(BDP)CuH: A "hot" Stryker's reagent for use in achiral conjugate reductions

Article abstract of DOI:10.1021/ol702689v

(Chemical Equation Presented) A ligand-modified, economical version of Stryker's reagent (SR) has been developed based on a bidentate, achiral bis-phosphine. Generated in situ, "(BDP)CuH" smoothly effects conjugate reductions of a variety of unsaturated substrates, including those that are normally unreactive toward SR. Substrate-to-ligand ratios typically on the order of 1000-10000:1 can be used leading to products in high yields.

Full text of DOI:10.1021/ol702689v

ORGANIC
LETTERS
2
008
Vol. 10, No. 2
89-292
(
BDP)CuH: A “Hot” Stryker’s Reagent
2
for Use in Achiral Conjugate Reductions
Benjamin A. Baker, Zˇ arko V. Bo sˇ kovi c´ , and Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received November 6, 2007
ABSTRACT
A ligand-modified, economical version of Stryker’s reagent (SR) has been developed based on a bidentate, achiral bis-phosphine. Generated
in situ, “(BDP)CuH” smoothly effects conjugate reductions of a variety of unsaturated substrates, including those that are normally unreactive
toward SR. Substrate-to-ligand ratios typically on the order of 1000−10000:1 can be used leading to products in high yields.
Copper(I) hydride is a mild and selective reducing agent,
whether used in stoichiometric or catalytic quantities. Among
the most extensively studied and routinely used is the
complex with CuH was examined. Treatment of inexpen-
sive Cu(OAc)
2
2
‚H O (directly from the bottle) at room tem-
7
perature with excess polymethylhydrosiloxane (PMHS) and
one-tenth the amount of ligand relative to Cu(II) led to a
yellow-colored solution in toluene (1.0 M; Scheme 1). The
3 6
phosphine-stabilized hexameric complex [(Ph P)CuH] , com-
1
monly referred to as Stryker’s reagent (SR). It smoothly
effects conjugate reductions of various R,â-unsaturated
2
compounds with considerable chemoselectivity. Originally,
Scheme 1. Preparation and Use of (BDP)CuH (2)
hydrogen gas was employed for its preparation and use as a
3
stoichiometric reductant. More recently, alternatives such
4
5
as stannanes, boranes, and in particular, silanes have been
6
developed as hydrogen equivalents in CuH chemistry.
Nonetheless, the reagent’s inherent sensitivity to air, limited
reactivity toward more challenging/hindered substrates, and
high cost have encouraged us to find an alternative that
addresses these issues. In this paper, we present a method
for preparation of a new, “hot” Stryker’s reagent capable of
not only reducing sterically congested substrates but also
doing so with exceptional substrate-to-ligand (S/L) ratios as
well as in excellent isolated yields.
The potential for 1,2-bis(diphenylphosphino)benzene (1;
o-BDPPB, shortened herein to “BDP”), a readily available,
achiral bidentate ligand, to form a more reactive 16-electron
presumed in situ formed copper hydride complex 2, (BDP)-
CuH, was found to be especially reactive in subsequent
8
1
0.1021/ol702689v CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

Table 1. Representative Reductions of R,â-Unsaturated Carbonyl Compounds
a
Isolated; purified by chromatography or Kugelrohr distillation. b Reaction run without t-BuOH. c Mixture (3:1) of inseparable isomers (see text).
conjugate reductions of both alkenes and alkynes activated
by an ester, ketone, aldehyde, or nitrile. Solutions prepared
in this fashion provide a S/L ratio of 1000:1 based on 1
equiv of substrate. Several representative examples are illu-
strated in Table 1. In most cases, limited amounts of t-BuOH
(
1) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc.
989, 111, 8818.
(
3 equiv) were used to achieve additional enhancements in
9
1
reaction rates.
290
Org. Lett., Vol. 10, No. 2, 2008

A direct comparison was made between Stryker’s reagent
and (BDP)CuH using isophorone, a particularly challenging
test case given both â,â-disubstitution and the geminal
methyl groups at C-5 (Scheme 2). While SR used at a S/L
slowly than enones (compare entry 3 vs 8), although an
unhindered acrylate (entry 7) gave the corresponding ester
within 2 h. Noteworthy is the case of tert-butyl enoate (entry
8) containing a distant tetrazolyl sulfide; no effect on the
rate of hydrosilylation by these heteroatoms was seen (per-
haps by competitive complexation with BDP for copper).
Ethyl sorbate (entry 9) reacts with little regioselectivity to
give an inseparable mixture of 1,4- and 1,6-reduction
products (1:3, favoring 1,6- followed by R-protonation). No
attempt was made to improve this ratio (e.g., by lowering
the temperature). An acetyleneic ester (entry 10) reduces
smoothly to the corresponding saturated derivative; no enoate
intermediate could be observed in the course of this conver-
Scheme 2. Comparison of Reagents Using Isophorone
10
sion. Cinnamylnitrile (entry 11) was slow to convert, even
at an S/L ratio of 100:1.
Attempts were made to mimic Stryker’s use of hydrogen
1b
gas as a stoichiometric reductant in several reactions. Under
our standard conditions, PMHS was replaced by hydrogen
at pressures up to 50 psi. Surprisingly, no reduction of sub-
strate was observed in any case. Perhaps the bidentate nature
a
Ligand 1 (0.1 mol %) was combined with 5% SR; GC
conversion.
3
of BDP on copper(I), as opposed to monodentate Ph P in
SR, prevents insertion of hydrogen to form the metal hydride.
The stability of toluene solutions of (BDP)CuH over time
has also been examined (Scheme 3). Best results were
)
20 afforded only 7% conversion after 24 h, 2 led to
quantitative reduction in less than 5 h with a S/L ratio of
1
000:1. Increasing the S/L ratio to 10,000:1 lengthened the
reaction time to 15 h (yield: 98%). Enhanced reactivity was
not observed, nor was the extent of conversion improved,
in the reaction of isophorone with SR in the presence of
Scheme 3. Room-Temperature Stability of (BDP)CuH
3
added triphenylphosphine (2 equiv relative to (Ph P)CuH).
However, addition of only 0.1% BDP to SR (4 mol %
relative to substrate) led to complete reduction of isophorone.
The examples in Table 1 depict the versatility of this
process. Other enones (entries 1-3) were also well-behaved
toward (BDP)CuH. Cholestenone (entry 4) was found to
over-reduce to the â-alcohol using 2 in the presence of
t-BuOH, although exclusive conjugate reduction to the ketone
could be realized in the absence of this additive (entry 5).
By contrast, 4% SR gave a 1:1 mix of 1,2- and 1,4-adducts,
along with ca. one-third of the starting material after 12 h.
No over-reduction was observed in the case of myrtanal
obtained when only 1% copper was present, which relative
to the amount of ligand present (0.1%) is still a 10-fold
excess. Under these conditions, some of the excess copper
precipitated out of solution, presumably as nonligated copper
hydride. The trivial addition of triphenylphosphine (1 equiv
relative to copper; 1%) prevents this occurrence and allows
for a stock solution that can be stored indefinitely at room
temperature under argon. tert-Butyl alcohol was omitted
from this formulation due to its tendency to decompose
silanes over time.
Reaction times could be reduced by employing somewhat
higher temperatures, conveniently achieved under microwave
irradiation (Table 2). Sixty degrees was determined to be
the upper limit for use of (BDP)CuH in conjugate reductions.
Higher temperatures resulted in competitive reagent decom-
position. In the specific case of isophorone, which requires
(entry 6). As expected, enoates reacted somewhat more
1
1
(
2) (a) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1
998, 39, 4627. (b) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473. (c) Hughes, G.;
Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253. (d)
Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793. (e)
Desrosiers, J.-N.; Charette, A. Angew. Chem., Int. Ed. 2007, 46, 5955.
(3) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker, J. M.
Tetrahedron Lett. 1988, 29, 3749.
(
(
(
4) Miao, R.; Li, S.; Chiu, P. Tetrahedron 2007, 63, 6737.
5) Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41, 4580.
6) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem.
Soc. 2003, 125, 8779.
7) Lawrence, N. J.; Drew, M. D. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 3381.
(
(10) Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755.
(11) Preparation of 10 mL of 1 M Stock Solution of (BDP)CuH. In
a flame-dried 50 mL amber vial which was cooled under argon were added
Cu(OAc)2‚H2O (20.0 mg, 0.1 mmol), bis-diphenylphoshinobenzene (4.46
mg, 0.01 mmol), and triphenylphosphine (27.0 mg, 0.1 mmol). The reagents
were dissolved in freshly distilled toluene (8.0 mL) and allowed to stir at
room temperature for 1 h. Polymethylhydrosiloxane (PMHS) (2.0 mL, 30
mmol) was added dropwise to the stirring solution. There was an immediate
color change from blue to red. The stock solution was thoroughly purged
with argon and sealed. Storage in a refrigerator is recommended.
1
(
8) H NMR (benzene-d6) δ 1.49. Treatment of Stryker’s reagent (δ 3.55)
with ligand 1 results in the total disappearance of the hydride signal with
concommitant appearance of a peak at δ 1.49. The addition of PPh3 to
(
1
BDP)CuH leads to no change in the spectrum for the hydride signal at δ
.49.
(
9) (a) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003,
5
, 2417. (b) Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet. Chem.
2
001, 624, 367.
Org. Lett., Vol. 10, No. 2, 2008
291

Table 2. Microwave-Assisted Reductions Using (BDP)CuH
Scheme 4. New Preparation of Ligand 1
time (min)
T (°C)
solvent
toluene
Et2O
THF
DMF
toluene
Et2O
GC conversion (%)
15
15
15
15
35
35
35
60
60
60
60
60
60
60
76
60
10
<5
100
useful in 1,4-reductions of a variety of activated alkenes and
alkynes, including hindered substrates.
a
Acknowledgment. Financial support provided by the
NSF (CHE 05-50232) is warmly acknowledged.
b
81
82
2:1 toluene/THF
Supporting Information Available: Characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
a
No reduction due to the reaction between DMF and PMHS. b 92%
isolated yield.
OL702689V
5
1
3
h to reach completion at room temperature (S/L ) 1,000:
; see Scheme 2), 1,4-reduction could be accomplished in
5 min. Although toluene seems to be the favored solvent,
(
12) (a) Preparation of 1,2-Bis(diphenylphosphino)benzene. A flame-
dried 250 mL round-bottom flask cooled under argon was charged with
freshly distilled THF (75 mL). Potassium (3.52 g, 90.0 mmol) was added
in small pieces with stirring. The reaction flask was fitted with a reflux
condenser under positive argon pressure, and chlorodiphenylphosphine (8
mL, 45.0 mmol) was added dropwise. The solution was then heated to reflux
until potassium was consumed and the mixture had assumed a characteristic
red color. To this refluxing solution was added o-difluorobenzene (2 mL,
clearly other selected media (e.g., Et
alternatives.
2
O) are reasonable
Finally, a new procedure was developed for the preparation
of ligand 1, further streamlining access to this otherwise
relatively expensive precursor.1 Thus, after considerable
experimentation, it was found that o-difluorobenzene under-
goes double displacement with potassium diphenylphosphide
in refluxing toluene (Scheme 4). This approach can be used
to obtain gram quantities of bis-phosphine 1.
In summary, a new, economically attractive,13 storable,
and yet highly kinetically reactive source of catalytic copper
hydride has been developed based on a readily available bis-
phosphine ligand. This species, (BDP)CuH, is especially
2
0.0 mmol) via syringe followed by freshly distilled toluene (100 mL).
2
The solution was refluxed for 24 h and then cooled to rt, and the volatiles
were removed by rotary evaporation. The solution was redissolved in
toluene, and 5 g of activated charcoal (Norit A) was added. The resulting
mixture was hot filtered through a Celite pad and concentrated in vacuo,
and the residue was recrystallized from toluene yielding 1,2-bis(diphen-
ylphosphino)benzene (6.7 g, 75%) as a white crystalline solid: mp 185-
2b
1
2
86 °C (lit.1 mp 183-185 °C). (b) McFarlane, H. C. E. Polyhedron 1983,
, 303.
(13) Based on prices quoted in the latest Sigma-Aldrich catalog, costs
to reduce 1 mol of substrate employing (a) stoichiometric Stryker’s reagent
SR) ) $18,000; (b) using 5 mol % SR ) $600. The same scale reduction
using (BDP)CuH (0.1 mol %) would cost $20.
(
292
Org. Lett., Vol. 10, No. 2, 2008