Homoallylboration and homocrotylboration of aldehydes

Article abstract of DOI:10.1021/ja2048682

A simple method for addition of homoallylic fragments to aldehydes is described. Cyclopropanated allylboration reagents react with aldehydes in the presence of PhBCl2 to give high yields of bishomoallyl alcohols. Cyclopropanated cis-and trans-crotyl reage

Full text of DOI:10.1021/ja2048682

COMMUNICATION
pubs.acs.org/JACS
Homoallylboration and Homocrotylboration of Aldehydes
Wenbo Pei and Isaac J. Krauss*
Department of Chemistry MS 015, Brandeis University, Waltham, Massachusetts 02454-9110, United States
S Supporting Information
b
Scheme 1. Utility and Current Limitations of
Homoallylation
ABSTRACT: A simple method for addition of homoallylic
fragments to aldehydes is described. Cyclopropanated allyl-
boration reagents react with aldehydes in the presence of
PhBCl2 to give high yields of bishomoallyl alcohols. Cyclopro-
panated cis- and trans-crotyl reagents afford the correspond-
ing 1,3-anti- and 1,3-syn-methyl-substituted “homocroty-
lated” alcohols with high selectivity, consistent with a
ZimmermanÀTraxler transition state. Accordingly, the op-
tically active α-substituted reactant affords the E-substituted
product in 97:3 er.
llylation and crotylation of aldehydes and ketones have been
A
studied in great detail, and numerous asymmetric methods
have been developed.1 By contrast, homoallylation reactions
(Scheme 1) have been comparatively little studied, despite their
utility in natural product synthesis. Substituted homoallylation
reagents based on Mg and Li (such as 1) react with aldehydes to
give ∼1:1 diastereomeric mixtures.2 By contrast, reductive
nickel-catalyzed homoallylation with dienes, introduced by Mori
and Tamaru, is a very promising method;3 however, regioselec-
tivity is not high in the case of simple homoallylations with 1,3-
butadiene, posing an obstacle to the development of desirable
asymmetric methods. Although 1,3-anti-“homocrotylated” pro-
ducts (2-a) are accessible this way, 1,3-syn products (2-s) are not.
The one reported asymmetric variant of this process is limited to
2,5-aryl-substituted products.4 Other asymmetric syntheses of
2-s or 2-a from aldehydes or terminal alkenes have been accom-
plished in sequences of 4À9 steps.5
Scheme 2. Homoallylboration Precedent
These limitations could be overcome with cyclopropanated
analogues of allylboration reagents (3; Scheme 2). If such reagents
were to react through cyclic ZimmermanÀTraxler transition
states,6 they would afford bishomoallylic alcohol products with
high diastereoselectivity and possibly enantioselectivity. Although
stannane 4 is known, it does not homoallylate aldehydes thermally
or in the presence of BF3 Et2O.7a In fact, its nucleophilicity was
3
measured to be >108-fold less than that of the corresponding
allylstannane. However, boranes 5aÀc, synthesized by Binger7b and
Hill,7c were significantly less stable and rearranged to homo-
allylboranes at moderate temperatures. Promisingly, these re-
arrangements appeared to be nonradical, as they were
stereospecific and could be inhibited by Lewis base.
We then proceeded to screen thermal and acid-promoted9 conditions
for homoallylation of hydrocinnamaldehyde (8a). No reaction
occurred when the aldehyde and boronate were heated together
in several solvents up to 80 °C (entry 1). Strong Lewis acids such
We interpreted the results of Binger and Hill as indications
that more stable and easily handled allylboronates such as 7
might be useful homoallylation reagents (Table 1). TFA-accel-
erated SimmonsÀSmith cyclopropanation8 of commercially available
allylboronate 6 readily afforded 7, which was stable at room tempera-
ture and could be isolated either by distillation or chromatography.
Received: May 26, 2011
Published: October 20, 2011
r
2011 American Chemical Society
18514
dx.doi.org/10.1021/ja2048682 J. Am. Chem. Soc. 2011, 133, 18514–18517
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Initial Studies with Pinacol Boronate 7
Table 2. Homoallylboration Scope with Boronate 13a
temp
additives
(equiv)
% yield/%
side
entry
(°C)
conv of 8a products
1
2
up to 80 none
0/0
none
none
10
rt
Sc(OTf)3 (1)
Sc(OTf)3 (1)
0/0
3
50
rt
0/0
4
BF3 Et2O (1)
0/0
10
3
5
50
rt
CSA (1)
0/0
none
10/11/12
none
6
BCl3 (1.1)
64/>90
0/0d
7
rt
PhBCl2 (1.1)
PhBCl2 (1.1), BCl3 (0.1)
8
rt
trace/>90 10/11/12
9
10c
rt
PhBCl2 (1.1), AgTFAb (0.1) 69/>90
10/11/12
10e
rt
PhBCl2 (1.1), AgTFA (0.1) 22/>90
a Conditions: 1.5 equiv of 7 + 1.0 equiv of aldehyde; the solvent was
CDCl3 in all cases, except that in entry 1, THF, benzene and Et2O were
also tried. Yields are isolated yields based on aldehyde. b AgTFA = silver
trifluoroacetate. c Octanal was used instead of 8a. d See note 10.
e Boronate 10, byproducts analogous to 11/12, and possible aldol
adducts were observed.
a All reactions were run with 0.2 mmol of aldehyde, 3 equiv of 13,
1.5 equiv of PhBCl2, and 6.0 equiv of K2CO3. b Isolated yields. c NMR
yields are given in parentheses. The low isolated yields are due to product
volatility. d dr = ∼1:1.5 anti/syn.
Scheme 3. Diastereoselective Homocrotylations
as BF3 Et2O caused rapid ring opening of the boronate (to give
3
10) without consuming the aldehyde, while weaker Lewis acids
and some Brønsted acids gave little or no ring opening but still no
conversion of the aldehyde (entries 2À5). We were thus
surprised and pleased to find that BCl3 promoted the desired
reaction to give homoallylation product 9a in 64% yield, albeit
together with side products 10 and 11 (entry 6). In search of
milder conditions, we tried PhBCl2, but this again resulted in no
conversion (entry 7).10 We hypothesized that the special reac-
tivity of BCl3 might originate from cationic boron species formed
via disproportionation (L BCl3 + BCl3 f L BCl2+ + BCl4À).11
3
3
After screening various additives, we found that addition of
catalytic silver trifluoroacetate to the PhBCl2/7 reagent mixture
resulted in complete reactions, giving up to 69% yield of
9a.12 Unfortunately, homoallylation of other aldehydes under
these conditions resulted in lower yields and inconsistent results
(entry 10).
We imagined that the less hindered propanediol-derived
reagent 13 (Table 2) might be much more reactive than 7,
enabling reactions under milder conditions. We thus converted 7
to 13 by oxidative hydrolysis of the pinacol group and condensa-
tion of 1,3-propanediol with the resulting boronic acid.13 13,
which was stable to ambient moisture but not to chromatogra-
phy, indeed proved to be much more reactive: it readily afforded
homoallylation products in the presence of PhBCl2 and no other
additive. With solid K2CO3 added to scavenge HCl, 8a was
homoallylated in excellent yield (entry 1). Using these standard
conditions, we then investigated the scope of the reaction.
Unbranched and branched aliphatic aldehydes 8aÀe reacted in
high yield (entries 1À5). Lower isolated yields with isobutyr-
aldehyde (8d; entry 4) and pivaldehyde (8e; entry 5) were due
only to product volatility, as the NMR yields were in the same
excellent range as for the other substrates. Enolization-prone
phenylacetaldehyde (8f; entry 6) was also cleanly homoallylated
under these conditions. The ester functionality of 8g (entry 7)
was also well-tolerated. Although chiral α-substituted aldehyde
8h (entry 8) was also cleanly homoallylated, very little facial
selectivity was observed.14
18515
dx.doi.org/10.1021/ja2048682 |J. Am. Chem. Soc. 2011, 133, 18514–18517

Journal of the American Chemical Society
COMMUNICATION
Scheme 4. ZimmermanÀTraxler Models for cis Reagent 16
Scheme 5. Enantioselective Homoallylation
We were then very excited to test whether substituted homo-
allylboration reagents would react selectively through ZimmermanÀ
Traxler transition states to afford products such as 2-s (Scheme 1),
which are awkward to access by other methods.5a,c,e We thus
synthesized homocrotylation reagents 16 and 17 by the same
method used for 13 and tested their regio- and diastereos-
electivity (Scheme 3). We were pleased to see that reaction of
cis reagent 16 with 8a under the standard conditions afforded
1,3-anti-methyl-substituted bishomoallylic alcohol 18-a as a single
diastereomer. Conversely, trans-cyclopropane reagent 17 af-
forded the syn diastereomer 18-s. Although the diastereoselec-
tivity in this case was 12:1, this is ratio is roughly consistent with
the geometric purity of the reagent, which was derived from
commercial ∼95% trans-boronate.15,16 This is the first example
of diastereoselective aldehyde alkylation to give the 1,3-syn-alkyl-
substituted bishomoallylic alcohol directly.
The high diastereo- and regioselectivity is consistent with
chair transition state models, as depicted in Scheme 4, which
illustrates possible reaction pathways of cis reagent 16. The
preferred transition state leading to the observed product
18-a is 19; the 1,2-regioisomer 21 was not observed, presumably
because of a gauche interaction in chair transition state 20.
Likewise, diastereomer 18-s was avoided because of unfavorable
diaxial interactions in transition state 22. For reagent 17, the
preferred transition state analogous to 19 affords the syn product
18-s.
Importantly, the methyl stereocenter in reagent 16 retains its
configuration in product 18-a and essentially behaves as a chiral
auxiliary.17 Thus, a single enantiomer of reagent 16 must yield a
single enantiomer of product 18-a. Development of asymmetric
homocrotylation is therefore dependent only on the develop-
ment of an asymmetric route to reagents 16 and 17.
To demonstrate the utility of these reagents in enantioselec-
tive synthesis, we prepared an optically active α-chiral homo-
allylation reagent that is readily accessible via Matteson’s
chemistry18 (Scheme 5). Cyclopropyl Grignard displacement
of pinanediol chloroethyl boronate 23 afforded 24. The unreac-
tive pinanediol boronate was converted to the reactive propane-
diol boronate 25 by conversion to the cesium fluoroborate salt19
and subsequent fluorophilic hydrolysis in the presence of silica
gel and 1,3-propanediol.20 To our delight, 25 reacted with 8a to
afford 26 in 93% yield and 97:3 er as a separable 9:1 mixture of
E and Z isomers.21
provides direct access to 1,3-syn-homocrotylated products not
previously available directly from carbonyl addition reactions.
Moreover, this chemistry opens the door to the development of
asymmetric homoallylations, which we have demonstrated with
the synthesis of a bishomoallylic alcohol with high enantiomeric
excess. Full evaluation of the reaction scope and the use of
additional optically active reagents and/or chiral promoters will
be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
the synthesis of reagents 13À17 and 23À25, their use in
homoallylation reactions, and spectral data for new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
kraussi@brandeis.edu
’ ACKNOWLEDGMENT
We thank Stephanie Chun, Gabrielle Dugas, and J. Sebastian
Temme for technical assistance. We thank Ala Nassar and the
Brandeis Mass Spectrometry Facility for HRMS analysis. I.J.K.
gratefully acknowledges Brandeis University.
’ REFERENCES
(1) (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1995, 93, 2207.
(b) Denmark, S. E.; Fu, J. P. Chem. Rev. 2003, 103, 2763. (c) Lachance, H.;
Hall, D. G. Org. React. 2008, 103, 1.
(2) Li, H.; Wu, J.; Luo, J.; Dai, W. M. Chem.—Eur. J. 2010, 16, 11530.
(3) TamaruÀMori reaction: (a) Sato, Y.; Takimoto, M.; Hayashi, K.;
Katsuhara, T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771.
(b) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998,
120, 4033. (c) Kimura, M.; Fujimatsu, H.; Ezoe, A; Shibata, K.; Shimizu,
M.; Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 397.
(d) Sato, Y.; Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000, 122, 1624.
(e) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Angew. Chem., Int. Ed.
2001, 40, 3600. (f) Sato, Y.; Sawaki, R.; Saito, N.; Mori, M. J. Org. Chem.
2002, 67, 656. (g) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y.
J. Am. Chem. Soc. 2006, 128, 8559.
In conclusion, we have demonstrated that it is possible to
homoallylate carbonyl compounds through a stereoselective
cyclic mechanism similar to that of allylboration. This chemistry
(4) Yan, Y.; Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou,
Q.-L. J. Am. Chem. Soc. 2007, 129, 2248.
18516
dx.doi.org/10.1021/ja2048682 |J. Am. Chem. Soc. 2011, 133, 18514–18517

Journal of the American Chemical Society
COMMUNICATION
(5) (a) Ghosh, A. K.; Xu, X. M. Org. Lett. 2004, 6, 2055. (b) Chen, J.;
Forsyth, C. J. Angew. Chem., Int. Ed. 2004, 43, 2148. (c) Ferrie, L.;
Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2006, 8, 3441.
(d) Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009,
74, 9531. (e) Tannert, R.; Milroy, L. G.; Ellinger, B.; Hu, T. S.; Arndt,
H. D.; Waldmann, H. J. Am. Chem. Soc. 2010, 132, 3063.
(18) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc.
1986, 108, 810.
(19) Matteson, D. S.; Maliakal, D.; Pharazyn, P. S.; Kim, B. J. Synlett
2006, 3501.
(20) Molander, G. A.; Cavalcanti, L. N.; Canturk, B.; Pan, P.-S.;
Kennedy, L. E. J. Org. Chem. 2009, 74, 7364.
(6) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
(21) The Z isomer was obtained in slightly lower er (93:7) with the
79, 1920.
opposite configuration. The er was measured using chiral HPLC.
(7) (a) Lucke, A. J.; Young, D. J. J. Org. Chem. 2005, 70, 3579.
(b) K€oster, R.; Arora, S.; Binger, P. Angew. Chem., Int. Ed. Engl. 1969,
8, 205. (c) Hill, E. A.; Park, Y. W. J. Organomet. Chem. 1988, 356, 1. For
reactivity of an analogous silane, see: (d) Grignon-Dubois, M.;
Dunoguꢀes, J.; Calas, E. Can. J. Chem. 1981, 59, 802.
(8) Yang, Z. Q.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998,
39, 8621.
(9) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002,
124, 11586. (b) Ishiyama, T.; Ahiko, T.; Miyaura, N. J. Am. Chem. Soc.
2002, 124, 12414. (c) Lachance, H.; Lu, X. S.; Gravel, M.; Hall, D. G.
J. Am. Chem. Soc. 2003, 125, 10160. (d) Rauniyar, V.; Hall, D. G.
J. Am. Chem. Soc. 2004, 126, 4518. (e) Gravel, M.; Lachance, H.; Lu,
X. S.; Hall, D. G. Synthesis 2004, 1290. (f) Carosi, L.; Lachance, H.; Hall,
D. G. Tetrahedron Lett. 2005, 46, 8981. (g) Ramachandran, P. V.;
Pratihar, D.; Biswas, D. Org. Lett. 2006, 8, 3877. (h) Rauniyar, V.; Hall,
D. G. Angew. Chem., Int. Ed. 2006, 45, 2426. (i) Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660. (j) Elford, T. G.;
Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org. Chem. 2007, 72, 1276.
(k) Ramachandran, P. V.; Pratihar, D. Org. Lett. 2007, 9, 2087. (l) Hall,
D. G. Synlett 2007, 1644. (m) Rauniyar, V.; Hall, D. G. Synthesis 2007,
3421. (n) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 4315. (o) Carosi, L.;
Hall, D. G. Angew. Chem., Int. Ed. 2007, 46, 5913. (p) Lou, S.; Moquist,
P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (q) Rauniyar, V.;
Zhai, H. M.; Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481. (r) Rauniyar,
V.; Hall, D. G. J. Org. Chem. 2009, 74, 4236. (s) Barnett, D. S.; Moquist,
P. N.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 8679. (t) Chen, M.;
Roush, W. R. Org. Lett. 2010, 12, 2706–2709. (u) Jain, P.; Antilla, J. C.
J. Am. Chem. Soc. 2010, 132, 11884.
(10) Aldehydes in fact react with PhBCl2 quantitatively to form
α-chloro ethers, which are hydrolyzed back to the aldehydes upon
aqueous workup. Similar boron species have been observed by Lappert,
and analogous silicon species have been reported by Denmark. See:
(a) Frazer, M. J.; Gerrard, W.; Lappert, M. F. J. Chem. Soc. 1957, 739.
(b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002,
124, 13405.
(11) (a) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett.
1999, 40, 4457. (b) Evans, D. A.; Halstead, D. P.; Allison, B. D.
Tetrahedron Lett. 1999, 40, 4461. (c) Evans, D. A.; Allison, B. D.; Yang,
M. G.; Masse, C. E. J. Am. Chem. Soc. 2001, 123, 10840.
(12) This result does not necessarily confirm the involvement of a
cationic reaction manifold, as we would expect Ag(OCOCF3) to replace
chloride with the more strongly coordinating trifluoroacetate. By con-
trast, use of Ag(SbF6) as the additive results in an intractable complex
mixture.
(13) Coutts, S. J.; Adams, J.; Krolikowski, D.; Snow, R. J. Tetrahedron
Lett. 1994, 35, 5109.
(14) When run at À35 °C, the reaction was incomplete after days
and the selectivity was not greatly improved.
(15) The minor diastereomer 18-a presumably is produced from a
cis impurity (16) present at a ∼5% level in the trans reagent 17. Since
16 is more reactive than 17 and 3 equiv of the reagent mixture was used,
the percentage of the minor diastereomer was slightly amplified in the
homocrotylation product 18-s relative to reagent 17.
(16) The diastereomeric ratios for 18-s and 17 were measured by
integration of 1H NMR signals.
(17) This is true under the assumption that only one bond of the
cyclopropane is cleaved during the conversion of 16 to 18-a. Alternative
mechanisms leading to 18-a but involving cleavage of the other cyclopro-
pane bonds would be very complex and are inconsistent with the high
observed diastereoselectivity.
18517
dx.doi.org/10.1021/ja2048682 |J. Am. Chem. Soc. 2011, 133, 18514–18517