Csp3-P versus Csp2-P bond formation: Catalyst-controlled highly regioselective tandem reaction of Ene-Yne-ketones with H-phosphonates

Article abstract of DOI:10.1021/acs.orglett.5b03415

Under copper-catalyzed or base-promoted conditions, a wide range of ene-yne-ketones react with H-phosphonates to afford various phosphorylated furans in good yields. A copper carbene generation or a Michael addition is proposed as the key step in the sele

Full text of DOI:10.1021/acs.orglett.5b03415

Letter
pubs.acs.org/OrgLett
3
2
Csp −P versus Csp −P Bond Formation: Catalyst-Controlled Highly
Regioselective Tandem Reaction of Ene-Yne-Ketones with
H‑Phosphonates
Yue Yu, Songjian Yi, Chuanle Zhu, Weigao Hu, Bingjie Gao, Yang Chen, Wanqing Wu,*
and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
*
S Supporting Information
ABSTRACT: Under copper-catalyzed or base-promoted con-
ditions, a wide range of ene-yne-ketones react with H-
phosphonates to afford various phosphorylated furans in
good yields. A copper carbene generation or a Michael addition
is proposed as the key step in the selective construction of the
3
2
Csp −P or Csp −P bond, which is supported by carbene
3
1
capture reactions and interval P NMR experiments.
Furthermore, this method features inexpensive metal catalysts, no usage of oxidant, and high atom economy, which make it
attractive and practical.
hosphorylated heterocycles and derivatives represent an
Scheme 1. Synthesis of P-Containing Heterocycles from
P
important class of molecules that are closely related to life
Alkenes or Alkynes through C−P Bond Formation
1
science. Recent studies have revealed that heterocycles
containing P-substituents show unique bioactivities and chemical
2
properties, which lead them to broad applications in organic
3
4
5
synthesis, medicinal chemistry, and materials chemistry. In
light of this, the development of more efficient and concise
synthetic methods for C−P bond construction on heterocycles is
6
highly desirable. In the past years, tremendous efforts have been
made toward the synthesis of phosphorylated heterocycles
through C−P bond construction from simple materials like
alkenes or alkynes. Several extensively valuable methods have
been established and developed. For example, Ag-catalyzed
radical cascade reactions have provided useful approaches to
synthesize phosphorylated oxindoles, coumarins, aza-decenones,
and so on. These reactions were initiated by the addition of P-
centered radicals to unsaturated alkenes or alkynes, constructing
3
2
7,8
the corresponding Csp −P or Csp −P bond. However, an
extra oxidant was needed in most of these methods, and the
substituted alkenes or alkynes, which have been reported to
afford the corresponding phosphorylated heterocycles, were still
very limited (Scheme 1a).
3
phosphorylated furans via Cu-catalyzed Csp −P or base-
2
promoted Csp −P bond construction between ene-yne-ketones
13
and H-phosphonates. To the best of our knowledge, the
selective construction of different C−P bonds to afford P-
containing heterocycles from the same starting materials by a
catalyst selection has not been reported before (Scheme 1b).
At the outset of our studies, we treated ene-yne-ketone 1a with
diethyl phosphite (2a) as the model substrates for reaction
development (Table 1). Initially, 3aa was obtained in 71% yield
under simple conditions, where CuBr was used as the catalyst in
Furan derivatives are important frameworks of many bio-
9
logically active molecules and drug intermediates. However,
synthetic methods of phosphorylated furans from alkenes or
10
alkynes have been less explored until now. Previously, our
group contributed to the study of the synthesis of highly
11
functionalized furans using alkynes as a building block. Among
1
2
Et O at 80 °C for 2 h (entry 1). The organic base DIPEA was
found to increase the yield to 89% (entry 2). Notably, when
Cs CO was added as a base, 4aa was detected while the yield of
these substituted alkynes, conjugated ene-yne-ketone is
supposed to be an active and innovative substrate because it is
not only a carbene precursor under transition-metal-catalyzed
conditions but also a Michael addition acceptor due to the α,β-
unsaturated ketone moiety. We herein report an efficient and
highly regioselective strategy for the synthesis of various
2
2
3
Received: November 29, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope for the Formation of (Furan-2-
ylmethyl)phosphonates
b
b
entry
[Cu]
base
yield of 3aa (%)
yield of 4aa (%)
1
2
3
4
5
6
7
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
71
nd
c
DIPEA
89 (87)
trace
39
nd
Cs CO
2
58
3
K CO
2
19
3
DABCO
t-BuOLi
Cs CO
trace
12
48
32
nd
62
2
3
e
d
8
Cs CO
2
nd
92 (89)
3
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), [Cu] (10 mol
), base (1.5 equiv), and 1.0 mL of Et O at 80 °C for 2 h unless
%
2
b
otherwise noted. Yields were analyzed by GC-MS using n-dodecane
as an internal standard. N,N-Diisopropylethylamine. 0.5 equiv. 100
c
d
e
°C for 1 h in DMF.
3
aa dropped dramatically (entry 3). Similar results were also
obtained when K CO , DABCO, or t-BuOLi was used (entries
2
3
4
−6). We suspected that a certain strong base might change the
a
Cs CO as the base, 4aa was also isolated with a yield of 27%.
Detected by GC/MS using n-dodecane as an internal standard.
2
3
reaction pathway in this catalytic system, and the copper salts
should not play a role in the formation of 4aa (see Supporting
Information for details). As expected, a single product of 4aa was
b
gained in 62% yield with only Cs CO as the base and without
CuBr as the catalyst (entry 7). Further investigation indicated
2
3
We next examined the scope of the synthesis of 4 through
Cs CO -promoted phosphonation and annulation. As shown in
2
3
that adding 0.5 equiv of Cs CO and heating at 100 °C for 1 h in
2
3
Scheme 3, a series of H-phosphonates afforded the correspond-
ing phosphorylated furans in good yields (4aa−4ac). Diphenyl-
phosphine oxide was also a suitable substrate for this cyclization,
by adding 1.5 equiv of Cs CO and heating for 12 h, and the
DMF led to the highest yield of 4aa (entry 8).
With the optimized reaction conditions in hand (Table 1,
entry 2), we first evaluated the scope for the formation of (furan-
2
3
2-ylmethyl)phosphonates (Scheme 2). In regard to the H-
target product 4ae was isolated in 46% yield. We then
2
3
2
phosphonates, dialkyl H-phosphonates (2a−2c and 2f) and
diphenyl H-phosphonates (2d) all could be used as the
substrates, generating the corresponding alkylphosphonates
investigated the scope of R and R groups. For R = OEt,
Scheme 3. Substrate Scope for the Formation of Furan-3-
ylphosphonates
(
3aa−3ad and 3af) in 64−87% yields. It is worth noting that
diphenylphosphine oxide can also be applied to the preparation
of alkyldiphenylphosphine oxide in 63% yield by using Cs CO
2
3
3
as the base, which should be a good supplement to the Csp −P
bond formation methods. The scope of this transformation was
next explored by using various ene-yne-ketones 1b−1m and 2a.
2
3
The influence of the R and R groups, which are adjacent to the
carbonyl moiety, were studied. This novel transformation
2
showed high functional group tolerance (such as R = OMe,
t
2
3
2
3
OEt, O Bu, NHMe, OCH CHCH ; R = R = Et; R = OEt, R =
2
2
Ph), and in most cases, the corresponding products (3ba−3fa,
ha−3ia) were obtained in good yields. Notably, the mixture of
E)- and (Z)-ene-yne-ketones afforded the single products, and
only the ketone carbonyl oxygen acted as a nucleophile in the
3
(
1
2c
cyclization.
Thus, to examine the regioselectivity, we
synthesized 1g for this transformation. Intriguingly, the desired
products 3ga and 3ga′ were obtained in 68% yield with a
regioselectivity of more than 10:1. We supposed that steric
hindrance acted as an important factor in this case. Moreover, the
4
reaction was found to tolerate a broad range of R groups on the
alkyne terminus, including substituted arenes and alkanes (3ja−
3
ma). Intriguingly, 5-phenyl-2-pivaloylpent-2-en-4-ynenitrile
(1n) could be also converted into 3na in 37% yield by Cu
a
catalysis.
1.5 equiv of Cs CO was used for 12 h.
2
3
B
DOI: 10.1021/acs.orglett.5b03415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
3
2
3
NHMe, R = R = Et, or R = OEt, R = Ph, the ene-yne-ketones
phosphonate 2a, and Cs CO was added into a solvent of N,N-
2
3
afforded the corresponding products in good yields (4ca, 4ea,
dimethylformamide-d . The sample was immediately tested for a
7
31
4ha, 4ia). Similarly, only the ketone carbonyl oxygen acted as
P NMR spectrum. The first spectrum showed a single signal at
.31 ppm, which was assigned as the starting material 2a. After
nucleophile in this process. Furthermore, substituted aryl alkynes
and alkyl alkynes participated in this transformation, as well, thus
leading to the furans 4ja−4ma in moderate yields. When 1n and
7
being heated at 100 °C for 5 min, the expected phosphorylated
product 4aa was produced (single peaks at 13.03 ppm), while
four other new peaks at 12.73, 12.42, 12.23, and 12.12 ppm
2
a were used in the Cs CO -promoted reaction system, the
2 3
transformation afforded diethyl (2-benzyl-4-cyano-5-methylfur-
an-3-yl)phosphonate (4na), albeit with lower efficiency.
To gain more insight into the Cu-catalyzed alkyl phosphona-
tion reaction, we first conducted radical capture reactions by
adding a radical-trapping reagent (TEMPO) or a radical inhibitor
31
appeared at the same time. As time passed, the P NMR signals
of 2a disappeared gradually and the signals of 4aa increased.
Importantly, the four uncertain peaks faded away as well in 50
min. Thus, we inferred that the signals might belong to the
reaction intermediates A , B , C , and D (see the proposed
2
2
2
2
(
BHT) to the reaction system. Under the above two conditions,
catalytic cycle in the Supporting Information). However, we
could not determine the four signals in these stacked spectra. The
reaction was completely finished after 1 h according to the
spectra (Figure 1).
the formation of 3aa was unaffected on the whole. These
observations indicated that there should not be a radical pathway
in this reaction (Scheme 4, eq 1). To confirm whether a copper
Taking the experimental results into account, we proposed the
mechanisms for the synthesis of 3 or 4 (see the proposed catalytic
cycle in the Supporting Information). For reaction (i), the alkyne
moiety of ene-yne-ketone 1a was activated by the copper species
at first, which was then attacked by the carbonyl oxygen through
Scheme 4. Mechanistic Studies
5
-exo-dig cyclization, leading to copper carbene species A . In the
1
presence of phosphinous acid 2a′, the tautomeric form of H-
phosphonate 2a, carbene intermediate A was trapped to form
1
15
the copper-associated ylide B1. Then, a copper carbene
migratory insertion process was followed to give intermediate
C . Finally, the phosphonation product 3aa was obtained by
1
catalyst dissociation and the Cu(I) species was regenerated. On
the other hand, reaction (ii) began with the process of Michael
addition between ene-yne-ketone 1a and H-phosphonate 2a
using Cs CO as the base, leading to intermediate A and allenyl
2
3
2
16
intermediate B2. Afterwards, a subsequent nucleophilic attack
carbene intermediate existed, we performed the reaction in the
absence of 2a to give the (2-furyl)carbene complex, which further
underwent oxidation or hydrolysis to generate 5aa in 44% yield.
What’s more, when ethyl diazoacetate (6a) was used to replace
by the carbonyl oxygen atom generated intermediate C . In the
2
presence of Cs CO , a deprotonation occurred to produce the
2
3
intermediate D , followed by a protonation to give the final
2
phosphorylated furan 4aa.
In summary, we have developed a highly efficient protocol for
2a under the standard conditions, vinyl furan 7aa was obtained in
4
7% yield. On the basis of these studies and several previous
the preparation of various phosphorylated furans via a Cu-
1
2a,14
reports,
we deduced that a copper carbene complex was
3
2
catalyzed Csp −P or base-promoted Csp −P bond formation,
involving 5-exo-dig cyclization, carbene migratory insertion, and
Michael addition. Not only H-phosphonates but also diphenyl-
phosphine oxides react with a wide range of ene-yne-ketones to
afford the products in moderate to good yields under mild
reaction conditions. Furthermore, no use of oxidant, high atom
economy, and good regioselectivity of products via catalyst-
controlled make this method a new valuable approach for the
formation of precious C−P bonds. Mechanistic studies including
possibly formed during this cascade process (Scheme 4, eqs 2 and
).
On the other hand, to analyze the reaction process for the
3
synthesis of 4aa, we tried to trap the intermediates but failed
since the transformation was a rapid process. Thus, the reaction
31
was traced by P NMR spectroscopy, as shown in Figure 1. In a
nuclear magnetic tube, a mixture of ene-yne-ketone 1a, H-
3
1
radical or carbene capture reactions and interval P NMR
experiments have been conducted to clarify the reaction
pathways. Further applications of this reaction are currently
underway in our laboratory.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03415.
Experimental section, characterization of all compounds,
1
13
and copies of H and C NMR spectra for selected
compounds (PDF)
Figure 1. 31P NMR stacked spectra for the formation of 4aa.
C
DOI: 10.1021/acs.orglett.5b03415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Niu, Y.; Zhao, X.-L.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 4350−
AUTHOR INFORMATION
■
*
*
4
354. (i) Zhou, L.; Zhang, M.; Li, W.; Zhang, J. Angew. Chem., Int. Ed.
014, 53, 6542−6545.
Corresponding Authors
2
E-mail: cewuwq@scut.edu.cn.
E-mail: jianghf@scut.edu.cn.
(13) For H-phosphonates, see: (a) Zhou, Y.; Yin, S.; Gao, Y.; Zhao, Y.;
Goto, M.; Han, L.-B. Angew. Chem., Int. Ed. 2010, 49, 6852−6855.
(b) Xu, W.; Hu, G.; Xu, P.; Gao, Y.; Yin, Y.; Zhao, Y. Adv. Synth. Catal.
Notes
2
014, 356, 2948−2954. (c) Kong, W.; Merino, E.; Nevado, C. Angew.
The authors declare no competing financial interest.
Chem., Int. Ed. 2014, 53, 5078−5082. (d) Wei, W.; Ji, J.-X. Angew. Chem.,
Int. Ed. 2011, 50, 9097−9099. (e) Zhang, C.; Li, Z.; Zhu, L.; Yu, L.;
Wang, Z.; Li, C. J. Am. Chem. Soc. 2013, 135, 14082−14085. (f) Thielges,
S.; Bisseret, P.; Eustache, J. Org. Lett. 2005, 7, 681−684. (g) Evano, G.;
Tadiparthi, K.; Couty, F. Chem. Commun. 2011, 47, 179−181.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21420102003 and 21472051) and the
Fundamental Research Funds for the Central Universities
(h) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756−
760. (i) He, Y.; Wu, H.; Toste, F. D. Chem. Sci. 2015, 6, 1194−1198.
(j) Gao, Y.; Li, X.; Xu, J.; Wu, Y.; Chen, W.; Tang, G.; Zhao, Y. Chem.
Commun. 2015, 51, 1605−1607. (k) Yang, J.; Chen, T.; Zhou, Y.; Yin, S.;
Han, L.-B. Chem. Commun. 2015, 51, 3549−3551. (l) Zhang, H.-Y.;
Mao, L.-L.; Yang, B.; Yang, S.-D. Chem. Commun. 2015, 51, 4101−4104.
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DOI: 10.1021/acs.orglett.5b03415
Org. Lett. XXXX, XXX, XXX−XXX