C-Propargylation Overrides O-Propargylation in Reactions of Propargyl Chloride with Primary Alcohols: Rhodium-Catalyzed Transfer Hydrogenation

Article abstract of DOI:10.1002/anie.201603575

The canonical S_N2 behavior displayed by alcohols and activated alkyl halides in basic media (O-alkylation) is superseded by a pathway leading to carbinol C-alkylation under the conditions of rhodium-catalyzed transfer hydrogenation. Racemic and asymmetric propargylations are described.

Full text of DOI:10.1002/anie.201603575

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Communications
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International Edition: DOI: 10.1002/anie.201603575
German Edition: DOI: 10.1002/ange.201603575
Hydrogenation
C-Propargylation Overrides O-Propargylation in Reactions of
Propargyl Chloride with Primary Alcohols: Rhodium-Catalyzed
Transfer Hydrogenation
Tao Liang, Sang Kook Woo, and Michael J. Krische*
Abstract: The canonical SN2 behavior displayed by alcohols
and activated alkyl halides in basic media (O-alkylation) is
superseded by a pathway leading to carbinol C-alkylation
under the conditions of rhodium-catalyzed transfer hydro-
genation. Racemic and asymmetric propargylations are de-
scribed.
T
he merger of carbonyl addition and transfer hydrogenation
À
has enabled a new class of metal-catalyzed C C couplings
wherein lower alcohols are converted directly into higher
alcohols.[1] Three mechanistic pathways are corroborated, in
À
which alcohol dehydrogenation mediates a) C C p-bond
hydrometalation (IrI, RuII), b) metalacycle transfer hydro-
0
0
À
genolysis (Ru , Os ), or c) reductive cleavage of a C X bond
(IrI).[1] In the latter context, iridium-based catalysts operate
exclusively, promoting the coupling of primary alcohols with
a diverse array of allylic carboxylates[2a–d] and related
pronucleophiles, such as vinyl epoxides[2e] and vinyl aziridi-
nes.[2f] The identification of metal catalysts, beyond iridium,
Figure 1. Rhodium versus iridium catalysts for redox-triggered carbonyl
addition.
À
À
that promote alcohol C H functionalization by C X bond
reductive cleavage pathways should enable further expansion
of substrate scope. Rhodium-based catalysts, being isostruc-
tural with respect to iridium, were viewed as promising
candidates. However, rhodium is used less frequently than
iridium in transfer hydrogenation,[3] with the vast majority of
examples involving analogues of the classic ruthenium-based
system [RuCl(Tsdpen)(h6-arene)].[4,5b–e] Indeed, rhodium
analogues of the broadly utilized cyclometalated p-allyliri-
dium ortho-C,O-benzoate complexes developed in our labo-
ratory have not yet proven effective (Figure 1).
As the pronucleophile serves as oxidant in all transfer
hydrogenative couplings, we reasoned that more easily
reduced pronucleophiles might be accommodated by rho-
dium, which is a weaker reductant than iridium.[6] Accord-
ingly, we turned our attention to the redox-triggered coupling
of primary alcohols and propargyl chloride, with the goal of
developing methods for enantioselective carbonyl propargy-
lation (Figure 2).[7–15] In earlier work from our laboratory,[16]
an iridium-catalyzed transfer hydrogenative carbonyl prop-
argylation was developed [Eq. (1)],[16c] but suffered from two
severe limitations in scope: a) trialkylsilyl substitution was
required at the acetylenic terminus of the propargyl chloride,
Figure 2. Selected methods for enantioselective carbonyl propargyla-
tion.[15–17]
[*] Dr. T. Liang, Dr. S. K. Woo, Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
105 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
À
and b) only benzylic alcohols would participate in C C
coupling. To determine whether rhodium catalysts could
overcome these restrictions, a series of experiments were
performed. The rhodium analogue of the optimal iridium
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603575.
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À
Table 1: Rhodium-catalyzed C C coupling of 1b with the alcohols 2a–o
catalyst, identified for the coupling of the silyl-terminated
propargyl chloride 1a with benzyl alcohols, was prepared and
evaluated in the coupling of the benzylic alcohol 2b with the
unsubstituted propargyl chloride 1b [Eq. (2)]. The desired
product, homopropargyl alcohol 3b, was obtained in 23%
yield. Further improvements in the yield of 3b were obtained
by conducting the reaction at 408C in toluene, a remarkably
low temperature for alcohol dehydrogenation, using a neutral
rhodium/BINAP catalyst and increasing the loading of 1b
(1000 mol%). Applied in concert, these changes enabled
formation of 3b in 80% yield [Eq. (3)]. Reactions conducted
at a lower loading of 1b (500 mol%) under otherwise
identical reaction conditions led to a modest but significant
decrease in the yield of 3b (10–15% lower). A comparable
decrease in the yield of 3b is observed upon omission of
2-propanol. Remarkably, products of O-propargylation by
SN2 substitution were not observed.[17]
to form homopropargyl alcohols 3a–o.[a]
[a] Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details. [b] 2-PrOH was
omitted. TBS=tert-butyldimethylsilyl.
To establish the generality of these reaction conditions, in
particular, the ability to engage aliphatic alcohols in
C-propargylation, these reaction conditions were applied to
the primary alcohols 2a–o (Table 1). The benzylic alcohols
2a–h, including the ortho-substituted benzylic alcohol 2 f and
heteroaromatic benzylic alcohol 2h, were converted into the
corresponding homopropargylic alcohols 3a–h in good to
excellent yield. Remarkably, the allylic alcohols 2i and 2j
were converted into the homopropargyl alcohols 3i and 3j,
respectively, without competing internal redox isomeriza-
tion.[18] Most importantly, the aliphatic alcohols 2k–o were
converted into the homopropargylic alcohols 3k–o, respec-
tively, in good yield. Finally, as illustrated in the conversion of
dehydro-2b to 3b, these reaction conditions are applicable to
the 2-propanol-mediated reductive coupling of 1b with
aldehydes [Eq. (4)].
The products 3a–o were generated using a racemic
rhodium/BINAP catalyst (Table 1). By using enantiomeri-
cally pure BINAP, moderate levels of enantioselectivity are
observed (40–55% ee). Efforts to improve enantioselectivity
while maintaining high levels of conversion have, thus far,
been unrequited. Hence, match-mismatch effects in the
C-propargylation of the enantiomerically enriched a-stereo-
genic amino alcohol 2p were explored [Eq. (5)]. First, to
establish the intrinsic diastereofacial bias, the rhodium
catalyst modified by racemic BINAP was used. The anti-
and syn-diastereomers 3p and epi-3p are formed in a 2.3:1
ratio. This diastereofacial bias suggests intervention of an
internal NH–O hydrogen bond in the transient aldehyde
dehydro-2p, which directs carbonyl addition to the sterically
less encumbered face of the chelate. When the propargylation
is conducted using (S)-BINAP, the mismatched case, 3p and
epi-3p are formed in a 1:2.6 ratio. When the reaction is
conducted using (R)-BINAP (the matched case), 3p and epi-
3p are formed in a 5:1 ratio. It was reasoned that reactions
conducted in a lower dielectric medium, which is more
conducive to hydrogen bonding, would display higher diaste-
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analysis of 3p, prepared through asymmetric propargylation,
was compared to a mixture of all four stereoisomers, revealing
that racemization of the transient aldehyde does not occur
(see the Supporting Information).
Although at this early stage precise details of the catalytic
mechanism are unknown, a very simple working model has
been proposed as a basis for further refinement (Scheme 1). It
is postulated that catalysis is initiated by oxidative addition of
1b to the rhodium complex A to form the h1-allenylrho-
dium(III) complex C. Precedent for this step in the catalytic
mechanism is found in the oxidative addition of 1b to Vaskaꢀs
complex, which provides well-defined h1-allenyliridium(III)
complexes.[19] Equilibration may occur between C and the
propargylrhodium(III) complex B, however, the h1-allenyl-
metal isomers are thermodynamically preferred.[20] Complex
C undergoes substitution with 2a to form the rhodium(III)
alkoxide complex D, which upon b-hydride elimination
generates the rhodium(III) hydrochloride complex E and
reoselectivities. Indeed, in toluene, 3p and epi-3p are formed
in an 11:1 ratio, albeit in slightly lower yield.
These reaction conditions were applied to the C-prop-
argylation of enantiomerically enriched a-amino alcohols
2p–u (Table 2). Because of the solubility issues, it was
À
Table 2: Rhodium-catalyzed C C coupling of 1b with the a-amino
alcohols 2p–u to form the homopropargyl alcohols 3p–u.[a]
À
dehydro-2a. At this stage, E may undergo C H reductive
elimination to form propyne, which may account for the
requirement of relatively high loadings of 1b. An ion
consistent with the molecular weight of propyne (or allene)
is observed by GC-MS analysis of aliquots taken from
reaction mixtures in the coupling of 1b and 2a. This pathway,
which effects net catalytic transfer hydrogenolysis of 1b,
delivers unreacted aldehyde, which is converted back into the
alcohol by 2-propanol-mediated reduction, reinitiating the
catalytic cycle. Nonconjugated aldehydes derived from the
alcohols 2k–u appear more reactive toward addition; hence,
2-propanol is not required. Alternatively, E may eliminate
HCl with the assistance of base, as documented in stoichio-
metric transformations.[21] The latter pathway delivers the h1-
allenylrhodium(I) complex F, which coordinates the aldehyde
to the form complex G, which, in turn, triggers carbonyl
addition to generate the homoallylic rhodium(I) alkoxide H.
Protonolytic cleavage then releases the 3a and regenerates A
to close the catalytic cycle. The stereochemistry of the
octahedral complexes B–E should be considered tentative.
In summary, new reactivity is the most fundamental basis
for innovation in the field of chemical synthesis. Here, using
[a] Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details. [b] Toluene
(1.0m).
À
necessary to use THF as the solvent. Nevertheless, the
products of asymmetric C-propargylation (3p–u) were
formed in a stereoselective manner, with diastereoselectivi-
ties increasing with increasing size of the a-substituent. HPLC
the concepts of C C bond formation transfer hydrogenation
pioneered in our laboratory, the canonical SN2 behavior
displayed by alcohols and activated alkyl halides in basic
media (O-alkylation) is superseded by an alternate pathway
Scheme 1. General catalytic mechanism for rhodium-catalyzed alcohol C-propargylation.[a]
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Acknowledgments
Acknowledgement is made to the Robert A. Welch Founda-
tion (F-0038) and the NIH (RO1-GM069445) for partial
support of this research.
Keywords: alcohols · hydrogenation · reaction mechanisms ·
rhodium · synthetic methods
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Published online: && &&, &&&&
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Communications
Hydrogenation
T. Liang, S. K. Woo,
M. J. Krische*
&&&& — &&&&
C-Propargylation Overrides O-
Propargylation in Reactions of Propargyl
Chloride with Primary Alcohols:
Rhodium-Catalyzed Transfer
Hydrogenation
A path less travelled: The canonical SN2
behavior displayed by alcohols and acti-
vated alkyl halides in basic media (O-
alkylation) is superseded by a pathway
leading to carbinol C-alkylation under the
conditions of rhodium-catalyzed transfer
hydrogenation. Racemic and asymmetric
propargylations are described.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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