Highly regio- and stereoselective synthesis of (Z)-trisubstituted alkenes via propyne bromoboration and tandem Pd-catalyzed cross-coupling

Article abstract of DOI:10.1021/ol901566e

Contrary to all previous reports, bromoboration of propyne with BBr ₃ proceeds in ≥98% syn-selectivity to produce (Z)-2-bromo- 1propenyldibromoborane (1). Although 1 Is readily prone to stereoisomerization, It can be converted to the pinacolboronate (2) of ≥ 98% isomeric purity by treatment with pinacol. which may then be subjected to Negishi coupling to give tri substituted (2)-alkenylpinacolboronates (3) containing various R groups In 73-90% yields. Iodinolysis of 3 affords alkenyl iodides (4) In 80-90% yields. All alkenes isolated and identified are ≥98% Z.

Full text of DOI:10.1021/ol901566e

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4092-4095
Highly Regio- and Stereoselective
Synthesis of (Z)-Trisubstituted Alkenes
via Propyne Bromoboration and Tandem
Pd-Catalyzed Cross-Coupling
Chao Wang, Tomas Tobrman, Zhaoqing Xu, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received July 9, 2009
ABSTRACT
Contrary to all previous reports, bromoboration of propyne with BBr3 proceeds in g98% syn-selectivity to produce (Z)-2-bromo-1-
propenyldibromoborane (1). Although 1 is readily prone to stereoisomerization, it can be converted to the pinacolboronate (2) of g98% isomeric
purity by treatment with pinacol, which may then be subjected to Negishi coupling to give trisubstituted (Z)-alkenylpinacolboronates (3) containing
various R groups in 73-90% yields. Iodinolysis of 3 affords alkenyl iodides (4) in 80-90% yields. All alkenes isolated and identified are g98% Z.
Zr-catalyzed carboalumination of alkynes,1 especially me-
thylalumination (ZMA, hereafter), has been widely used for
the synthesis of (E)-trisubstituted alkenes, especially those
of the terpenoid origin.2 Although the corresponding meth-
ylcupration of alkynes has not been well developed, alkyl-
cupration3 of propyne can provide a potentially attractive
route to (Z)-trisubstituted alkenes of terpenoid origin with a
Me branch. One general deficiency common to these alkyne
carbometalation reactions is that their current scope is
practically limited to those cases where alkylmetals including
allyl- and benzylmetals are used. Haloboration reported in
1964 by Lappert4 is a rare example of halometalation which
is thermodynamically favorable due mainly to the relatively
high electronegativity of boron. Subsequent Pd-catalyzed
cross-coupling would provide a potentially selective route
to trisubstituted alkenes of unprecedentedly wide scope.
Although this was realized first by Suzuki in 1988 with a
Pd-catalyzed tandem Negishi-Suzuki coupling process5 and
more recently by Wang6 with a double Negishi coupling
process, these previous studies collectively fell short of the
above-stated promise. Notably, in the single most desirable
(4) Lappert, M. F.; Prokai, B. J. Organomet. Chem. 1964, 1, 384–400.
(5) Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki, A. Tetra-
hedron Lett. 1988, 29, 1811–1814.
(1) (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252–
2254. (b) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639–6647.
(6) (a) Wang, K. K.; Wang, Z. Tetrahedron Lett. 1994, 35, 1829–1832.
(b) Wang, K. K.; Wang, Z.; Tarli, A.; Gannett, P. J. Am. Chem. Soc. 1996,
118, 10783–10791. (c) Tarli, A.; Wang, K. K. J. Org. Chem. 1997, 62,
8841–8847.
(2) Negishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233–257.
(3) (a) Normant, J. F.; Bourgain, M. Tetrahedron Lett. 1971, 12, 2583–
2586. (b) Normant, J. F.; Alexakis, A. Synthesis 1981, 841–870.
(7) Xu, Z.; Negishi, E. Org. Lett. 2008, 10, 4311–4314.
10.1021/ol901566e CCC: $40.75
Published on Web 08/20/2009
 2009 American Chemical Society

Table 1. Highly (-98%) Selective Conversion of 1-Propyne to (Z)-2-Bromo-1-alkenylboronates (2) by Bromoboration and Their
Negishi Coupling-Iodinolysis to Produce 3 and 4 of g98% Isomeric Purity
3a
4a
entry
R
suffix to 3 and 4 isolated yield (%)
NOE (%)
isolated yield (%)
NOE (%)
1
2
3
4
5
6
7
8
n-Hex
i-Bu
c-Hex
Me2CdCHCH2
PhCH2
Me2CdCCH2CH2
PhCH2CH2
i
ii
iii
iv
v
vi
vii
viii
ix
87
86
84
79
83
73
76
79
82
96
83
-
90
86
87
85
2.8
2.9
4.6
2.7
2.9
3.1
4.8
4.6
5.0
4.1
3.2
-
3.7
3.5
3.7
3.7
1.9
6.1
86
82
88
84
81
87
80
90
84
1.4
2.8
2.0
1.9
1.3
2.4
1.3
3.5
1.4
-
1.2
2.1
1.5
1.3
1.3
1.4
1.3
1.2
n-HexCtCCH2CH2
CH2dCH
9
b
10
11
12
13
14
15
16
17
18
(E)-n-HexCHdCH
(E)-n-HexC(Me)dCH
(E)-HOCH2CHdCH
(E)-TBSOCH2CdCH
Ph
4-MeOC6H4
4-ClC6H4
n-BuCtC
TBSCtC
x
xi
-
81
77d
84
86
89
85
87
88
c
xii
xiii
xiv
xv
xvi
xvii
xviii
83
90e
a The isomeric purities of 3 and 4 are uniformly g98%. The overall isomeric purity was determined by 13C NMR spectroscopy, and the alkene geometry
was determined by 1H NMR NOE measurements. b Iodinolysis was not performed in this case. c For further details, see Scheme 1. In this case, PEPPSI (1%)
was used instead of Pd(PPh3)2Cl2 (1%). Compound 3xii was crudely obtained and directly used for its conversion to 4xii. d Overall yield from propyne and
propargyl alcohol. e In this case, Pd(t-Bu3P)2 (0.1%) was used instead of Pd(PPh3)2Cl2 (1%).
case of propyne haloboration for the selective synthesis of
(Z)-alkene-containing terpenoids, all reported stereoselectivity
values were e89%.6c,8,9 Second, although haloboration itself
appears to proceed satisfactorily not only with alkyl-
substituted alkynes but also with other types of alkynes
substituted with Ph and cyclohexenyl,8a,9a,10 those subjected
to Pd-catalyzed cross-coupling have been strictly limited to
the cases of alkyl-substituted alkynes.5-7
panol, as well as some amines and S-based nucleophiles,
tested so far have led to stereoisomerization occurring to
unacceptable extents (>10%). As expected, the Pd-catalyzed
cross-coupling of 2 with a wide range of organozincs
(Negishi coupling)11 including alkyl, allyl, benzyl, alkenyl,
aryl, and alkynyl groups proceeds to give 3 in high yields
with full retention (g98%) of stereochemistry (Table 1). It
should be noted that those obtained with the use of
organozincs containing alkenyl, aryl, and alkynyl groups may
not be readily accessible via known alkyne carbometalation,
such as those mentioned above.1-3 Our brief survey of the
metal countercations (M) of the organometallic reagents
(RM) for the substitution of Br with a carbon group (R) has
indicated Zn is indeed the most satisfactory metal counter-
cation, although In and Zr are also satisfactory. Thus, for
example, 3x (R ) (E)-n-HexCHdCH), prepared in 96%
yield by using (E)-n-HexCHdCHZnBr (entry 10), was
obtained by the use of (E)-n-HexCHdCHM in lower NMR
yields of e2% (M ) Mg or Al), 82% (M ) In), 18% (M )
Cu), and 73% (M ) Zr).
We herein report that, contrary to the previous claim,8b
bromoboration of propyne with BBr3 does proceed in g98%
syn-selectiVity to produce (Z)-2-bromo-1-propenyldibro-
moborane (1) and that, although 1 is indeed highly prone to
stereoisomerization under a variety of condtions, it can be
conVerted to the corresponding cyclic boronate (2) of g98%
stereoisomeric purity by its treatment with pinacol at room
temperature. Compound 2 is stable and can be stored in air
at 23 °C for days without any changes by NMR analyses.
All other alcohols including methanol, ethanol, and isopro-
(8) (a) Satoh, Y.; Serizawa, H.; Hara, S.; Suzuki, A. Synth. Commun.
1984, 14, 313–319. (b) Sato, M.; Yamamoto, Y.; Hara, S.; Suzuki, A.
Tetrahedron Lett. 1993, 34, 7071–7014
.
Org. Lett., Vol. 11, No. 18, 2009
4093

Scheme 1. Some (Z)-1-Iodo-2-methyl-1-alkenes of Interest in Efficient and Selective Syntheses of (Z)-Trisubstituted Alkene-Containing
Natural Products
To complete the synthesis of trisubstituted alkenes free
of both Br and B, the most obvious and straightforward route
would be to resort to the Suzuki coupling12 of 3. However,
direct Pd-catalyzed Suzuki coupling of (Z)-ꢀ-substituted
alkenylboranes with alkenyl and alkynyl halides run under
the previously reported conditions5 has tended to give the
desired products in relatively low (<50-60%) yields.5,13 Pd-
catalyzed reactions of alkenylboranes with alkyl and cyano-
gen halides tend to be less satisfactory than those of the
corresponding alkenyl iodides with alkylmetals and metal
cyanides.11 As shown in Table 1, alkenyl iodides (4) required
in the latter protocol are obtained by treatment of 3 with I2
(2 equiv) and NaOH (3 equiv) in THF and H2O at 23 °C14
in uniformly high yields of 80-90% with full (g98%)
retention of isomeric purity of 3. It should be emphasized
that the propyne bromoboration-Negishi coupling protocol
summarized in Table 1 represents an efficient and highly
(g98%) selective route to (Z)-2-methyl-1-alkenylboranes (3)
and the corresponding iodides (4)15 of unprecedentedly broad
potential scope and that none of the examples of 3 or 4 in
Table 1 have previously been prepared in a highly selective
(g98%) manner via propyne haloboration.
Some of the alkenyl iodides (4) have been previously
prepared via more circuitous routes in considerably lower
yields. Thus, for example, 4ix, obtained in three steps from
propyne in 60% overall yield and g98% Z selectively, was
previously prepared from 3-butyn-1-ol also in three steps
but only 41% yield and ca. 95-97% Z selectivity16 (eq 1 of
Scheme 1). It should be remembered that treatment of 4ix
with just 1 equiv of n-BuLi followed by addition of geranyl
bromide of g98% isomeric purity furnished (3Z,6E)-R-
farnesene (6) of g98% isomeric purity in 80% yield without
using any catalyst.16 We recently reported the preparation
of a key intermediate 7 for the synthesis of the side chain of
(9) For papers reporting the use of propyne haloboration without
specifying the Z/E ratio, see: (a) Satoh, Y.; Serizawa, H.; Hara, S.; Suzuki,
A. J. Am. Chem. Soc. 1985, 107, 5225–5228. (b) Miyaura, N.; Satoh, Y.;
Hara, S.; Suzuki, A. Bull. Chem. Soc. Jpn. 1986, 59, 2029–2031. (c) Trost,
B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025–5036.
(11) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340–348. (b) Negishi,
E., Ed. Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley-Interscience: New York, 2002; pp 215-1119, Part III. (c) Negishi,
E.; Hu, Q.; Huang, Z.; Wang, G.; Yin, N. The Chemistry of Organozinc
Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley & Sons Ltd.:
Chichester, England, 2006; p 453, Chapter 11.
(10) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731–734. (b) Hara, S.; Satoh, Y.; Ishiguro, H.; Suzuki, A.
Tetrahedron Lett. 1983, 24, 735–738. (c) Hara, S.; Kato, T.; Shimizu, H.;
Suzuki, A. Tetrahedron Lett. 1985, 26, 1065–1068. (d) Hara, S.; Hyuga,
S.; Aoyama, M.; Sato, M.; Suzuki, A. Tetrahedron Lett. 1990, 31, 247–
250. (e) Aoyama, M.; Hara, S.; Suzuki, A. Synth. Commun. 1992, 22, 2563–
2569. (f) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 1491–1493.
(g) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu, Z. Org. Lett. 2005, 7,
2865–2867. (h) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Wu, Z. Chem.
Commun. 2005, 2492–2494.
(12) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b)
Suzuki, A.; Brown, H. C. Suzuki Coupling. Organic Synthesis Via Boranes;
Aldrich Chem. Co: Milwaukee, WI, 2003; pp 1-314, Vol. 3.
(13) For difficulties associated with some ꢀ-(Z)-alkenylboranes in Pd-
catalyzed alkenyl-alkenyl coupling, see also: Huang, Z.; Negishi, E. J. Am.
Chem. Soc. 2007, 129, 14788–14792.
4094
Org. Lett., Vol. 11, No. 18, 2009

mycolactone A17,18 from propargyl alcohol in 42% yield over
six steps and g98% selectivity.17 The same compound 7 can
now be synthesized from propyne and propargyl alcohol in
a mere two steps in 62% overall yield (eq 2 of Scheme 1).
Finally, treatment of 2 with TBSCtCZnBr in the presence
of 0.1 mol % of Pd(t-Bu3P)2 and with I2 and NaOH gave
iodoenyne 4xviii (g98% Z) in 79% yield. Pd-catalyzed
cyanation19 of 4xviii with Zn(CN)2 in the presence of
Pd(PPh3)4 followed by desilylation with TBAF provided
9 (g98% Z) in 82% yield (55% from propyne). Compound
9 promises to serve as a useful intermediate for the
synthesis of (+)-calyculin A20 and related compounds (eq
3 of Scheme 1).
selectivity to produce (Z)-2-bromo-1-propenyldibromoborane
(1) in excellent yield. Second, although 1 is readily prone to
stereoisomerization, it can be converted to (Z)-2-bromo-1-
propenyl(pinacolyl)borane (2) of g98% isomeric purity in
85% yield from propyne. Third, Pd-catalyzed cross-coupling
of 2 with a wide variety of organozincs containing n-, i-,
c-alkyl, allyl, benzyl, homoallyl, homobenzyl, homopropar-
gyl, alkenyl, aryl, and alkynyl in the presence of Pd catalyst
(1 mol % or less) provides the corresponding (Z)-alkenylpi-
nacolboronates (3) in 73-90% yields as g98% isomeric pure
compounds. Fourth, treatment of 3 with I2 (2 equiv) and
NaOH (3 equiv) in THF-H2O at 23 °C for 1 h affords the
corresponding alkenyliodides (4) in 80-90% yields as g98%
isomerically pure compounds. Fifth, the propyne bromobo-
ration-based (Z)-trisubstituted alkene syntheses herein re-
ported promises to provide an unprecedentedly stereoselec-
tive (g98%) and widely applicable route to methyl-branched
(Z)-trisubstituted alkenes of biological and medicinal sig-
nificance, as indicated by highly efficient and selective
syntheses of (3Z,6E)-R-farnesene16 (6) as well as proven and
promising intermediates for the syntheses of mycolactone
A17,18 and (+)-calyculin A.20
In summary, the following new findings have been
obtained: First, contrary to all previous reports, bromobo-
ration of propyne with BBr3 prodeeds in g98% syn-
(14) Brown, H. C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc. 1973,
95, 5786–5788
.
(15) For previuos syntheses of 4i, 4vi, 4ix, 4xiii, and 4xiv, see the
following references: (a) 4i: Kasatkin, A.; Whitby, R. J. J. Am. Chem. Soc.
1999, 121, 7039–7049. (b) 4vi: Cahiez, G.; Bernard, D.; Normant, J. F.
Synthesis 1976, 245–248. (c) 4ix: Ma, S.; Negishi, E. J. Org. Chem. 1997,
62, 784–785. (d) 4xiii: Huang, Z.; Negishi, E. J. Am. Chem. Soc. 2007,
129, 14788–14792. (e) 4xiv: Gronheid, R.; Lodder, G.; Ochiai, M.; Sueda,
T.; Okuyama, T. J. Am. Chem. Soc. 2001, 123, 8760–8765
(16) (a) Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784–785. (b) Wang,
G.; Negishi, E. Eur. J. Org. Chem. 2009, 11, 1679–1682
(17) Yin, N.; Wang, G.; Qian, M.; Negishi, E. Angew. Chem., Int. Ed.
2006, 45, 2916–2920
.
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research. We also thank Sigma-Aldrich, Albemarle, and
Boulder Scientific for their support.
.
.
(18) For earlier synthetic works, see: (a) Benowitz, A. B.; Fidanze, S.;
Small, P. L. C.; Kishi, Y. J. Am. Chem. Soc. 2001, 123, 5128–5129. (b)
Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett. 2002, 4, 647–
650.
Supporting Information Available: Experimental details
1
and representative H and 13C NMR spectra. This material
(19) Tschane, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik,
B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887–890.
(20) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434–9453.
is available free of charge via the Internet at http://pubs.acs.org.
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