Chemo- and regioselective reductive transposition of allylic alcohol derivatives via iridium or rhodium catalysis

Article abstract of DOI:10.1039/c5cc07993d

We report highly chemo- and regioselective reductive transpositions of methyl carbonates to furnish olefin products with complementary regioselectivity to that of established Pd-catalysis. These Rh- and Ir-catalysed transformations proceed under mild conditions and enable selective deoxygenation in the presence of functional groups that are susceptible to reduction by metal hydrides.

Full text of DOI:10.1039/c5cc07993d

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: R. Lundgren and
B. N. Thomas, Chem. Commun., 2015, DOI: 10.1039/C5CC07993D.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C5CC07993D
Journal Name
COMMUNICATION
Chemo- and Regioselective Reductive Transposition of Allylic
Alcohol Derivatives via Iridium or Rhodium Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Rylan J. Lundgren* and Bryce N. Thomas
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report highly chemo- and regioselective reductive observed with internal branched substrates (Fig.1 B-2).7 Similar
transpositions of methyl carbonates to furnish olefin products to Pd-catalysed allylic reductions employing formate,11,12
with complementary regioselectivity to that of established Pd- generation of the alternative olefin regioisomers is not
catalysis. These Rh- and Ir- catalyzed transformations proceed possible; thus complete regiocontrol of catalytic reductive
under mild conditions and enable selective deoxygenation in the transposition of allylic alcohol derivatives remains a significant
presence of functional groups that are susceptible to reduction by unmet challenge. Furthermore, catalytic and chemoselective
metal hydrides.
diazene-mediated deoxygenation in the presence of other
reducible functional groups has not been demonstrated
broadly. Herein we report a strategy to address these deficits
by employing Ir- and Rh-catalysis (Fig. 1C). Under mild conditi
ons, highly chemo- and regioselective reductive transposition
Deoxygenation reactions are important transformations in
synthetic organic chemistry, finding applications in areas
ranging from biomass conversion to the preparation of
complex bioactive molecules.1,2 Mild, catalytic, chemoselective
reductive deoxygenation of alcohols remains underdeveloped
owing in large part to the difficulties associated with delivery
of hydride equivalents to C–O sigma bonds in preference to
C=C, C=O or C–X bonds.3 Thus classical methods that use
stoichiometric additives such as the Barton-McCombie
reaction4 or Mitsunobu reactions with diazene-precursors5,6
are still widely employed.
A. Mitsunobu Conditions (Stoichiometric Activators)
NBSH or IPNBSH
OH
PPh3, DEAD
R2
SN2 reductive transposition
O
S
O
R1
R2
NR
R1
N
H
NO2
NBSH
R = H2
N
ArO2S
NR2
N
H
N
IPNBSH
R = C(CH3)2
R1
R2
R1
R2
With specific regard to allylic substrates, Pd-based
strategies have been developed to address some of the
limitations associated with selective deoxygenation catalysis.
For example, while deoxygenation of allylic alcohols via
Mitsunobu reaction with diazene precursors NBSH or IPNBSH
B. Pd Catalysis (Alternative Regioisomer Inaccessible)
IPNBSH, KH
cat. [Pd]
OR
1.
OR
or
R1
R1
R1
reductive transposition gives terminal olefins
IPNBSH, KH
R1
R2
R2
requires
stoichiometric
reagents
such
as
diethyl
OR
2.
cat. [Pd]
azodicarboxylate (DEAD) (Fig. 1A),4 Movassaghi and co-
workers reported an alternative IPNBSH-mediated reductive
transposition using Pd-catalysis (Fig. 1B).7,8 The regiochemical
outcome of the amination follows that expected for Pd-
catalysed allylic substitution, generally featuring substrate
steric control in the amination of a Pd-allyl species.9 Under
these conditions, terminal olefin products are formed from
both branched and linear allylic carbonates after sigmatropic
elimination of dinitrogen from a linear monoalkyl diazene (Fig.
1 B-1),10 while both formal SN2 and SN2’ displacement are
or
R1
R2
R1
formal SN2 or SN2' substitution of internal allylic carbonates
C. This Work: Complementary Catalytic Regiocontrol
IPNBSH
OR
cat. [Ir]
FG
Me
FG
OR
n
n
reductive transposition gives internal olefins
IPNBSH, K2CO3
cat. [Rh]
FG
FG
R1
n
R1
n
formal SN2 substitution of internal allylic carbonates
Ir and Rh: high chemo- and regioselectivity, tolerates sensitive
reducible groups (FG = halide, carbonyl, alkene, alkyne)
Fig. 1 Overview of diazene-mediated reductive transposition of allylic
alcohol derivatives.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please dCohneomtCadojmusmt margins
Page 2 of 4
COMMUNICATION
Journal Name
Table 2. Reductive deoxygenation of alkyl substituted
View Article aOlnlylinliec
is observed for allylic methyl carbonates. This new method can
be considered a direct, catalytic alternative to stoichiometric
Mitsunobu protocols for deoxygenation of allylic alcohols
embedded within functionalised molecules.13
carbonates.
DOI: 10.1039/C5CC07993D
1. 2.5 mol% [Ir(COD)Cl]2
1.2 equiv. IPNBSH, MeCN
OCO2Me
Me
alkyl
alkyl
Conditions were optimized such that reactive
functionalities, such as aliphatic chlorides are tolerated. Table
1 highlights how simple modifications to the conditions have a
significant effect on the selectivity of the transformation when
employing bulky diazene precursors.14,15a Under optimized
conditions employing 2.5 mol% [Ir(COD)Cl]2, the desired
branched N-alkyl N-sulfonyl hydrazone product formed in 91%
yield at room temperature with no detectable amount of the
linear allylic isomer. Rh- and Ru-based catalysts proved
ineffective under these conditions (Table 1, entries 2 and 3). In
solvents other than MeCN product yields were significantly
lower and formation of the undesired byproducts was
observed. The hydrazine reagent NBSH provided suboptimal
yields (10%, Table 1, entry 6). Methyl carbonate is the
preferred leaving group, as use of alternative alkyl carbonates
or a phosphate ester resulted in lower yields.15b Finally, in situ
hydrolysis and sigmatropic rearrangement of the allylic
sulfonyl hydrazone at room temperature yielded the desired
internal olefin in 71% isolated yield (eq 1).15c Of note,
experiments under similar conditions using ammonium
formate as the reducing agent resulted in unselective
consumption of the substrate.
2. AcOH, TFE/THF/H2O (1:2:1)
entry
substrate
OCO2Me
product
yield
Me
Me
1
84%
Ph
Ph
Me OCO2Me
Me
2
68%a
71%
88%
71%
Ph
Ph
OCO2Me
BnO
Me
3b
4
BnO
OCO2Me
OCO2Me
Me
TsMeN
Cl
TsMeN
Cl
5
Me
3
3
OCO2Me
Me
6
7
74%
57%
Ph
Ph
Me
Me
Me OCO2Me
Me
Me
Me
Me
OCO2Me
OCO2Me
Both simple and functionalised alkyl-substituted allylic
carbonates can be converted to the corresponding internal
olefins in moderate to excellent yields with very high
regioselectivities (Table 2).16 The reaction is tolerant of
substitution β to the carbonate (Table 2, entries 2, 3 and 7), as
well as oxygen, nitrogen, and halogen functional groups (Table
2, entries 2–5).15d For substrates containing pendant
unsaturation in the form of an alkyne, alkene or α,β-
unsaturated ester, no over-reduction is observed allowing for
facile deoxygenation of polyunsaturated carbonates (Table 2,
Me
8
75%
EtO2C
AcO
EtO2C
AcO
Me
9c
65%d
Yields are of isolated material. Regioisomer ratios are ≥95:5, E/Z ratios
are ≥92:8 in all cases. See Supporting Information for details. a91:9
regioisomer ratio. b5 mol% [Ir(COD)Cl]2 callylic acetate E/Z = 85:15 in
starting material dallylic acetate E/Z = 85:15.
proceeds smoothly in the presence of an allylic acetate group
(Table 2, entry 9).18
entries 6–8).17 In
a
particularly striking example of
Without change to the standard conditions, aryl-
substituted allylic carbonates are suitable substrates, allowing
for the synthesis of functionalised β-methyl styrenes (Table 3).
Electron-rich and electron-poor aryl-substituted carbonates
can be deoxygenated under mild conditions. Potentially
reactive functional groups that are prone to reduction under
radical or metal hydride treatment, such as an aryl bromide
and chloride, an allylic ether, ester, nitrile, ketone, and an aryl
boronic ester, are tolerated highlighting the excellent
chemoselectivity of the reduction.
chemoselective deoxygenation, methyl carbonate reduction
Table 1. Effect of reaction parameters on the catalytic, chemoselective
allylic amination employing diazene precursors
ArO2S
NR'
2.5 mol% [Ir(COD)Cl]2
OCO2Me
N
Cl
Cl
1.2 equiv. IPNBSH
MeCN (0.2 M), rt
standard conditions
4
4
entry
change from the standard conditions
conv yield (%)
Allylic carbonates with an internal alkene were resistant to
amination with IPNBSH under the standard Ir-catalysed
conditions described above. Subsequent optimization,
however, revealed that the use of catalytic mixtures of
1
2
3
4
5
6
7
none
>98
8
91
<2
10
15
12
10
44
[Rh(COD)Cl]2 instead of [Ir(COD)Cl]2
RuCp*(MeCN)3 PF6 instead of [Ir(COD)Cl]2
THF instead of MeCN
94
74
61
23
64
CH2Cl2 instead of MeCN
NBSH instead of IPNBSH
CO2t-Bu instead of CO2Me
[Rh(COD)Cl]2 and P(OPh)3 with K2CO3 led to good yields and
f, 19
excellent regioselectivities (Table 4).15e,
Aryl, alkenyl,
alkynyl, and ethereal allylic methyl carbonates can be
deoxygenated under these Rh-catalysed conditions, providing
a 0.05 mmol scale, 24 h, conversions and yields determined by 1H NMR
using Bn2O as an internal standard.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
Table 3. Scope of reductive deoxygenation of aryl substituted allylic
carbonates.
Table 4. Rh-catalysed reductive deoxygenation of substituted
allylic carbonates.
View Article Online
DOI: 10.1039/C5CC07993D
1. 2.5 mol% [Ir(COD)Cl]2
1. 2.5 mol% [Rh(COD)Cl]2 10 mol% P(OPh)3
OCO2Me
OCO2Me
R'
1.2 equiv. IPNBSH, MeCN
1.2 equiv. IPNBSH, K2CO3, MeCN, rt
2. AcOH, TFE/THF/H2O (1:2:1)
Me
R
R'
aryl
aryl
R
2. AcOH, TFE/THF/H2O (1:2:1)
entry
1
substrate
OCO2Me
product
Me
entry
substrate
OCO2Me
Me
product
yield (%)
yield (%)
1a
2a
3a,b
4a
5
62
69
Ph
Me
Ph
OCO2Me
OCO2Me
NC
Cl
NC
Cl
Me
57
79
64
66
71
69
2
3
4
5
6
7
8
Ar
Me
63
71
94
56a
45
55
77
Ar
Me
Ar = 4-ClC6H4
OCO2Me
BnO
BnO
OCO2Me
Me
Me
Me
O
O
OCO2Me
Me
OCO2Me
Br
F
Me
Me
Br
F
Ph
Ph
Ph
Ph
OCO2Me
OCO2Me
OEt
O
Me
OEt
O
MeO2C
MeO
MeO2C
MeO
OCO2Me
OCO2Me
OCO2Me
OEt
O
Ph
OEt
Me
Ph
6
O
OCO2Me
OEt
O
OEt
Me
Me
7b
O
PinB
PinB
O
OCO2Me
Me
O
O
OCO2Me
Me
Ph
Ph
56
78
52
65
8
Me
Me
O
BnO
OCO2Me
OCO2Me
9b
BnO
Br
Yields are of isolated material, 1.0–0.6 mmol scale. Regioisomer ratios
are ≥93:7 and E/Z ratios are ≥95:5 unless noted. See Supporting
Infomation for details. a 83:17 regioisomer ratio.
S
10b
11b
S
Br
OCO2Me
a simple and mild strategy for the preparation of sensitive
skipped dienes and enynes (Table 4, entries 2 and 4). Allylic
carbonates substituted with electron-withdrawing groups,
such as an ester or ketone, also undergo amination with high
formal SN2-selectivity, and upon reductive transposition, γ-
unsaturated carbonyl compounds can be obtained (Table 4
entries 5–8). The reaction tolerates sterically demanding
carbonates, such as an α-branched substrate (Table 4, entry 7).
Collectively, these results demonstrate an attractive means to
convert easily accessible conjugated systems into more
valuable 1,4-polyunsaturated compounds that are otherwise
difficult to prepare. In keeping with the observation of
remarkably high formal SN2 amination selectivity, alkyl-,
heteroaryl-, and alkenyl-substituted primary allylic carbonates
generate terminal olefin products under the standard Rh-
catalysed reaction conditions (Table 4, entries 9–11).
Ph
Ph
Yields are of isolated material, 0.7–0.3 mmol scale. Regioisomer ratios are
≥95:5 and E/Z ratios are ≥94:6 in all cases. a Reaction performed at 40 ºC.
b Using 5 mol% [Rh(COD)Cl]2 and 20 mol% P(OPh)3.
see table 3
1.3 mol% [Ir(COD)Cl]2
OCO2Me
Br
F
Me
Br
F
(2)
(3)
73%
[1.16 g]
see table 4
2.5 mol% [Rh(COD)Cl]2
OCO2Me
CO2Et
Bn
Bn
CO2Et
81%
[1.40 g]
In summary, we have developed new catalytic strategies
for the mild and selective reductive transposition of allylic
alcohol derivatives employing Ir- or Rh-based catalysts. The
deoxygenation process tolerates a wide range of functional
groups that are susceptible to radical or hydride reduction and
Both of the methods reported herein proceed well on
larger scales, as demonstrated by the gram-scale syntheses of
a halogenated β-methyl styrene via Ir-catalysis (eq 2) and a γ-
unsaturated ester via Rh-cataysis (eq 3).15g
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please dCohneomtCadojmusmt margins
Page 4 of 4
COMMUNICATION
Journal Name
9
For a detailed discussion of the topic see: B. S. Kim, M. M.
provides complementary regioselectivity to that of Pd-
catalyzed methodologies. The ability of this method to be used
in place of stoichiometric Mitsunobu-type deoxygenation
processes should result in widespread appeal.
View Article Online
Hussain, P. O. Norrby, P. J. Walsh, ChDeOmI:.1S0c.1i.03290/1C45,C5C,071929431D-
1250 and references therein.
10 A. Jabbari, E. J. Sorensen, K. N. Houk, Org. Lett. 2006, 8,
3105-3107.
11 For a review see: (a) J. Tsuji, T. Mandai, Synthesis 1996, 1-24;
strong hydride donors such as DIBAL-H or SmI2 can afford
the opposite regioisomers, but these reagents would exhibit
minimal chemoselectivity in the presence of reducible
groups. For more recent examples of Pd-catalyzed formate
reduction see: (b) A. Chau, J.-F. Paquin, M. Lautens, J. Org.
Chem. 2005, 71, 1924-1933; (c) T. Konno, T. Takehanna, M.
Mishima, T. Ishihara, J. Org. Chem. 2006, 71, 3545-3550; in
very rare cases, select substrates can be converted to the
internal alkene, see: (d) H. Cheng, C. Sun, D. Hou, J. Org.
Chem. 2007, 72, 2674-2677;
Acknowledgments
We thank NSERC Canada (Discovery Grant, Research Tools and
Infrastructure Grant), the Canadian Foundation for Innovation,
the University of Alberta, and faculty within the Department of
Chemistry for generous donations of equipment and
chemicals. Chris Godwin is acknowledged for assistance with
substrate synthesis
12 For the phosphine-catalysed reduction of allylic bromides
with LiAlH(OtBu)3 to terminal olefins see: K. D. Reichl, N. L.
Dunn, N. J. Fastuca, A. T. Radosevich, J. Am. Chem. Soc. 2015,
137, 5292-5295.
Notes and references
1
For a review see: J. M. Herrmann, B. König, Eur. J. Org. Chem.
2013, 2013, 7017-7027.
13 For an unselective Ir-catalysed deoxygenation process
o
(alkenes are also reduced) employing hydrazine at 160 C,
2
For select recent examples of new deoxygenation methods
see: (a) L. L. Adduci, T. A Bender, J. A. Dabrowski, M. R.
Gagné, Nature Chem. 2015, 7, 576-581; (b) H. Dang, N. Cox,
G. Lalic, Angew. Chem. Int. Ed. 2014, 53, 752-756; (c) L. L.
Adduci, M. P. McLaughlin, T. A. Bender, J. J. Becker, M. R.
Gagne, Angew. Chem. Int. Ed. 2014, 53, 1646-1649; (d) M.
Shiramizu, F. D. Toste, Angew. Chem. Int. Ed. 2013, 52,
12905-12909; (e) J. Cornella, E. Gómez-Bengoa, R. Martin, J.
Am. Chem. Soc. 2013, 135, 1997-2009.
see: J. L. Huang, X. J. Dai, C. J. Li, Eur. J. Org. Chem. 2013,
6496-6500.
14 For early examples of Ir- and Rh-catalysed allylic amination
see: (a) P. A. Evans, J. E. Robinson, J. D. Nelson, J. Am. Chem.
Soc. 1999, 121, 6761-6762; (b) R. Takeuchi, N. Ue, K. Tanabe,
K. Yamashita, N. Shiga, J. Am. Chem. Soc. 2001, 123, 9525-
9534. For Ir-catalysed allylation of hydrazines and
hydrazones see: c) R. Matunas, A. J. Lai, C. Lee, Tetrahedron
2005, 61, 6298-6308.
3
4
For reviews that discuss such problems in modern organic
chemistry see: (a) J. Mahatthananchai, A. M. Dumas, J. W.
Bode, Angew. Chem. Int. Ed. 2012, 51, 10954-10990; (b) N. A.
Afagh, A. K. Yudin, Angew. Chem. Int. Ed. 2010, 49, 262-310.
For a review see: (a) S. W. McCombie, W. B. Motherwell, M.
J. Tozer, The Barton-McCombie Reaction. In Org. React. Vol.
77, John Wiley & Sons, Inc.: 2012; for recent applications in
complex molecule synthesis see: (b) H. Sugimura, S. Sato, K.
Tokudome, T. Yamada, Org. Lett. 2014, 16, 3384-3387; (c) M.
Zhang, N. Liu, W. Tang, J. Am. Chem. Soc. 2013, 135, 12434-
12438; (d) B. S. Fowler, K. M. Laemmerhold, S. J. Miller, J.
Am. Chem. Soc. 2012, 134, 9755-9761; (e) M. Bian, Z. Wang,
X. Xiong, Y. Sun, C. Matera, K. C. Nicolaou, A. Li, J. Am. Chem.
Soc. 2012, 134, 8078-8081.
15 Notes: (a) the stable, crystalline reagents NBSH and IPNBSH
are commercially available, or readily synthesized on
decagram scale; (b) for additional optimization data see the
supporting information; (c) hydrolysis was performed by
removal of MeCN prior to addition of THF/TFE/H2O (2:1:1)
and AcOH, direct addition of TFE/H2O without THF resulted
in ~10% lower yields; (d) electron-rich aryl methyl
carbonates are prone to rearrangement to the linear isomer,
pyridine and quinoline substrates are aminated effectively
but undergo reduction with low yield and regioselectivity,
cyclic allylic methyl carbonates are not viable substrates, as
is generally observed in Ir- and Rh-catalysed allylic
functionization; (e) see supporting information for details on
optimization of internal allylic substrates; (f) these conditions
are effective for terminal allylic carbonates, however the
reactions proceeds with slightly diminished branched/linear
selectivity compared to the use of [Ir(COD)Cl]2; (g) no
glovebox is required for these reactions, see the supporting
information.
16 Aside from being useful chemical building blocks, methyl-
substituted olefins are found in numerous bioactive
molecules, such as cyclosporines, corallopyronins and
penibruguieramide A.
17 Free diazene generated from sulfonyl hydrazines can reduce
olefins, for examples see: (a) B. J. Marsh, D. R. Carbery, J.
Org. Chem. 2009, 74, 3186-3188; (b) M. H. Haukaas, G. A.
O'Doherty, Org. Lett. 2002, 4, 1771-1774.
5
6
For diazene mediated alcohol reduction with sulfonyl
hydrazine reagents see: (a) M. Movassaghi, O. K. Ahmad, J.
Org. Chem. 2007, 72, 1838-1841; (b) A. G. Myers, M.
Movassaghi, B. Zheng, J. Am. Chem. Soc. 1997, 119, 8572-
8573; (c) A. G. Myers, B. Zheng, J. Am. Chem. Soc. 1996, 118,
4492-4493; (d) A. G. Myers, B. Zheng, Tetrahedron Lett.
1996, 37, 4841-4844.
For selected applications of reductions employing sulfonyl
hydrazine reagents in complex molecule synthesis see: (a) D.
Yang, G. C. Micalizio, J. Am. Chem. Soc. 2012, 134, 15237-
15240; (b) M. Shan, E. U. Sharif, G. A. O'Doherty, Angew.
Chem. Int. Ed. 2010, 49, 9492-9495; (c) M. Movassaghi, G.
Piizzi, D. S. Siegel, G. Piersanti, Angew. Chem. Int. Ed. 2006,
45, 5859-5863; (d) M. G. Charest, C. D. Lerner, J. D. Brubaker,
D. R. Siegel, A. G. Myers, Science 2005, 308, 395-398.
M. Movassaghi, O. K. Ahmad, Angew. Chem. Int. Ed. 2008,
47, 8909-8912.
18 Secondary allylic acetates are less reactive substrates. Under
the standard Ir-catalysed conditions with the acetate version
of the substrate in Table 3, entry 1, 27% (>20:1 b/l) product
is observed, compared to >95% for the allylic methyl
carbonate substrate, (the isolated yield of olefin is lower due
to volitility of the product). Under the standard Rh-catalysed
conditions 34% (20:80 b/l) product is observed.
19 For the Rh-catalyzed allylation of sulfonamides see: P. A.
Evans, J. E. Robinson, K. K. Moffett, Org. Lett. 2001, 3, 3269-
3271.
7
8
For acid catalysed substitution reactions of activated
propargylic substrates with sulfonyl hydrazines to generate
allenes see: (a) Z. Liu, P. Q. Liao, X. Bi, Chem. Eur. J. 2014, 20,
17277-17281; (b) D. A. Mundal, K. E. Lutz, R. J. Thomson, J.
Am. Chem. Soc. 2012, 134, 5782-5785.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins