Stereospecific synthesis of cyclobutylboronates through copper(I)-catalyzed reaction of homoallylic sulfonates and a diboron derivative

Article abstract of DOI:10.1021/ja101793a

A copper(I)-catalyzed stereospecific reaction for the preparation of cis- and trans-1-silyl-2-borylcyclobutanes as well as 1-phenyl-2-borylcyclobutanes is reported. (Z)- and (E)-Homoallylic methanesulfonates were converted to the corresponding trans- and

Full text of DOI:10.1021/ja101793a

Published on Web 04/12/2010
Stereospecific Synthesis of Cyclobutylboronates through Copper(I)-Catalyzed
Reaction of Homoallylic Sulfonates and a Diboron Derivative
Hajime Ito,*,†,‡ Takashi Toyoda,† and Masaya Sawamura†
Department of Chemistry, Faculty of Science, Hokkaido UniVersity, Sapporo 060-0810, Japan, and PRESTO,
Japan Science and Technology Agency (JST), Honcho, Kawaguchi, Saitama 332-0012, Japan
Received March 3, 2010; E-mail: hajito@sci.hokudai.ac.jp
Cyclobutanes have received considerable attention as prevalent
structures in natural products and as versatile synthetic inter-
mediates.1 However, synthetic methods for cyclobutanes with
multiple stereocenters are relatively less developed than those
for other ring systems. [2 + 2] Photocycloadditions are the most
widely used and reliable method for stereoselective cyclobutane
synthesis; however, high regio- and stereoselectivity is almost
limited to the enone-alkene reactions.1 Cyclobutylboronates
with stereodefined structures are expected to be a promising
synthetic intermediate because they have high configurational
stability and many stereospecific transformations of C-B bonds
exist. However, highly general methods for the stereoselective
synthesis of such compounds have been scarcely reported.2
Herein, we describe a novel catalytic protocol for accessing cis-
and trans-1-silyl-2-borylcyclobutanes as well as 1-aryl-2-boryl-
cyclobutanes. The synthetic utility of the compounds is also
demonstrated by their stereospecific derivatization.
During the course of our studies on copper(I)/diboron catalytic
reactions,3,4 we reported the enantio- and stereoselective reaction
that produces trans-1-silyl-2-borylcyclopropane compounds
(Scheme 1a).3d The reaction mechanism involves intramolecular
ring closing of the organocopper intermediate formed by the
reaction between a borylcopper intermediate and a carbonate
derivative of a 3-silyl-substituted allylic alcohol. The starting
point of this investigation was to determine whether 1,2-
bimetallic cyclobutanes could be obtained by the reaction of
4-silyl-3-buten-1-ol derivatives (Scheme 1b). This was antici-
pated to be more challenging because it involves the kinetically
unfavorable closure of a four-membered ring.5 To the best of
our knowledge, no transition-metal-catalyzed reaction involving
such ring closures has been reported. The initial attempts using
a carbonate derivative (Scheme 1b, X ) OCO2Me) with
copper(I)/diboron systems gave no desired products.
4-(dimethylphenylsilyl)buten-3-yl methanesulfonate [(Z)-1a] with
2.0 equiv of bis(pinacolato)diboron (2) in the presence of 5 mol
% CuCl, 5 mol % dppp, and 1.0 equiv of K(O-t-Bu)/THF for
20 h at room temperature, which afforded the desired trans-1-
silyl-2-borylcyclobutane (trans-3a) in high yield with excellent
diastereoselectivity (93%, trans/cis >99:1) (Table 1, entry 1).6
The reaction with a lower catalyst loading (1 mol %) or a smaller
amount of diboron (1.2 equiv) also resulted in good yields (entry
2, 83%; entry 3, 95%) with excellent selectivities (trans/cis >99:
1). Use of CuI instead of CuCl gave a comparable yield and
selectivity (entry 4). The copper(I) salt,7 a phosphine ligand,
and the base [K(O-t-Bu)] are essential for the reaction (entries
5-7). The reaction with K2CO3 as the base resulted in a poor
yield (entry 8). A slightly lower yield was observed when dppe
rather than dppp was used (entry 9). The use of dppb, dppf,
Xantphos, and PPh3 resulted in moderate to low yields (entries
10-13). We could not find side products that occurred from the
regioisomeric Cu-B insertion in any case.
Table 1. Reaction of Methanesulfonate 1 with Diboron 2 Using
Various Cu(I) Catalystsa
entry
CuX
ligand
base
yield (%)b
dr (trans/cis)c
1
CuCl
CuCl
CuCl
CuI
none
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
dppp
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
none
93
83
95
97
0
2
0
5
86
47
63
40
15
>99:1
>99:1
>99:1
>99:1
-
2d
3e
4
dppp
dppp
dppp
dppp
none
dppp
dppp
dppe
dppb
dppf
5
6
7
8
-
-
-
>98:2
>98:2
15:1
>98:2
>98:2
K2CO3
9
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
10
11
12
13
Scheme 1. Copper(I)-Catalyzed Small-Ring Formation
Xantphos
PPh3
a Reaction conditions: sulfonate 1 (0.5 mmol), 2 (1.0 mmol), CuCl
(0.025 mmol), ligand (0.025 mmol), and K(O-t-Bu)/THF (1.0 M, 0.5
mL) at room temperature. b Determined by GC analysis. c Determined
by GC analysis. d Using 1 mol % CuCl and dppp. e Using 1.2 equiv of
2; the isolated yield was 74%.
As summarized in Table 2, this reaction proceeds with various
(E)- and (Z)-homoallylic sulfonates in a stereospecific manner with
high fidelity in the transfer of stereochemical infomation. This is
in stark contrast to our previous results for cyclopropylboronate
formation, where only trans-cyclopropane derivatives were obtained
as the major products, irrespective of the configuration (E or Z) of
the starting allylic carbonates.3d (E)-4-(Dimethylphenylsilyl)buten-
Extensive optimization of leaving groups, copper catalysts,
ligands, and additives was performed to ascertain the conditions
under which the four-membered-ring formation reaction would
proceed. The result of this optimization led the reaction of (Z)-
† Hokkaido University.
‡ Japan Science and Technology Agency.
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10.1021/ja101793a  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stereospecific Formation of Cycloalkylboronatesa
the product yield (trans-3e, 76%, entry 7), but para substitution
of an electron-withdrawing CF3 group resulted in a poor yield
(28%) and the formation of many side products. (E)-Configured
homoallyl compounds showed a similar trend in yield (entries
9-11), but the more strongly electron-donating p-MeO group
resulted in a moderate yield (60%, entry 12). As expected on
the basis of the requirement that the alkene substrates should
have a low LUMO level for the borylcupration process, an alkyl-
substituted compound [(Z)-1h] remained intact (entry 13).8 The
reactions with (Z)- and (E)-1i afforded five-membered-ring
products, trans- and cis-1-silyl-2-borylcyclopentanes, in good
yields with high stereospecificity (entries 14 and 15). In the case
of the six-membered-ring version, however, only trace amounts
of the products were detected (entries 16 and 17). Side products
originating from the regioisomeric insertion could not be detected
in the reactions shown in Table 2.
Stereospecific H2O2 oxidation of the B-C bonds in the above
products afforded the corresponding trans- and cis-cyclobutanols
with high diastereomeric purity. Other derivatization examples
are also shown in Schemes 2 and 3. One-carbon homologation
of trans- and cis-3c9 and subsequent oxidation and esterification
afforded trans- and cis-4, respectively. Oxidation of the Si-C
bonds of the isomers of 4 gave trans- and cis-5 with excellent
diastereomeric purities (Scheme 2).10 Monobenzoate derivatives
of 1,2-butandiol (trans and cis-7) were also synthesized by
oxidation of the B-C bonds of trans- and cis-3c followed by
benzoate protection and subsequent Si-C bond oxidation. The
cyclobutylamine derivatives trans- and cis-8 were also obtained
without detectable erosion of diastereomeric purity from trans-
and cis-3d, respectively (Scheme 3).11
Scheme 2. Stereospecific Derivatization of Cyclobutylboronatesa
a Conditions: 1 (0.5 mmol), 2 (1.0 mmol), CuCl (0.025 mmol), dppp
(0.025 mmol), and K(O-t-Bu)/THF (1.0 M, 0.5 mL). b Isolated yield.
c Determined by GC analysis. d Run on a 3 mmol scale. e NMR yield.
f Using 10 mol % catalyst. g Using CuI instead of CuCl. h Run on a 0.25
mmol scale.
a Conditions: (a) LiCH2Cl, THF, -78°C to rt, 3-5 h; (b) H2O2,
NaOH(aq), THF, 0 °C, 2-3 h; (c) PhCOCl, pyridine, CH2Cl2, 0 °C, 3.5-4
h; (d) TBAF, THF, rt, 30 min; (e) H2O2, KHCO3, MeOH, rt, 30 min. The
1
yields of trans- and cis-7 were determined by H NMR spectroscopy.
Scheme 3. Stereoselective Synthesis of trans- and cis-2-
Phenylcyclobutylamines
3-yl methanesulfonate [(E)-1a, E/Z 95:5] was efficiently converted
to cis-1-silyl-2-borylcyclobutane (cis-3a) in high yield with high
diastereoselectivity (99% NMR yield, 76% isolated yield, trans/
cis 5:95) (entry 1). The reaction of trimethylsilyl and benzyldim-
ethylsilyl derivatives afforded the corresponding products with very
high fidelity in the transfer of stereochemical information (entries
2-5).
Substrates with an aryl group instead of the silyl group were
also converted into the corresponding cyclobutanes with a high
degree of stereospecificity (entries 6-12). The reaction of (Z)-
4-phenylbuten-3-yl methanesulfonate [(Z)-1d] gave trans-3d in
89% NMR yield and 51% isolated yield. Substituting an electron-
donating methyl group at the para position did not greatly affect
A proposed mechanism is depicted in Figure 1.3,4,8 This
reaction is initiated by the generation of borylcopper(I) inter-
mediate B through the σ-bond metathesis reaction between
diboron and species A formed by the reaction of CuCl, K(O-t-
Bu), and dppp. Insertion of the double bond in 1 into the Cu-B
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C O M M U N I C A T I O N S
bond produces C, in which the Cu-C bond is stabilized by the
electronic effect of the adjacent silyl- or aryl- group (R1 or R2).
These effects would be responsible for the high insertion
regioselectivities.8 Alkyl-substituted starting compounds cannot
undergo this step because of the high alkene LUMO level and
the lack of the electronic effect in C. Ring closure then proceeds
through alkoxycuprate D, which is formed by coordination of
K(O-t-Bu) to C and would facilitate the intramolecular nucleo-
philic substitution.12 The poor product yields observed for the
aryl substrate bearing an electron-withdrawing group could be
attributed to low intermediate nucleophilicity in this ring-closing
step. The stereochemical outcome suggests that the intramo-
lecular substitution proceeds with retention of the configuration
on the carbon atom at the copper center. We thus speculate that
the ring-closing step proceeds through Cu(III) metallacycle
structure E. This explains the significant drop in the yield of 3j
(n ) 3), as the formation of seven-membered Cu(III) metalla-
cycle would be unfavorable in comparison with five- and six-
membered ones (n ) 1, 2). The catalytic cycle is closed by the
formation of 3 and potassium methanesulfonate accompanied
by the regeneration of A.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(6) This is the first example of 1-silyl-2-borylcyclobutanes. All of the products
(trans- and cis-3a-i) of the copper(I)-catalyzed reaction are new com-
pounds.
(7) For a metal-free reaction, see: Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2009, 131, 7253–7255.
(8) The highly reactive and regioselective feature observed in the reaction of
the silyl substrates is due to the R-stabilization effect of the silyl groups.
See: (a) Brinkman, E. A.; Berger, S.; Brauman, J. I. J. Am. Chem. Soc.
1994, 116, 8304–8310. Also see ref 3d. For a similar effect in the borylation
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Figure 1. Proposed mechanism for the copper(I)-catalyzed ring forma-
tion.
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In summary, we have developed a copper(I)-catalyzed reaction
that produces 1,2-disubstituted cyclobutanes, which are useful
synthetic building blocks for the preparation of cyclobutane
derivatives. The reaction proceeds in a stereospecific manner, with
(Z)- and (E)- homoallylic sulfonates being converted to the trans
and cis products, respectively. The development of enantioselective
versions of this reaction with chiral ligands is currently under
investigation.
(12) Using an excess amount of tert-butoxide with respect to the copper(I)
salt was crucial for ensuring ring closure. The reaction of (Z)-1a and 2
in the presence of CuCl (110 mol %), K(O-t-Bu) (100 mol %), and
dppp (10 mol %) in THF was very slow, despite the presence of a large
amount of copper(I), and afforded trans-3a in yields of 7% after 3 h
and 10% after 20 h. Conversely, a similar reaction with CuCl (110 mol
%), excess K(O-t-Bu) (150 mol %), and dppp (10 mol %) went to
completion smoothly within 3 h, affording trans-3a with a yield of 97%.
It is known that the formation of borylcopper(I) intermediates and their
addition to activated alkenes proceeds without excess base, which
suggests that K(O-t-Bu) most probably affects the cyclization step (see
refs 3d and 8).
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research (B) (JSPS) and the PRESTO Program (JST).
We thank Prof. K. Tanino for helpful discussions.
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