Carbonyl propargylation from the alcohol or aldehyde oxidation level employing 1,3-enynes as surrogates to preformed allenylmetal reagents: A ruthenium-catalyzed C-C bond-forming transfer hydrogenation

Article abstract of DOI:10.1002/anie.200801359

(Chemical Equation Presented) Transcending oxidation level: Under the conditions of ruthenium-catalyzed transfer hydrogenation, conjugated enynes couple to benzylic, allylic, and aliphatic alcohols or aldehydes to furnish products of carbonyl propargylation (see scheme; dppf = 1,1′- bis(diphenylphosphino)ferrocene, TBS = tert-butyldimethylsilyl). Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the alcohol to the enyne.

Full text of DOI:10.1002/anie.200801359

Communications
DOI: 10.1002/anie.200801359
Ruthenium Catalysis
Carbonyl Propargylation from the Alcohol or Aldehyde Oxidation
Level Employing 1,3-Enynes as Surrogates to Preformed Allenylmetal
À
Reagents: A Ruthenium-Catalyzed C C Bond-Forming Transfer
Hydrogenation**
Ryan L. Patman, Vanessa M. Williams, John F. Bower, and Michael J. Krische*
Over the past half century, numerous protocols for carbonyl
propargylation using allenylmetal reagents have been devel-
oped.[1] Allenic Grignard reagents were used by PrØvost
et al.[2a] in carbonyl additions to furnish mixtures of
b-acetylenic and a-allenic carbinols, which led to them to
coin the term “propargylic transposition.”[2a,b] Subsequent
studies by Chodkiewicz and co-workers[2c] demonstrated
relative stereocontrol in such additions. Shortly thereafter,
Lequam and Guillerm[2d] reported that isolable allenic
stannanes provide products of carbonyl propargylation upon
exposure to chloral. Later, Mukaiyama and Harada[2e] dem-
onstrated that stannanes generated in situ from propargyl
iodides and stannous chloride reacted with aldehydes to
provide mixtures of b-acetylenic and a-allenic carbinols.
Related propargylations employing allenylboron reagents
were first reported by Favre and Gaudemar,[2f] and prop-
Scheme 1. Chirally modified allenylmetal reagents for carbonyl propar-
argylations employing allenylsilicon reagents were first
reported by Danheiser and Carini.[2g] Asymmetric variants
followed (Scheme 1). Allenylboron reagents chirally modi-
fied at the boron center engage in asymmetric propargylation,
as was first reported by Yamamoto and co-workers[2h] and
Corey et al.[2i] Allenylstannanes chirally modified at the tin
center also induce asymmetric carbonyl propargylation, as
was first reported by Minowa and Mukaiyama.[2j] Axially
chiral allenylstannanes, allenylsilanes, and allenylboron
reagents propargylate aldehydes enantiospecifically, as was
first described by Marshall et al.,[2k,l] and Hayashi and co-
workers,[2m] respectively. Finally, asymmetric aldehyde prop-
argylation using allenylmetal reagents may be catalyzed by
chiral Lewis acids or chiral Lewis bases, as was first reported
by Keck et al.,[2n] and Denmark and Wynn,[2o] respectively.
Here, we report a new approach to carbonyl propargyla-
gylation. Tf=trifluoromethanesulfonyl, Ts=para-toluenesulfonyl.
[RuHCl(CO)(PPh3)3]/dppf (dppf = 1,1’-bis(diphenylphosph-
ino)ferrocene), hydrogen shuffling between reactants occurs
to generate nucleophile–electrophile pairs that regioselec-
tively combine to furnish products of carbonyl propargyla-
tion.[6] Under related transfer hydrogenation conditions and
employing isopropanol as the terminal reductant, 1,3-enynes
couple to aldehydes to furnish identical products of carbonyl
propargylation. The observed regiochemistry is unique with
respect to related enyne–carbonyl reductive coupling reac-
tions that are catalyzed by rhodium[5,7] and nickel complexes,
[8,9,10]
which favor coupling at the acetylenic terminus of the
enyne. Significantly, this protocol enables carbonyl propargy-
lation from the alcohol or aldehyde oxidation level in the
absence of preformed allenylmetal reagents (Scheme 2).
In connection with our efforts to exploit catalytic hydro-
À
tion based on ruthenium-catalyzed C C bond-forming trans-
fer hydrogenation.[3–5] Specifically, upon exposure of
À
1,3-enynes 1a–1g to alcohols 2a–2o in the presence of
genation in C C coupling reactions beyond hydroformyla-
tion,[5] we recently demonstrated that C C bond formation
À
may be achieved under the conditions of iridium- and
ruthenium-catalyzed transfer hydrogenation.[11] These pro-
cesses enable direct carbonyl allylation from the alcohol or
aldehyde oxidation level by using commercially available
allenes or dienes as allyl donors. Seeking to develop
corresponding carbonyl propargylations, diverse iridium and
ruthenium complexes were assayed for their ability to
catalyze the coupling of enyne 1a and alcohol 2a. Gratify-
ingly, both [{Ir(cod)Cl}2]/biphep (biphep = diphenylphos-
phine, cod = cycloocta-l,5-diene) and [RuHCl(CO)(PPh3)3]/
dppf catalyze the desired coupling. The ruthenium-based
[*] R. L. Patman, V. M. Williams, Dr. J. F. Bower, Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry and Biochemistry
1 University Station—A5300, Austin, TX 78712-1167 (USA)
Fax: (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
[**] Acknowledgements are made to Merck, the Robert A. Welch
Foundation, the American Chemical Society Green Chemistry
Institute Pharmaceutical Roundtable, and the NIH (Grant No. RO1-
GM069445) for partial support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801359.
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Chemie
structural and interactive features of the ruthenium complex
that influence relative and absolute stereocontrol, are cur-
rently under investigation.
A general catalytic mechanism is likely to involve the
following steps:[11] a) alcohol dehydrogenation to generate a
ruthenium hydride is followed by b) enyne hydrometalation
to generate an allenyl metal–aldehyde/nucleophile–electro-
phile pair, which undergoes c) carbonyl addition with prop-
argylic transposition. Consistent with this interpretation, the
coupling of enyne 1a to [D]-2b under standard reaction
Scheme 2. Divergent regioselectivity
observed in metal-catalyzed enyne–car-
bonyl coupling.
Table 1: Carbonyl propargylation from the alcohol oxidation level by ruthenium-catalyzed transfer
hydrogenation.[a]
catalyst was most effective and,
under optimized conditions, enyne
1a coupled to benzylic, allylic, and
aliphatic alcohols 2a–2o to form
homopropargyl alcohols 3a–3o in
good to excellent yields (Table 1).
To probe the scope of the enyne
coupling partner, enynes 1b–1g
were coupled to benzyl alcohol 2b
under standard reaction conditions.
Good to excellent yields of prop-
argylation products 3p–3u were
observed (Table 2). Substitution at
the olefinic terminus of the enyne
was found to diminish conversion to
product. Finally, carbonyl allylation
can also be achieved from the
aldehyde oxidation level by
employing isopropanol as the ter-
minal reductant. Under standard
reaction conditions, aldehydes 4a–
4c couple to enyne 1a to provide
the products of carbonyl propargy-
lation 3a–3c, respectively, in good
to excellent yield. Thus, carbonyl
propargylation may be achieved
from either the alcohol or aldehyde
oxidation level (Table 3). The cou-
pling products 3a–3u are remark-
ably resistant to over-oxidation to
form the corresponding b,g-acetyl-
enic ketones. However, such over-
oxidation is observed if cationic
ruthenium complexes are employed
as catalysts. This result suggests
that, for the neutral ruthenium
complexes employed in this study,
the alkyne moiety of the coupling
product blocks a coordination site
required for b hydride elimination
2a, R=p-NO2Ph
2b, R=phenyl
2c, R=p-MeOPh
2d, R=o-MeOPh
2e, R=5-piperonyl
2 f, R=p-BrPh
2g, R=2-furyl
2h, R=3-indolyl
2i, R=2-(6-BrPy)
2j, R=cinnamyl
2k, R=geranyl
2l, R=crotyl
2m, R=cyclopropyl
2n, R=benzyl
2o, R=n-pentyl
Coupling to benzylic alcohols
3a
65% yield
1:1 d.r.
3b
81% yield
1:1 d.r.
3c
81% yield
1:1 d.r.
3d
91% yield
2:1 d.r.
3e
83% yield
2:1 d.r.
3 f
73% yield
1:1 d.r.
3g
71% yield
1.5:1 d.r.
3h
94% yield
1:1 d.r.
3i
42% yield
1.3:1 d.r.
Coupling to allylic alcohols
3j
3k
63% yield
1.5:1 d.r.
3l
68% yield
1:1 d.r.
72% yield
2:1 d.r.
Coupling to aliphatic alcohols
3m
75% yield
2:1 d.r.
3n
70% yield
1:1 d.r.
3o
72% yield
2:1 d.r.
À
of the carbinol C H bond. Other
aspects of the catalytic mechanism,
including determination of the
[a] Yields of isolated material. Standard reaction conditions employed 1 equivalent of alcohol/aldehyde
and 2 equivalents of enyne. See the Supporting Information for detailed experimental procedures.
Py=pyridine.
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Communications
Table 2: Coupling of enynes 1b–1g to benzyl alcohol 2b by ruthenium-
catalyzed transfer hydrogenation.[a]
nucleophile–electrophile pairs, thus enabling carbonyl addi-
tion from the aldehyde or alcohol oxidation level. In this way,
carbonyl additions that transcend the boundaries of oxidation
level are devised. In the present study, we have demonstrated
that 1,3-enynes serve as allenylmetal equivalents under the
conditions of transfer hydrogenative coupling, thus also
enabling carbonyl propargylation from the alcohol or alde-
hyde oxidation level. These studies contribute to a growing
body of catalytic methods for the direct functionalization of
1b, R=2-thienyl
1d, R=TBSO(CH2)4 1 f, R=TBSOC(CH3)2
1c, R=BocNH(CH2)2 1e, R=TBSOCH2
1g, R=cyclohexyl
[11,12]
À
carbinol C H bonds.
Future studies will focus on the
À
development of related alcohol–unsaturate C C coupling
processes.
3p[b]
3q
3r
71% yield
1:1 d.r.
54% yield
1:1 d.r.
63% yield
1:1 d.r.
Received: March 20, 2008
Published online: June 4, 2008
Keywords: cross-coupling · enynes · propargylation · ruthenium ·
.
transfer hydrogenation
3s
78% yield
1.5:1 d.r.
3t[b]
56% yield
1:1 d.r.
3u[b]
70% yield
1:1 d.r.
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4a, Ar=p-NO2Ph
4b, Ar=Ph
4c, Ar=p-MeOPh
3a
61% yield
1:1 d.r.
3b
74% yield
1:1 d.r.
3c
91% yield
1:1 d.r.
[a] Formation of 3a and 3b were accompanied by about 10% alkyne
reduction. See the Supporting Information for detailed experimental
procedures.
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À
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À
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