Pd-catalyzed cross-coupling of highly sterically congested enol carbamates with grignard reagents via c-o bond activation

Article abstract of DOI:10.1021/acs.orglett.0c01127

The palladium-catalyzed cross-coupling reaction of enol carbamates to construct highly sterically congested alkenyl compounds is presented for the first time. This protocol demonstrates the potential of using thermally stable and highly atom-economic enol electrophiles as building blocks in bulky alkene synthesis. This reaction accommodates a broad substrate scope with excellent Z/E isomer ratios, which also provides a new synthetic pathway for accessing Tamoxifen.

Full text of DOI:10.1021/acs.orglett.0c01127

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Letter
Pd-Catalyzed Cross-Coupling of Highly Sterically Congested Enol
Carbamates with Grignard Reagents via C−O Bond Activation
Zicong Chen and Chau Ming So*
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ABSTRACT: The palladium-catalyzed cross-coupling reaction of enol carbamates to construct highly sterically congested alkenyl
compounds is presented for the first time. This protocol demonstrates the potential of using thermally stable and highly atom-
economic enol electrophiles as building blocks in bulky alkene synthesis. This reaction accommodates a broad substrate scope with
excellent Z/E isomer ratios, which also provides a new synthetic pathway for accessing Tamoxifen.
lkenes are important structures constituting valuable
materials1 and bioactive agents (Figure 1).2 The Wittig
carbonyl compounds electrophiles with respect to alkenyl
halides (Figure 2). Recent advancements demonstrate the
A
Figure 1. Bioactive agents containing alkene motifs.
olefination3 represents a classical approach to prepare alkenes.
However, the disadvantages are obvious due to the multiple
synthetic steps and wasted stoichiometric phosphorus oxide
side products.
The past few decades have seen the dramatic development
of transition-metal-catalyzed cross-coupling in organic syn-
thesis.4 Developed reactions involving diverse mechanisms
have provided alternative routes to desired alkenyl com-
pounds.5 Pd-catalyzed cross-coupling reactions using alkenyl
halides have proven successful, affording corresponding
products in intra-/intermolecular manners.6 However, multi-
substituted alkenyl halides are not broadly available, which
limits their utility in cross-coupling reactions. Thus, exploring
alternative electrophiles remains a valuable pursuit.
Figure 2. Features of enol electrophiles.
practical application of enol sulfonates in cross-coupling
reactions8 and other transformations.9 Enol phosphates10
also have emerged as applicable alkenyl precursors. Never-
theless, sporadic reports focusing on enol carboxylates11 as well
as enol carbamates12 show relatively higher atom efficiency in
cross-coupling reactions.
Among diverse transformations, transition-metal-catalyzed
cross-coupling reactions for C−C bond construction remain
indispensable tools.13 With regard to nucleophiles, Grignard
reagents remain common carbon synthons due to their high
reactivity and variety (Figure 3). Shi and co-workers14 reported
In the past few decades, O-based electrophiles from phenols
have risen to become powerful alternatives to aryl halides.7
Indeed, enol electrophiles are also a highly attractive
complement to alkenyl halides: (1) they can be prepared
easily from carbonyl compounds, one of the most abundant
feedstocks from nature or the chemical industry; and (2) they
can provide easy access for various substitution patterns of
Received: March 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01127
© XXXX American Chemical Society
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the screening (Scheme 1). Classical phosphine ligands, PPh3
and PCy3, gave low yields. Ligands previously used in the
a
Scheme 1. Evaluation of Ligands
Figure 3. Transition-metal-catalyzed cross-coupling reactions of enol
carboxylates and carbamates using organometallics.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), THF (total
around 1 mL), Pd(OAc)2 (4 mol %), ligand (8 mol %), under N2 at
50 °C for 1 h; calibrated GC−FID yields are reported using dodecane
as the internal standard.
on a representative iron-catalyzed cross-coupling reaction of
alkenyl pivalates with Grignard reagents; however, the study
only included alkylation examples, and the attempt to couple
unactivated electrophiles was unsuccessful. In another study,
Jacobi von Wangelin and co-workers15 investigated the iron-
catalyzed cross-coupling of alkenyl acetates with Grignard
reagents. Although the scope of alkenyl electrophiles is
advanced, the sensitivity of this Fe-catalyzed system to steric
bulk is a recognized deficiency. Frantz and co-workers16
developed an Fe-catalyzed cross-coupling reaction between
stereodefined enol carbamates and Grignard reagents for
stereoselective acrylates synthesis. However, the literature
seldom reports on examples other than alkylation. Recently,
Knochel and co-workers17 demonstrated successful arylation
and alkenylation of alkenyl acetates under Co-catalyzed
conditions. Nevertheless, these electrophiles were limited to
activated substrates.
Palladium catalytic systems have exhibited effectiveness in
synthesizing multisubstituted alkenes with alkenyl tosylates, yet
the formation of extremely sterically congested alkene remains
challenging.18 On the other hand, enol carbamates are highly
attractive electrophiles for several reasons: (1) they possess
higher atom economy compared to their sulfonate and
phosphate counterparts; (2) they have excellent tolerance to
thermal decomposition with respect to corresponding alkenyl
pivalates and alkenyl tosylates, which is beneficial to its shelf
life;19 and (3) they can be prepared easily from carbonyl
compounds. However, the activation of inert enol carbamate
C−O via the less nucleophilic and oxophilic palladium system
remains challenging. Herein, we report the first Pd-catalyzed
sterically congested cross-coupling reaction between enol
carbamates and Grignard reagents (Figure 3).
activation of alkenyl tosylates, such as CMPhos,20 were found
to be inactive. Screened Buchwald-type ligands (SPhos, XPhos,
and BrettPhos) led to relatively low yields, while ligands from
Beller’s group (Scheme 1, L7−L10) did not promote this
reaction. MorDalphos was successfully employed in the
activation of relatively challenging C−O bonds in our previous
reports,21 but it was not effective in this transformation.
Fortunately, N-heterocyclic carbenes (NHCs) afforded prom-
ising yields (Scheme 1, L14, L15). IPr·HCl was superior to
other derivatives. We speculated that the electron-donating
properties as well as steric effects of NHCs facilitated the
coupling process.22 According to the screening results, the
steric bulk of the N-substitutions greatly impacted the
outcome.23
Encouraged by the screening results, we selected IPr·HCl to
evaluate other condition parameters (Table 1). The conditions
without alteration afforded an excellent yield by GC detection
as well as isolation (Table 1, entry 1). The use of NiCl2 as a
metal source only afforded a moderate product yield for this
reaction (Table 1, entry 2). This Pd-catalyzed reaction
proceeded smoothly at room temperature without diminishing
the yield (Table 1, entry 3). When the catalyst loading was
lowered by 2 mol % of Pd, good yields were still obtained
under the condition of elevated temperature (Table 1, entries 4
and 5). Elevation of temperature and extended reaction time
enabled a further decrease in the catalyst loading with good
yields (Table 1, entries 6−8).
Following condition optimization, we first examined the
scope of sterically hindered cross-coupling between enol
carbamates and Grignard reagents (Scheme 2). According to
the condition screening, the attempt to reduce the catalyst
loading may be influenced by the reaction temperature. In view
of the bulky coupling partners that could participate in the
The ligand effect to this reaction was first investigated. 3,4-
Dihydronaphthalen-1-yl dimethylcarbamate 1a and mesityl-
magnesium bromide 2a were selected as model substrates for
B
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a
we found that the reaction proceeded well in the presence of
sterically hindered arylmagnesium bromides, obtaining diverse
triaryl ethylene compounds (Scheme 2, 3e−3h) in good yields.
We further tested deactivated substrates (Scheme 2, 3i and 3j),
and though a prolonged reaction time was needed, we
obtained coupling products with good-to-moderate yields.
High stereoselectivity is critical in alkene synthesis.
Table 1. Optimization of Reaction Conditions
In this reaction, the configuration retention of alkenyl
skeletons was achieved, affording multisubstituted products
with excellent Z/E isomer ratios (Scheme 2, 3e−3j). It is
worth noting that extremely sterically congested alkene can
also be synthesized in excellent yield (Scheme 2, 3g−3j). We
have also attempted to investigate the reactivity of (E)-1,2-
diphenylvinyl dimethylcarbamate. However, the preparation of
the corresponding (E)-enol carbamate was unsuccessful.
Next, we turned our attention to the reactivity of this Pd/
NHC system, studying the cross-coupling reactions of less
sterically hindered and/or unactivated enol carbamates
(Scheme 3). In general, substrates participating in the sterically
hindered cross-coupling reaction also successfully coupled with
less hindered Grignard reagents (Scheme 3, 6a−6c, 6e, and
6f). Unactivated substrate bearing a bulky group at the α-
position was also converted into the symmetrical alkenyl
entry
catalyst (mol %)
condition [°C/h]
3a [%]
b
b
1
2
3
4
5
6
7
8
Pd(OAc)2 (4)
NiCl2 (4)
50/1
50/1
25/8
50/1
25/1
50/1
50/3
25/8
98%, 93%
56%
95%, 91%
93%
64%
66%
Pd(OAc)2 (4)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
90%
44%
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), THF (total
around 1 mL); under N2, temperatures and reaction time are
indicated; calibrated GC−FID yields are reported using dodecane as
the internal standard. Isolated yields.
b
Scheme 2. Pd/NHC-Catalyzed Sterically Hindered Cross-
Coupling between Enol Carbamates and Grignard Reagents
Scheme 3. Cross-Coupling of Less Sterically Hindered/
Unactivated Enol Carbamates
a
Reaction conditions: Pd(OAc)2 (4 mol %), ligand IPr·HCl (8 mol
%), ArMgBr (0.4 mmol), 50 °C, under N2; isolated yields are
reported. Reaction conditions: Pd(OAc)2 (4 mol %), ligand IMes·
b
HCl (8 mol %), ArMgBr (0.4 mmol), 50 °C, under N2; isolated yields
are reported; Z/E ratios were determined by GCMS analysis of the
c
d
crude reaction mixture. Reaction time: 1 h. Reaction time: 3 h.
e
f
Reaction time: 12 h. The reaction was conducted on 1 mmol scale at
50 °C for 4 h under N2.
scope, we decided to perform the reaction at 50 °C. The Pd/
NHC catalytic system efficiently promoted the cross-coupling
reaction of α-naphthalenlyl carbamates with sterically hindered
arylmagnesium bromides, affording corresponding products
with quantitative yields (Scheme 2, 3a and 3b). The excellent
yield was maintained when the reaction was scaled up (Scheme
2, 3a). Carbamate with a larger seven-membered ring also
smoothly coupled with highly hindered 2,6-substituted aryl
Grignard reagents (Scheme 2, 3c and 3d). Acyclic enol
carbamates constituted the second part of the scope (Scheme
2, 3e−3j). Compared to the cyclic electrophiles, cross-coupling
of carbamates with congested α-substitutions could be more
demanding. However, by adjusting the size of the NHC ligand,
a
Reaction condition: Pd(OAc)2 (4 mol %), IMes·HCl (8 mol %),
ArMgBr (0.4 mmol), 50 °C, under N2; isolated yields are reported. Z/
E ratios were determined by GCMS analysis of the crude reaction
b
c
d
mixture. Reaction time: 3 h. Reaction time: 12 h. Reaction
condition: Pd(OAc)2 (4 mol %), IMes·HCl (8 mol %), NaOtBu (16
mol %), ArZnCl (0.4 mmol), rt, 12 h, under N2; isolated yield.
e
f
Reaction time: 14 h. Reaction condition: Pd(OAc)2 (0.5 mol %),
IMes·HCl (1 mol %), ArMgBr (0.4 mmol), rt, 1 h, under N2; isolated
yields.
C
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product (Scheme 3, 6d). The transformation of heterocyclic
carbamates was also applicable (Scheme 3, 6h), and we found
an aryl zinc reagent to be a feasible nucleophile for the base
sensitive lactone (Scheme 3, 6g). Cycloalkanone-derived
deactivated enol carbamates also reacted under this condition,
affording good-to-excellent yields (Scheme 3, 6i−6m). Enol
pivalate (3,4-dihydronaphthalen-2-yl pivalate) was also suc-
cessfully employed as an electrophile with (4-fluorophenyl)
magnesium bromide to obtain the corresponding product 6m
with a 93% product yield. A heterocyclic nucleophile was also
transformed into the desired product (Scheme 3, 6n). It is
worth noting that this system showed high efficacy in the
activation of unactivated substrates at a low catalyst loading.
Reducing the catalyst loading to 0.5 mol % of Pd still led to the
desired products in excellent yields (Scheme 3, 6o and 6p).
These results exemplify the feasibility of significantly
minimizing the metal residual in products, compared to
related methods involving other transition metals (Fe, Co,
etc.).14−17
Scheme 5. Selective Coupling of Activated Enol Carbamate
with Organozinc Reagent
Scheme 6. Synthesis of Tamoxifen
Palladium-catalyzed alkylation and alkenylation via coupling
reaction are known to be challenging due to the potential rapid
β-hydride elimination and isomerization.24 To investigate the
generality of the scope, we further examined other types of C−
C bond formations with this catalytic system. To our delight,
successful transformations were achieved in the presence of
primary/secondary alkyl nucleophiles (Scheme 4, 9a−9e).
Alkenylation of enol carbamate was also applicable, affording
the conjugated alkene in a moderate yield (Scheme 4, 9f).
selectivity. To access this important compound, various cross-
coupling methods have been developed involving the use of
corresponding alkenyl halide or alkenyl boronate as the
counterpart, which requires tedious synthetic procedures.27
To the best of our knowledge, there exist no reports on using
easily accessible enol as a coupling counterpart to prepare
Tamoxifen. This protocol distinguishes itself from other
methods, representing an alternative approach for synthesizing
Tamoxifen and its derivatives with good atom efficiency.
In conclusion, we have developed a Pd-catalyzed highly
sterically congested cross-coupling reaction between enol
carbamates and Grignard reagents. A range of alkenes bearing
bulky substitutions were synthesized with high Z/E isomer
ratios. The scope was further extended to alkylation and
alkenylation. This catalytic system exhibited high reactivity
toward less-hindered substrates under the condition of low
catalyst loading. Selective C−O bond activation toward
different substrates was demonstrated. Furthermore, this
cross-coupling reaction provided a new and practical synthetic
route to Tamoxifen and (E)-Tamoxifen. We believe that this
strategy could contribute to the synthesis of challenging
multisubstituted alkenes by utilizing the skeletons from
carbonyl compounds.
Scheme 4. Pd/NHC-Catalyzed Alkylation/Alkenylation of
Enol Carbamates
a
Reaction conditions: Pd(OAc)2 (4 mol %), IMes·HCl (8 mol %),
R′MgBr (0.4 mmol), 50 °C, 3 h; isolated yields are reported.
b
R′MgCl (0.4 mmol) was used.
In light of the applicable arylation of coumarin carbamate
(Scheme 3, 6g) using organozinc reagent, we attempted a
selective cross-coupling investigation (Scheme 5). When aryl
zinc reagent was employed, only the coumarin product 6g was
selectively formed.25 This result indicates that selective
functionalization of a more complex substrate with multiple
C−O bonds could be realized using a weaker nucleophile.
Tamoxifen, one of the most-prescribed anticancer drug,26
was selected as a representative standard for evaluating the
practicability of this cross-coupling strategy (Scheme 6).
Carbamate precursors 10a and 10b were prepared as single
isomers from commercially available 1,2-diphenylbutan-1-one.
Subsequent cross-coupling afforded Tamoxifen 11a and its
(E)-isomer 11b separately without deterioration of stereo-
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01127.
Procedure details and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Chau Ming So − State Key Laboratory of Chemical Biology and
Drug Discovery and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University,
D
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2009, 2009, 2251−2261. (d) Hofmayer, M. S.; Lutter, F. H.;
Grokenberger, L.; Hammann, J. M.; Knochel, P. Org. Lett. 2019, 21,
36−39.
Kowloon, Hong Kong; The Hong Kong Polytechnic University,
Shenzhen Research Institute, Shenzhen, People’s Republic of
China; orcid.org/0000-0001-6268-651X;
Email: chau.ming.so@polyu.edu.hk
(9) For selected Pd-catalyzed exmaples: (a) Fu, W. C.; Wu, Y.; So,
C. M.; Wong, S. M.; Lei, A.; Kwong, F. Y. Org. Lett. 2016, 18, 5300−
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Author
Zicong Chen − State Key Laboratory of Chemical Biology and
Drug Discovery and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University,
Kowloon, Hong Kong
̈
(b) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12,
724−726.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01127
(11) For cross-coupling reactions of enol pivalates: (a) Li, B.-J.; Li,
Y.-Z.; Lu, X.-Y.; Liu, J.; Guan, B.-T.; Shi, Z.-J. Angew. Chem., Int. Ed.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank the Shenzhen Strategic New Industry
Development Research Fund of the Shenzhen Science,
Technology and Innovation Commission (SZSTI)
(JCYJ20180306173843318), the National Natural Science
Foundation of China (21972122), and the Research Grants
Council of Hong Kong, Early Career Scheme (ECS 25301819)
for financial support. We are grateful to Dr. Siu Cheong Yan
(PolyU) for NMR analysis.
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DEDICATION
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Dedicated to Professor Chak-Po Lau on the occasion of his
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