Arylethyne bromoboration-Negishi coupling route to E- Or Z-aryl-substituted trisubstituted alkenes of ≥ 98% isomeric purity. New horizon in the highly selective synthesis of trisubstituted alkenes

Article abstract of DOI:10.1002/adsc.200900766

The hitherto unprecedented palladiumcatalyzed cross-coupling of (Z)-β-bromo-β-arylethenylboranes can be made to proceed satisfactorily through (1) the use of highly catalytically active bis(tri-tert-butylphosphine) palladium or dichloro[N,N-bis-(2,6-diisopropylphenyl)imidazol-2-yl](m- chloropyridine)palladium and (2) conversion of the dibromoboryl group to the (pinacol)boryl group. Thus, a wide variety of carbon groups can be used to substitute bromine in ≥ 98% stereo- and regioselectivity, while suppressing the otherwise dominant β-debromoboration. Together with the alkylethyne-based protocols, the alkyne bromoboration-Negishi coupling tandem process has emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to access.

Full text of DOI:10.1002/adsc.200900766

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DOI: 10.1002/adsc.200900766
Arylethyne Bromoboration–Negishi Coupling Route to E- or
Z-Aryl-Substituted Trisubstituted Alkenes of ꢀ98% Isomeric
Purity. New Horizon in the Highly Selective Synthesis of
Trisubstituted Alkenes
Chao Wang,a Zhaoqing Xu,a Tomas Tobrman,a,b and Ei-ichi Negishia,*
a
Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907-2084, USA
Fax : (+1)-765-494-0239; e-mail: negishi@purdue.edu
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technicka 5, 166 28 Prague 6, Czech
b
Republic
Received: November 5, 2009; Published online: February 19, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900766.
Abstract: The hitherto unprecedented palladium-
highly selective and widely used method for the syn-
thesis of trisubstituted alkenes.[4b] Although this
method is broad in synthetic scope with respect to R1
catalyzed cross-coupling
of
(Z)-b-bromo-b-
arylethenACHTUNGTRENNUNGylboranes can be made to proceed satis-
factorily through (1) the use of highly catalytically
1
2
ꢁ
of the starting alkyne (R C CH), the R group of the
1
ꢁ
active
bis(tri-tert-butylphosphine)palladium
or
organoalanes to be added to R C CH has been prac-
dichloro
A
tically limited to Me and a limited number of alkyl
groups including allyl and benzyl groups.[3–6] On the
other hand, in an alkyne bromoboration–Negishi–
Suzuki tandem cross-coupling process [Eq. (2) in
yl](m-chloropyridine)palladium and (2) conversion
of the dibromoboryl group to the (pinacol)boryl
group. Thus, a wide variety of carbon groups can be
used to substitute bromine in ꢀ98% stereo- and re-
gioselectivity, while suppressing the otherwise domi-
nant b-debromoboration. Together with the alkyle-
thyne-based protocols, the alkyne bromoboration–
Negishi coupling tandem process has emerged as
the most widely applicable and highly selective
route to trisubstituted alkenes including those that
are otherwise difficult to access.
Scheme 1] reported by Suzuki in 1988,[7] bromobora-
1
ꢁ
tion of R C CH is followed by incorporation of both
R2 and R3 groups by Pd-catalyzed cross-coupling reac-
tions of wide synthetic scopes, thereby promising to
provide a method of very wide applicability for syn-
thesizing trisubstituted alkenes. In reality, however,
all reported examples[7] of Eq. (2) in Scheme 1 and of
its modification involving double Negishi coupling re-
actions[8,9] [Eq. (3) in Scheme 1] involve the use of
Keywords: arylethyne bromoboration; bis(tri-tert-
butylphosphine)palladium; (Z)-b-bromo-b-aryleth-
only alkylACTHNGUTERNNUeG thynes, even though haloborations of aryl-
and alkenyl-substituted ethynes are known to proceed
N
ACHTUNGTRNE[NUNG N,N-bis-(2,6-diisopropylphen-
well.[10]
A
As readily suspected, competitive debromoboration
of 2 to revert to the starting alkynes would be the
main cause of difficulty in the Pd-catalyzed cross-cou-
pling of 2, and the fact that those derived from aryl-
and alkenyl-substituted ethynes are benzylic and allyl-
ic bromides, respectively, besides being alkenyl bro-
Despite major advances in the syntheses of strictly mides must undoubtedly be responsible for their sig-
(ꢀ98%) regio- and stereodefined alkenes via “ele- nificantly higher propensity to undergoing debromo-
mentometalation”[1] Pd- or Ni-catalyzed cross-cou- boration, as compared with that of alkylethyne-de-
pling developed since 1976,[2–4] efficient and highly rived 2. Thus, for example, the reaction of 2a, generat-
(ꢀ98%) selective syntheses of tri- and tetrasubstitut- ed by bromoboration of phenylethyne followed by
ed alkenes continue to provide major synthetic chal- treatment with pinacol, with (E)-1-octenylzinc bro-
lenges. The Zr-catalyzed alkyne carboalumination-Ne- mide in the presence of Pd
ACHTUNGTREN(NUGN DPEphos)Cl2 (0.5 mol%)
gishi coupling[3,4] [Eq. (1) in Scheme 1] has provided a at 238C for 2 h led to the formation of the desired 3a
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Chao Wang et al.
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Scheme 1. Highly (ꢀ98%) selective “elementometalation”–Pd-catalyzed cross-coupling routes to trisubstituted alkenes.
ꢁ
in <2% yield along with PhC CH (20%) and the un- or alkenyl halides represented by 3 and 4 into the cor-
reacted 2a (67%). The results indicate that the reac- responding trisubstituted alkenes 1[4,15] our attention
tion not only is slow but also produces at least ten in this study is focused on the synthesis of 3 and 4.
ꢁ
times as much PhC CH as 3a.
Many of the alkenes represented by 3 and 4 shown in
To our delight, however, the use of highly active Pd Table 1 are very difficult to prepare in a highly
[11,12]
catalysts, such as Pd
N
and PEPPSITM-IPr (ꢀ98%) selective manner by any previously known
(5),[12c,13,14] almost fully suppressed debromoboration methods except for those that are accessible by Zr-
of 2a and led to the production of the desired 3a of catalyzed carboalumination[5] and carbocupration[16] of
ꢀ98% isomeric purity in high yields along with only alkynes. To demonstrate the synthetic utility of the
ꢁ
traces (<2%) of PhC CH and the unreacted starting alkyne bromoboration–Pd-catalyzed cross-coupling
compound 2a [Eq. (4) in Scheme 2]. Earlier in this route to 3 and 4, a pair of (E)- and (Z)-2-iodo-1,1-dia-
study, we treated 2b (Y=Br) with n-HexZnBr in rylethenes 4h and 4i were synthesized as ꢀ98% ste-
THF in the presence of 0.5 mol% of PdACTHNUGTRNEUNG[(t-Bu]3P]2 and reoisomerically pure compounds in 42% and 46%
ꢁ
ꢁ
obtained, after iodinolysis, the desired (E)-a-(n- yields in two steps from PhC CH and p-ClC6H4C
hexyl)-b-iodostyrene (4b) only in 14% yield along CH, respectively (Scheme 3).
ꢁ
with PhC CH formed in 78% yield [Eq. (5) in
In summary, the following findings have significant-
Scheme 2]. However, the use of Pd
A
catalyst later proved to be appropriate, since its use cable and highly selective route to trisubstituted al-
along with 2a in place of 2b gave 4b in 86% yield kenes via alkyne elementometalation–Pd-catalyzed
[Eq. (6) in Scheme 2]. The results shown in Scheme 2 cross-coupling.
clearly indicate that proper selection of not only Pd
catalysts, e.g., Pd
[(t-Bu)3P]2 and PEPPSITM-IPr (5), readily preparable by treatment of arylethyne with
but also boryl groups, e.g., pinacolboryl rather than BBr3,[10] do not satisfactorily undergo Pd-catalyzed
Firstly, (Z)-b-bromo-b-arylethenyldibromoboranes,
AHCTUNGTRENNUNG
dibromoboryl, is critically important.
cross-coupling due to competitive b-debromoboration
As summarized in Table 1, a wide range of R2 under all conditions tested thus far. However, the
groups including alkyl, alkenyl, aryl, and alkynyl may combined use of the corresponding (Z)-b-bromo-b-
now be introduced into 3 and 4 derived from aryl- arylethenylCAHTUNGTERN(NNUG pinacol)boranes and highly active Pd cat-
and PEPPSITM-IPr
[11,12]
ethynes, such as phenylethyne, p-chlorophenylethyne, alysts, such as Pd
E
and p-tolylethyne, by using (i) (Z)-b-aryl-b- (5),[13] leads to highly (ꢀ98%) regio- and stereoselec-
bromoalkenylACHTUNGTRENNUNG(pinacol)boranes (2), (ii) either PdAHCTUNGTREN[NUGN (t- tive syntheses of the corresponding trisubstituted
Bu)3P]2 or PEPPSITM-IPr (5). Since a wide range of alkenyl
ACTHNUGRTENUNG(pinacol)boranes (3) in one or two steps from
Pd-catalyzed alkenylation reactions are known to se- arylethynes via Negishi coupling in 53 to 66% isolated
lectively and satisfactorily convert alkenylmetals and/ overall yields. The corresponding alkenyl iodides (4)
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Arylethyne Bromoboration–Negishi Coupling Route to E- or Z-Aryl-Substituted Trisubstituted Alkenes
Scheme 2. Pd-catalyzed cross-coupling reactions of (Z)-b-bromo-b-phenylethenylboranes (2a and 2b). Effects of Pd catalysts
and boryl groups.
can be obtained as ꢀ98% isomerically pure com- 48 mmol) in dry CH2Cl2 (20 mL) was added. The resultant
reaction mixture was warmed to 238C, stirred for 1 h,
washed with brine, dried over Na2SO4, filtered, concentrat-
ed, and purified by column chromatography (silica gel, 98:2
hexane-EtOAc) to give 2a; yield: 4.51 g (73%). 1H NMR
(300 MHz, CDCl3): d=1.36 (s, 12H), 6.44 (s, 1H), 7.3–7.4
(m, 3H), 7.55–7.65 (m, 2H); 13C NMR (75 MHz, CDCl3):
d=27.74 (4C), 83.29 (2C), 119–122 (br s), 127.47 (2C),
128.08 (2C), 129.21, 140.06, 140.86; HR-MS: m/z=308.0588,
calcd. for C14H18BBrO2 [M]+: 308.0583.
pounds by known iodinolysis of 3 with I2 and NaOH
in 80–86% isolated yields from 3. In a couple of cases,
the feasibility of one-pot conversion of arylethynes to
4 in ca. 60% overall yields has also been demonstrat-
ed (Table 1).
Secondly, the arylethyne bromoboration–Negishi
coupling protocol reported herein makes available 3
and 4, and hence their fully carbo-trisubstituted deriv-
atives as well,[4,15] many of which have been very diffi-
cult to prepare as highly (ꢀ98%) isomerically pure
compounds by any other known methods. Together
with the related alkylethyne-based protocols,[7–9] the
alkyne bromoboration–Negishi coupling protocol rep-
resents the hitherto most widely applicable and highly
(ꢀ98%) selective route to trisubstituted alkenes.
Further development with the use of conjugated
1,3-enynes and 1,3-diynes is currently in progress.
A
ACHTUNGERTN(NUNG pinacol)borane (3a):
AHCTUNGTRENNUNG
To a stirred solution of BBr3 (0.11 mL, 1.1 mmol) in dry
CH2Cl2 (2 mL) was added phenylethyne (102 mg, 0.11 mL,
1 mmol) at À788C. After stirring at À788C for 1 h, a solu-
tion of pinacol (142 mg, 1.2 mmol) and (i-Pr)2NEt (310 mg,
0.42 mL, 2.4 mmol) in dry CH2Cl2 (2 mL) was added. The
reaction mixture was warmed to 238C and stirred for 1 h. In
another flask, PdACHTNUGTRNEG[UN (t-Bu)3P]2 (2.6 mg, 0.005 mmol) was dis-
solved in dry THF (2 mL) and treated consecutively with
(E)-1-octenylzinc bromide [1.2 mmol, generated by treating
(E)-1-iodo-1-octene (0.30 g, 1.2 mmol) with n-BuLi
(0.53 mL, 1.3 mmol, 2.5M solution in hexanes) in dry THF
(2 mL) for 30 min at À788C, followed by treatment with a
solution of ZnBr2 (0.27 g, 1.2 mmol) in dry THF (2 mL) for
30 min at 08C] and (Z)-b-phenyl-b-bromoethenyl-
Experimental Section
(Z)-b-Bromo-b-phenylethenylACHTUNTRGNEUNG(pinacol)borane (2a)
To a stirred solution of BBr3 (2.08 mL, 22 mmol) in dry
CH2Cl2 (10 mL) was added phenylethyne (2.20 mL,
20 mmol) at À788C. After stirring for 1 h at À788C, a solu-
tion of pinacol (2.84 g, 24 mmol) and (i-Pr)2NEt (8.36 mL,
AHCTUNGTREG(NNNU pinacol)borane 2a generated as described above at 238C.
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Table 1. Arylethyne bromoboration–Negishi coupling route
After stirring for 2 h at 238C, the reaction mixture was
quenched with 0.5M HCl, extracted with Et2O, washed with
brine, dried, filtered, concentrated, and purified by column
chromatography (silica gel, 98:2 hexane-EtOAc) to give
to b,b-disubstituted alkenyl
ACHTUNGTRNE(NUNG pinacol)boranes (3) and the cor-
responding iodides (4).
(1E,3E)-2-phenyl-1,3-decadienylACTHUNTGRNEUNG(pinacol)borane 3a as a pale
yellow oil; yield: 204 mg (60%). 1H NMR (300 MHz,
CDCl3): d=1.07 (t, J=6.6 Hz, 3H), 1.50 (s, 12H), 1.2–1.7
(m, 8H), 2.33 (m, 2H), 5.52 (s, 1H), 5.8–5.9 (m, 1H), 7.37
(d, J=15.7 Hz, 1H), 7.3–7.4 (m, 5H); 13C NMR (75 MHz,
CDCl3): d=14.27, 22.77, 25.65 (4C), 29.02, 29.09, 31.92,
33.27, 83.19 (2C), 117–120 (br s), 126.53, 127.46, 127.97
(2C), 128.59 (2C), 138.73, 143.50, 160.68; HR-MS: m/z=
340.2571, calcd. for C22H33BO2 [M]+: 340.2574.
Representative Procedure for the Synthesis of b,b-
Disubstituted Alkenyl Iodides (4) by Iodinolysis of
Pinacolboranes (3)
To a stirred solution of 3i (170 mg, 0.5 mmol) in THF
(1 mL) was added a solution of NaOH (0.5 mL, 1.5 mmol,
3M in water). The resultant mixture was stirred for 10 min
at 238C, followed by dropwise addition of a solution of I2
(0.25 g, 1 mmol) in THF (5 mL). After 1 h at 238C, the reac-
tion mixture was quenched with aqueous Na2S2O3, extracted
with ether, washed successively with saturated NaHCO3 and
brine, dried over Na2SO4, filtered, concentrated, and puri-
fied by column chromatography (silica gel, hexane) to give
(E)-b-iodo-a-(p-chlorophenyl)styrene (4i) as a colorless oil;
1
yield: 138 mg (81%). H NMR (300 MHz, CDCl3): d=6.98
(s, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.25–7.3 (m, 3H), 7.28 (d,
J=8.7 Hz, 2H), 7.4–7.5 (m, 3H); 13C NMR (75 MHz,
CDCl3): d=79.53, 128.14, 128.40 (2C), 128.48 (2C), 128.73
(2C), 129.30 (2C), 133,98, 139.47, 141.28, 151.44; HR-MS:
m/z=339.9512, calcd. for C10H14ClI [M]+: 339.9516.
[a]
Isolated yields of ꢀ98% pure compounds. The indicated
stereochemical assignments were made by NOE meas-
urements.
Yields are based on arylethyne.
Yields are based on 3.
Compound 3 was crudely obtained and directly used for
its conversion to 4.
Overall yield from phenylethyne.
[b]
[c]
[d]
Acknowledgements
[e]
[f]
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.
Overall yield from p-tolylethyne.
Scheme 3. Highly selective (ꢀ98%) synthesis of (E)- and (Z)-a-(p-chlorophenyl)-b-iodostyrenes (4h and 4i) via arylethyne
bromoboration–Negishi coupling–iodinolysis.
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Arylethyne Bromoboration–Negishi Coupling Route to E- or Z-Aryl-Substituted Trisubstituted Alkenes
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