a product
that is also commercially available. This bis-allylic bromide 1
was reported to react with alkyl Grignard reagents, forming
almost exclusively SN2′ product 3.6 This reaction was also
reported for benzyl Grignard in the presence of catalytic
copper(I) iodide.7,8 We noted that dehydrohalogenation of 3
would then yield a direct route to 2-substituted 1,3-dienes 4.
Treatment of a THF solution of dibromide 1 with commercial
benzylmagnesium bromide in the presence of CuI was found
to yield a mixture of both SN2 and SN2′ products. In contrast,
selectivity for SN2′ was was high in diethyl ether, which was
used in all subsequent reactions, Table 1. Previous studies
utilized ether6 or mixtures of ether and THF.7 For primary and
secondary alkyl Grignard reagents, 3-5% CuI was often found
to be adequate, but with the benzyl Grignard reagent 20% CuI
was required to achieve a good yield, and the isopropyl Grignard
reagent required 50% CuI for the preparative procedure.
Dehydrohalogenation of 3 with DBU in dichloromethane at
reflux gave complete consumption of the starting bromide and
formation of 1,3-diene product in good yield.9 To ascertain the
yield of the volatile 1,3-diene product 4, it was trapped as the
N-phenylmaleimide (NPM) Diels-Alder adduct 5.10 In all cases,
the yield of this two-step process was good (51-72%).
(1) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley-
Interscience: New York, 1990. (b) Mehta, G.; Rao, H. S. P. In The Chemistry of
Dienes and Polyenes; Rappoport, Z., Eds.; John Wiley & Sons: New York, 1997;
Vol. 1, pp 359-480.
(2) Sen, S.; Purushotham, M.; Qi, Y.; Sieburth, S. McN. Org. Lett. 2007, 9,
4963–4965.
(3) Review: Mehta, G.; Rao, H. S. P. In The Chemistry of Dienes and
Polyenes; Rappoport, Z., Eds.; John Wiley & Sons: New York, 1997; Vol. 1,
pp 359-480.
(4) For examples, see: (a) Braun, J. v.; Keller, W. Chem. Ber. 1931, 64B,
2617–2621. (b) Marvel, C. S.; Myers, R. L.; Saunders, J. H. J. Am. Chem. Soc.
1948, 70, 1694–1699. (c) Overberger, C. G.; Fischman, A.; Roberts, C. W.;
Arond, L. H.; Lal, J. Am. Chem. Soc. 1951, 73, 2540–2543. (d) Aufdermarsh,
C. A. J. Org. Chem. 1964, 29, 1994–1996. (e) Kaempf, B.; Kieffer, R. Bull. Soc
Chim. Fr. 1967, 3062–3063. (f) Nunomoto, S.; Yamashita, Y. J. Org. Chem.
1979, 44, 4788–4791. (g) Brown, P. A.; Jenkin, P. R. Tetrahedron Lett. 1982,
23, 3733–3734. (h) Sahlberg, C.; Quader, A.; Claesson, A. Tetrahedron Lett.
1983, 24, 5137–5138. (i) Djahanbini, D.; Cazes, B.; Gore, J. Tetrahedron 1984,
40, 3645–3655. (j) Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. 1985,
58, 1942–1945. (k) Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.;
Hutchinson, J.; Iyer, R.; Laffitte, J. A.; Wall, A. J. Am. Chem. Soc. 1986, 108,
4568–4580. (l) Arenz, T.; Vostell, M.; Frauenrath, H. Synlett 1991, 23–24. (m)
Brown, P. A.; Bonnert, R. V.; Jenkins, P. R.; Lawrence, N. J.; Selim, M. R.
J. Chem. Soc., Perkin Trans. 1 1991, 1893–1900. (n) Katritzky, A. R.; Serdyuk,
L.; Toader, D.; Wang, X. J. Org. Chem. 1999, 64, 1888–1892. (o) Trost, B. M.;
Pinkerton, A. B.; Seidel, M. J. Am. Chem. Soc. 2001, 123, 12466–12476. (p)
Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235–2238. (q) Diver, S. T.;
Giessert, A. J. Synthesis 2003, 466–471.
(5) (a) Shantz, E. M. J. Am 1946, 68, 2553–2557. (b) Hatch, L. F.; Gardner,
P. D.; Gilbert, R. E. J. Am. Chem. Soc. 1959, 81, 5943–5946.
(6) Mesnard, D.; Miginiac, L. Compt. Rend. 1973, 277, 567–560.
(7) Jennings-White, C.; Almquist, R. G. Tetrahedron Lett. 1982, 23, 2533–
2534.
(8) Recently copper thiophene carboxylate has been found to provide very
high SN2′ chemoselectivity: (a) Falciola, C. A.; Tissot-Croset, K.; Alexakis, A.
Angew. Chem., Int. Ed. 2006, 45, 5995–5998. (b) Falciola, C. A.; Alexakis, A.
Angew. Chem., Int. Ed. 2007, 46, 2619–2622.
(9) (a) Oediger, H.; Mo¨ller, F.; Eiter, K. Synthesis 1972, 59, 1–598. (b)
Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
2884 J. Org. Chem. 2009, 74, 2884–2886
10.1021/jo802737x CCC: $40.75 2009 American Chemical Society
Published on Web 03/04/2009

TABLE 2. Triisopropylsilanol-Catalyzed Dehydrohalogenation
5.19 (d, 1H, J ) 7.2 Hz), 5.16 (d, 1H, J ) 13.5 Hz), 3.44 (m, 2H),
2.40 (m, 1H), 1.63 - 1.26 (m, 10H), 0.93 (t, 3H, J ) 6 Hz). 13C
NMR (75 MHz, CDCl3): δ 139.7, 116.6, 45.6, 38.9, 32.9, 31.7,
29.7, 26.8, 22.7, 14.1. IR (neat): 2850, 2960, 1620, 910, 980, 675
cm -1. Exact mass (MH+): calcd for C10H20Br 221.0728, found
221.0720.
solvent
distilled yield (%)
3-(Bromomethyl)-5-methylhex-1-ene (3c).7,8 The procedure for
3d using isobutylmagnesium chloride gave 3c as a colorless oil
DMF
77
68
60
50
a
DMPU
xylene
diglyme
THF
1
(3.3 g, 75%). H NMR (300 MHz, CDCl3): δ 5.45 (m, 1H), 4.98
(m, 2H), 3.22 (m, 2H), 2.31 (m, 1H), 1.46 (m, 1H), 1.20 (m, 2H),
0.75 (d, 3H, J ) 6.6 Hz), 0.71(d, 3H, J ) 6.6 Hz). 13C NMR (75
MHz, CDCl3): δ 140.1, 117.0, 43.9, 42.6, 39.8, 25.6, 23.7, 22.1.
DBU
30
IR (neat): 3095, 2970, 1630, 1480, 1345, 1360, 1176 cm-1
.
(1-Bromobut-3-en-2-yl)cyclohexane (3e).8 A 0 °C mixture of
cyclohexylmagnesium chloride (2 M, 15 mL, 30 mmole) and CuI
(0.16 g, 0.9 mmole) in ether (10 mL) was stirred under argon for
2 h and then transferred via cannula to a -78 °C solution of 1,4-
dibromo-2-butene 1 (5.0 g, 23 mmol) in ether (75 mL). The
resulting dark mixture was allowed to warm to rt over a period of
6 h. Aqueous ammonium chloride was added, and the aqueous
phase was extracted with ether (3 × 50 mL). The combined organic
phases were washed with brine (2 × 30 mL), dried over magnesium
sulfate, concentrated, and distilled under vacuum (60-75 °C/10
a Product could not be separated from solvent.
In addition to the DBU conditions, we also evaluated
Soderquist’s triisopropylsilanol-catalyzed KOH method with
2-isopropyl-1,3-butadiene as the product.11 In this case, the
reactions were run on a larger scale (ca. 25 mmol) and the diene
was distilled. To enhance purification of the product (bp )
85-87 °C4a,b), higher boiling solvents were used, and the results
are shown in Table 2. Consistent with the findings of Soderquist,
use of DMF as solvent gave a good isolated yield of the diene.
We observed traces of a contaminant, however, tentatively
identified as dimethylamine. In an attempt to avoid this
byproduct, other solvents were evaluated, but none were as
effective as DMF. THF as solvent gave the desired product 4d,
but this could not be separated from the THF.
Overall, this two-step process is easily conducted on a
multigram scale. Beginning with the commercially available 1,4-
dibromo-2-butene 1, alkyl Grignard reagents readily yield the
SN2′ product 3. Dehydrohalogenation of the primary halide can
be effectively conducted with DBU or Soderquist’s reagent.
When low molecular weight diene products require isolation,
Soderquist’s reagent is preferred. Where isolation of the diene
is not required or the product is less volatile, the DBU method
is simple and effective.
1
mmHg) to give 3e as a colorless liquid (3.6 g, 73%). H NMR
(300 MHz, CDCl3): δ 5.70 (m, 1H), 5.20 (d, 1H, J ) 10.5 Hz),
5.14 (d, 1H, J ) 16.5 Hz), 3.51 (m, 2H), 2.22 (m, 1H), 1.81-1.73
(m, 5H), 1.29-1.21 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 138.2,
117.4, 65.9, 51.4, 39.6, 36.8, 30.8, 26.3. IR (neat): 2850, 2932,
1605, 1445, 1234, 1164, 970 cm-1
.
2-Isobutyl-1,3-butadiene (4c). To a solution of 3-(bromo-
methyl)-5-methylhex-1-ene (5.0 g, 26 mmol) in CH2Cl2 (90 mL)
was added DBU (5.4 g, 39 mmol), and the mixture was heated to
reflux for 8 h. The mixture was cooled and washed with 10% HCl
(20 mL), and the aqueous phase was extracted with CH2Cl2 (3 ×
20 mL). The combined organics were dried over sodium sulfate
and filtered. The solvent was removed by Kugelrohr distillation to
give the diene as a colorless oil (1.5 g, 52%). 1H NMR (300 MHz,
CDCl3): δ 6.30 (dd, 1H, J ) 10.8, 17.7 Hz), 5.21-4.86 (m, 4H),
2.01 (d, 2H, J ) 7.2 Hz), 1.73 (m, 1H), 0.80 (d, 6H, J ) 6.6 Hz).
13C NMR (75 MHz, CDCl3): δ 145.4, 139.1, 116.7, 113.3, 41.3,
26.7, 22.7. IR (neat): 3190, 2879, 1280 cm-1
.
Dehydrohalogenation with TIPSOH: 2-Isopropyl-1,3-buta-
diene (4d).4b,c,e To a solution of KOH (3.14 g, 48 mmol) in DMF
(70 mL) was added triisopropylsilanol (39 mg, 0.2 mmol). After
the mixture was stirred at rt for 1 h, 3-bromomethyl-4-methylpent-
1-ene (5 g, 28 mmol) was added dropwise. After being stirred for
an additional 12 h, the reaction was judged complete by TLC and
the product was distilled directly from the reaction mixture using
a Kugelrohr apparatus at 70 °C to give 3d as a colorless oil (2.08
Experimental Section
3-Bromomethyl-4-methylpent-1-ene (3d).6,12 To a -10 °C
mixture of CuI (3.31 g, 17.5 mmol) and 1,4-dibromo-2-butene (4.8
g, 23 mmol) in ether (35 mL) was added dropwise a freshly
prepared solution of isopropylmagnesium bromide in ether (2.5 M,
14 mL, 35 mmol). The reaction was followed by TLC (hexanes),
and after consumption of 1 the mixture was diluted with saturated
NH4Cl solution. The aqueous phase was extracted with ether (2 ×
20 mL), and the combined organics were washed with brine (20
mL), dried over MgSO4, and concentrated. Kugelrohr distillation
(100-120 °C/7 mmHg) gave 3d as a colorless oil (3.2 g, 79%).
1H NMR (400 MHz, CDCl3): δ 5.57 (m, 1H), 5.05 (m, 2H), 3.40
(m, 2H), 2.11 (m, 1H), 1.86(m, 1H) 0.83 (d, J ) 6.9 Hz, 3H), 0.76
(d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 138.9, 118.2,
1
g, 77%). H NMR (300 MHz, CDCl3): δ 6.24 (dd, 1H, J ) 10.8,
17.7 Hz), 5.15 (d, 1H, J ) 17.4 Hz), 5.03 (m, 3H), 2.64 (septet,
1H, J ) 6.9 Hz), 0.99 (d, 6H, J ) 6.9 Hz). 13C NMR (75 MHz,
CDCl3): δ 153.4, 139.5, 112.9, 112.3, 29.5, 22.1. IR (neat): 3221,
3073, 2926, 2852, 1618, 1441, 1312 cm-1
.
Dehydrohalogenation and Diels-Alder Reaction: 5-Cyclo-
hexyl-3a,4,7,7a-tetrahydro-2-phenyl-2H-isoindole-1,3-dione (5e).
To a solution of 3e (1.0 g, 4.6 mmol) in CH2Cl2 (18 mL) was added
DBU (1.1 g, 7.2 mmol) and the solution was heated to reflux for
8 h. The mixture was cooled, washed with 10% HCl (4 mL), dried
over sodium sulfate, and filtered.
52.2, 37.4, 29.9, 21.1, 18.9. IR (neat): 2960, 1670, 1486, 905, 790
-1
cm
.
3-(Bromomethyl)non-1-ene (3b). The procedure for 3d using
1-hexylmagnesium bromide and 1.0 g of 1 gave 3b as a colorless
1
To this filtrate was added N-phenylmaleimide (1.6 g, 9.2 mmol),
and the resulting solution was stirred at rt for 24 h. Saturated
ammonium chloride was added, and the aqueous phase was
extracted with CH2Cl2 (10 × 3 mL). The combined organic extracts
were dried over sodium sulfate and concentrated. Purification by
flash chromatography (1:4 ethyl acetate/hexanes) gave 5e as a
colorless solid (1.01 g, 71%, for two steps). Rf ) 0.25 (1:4 ethyl
oil (0.76 g, 74%). H NMR (300 MHz, CDCl3): δ 5.67 (m, 1H),
(10) (a) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41,
152–154. (b) Caballero, E.; Alonso, D.; Pela´ez, R.; Alvarez, C. A. A.; Puebla,
´
P.; Sanz, F.; Medarde, M.; Tome´, F. Tetrahedron 2005, 61, 6871–6878.
(11) Soderquist, J. A.; Vaquer, J.; Diaz, M. J.; Rane, A. M.; Bordwell, F. G.;
Zhang, S. Tetrahedron Lett. 1996, 37, 2561–2564.
(12) DeGraw, J. I.; Almquist, R. G.; Hiebert, C. K.; Colwell, W. T.; Crase,
J.; Hayano, T.; Judd, A. K.; Dousman, L.; Smith, R. L.; Waud, W. R.; Uchida,
I. J. Med. Chem. 1997, 40, 2386–2397.
1
acetate/hexanes). H NMR (300 MHz, CDCl3): δ 7.39-7.11 (m,
5H), 5.50 (m, 1H), 3.16 (m, 2H), 2.62(m, 2H), 2.17 (m, 2H), 1.88
J. Org. Chem. Vol. 74, No. 7, 2009 2885

(m, 1H), 1.64-1.59 (m, 5H), 1.15-1.05 (m, 5H). 13C NMR (75
MHz, CDCl3) δ 179.6, 179.4, 146.0, 127.9, 129.2, 128.6, 126.4,
118.1, 55.2, 40.0, 39.8, 32.0, 27.7, 27.5, 26.8, 23.4. IR (neat): 2940,
1705, 1690, 1410, 1230, 760 cm-1. Exact mass (MH+): calcd for
C20H24NO2 310.1802, found 310.1806.
5-Benzyl-3a,4,7,7a-tetrahydro-2-phenyl-2H-isoindole-1,3-di-
one (5a).4n Following the procedure for 5e, 2-(bromomethyl)-3-
buten-1-yl-benzene 3a (1.0 g, 4.4 mmol) gave 5a (0.86 g, 62%).
Rf ) 0.24 (1:4 ethyl acetate/hexanes). 1H NMR (300 MHz, CDCl3):
δ 7.56-7.02 (m, 10H), 5.58 (m, 1H), 3.27 (s, 2H), 3.15 (m, 2H),
2.62-2.49 (m, 2H), 2.22 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
178.1, 177.7, 138.9, 130.9, 128.0, 127.9, 127.6, 127.4, 125.3, 120.5,
mmol) gave 5c (0.98 g, 67%). Rf ) 0.23 (1:4 ethyl acetate/hexanes).
1H NMR (300 MHz, CDCl3): δ 7.14-7.40 (m, 5H), 5.54 (m, 1H),
3.17 (m, 2H), 2.51-2.56 (m, 2H), 2.23 (m, 2H), 1.82 (d, 2H, J )
6.9 Hz), 1.63 (m, 1H), 0.75 (d, 3H, J ) 6.3 Hz), 0.72 (d, 3H, J )
6.6 Hz). 13C NMR (75 MHz, CDCl3): δ 179.2, 139.8, 129.1, 128.5,
126.38, 126.3, 121.2, 47.0, 39.8, 39.4, 27.7, 25.7, 24.4, 22.5. IR
(neat): 2945, 1710, 1690, 1405, 1230 cm-1. Exact mass (MH+):
calcd for C18H22NO2 284.1645, found 284.1650.
3a,4,7,7a-Tetrahydro-5-isopropyl-2-phenyl-2H-isoindole-1,3-
dione (5d).4n Following the procedure for 5e, compound 3d (1.0
g, 4.4 mmol) gave 5d (1.1 g, 72%). Rf ) 0.25 (1:4 ethyl acetate/
hexanes). 1H NMR (300 MHz, CDCl3): δ 7.38-7.12 (m, 5H), 5.56
(m, 1H), 3.19 (m, 2H), 2.64 (m, 2H), 2.20 (m, 3H), 0.90 (d, 6H, J
) 6.9 Hz). 13C NMR (75 MHz, CDCl3): δ 179.5, 179.2, 146.6,
132.1, 129.1, 128.6, 126.4, 117.1, 40.0, 39.8, 34.6, 26.6, 24.3, 20.9,
20.8. IR (neat): 1710, 1685, 1495, 1350 cm-1. Exact mass (MH+):
calcd for C17H20NO2 270.1496, found 270.1479.
42.7, 38.8, 38.6, 26.6, 23.3. IR (neat): 3028, 2938, 2842, 1710,
-1
1700, 1456, 1186, 1070 cm
.
5-Hexyl-3a,4,7,7a-tetrahydro-2-phenyl-2H-isoindole-1,3-di-
one (5b). Following the procedure for 5e, compound 3b (1.0 g,
4.6 mmol) gave 5e (0.72 g, 51%). Rf ) 0.27 (1:4 ethyl acetate/
hexanes). 1H NMR (300 MHz, CDCl3): δ 7.27-7.13 (m, 5H), 5.53
(m, 1H), 3.17, (m, 2H), 2.60 (m, 2H), 2.21 (m, 2H), 1.95 (t, 2H, J
) 7.5 Hz), 1.31-1.16, (m, 8H), 0.78 (t, 3H, J ) 6.3 Hz). 13C NMR
(75 MHz, CDCl3): δ 178.4, 139.9, 131.0, 128.0, 127.4, 125.3, 118.6,
38.7, 38.4, 36.1, 30.5, 28.1, 26.7, 26.3, 23.3, 21.5, 13.0. IR (neat):
2940, 1700, 1410, 1230, 760 cm -1. Exact mass (MH+): calcd for
C20H26NO2 312.1964, found 312.1974.
Acknowledgment. This work was supported by a grant from
the NIH (5R01GM076471).
Supporting Information Available: Proton and carbon NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
3a,4,7,7a-Tetrahydro-5-isobutyl-2-phenyl-2H-isoindole-1,3-di-
one (5c). Following the procedure for 5e, compound 3c (1.0 g, 5.2
JO802737X
2886 J. Org. Chem. Vol. 74, No. 7, 2009