Base-Catalyzed [1, n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers

Article abstract of DOI:10.1021/acscatal.9b02478

The isomerization of dienyl alcohols and polyenyl alkyl ethers catalyzed by TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) under metal-free conditions is presented. Two reaction pathways have been observed. For dienyl alcohols, the reaction proceeds by a [1,3]

Full text of DOI:10.1021/acscatal.9b02478

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Article
Base-Catalyzed [1,n]-Proton Shifts in
Conjugated Polyenyl Alcohols and Ethers
Nagaraju Molleti, Samuel Martinez-Erro, Alba Carretero Cerdan,
Amparo Sanz-Marco, Enrique Gomez-Bengoa, and Belen Martin-Matute
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02478 • Publication Date (Web): 26 Aug 2019
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ACS Catalysis
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Nagaraju Molleti, Samuel Martinez-Erro, Alba Carretero Cerdán,†,# Amparo Sanz-Marco, Enrique
†,⊥
†,⊥
†
#
†
Gomez-Bengoa, and Belén Martín-Matute*
†Department of Organic Chemistry, Stockholm University, Stockholm SE-10691, Sweden.
Department of Organic Chemistry I, Universidad País Vasco, UPV/EHU, 20080 San Sebastián, Spain.
#
Supporting Information Place holder
ABSTRACT: The isomerization of dienyl alcohols and polyenyl
alkyl ethers catalyzed by TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene)
under metal-free conditions is presented. Two reaction pathways have
been observed. For dienyl alcohols, the reaction proceeds by a [1,3]-
proton shift to give -unsaturated ketones exclusively. On the other
hand, the reaction with polyenyl alkyl ethers gives the corresponding
conjugated vinyl ethers in good yields (up to 83%), with
regioselectivities up to >20:1. Experimental and computational
investigations suggest that the mechanism proceeds through
consecutive “chain-walking” proton shifts (“base-walk”) mediated by
TBD.
KEYWORDS: base-catalysis, mechanism, superbase, isomerization, proton shift, base-walk
The isomerization of allylic alcohols into carbonyl compounds
is a fundamental and powerful tool in organic synthesis. The
reaction results in a functional-group interconversion, thus
the formation of stable diene–metal complexes that prevent
hydride migration.
In this article, we describe the first examples of the
isomerization of conjugated allylic alcohols and ethers, using a
base catalyst (Scheme 1c). The process is reminiscent to the
recently explored metal-catalyzed “chain-walking” or “metal-
1
2
1
,
allylic moieties may be treated as carbonyl equivalents. Since
2a
the pioneering work of Logn et al., some effort has gone into
the development of more efficient catalytic systems for this
3,3
transformation. Our own group has reported the use of a
Scheme 1. Isomerization of unsaturated alcohols and
ethers
family of complexes with the general structure [Cp*Ir(III)X]
for the isomerization of primary and secondary allylic alcohols,
as well as for the synthesis of -functionalized carbonyl
compounds from allylic alcohols under very mild conditions
4
(
Scheme 1a). Although the isomerization of allylic alcohols
has traditionally been accomplished using metal catalysts, a few
examples of transition-metal-free isomerizations are also
5
known. In 2016 we reported that the isomerization of electron-
poor allylic alcohols and allylic ethers could be mediated by a
simple base, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),
6
through a stereospecific [1,3]-proton shift (Scheme 1b).
Extended conjugated systems such as dienyl alcohols and
dienyl ethers (Scheme 1c) are common structural motifs in
7
biologically active natural products. Compounds containing
these structures are also extensively used as key intermediates
8
-11
in organic synthesis.
Despite the importance of these
structural motifs, their isomerization into carbonyl compounds
or enol ethers has proved challenging, though. A reason for this
is that transition-metal-catalyzed approaches are ineffective for
the isomerization of such complex conjugated systems due to
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walk” processes, which refer to the ability of certain metal
complexes to perform a series of consecutive [1,2]- or [1,3]-
good yields. Both electron-donating and electron-withdrawing
substituents in the para position of the aryl ring at R were
tolerated and ketones 2g and 2h were obtained in good yields
(72% and 65% respectively).
5
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3
hydride shifts along a hydrocarbon chain. This formal alkene
1
4,15
migration might be terminated by an enol tautomerization.
The work presented here consists, in contrast, of a formal proton
migration alongside a polyenylic chain, constituting the first
Similarly, when the second alkene was part of a cyclic
structure (1i1l), very good yields were obtained. The presence
of a bromide or an alkyne was tolerated, and compounds 2i and
2j were formed in 91 and 82% yields. The introduction of a
1
6
example of a “base-walk” process in these type of substrates.
The reaction is regioselective: the isomerization of conjugated
allylic alcohols proceeds through a [1,3]-proton shift. On the
other hand, the analogous ethers follow a formal [1,n]-proton
shift where n = 3, 5 or 9. The substrate scope, experimental and
computational mechanistic investigations are presented.
2
trifluoromethyl group at R was also found to be beneficial, and
1l gave the product in an excellent yield of 90%. Products
derived from [1,5]-proton shifts were not detected in the
isomerization of dienyl alcohols 1a1l.
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We started by investigating the isomerization of conjugated
dienyl alcohols, and we selected dienol 1a as a model substrate.
As the catalyst, we used the base TBD, as it gave excellent
Next, we turned our attention to the isomerization of dienyl
ethers.
When
((1E,3E)-5-methoxypenta-1,3-diene-1,5-
diyl)dibenzene (3a) was treated with TBD (20 mol%) in toluene
at 60 °C overnight, interestingly, and in contrast to the reaction
of conjugated dienyl alcohols, diene 4a formed as the major
product as a result of a formal [1,5]-proton shift ([1,5]:[1,3] >
20:1). Compound 4a was obtained in 70% yield, as a mixture
of stereoisomers [(1Z,3E)/(1Z,3Z) = 78:22] (Table 1, entry 1).
We also tested other bases, and found that 1,8-
6
results in the isomerization of allylic alcohols. A first attempt
conducted with 10 mol% of TBD in toluene at 60 °C overnight
did not give any product, and 1a was recovered. When 20 mol%
of TBD was used in refluxing toluene (Scheme 2), dienol 1a
was converted completely and exclusively into -unsaturated
ketone 2a, albeit in a moderate yield of 45%. The introduction
of a chloride group in the para position of the aryl ring at R1
was detrimental to the reaction, and a yield of only 32% of 2b
was obtained. Decomposition was also observed when a
terminal dienol 1c was tested, and 2c was obtained in a low
yield of 40%. Dienyl alcohol 2d bearing a trifluoromethyl
diazabicyclo[5.4.0]undec-7-ene
diazabicyclo[2.2.2]octane (DABCO) did not catalyze the
reaction under similar reaction conditions (i.e.,
(DBU)
and
1,4-
substoichiometric amount of base, 60 °C, entries 2–4). A
stoichiometric amount of DBU (1.0 equiv.), on the other hand,
gave 4a in 52% yield (entry 5).
As the best results were obtained with TBD, we carried out
further optimization experiments with this base. We found that
the catalyst loading could be lowered to 10 mol% when the
temperature was raised to 85 °C; under these conditions, 4a was
formed in 83% yield (entry 6). Increasing the reaction time did
not have any significant effect on the formation of the product
5
group in the para position of the aryl ring at R was converted
to the corresponding -unsaturated ketone with a yield of
46%. In contrast, the introduction of substituents onto the
3
4
terminal alkene (i.e., R and R ) prevented the decomposition
of the starting dienyl alcohols, and significantly enhanced the
yields of the products (2e2l). For instance, compounds 1e and
3
4
1
f, bearing a methyl group at either R (1e) or R (1f), were
(entry 7). In all instances, the stereoisomeric ratio of the product
4
a, i.e., (1Z,3E)/(1Z,3Z), remained essentially constant, at ca.
Scheme 2. Substrate scope of the isomerization of dienyl
a
78:22, suggesting that a thermodynamic equilibrium was
reached. A complete list of the optimization experiments can be
found in the Supporting Information (Table S1). The reaction
did not take place in the absence of the base catalyst (entry 8).
alcohols
Table 1. Base-catalyzed isomerization of 3aa
OMe
H
TBD
H
OMe
Ph
toluene,
Ph
overnight
4a
3a
Entry
TBD
mol%)
T [°C]
4a [%] /
1Z,3E)/(1Z,3Z)
b,c
(
(
1
2
TBD (20)
DBU (20)
DBU (40)
60
60
60
60
80
85
85
85
70 / 78:22
< 5 / -
3
< 5 / -
4
DABCO (40)
DBU (100)
TBD (10)
TBD (10)
-
< 5 / -
5
52 / 77:23
d
6
83 (80%) / 78:22
83 / 78:22
7e
8f
< 5 / -
a
a1a1l (0.1 mmol) and TBD (20 mol%) in toluene (1.0 mL). Isolated
yields in parentheses.
Unless otherwise noted, 3a (0.1 mmol) in toluene (1 mL).
b
1
Yields determined by H NMR spectroscopy using an internal
standard. E/Z ratios were calculated by H NMR spectroscopy.
Isolated yield in parentheses. Run for 24 h. Without TBD.
c
1
converted into the corresponding ,-unsaturated ketones in
d
e
f
2
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We went on to study the substrate scope of the reaction under tolerated, and 4g was obtained in 72% yield. Dienyl ether 3h,
1
5
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2
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9
these optimal reaction conditions. We tested substrates bearing
electron-donating and electron-withdrawing substituents on the
bearing two heterocyclic thiophenyl substituents at R and R ,
gave 4h in 57% yield. Fluoride, chloride, and methyl groups at
1
5
1
phenyl groups at R and R (Scheme 3). Dienyl ethers bearing
electron-withdrawing groups in both aryl rings (4b4c) were
converted into the products in good yields. The introduction of
electron-donating substituents in both aryl rings in the para
position decreased the rate of the reaction (3d3e), but good
yields were still obtained at 110 °C. The presence of a methoxy
group at the meta position of the phenyl ring had no effect on
the rate, and 4f was obtained in 75% yield under standard
conditions. A chloride group at the ortho position was well
the para position of the aryl ring at R were all well tolerated,
and 4i4k were obtained in good yields. Dienyl ethers with
additional substitutents on the double bonds of the conjugated
3
4
system, i.e., at R or R (3l3o), underwent the isomerization
reaction to give the products in moderate to good yields (60–
75%). Interestingly, 4m, 4n, and 4o were obtained with a high
(1Z,3E)/(1Z,3Z) ratio of >95:5. We also tested substrates
6
bearing different substituents at R . The [1,5]-proton shift
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worked well for ethyl (3p), isopropyl (3q), benzyl (3r) and 2-
methoxyethyl (3s) ethers under the optimized
conditions. Next, we investigated the introduction of
Scheme 3. Substrate scope of the isomerization of dienyl ethersa,b
5
an aliphatic substituent at R (3t). Surprisingly, the
reaction gave a mixture of products (3:1) in a total
yield of 20%. The major product was derived from
the [1,3]-proton shift pathway (4t´); the product of
the [1,5]-shift (4s) was the minor product. However,
when the catalyst loading was increased to 20 mol%
and the temperature to reflux temperature, 4t was
formed in a better yield of 53%. Notably, compound
2
3
u, with a CF
3
substituent at R , gave only the
product derived from the corresponding [1,3]-
proton shift (4u) in 71% yield. From (E)-6-phenyl-
4-styryl-3,6-dihydro-2H-pyran (3v), the reaction
proceeded smoothly and gave 4v in very good yield
with an excellent E/Z ratio (96:4).
To test the generality of the method, more
extended conjugated polyenyl ethers were tested,
(Scheme 4). Tetraenyl ether 3w afforded 46% yield
of 4w as a result of an overall [1,9]-proton shift. A
tetraenyl ether with additional substituents along the
conjugated chain (3x) reacted also in a [1,9]-proton
shift yielding 4x in an isolated 69% yield.
Deuterium-labeling studies were carried out with
1
1
dienyl alcohol 1a-d and dienyl ether 3a-d (Scheme
1
7
5). The KIEs were found to be 2.4 ± 0.5 and 3.8 ±
0.5 for the dienol and dienyl ether, respectively.
These results suggest that in both cases the reaction
starts with a rate-determining deprotonation at C-1.
1
In the reaction of 1a-d , 24% deuterium content was
found at C-3 (54% of deuterium transfer) and no
deuterium was found at C-5 in the product; this
indicates that this substrate reacts exclusively
through a [1,3]-proton-shift mechanism (Scheme
5
a). The presence of deuterium (12%) at C-2 in the
a
3a3u (0.1 mmol) and TBD (10 mol%) in toluene (1.0 mL). Isolated yields in
product is due to keto/enol tautomerization. These
results are consistent with our previous work. In the
reaction of 3a-d , the deuterium content at C-5 was
28% which corresponds to 61% of deuterium
transfer to that position (Scheme 5b). The deuterium
content at C-3 was found 20% suggesting that the
mechanism follows, at least partially, a pathway
involving two consecutive [1,3]-proton shifts, i.e., a
b
1
parentheses. Ratio of (1Z,3E)/(1Z,3Z) in brackets determined by H NMR spectroscopy.
10 °C instead of 85 °C.
6
c
1
1
Scheme 4. Isomerization of tetraenyl ethers.a,b
[
3
1,3]-shift followed by a [3,5]-shift. To test this idea,
a-d was subjected to the reaction conditions; the
3
product of this reaction had 20% deuterium at C-5
(41% of deuterium transfer from C-3 to C-5), which
confirms that the [3,5]-proton shift does take place
(Scheme 5c). Cross-over experiments performed
a3v3w (0.1 mmol) and TBD (10 mol%) in toluene (1.0 mL). Isolated yields in
1
with substrates 3a-d and 3s at different
parentheses.
concentrations suggest that the proton shift does not
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occur exclusively by an intramolecular pathway (See SI,
Page 4 of 6
To better understand the reaction, DFT calculations (Figure
1) were carried out on dienyl ethers using the Gaussian 16
software (see Supporting Information for details). Substrate 3a
was chosen as a simplest model compound for the calculations.
This compound exists as an equilibrium mixture of conformers
I/I’ (Figure 1), interconverting by easy rotation around a -
1
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Scheme S2).
ǂ
bond (G = 6.4 kcal/mol). The reaction starts with the rate-
limiting deprotonation of the C-1H bond in I or I’ by the TBD
base with activation energies of 22.2 kcal/mol (TSI-II) and 24.4
kcal/mol (TSI’-II’), respectively. After this step, an
intimate ion pair consisting of the dienylic anion and
the protonated base is formed; the two intermediates
Scheme 5. Deuterium-labeling studies
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4
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0
ǂ
II and II’ cannot interconvert easily (G = 16.9
kcal/mol). Each anion, for example II, can undergo
then protonation at C-3 (TSII-III), at C-5 (TSII-IV), or
at C-1 (in a reversible TSI-II) to form the three
possible adducts III, IV, and I, respectively, with
similar energies (22.0 kcal/mol for TSII-III, 20.3
kcal/mol for TSII-IV, and 22.2 kcal/mol for TSI-II).
The low activation barriers seem to indicate that all
possible adducts might be in equilibrium under the
reaction conditions. The fact that the energies of the
transition states for the transformations of I into the
(1Z,3E) product (IV) and of I’ into the (1Z,3Z)
isomer (IV’) are very similar for both of the two
steps (22.2 vs 22.5 and 20.3 vs 20.3 kcal/mol)
confirms that the stereoselectivity of this reaction is
not expected to be under kinetic control. Rather, the
observed experimental selectivities are in good
agreement with the relative stabilities of all the
2
2.5
2.2
TSI’-II’
TSI-II
OMe
Ph
22.0 TSII-III 1,3-addition
2
possible
products.
This
indicates
that
2
0.3 TSII’-IV’
0.3 TSII-IV
thermodynamic equilibrium is reached between I,
I’, III, IV, and IV’, with the latter two species being
the most stable (–2.7 and –2.0 kcal/mol). Thus, the
stereoisomeric ratio depends exclusively on the
relative stabilities of the products. The (1Z,3E)
stereoisomer (IV), which is the major isomer
observed experimentally, is 0.7 kcal/mol lower in
energy than the (1Z,3Z) isomer (IV’). The reaction
kinetics was also simulated with COPASI
Ph
1,5-addition
2
II’
15.1
14.0 TBD-H+
II
TBD
H
OMe
OMe
Ph
Ph
0
H
OMe
Ph
0.7
Ph
Ph
Ph
I
III
TBD
OMe
Common intermediate for
Z
-1.9
protonation at C , C and C5
1
3
-2.0
Ph
Z
I'
IV’
H
OMe
Ph
18
H
Ph
software; we calculated a ratio of stereoisomers of
71:29, which is in perfect agreement with the
experimental selectivity, 78:22 (Scheme 3), and
IV
H
OMe
E
-2.7
conformers I/I' of 3a in
equilibrium conditions
Ph
Ph
Z
Ph
>
20:1 ratio of [1,5]- vs [1,3]-proton shift. We were
Thermodynamic distribution
also able to explain the results obtained in the
deuterium labeling experiments using DFT
calculations. The calculated energies of the rate-
N
N
N
N
N
N
N
N
H
N
H
N
H
N
N
H
N
N
determining transition states (TSI-II and TSI-II’,
N
H
OMe
Ph
H
H
H
OMe
Ph
H
OMe
Ph
OMe
Ph
OMe
Ph
Figure 1) increase by 0.6–0.9 kcal/mol when H is
replaced with D (see Supporting Information for
further details). This explains the KIE, and also the
lower rates observed for the deuterated substrate 3a.
To summarize, we have described the first method
for the remote transfer of protons through extended
conjugated allylic ethers. As a catalyst, the base
TBD was used. The method was found to be
H
Ph
Ph
Ph
Ph
Ph
TSI-II
TSI-II’
TSII-IV
TSII’-IV’
TSII-III
Figure 1. Calculated energy profile of the reaction. Values correspond to
Gibbs free energies in kcal/mol.
remarkably general and the proton was successfully transferred
as far as to 8 carbons away, resulting in a formal [1,9]-proton
shift. In the case of extended conjugated allylic alcohols, the
proton selectively transfers only to C-3 through a [1,3]-proton
shift, yielding the corresponding  -unsaturated carbonyl
compounds. Based on deuterium-labeling studies, it was
established that the rate-determining step is the deprotonation
at C-1. For polyenyl ethers, DFT studies suggest that the rate-
4
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determining deprotonation is then followed by a consecutive
1
2
3
4
5
6
7
8
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number of proton shifts until the last carbon of the conjugated
system. The “base-walking” stops when the most
thermodynamically stable product is formed. Thus, a simple
base enables the isomerization reaction, which cannot be
accomplished with transition-metal catalysts due to formation
of stable coordination complexes. To the best of our knowledge,
this is the first example of a proton being transferred alongside
a polyenylic hydrocarbon chain via iterative proton shifts.
(
Double-Bond Migration) Procedure for Allyl Acetals and Allyl Ethers
Mediated by Nickel Complexes. Synthesis 1998, 305308. (b)
Mereyala, H. B.; Gurrala, S. R.; Mohan, S. K. Study of Metal and Acid
Catalysed Deprotection of Propargyl Ethers of Alcohols via their
Allenyl Ethers. Tetrahedron 1999, 55, 1133111342. (c) Taskinen, E.
Thermodynamic, Spectroscopic, and Density Functional Theory
Studies of Allyl Aryl and Prop-1-Enyl Aryl Ethers. Part 1.
Thermodynamic Data of Isomerization. J. Chem. Soc., Perkin Trans.
2001, 2, 18241834. (d) Reid, J. P.; McAdam, C. A.; Johnston, A. J.
S.; Grayson, M. N.; Goodman, J. M.; Cook, M. J. J. Org. Chem. 2015,
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AUTHOR INFORMATION
Corresponding Author
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(4) (a) Ahlsten, N.; Martín-Matute, B. Ir-Catalysed Formation of
*
e-mail: belen.martin.matute@su.se
Author Contributions
These authors contributed equally to this work.
C−F Bonds. From Allylic Alcohols to α-Fluoroketones. Chem.
Commun. 2011, 47, 8331−8333. (b) Ahlsten, N.; Bermejo Gómez, A.;
Martín-Matute, B. Iridium‐Catalyzed 1,3‐Hydrogen Shift/Chlorination
of Allylic Alcohols. Angew. Chem., Int. Ed. 2013, 52, 6273−6276. (c)
Gomez, A. B.; Erbing, E.; Batuecas, M.; Vázquez-Romero, A.; Martín-
⊥
NOTES
The authors declare no competing financial interest.
Matute, B. Iridium‐Catalyzed Isomerization/Bromination of Allylic
Alcohols: Synthesis of α‐Bromocarbonyl Compounds. Chem. - Eur. J.
ASSOCIATED CONTENT
Supporting Information
2
014, 20, 10703−10709. (d) Vázquez-Romero, A.; Bermejo Gómez,
A.; Martín-Matute, B. An Acid- and Iridium-Catalyzed Tandem 1,3-
Transposition / 3,1-Hydrogen Shift / Chlorination of Allylic Alcohols.
ACS Catalysis 2015, 5, 708714. (e) Martinez-Erro, S., Bermejo
Gómez, A.; Vázquez-Romero, A.; Erbing, E.; Martín-Matute, B. 2,2-
Diiododimedone: a Mild Electrophilic Iodinating Agent for The
Selective Synthesis of α-Iodoketones from Allylic Alcohols. Chem.
Commun. 2017, 53, 98429845. (f) Sanz-Marco, A.; Mozina, S.;
Martinez-Erro, S.; Iskra, J. Martín-Matute, B. Synthesis of -
iodoketones from Allylic Alcohols through Aerobic Oxidative
Iodination. Adv. Synth. Catal. 2018, 360, 38843888. (g) Sanz-Marco,
A.; Martinez-Erro, S.; Martín-Matute, B. Selective Synthesis of
Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium
Enolates. Chem. Eur. J. 2018, 45, 1156411567.
(5) (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.;
Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. A
Catalytic Enantioselective Synthesis of the Endothelin Receptor
Antagonists SB-209670 and SB-217242.
Stereospecific Formal 1,3-Hydrogen Transfer of
Arylindenol. J. Am. Chem. Soc. 1998, 120, 45504551. (b) Johnston,
A. J. S.; McLaughlin, M. G.; Reid, J. P.; Cook, M. NaH mediated
isomerisation–allylation reaction of 1,3-substituted propenols. J. Org.
Biomol. Chem. 2013, 11, 76627666. (c) Zheng, H.-X.; Xiao, Z.-F.;
Yao, C.-Z.; Li, Q.-Q.; Ning, X.-S.; Kang, Y.-B.; Tang, Y. Transition-
Metal-Free Self-Hydrogen-Transferring Allylic Isomerization. Org.
Lett. 2015, 17, 61026105. (d) Mondal, K.; Mondal, B.; Pan, S. C.
Organocatalytic Redox Isomerization of Electron-Deficient Allylic
Alcohols: Synthesis of 1,4-Ketoaldehydes. J. Org. Chem. 2016, 81,
The Supporting Information is available free of charge on the ACS
Publications website. Experimental details, spectroscopy data and
computational details (PDF).
ACKNOWLEDGMENT
We are grateful for support from the Swedish Research Council
through Vetenskapsrådet and Formas, the Knut and Alice
Wallenberg Foundation, and the Göran Gustafsson Foundation.
This project was also funded by the European Union’s Horizon
2020 research and innovation programme under grant agreement
No 721223. We thank Alexander Röther for preliminary
experiments and IZO-SGI SGIker of UPV/EHU for human and
technical support.
A
Base-Catalyzed
Chiral 3-
a
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