Cooperativity of regiochemistry control strategies in reductive couplings of propargyl alcohols and aldehydes

Article abstract of DOI:10.1021/ol902561r

[Chemical Equation Presented] The nickel-catalyzed reductive coupling of propargyl alcohols and alkynes proceeds with excellent reglochemical control with an underlying electronic preference that can be supplemented by ligand size effects. The products ob

Full text of DOI:10.1021/ol902561r

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5734-5737
Cooperativity of Regiochemistry Control
Strategies in Reductive Couplings of
Propargyl Alcohols and Aldehydes
Hasnain A. Malik, Mani Raj Chaulagain, and John Montgomery*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
jmontg@umich.edu
Received November 4, 2009
ABSTRACT
The nickel-catalyzed reductive coupling of propargyl alcohols and alkynes proceeds with excellent regiochemical control with an underlying
electronic preference that can be supplemented by ligand size effects. The products obtained may be readily converted to substructures that
are not directly available by an aldehyde-alkyne reductive coupling. A simple model for how steric and electronic factors are both important
in governing regiochemistry in couplings of this type is presented, along with examples of how the effects can combine in either a constructive
or destructive manner.
The reductive coupling of aldehydes and alkynes provides
a powerful strategy for the preparation of stereodefined
allylic alcohols.1 Numerous strategies either involving
stoichiometrically generated, alkyne-derived vinyl orga-
nometallic reagents2 or the catalytic assembly of an allylic
alcohol directly from the alkyne3 have been described. A
common issue that plagues intermolecular strategies of
this type is the control of regiochemistry in the alkyne
insertion. Indeed, controlling regioselectivity is arguably
the most challenging task in developing 1,2-difunction-
alization reactions of alkynes. The vast majority of
regioselective additions to alkynes involve alkynes with
a major bias in either the size or the electronic charac-
teristics of the acetylenic substituents.4 Internal alkynes
with only subtle biases between the two acetylenic termini
are notoriously difficult substrates for the development
of regioselective processes.
(1) (a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467–473. (b)
Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890–3908. (c)
Montgomery, J.; Sormunen, G. J. In Metal Catalyzed ReductiVe C-C Bond
Formation: A Departure from Preformed Organometallic Reagents; Springer:
Dordrecht, 2007; Vol. 279, pp 1-23. (d) Moslin, R. M.; Miller-Moslin,
K.; Jamison, T. F. Chem. Commun. 2007, 4441–4449. (e) Ikeda, S. Angew.
Chem., Int. Ed. 2003, 42, 5120–5122. (f) Skukcas, E.; Ngai, M.-Y.;
Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394–1401. (g)
Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am.
Chem. Soc. 2009, 131, 2066–2067.
(2) (a) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115,
1593–1594. (b) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197–5200.
(c) Kerrigan, M. H.; Jeon, S.-J.; Chen, Y. K.; Salvi, L.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2009, 131, 8434–8445.
In the nickel-catalyzed reductive coupling of aldehydes
with electronically biased alkynes, regioselectivities are often
(3) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065–
9066. (b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098–
6099. (c) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc.
2004, 126, 3698–3699. (d) Knapp-Reed, B.; Mahandru, G. M.; Montgomery,
J. J. Am. Chem. Soc. 2005, 127, 13156. (e) Sa-ei, K.; Montgomery, J. Org.
Lett. 2006, 8, 4441–4443. (f) Baxter, R. D.; Montgomery, J. J. Am. Chem.
Soc. 2008, 130, 9662–9663. (g) Huang, W. S.; Chan, J.; Jamison, T. F.
Org. Lett. 2000, 2, 4221–4223. (h) Miller, K. M.; Luanphaisarnnont, T.;
Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130–4131. (i)
Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342–15343.
(j) Moslin, R. M.; Jamison, T. F. Org. Lett. 2006, 8, 455–458. (k) Moslin,
R. M.; Miller, K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598–7610. (l)
Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829–3822.
(4) For examples of regioselective alkyne addition reactions, see: (a)
Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119,
11313–11314. (b) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.;
Radhakrishnan, U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391–
6402. (c) Friedman, R. K.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 10775–
10782. (d) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.;
Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774–7780. (e) Murakami,
M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005, 127, 6932–6933. (f)
Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838–12839.
(g) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 5070–5071. (h) Ohnishi, Y.; Nakao, Y.; Sato, H.; Nakao, Y.;
Hiyama, T.; Sakaki, S. Organometallics 2009, 28, 2583–2594.
10.1021/ol902561r  2009 American Chemical Society
Published on Web 11/17/2009

exceptional and are determined predominantly by substrate
structure. This outcome is typically seen with terminal, aryl,
and silyl alkynes as well as with conjugated enynes and
ynamides.3,5 Internal alkynes without a strong electronic bias,
however, often lead to regioisomeric mixtures (Scheme 1).
Table 1. Reductive Couplings of 2-Hexynea
Scheme 1
.
Regiocontrol in Aldehyde-Alkyne Reductive
Couplings
entry
L
reducing agent yield (%) (regioselectivity)
1
2
3
4
5
IMes
IPr
PBu3
PCy3
P(t-Bu)3
i-Pr3SiH
i-Pr3SiH
Et3B
Et3B
Et3B
83 (67:33)
84 (20:80)
74 (51:49)
79 (40:60)
67 (38:62)
Of the various reducing agent-ligand combinations reported
for nickel-catalyzed intermolecular couplings, Et3B-mediated
couplings with phosphine ligands developed by Jamison and
R3SiH-mediated couplings with N-heterocyclic carbene
(NHC) ligands from our work are of the broadest scope.3
Recently developed strategies that allow regioselective
outcomes with nonbiased internal alkynes include ligand size
modifications3d,f as well as olefin-directed reactions.3h-k,5
These more recent approaches have the advantage of being
tunable, with either regioselectivity outcome being possible
depending on experimental setup. Directed reactions are
especially effective at exerting regiochemical influences but
are limited by the ease with which the directing group can
be either removed or converted to a desirable functional
group.6 Herein, using propargyl alcohols as a test case, we
describe that subtle electronic influences of an alkyne may
be enhanced with protecting group strategies and then
matched with ligand size effects to allow excellent control
of regiochemistry in aldehyde-alkyne reductive couplings.
The predictable synergy of multiple subtle effects often
provides highly regioselective couplings that are relatively
unselective using standard protocols.
a The catalysts were generated from Ni(COD)2 (12 mol %) in THF.
IMes and IPr were generated in situ from the HCl salts and KO-t-Bu
(10 mol % each), or phosphines were used neat (20 mol %).
Alternatively, reductive couplings involving trialkyl phosphines
as ligands and Et3B as the reducing agent exhibit a smaller
regiochemical change with this combination of substrates as
the ligand size is varied (entries 3-5). These experiments
establish a benchmark for ligand size effects where an electronic
bias in the alkyne is largely absent.
Given the wide availability of propargyl alcohols and the
utility of the allylic alcohols derived from their couplings, we
next examined the performance of propargyl alcohols in
reductive couplings with aldehydes (Table 2). A simple prop-
Table 2. Optimization of Reductive Couplings of Propargyl
Alcohol Derivativesa
The inherent regioselectivity with unsymmetrical internal
alkynes governed by ligand size is illustrated in couplings of
2-hexyne (Table 1).7 Comparing couplings involving the larger
ligand IPr and the smaller IMes using i-Pr3SiH as reducing agent
demonstrates that the smaller ligand IMes favors the regioisomer
derived from the less hindered alkyne terminus undergoing
addition to the aldehyde (entry 1), whereas the larger ligand
IPr favors the regioisomer derived from the more hindered
alkyne terminus undergoing addition to the aldehyde (entry 2).
reducing
agent
yield (%)
(regioselectivity)
entry
R1
R2
Pr
Pr
Pr
Pr
Hept
n
L
1
2
3
4
5
6
7
8
H
H
H
H
1
1
1
2
1
1
1
1
1
1
1
IMes
IPr
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
i-Pr3SiH
Et3B
92 (80:20)
78 (67:33)
80 (67:33)
82 (50:50)
57 (75:25)
75 (75:25)
75 (87:13)
86 (71:29)
65 (57:43)
73 (58:42)
71 (53:47)
PCy3
IMes
IMes
IMes
IMes
IPr
Me
t-Bu Hept
TBS Pr
TBS Pr
TBS Pr
TBS Pr
TBS Pr
(5) For rhodium-catalyzed reductive coupling of 1,3-enynes to carbonyl
compounds and imines, see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4664–4668. (b) Kong, J.-R.; Cho, C.-
W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269–11276. (c) Kong,
J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718–719.
(d) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448–
16449. (e) Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org. Lett.
2007, 9, 3745–3748.
9
10
11
PBu3
PCy3
Et3B
P(t-Bu)3 Et3B
a The catalysts were generated from Ni(COD)2 (12 mol %) in THF.
IMes and IPr were generated in situ from the HCl salts and KO-t-Bu
(10 mol % each), or phosphines were used neat (20 mol %).
(6) (a) For site-selective hydrogenations of the products from alkene-
directed Ni-catalyzed reactions, see reference 3h. (b) For a general review,
see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307–
1370.
(7) For relevant discussions of ligand size effects, see: (a) Tekavec, T. N.;
Arif, A. M.; Louie, J. Tetrahedron 2004, 60, 7431–7437. (b) Dorta, R.;
Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo, L.; Hoff, C. D.; Nolan,
S. P. J. Am. Chem. Soc. 2005, 127, 2485–2495.
argyl alcohol (2-hexyn-1-ol) underwent i-Pr3SiH-mediated
reductive coupling with heptanal using IMes as ligand to favor
the product derived from aldehyde coupling with the hy-
Org. Lett., Vol. 11, No. 24, 2009
5735

droxymethyl-substituted alkyne terminus in 4:1 regioselectivity
(entry 1). The identical conditions using IPr or PCy3 as ligand
afforded the same product in 2:1 regioselectivity (entries 2 and
3). Using IMes as ligand, a homopropargylic alcohol underwent
coupling with 1:1 regioselectivity (entry 4), suggesting that the
modest regiocontrol in couplings of propargyl alcohols is
derived from an inductive bias rather than via direct coordination
of the hydroxyl group to nickel. Upon further examination of
couplings using IMes as ligand, protection of the propargyl
alcohol as the Me or t-Bu ether resulted in an erosion of
regioselectivity (entries 5 and 6) in comparison to leaving the
hydroxyl unprotected, but protection as the TBS (tert-butyldim-
ethylsilyl) ether improved regioselectivity to 7:1 (entry 7). Use
of more bulky IPr as ligand in this latter case resulted in erosion
of regioselectivity (entry 8). To further evaluate the effective-
ness of phosphine complexes in impacting regioselectivity, we
examined several phosphine-Et3B combinations and found that
only minimal regiochemical bias was observed (entries 9-11).
Therefore, the TBS ether-IMes combination using i-Pr3SiH as
reducing agent was the optimal set of conditions for maximizing
regioselectivity with this pair of substrates (entry 7).
Significantly, a simple model that combines the predictive
influences of ligand sterics and of substrate electronic and steric
biases may now be formulated based on examples from the
current study and previous work3 (Scheme 2).
Scheme 2. Predictive Model for Regiocontrol
The formation of a nickel metallacycle intermediate is
typically invoked in reactions of this type,3a,b,8 and we envision
that the inductive influence of the silyloxy group is respon-
sible for the regioselectivity bias of couplings of protected
propargyl alcohols. The observations that homopropargyl
alcohols proceed with very poor selectivity (Table 2, entry
4) and that silyl-protected propargyl alcohols proceed with
higher regioselectivities than unprotected propargyl alcohols
(Table 2, compare entries 1 and 7) both suggest that hydroxyl
direction via coordination to nickel is not responsible for
the effect.9 As depicted, electronic and/or steric biases of
the alkyne can combine in either a constructive or destructive
manner with ligand sterics, and one must consider the
characteristics of the aldehyde, alkyne, and ligand in order
to predict the regiochemical outcome. For simplicity, steric
and electronic biases are illustrated separately in the predic-
tive model, but there is clear synergy between the effects
(Scheme 2).
Whereas the substructures examined in Table 3 are best
optimized using IMes as ligand, the predictive model (Scheme
2) suggests that the best ligand choice for a particular coupling
will depend on a complete evaluation of multiple factors. The
cooperative nature of steric and electronic control features is
illustrated by couplings of substituted propargyl alcohols 1a and
1b (eq 1). Initial couplings with substrate 1a and IMes as ligand
provide a 1.3:1 mixture of regioisomers 2 and 3. Protection as
the TBS ether 1b maximizes the inductive influences to afford
a 3.3:1 mixture of regioisomers 2 and 3. Steric influences are
then maximized by matching substrate 1b with IPr as ligand to
afford product 2 with >98:2 regioselectivity. Importantly, these
substantial changes in regioselectivity can be predicted by
considering the simple model (Scheme 2), wherein matching
Given the potential utility of reductive couplings of simple
silyloxymethyl-substituted alkynes with aldehydes, a variety
of couplings were examined using i-Pr3SiH as reducing agent
and IMes as ligand (Table 3). Couplings of a branched and
Table 3. Scope of Reductive Couplings of Propargyl Alcohol
Derivativesa
yield (%)
(regioselectivity) (anti:syn)
entry
R1
1
2
3
4
5
6
7
Hex
c-Hex
Ph
p-(CH3CO)C6H4
Furyl
75 (87:13)
87 (87:13)
85 (91:9)
83 (91:9)
82 (91:9)
CH3(CH2)4(TBSO)CH
CH3(CH2)4(TIPSO)CH
74 (>98:2)
75 (92:8)
(75:25)
(80:20)
a The catalysts were generated from Ni(COD)2 (12 mol %) in THF.
IMes and IPr were generated in situ from the HCl salts and KO-t-Bu
(10 mol % each), or phosphines were used neat (20 mol %).
an unbranched aldehyde proceeded with 7:1 regioselectivity
(entries 1 and 2), and couplings of benzaldehyde derivatives
or furaldehyde (entries 3-5) proceeded in 10:1 regioselec-
tivity. R-Silyloxyaldehydes were also excellent participants,
with couplings proceeding in excellent yields and regiose-
lectivities ranging from 11:1 to >98:2 (entries 6 and 7).
As the examples above illustrate, regiocontrol derived from
variation in size of the NHC ligand is somewhat subtle (Table
1). Electronic biases of simple propargyl alcohols are similarly
modest (Table 2, entries 1-2). However, proper choice of
protecting groups and ligands can result in preparatively useful
levels of regiocontrol in relatively unbiased cases (Table 3).
(8) (a) For a recent computational study: McCarren, P. R.; Liu, P.;
Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2009,
131, 6654–6655. (b) For metallacycle isolation, see: Ogoshi, S.; Arai, T.;
Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347–1349
.
(9) For representative examples of hydroxyl-directed reductive couplings,
see: (a) Qun, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem., Int.
Ed. 2002, 41, 2160. (b) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006,
128, 2764. (c) Chen, M. Z.; Micalizio, G. C. Org. Lett. 2009, 11, 4982.
5736
Org. Lett., Vol. 11, No. 24, 2009

steric and electronic influences synergistically maximizes re-
gioselectivity.
to a Pd(0)-catalyzed reductive transposition to afford product
14,10c which is the opposite regioisomer from that derived
from a terminal alkyne reductive couplings (compound 11).
Finally, TBS deprotection may be directly followed by a
sulfonylation/reduction procedure10d to directly afford prod-
uct 15, which is the opposite regioisomer from that prefer-
entially obtained from reductive couplings of 2-alkynes using
IPr as ligand (compound 12, Table 1, entry 2; Scheme 3).
Scheme 3. Post-Coupling Manipulations
Similarly, a reductive coupling of protected 2-butyn-1-ol (4)
with heptanal proceeds with modest regioselectivity using IMes
as ligand to afford a 2.2:1 mixture of products 5 and 6 (eq 2).
However, synergy of electronic and steric biases is predicted
by the use of a large ligand in this case, and the use of IPr as
ligand generates product 5 with 9:1 regioselectivity.
As a final illustration, if one reverses the relative size of
the alkyne substituents, as seen in alkyne 7, the ligand steric
model predicts that a smaller ligand would favor the major
product 8 (eq 3). Indeed, in this instance, couplings using
IPr as ligand are quite selective (10:1), but the use of the
smaller ligand IMes provides exceptional regiocontrol (>98:
2) over the alternate regioisomer 9. The optimized choice
of ligand in each of these examples (eq 1-3) may be readily
predicted from the model presented above (Scheme 2).
In summary, highly regioselective nickel-catalyzed reductive
couplings of propargyl alcohol derivatives and aldehydes have
been developed. This work addresses strategies to control the
regiochemistry in alkyne insertions; an issue that plagues nearly
every intermolecular metal-catalyzed process involving alkynes.
The interplay of steric and electronic considerations in nickel-
catalyzed reductive couplings provides a predictable strategy
for controlling regiochemistry for a variety of substrate com-
binations, including couplings of propargyl alcohols. In compar-
ing a variety of phosphines and NHCs as ligands, the NHCs
examined are best able to exert steric influences in controlling
regiochemistry. For a number of desirable regiochemical
outcomes that are elusive by direct coupling strategies, the
derivatization of propargyl alcohol-derived products provides
an indirect but effective alternative. The examination of different
classes of NHCs that exert even greater regiochemical biases
with a range of alkynes is in progress.
As noted above, a limitation of any substrate-controlled
strategy for product selection is the ease with which the
controlling functionality may be converted into a desired
product. Propargyl alcohols are especially valuable in this
respect. For example, the products of the type described in
Table 3 may be converted to three classes of compounds
that currently cannot be directly accessed in high regiose-
lectivity by a nickel-catalyzed silane-mediated aldehyde-
alkyne reductive coupling. A protecting group swap from
TBS to acetate may be followed by Pd(0)-catalyzed conver-
sion to diene 13,10a which is the opposite regioisomer from
that directly accessed by 1,3-enyne reductive couplings
(compound 10).10b The same acetate may also be subjected
Acknowledgment. Support for this work was provided
by the National Institutes of Health (GM 57014). Scott Bader
(Pfizer) is thanked for helpful discussions. This article is ded-
icated to the memory of Professor Keith Fagnou.
Supporting Information Available: Experimental pro-
cedures and copy of spectral data for all new compounds is
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) (a) Takacs, J. M.; Lawson, E. C.; Clement, F. J. Am. Chem. Soc.
1997, 119, 5956–5957. (b) For an exception, see ref 9c. (c) Tsuji, J.; Mandai,
T. Synthesis 1996, 1–24. (d) Corey, E. J.; Achiwa, K. J. Org. Chem. 1969,
34, 3667–3668.
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