Catalytically Generated Allyl Cu(I) Intermediate via Cyclopropene Ring-Opening Coupling en Route to Allylphosphonates

Article abstract of DOI:10.1021/acs.orglett.6b02307

An efficient generation of functionalized allyl copper(I) species via cyclopropene ring-opening coupling reaction is reported, which enables stereoselective access to allylphosphonates. Mechanistic studies uncovered stereochemistry to be controlled by both ligand and substrate electronics, with the latter likely arising from pronounced arene-Cu(I) interaction in electron-deficient substrates. The study unravels a novel approach to access functionalized nucleophilic allylcopper species upon which three-component coupling reactions might be developed.

Full text of DOI:10.1021/acs.orglett.6b02307

Letter
pubs.acs.org/OrgLett
Catalytically Generated Allyl Cu(I) Intermediate via Cyclopropene
Ring-Opening Coupling en Route to Allylphosphonates
Zhanyu Li,† Guochun Peng,† Jinbo Zhao,*,†,‡ and Qian Zhang*,†
†Jilin Province Key Laboratory of Functional Organic Molecule Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun, Jilin 130024, China
‡Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Chinese Academy of Sciences,
Shanghai Institute of Organic Chemistry, CAS, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: An efficient generation of functionalized allyl
copper(I) species via cyclopropene ring-opening coupling
reaction is reported, which enables stereoselective access to
allylphosphonates. Mechanistic studies uncovered stereo-
chemistry to be controlled by both ligand and substrate
electronics, with the latter likely arising from pronounced
arene-Cu(I) interaction in electron-deficient substrates. The
study unravels a novel approach to access functionalized nucleophilic allylcopper species upon which three-component coupling
reactions might be developed.
Scheme 1. Catalytic Processes for Generation of Nu-
Containing Allylcopper(I) Intermediates
ntensive studies on the allylation of carbonyl derivatives with
Isemimetallic reagents (boron, silicon, stannane, etc.), one of
the most useful transformations in organic synthesis,1 identified
Cu(I) catalysis to be exceptionally efficient, wherein
nucleophilic allyl Cu(I) intermediates are invoked as reactive
species.1f Due to the limited availability of stereodefined,
multisubstituted allylic reagents, direct access to multi-
substituted allylcopper(I) intermediate offers a straightforward
alternative. Stoichiometric generation of allylic copper(I)
intermediates via carbo-2 and silacupration3 of dienes with in
situ formed organocuprates offers an entry to multisubstituted
alkenes and allylic derivatives. A lack of functional group
tolerance due to employment of strongly basic organometallic
reagents, however, is an intrinsic limitation. Many recent efforts
have therefore been made to develop processes to form
allylcopper(I) species via addition of catalytically generated X−
Cu(I) (X = heteroatom) species with unsaturated carbon−
carbon bonds. This approach encompasses the advantage of
high efficiency and atom economy as well as enabling of
multicomponent processes. X−Cu(I) intermediates where X is
Lewis acidic or neutral elements such as B or Si demonstrated
exceptional reactivities, as shown in numerous reports on
intermolecular bora-4 and silylcupration5 of allenes as viable
routes to allyl Cu(I) intermediate generation, highlighting the
advantage of this strategy in the construction of complex
molecular architectures. Despite these remarkable advances, the
generation of allyl Cu(I) intermediates via heteroatomcupration
where heteroatoms are nucleophilic centers (such as N and O)
still represents an unmet challenge. Intramolecular version of
such process has recently been attained by Kanai and co-
workers with allenes (Scheme 1a);6 however, intermolecular
nucleocupration remains elusive.
Cyclopropene (CPE) is a highly strained yet readily available
unsaturated carbocycle that exhibits rich reactivity patterns
under transition-metal catalysis.7 Recently, noble metals,
notably rhodium and gold, catalyzed CPE ring-opening
reactions have been well documented.8 In contrast, a paucity
of reports on earth-abundant first-row transition-metals
catalyzed CPE ring-opening prevails. This is reflected in the
fact that only one or a couple of examples have been reported
each for Ni-,9 Cu-,10 and recently, Zn-catalyzed11 CPE ring-
opening initiated reactions. Based on our long-standing interest
in copper catalysis,12 we conceived a copper-catalyzed strain-
driven CPE nucleocupration13/β-carbon elimination14 se-
quence to access the functionalized allyl Cu(I) intermediate.
Herein, we report that catalytic generation of this intermediate
can be realized under ambient conditions and the application of
the approach enables stereoselective synthesis of allylphosph-
onates (Scheme 1, b).
Received: August 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02307
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Organic Letters
Letter
Multisubstituted functionalized alkene is a key functional
moiety in organic and medicinal chemistry. Organophosphates
are widely used olefination reagents in the Horner−Wads-
worth−Emmons (HWE) reaction that allow a high degree of
stereochemical control over the generated carbon−carbon
double bond.15 At the onset of this study, we examined the
reactivity of 3-phenyl-3-methylcyclopropene 1a under the
catalysis of various copper salts in the presence of diethyl
phosphite 2a as a model nucelophile. We envisioned that the
incipient catalytically generated allylcopper(I) species might be
sufficiently basic to deprotonate the phosphonate 2a,
suggesting a substoichiometric base-initiated process. Initial
optimization identified CuBr2 as the optimal catalyst, which,
with 0.2 equiv of DBU as base, afforded product 3a with high
yield and a selectivity of 9/1 at room temperature (entry 1,
Table 1). A control experiment performed without base led to
phosphite 2c afforded the product 3c with almost quantitative
yield and high (>20/1) selectivity. Neither diphenyl phosphite
(2d) nor diphenylphosphine oxide (2e) gave better selectiv-
ities.
Substrate scope studies revealed that a wide range of
functionalities with distinct electronic properties were compat-
ible, affording the corresponding products with high yields
(Table 2). Notably, CPEs bearing electron-neutral and
a
Table 2. Substrate Scope Studies
a
Table 1. Ligand Effects
b
entry
ligand
yield (%)
E/Z
1
2
3
4
5
6
7
90
76
98
70
60
85
75
9/1
TMEDA
P(o-tol)3
DAP
8/1
9/1
13/1
16/1
24/1
20/1
dppf
dppbz
xantphos
a
Conditions: cyclopropene 1a (0.30 mmol, 1.5 equiv), diethyl
phosphite 2a (0.20 mmol), DBU (0.04 mmol, 20 mol %), CuBr2
(0.02 mmol, 10 mol %), ligand (0.024 mmol, 12 mol %), DCE (2
b
mL), rt. Ratios of isolated products due to the unidentifiable crude
NMR residue.
no conversion. To further optimize the selectivity, the effects of
various phosphine and nitrogen based ligands were studied.
Notably, additional ligands indeed imparted significant
influences with respect to both reactivity and selectivity.
Specifically, TMEDA led to lower yield and selectivity (entry
2). The use of sterically hindered P(o-tol)3 achieved almost
quantitative yield but a similar selectivity (entry 3). With DAP
(2,9-bis(p-anisyl)-1,10-phenanthroline) and dppf, the selectiv-
ities were improved at the sacrifice of yields. Delightfully, with
dppbz, 3a was obtained in 85% yield and 24/1 selectivity and
thus used as the optimal conditions in the following studies.
The reactivities of several P-based nucleophiles were also
examined under the optimized conditions (Scheme 2).
a
Conditions: cyclopropene (0.30 mmol, 1.5 equiv), phosphine reagent
(0.20 mmol, 1.0 equiv), copper (0.02 mmol, 10 mol %), dppbz (0.024
mmol, 12 mol %), DBU (0.04 mmol, 20 mol %) in DCE (2 mL).
b
c
Isolated yields. E/Z ratios were determined by 1H NMR
d
spectroscopy. The gram-scale reaction was performed with 5 mol
% of CuBr2/6 mol % of dppbz as catalyst. 2 equiv of cyclopropene
was used.
e
electron-rich aryl groups afforded products with high E/Z
ratios (3a,f−h, entries 1 and 2), while those bearing electron-
withdrawing groups (EWGs) retrieved the corresponding
products with decreased selectivities (3i−k, entry 2). Substrates
bearing moderately strong (3-Cl) and strong (4-CF3) EWGs on
the aryl moiety afforded products with much lower selectivities
(entries 3 and 4). The reactions of these reactants with the
more sterically hindered diisopropyl phosphite 2b were found
to be more selective, and product 3m was obtained with a
selectivity of 15/1 (entry 3). However, the strategy was not as
effective for 4-CF3-substituted substrate, as only a moderate
improvement of selectivity was obtained for 3o (entry 4).
Variations on the aryl and alkyl moieties showed that 2-
naphthyl (instead of phenyl), ethyl (instead of methyl), and
bicyclic systems were also readily applicable (entries 5−7). 3,3-
Diaryl substrate was also viable, giving the allylic phosphonate
product 3r in 45% yield. 3,3-Dialkylcyclopropene was not
Although the diisopropyl phosphite 2b led to higher
selectivities and a slight drop of yield, the reaction of diisobutyl
Scheme 2. Reactivities of Different P-Based Nucleophiles
B
DOI: 10.1021/acs.orglett.6b02307
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Organic Letters
Letter
reactive (entry 9), and substrate decomposition was observed.
A gram-scale reaction readily afforded 3a in 80% yield and 28/1
selectivity under a reduced catalyst loading (entry 1).
Furthermore, preliminary studies revealed that at slightly
elevated temperature less electron-rich 3-EWG-substituted
cyclopropene 4 produced the diastereoisomeric products 5/5′
in moderate yields, which were facilely separated on silica (eq
1). Their configurations were determined by NOESY experi-
might reflect the requirement of a suitably stabilized allylcopper
intermediate.
Hammett analysis was then conducted to examine if the
stereoselectivity correlates with electronic effects. Plotting the
logarithmic selectivity ratios of substituted products 3 (3a,f−
k,l,n) over that of 3a (Table 2) against the substituents’
ments of 5. Cycloisomerization, a facile transformation of these
substrates,16 did not occur owing to the mildness of the
conditions. As an exemplified synthetic application, HWE
reaction of 3a with benzaldehyde afforded diene 6 in high yield
and exclusive stereoselectivity (eq 1).
18
Hammett constants σR (Figure 1) revealed a rough
On the basis of the above observations and some related
literature,17 a plausible mechanism was outlined in Scheme 3.
Scheme 3. Plausible Catalytic Cycle for Copper-Catalyzed
Stereoselective Ring-Opening Coupling of Cyclopropene
Figure 1. Hammett analysis of reaction selectivity. Hammett linear
correlations with electron-rich to -neutral (red line), electron-rich to
deficient (dashed line), as well as electron-neutral to -deficient
substrates (blue line).
correlation by electron-releasing and -neutral groups (4-MeO,
4-Me, and H) (red line) and a significant correlation by
electron-releasing to electron-withdrawing groups but with
obvious trend discrepancy (dashed line). Omitting 4-Me led to
better correlation (blue line), lending more support for the role
of EWGs in deviating from the trend in favor of the Z-isomer.
This effect could be attributed to appreciable Cu(I)−arene
interaction in the allylcopper species (C and D) in EWG-
substituted substrates.19 This trend is opposite to those
observed in cationic Cu(I)− and Cu(II)−arene complexes,
where electron-donating groups facilitate charge transfer,19a,b
implying a possible interaction engaging the electron-rich Cu(I)
center in C/C′ to be dominated by d−π* interaction. The
interaction presumably disfavors the ligation of exogenous
ligands, thereby overriding the ligand and steric effects in
electron-deficient substrates (entry 4, Table 2). Indeed, dppbz
was not as effective in improving the E/Z ratio in the reaction
of 3n, as only marginal improvement was observed when PCy3
was employed (from 2.5/1 to 3/1, data not shown). A detailed
mechanistic investigation is warranted and is currently ongoing.
In conclusion, we have realized an efficient generation of
allylcopper(I) species via cyclopropene ring-opening coupling.
As a preliminary synthetic application, a stereoselective access
to allylphosphonates was established. Mechanistic studies not
only provided clues for the putative allylcopper(I) species but
revealed a noteworthy dependence of stereochemistry on ligand
and substrate electronic effects. The present work unravels a
novel approach to access functionalized allyl Cu(I) species
First, DBU deprotonation of 2a facilitates the formation of P−
Cu(I) complex A. Cyclopropene phosphoracupration13 fol-
lowed by β-carbon elimination14 leads to η1-allyl copper species
C and C′, possibly equilibrating via η3-allyl copper D.1f
Protonation of the allylcopper species with the nucleophile
2a releases the product 3 and regenerates catalyst A (path a).
An alternative pathway involving first generation of vinylcopper
carbenoid species B followed by intra- or intermolecular attack
of the nucleophile Nu to form allyl copper intermediates could
not be strictly excluded at the current stage.10 Consistent with
the mechanistic proposal, an isotope-labeling experiment
performed with added D2O (5 equiv) resulted in high
deuterium incorporation in the product 3a-D (eq 3). Subjecting
3a to a mixture of 2a and D2O under the conditions of entry 2
resulted in no isotope incorporation, disclaiming the proposi-
tion of catalytic DBU-promoted H/D exchange.
The reaction of N-phenylsulfonamide under slightly modified
conditions afforded a mixture of constitutional isomers enamide
7 and allylic amide 7′ in 46% and 39% yields, respectively (eq
4), supporting the possible existence of equilibrating η1-allyl
copper species C and C′. Furthermore, the observation that
3,3-dialkylcyclopropenes are unreactive (entry 9, Table 2)
C
DOI: 10.1021/acs.orglett.6b02307
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Organic Letters
Letter
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upon which three-component coupling reactions might be
developed. Endeavors toward this direction are currently
underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02307.
Detailed experimental procedure, characterization data,
and NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
(11) Gonzal
Chem., Int. Ed. 2015, 54, 12139−12143.
́ ́ ́
ez, M. J.; Gonzalez, J.; Lopez, L. A.; Vicente, R. Angew.
■
Corresponding Authors
(12) (a) Xiong, T.; Li, Y.; Bi, X.; Lv, Y.; Zhang, Q. Angew. Chem., Int.
Ed. 2011, 50, 7140−7143. (b) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.;
Li, Y.; Zhang, H.; Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51,
1244−1247. (c) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun,
K.; Liu, Q.; Zhang, Q. Angew. Chem., Int. Ed. 2013, 52, 2529−2533.
(d) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.; Zhang, Q. Angew. Chem.,
Int. Ed. 2014, 53, 11079−11083. (e) Zhang, G.; Xiong, T.; Wang, Z.;
Xu, G.; Wang, X.; Zhang, Q. Angew. Chem., Int. Ed. 2015, 54, 12649−
12653.
*E-mail: zhaojb100@nenu.edu.cn.
*E-mail: zhangq651@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21372041 and 21402025), the Fundamental Research
Funds for the Central Universities (2412015KJ014), and Key
Laboratory of Synthetic and Self-Assembly Chemistry for
Organic Functional Molecules, Shanghai Institute of Organic
Chemistry, CAS (K2015-12) for generous financial support.
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