Direct Formic Acid Mediated Z-Selective Reductive Coupling of Dienes and Aldehydes

Article abstract of DOI:10.1002/anie.201905540

Methods for the addition of unsaturated nucleophiles to carbonyls to generate Z-olefin products remain rare and often require either alkyl borane or zinc reductants, limiting their utility. Demonstrated here is that formic acid mediates the Rh-catalyzed,

Full text of DOI:10.1002/anie.201905540

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Formic Acid Mediated Direct Z-Selective Reductive Coupling of
Dienes and Aldehydes
Authors: Christopher Cooze, Raphael Dada, and Rylan J. Lundgren
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905540
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10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
Formic Acid Mediated Direct Z-Selective Reductive Coupling of
Dienes and Aldehydes
Christopher Cooze, Raphael Dada, and Rylan J. Lundgren*[a]
classes.[7] The lack of generality in Z-selective diene additions
Abstract: Methods for the addition of unsaturated nucleophiles to
carbonyls to generate Z-olefin products remain rare and often require
alkyl borane or zinc reductants, limiting their utility. We demonstrate
that formic acid mediates the Rh-catalyzed, Z-selective coupling of
dienes and aldehydes. The process is distinguished by broad
tolerance towards reducible or electrophilic groups. Kinetic analysis
suggests that generation of the catalytically active Rh-intermediate by
ligand dissociation is the rate determining step. The rapid generation
and trapping of Rh-allyl intermediates is key to preventing chain-
walking isomerization events that plague related protocols. Insights
gained through this study may have wider implications in selective
metal-catalyzed hydrofunctionalization reactions.
highlights the difficulty in controlling both site- and
stereoselectivity in catalytic diene functionalization,[8] particularly
in those reactions that generate thermodynamically less favorable
product isomers.[9]
From
a mechanistic perspective, improving reductive
chemoselectivity while inhibiting chain-walking events in diene-
aldehyde coupling can potentially be realized by tailoring the
reactivity of the Rh-intermediates involved in the reaction pathway.
Specifically, if both diene insertion into the Rh–hydride catalyst
and electrophilic capture of the resultant Rh-allyl outpace
undesirable isomerization, b-hydride elimination, or other
reductive processes, a direct and selective coupling process
should be possible. We recently reported that formic acid acts as
reducing agent for the Z-selective 1,6-reduction of dienyl esters[10]
and questioned whether this pathway could be diverted to enable
reductive coupling. Formic acid has been used as a reductant for
metal-catalyzed C-C bond forming carbonyl allylation and
vinylation processes.[11] In this report, we demonstrate that
mixtures of Rh-precatalysts, 1,5-cyclooctadiene (COD), and PPh3
mediate the isomerization-free, stereoselective addition of diene-
derived nucleophiles to aldehydes (Figure 1). The process
delivers substituted Z-homoallylic alcohols with typically >95:5
syn- and Z-selectivity without interference from other reducible
functionality. The role of each of the catalyst components is
delineated through kinetic studies; generation of the catalytically
active Rh-species is the overall rate determining step which helps
to impart high selectivity at reduced catalysts loadings.
Introduction
The addition of carbon-based nucleophiles to carbonyl units is
one of the most fundamental reactions in synthetic organic
chemistry. Since organometallic reagents often require an
additional preparative step to obtain and exhibit limited functional
group compatibility,[1] reductive coupling strategies that use
olefins as pro-nucleophiles can streamline synthetic routes that
involve carbonyl alkylation.[2] Early olefin-aldehyde reductive
coupling protocols employed aggressive reducing agents like
alkyl borane or alkyl zinc reagents to generate the metal hydride
intermediate required for nucleophile formation. More recently,
the use of milder reductants, such as molecular hydrogen or
isopropanol, in combination with suitable transition metal
catalysts, has been pioneered by Krische to dramatically
broadened the scope and utility of olefin-based carbonyl
additions.[3] Despite advances in catalytic carbonyl reductive
coupling processes,[4] addition reactions involving diene or alkyne
pro-nucleophiles that generate less thermodynamically stable Z-
olefin products remain rare.[5] The Z-selective coupling of
aldehydes and dienes can be promoted by Rh-based catalysts,
however the requirement for stoichiometric Et3B to generate a Rh-
hydride intermediate limits chemoselectivity.[6] Under these
conditions, products derived from chain-walking isomerization are
observed,[6b] restricting access to a narrow range of product
[Rh(COD)Cl]2, PPh3, COD
rate determining step
precatalyst mixture
OH
R'
(COD)Rh(solv)+
HCO2H
G
O
H
R'
R
G
R
>95:5 dr
>95:5 Z:E
R, R':
alkyl, aryl
G: ester
amide, aryl
• COD essential for selectivity, PPh3 extends catalyst lifetime
• direct reductive coupling: no chainwalking or isomerization
• no over-reduction of sensitive functional groups by Rh–H
[a]
C. Cooze, R. Dada, Prof. R. J. Lundgren
Department of Chemistry
University of Alberta
Edmonton, Alberta, T6G 2G2, Canada
E-mail: rylan.lundgren@ualberta.ca
Figure 1. Formic acid enables the Rh-catalyzed Z-selective reductive coupling
of dienes and aldehydes without isomerization or competitive reduction of other
functional groups.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
A
Results and Discussion
3 equiv. PhCHO
2.5 mol% [Rh(COD)Cl]2
5 mol% PPh3
OH
CO2Bn
We surveyed a range of experimental conditions to ultimately find
that dienoate 1a can be reductively coupled to benzaldehyde
using formic acid/diisopropylethylamine (DIPEA) in the presence
of [Rh(COD)Cl]2 and PPh3 to generate Z-homoallylic alcohol 2a
as a single isomer in good yield (>98:2 syn/anti and Z/E, 77%
yield). Figure 2a provides an overview of important reaction
parameters. The use of other Rh-based catalysts, including
Wilkinson’s catalyst or [Rh(COE)Cl]2, as well as [Ir(COD)Cl]2
consumed diene without significant product formation, while other
transition metal complexes (Ru-, Pd-, and Cu-based) were
completely inactive. Catalyst loadings as low as 0.25 mol%
[Rh(COD)Cl]2 gave good yields when additional COD was added.
DIPEA was essential to observe good yields of reductive coupling
product over diene transfer hydrogenation. The stereochemistry
of the diene starting material (E,E-, Z,E- or E,Z-) had minimal
impact on reaction outcomes and rates, allowing for the use of
crude mixtures of substrates obtained from standard diene
syntheses.[12]
Ph
CO2Bn
HCO2H/DIPEA, MeCN
standard conditions
n-Pr
n-Pr
1a
2a
(97% conv.) 77% [>98:2]a
Effect of Reaction Parameters
catalyst
base
(79) 6
Rh(PPh)3Cl (no PPh3)
[Rh(COE)2Cl]2
[Ir(COD)Cl]2
NEt3
(>98) 47
(90) 10
(36) <2
(98) 6
DBU
(89) <2
Cs2CO3
(<2) <2
Ru(COD)Cl2
conditions
(<2) <2
(<2) <2
(<2) <2
b (98) 76
RuCp*(MeCN)3 PF6
Pd(OAc)2
no PPh3
(88) 48
(>98) 39
(5) 5
CuI
1 equiv PhCHO
0.25 mol% [Rh] + 10% COD
NaHCO2 instead of HCO2H
Functional Group Compatibility
B
tolerated
not tolerated
O
O
O
H
N
H
Ph
Ac
Ph
NH2
Ph
Me Ph
OMe
OH
Ph
O
O
TMS
hexyl
Ph NH2
Ph OH
S
Tol
NH2
Ph
Et
pentyl
octyl
H2O
O
Et
Cl
pentyl
The reductive chemoselectivity of the reaction was
assessed by a comprehensive functional group compatibility
screen (Figure 2b), which demonstrated that related carbonyl
groups (ketones, esters, amides), activated and unactivated
olefins, other dienes, alkyl halides, epoxides, and protic NH- and
OH-groups are well tolerated (>60% product yield with one
equivalent of additive and >85% recovery of additive, see the SI
for complete details). Of the functional groups screened, only
alkynes and alkyl bromides were impacted under the standard
reaction conditions.
Ph
decyl
Br
Ph
N
9
H
Isomerization Test: <5% chain-walking in both cases
C
PhCHO
cat.
OH
CO2Et
Ph
CO2Bn
2b 73%
EtO2C
std. cond.
direct coupling
CO2Bn
1b
1c
ArCHO
cat.
OH
Ar
MeO2C
Ph
std. cond.c
direct coupling
The formic acid mediated coupling process yields products
of direct aldehyde Z-allylrhodation without isomerization (Figure
2c). For example, diester 1b underwent reaction to give a single
coupling product in 73% yield, chain-walking and addition
adjacent to the remote ester was not observed. Even where there
is a clear thermodynamic driving force for isomerization, like in the
cases of ester-tethered aryl diene 1c, only direct coupling product
2c is obtained, contrasting approaches with alternative reducing
agents.[6b]
MeO2C
Ph
2c 56%
Figure 2. A Effect of reaction parameters on the Rh-catalyzed formic acid-
mediated reductive coupling. B Functional group compatibility, one equivalent
of additive, tolerated indicates >60% product yield and >85% additive recovery.
C Direct reductive coupling of dienes that can undergo isomerization prior to
addition to the aldehyde. Conversions (indicated in parentheses) and yields
(indicated in bold) determined by calibrated 1H NMR spectroscopy, 0.2-0.5
mmol scale, 0.25 M at 35 ˚C, 1.2 equiv. of HCO2H unless otherwise noted. Ar =
4-CF3C6H4. [a] Isolated yield. [b] At 45 ˚C. [c] 1.7 equiv. of HCO2H.
The role of the catalyst components was elucidated by
mechanistic studies (Figure 3). Overall, the process exhibits
pseudo zero-order kinetics and is not positive order in any of the
substrate components (Figure 3a, essentially zero order in
aldehyde and formic acid/DIPEA, partial negative order in diene,
see the SI for plots).[13] The reaction is positive order in Rh and
COD, while is negative order in PPh3. We rationalize these
observations by proposing that diene substrate, COD, and PPh3
ligate Rh in various species that undergo ligand exchange
processes. Most of the Rh-species exist as off-cycle
intermediates and the active species that enters the catalytic cycle
is likely a solvated Rh(COD)+. The generation of this species by
ligand dissociation is rate determining and subsequent reaction
with formate generates a Rh–H to initiate the reductive coupling
of substrates. COD is essential for reactivity, [Rh(COE)2Cl]2 or
[Rh(ethylene)2Cl]2 are inactive until COD is added. The validity of
ancillary diene ligated Rh intermediates being involved in the
catalytic cycle was confirmed by the observation of modest
enantio-induction by use of structurally related chiral diene
ligands in place of COD.[13c] The role of phosphine ligand is to
prevent the irreversible decomposition of off-cycle Rh-species
under the reductive conditions (Figure 3b). While PPh3 slows the
rate of reaction, its presence prevents precipitation of Rh from
solution, an event that leads to an erosion in selectivity. The
impact of PPh3 and COD are more dramatic at reduced catalyst
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10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
A
Rate Law Data
COD, suggesting that while the diene substrate does not undergo
reversible Rh–hydride insertion/b-hydride elimination, the
ancillary diene ligand can, further demonstrating the importance
of the COD ligand framework on catalysis. Figure 4 provides a
complete potential catalytic cycle. These individual steps likely
mirror those in reductive coupling reactions employing Et3B, with
the notable exception that catalyst generation is the rate
determining step and the Rh-allyl species is trapped faster than
undesirable isomerization events. Upon product release from the
catalyst, Rh is likely re-trapped by PPh3 (at higher loadings, PPh3
significantly slow the reaction rate, see the SI for details).
(COD)Rh(solv)+ active catalyst
Catalyst
positive
positive
Reactants
aldehyde
HCO2H
rate determining
– L
(COD)Rh(Ln)+
0
0
Rh
COD
Rh(Ln)+
diene negative
PPh3 negative
L = diene, COD, PPh3
B
C
PPh3 enhances catalyst lifetime
D-label / stereochemical model
80
CO2Bn
n-Pr
O
standard conditions
60
40
syn-Rh–D addition
D
OH
h
h
a
a
l
l
f
f'
.'
o'
P
P
P
P
hh33
d.
hh33
H
20
0
CO2Bn
Rh
O
s
s
t
t
d
d
.
c
c
o
o
n
n
d
Ph
n-Pr
n
n
o
P
P
P
P
The mechanistic features of the reductive coupling allow for
the use of a broad range of diene and aldehyde partners with
functional groups that would be incompatible with more
aggressively reducing conditions (Figure 5). Alkyl substituted
dienoates, including those with bulky groups (2f, 2g), isolated
alkene units (2h, 2m), halogen (2i), nitrile (2j), carbamates and
imides (2k, 2n), ester, and (hetero)aryl substitution undergo
reaction to give products with good to moderate yields and
uniformly high syn- and Z-selectivity. The aryl aldehyde partner
can take on a range of electronic properties (2r, 2s; more
electron-poor aryl aldehydes react selectively in competition
studies, see the SI for details) or contain boronic ester (2t), aryl
halide (2u, 2v, 2w, 2z), or reducible functional groups (nitrile 2y,
ketone 2aa, or nitro 2ae), as well as heterocyclic groups (2ab,
2ac). The reaction accommodates a range of ester groups,
including i-Pr (2af), t-Bu (2ag), and more complex alkene (2ah,
2ai), carbamates (2aj, 2ak), alkyl chloride (2al) or
polyfunctionalized groups (2am). Aryl dienes are reductively
coupled to aldehydes with similar efficiency and selectivity,
including those with alcohol (2ao), ester (2c), nitrile (2aq), and
ketone groups (2ar). Weinreb (2as) and morpholine (2at) dienyl
amides are viable substrates, as are alkyl (2au, 2av) or a,b-
unsaturated aldehydes (2aw).[13d]
D
0
2
4
6
time'(h)
aldehyde allylrhodation
COD and PPh3 essential at low [Rh]
yield (conv.)
76 (>99)
41 (62)
0.5 mol% [Rh] 45 ºC
10% COD + 1% PPh3
10% COD + no PPh3
no COD + 1% PPh3
no COD, no PPh3
OH
86%
16%
Ph
CO2Bn
COD–D1
26 (47)
25 (62)
D
n-Pr
Figure 3. A Reaction rate law data and mechanistic proposal that generation of
the catalytically active (COD)Rh(solv)+ is the overall rate determining step. B
Effect of PPh3 concentration on reaction rate and overall efficiency. C D-
labelling studies give products from syn-Rh–D addition and allylrhodation, some
of the D-label is incorporated into COD. Unless noted, reactions conducted
under standard conditions noted in Figure 2 except at 50 °C.
loadings, where both reaction rates and selectivities are reduced
without the co-additives (Figure 3b, see the SI for a more detailed
plot and analysis). Experiments using formyl labelled d1-formic
acid gave results consistent with a syn-hydrorhodation of diene
substrate followed by aldehyde allylrhodation that occurs via a
chair-like transition state (Figure 3c).[6] No D-label was found at
any other position; however, D-label was found incorporated into
(COD)Rh(Ln)+
Rh(Ln)+
The value of the reaction to generate complex bio-active
molecules was demonstrated by the diastereoselective
preparation of diarylmethane 6, a key intermediate in the
synthesis of a glucagon receptor antagonist (Figure 5). The
carbon–carbon bond framework was readily obtained by
reductive coupling of diene 3 with 4-chlorobenzaldehyde using 1
mol% [Rh(COD)Cl]2 followed by alkene hydrogenation and ester
hydrolysis to give 4 in 69% overall yield over three steps. Friedel–
Crafts alkylation of the alcohol with substituted indole 5 delivers
the target molecule 6 in 76% yield, which can be converted to the
drug-candidate via an established protocol.[14]
ligand dissocation
+ L
– L
[rate determining]
Rh(solv)+
product, DIPEA
HCO2H, DIPEA
HDIPEA+
CO2, HDIPEA+
R
protonation
hydride generation
H
G
Rh
G
H
Rh
Rh
reversible
metallation
O
R'
H
R
H
R
O
R'
The stereochemically defined Z-allylic alcohols generated
by formic acid mediated reductive coupling are useful building
blocks for more complex fragments (Figure 6). Straight-forward
access to 2,5-dihydrofurans (7),[15] epoxide[16] and aziridine[17]
stereotetrads (8, 9), tertiary alcohols (10),[18] and tetrasubstituted
tetrahydrofurans (11)[12] is possible by the high-yielding
stereoselective functionalization of product 2a by standard
synthetic protocols.
Rh
allylrhodation
hydrometallation
G: ester, amide, aryl
R': aryl, alkenyl, alkyl
G
[rapid trapping, no chain-walking]
Figure 4. Complete catalytic cycle for the formic acid mediate reductive coupling
of dienes and aldehydes. L = PPh3, diene substrate or COD, solv = MeCN.
Steps are shown as irreversible for clarity. See the SI for additional details.
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10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
3 equiv. R'CHO
[Rh(COD)Cl]2, PPh3
OH
R'
40+ examples
>95:5 Z-selective
G = ester, amide or aryl
G
R = functionalized alkyl, aryl, H
R' = aryl, alkyl, alkenyl
diene geometry inconsequential
typically >95:5 syn-selective
no chainwalking/isomerization
HCO2H/DIPEA
MeCN, 35ºC
R
G
R
1
2
Dienoate Scope
OH
OH
OH
OH
OH
OH
Ph
CO2Bn
Ph
CO2Bn
Ph
Ph
Ph
CO2Bn
Ph
Me
CO2Bn
CO2Et
Ph
CO2Bn
Cy
Me
2a 71% [>98:2]
2d 69% [>98:2]
2e 51% [91:9]
2f 65% [82:18]
2g 70% [98:2]
2h 60% [>98:2]
OH
OH
OH
OH
OH
Ph
Me
Cl
NC
Ph
CO2Bn
Ph
CO2Bn
Ph
Ph
CO2Bn
BocHN
CO2Et
Me
CO2Bn
2m 68% [>98:2]
2i 64% [>98:2]
2j 60% [>98:2]
2k 67% [>98:2]
OH
2l 56% [>98:2]
OH
OH
Ph
OH
OH
Ph
Ph
CO2Bn
Ph
CO2Bn
Ph
CO2Bn
CO2Et
F
CO2Et
PhthN
EtO2C
Ph
2o 69% [>98:2]
NBoc
Br
2n 71% [>98:2]a
2b 73% [>98:2]
2p 63% [>98:2]
2q 71% [>98:2]
Aryl Aldehyde Scope [R = n-Pr] [G = CO2Bn]
O
O
CF3
B(pin)
OMe
Cl
Br
F
OMe
2r 81% [>98:2]
2s 51% [>98:2]
2t 75% [>98:2]
2u 69% [>98:2]
2v 60% [>98:2]a
2w 72% [>98:2]
2x 57% [>98:2]
Br
CN
Ac
S
N
Ar'
N
NO2
N
OMe
F
F
2y 75% [>98:2]
2z 75% [>98:2]
2aa 79% [>98:2]
2ab 44% [>98:2]
2ac 45% [>98:2]a
2ad 74% [>98:2]
2ae 74% [>98:2]
Ester Scope [R = Me] [R' =Ph]
H
O
N
Me
Me
Me Me
R' = i-Pr
O
Cl
CO2Me
NHBoc
NBoc
2af 61% [>98:2]
Me
Me
Me
N
O
Me
R' = t-Bu
2ag 60% [>98:2]
2ah 71% [nd]
2ai 70% [nd]b
2aj 71% [nd]
2ak 61% [nd]b
2al 70% [>98:2]
2am 51% [nd]b
OH
Ph
2aq R = CN
Aryl Diene Scope [Ar = 4-CF3C6H4]
OH
Ar
OH
OH
OH
Ar
Ar
Ar
Me
Ph
Ph
MeO2C
Ph
Me
Ph
77% [>98:2]
2ar R = Ac
64% [>98:2]
Me
HO
2an 60% [>98:2]
2ao 68% [>98:2]
2c 56% [>98:2]
Other Examples
OH
2ap 62% [>98:2]
R
OH
OH
OH
Me
Me
OH
H
H
butyl
Ph
Ar
OMe
butyl
n-Pr
n-Pr
n-Pr
O
N
2aw
52%
[96:4]
2av
Me
O
N
CO2Bn
n-Pr
53%
[>98:2]
O
Me
2as 65% [>98:2]
2at 61% [>98:2]
2au 59% [>98:2]
CN
Ac
Me
Application
F
H
N
Ns
F
OH
1. ArCHO
[Rh(COD)Cl]2, PPh3,
COD, HCO2H/DIPEA
F
N
Me
NNs
Cl
Me
5
Cl
Me
Me
2. hydrogenation
3. hydrolysis
Me
CO2H
CO2Et
glucagon receptor
antagonist (Merck)
6
4
3
Ar
69% (3 steps)
76%
CO2H
NH
Cl
O
Figure 5. Scope for the formic acid mediated reductive coupling of dienes and aldehydes. Yields are of isolated material under standard conditions (Fig. 2). See
the SI for examples at lower [Rh] loading and minor modifications conditions dependent on substrate. Ar’ = 4-CF3C6H4, dr with chiral esters is ~1:1. [n.d] = crude
reaction mixture dr could not be measured, syn dr of isolated material is >95:5.
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10.1002/anie.201905540
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RESEARCH ARTICLE
[1] Handbook of Functionalized Organometallics: Applications in
Synthesis, Blackwell Science Publ, Oxford, 2005.
OH
Ph
O
O
R
R
a
f
[2] a) J. Montgomery, Angew. Chem. Int. Ed. 2004, 43, 3890-3908; b) S.
S. Ng, C. Y. Ho, K. D. Schleicher, T. F. Jamison, Pure. Appl. Chem.
2008, 80, 929-939; c) K. Sato, M. Isoda, Y. Tokura, K. Omura, A. Tarui,
M. Omote, I. Kumadaki, A. Ando, Tetrahedron Lett. 2013, 54, 5913-
5915.
[3] a) K. D. Nguyen, B. Y. Park, T. Luong, H. Sato, V. J. Garza, M. J.
Krische, Science 2016, 354, aah5133 1-5; b) M. Holmes, L. A.
Schwartz, M. J. Krische, Chem. Rev. 2018, 118, 6026-6052; c) J. F.
Bower, I. S. Kim, R. L. Patman, M. J. Krische, Angew. Chem. Int. Ed.
2009, 48, 34-46; d) S. W. Kim, W. D. Zhang, M. J. Krische, Acc. Chem.
Res. 2017, 50, 2371-2380.
Ph
Ph
I
CO2Bn
CO2Bn
7
78%
11
76%
CO2Bn
R
c
b
d, e
8
70%
9
62%
10
79% (5:1 dr)
OH
OH
Me
HO
O
HN
Ph
CO2Bn
Ph
CO2Bn
Ph
CO2Bn
R
R
R
[4] For selected examples see: a) Y. Yang, I. B. Perry, G. Lu, P. Liu, S. L.
Buchwald, Science 2016, 353, 144-150; b) T. Y. Chen, R. Tsutsumi,
T. P. Montgomery, I. Volchkov, M. J. Krische, J. Am. Chem. Soc. 2015,
137, 1798-1801; c) A. M. Haydl, B. Breit, T. Liang, M. J. Krische,
Angew. Chem. Int. Ed. 2017, 56, 11312-11325; d) H. D. Xiao, G. Wang,
M. J. Krische, Angew. Chem. Int. Ed. 2016, 55, 16119-16122; e) M.
Takeda, A. Mitsui, K. Nagao, H. Ohmiya, J. Am. Chem. Soc. 2019,
141, 3664-3669; f) R. Y. Liu, Y. Zhou, Y. Yang, S. L. Buchwald, J. Am.
Chem. Soc. 2019, 141, 2251-2256; g) R. A. Swyka, W. Zhang, J.
Richardson, J. C. Ruble, M. J. Krische, J. Am. Chem. Soc. 2019, 141,
1828-1832; h) A. Köpfer, B. Sam, B. Breit, M. J. Krische, Chem. Sci.
2013, 4, 1876-1880; i) C. Li, R. Y. Liu, L. T. Jesikiewicz, Y. Yang, P.
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Figure 6. Derivatization of Z-b-ester homoallylic alcohols. a) 10% Ph2Se2,
(NH4)2S2O8, b) 2% VO(acac)2, t-BuO2H, c) 2% Rh2(esp)2, hydroxylamine O-
sulfonic acid, d) Dess-Martin periodinane e) AlMe3, f) I2, NaHCO3. R = n-Pr, see
SI for complete details.
Conclusion
The Rh-catalyzed, formic acid mediated reductive coupling of
dienes and aldehydes provides a direct route to stereochemically
defined Z-homoallylic alcohols. The mildly reducing conditions
allow for tolerance towards functional groups that would interfere
with organometallic reagents or highly polarized hydride donors.
A complete absence of chain-walking isomerization is facilitated
by comparatively slow liberation of the active catalyst species
followed by rapid Rh–H insertion and trapping. This general
concept should be amendable to related chemoselective olefin
hydrofunctionalization processes.
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53, 11605-11610.
Experimental Section
General Procedure: In an atmosphere controlled glovebox, [Rh(COD)Cl]2
(6.2 mg, 0.0125 mmol, 0.025 equiv.) and PPh3 (6.6 mg, 0.025 mmol, 0.05
equiv.) were weighed into separate one dram vials. To the vial containing
[Rh(COD)Cl]2 was added MeCN (1 mL) and the solution was transferred
into the vial containing PPh3. MeCN (0.4 mL) was used to wash the
remaining Rh solution into the vial containing the PPh3 catalyst mixture. To
a separate one dram vial was weighed diene (0.5 mmol, 1 equiv.) followed
by aldehyde (1.5 mmol, 3 equiv.). To this mixture was transferred the
catalyst solution using MeCN (0.3 mL) to rinse the remaining solution into
the reaction mixture. DIPEA (174 µL, 1 mmol, 2 equiv.) was added followed
by a freshly prepared 2 M HCO2H solution (0.3 mL, 0.6 mmol, 1.2 equiv).
A stir bar was added to the vial which was capped with a PTFE-lined cap,
taken out of the glovebox and placed in an aluminum block heated to 35
°C. The reaction progress was monitored periodically via 1H NMR. At
>95% conversion, the solution was diluted with toluene, concentrated and
purified by silica gel chromatography. Reactions set up without the use of
a glovebox and conducted under air provide similar results. See the SI for
complete details.
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[9] For examples of Z-selective diene, alkyne, or allene functionalization
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15822; b) Z.-L. Tao, A. Adili, H.-C. Shen, Z.-Y. Han, L.-Z. Gong,
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Liao, T. Ju, J.-H. Ye, Z. Zhang, J. Li, D.-G. Yu, J. Am. Chem. Soc.
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Wang, Y. W. Tan, S. Ge, Angew. Chem. Int. Ed. 2017, 56, 4328-4332
g) Y. Luo, S. M. Wales, S. E. Korkis, I. D. Roy, W. Lewis, H. W. Lam,
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Li, X. Liu, L. Lin, X. Feng, Angew. Chem. Int. Ed. 2012, 51, 2776-2779;
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Acknowledgements
We acknowledge NSERC Canada and the Canadian Foundation
for Innovation for support.
[10] R. Dada, Z. Wei, R. Gui, R. J. Lundgren, Angew. Chem. Int. Ed. 2018,
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Keywords: homogeneous catalysis • reductive coupling •
chemoselectivity • Z-alkenes • rhodium
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10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
Leung, R. L. Patman, B. Sam, M. J. , Chem. Eur. J. 2011, 17, 12437-
12443.
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reduction was ruled out with control experiments. The addition of
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hydrorhodation in this study have been reported to add to aldehydes
with low diastereoselectivity, see: P. Galatsis, S. D. Millan, P. Nechala,
G. Ferguson, J. Org. Chem. 1994, 59, 6643-6651.
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Chem. Int. Ed. 2016, 55, 2028-2031; c) up to 30% ee was observed,
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any case, see the SI for details; d) for less successful substrate scope
examples, see the SI.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201905540
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of
Contents
RESEARCH ARTICLE
C. Cooze, R. Dada, R. J. Lundgren*
OH
R'
(COD)Rh(solv)+
G
O
Page No. – Page No.
H
R'
HCO2H
R
G
R
>95:5 dr and Z:E
Formic Acid Mediated Direct Z-
Selective Reductive Coupling of
Dienes and Aldehydes
no chain-walking isomerization
tolerates reducible groups
Z-selective
Formic acid mediates the Rh-catalyzed, Z-selective coupling of dienes and
aldehydes. The process is distinguished by broad tolerance towards reducible or
electrophilic groups without chain-walking isomerization.
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