Rhodium-catalyzed redox allylation reactions of ketones

Article abstract of DOI:10.1039/c1cc14691b

Ketones react with allyl acetate to generate tertiary homoallylic alcohols in the presence of a rhodium catalyst and bis(pinacolato)diboron. A range of substrates, including aryl, alkyl and cyclic ketones react smoothly under these conditions. Diastereoselective allylation reactions of functionalized ketones such as pregnenolone acetate are also reported.

Full text of DOI:10.1039/c1cc14691b

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COMMUNICATION
Rhodium-catalyzed redox allylation reactions of ketoneswz
Florence J. Williams, Robin E. Grote and Elizabeth R. Jarvo*
Received 30th July 2011, Accepted 20th September 2011
DOI: 10.1039/c1cc14691b
Ketones react with allyl acetate to generate tertiary homoallylic
alcohols in the presence of a rhodium catalyst and bis-
to a group 8 metal catalyst could provide several benefits.
First, it could provide a system capable of reacting with
recalcitrant electrophiles, such as ketones, as we have observed
that allyliridium(I) complexes are potent nucleophiles that
(
pinacolato)diboron. A range of substrates, including aryl, alkyl
and cyclic ketones react smoothly under these conditions.
Diastereoselective allylation reactions of functionalized ketones
such as pregnenolone acetate are also reported.
1
2
attack ketones at room temperature. Second, the switch
could streamline the mechanism, minimizing potential for side
reactions and provide a more tractable system for ligand
tuning. In palladium-catalyzed reactions, we hypothesized
allylpalladium complex 1 is formed, but rapid reductive
elimination consumes this intermediate before it reacts with
Redox allylation reactions couple an allylic alcohol, acetate, or
halide with an electrophile in the presence of a reducing agent
1
–5
(
eqn (1)).
These transformations eliminate the multi-step
1
3
the imine (Scheme 1a). A fluoride-promoted transmetalla-
tion reaction is required to generate a second allylpalladium
intermediate that can react with imine. We reasoned that if we
could avoid or redirect the reductive elimination reaction that
forms allylsilane, the first allylmetal intermediate could serve
as the nucleophile. The catalytic process would be simplified
and likely become more efficient. Our working hypothesis is that
rhodium and iridium complexes would avoid the undesired
reductive elimination reaction by virtue of their higher oxida-
tion state. Upon oxidative addition and transmetallation, an
synthetic sequence needed to first transform the allylic acetate
to an allylmetal reagent such as an allylic boronic ester or an
allylic stannane. Therefore, they can reduce the environmental
6
and practical costs associated with a longer synthetic sequence.
For these reasons, redox allylation reactions can be very useful
in complex molecule synthesis. The wide application of the
Nozaki–Hiyama–Kishi (NHK) reaction in allylation reactions
7
of complex synthetic intermediates exemplifies this point. In
recent years, Krische has developed redox allylation reactions
of aldehydes where isopropanol or the substrate itself serves as
reducing agent. This method sets a high bar for atom economy
in redox allylation reactions of aldehydes. However, few
8
examples of redox allylation reactions of ketones exist.
Notably, Sigman has developed an enantioselective NHK
9
reaction of ketones. In this communication, we report a
rhodium-catalyzed redox allylation reaction of ketones. This
reaction has broad scope, including aryl and alkyl ketones,
and provides diastereoselective allylation reactions of poly-
cyclic synthetic intermediates.
ð1Þ
We previously developed a redox allylation reaction of imines
utilizing a palladium catalyst and hexamethyldisilane as the
1
0,11
terminal reducing agent.
Upon analysis of the proposed
mechanism of the transformation, we thought that switching
Natural Sciences I 4114, Department of Chemistry, University of
California, Irvine, Irvine, California, USA. E-mail: erjarvo@uci.edu
w This article is part of the ChemComm ‘Emerging Investigators 2012’
themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic and analytical data for all new compounds.
See DOI: 10.1039/c1cc14691b
Scheme 1 Possible mechanisms for palladium- and rhodium-catalyzed
redox allylation reactions.
1
496 Chem. Commun., 2012, 48, 1496–1498
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allylrhodium(III) complex (2) would be formed (Scheme 1b).
III
This Rh intermediate has three X-type ligands, and should
may indicate an unusually important role of the acetate group
17
in the reaction progress.
undergo a reductive elimination reaction to form a Si–O, not
Si–C bond, based on the difference in bond strengths. A new
allylrhodium(I) complex (3) would be formed, and we
hypothesize, in analogy to our work with allyliridium(I) com-
plexes, that this complex will be highly nucleophilic.
Having optimized the reaction conditions, we examined a
series of ketones to determine the scope of the reaction
(Table 2). Electron-rich or electron-poor acetophenone
derivatives underwent smooth allylation reaction, with the
electron deficient p-chloroacetophenone substrate affording
the highest yield. Aliphatic ketones proved to be the best
substrates (entries 7 and 8). This is significant, as many
metal-catalyzed nucleophilic additions to carbonyl derivatives
cannot be utilized with aliphatic substrates due to competative
enolization. The optimized reaction conditions are sufficiently
neutral and mild such that products arising from enolization are
not observed. The reaction showed a pronounced sensitivity to
steric effects and the use of MeDuphos as ligand typically
improves yield for challenging substrates (entries 6 and 9).
With the knowledge that the reaction conditions were mild
and neutral, we sought to examine more complex ketones to
probe functional group tolerance and highlight the utility of
the method for more difficult reactions of synthetic inter-
mediates (Scheme 2). Pregnenolone acetate was chosen as a
sterically encumbered ketone containing an a-stereocenter
(eqn (2)). With a simple increase in equivalents of allyl acetate
and a longer reaction time, homoallylic alcohol 5 was obtained
Based upon these principles, we set out to identify a rhodium
complex that could catalyze a redox allylation reaction in the
14
presence of a diboron or disilane reducing agent (Table 1).
A combination of [Rh(cod)Cl] and bis(pinacolato)diboron
provided an encouraging yield of product (entry 2). We found
that [Rh(cod)Cl] was superior to other rhodium sources
2
2
because it afforded the cleanest reactions with minimal decom-
position of acetophenone. Electron-rich bidentate phosphine
ligands were examined with thought of facilitating oxidative
addition and increasing the nucleophilicity of the putative
allylrhodium intermediate (3). Dimethylphosphinoethane
(
dmpe) was found to be the optimal ligand for the transforma-
1
5
tion (entries 6–9). Added equivalents of allyl acetate and
diboron reagent provided a slight increase in the yield
(cf. entries 5 and 6). Importantly, control experiments are
consistent with rhodium-catalysis of the key C–C bond forming
step; in the presence or absence of rhodium catalyst, allyl-
boronic ester does not allylate acetophenone (entry 15).
a
Interestingly, when examining the effect of additives, we
noted that added acetate, a potential byproduct of the reaction,
was detrimental to the reaction (entries 10–12). We examined
other allyl oxidative addition partners to avoid formation of
this byproduct, however, only the use of allyl acetate resulted in
Table 2 Scope of allylation reaction
1
6
the desired transformation (entries 13 and 14). These data
b
Entry
Ketone
Product
Yield (%)
a
Table 1 Optimization of rhodium-catalyzed redox allylation reaction
1
2
3
4
4a
4b
4c
4d
71
83
61
c
54(64)
5
4e
4f
65
46
Yield
(%)
b
c
Entry Change from standard reaction conditions Ligand
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
[(CH
None
Rh(cod)BF
3
)
3
Si]
2
instead of (Bpin)
2
None
None
None
None
dppe
dppe
o5
20
d
6
d
4
instead of [Rh(cod)Cl]
Cl instead of [Rh(cod)Cl]
2
2
25
o5
45
Rh(PPh
None
3
)
3
2 equiv allyl acetate and 2 equiv (Bpin)
2 equiv allyl acetate and 2 equiv (Bpin)
2 equiv allyl acetate and 2 equiv (Bpin)
2 equiv allyl acetate and 2 equiv (Bpin)
Added KOAc (20 mol%)
Added KOAc (1 equiv)
Added NaOAc (1 equiv)
Allylbromide instead of allyl acetate
Allyl triflate instead of allyl acetate
AllylB(pin) instead of allyl acetate
2
2
2
2
50
MeDuphos 50
7
8
4g
82
99
dcpe
dmpe
dppe
dppe
dppe
dppe
dppe
dppe
65
70
30
5
o5
o5
o5
o5
0
1
2
3
4
5
4h
4i
d
9
c
42(65)
and (Bpin)
2
a
b
Acetophenone] = 0.4 M. MeDuphos = 1,2-Bis[(2S,5S)-2,5-di-
[
a
b
methylphospholano]benzene; dppe = diphenylphosphinoethane; dcpe =
dicyclohexylphosphinoethane; dmpe dimethylphosphinoethane.
Yield determined by H NMR spectroscopy by comparison to
[Ketone] = 0.4 M. See ESIz for full experimental details. Isolated
c
yield after column chromatography. Yield determined by H NMR
d
spectroscopy by comparison to Ph SiMe internal standard. (S,S)-
MeDuphos used instead of dmpe.
1
=
c
1
2
2
d
Ph SiMe
2
2
or PhSiMe
3
internal standard. No acetophenone remaining.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1496–1498 1497

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1
8
in good yield and with high diastereoselectivity (10 : 1). No
epimerization was observed, implying that no enolization
occurred under the reaction conditions.
3 For a review of palladium-catalyzed reactions using diethylzinc or
trialkylboranes as terminal reducing agents, see: J. Tsuji, in
Palladium Reagents and Catalysts, 2nd edn, John Wiley & Sons
Ltd., Chichester, 2004, p. 431.
4
(a) J. F. Bower, I. S. Kim, R. L. Patman and M. J. Krische, Angew.
Chem., Int. Ed., 2009, 48, 34; (b) I. S. Kim, M. Y. Ngai and
M. J. Krische, J. Am. Chem. Soc., 2008, 130, 6340; (c) J. F. Bower,
E. Skucas, R. L. Patman and M. J. Krische, J. Am. Chem. Soc.,
2
007, 129, 15134.
5
For coupling of aldehydes and imines with allylic alcohols and
acetates in the presence of diboron or ditin reagents, see:
(
a) N. Selander, A. Kipke, S. Sebelius and K. J. Szabo
Chem. Soc., 2007, 129, 13723; (b) S. Sebelius and K. J. Szabo
Eur. J. Org. Chem., 2005, 2539; (c) O. A. Wallner and K. J. Szabo
´
, J. Am.
´
,
,
ð2Þ
ð3Þ
´
Org. Lett., 2004, 6, 1829; (d) M. Gagliardo, N. Selander,
N. C. Mehendale, G. van Koten, R. J. M. Klein Gebbink and
´
K. J. Szabo, Chem.–Eur. J., 2008, 14, 4800.
For a discussion, see ref. 3a. For a select example, see: S. B. Han,
A. Hassan, I. S. Kim and M. J. Krische, J. Am. Chem. Soc., 2010,
132, 15559.
G. Hargaden and P. J. Guiry, Adv. Synth. Catal., 2007, 349, 2407.
Palladium-catalyzed intramolecular coupling of allylic acetates and
6
7
8
ketones using (Bpin)
Chem. Lett., 1997, 811.
J. J. Miller and M. S. Sigman, J. Am. Chem. Soc., 2007, 129, 2752.
2
T. Ahiko, T. Ishiyama and N. Miyaura,
9
1
1
0 R. E. Grote and E. R. Jarvo, Org. Lett., 2009, 11, 485.
We examined bicyclic ketone 6 as a second example of a
functionalized electrophile as it contains a silyl ether, aryl
ether, and tetrasubstituted alkene (eqn (3)). Ketone 6 was
1 For related enantioselective coupling of allenes with aldehydes
and imines using diboron reagents, see: (a) J. D. Sieber and
J. P. Morken, J. Am. Chem. Soc., 2006, 128, 74; (b) A. R.
Woodward, H. E. Burks, L. M. Chan and J. P. Morken, Org. Lett.,
1
9
obtained as a byproduct during the synthesis of sieboldine A.
2
005, 7, 5505.
2 (a) T. J. Barker and E. R. Jarvo, Org. Lett., 2009, 11, 1047;
b) T. J. Barker and E. R. Jarvo, Synthesis, 2010, 3259.
Using the reaction conditions optimized for pregnenolone
acetate, we were pleased to observe quantitative conversion
1
(
2
0
to tertiary alcohol 7 with high diastereoselectivity.
13 For palladium-catalyzed synthesis of allylmetal reagents from
allylic acetates, see: (a) Y. Tsuji, M. Funato, M. Ozawa,
H. Ogiyama, S. Kajita and T. Kawamura, J. Org. Chem., 1996,
In conclusion, we have developed a rhodium catalyzed
redox allylation method for the allylation of ketones. The
mild reaction conditions allow the use of enolizable aliphatic
ketones as well as complex synthetic intermediates with good
diastereoselectivity.
6
1, 5779; (b) B. M. Trost and J. W. Herndon, J. Am. Chem. Soc.,
1984, 106, 6835; (c) J. A. Marshall, Chem. Comm., 2000, 100, 3163.
4 For palladium-catalyzed redox allylation reactions of aldehydes
and imines utilizing diboron and ditin reagents, see ref. 5.
5 Select examples are illustrated in Table 1. In general, triarylphos-
phine ligands (including BINAP, Xantphos, and dppf) provided
diminished yields.
1
1
This work was supported by an NSF CAREER Award
(
CHE-0847273). We thank Mr Stephen Canham and
1
6 Other allylic electrophiles examined included allyl chloride, allyl tri-
fluoroacetate, and allyl ethyl carbonate; all provided o5% yield of 4a.
7 For a review of additive effects in transition metal catalyzed
reactions, see: K. Fagnou and M. Lautens, Angew. Chem., Int.
Ed., 2002, 41, 26.
8 Spectral data is consistent with the literature for the diastereomer
shown. See: M. T. Reetz, R. Steinbach, J. Westermann, R. Peter
and B. Wenderoth, Eur. J. Org. Chem., 1985, 118, 1441.
Professor Larry Overman for ketone 6. We thank Heraeus
Metal Processing, Solvias and Frontier Scientific for donations
of rhodium complexes, ligands and bis(pinacolato)diboron,
respectively.
1
1
Notes and references
1
For an example and summary of the field, see: S. E. Denmark and
S. T. Nguyen, Org. Lett., 2009, 11, 781.
19 S. M. Canham, D. J. France and L. E. Overman, J. Am. Chem.
Soc., 2010, 132, 7676.
2
(a) Y. Okude, S. Hirano, T. Hiyama and H. Nozaki, J. Am. Chem.
Soc., 1977, 99, 3179; (b) H. Jin, J. Uenishi, W. J. Christ and
¨
Y. Kishi, J. Am. Chem. Soc., 1986, 108, 5644; (c) A. Furstner and
20 The identity of the major diastereomer is assigned using conforma-
tional analysis to predict the least hindered side of attack. NMR
nOe experiments did not provide any diagnostic information to
conclusively assign the diastereomer.
N. Shi, J. Am. Chem. Soc., 1996, 118, 12349.
1
498 Chem. Commun., 2012, 48, 1496–1498
This journal is c The Royal Society of Chemistry 2012