Studies on highly stereoselective addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. An efficient synthesis of 3-(methoxycarbonyl)-2-halo-1,3(Z)-dienes

Article abstract of DOI:10.1021/jo070725m

(Chemical Equation Presented) 3-(Methoxycarbonyl)-2-halo-1,3(Z)-dienes were prepared highly stereoselectively via S_N2′-type addition-elimination reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX. These products may easily undergo Negishi

Full text of DOI:10.1021/jo070725m

TABLE 1. Preparation of 3-(Methoxycarbonyl)-1,2-allen-4-ols
Studies on Highly Stereoselective
Addition-Elimination Reactions of
3-(Methoxycarbonyl)-1,2-allen-4-ols with MX. An
Efficient Synthesis of
3-(Methoxycarbonyl)-2-halo-1,3(Z)-dienes
Entry
R
time (h)
yield of 3 (%)
Youqian Deng, Xin Jin, and Shengming Ma*
1
2
3
4
5
6
C2H5
30
36
14
36
22
24
59 (3a)
61 (3b)
83 (3c)
59 (3d)
78 (3e)
68 (3f)
Laboratory of Molecular Recognition and Synthesis, Department
of Chemistry, Zhejiang UniVersity, Hangzhou 310027,
Zhejiang, People’s Republic of China
n-C3H7
i-C3H7
n-C5H11
Ph
masm@mail.sioc.ac.cn
p-CH3C6H4
ReceiVed April 6, 2007
of alka-2,3-dienylamines can afford 2-amido-1,3-dienes highly
stereoselectively (g95/5).6 Hammond and Shen reported an
efficient synthesis of 1,1-difluoro-2-aryl or vinyl-substituted
3-silyl-1,3-dienes7 from 2,3-butadienyl bromides via palladium-
catalyzed cross-coupling reactions with aryl halides or boronic
acids and terminal alkynes. We also found a highly regio- and
stereoselective protocol for the synthesis of 2(E),4-alkadienoates1
via the Pd(0)-catalyzed reaction of aryl halides with 3,4-
alkadienoates. 2,3-Allenylic trimethylsilyl ether can react with
TiCl4 forming 2-chloro-1,3-butadienes.8 Rearrangement of
tertiary R-allenic carbamates may afford 2-O-carbamoyl-4,4-
disubstituted 1,3-dienes9 with poor stereoselectivity. Recently,
Alcaide et al. reported a novel stereoselective synthesis of 1,2,3-
trisubstitued 1,3-dienes10 through [3,3]-sigmatropic rearrange-
ments in R-allenic methanesulfonates. The reactions of 2-(tri-
methylsilyl)-2,3-allenols with lithium aluminum hydride afforded
2-(trimethylsilyl)-1,3-butadienes11 with rather poor stereoselec-
tivity. We have observed that the reaction of 1-aryl-2,3-allenols
with lithium halides in HOAc affords 1-aryl-3-halo-1,3-dienes12
in the absence of any Pd catalyst; however, no reaction was
observed with 1-alkyl or perfluoroalkyl-2,3-allenols. We wish
to report here a highly stereoslective SN2′-type addition-
elimination reaction of MX and 3-(alkoxycarbonyl)-1,2-allen-
4-ols with an alkyl or aryl group at the 4-position.
3-(Methoxycarbonyl)-2-halo-1,3(Z)-dienes were prepared
highly stereoselectively via SN2′-type addition-elimination
reactions of 3-(methoxycarbonyl)-1,2-allen-4-ols with MX.
These products may easily undergo Negishi or Sonogashira
coupling reactions to yield a series of stereodefined polysub-
stituted (E)-1,3-dienes.
Stereoselective synthesis of conjugated 1,3-dienes is of current
interest1 since they are very important intermediates in organic
synthesis.2 It was observed that the reactions of the esters of
2,3-allenols in the presence of Pd(0) catalysts with hard
carbonucleophiles such as Mg,3a Zn,3b and Cu3b reagents may
afford 1,3-dienes with poor stereoselectivity. Recently, Ba¨ckvall
and Horva´th reported a Pd-catalyzed reaction of R-allenic
acetates with LiBr to afford (1Z,2E)-2-bromo-1,3-dienes4 in
good yields with good stereoselectivity (g86). The carbonylation
of allenyl methyl carbonates in CH3OH in the presence of Pd-
(PPh3)4 may yield methyl 2-(methoxycarbonyl)-1,3-dienes in
high yields with rather poor stereoselectivity.5 The carbonylation
Synthesis of Starting Materials. 3-(Methoxycarbonyl)-1,2-
allen-4-ols 3 are easily available from a modified one-step high-
yielding reaction of 3-(methoxycarbonyl) propargyl bromide 1,13
aldehydes 2, and SnCl2/NaI14 in DMPU15 (Table 1).
Addition-Elimination Reactions of 3-(Methoxycarbonyl)-
1,2-allen-4-ols with MX. Our initial work began with the
reaction of 3-(methoxycarbonyl)-1,2-heptadien-4-ol 3b with NaI.
* Corresponding author. Tel.: 86-21-549-25147; fax: 86-21-641-67510.
(1) For summary of some representative reports on the synthesis of 1,3-
dienes, see the references cited in: Fu, C.; Ma, S. Org. Lett. 2005, 7, 1707.
(2) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
John Wiley: New York, 1990. (b) Fringuelli, F.; Taticcchi, A. Diels-Alder
Reaction. Selected Practical Methods; John Wiley: New York, 2002. (c)
Wasserman, A. Diels-Alder Reactions; Elsevier: Amsterdam, 1965. (d)
Wallweben, H. Diels-Alder Reaction; Thieme: Stuttgart, Germany, 1972.
(e) Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK 1991, Vol. 5, Chapter 4.1,
pp 315-400. (f) Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Ch. 4.4,
pp 513-550. (g) Mehta, G.; Rao, S. P. In The Chemistry of Dienes and
Polyenes; Rappoport, Z., Ed.; John Wiley: New York, 1997; Ch. 9, pp
361-467.
(6) Imada, Y.; Vasapollo, G.; Alper, H. J. Org. Chem. 1996, 61, 7982.
(7) Shen, Q.; Hammond, G. B. Org. Lett. 2001, 3, 2213.
(8) Pornet, J. Tetrahedron Lett. 1981, 22, 453.
(9) Friesen, R. W.; Kolaczewska, A. E.; Khazanovich, N. Tetrahedron
Lett. 1992, 33, 6715.
(10) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C. Eur.
J. Org. Chem. 2005, 98.
(11) Wang, K. K.; Nikam, S. S.; Marcano, M. M. Tetrahedron Lett. 1986,
27, 1123.
(12) Ma, S.; Wang, G. Tetrahedron Lett. 2002, 43, 5723.
(13) (a) Larock, R. C.; Liu, C. J. Org. Chem. 1983, 48, 2151. (b)
Maclnnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987, 1077.
(14) For the reactions of propargyl iodides with aldehydes in DMI, see:
Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 621.
(15) For the reaction of 3-(methoxycarbonyl) propargyl iodide with
aldehydes in DMPU, see: Winkler, J. D.; Quinn, K. J.; MacKinnon, C. H.;
Hiscock, S. D.; McLaughlin, E. C. Org. Lett. 2003, 5, 1805.
(3) (a) Djahanbini, D.; Cazes, B.; Gore, J. Tetrahedron 1987, 43, 3441.
(b) Kleijn, H.; Wertmijze, H.; Meijer, J.; Vermeer, P. Recl. TraV. Chim.
Pays-Bas. 1983, 102, 378.
(4) Horva´th, A.; Ba¨ckvall, J.-E. J. Org. Chem. 2001, 66, 8120.
(5) Nokami, J.; Maihara, A.; Tsuji, J. Tetrahedron Lett. 1990, 31, 5629.
10.1021/jo070725m CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
J. Org. Chem. 2007, 72, 5901-5904
5901

TABLE 2. Reaction of 3-(Methoxycarbonyl)-1,2-heptadien-4-ol
with NaI
TABLE 4. Reactions of 3-(Methoxycarbonyl)-1,2-allen-4-ols with
MX
entry
solvent
NaI (equiv) temp (°C) time (h) yield of 4ba (%)
entry
R
solvent MX (equiv) time (h) yield of 4 (%)
1
2
3
4
5
6
7
CH3COOH
Ac2O
HI
1.2
1.2
reflux
110
80
reflux
reflux
reflux
rt
1
1
3
1
1
trace
41
trace
61
73
68
1
2
3
4
5
6
7
8
9
C2H5 (3a)
C2H5 (3a)
C2H5 (3a)
n-C3H7 (3b)
n-C3H7 (3b)
n-C3H7 (3b)
i-C3H7 (3c)
i-C3H7 (3c)
i-C3H7 (3c)
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
NaI (2.0)
1
2
3
1
2
6
2
1
2
1
3.5
4
1
1
4
2
3
4
1
1
1
50 (4aa)
56 (4ab)
39 (4ac)
73 (4ba)
76 (4bb)
55 (4bc)
53 (4ca)
64 (4cb)
39 (4cc)
75 (4da)
67 (4db)
47 (4dc)
0 (4ea)a
44 (4eb)
26 (4ec)
40 (4ea)
44 (4eb)
30 (4ec)
73 (4fa)
62 (4fb)
59 (4fc)
LiBr‚H2O (2.0)
LiCl‚H2O (4.0)
NaI (2.0)
LiBr‚H2O (2.0)
LiCl‚H2O (4.0)
NaI (2.0)
LiBr‚H2O (2.0)
LiCl‚H2O (4.0)
NaI (2.0)
LiBr‚H2O (2.0)
LiCl‚H2O (4.0)
NaI (2.0)
TFAa
TFA
1.2
2.0
4.0
2.0
TFA
TFA
1
24
32
a TFA ) CF3COOH.
10 n-C5H11 (3d)
11 n-C5H11 (3d)
12 n-C5H11 (3d)
13 Ph (3e)
14 Ph (3e)
15 Ph (3e)
16 Ph (3e)
17 Ph (3e)
18 Ph (3e)
SCHEME 1
LiBr‚H2O (2.0)
LiCl‚H2O (4.0)
HOAc NaI (2.0)
HOAc LiBr‚H2O (2.0)
HOAc LiCl‚H2O (4.0)
19 p-CH3C6H4 (3f) HOAc NaI (2.0)
20 p-CH3C6H4 (3f) HOAc LiBr‚H2O (2.0)
21 p-CH3C6H4 (3f) HOAc LiCl‚H2O (4.0)
TABLE 3. Reaction of 3-(Methoxycarbonyl)-1,2-heptadien-4-ol
with MX
a No 4ea was formed when the reaction was conducted in TFA.
With the optimized conditions in hand, the scope of this
reaction was explored with some of the typical results being
summarized in Table 4. It may be concluded from Table 4 that
R can be not only an aryl group but also an alkyl group, which
was different from our previous report.12 When R is an alkyl
group, the reaction can occur smoothly to afford the products
in moderate to good yields in TFA (Table 4, entries 1-12); it
should be noted that when R is the phenyl group, the product
4ea cannot be afforded in TFA (Table 4, entry 13). After some
screening, it was found that when HOAc was used, 4ea was
produced in 40% yield (entry 16, Table 4). HOAc is also suitable
for other similar reactions (Table 4, entries 16-21). It was
obvious that the aryl group bearing an electron-donating group
afforded the products in higher yields (compare Table 4, entries
16-21).
Synthetic Application. The synthetic potentials of the
addition-elimination products 4 are demonstrated by transfor-
mations of the representative product 4ba (Scheme 2). Treatment
of 4ba with terminal alkynes gave corresponding Sonogashira
coupling16 products (i.e., the stereodefined conjugated dienynes
6ba (87%), 6bb (64%), and 6bc (69%)). The Negishi coupling17
reaction of 4ba with phenyl, 1(E)-hexenyl, or n-butyl zinc
Entry
MX (equiv)
time (h)
yield (%)
1
2
3
4
5
6
7
NaI (2.0)
LiI‚3H2O (2.0)
KI (2.0)
LiBr‚H2O (2.0)
KBr (2.0)
LiCl‚H2O (4.0)
NaCl (4.0)
1
1
1
2
3
73 (4ba)
58 (4ba)
44 (4ba)
76 (4bb)
58 (4bb)
55 (4bc)
trace (4bc)
3
14
Some typical results are summarized in Table 2. Among the
solvents tested, TFA (Table 2, entry 4) is the best, while HOAc,
Ac2O, or HI (Table 2, entries 1-3) are all inferior. A higher-
yielding reaction was observed when the reaction was conducted
in TFA under reflux (compare Table 2, entries 5 and 7). Best
results were obtained with the use of 2 equiv of NaI (compare
Table 2, entries 4-6). In conclusion, the reaction may afford
methyl 2-(1′-iodovinyl)hex-2(Z)-enoate 4ba in 73% yield when
the reaction was conducted with 2 equiv of NaI in TFA under
reflux (Table 2, entry 5). 1H NMR spectra of the crude product
indicated the formation of only one stereoisomer. The stereo-
chemistry was established by the NOESY analysis of 5ba, which
was formed by the reduction of 4ba with DIBAL-H in toluene
in 73% yield (Scheme 1).
(16) For the seminal report of the Sonogashira coupling reaction, see:
(a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
For some the most recent examples, see: (b) Ko¨llhofer, A.; Pullmann, T.;
Plenio, H. Angew. Chem., Int. Ed. 2003, 42, 1056. (c) Tykwinski, R. R.
Angew. Chem., Int. Ed. 2003, 42, 1566. (d) Gelman, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2003, 42, 5993. (e) Sakai, N.; Annaka, K.;
Konakahara, T. Org. Lett. 2004, 6, 1527. (f) Ma, S.; Ren, H.; Wei, Q. J.
Am. Chem. Soc. 2003, 125, 4817. (g) Lu, Z.; Ma, S. J. Org. Chem. 2006,
71, 2655.
(17) For the seminal report of Negishi coupling reactions, see: Negishi,
E.; King, A. O.; Okudado, N. J. Org. Chem. 1977, 42, 1821. For a review,
see: Negishi, E.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions;
Stang, P., Diederich, F., Eds.; VCH: Weinheim, Germany, 1998; pp 1-47.
On the basis of these results, other I- sources were tested
(Table 3). It was obvious that NaI afforded better results than
LiI‚3H2O and KI (Table 3, entries 1-3). As for Br- and Cl-
sources, LiBr‚H2O and LiCl‚H2O are better (Table 3, entries
4-7). By applying the standard reaction conditions, the corre-
sponding methyl 2-(1′-bromovinyl)hex-2(Z)-enoate 4bb and
methyl 2-(1′-chlorovinyl)hex-2(Z)-enoate 4bc can be prepared
in 76 and 55% yields, respectively (Table 3, entries 5 and 6).
5902 J. Org. Chem., Vol. 72, No. 15, 2007

SCHEME 2
NMR (400 MHz, CDCl3) δ 5.20 (d, J ) 2.0 Hz, 2H), 4.32-4.24
(m, 1H), 3.70 (s, 3H), 3.20-2.94 (bs, 1H), 1.66-1.57 (m, 2H),
0.89 (t, J ) 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 212.4,
167.3, 102.6, 80.5, 70.4, 52.1, 28.2, 10.0; MS (m/z): 156 (M+,
0.12), 127 (100); IR (neat, cm-1): 3490, 2965, 1964, 1935, 1713,
1266. HRMS calcd for C8H12NaO3 (M+ + Na): 179.0679, found:
179.0676.
Addition-Elimination Reactions of 3-(Methoxycarbonyl)-1,2-
allen-4-ols with MX. Preparation of Methyl 2-(1′-Iodovinyl)-
pent-2(Z)-enoate (4aa). Typical Procedure. To a mixture of NaI
(151.1 mg, 1.0 mmol) and 3a (77.0 mg, 0.49 mmol) was added
1.0 mL of TFA at room temperature. After the addition, the reaction
was refluxed at 80 °C with stirring for 1 h. After the reaction was
complete as monitored by TLC, it was cooled to room temperature
and slowly quenched by 10 mL of water followed by neutralization
with NaHCO3 until no gas was released. The mixture was extracted
with diethyl ether (3 × 25 mL) and washed with a saturated aqueous
solution of Na2S2O3 and brine. The organic layer was dried over
anhydrous Na2SO4. Evaporation and column chromatography on
silica gel (30-60 °C petroleum ether/diethyl ether ) 30:1) afforded
1
4aa (65.4 mg, 50%): liquid; H NMR (300 MHz, CDCl3) δ 6.75
(t, J ) 7.8 Hz, 1H), 6.08 (d, J ) 1.1 Hz, 1H), 6.03 (d, J ) 1.1 Hz,
1H), 3.77 (s, 3H), 2.29-2.18 (m, 2H), 1.06 (t, J ) 7.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 165.3, 146.6, 135.7, 131.2, 96.3,
52.1, 22.8, 12.3; MS (m/z): 267 (M+ + 1, 100); IR (neat, cm-1):
2962, 1722, 1603, 1434, 1243. HRMS calcd for C8H11IO2 (M+):
265.9798, found: 265.9790.
Reduction of Methyl 2-(1′-Iodovinyl)hex-2(Z)-enoate (4ba).
DIBAL-H (1.4 mL, 1 M in toluene, 1.4 mmol) was added dropwise
to a solution of 4ba (180.0 mg, 0.64 mmol) in toluene (3 mL) at
-78 °C. After complete conversion of the starting material as
monitored by TLC, the reaction mixture was quenched with 2 mL
of CH3OH and 5 mL of water. The organic layer was separated,
and the aqueous layer was extracted with diethyl ether (3 × 25
mL). The combined organic layer was dried over Na2SO4. Evapora-
tion and column chromatography on silica gel (petroleum ether/
ethyl acetate ) 10:1) afforded 118.7 mg (73%) of 5ba: liquid; 1H
NMR (400 MHz, CDCl3) δ 6.03 (d, J ) 1.2 Hz, 1H), 5.99 (d, J )
1.2 Hz, 1H), 5.53 (t, J ) 7.4 Hz, 1H), 4.15 (s, 2H), 2.13-2.00 (m,
3H), 1.45-1.34 (m, 2H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 142.4, 129.9, 129.8, 102.5, 64.9, 30.7, 22.0, 13.8;
MS (m/z): 252 (M+, 4.26), 79 (100); IR (neat, cm-1): 3333, 2958,
2929, 2870, 1608, 1456, 1107, 900. HRMS calcd for C8H13IO
(M+): 274.9903, found: 274.9914.
bromides gave the coupling products 6bd (86%), 6be (80%),
and 6bf (51%), respectively.
In conclusion, we have developed a SN2′-type addition-
elimination reaction of 3-(methoxycarbonyl)-1,2-allen-4-ols with
MX forming 3-(methoxycarbonyl)-2-halo-1,3(Z)-dienes highly
stereoselectively in moderate yields, providing an efficient route
for the synthesis of a series of polysubstituted (E)-1,3-dienes.
Further studies including the scope and synthetic applica-
tion of this type of reaction are being carried out in our
laboratory.
Synthetic Application of Methyl 2-(1′-Iodovinyl)hex-2(Z)-
enoate (4ba). Methyl 2-(4′-Phenylbut-1′-en-3′-yn-2′-yl)hex-2(E)-
enoate (6ba). A mixture of Pd(PPh3)2Cl2 (6.8 mg, 5 mol %, 0.01
mmol), CuI (4.1 mg, 10 mol %, 0.02 mmol), Et2NH (22.2 mg,
0.30 mmol), phenylacetylene (41.6 mg, 0.41 mmol), and 4ba
(55.9 mg, 0.20 mmol) in CH3CN (2 mL) was stirred at room
temperature over a period of 24 h under nitrogen. After complete
conversion of the starting materials as monitored by TLC, the
reaction mixture was diluted with 10 mL of Et2O and quenched
with 5 mL of water. The organic layer was separated, and the
aqueous layer was extracted with diethyl ether (3 × 25 mL). The
combined organic layer was dried over Na2SO4. Evaporation and
column chromatography on silica gel (petroleum ether/diethyl ether
) 30:1) afforded 6ba (44.1 mg, 87%): liquid; 1H NMR (400 MHz,
CDCl3) δ 7.46-7.38 (m, 2H), 7.34-7.26 (m, 3H), 6.94 (t, J )
7.6 Hz, 1H), 5.85 (s, 1H), 5.39 (s, 1H), 3.79 (s, 3H), 2.32 (q, J )
7.3 Hz, 2H), 1.59-1.45 (m, 2H), 0.96 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.6, 145.8, 131.8, 131.6, 128.23,
128.18, 126.7, 125.1, 123.0, 89.1, 88.7, 52.0, 31.4, 21.9, 13.8; MS
(m/z): 254 (M+, 62.02), 165 (100); IR (neat, cm-1): 2959, 1720,
1639, 1600, 1489, 1435, 1250, 1058. HRMS calcd for C17H18NaO2
(M+ + Na): 277.1199, found: 277.1196.
Experimental Section
Synthesis of 3-(Methoxycarbonyl)-1,2-allen-4-ols. 3-(Meth-
oxycarbonyl)-1,2-hexadien-4-ol (3a). Typical Procedure.15 To a
solution of 3-(methoxycarbonyl)propargyl bromide (3.4806 g,
19.7 mmol)13 in 30 mL of DMPU were added SnCl2 (4.6011 g,
24.2 mmol) and NaI (3.6107 g, 24.1 mmol) at room temperature.
The resulting yellow slurry was stirred in the absence of light (the
reaction tube was wrapped with a black plastic bag) for 6 h. A
solution of propionaldehyde (0.9281 g, 16.0 mmol) in 10 mL of
DMPU was then added dropwise over 15 min at 0 °C. The orange
reaction mixture was allowed to warm up to room temperature and
stirred in the dark for an additional 24 h. The reaction was cooled
to 0 °C, diluted with Et2O, and quenched with 30 mL of saturated
aqueous NH4Cl. The organic phase was separated, and the aqueous
phase was extracted with Et2O (4 × 30 mL). The combined organic
layer was washed with brine and dried over anhydrous Na2SO4.
Evaporation and column chromatography on silica gel (petroleum
ether/ethyl acetate ) 5:1) afforded 3a (1.4606 g, 59%): liquid; 1H
J. Org. Chem, Vol. 72, No. 15, 2007 5903

Supporting Information Available: Complete set of experi-
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20332060), the Major
State Basic Research Development Program (2006CB806105),
and Cheung Kong Scholar Program is greatly appreciated. S.M.
is jointly appointed by Zhejiang University and Shanghai In-
stitute of Organic Chemistry. We thank Xinpeng Jiang for re-
producing the results presented in entries 1, 8, and 12 of Table 4.
1
mental procedures and copies of H and 13C NMR spectra of all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO070725M
5904 J. Org. Chem., Vol. 72, No. 15, 2007