Boron-directed regio- and stereoselective enyne cross metathesis: Efficient synthesis of vinyl boronate containing 1,3-dienes

Article abstract of DOI:10.1021/ol050542r

(Chemical Equation Presented) Regio- and stereoselective enyne cross metathesis reactions between borylated alkynes and terminal alkenes were realized to provide a variety of functionalized vinyl boronates. High chemical yield and regioselectivity was ach

Full text of DOI:10.1021/ol050542r

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1865-1868
Boron-Directed Regio- and
Stereoselective Enyne Cross
Metathesis: Efficient Synthesis of Vinyl
Boronate Containing 1,3-Dienes
Mansuk Kim and Daesung Lee*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received March 11, 2005
ABSTRACT
Regio- and stereoselective enyne cross metathesis reactions between borylated alkynes and terminal alkenes were realized to provide a
variety of functionalized vinyl boronates. High chemical yield and regioselectivity was achieved irrespective of substituents on the alkyne and
alkene counterparts, whereas Z/E-selectivity was found to be dependent upon the substituents both on the alkyne and alkene.
Vinylboronates are versatile building blocks in the synthesis
of natural products and unnatural compounds of medicinal
importance. Because they can serve as one of the most
general substrates for transition-metal-mediated coupling
reactions, such as the Suzuki-Miyaura coupling1 and Heck-
type reactions,2 the efficient and stereocontrolled synthesis
of this functional group constitutes an important goal in
synthetic organic chemistry.
The ring closing metathesis (RCM)3 of enynes possessing
alkynyl boronate has been employed for the synthesis of vinyl
boronates embedded in cyclic structures.4 However, the tether
between the alkene and alkyne counterparts imposes a
significant limitation to structural diversification in this
process. Recently, Grubbs and co-workers5 utilized the cross
metathesis (CM)6 between terminal vinlyl boronate and
alkene to generate more functionalized vinyl boronates.
To expand the scope and utility of enyne metathesis,7 we
envisioned using borylated alkyne 1 in CM, which would
provide a straightforward access to vinyl boronate 2 or 2′
(Scheme 1). Having no precedent for enyne CM reaction of
borylated alkynes, the regio- and stereochemical consequence
providing 2 or 2′ cannot be predicted. However, the favored
regiochemistry in the formation of a putative intermediate 3
(1) Review: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11.
Scheme 1
(2) Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W. Org.
Lett. 2004, 6, 4037 and references therein. For reviews, see: (b) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(3) Reviews: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (c) Schrock, R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (d) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199. (d) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371-388. (e) Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2.
(4) (a) Renaud, J.; Ouellet, S. G. J. Am. Chem. Soc. 1998, 120, 7995.
(b) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39,
3101. (c) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002,
41, 3272.
10.1021/ol050542r CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/26/2005

from the reaction between 1 and 5 leading to 2 might be
inferred from a Fisher carbene complex 4 formed from
borylated alkynes as an intermediate in the benzannulation
reaction.8
Herein we report a highly regio- and stereoselective CM9
of borylated alkyne 1, showing a strong directing effect of
the boron substituent, thereby providing a general and
stereocontrolled synthesis of vinylboronates, providing se-
lectively 2 over 2′.
First, the reactivity and selectivity of borylated alkynes10
possessing different substituents was examined by treating
the mixture of alkynes 1a-g and 1-octene (2 equiv) with 5
mol % of Grubbs catalyst 511 at 40 °C (Table 1). The CM
least hindered terminal alkyne 1a and most hindered gemi-
nally substituted substrate 1g did not afford the expected CM
products 2a and 2g, giving only recovery of starting material
(entries 1 and 7). The stereoselectivity of formation of 2b-f
is sensitive to the nature of substituents at the propargylic
site, providing low selectivity with small substituents (entries
2 and 3) while giving high selectivity with larger substituents
(entries 4-6).
Noting the excellent CM reactivity of 1b-f with 1-octene,
we next explored the CM with heteroatom-containing alkenes
(Table 2). The CM of alkynes 1b and 1c with alkenes
Table 2. Cross Metathesis of Alkynyl Boronate with Various
Alkenesa
Table 1. Cross Metathesis of Alkynyl Boronate with 1-Octenea
a Alkyne 1 and 1-octene (2.5 equiv) with catalyst 5 (5 mol %) in CH2Cl2
(0.02 M) under reflux for 4-6 h. b Isolated yield. c The ratio was determined
1
by H NMR, and the stereochemistry was inferred from the NOE data of
2e. d No reaction. e The stereochemistry of the major isomer was confirmed
by NOE experiment.
products 2b-f were isolated in high yields as single
regioisomers (entries 2-6).12 However, both the sterically
(5) For acyclic vinyl boronate via CM, see, (a) Morrill, C.; Grubbs, R.
H. J. Org. Chem. 2003, 68, 6031. (b) Morrill, C.; Funk, T. W.; Grubbs, R.
H. Tetrahedron Lett. 2004, 45, 7733.
(6) Review of cross metathesis: (a) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900. A leading reference: Chatterjee, A. K.;
Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125,
11360 and references therein.
(7) Review on enyne metathesis: (a) Giessert, A. J.; Diver, S. T. Chem.
ReV. 2004, 104, 1317. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1.
(c) Mori, M. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vol. 2, pp 176-204. (d) Mori, M. Top.
Organomet. Chem. 1998, 1, 133-154.
(8) Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. J. Org. Chem. 2001,
66, 3525.
(9) For regio- and stereoselective cross enyne metathesis with silylated
alkynes, see: Kim, M.; Park, S.; Maifeld, S. V.; Lee, D. J. Am. Chem. Soc.
2004, 126, 10242.
(10) For the preparation of alkynyl boronate, see Supporting Information.
(11) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
a A solution of 1 and alkene (2-2.5 equiv) with catalyst 5 (5 mol %) in
CH2Cl2 (0.02 M) was heated to reflux for 4-6 h. b Isolated yield. c Ratio
was determined by 1H NMR. d The stereochemistry was confirmed by NOE
experiment. e Inseparable mixture of the desired product and the minor
adduct resulting from the CM between styrene and alkene.
possessing homoallylic substituents provided nearly 1:1
mixtures of E/Z-isomers in good yields (entries 1 and 2),
whereas that of 1c with allyltrimethylsilane gave only
Z-isomer 3c in moderate yield (59%, entry 3). The substituent
effect can be seen more clearly in the CM of alkynes 1c and
1866
Org. Lett., Vol. 7, No. 9, 2005

1d with 3-butenyl-1-bromide (entries 2 and 6), providing an
E/Z-mixture (42:58) of 3b from the former and a 98:2 ratio
of 3f from the latter. Reactions of alkyne 1d with two
different alkenes also showed different E/Z-selectivity,
providing marginal selectivity with an acetate substituent (87:
13) but excellent selectivity with an acetyl group (96:4). The
combination of more heavily functionalized alkyne 1e and
an alkene afforded high yield and selectivity (86%, >99:1)
in the formation of 3g (entry 7). Alkyne 1f with a branched
carbon at the propargylic site is well-tolerated13 in the CM
reaction with a diverse array of alkenes, providing good
yields of the corresponding vinyl boronates 3h-l with
excellent regio- and E/Z-selectivity (entries 8-12). Even
vinyl carbazole,14 which would generate a Fisher carbene-
like stable alkylidene intermediate provided high yield of 3l
with excellent E-selectivity (entry 12). However, CM
between borylated alkynes and vinyl ethers gave low yield
and selectivity accompanied with a significant amount of
deborylated product.15
Scheme 3. Vinyl Boronate Functionalization
high (98:2) E/Z ratio (Scheme 3). Under typical Suzuki
coupling conditions (Pd(PPh3)4, TlOEt, wet THF),17 vinyl
boronate 3m was converted into a cross conjugated triene 8
in 87% yield. Oxidation of the CdC-B(Pin) bond in 3m
under mild conditions (Me3NO‚2H2O, THF, reflux)18 fol-
lowed by acid treatment (TsOH, aq MeCN) induced spiro-
ketalization, thereby providing spiroketal 9 in 78% yield (two
steps).
To take advantage of the regio- and stereoselective nature
of the cross enyne metathesis between borylated alkynes and
alkenes, a tandem CM-RCM19 sequence employing enyne
1i and 1-octene was envisioned (Scheme 4). As expected,
Not only acyclic 1,3-dienes but also cyclic dienes can be
generated via enyne CM by employing an R,ω-diene. The
CM of alkyne 1c with 1,5-hexadiene (2.5 equiv) provided a
4:1 mixture of cyclic and acyclic vinyl boronates 6 and 7
(major, n ) 1; minor, n ) 2 and/or 3) in 67% yield (Scheme
2).16 Interestingly, the ratio between cyclic dinene 6 and
Scheme 2. Cross Metathesis of Alkyne with 1,5-Hexadiene
Scheme 4. Tandem CM-RCM Followed by Diels-Alder
Reaction
acyclic diene 7 does not change with respect to the change
in the steric and stereoelectronic environment of borylated
alkynes.
To demonstrate the utility of the vinyl boronates formed
via the enyne CM, subsequent transformations of these vinyl
boronates were explored. The CM reaction of alkyne 1h with
TBS-protected 4-penten-1-ol provided 3m in 84% yield with
borylated 1,3-diene 3n was generated as a single regio- and
stereoisomer, which readily underwent Diels-Alder reaction
with N-methyl maleimide to yield boronate 1020 as a single
isomer in 64% overall yield (Scheme 4). This is a rare
example of forming a 1,2,3,4-tetrasubstituted 1,3-diene with
controlled double bond geometry via enyne metathesis.21
(12) The regiochemistry of 2c was assigned after oxidation of the vinyl
boronate to the corresponding enone (2c′; see Support Information). The
regiochemistry of other compounds was assigned by analogy.
(13) The corresponding silylated alkyne showed no reactivity in CM;
see ref 9.
(14) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153.
(15) CM of 1d and ethyl vinyl ether gave low conversion, and the product
obtained was only the protodeboronated compound as an E/Z mixture.
(16) For synthesis of monosubstituted 1,3-cyclohexadienes via enyne CM-
RCM, see: (a) Smulik, J. A.; Diver, S. T. Tetrahedron Lett. 2001, 42, 171.
(b) Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126, 8110.
(17) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush,
W. R. Org. Lett. 2000, 2, 2691.
(18) Kabalka, G. W.; Slayden, S. W. J. Organomet. Chem. 1977, 125,
273. Reference 4b.
(19) For related CM-RCM sequences with alkenes and diynes, see:
Stragies, R.; Schuster, M.; Blechert, S. Chem. Commun. 1999, 237.
(20) The preparation and Diels-Alder reaction of 2-borono-1,3-diene,
see: Kamabuchi, A.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1993, 34,
4827.
Org. Lett., Vol. 7, No. 9, 2005
1867

In conclusion, we have developed an efficient enyne cross
metathesis between borylated alkynes and terminal alkenes
to generate functionalized vinyl boronates. High yields with
excellent regioselectivity were obtained irrespective of sub-
stituents on the alkyne and alkene, whereas the E/Z-
selectivity was found to be dependent upon the substituents
both on the alkyne and alkene. Further investigation to
elucidate the origin of the selectivity and the subsequent
functionalization of the vinyl boronate are in progress.
Acknowledgment. We thank WARF, NSF (CHE-
0401783), and NIH (R01 CA106673-01) for financial support
of this work as well as the NSF and NIH for NMR and Mass
Spectrometry instrumentation. We also thank Dr. Charles Fry
for obtaining NOE data for compounds 2e, 3c, and 3l.
Supporting Information Available: General procedures
and characterization of represented compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) For examples of the formation of 1,1,3,4-tetrasubstituted 1,3-diene
synthesis via tandem RCM-CM sequence, see: Lee, H.-Y.; Kim, H. Y.;
Tae, H. Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439.
OL050542R
1868
Org. Lett., Vol. 7, No. 9, 2005