Ruthenium-catalyzed reductive coupling of 1,3-enynes and aldehydes by transfer hydrogenation: Anti-diastereoselective carbonyl propargylation

Article abstract of DOI:10.1002/chem.201202446

Under the conditions of ruthenium-catalyzed transfer hydrogenation employing isopropanol as a source of hydrogen, isopropoxy-substituted enyne 1 b and aldehydes 3 a-3 l engage in reductive coupling to provide products of propargylation 4 a-4 l with good to complete levels of anti- diastereoselectivity. The unprotected tertiary hydroxy moiety of isopropoxy enyne 1 b is required to enforce diastereoselectivity. Deuterium-labeling studies corroborate reversible enyne hydrometalation in advance of carbonyl addition. As demonstrated in the conversion of 4 f-h and 4 k to 5 f-h and 5 k, the isopropoxy group of the product is readily cleaved upon exposure to aqueous sodium hydroxide to reveal the terminal alkyne. Unprotected coupling is better! Ruthenium-catalyzed transfer hydrogenation of enynes in the presence of aldehydes promotes reductive C-C coupling to provide products of propargylation with good to complete levels of anti-diastereoselectivity (see scheme). The unprotected hydroxy group of the isopropoxy-substituted enyne is required to enforce high levels of anti-diastereoselectivity. Copyright

Full text of DOI:10.1002/chem.201202446

FULL PAPER
DOI: 10.1002/chem.201202446
Ruthenium-Catalyzed Reductive Coupling of 1,3-Enynes and Aldehydes by
Transfer Hydrogenation: anti-Diastereoselective Carbonyl ProparACTHUNTGRENNGgU ylation
Laina M. Geary, Joyce C. Leung, and Michael J. Krische*[a]
Abstract: Under the conditions of
ruthenium-catalyzed transfer hydrogen-
ation employing isopropanol as
source of hydrogen, isopropoxy-substi-
tuted enyne 1b and aldehydes 3a–3l
engage in reductive coupling to provide
products of propargylation 4a–4l with
good to complete levels of anti-dia-
ary hydroxy moiety of isopropoxy
enyne 1b is required to enforce dia-
studies corroborate reversible enyne
hydrometalation in advance of carbon-
G
R
ACHTUNGTRENNUNG
G
a
A
E
Deuterium-labeling
yl addition. As demonstrated in the
conversion of 4 f–h and 4k to 5 f–h and
5k, the isopropoxy group of the prod-
uct is readily cleaved upon exposure to
aqueous sodium hydroxide to reveal
the terminal alkyne.
Keywords: homogeneous catalysis ·
diastereoselectivity propargyla-
tion · ruthenium · transfer hydro-
genation
·
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNGstereoACHTUNGTRENNUNGselectivity. The unprotected terti-
Introduction
The propargylation of carbonyl compounds represents a
À
subset of C C bond-forming reactions that have found
broad use in the construction of polyketide natural prod-
ucts.[1,2] Most methods for enantioselective carbonyl propar-
gylation promote formation of the parent a-unsubstituted
homopropargylic alcohols. In this capacity, allenylboron,[3]
indium,[4] and tin[5] reagents that possess chiral modifiers at
the metal center have proven effective. Beyond stoichiomet-
ric chiral reagents, catalytic enantioselective additions of
achiral allenyltin[6] and allenylsilicon[7] reagents promoted by
either chiral Lewis acidic or chiral Lewis basic catalysts
have been developed. Similarly, chiral copper catalysts pro-
mote enantioselective aldehyde propargylation employing
allenylboron and propargylboron reagents.[8] More recently,
chiral hydrogen-bond donors and Brønsted acids have been
found to catalyze the asymmetric addition of allenylboron
reagents to aldehydes to form homopropargyl alcohols.[9] Fi-
nally, catalytic enantioselective Nozaki–Hiyama propargyla-
tions have been described (Figure 1).[10]
Less attention has been devoted to the development of
diaACHTUNGTRENNUNGstereo- and enantioselective propargylation protocols
Figure 1. Selected protocols for enantioselective carbonyl propargylation.
that generate (a-methyl)homopropargyl alcohols, despite
their importance vis-ꢀ-vis polypropionate construction
(Figure 1).[11] Typically, allenylstannanes,[12] allenylsilanes,[13]
and allenylboronates[14] reagents are used as propargyl
donors to form (a-methyl)homopropargylic alcohols. Al-
though such reagents promote diastereo- and enantioselec-
tive propargylation, their syntheses are lengthy and require
successive use of multiple stoichiometric organometallic re-
agents. The research group of Marshall has developed a
more desirable protocol wherein enantiomerically enriched
propargyl mesylates are reductively coupled to aldehydes
through generation of either transient allenylzinc[15] or tran-
sient allenylindium[16] species. Although their protocol cir-
cumvents the need for isolation of discrete allenylmetal spe-
cies, the reactions employ superstoichiometric quantities of
a pyrophoric metallic reagent (ZnEt2), the propargyl mesy-
[a] Dr. L. M. Geary, J. C. Leung, Prof. Dr. M. J. Krische
Department of Chemistry & Biochemistry
The University of Texas at Austin
1 University Station - A5300
Austin, TX, 78712-1167 (USA)
Fax : (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202446.
Chem. Eur. J. 2012, 18, 16823 – 16827
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late requires several steps to prepare, and the levels of dia-
stereoselectivity are highly variable.
cohol 2g under our previously reported reaction condition-
s,[18a] which led to the isolation of the homopropargylic alco-
hol 4g-Ph in moderate yield and with 7:1 anti-dia-
À
In the course of developing C C bond-forming hydro
gen-
N
ACHTUNGTRENsNUGN tereoselectivity (Table 1, entry 1). Changing the ligand
damentally new approach to the synthesis of (a-methyl)ho-
from DPPF to DPPB led to an increase in the yield of iso-
lated 4g-Ph with similar levels of anti-diastereoselectivity
(Table 1, entry 2).
À
mopropargyl alcohols based on the redox-triggered C C
coupling of alcohols and 1,3-enynes by transfer hydrogena-
tion.[18] These results were surprising, as rhodium- and
nickel-catalyzed enyne–carbonyl reductive couplings provide
products of dienylation.[19–20] In an initial study employing a
ruthenium catalyst, the essential reactivity was established,
however, the desired (a-methyl)homopropargyl alcohols
were not formed stereoselectively.[18a] Later, using an iridium
catalyst modified by either (R)-SEGPHOS or (R)-DM-
SEGPHOS, highly anti-diastereo- and enantioselective (a-
methyl)propargylation was achieved using a sterically de-
manding enyne substituted by the isopropoxy silyl ether,
(TIPSO)Me2C (TIPS=triisopropylsilyl).[18b] Herein, we
report that ruthenium-catalyzed transfer hydrogenation of
the unprotected isopropoxy enyne 1b in the presence of al-
dehydes 3a–3l results in reductive coupling to form (a-
methyl)homopropargyl alcohols 4a–4l with good to excel-
lent levels of anti-diastereoselectivity, and that the hydroxy
moiety of enyne 1b is itself required to enforce high levels
of anti-diastereoselectivity (Scheme 1).
Table 1. Defining structure-selectivity relationships in the ruthenium-cat-
À
alyzed C C coupling of enynes 1 to isobutyl alcohol 2g and isobutyralde-
hyde 3g.
[a] 1a or 1c (200 mol%), 2g (100 mol%). [b] 1b or 1d (100 mol%), 2g
(200 mol%). [c] 1b (100 mol%), 3g (300 mol%). [d] 1b (200 mol%), 3g
(100 mol%), 1008C
Whereas the phenyl-substituted enyne 1a displayed good
reactivity, enyne 1b was deemed more desirable, as the iso-
propoxy group is subject to removal to reveal the terminal
alkene, and dimethyl propargyl alcohol is one of the least
expensive alkynes commercially available (47 USD/Kg).[21]
However, upon use of enyne 1b under the aforementioned
reaction conditions employing isobutyl alcohol 2g as the
limiting reagent, conversion to the desired homopropargylic
alcohol 4g-C(Me)2OH was not observed (Table 1, entry 3).
In contrast, upon use of enyne 1b as the limiting reagent in
the presence of excess isobutyl alcohol 2g (200 mol%), the
homopropargylic alcohol 4g-C(Me)2OH was isolated in
moderate yield as a single diastereomer (Table 1, entry 4).
Notably, although the corresponding methyl ether enyne 1c
displayed excellent reactivity, leading to the isolation of ho-
mopropargylic alcohol 4g-C(Me)2OMe in 75% yield, dia-
stereoselectivity was poor (Table 1, entry 5).[22] Using the N-
tosyl substituted enyne 1d, the homopropargylic alcohol 3g-
Scheme 1. Ruthenium- and iridium-catalyzed a-(methyl)propargylations
À
based on the redox-triggered C C coupling of alcohols and 1,3-enynes by
transfer hydrogenation. cod=1,5-cyclooctadiene, DM-SEGPHOS=5,5’-
bis[di(3,5-xylyl)phosphino]-4,4’-bi-1,3-benzodioxole, DPPB=1,4-bis(di-
phenylphosphino)butane, DPPF=1,1’-bis(diphenylphosphino)ferrocene.
Results and Discussion
À
Our initial studies began with the ruthenium-catalyzed C C
coupling of the phenyl-substituted enyne 1a and isobutyl al-
CH2NHTs is formed with poor diaACTHNGUETRNNUsG tereoselectivity (Table 1,
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Reductive Coupling of 1,3-Enynes and Aldehydes
FULL PAPER
entry 6). These results suggest the free hydroxy moiety of
enyne 1b is essential for achieving high levels of anti-dia-
aliphatic aldehydes 3a–3c, aldehydes with branching at the
b-position, 3d, and aldehydes with branching at the a-posi-
tion, 3e–3i, are converted into homopropargyl alcohols 4a–
4i, which were isolated in modest to good yields. In general,
the degree of anti-diastereoselectivity increased with in-
creasing steric demand at the position adjacent to the car-
bonyl moiety of the aldehyde. For example, a-branched al-
dehydes 3 f–3i provides homopropargyl alcohols 4 f–4i as
single diastereomers. a,b-Unsaturated aldehydes 3j–3l also
undergo anti-diastereoselective propargylation to deliver ad-
ducts 4j–4l. Under these conditions, the propargylation of
A
ACHTUNGTRENNUNGselectivity.
yield of the isolated homopropargylic alcohol 4g-C(Me)2OH
could not be improved. Hence, related reductive couplings
of enyne 1b to isobutyraldehyde 3g were explored. Al-
though initial attempts at the reductive coupling of enyne
1b to isobutyraldehyde 3g mediated by formic acid were
disappointing (Table 1, entries 7–9), the use of excess isopro-
panol as the terminal reductant over longer reaction times
ultimately provided the homopropargylic alcohol 4g-
C(Me)2OH in 63% yield as a single anti-diastereomer
(Table 1, entries 10–14). Finally, using aldehyde 3g as the
limiting reagent, in combination with an excess of enyne 1b
(200 mol%) and isopropanol (500 mol%) at 1008C, the de-
sired homopropargylic alcohol 4 f-C(Me)2OH is generated
aryl aldehydes is unselective albeit high yielding. Propar
ACHTUNGTRENNUNGgyl-
AHCTUNGTREGaNNNU tion products 4 f–h and 4k are directly converted into the
corresponding terminal alkynes 5 f–h and 5k upon exposure
to NaOH in refluxing toluene (Scheme 2).
in 73% yield as
entry 15).
a single anti-diastereomer (Table 1,
Withstanding minor variations in isopropanol loading to
further optimize the yield of isolated product, the optimal
reaction conditions identified for the propargylation of alde-
hyde 3g were applied to aldehydes 3a–3l (Table 2). Linear
Table 2. Ruthenium-catalyzed reductive coupling of enyne 1b to alde-
hydes 3a–3l to form anti-propargylation products 4a–4l.
Scheme 2. Deprotection of adducts 4 f–h and 4k to give terminal alkynes
5 f–h and 5k.
A catalytic mechanism for the propargylation has been
formulated and challenged through isotopic labeling
(Scheme 3). Specifically, reaction of isopropoxy-substituted
enyne 1b with cyclohexane carboxaldehyde 3 f employing
[D8]-isopropanol as the terminal reductant delivers deuter-
io-4 f. The distribution of deuterium in deuterio-4 f suggests
[a] iPrOH (400 mol%). [b] iPrOH (500 mol%). [c] iPrOH (700 mol%).
[d] iPrOH (1000 mol%). [e] 1b (100 mol%), 3d (300 mol%), [f] 1008C.
Scheme 3. Deuterium-labeling studies and proposed catalytic mechanism
(apical ligands omitted for clarity). See the Supporting Information for
images of H and H NMR spectra.
1
2
[g] 24 h. [h] [RuHCl(CO)
G
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M. J. Krische et al.
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both the internal and terminal positions. Reversible hydro-
metalation in advance of carbonyl addition suggests the
latter process is slow, possibly even turnover limiting, and
may explain why corresponding reactions performed from
the alcohol oxidation level display lower conversions with
essentially identical selectivities. The conversion of inter-
mediate V to intermediate VI serves as a stereochemical
model accounting for the observed anti-diastereoselectivity.
The roughly perpendicular orientation of the allenylrutheni-
um moiety finds precedent in a related h1-allenylmetal com-
plexes.[23]
Conclusion
In conclusion, ruthenium-catalyzed transfer hydrogenation
of isopropoxy-substituted enyne 1b in the presence of alde-
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À
hydes 3a–3l promotes reductive C C coupling to provide
products of propargylation 4a–4l with good to complete
levels of anti-diastereoselectivity. The unprotected hydroxy
group of the the enyne isopropoxy substituent is required to
enforce high levels of anti-diastereoselectivity. However,
several limitations in scope remain. Although the present
ruthenium-based catalyst system displays good levels of
anti-diastereoselectivity in propargylations of aliphatic alde-
hydes and enals, corresponding additions to aryl aldehydes
remain unselective. Additionally, poor conversion is ob-
served in reactions conducted from the alcohol oxidation
level, although essentially identical levels of selectivity are
observed. Studies are currently underway to address these
limitations and will be reported in due course.
Experimental Section
General procedure for the ruthenium-catalyzed propargylation: To an
oven-dried pressure tube sealed with a septum under an argon atmos-
phere was added [RuHCl(CO)ACHTNUGTRNEGNU(PPh3)3] (14.3 mg, 0.015 mmol, 5 mol%)
and DPPB (6.4 mg, 0.015 mmol, 5 mol%). The pressure tube was purged
with argon and THF (0.3 mL, 1.0m) was added, followed by enyne 1b
(72 mL, 0.6 mmol, 200 mol%), aldehyde (0.3 mmol, 100 mol%), and iso-
propanol (115 mL, 1.5 mmol, 500 mol%). The septum was replaced with a
screw cap and the reaction vessel was placed in 908C oil bath. After 48 h,
the reaction vessel was removed from the oil bath and was allowed to
cool to room temperature. The volatiles were removed and the residue
was purified by silica-gel flash chromatography.
[8] For copper-catalyzed enantioselective carbonyl propargylation em-
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[9] For either chiral hydrogen-bond donor or Brønsted-acid-catalyzed
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Acknowledgements
Acknowledgements is made to the Robert A. Welch Foundation (F-
0038), the NSF (CHE-1008551) and the Government of Canadaꢂs Bant-
ing Postdoctoral Fellowship Program (L.M.G.) for financial support. Dr.
Ryan Patman is recognized for preliminary experiments.
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Reductive Coupling of 1,3-Enynes and Aldehydes
FULL PAPER
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À
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and a similar yield of alcohol 3 f-C(Me)2OMe was obtained (76%).
Diastereoselectivity remained low (2:1 d.r.).
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Received: July 9, 2012
Revised: September 12, 2012
Published online: November 12, 2012
Chem. Eur. J. 2012, 18, 16823 – 16827
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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