Chemoselective Synthesis of Z-Olefins through Rh-Catalyzed Formate-Mediated 1,6-Reduction

Article abstract of DOI:10.1002/anie.201800361

Z-olefins are important functional units in synthetic chemistry; their preparation has thus received considerable attention. Many prevailing methods for cis-olefination are complicated by the presence of multiple unsaturated units or electrophilic functio

Full text of DOI:10.1002/anie.201800361

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Chemoselective Z-Olefin Synthesis via Rh-Catalyzed, Formate
Mediated 1,6-Reduction
Authors: Raphael Dada, Zhongyu Wei, Ruohua Gui, and Rylan J.
Lundgren
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800361
Angew. Chem. 10.1002/ange.201800361
Link to VoR: http://dx.doi.org/10.1002/anie.201800361
http://dx.doi.org/10.1002/ange.201800361

Angewandte Chemie International Edition
10.1002/anie.201800361
COMMUNICATION
Chemoselective Z-Olefin Synthesis via Rh-Catalyzed, Formate
Mediated 1,6-Reduction
†
†
[a]
Raphael Dada, Zhongyu Wei, Ruohua Gui, Rylan J. Lundgren*
Abstract: Z-olefins are important functional units in synthetic
chemistry; thus their preparation has received considerable attention.
Many prevailing methods for cis-olefination are complicated by the
presence of multiple unsaturated units or electrophilic functional
groups. In this study, Z-olefin products are delivered via selective
reduction of activated dienes using formic acid. The reaction proceeds
with high regio- and stereoselectivity (typically >90:10 and >95:5
respectively) and preserves other alkenyl, alkynyl, protic and
electrophilic groups.
of the reaction is required to prevent substrate over-reduction and
1
1
isomerization. Herein, we report a formate-mediated reduction
1
2
of activated dienes to generate Z-olefins. Substrate coordination
and hydride delivery from a Rh-catalyst dictate a chemo- and
regioselective process. Other unsaturated groups such as non-
activated olefins or dienes, a,b-unsaturated esters, internal
alkynes and a host of electrophilic groups are tolerated (Figure 1).
The process offers
a
new opportunity to prepare
polyfunctionalized Z-olefins in complex substrate environments
without protecting groups.
A large number of bioactive molecules contain cis-alkene units,
and stereospecific transformations of Z-olefins are commonly
used to develop molecular complexity. Thus, the synthesis of less
thermodynamically stable alkenes is an important goal. An array
Rh-catalyzed, formate mediated reduction of dienes:
Access to polyfunctionalized Z-alkenes
R
cat. [Rh], PAr3
1
R
of methods generate Z-olefins with high stereoselectivity;
G
HCO H/NEt3
2
G
however control over chemo- and regioselectivity when
employing unprotected, polyfunctionalized substrates remains a
challenge. Cis-selective carbonyl olefination reactions using
phosphorus-, silicon- or sulfur-containing precursors have
dienyl-Rh
intermediate
Z-selective
1,6-addition
R
H
Rh
L
[
chemoselectivity]
[stereoselectivity]
G = ester or amide
G
2
enabled the preparation of Z-olefins in a myriad of settings. The
tolerates
requirement for stoichiometric generation of main-group element
ylide intermediates limits efficiency. Furthermore, the strongly
basic reaction conditions are often incompatible with protic or
R
CO R
2
R
R
R
3
H
O
H
N
electrophilic functionality. Alternative methods for Z-olefin
Ar Br
Cl
OH
4
synthesis include Z-selective alkyne reductions and alkene
5
,6
metathesis reactions. Despite their remarkable and growing
utility, alkyne semi-reduction and Z-selective metathesis reactions
can exhibit poor chemoselectivity on targets bearing multiple
alkyne or olefin units. There remains a need for complementary
catalytic approaches to Z-olefin synthesis in the presence of other
carbon-carbon p-bonds and protic or electrophilic groups.
Figure 1. Rh-catalyzed hydride addition to generate Z-olefins: overview of the
developed method.
We found 2.5 mol% [Rh(COD)Cl] and 15 mol% PPh in the
2
3
Catalyst-controlled addition of nucleophiles to carbonyl-
activated dienes is a pivotal method to generate functionalized
presence of formic acid/NEt in acetonitrile provided the desired
3
mono-reduced olefin 2a in 80% yield with 96:4 Z/E selectivity
(Figure 2a, entry 1). RhCl(PPh ) , alternative Rh/PPh3
7
olefins. In select cases, these transformations enable highly
3
3
8
regioselective 1,6-addition to deliver g-substituted E-alkenes. By
stoichiometries, or the use of other ligands resulted in reduction
with moderate to low E-selectivity (Figure 2a, entries 2-7). Other
metals, including Ir, Cu, and Pd did not generate the Z-olefin
product (entries 8-11). Reactions conducted with lower catalysts
2
contrast, Z-selective 1,6-additions to electron-poor dienes remain
9
rare. The addition of hydrogen or hydride equivalents to
extended Michael acceptors generating cis-olefin products are
limited to Cr-promoted reactions requiring forcing conditions
loadings (0.5 mol% [Rh(COD)Cl] ) at 50 °C resulted in similar
1
0
13
(
typically ≥150 °C). The 1,6-cis reduction of sorbic acid has been
product yields and selectivities (entry 12).
documented with Ru-based catalysts, however careful monitoring
A preliminary mechanistic hypothesis involved a chelation-
controlled 1,6-reduction of the diene substrate. Concomitant over-
reduction or isomerization was not observed under the standard
reaction conditions, suggesting the potential to conduct
chemoselective hydride additions. We reasoned electron-rich
olefins, polar unsaturates, and suitably substituted alkynes should
not be reduced at rates competitive with bidentate extended
Michael acceptors. To rapidly test this hypothesis, a functional
group tolerance screen with an array of unsaturated substrates
[a]
R. Dada, Z. Wei, R. Gui, Prof. R. J. Lundgren
Department of Chemistry
University of Alberta
Edmonton, Alberta, T6G 2G2, Canada
E-mail: rylan.lundgren@ualberta.ca
†
these authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
1
4
was conducted (Figure 2b). Under standard reaction conditions,
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800361
COMMUNICATION
aryl/silyl and dialkyl alkynes, internal and terminal olefins, a,b-
unsaturated esters, electron-rich dienes and aldehydes were
tolerated (>70% product formation, <20% additive consumption).
Terminal and diaryl alkynes were found to be incompatible.
R
5
mol% [Rh]
CO R'
2
R
HCO
H/NEt
3
2
CO R'
2
diene scope [R' = Bn or Et]
Me
2a 74%a
91% conv.
nmr yield [Z/E] 80% [96:4]
Me
H
R
=
2
.5 mol% [Rh(COD)Cl]2
5 mol% PPh3
n-Pr
2b 75%a
95% conv.
82% [96:4]
2c 67%a
92% conv.
72% [97:3]
2d 69%a
94% conv.
80% [90:10]
1
yield
CO
2
Bn
conv. (nmr)
n-Pr
HCO H/NEt (5:2)
2
3
2
CO Bn
1
a
2a
Br
MeCN, 35 ºC
a effect of catalyst and reductant
entry
deviation from above
conv. (%) yield (%) [Z/E]
N
2
e 65%a
2f 75%a
93% conv.
81% [96:4]
2g 74%a
95% conv.
79% [96:4]
H
2h 73%b
90% conv.
77% [96:4]
1
2
3
4
5
6
7
8
9
none
91
94
93
93
59
76
41
24
<2
20
80 [96:4]
41 [31:69]
40 [28:72]
52 [25:75]
47 [50:50]
53 [90:10]
11 [36:64]
<2
91% conv.
81% [85:15]
Rh(PPh) Cl (no PPh )
3
3
[
gram scale 69%]
1:1 Rh:PPh3 instead of 1:3
no PPh3
O
N
N
CHO
P(OPh)3 instead of PPh3
N
Ac
dppp instead of PPh3
BINAP instead of PPh3
2
i 61%b
83% conv.
68% [96:4]
2j 62%b
90% conv.
75% [95:5]
2k 66%b
90% conv.
73% [96:4]
2l 69%a
93% conv.
78% [97:3]
O
[Ir(COD)Cl]
CuI
2
<2
Cl
CN
2o 70%a
85% conv.
77% [98:2]
1
1
Pd(OAc)2
<2
NHBoc
2p 71%b
93% conv.
74% [97:3]
TIPS
2a
0.5 mol% [Rh(COD)Cl]2 3 mol% PPh3 89
2m 71%b
3% conv.
74% [97:3]
2n 78%a
91% conv.
82% [98:2]
1
79 [96:4]
9
0
.2 mmol scale, 1.0 equiv. HCO H, 0.2 M, 20-30 h; yields, selectivities, and
2
conversions determined by calibrated 1H NMR. aat 50 ºC, 48h;
OEt
O
b unsaturated functional group tolerance survey
tolerated [>70% y, <20% additive conv.]
HO
not tolerated
2
8
7
q 62%b
6% conv.
1% [93:7]
2r 74%a
86% conv.
79% [97:3]
Me
2s 67%b
93% conv.
70% [96:4]
TMS
Et
5 11
C H
Et
Ph
see Fig 2 for conditions and SI for full details, a R' = Bn; b R' = Et;
C
4
H
9
Ph
5 11
C H
4 9
C H
Ph
Me
Ph
Figure 3. Diene scope of the Rh-catalyzed formate-mediated Z-selective 1,6-
CO
2
Me
2
CO Me
Ph
reduction.
Ph
Figure 2. (a) Effect of selected reaction parameters on the Rh-catalyzed Z-
selective 1,6-reduction of dienyl esters. (b) Unsaturated functional group
tolerance screen.
containing multiple olefin units (3d, 3e) (Figure 4). The functional
group tolerance of the reaction was also examined with
derivatives of bioactive molecules. Dienyl esters of the
hydroxylated sterol methyl cholate (3f), nucleoside analog
stavudine (3g), polyketide ivermectin (3h) and quinoline alkaloid
camptothecin (3i) could be reduced with acceptable yields and
minimal complication from the array of chemical functionality
present. Complex substrates like 3f-3i would pose considerable
difficulty in established Z-olefin forming processes. Under slightly
modified conditions, a series of amidyl dienes, including the
Weinreb amide (3m) were reduced with good selectivity (3j-
The scope of the Rh-catalyzed Z-selective 1,6-reduction
was evaluated (Figure 3 and 4). Aliphatic and aryl groups at the
terminal position of the dienoate led to product formation in
similarly high selectivities (2a-2g), including unsubstituted (2d)
and cyclopropyl (2c) substituted species. Substrates bearing
electron-rich- (2h) or electron-poor heterocycles (2i), electrophilic
ketone (2j) and aldehyde (2k) functionality, as well as amines (2l,
1
3b
2
m), alkyl chlorides (2n), and alkyl nitriles (2o) gave Z-olefin
3
m).
products in good yield and typically >95:5 Z:E selectivity. The
formate-mediated reduction method allowed for the preparation of
Z-olefin containing molecules that contain pendent C–C
unsaturation, including terminal olefins (2q), internal olefins (2r),
a,b-unsaturated esters (2s), and alkynes (2m). These types of
stereochemically defined polyunsaturated products would be
difficult to obtain directly via established catalytic semi-reduction
or metathesis reactions. The process can be scaled to deliver
gram-quantities of product (1.2 g 2f, 69% yield).
The b-carbonyl containing Z-olefins are useful precursors to
a range of other product classes (Figure 5). Z-homoallylic alcohols
4a), skipped Z,E-dienes (4b), propargylic Z-1,5- enynes (4c), and
(
a-amino esters (4d) can be readily obtained in good yields using
standard synthetic protocols.
Mechanistic experiments help to rationalize the high
selectivity for Z-1,6 addition. Reduction of dienoate 1a with D-
labelled formic acid at the formyl position under otherwise
standard conditions leads to exclusive hydride addition to the
remote 6-position. Formic acid labelled at the carboxylic site
The ester group of the dienoate can be varied from benzyl
or ethyl to a bulky tert-butyl group (3a); amine-containing moieties,
including a protected amino acid derivative (3b, 3c); and esters
1
3c
results in labelling at the a-carbonyl position (Figure 6a). This
suggested a mechanism in which Rh–H conjugate addition is
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800361
COMMUNICATION
after diene substrate 1a is consumed (Figure 6b). Reintroduction
of 1a inhibits these side reactions and olefin 2a is smoothly
generated again (see the SI for a plot).
R
5
mol% [Rh]
CO R'
2
R
HCO H/NEt3
2
CO R'
2
ester scope [R = n-Pr or Me]
Me
Me
Me
NBoc
CO2Me
O
a formic acid D-labelling studies
R'
=
O
O
NHBoc
3c 57%b
92% conv.
68% [94:6]
CO2Bn
3a 56%a
91% conv.
80% [96:4]
3b 64%a
92% conv.
73% [95:5]
yield
conv. (nmr)
nmr yield [Z/E]
n-Pr
1a
DCO2H
[formyl label] [carboxyl label]
n-Pr
HCO2D
Me
Me
d 64%b
5% conv.
1% [95:5]
3e 72%b
87% conv.
78% [95:5]
n-Pr
3
8
7
Me
Me
Me
O
D
cat. [Rh(COD)Cl]2
cat. PPh3
Me
Me
O
CO2Bn
D
CO2Bn
OH
d1-2a 70% incorporation formate/NEt (5:2)
3
d1-2a' 90% incorporation
O
N
MeO
Me MeO C
Me OH
3g 52%b,c
2
Me
Me
b reaction with excess formate / kinetic analysis
9
1% conv.
HN
O
3f 53%b
70% [94:6]
1
00
OMe
H
Me
H
selective1,6-reduction
9
4% conv.
1
a
O
O
5
8% [95:5]
Z*2a
E*2a
3
high [1a]
H
H
75
R
R
[Rh–H]
O
HO
O
Me
O
O
O
4
5
1a
Z-2a
G
G
5
0
Me
Me
low [1a]
[Rh–H]
h 59%b
3
O
9
2% conv.
O
25
0
R
R
R
7
0% [90:10]
N
3
4
5
N
O
O
G
G
G
HO
O
O
O
Me
0
4
8
12
isomerization / reduction
time&(h)
O
i 50%b,c
94% conv.
3
Me
O
positive order in catalyst
positive order in HCO2H/NEt3
negative order in diene
redn/isomerization with >1 eq. HCO2H
O
Me
82% [83:17]
Me
Me
amide scope [R = n-Pr or Me]
c potential mechanism / selectivity rationalization
R
Ph
Me
cat. [Rh(COD)Cl] , PPh3
2
N
Ph
N
N
N
R
Me
O
OMe
G
HCO H / NEt3
G
2
Ph
R
3
9
6
j 59%a,d
3% conv.
3% [95:5]
3k 51%a,d
93% conv.
61% [92:8]
3l 51%a,d
90% conv.
61% [94:6]
3m 69%a
86% conv.
78% [nd]
Z-selective
1,6-addition
Rh-enolate
protonolysis
diene coordination
hydride generation
R
H
L
H
Rh
[Rh]
see Fig 2 for conditions and SI for full details, a R = n-Pr; b R = Me; c 5 mol%
Rh(COD)Cl] , 30 mol% PPh , 4:1 MeCN:DMSO, 2-3 equiv HCO H; (4-
G
d
G
[
2
3
2
C H F) P instead of PPh at 60 ºC.
d effect of diene geometry on regioselectivity
6
4
3
3
R
G
R
Figure 4. Ester and amide scope of the Rh-catalyzed formate-mediated Z-
R
G
G
selective 1,6-reduction.
R = n-Pr G = CO2Bn [can adopt s-cis geometries] [s-cis disfavoured]
diene geometry:
E,E
Z,E
E,Z
product β,γ : α,β =
13:1
12:1
1.5:1
a
a, b
CO2Et
OH
Bn
Bn
Bn
Figure 6. (a) D-labelling studies using DCO
2
H and HCO
2
D; (b) Kinetic profile of
CO R'
4
a 85%
CO Et
2
4b 62% [two steps]
OH
reaction conducted with excess formic acid and reaction order. (c) Potential
selectivity driving steps in the reduction process; (d) Impact of diene geometry
on reduction selectivity.
R
2
NHPh
d, e
a, c
n-Pr
TMS
4c 66% [two steps]
4
d 65% [two steps]
A mechanism to explain the observed selectivity involves
coordination of the electron-poor diene moiety to a Rh(I) species
which then undergoes selective hydride addition. The chelation-
driven, Z-selective process generates a Rh-enolate species
readily protonated to deliver the non-conjugated cis-olefin. (Figure
4
Figure 5. (a) LiAlH ; (b) DMP then triethyl phosphonoacetate (c) DMP then Li-
2 4 2
TMS acetylene; (d) p-ABSA, DBU; (e) Rh (OAc) , PhNH . See the SI for full
details.
6
c). The ability to selectively generate a diene coordinated Rh-
followed by protonolysis of a Rh-enolate. Reaction progress
kinetic analysis of the reduction revealed the process to be
positive order in catalyst mixture and formic acid, and partial
hydride under the optimized conditions appears to be key to an
1
5,16
efficient transformation.
In line with this argument, both E,E
1
3d
and Z,E-dienoates that can readily adopt s-cis conformations
undergo 1,6-reduction with high regioselectivity (>10:1 for the
b,g product). A E,Z-dienoate that would experience significant
steric repulsion in an s-cis configuration from the Z-positioned
negative order in substrate (see the SI). High selectivity for Z-
,6-reduction is maintained throughout the reaction under
1
standard conditions. When excess formate is added both olefin
isomerization and reduction to the saturated ester is observed
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800361
COMMUNICATION
alkyl group is reduced with low selectivity (Figure 6d, b,g:a,b =
Kaya, D. Enders, Adv. Synth. Catal. 2017, 359, 888. e) T. Nishimura,
Y. Yasuhara, T. Hayashi, Angew. Chem. Int. Ed., 2006, 5164.
1
.5:1).
In summary, a simple Rh(I)/phosphine catalyst system
[
8] a) D. Uraguchi, K. Yoshioka, Y. Ueki, T. Ooi, J. Am. Chem. Soc.
2
012, 134, 19370; b) M. Tissot, A. Alexakis, Chem. Eur. J. 2013, 19,
enables the formate-mediated Z-selective reduction of activated
dienes via a 1,6-addition process. Mechanistic studies suggest
the 1,6-addition process is key to enabling chemoselective diene
reductions in the presence of alternative olefin and alkyne units,
overcoming difficulties associated with existing catalytic methods.
We envision this general concept to extend to related Z-selective
diene hydrofunctionalization reactions.
1
1352; c) Z. Wang, T. F. Kang, Q. Yao, J. Ji, X. H. Liu, L. L. Lin, X. M.
Feng, Chem. Eur. J. 2015, 21, 7709; d) F. K. Meng, X. B. Li, S. Torker,
Y. Shi, X. Shen, A. H. Hoveyda, Nature 2016, 537, 387; e) D. Uraguchi,
K. Yoshioka, T. Ooi, Nat. Commun. 2017, 8, 10.
[
5
9] a) G. de la Herran, C. Murcia, A. G. Csaky, Org. Lett. 2005, 7,
629; b) S. Okada, K. Arayama, R. Murayama, T. Ishizuka, K. Hara,
N. Hirone, T. Hata, H. Urabe, Angew. Chem. Int. Ed. 2008, 47, 6860;
c) K. S. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898; d)
K. S. Lee, H. Wu, F. Haeffner, A. H. Hoveyda, Organometallics 2012,
3
1, 7823.
[
10] a) M. Sodeoka, M. Shibasaki, Synthesis 1993, 643; b) A. A.
Acknowledgements
Vasilev, A. L. Vlasyuk, G. D. Gamalevich, E. P. Serebryakov, Bioorg.
Med. Chem. 1996, 4, 389.
We thank the University of Alberta and NSERC Canada for
support.
[11] a) S. Steines, U. Englert, B. Driessen-Holscher, Chem. Commun.
2
000, 217; b) M. Kotova, E. Vyskocilova, L. Cerveny, Catal. Lett. 2017,
47, 1665.
1
[
12] For recent examples of E-selective, Rh-catalyzed diene
Keywords: Z-alkenes • homogeneous catalysis •
hydrofunctionalizations see: a) M. J. Goldfogel, S. J. Meek, Chem. Sci.
2016, 7, 4079; (b) X. H. Yang, V. M. Dong, J. Am. Chem. Soc. 2017,
chemoselectivity • rhodium • 1,6-addition
1
39, 1774; (c) J. S. Marcum, C. C Roberts, R, S. Manan, T. N.
Cervarich, S. J. Meek, J. Am. Chem. Soc. 2017 139, 15580; for Z-
selective hydrofunctionalizations of simple 1,3-dienes see
[
1] a) W. Y. Siau, Y. Zhang, Y. Zhao, in Stereoselective Alkene
:
Synthesis, Vol. 327 (Ed.: J. Wang), 2012, pp. 33 b) C. Oger, L. Balas,
T. Durand, J. M. Galano, Chem. Rev. 2013, 113, 1313; c) M. B.
Herbert, R. H. Grubbs, Angew. Chem. Int. Ed. 2015, 54, 5018; d) A.
H. Hoveyda, R. K. M. Khan, S. Torker, S. J. Malcolmson, in Handbook
of Metathesis Vol. 2: Applications in Organic Synthesis, Second
Edition, Vol. 2 (Eds.: R. H. Grubbs, D. J. O’Leary), Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, 2015, pp. 503.
(
1
hydroboration) d) R. J. Ely, J. P. Morken, J. Am. Chem. Soc. 2010,
32, 2534; (hydrovinylation) e) S. M. Jing, V. Balasanthiran, J. C.
Gallucci, T. V. RajanBabu, J. Am. Chem. Soc. 2017,
0.1021/jacs.7b10055; (hydroxymethylation) f) Y. Y. Gui, N. Hu, X. W.
1
Chen, L. Liao, T. Ju, J. H. Ye, Z. Zhang, J. Li, D. G. Yu, J. Am. Chem.
Soc. 2017, 139, 17011; Examples of the use of formic acid in Rh-
catalysis: g) X. Wu, X. Li, A. Zanotti-Gerosa, A. Pettman, J. Liu, A. J.
Mills J. Xiao, Chem. Eur. J. 2008, 14, 2209 (i) Y. J. Jang, E. M. Larin,
M. Lautens, M. Angew. Chem. Int. Ed. 2017, 56, 11927.
[
2] T. Takeda, WILEY-VCH Verlag GmbH & Co. KGaA,, Weinheim,
004.
3] Y. Gu, S.-K. Tian, in Stereoselective Alkene Synthesis (Ed.: J.
Wang), Springer Berlin Heidelberg, Berlin, Heidelberg, 2012, pp. 197.
4] Recent examples: a) E. D. Slack, C. M. Gabriel, B. H. Lipshutz,
2
[
[
13] a) Remaining mass balance is typically 5-10% a,b-unsaturated
ester, see the SI for the complete product distribution of the standard
reaction and examples of other phosphines examined. The use of
[
Angew. Chem. Int. Ed. 2014, 53, 14051; b) A. Fedorov, H. J. Liu, H.
K. Lo, C. Coperet, J. Am. Chem. Soc. 2016, 138, 16502; c) S. M. Fu,
N. Y. Chen, X. F. Liu, Z. H. Shao, S. P. Luo, Q. Liu, J. Am. Chem. Soc.
silane, borane or H reducing agents resulted in poor yields of the 1,6
addition product b) See the SI for amide optimization data and
2
examples of less successful substrates. c) Rationalization for
incomplete D-incorporation could involve Rh–D/H exchange with non-
formic acid hydrogens, D-incorporation at other sites was not detected.
2
016, 138, 8588; d) C. Y. Chen, Y. Huang, Z. P. Zhang, X. Q. Dong,
X. M. Zhang, Chem. Commun. 2017, 53, 4612; e) A. M. Whittaker, G.
Lalic, Org. Lett. 2013, 15, 1112.
+
d) Formation of off-cycle Rh(dienoate)2 species could explain the
[
5] For selected recent examples see: a) M. J. Koh, R. K. M. Khan, S.
observed negative order in substrate, excess phosphine may be
+
Torker, M. Yu, M. S. Mikus, A. H. Hoveyda, Nature 2015, 517, 181; b)
M. J. Koh, T. T. Nguyen, H. M. Zhang, R. R. Schrock, A. H. Hoveyda,
Nature 2016, 531, 459; c) S. X. Luo, J. S. Cannon, B. L. H. Taylor, K.
M. Engle, K. N. Houk, R. H. Grubbs, J. Am. Chem. Soc. 2016, 138,
beneficial in formation of Rh(PPh
intermediates.
3
)(dienoate)
from such
[14] K. D. Collins, F. Glorius, Nature Chem. 2013, 5, 597.
[
15] For a Rh-catalyzed process that generates Z-olefin products from
1
4039; d) M. J. Koh, T. T. Nguyen, J. K. Lam, S. Torker, J. Hyvl, R. R.
Schrock, A. H. Hoveyda, Nature 2017, 542, 80.
6] Alkyne Z-carbofunctionalization see: (a) C. W. Cheung, F. E.
a proposed Rh–H intermediate see: J. I. Martinez, J. J. Smith, H. B.
Hepburn, H. W. Lam, Angew. Chem. Int. Ed. 2016, 55, 1108.
[
[
16] a) For a Rh-catalyzed reductive coupling reaction of aldehydes
Zhurkin, X. L. Hu, J. Am. Chem. Soc. 2015, 137, 4932. (b) H. P. Deng,
X. Z. Fan, Z. H. Chen, Q. H. Xu, J. Wu, J. J. Am. Chem. Soc. 2017,
1
with dienes using BEt that, in a single example, gives a Z-addition
3
product see: M. Kimura, D. Nojiri, M. Fukushima, S. Oi, Y. Sonoda, Y.
Inoue, Org. Lett. 2009, 11, 3794; b) Rh-catalyzed codimerization of
olefins can give Z-addition products for a pioneering example see: T.
Alderson, E. L. Jenner, R. V. Lindsey Jr. J. Am. Chem. Soc. 1965, 87,
5638.
39, 13579.
[
2
3
7] a) A. G. Csaky, G. de la Herran, M. C. Murcia, Chem. Soc. Rev.
010, 39, 4080; b) E. M. P. Silva, A. M. S. Silva, Synthesis 2012, 44,
109; c) T. E. Schmid, S. Drissi-Amraoui, C. Crevisy, O. Basle, M.
Mauduit, Beilstein J. Org. Chem. 2015, 11, 2418; d) P. Chauhan, U.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800361
COMMUNICATION
COMMUNICATION
[
chemoselective] tolerates:
Raphael Dada, Zhongyu Wei, Ruohua
Gui, Rylan J. Lundgren *
R
R
cat. [Rh], PAr3
R
R
HCO H/NEt
R
O
2
3
CO R
CO R
2
2
Page No. – Page No.
CO2R
H
regio- and stereoselective 1,6-reduction
Chemoselective Z-Olefin Synthesis
via Rh-Catalyzed, Formate Mediated
1
,6-Reduction
The stereoselective formation of Z-alkenes in the presence of related unsaturated
or electrophilic groups remains a challenge. Herein, we report the Rh-catalyzed Z-
selective 1,6-reduction of activated dienes. The reaction proceeds with high regio-
and stereoselectivity while preserving other alkenyl, alkynyl, protic and electrophilic
groups.
This article is protected by copyright. All rights reserved.