Copper-catalyzed allylic C-H phosphonation

Article abstract of DOI:10.1039/c4ob02687j

An efficient copper-catalyzed allylic C-H phosphonation reaction has been developed under mild reaction conditions. This method exhibits high regioselectivity and stereoselectivity. Various alkenes with useful functional groups are compatible in this tran

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Copper-Catalyzed Allylic C-H Phosphonation
Bin Yang,a Hong-Yu Zhang,a Shang-Dong Yang*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
An efficient copper-catalyzed allylic C-H phosphonation
reaction has been developed under mild reaction conditions.
This
method
exhibits
high
regioselectivity
and
stereoselectivity. Various alkenes with useful functional
groups are compatible in this transformation. Preliminary
10 mechanistic studies reveal that the pH value and the loading
of Ag-salt were the key factors to change the composition of
products.
Introduction
Allylphosphonates are synthetic intermediates valuable for
15 application in pharmaceutical chemicals, agrochemicals, organic
synthesis, material science, as well as in biochemistry.1 As a
consequence, the development of more concise and efficient
methodologies for synthesis allylphosphonates is desirable but
presents a challenge. At present, advancements mainly include
20 hydrophosphination of allenes2 and transition-metal-catalyzed
Heck reactions3 and cross-coupling reactions with allyl-halides or
carboxylic esters.4 However, all the aforementioned methods
generally require a specifically functionalized precursor which
limits their application in scope. Recently, transition metal-
25 catalyzed allyl C-H bond functionalizations have garnered much
attention because of their wide scope and high atom economy,5, 6,
Scheme 1 Copper-catalyzed Allylic C-H Phosphonation Reaction
Results and discussion
50
Initially, our study began with allylbenzene (1a) and
diphenylphosphine oxide (2a) in the presence of 10 mol % Cu2O
and 2.0 equiv of AgOAc in DMAc at 90oC under an argon
atmosphere (Table 1, entry 1). We were very excited to find that
an allyl phosphorylated product (3aa) can be detected as the
55 major product with a mixture of other three byproducts and to our
surprise no branched products were detected. Encouraged by this
result, next we needed to improve the yield and the ratio of 3aa in
all products. Initially, the total yield improved when we reversed
the ratio of 1a and 2a, but as a result of this shift, 4aa became the
60 major product (entry 2), which indicated more phosphorus leads
hydrophosphination. Next, we employed other oxidants and
found that AgOAc was still the best choice (see the Supporting
Information). We were surprised to find that the addition of 2.0
equiv DABCO (1, 4-diazabicyclooctane) as a base, the yield and
65 the ratio improved significantly (entry 3). Other bases produced
poorer performance (entries 4-5). Reduced the loading of
DABCO to 30 mol %, the three byproducts were almost entirely
suppressed (entry 6). But if the loading of DABCO was reduced
more, we observed no improvements (entry 7). This indicates that
70 base-loading represents a crucial factor affecting selectivity.
Furthermore, lowering the reaction temperature to 70 oC,
increased the yield to 64 % (entry 8). The reaction could not
occur at a lower temperature (entry 9). When we changed the
ratio of 1a / 2a to 3: 1, the yield reached 74 % (entry 10). Notably,
75 using 3.0 equivalent AgOAc resulted in 81 % yield with a trace
amount of byproducts (entry 11). Use of more AgOAc decreased
the yield (entry 12). Other copper salts were screened, but none
7
which also provide a novel and potentially rewarding strategy
for the synthesis of allylphosphonates by direct phosphonation of
allyl C(sp3)-H bonds. To date, however, the direct allylic
30 phosphonation reaction has yet to be established. It is well known
that P(O)-H compounds are the best nucleophiles which are
easily added to the double bonds of alkenes and lead to
hydrophosphination frequently ( Path A, Scheme 1);8 indeed, the
allylic phosphonation reaction is very difficult to control.
35 Furthermore, achieving high regioselectivity and stereoselectivity
represents a giant challenge for the allylic phosphonation reaction.
In the past few years, we have been committed to unveiling novel
organophosphorus transformations,9,10b and recently we disclosed
a copper-catalyzed direct dehydrogenative allylic phosphination
40 to synthesize allylphosphonates (Path B, Scheme 1). Gratifyingly,
the hydrophosphination product is almost completely suppressed
in our reaction. It is worth noting that high regioselectivity and
stereoselectivity are also achieved in our reaction system. In
addition, our new reaction starts with simple allyl-compounds
45 without pre-functionalizing and shows good functional group
tolerance.
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performed better than Cu2O (entries 13-15). It is important to 30 applicable (3oa) and it provided the condition for a further
note that in the absence of AgOAc or Cu2O in the reaction system,
we only got 4aa (entries 16-17). Without addition of DABCO,
the yield of product decreased to 21% with relative lower ratio
(entry 18). Supporting Information lists optimization information
in more detail.
transformation. The p-toluenesulfonyl (Ts) ether protecting group
was also tolerated, but with a lower yield (3pa). Remarkably, the
aldehyde group (3qa), which is incompatible under oxidative
conditions, still remained intact in this reaction. The free
35 hydroxyl (3ra) was also unaffected and the desired product was
obtained in a moderate yield. To our delight, the internal alkene
cyclohexene could also react with 2a, thus affording the
corresponding phosphorylate cycloalkene structure (3sa). In
5
Table 1 Reaction Conditions Screening.a
addition
to
diphenylphosphine
oxide
(2a),
ethyl
40 phenylphosphinate (2b) and diethyl phosphite (2c) were also
candidates for this transformation, underwent phosphorylation to
obtain products 3db, 3dc but with lower yields.
Table 2 Scope of Allylic Phosphorylation a, b ,c
a
The reactions were conducted on a 0.2 mmol scale under the following
reaction conditions: 1a, 2a, Cu (10 mol %), AgOAc, DMAc (2.0 mL) and
10 additive under Ar for 10h, DMAc= N, N-dimethylacetamide; b Total yield
of isolated products; c Determined by 1H NMR and 31P NMR.
Upon optimization of the reaction conditions, we examined
the scope of this reaction and found that a series of olefins were
15 applicable to the transformation (Table 2). In most of the
reactions, we observed that compound 3 was generated as the
major product, whereas compounds 4, 5 and 6 were produced as
byproducts. The reaction of simple alkenes with different carbon
chain lengths proceeded efficiently (3ba-3fa). For the
20 cycloalkane-substituted alkenes, we observed good yields and
few byproducts regardless of whether the double bonds were
located in the ring or outside the ring (3ga and 3ha). The 4-
Allylanisole and 4-Phenyl-1-butene underwent the reaction
smoothly and produced moderate- to good yields (3ia and 3ja). A
25 range of functional groups, including amide (3ka),
heteroaromatic rings (3la), and ester (3ma) was also tolerated
well in this reaction. When we changed the substituent to phenyl
ether (3na), the major products became 3 and 5 with a ratio of 1:
1. It is worth noting that the halogen-substituted olefin was also
a
alkene 1 (0.6 mmol), 2 (0.2 mmol), Cu2O (10 mol %), AgOAc (0.6
45 mmol), DABCO (30 mol %) in 2 mL DMAc at 70 oC for 10h; b The given
yield represents the total yield of four products; c The ratio of 3:4:5: 6 was
determined by 31P NMR and is shown in the parentheses.
2
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The simplicity and convenience of the metal-catalyzed direct
C-H functionalization approach lends itself well to wide
applications within the fields of natural products modification.
Phosphonation is a common method used in medicinal and
ligand-synthesis; indeed, direct allylic phosphonation may prove
quite useful. To demonstrate the potential, we subjected the
derivative of estrone (3t) to copper-catalyzed allylic C-H
phosphonation conditions (Scheme 2). The allylic phosphonation
product 3ta was isolated in 40 % yield. The natural product D(+)-
5
10 Carvone (3u) also underwent the reaction smoothly and produced
3ua with high regioselectivity which may be potential chiral
P/olefin ligand.
45
Scheme 3 Control experiments
Scheme 2 Direct Phosphonation of Derivatives of Natural Product
found that the major product changed from 4aa to 3aa gradually
along with the increase of AgOAc-equivalents. When the above
experimental results were combined (Scheme 3, b), we speculated
15
In order to gain insight into the mechanism of this
transformation, preliminary mechanistic studies were carried out.
First, we surveyed a series of control experiments. In the radical
trapping experiments (a, Scheme 3), the reaction was completely
suppressed in the presence of 2.0 equiv. TEMPO or BHT.
50 that in addition to the formation of complex 9, AgOAc might be
used as an oxidant to promote the cycle of CuI to CuII.
20 Furthermore, the addition of 1, 1-diphenylethylene (7) led to a
compete reaction, yielding the alkenyl diphenylphosphine oxide 8.
The above results indicate that a [P(O)Ph2] radical was involved
in this reaction. We deduced that the first step involves
phosphonation with AgOAc.10 Thus, some experiments of allylic
25 phosphonation with AgP(O)Ph2 were carried out (b, Scheme 3).
When [Ph2P(O)Ag] 9 replaced 2a, 3aa could be obtained
smoothly under standard conditions. It is important to note that
adding 1.0 equiv HOAc to such reaction, the selectivity was
significantly improved. This result implies that the pH of the
30 reaction system may be a key factor to change the composition of
products. In addition, when employing 9 as substrate in the
absence of AgOAc, no products were detected. This indicates that
AgOAc plays roles beyond the formation of complex 9.
Second, in order to arrive at a clear understanding of this
35 reaction, we tested the pH value of the reaction system at
different time points. As shown in the chart (Figure 1, C-A), the
pH value of the proceeding reaction system gradually declined in
the first three hours until it reached its lowest value. The pH
value rose from this point as the reaction continued and then
40 maintained a stable value. This result proves that over the course
of the reaction HOAc was first generated and then neutralized.
Third, in the process of optimizing the reaction, we found that
major product differed depending on what equivalents of AgOAc
we used (Figure 1, C-B). When we ignored other byproducts, we
Figure 1 (C-A): pH values at different time points. (C-B): Composition
of 3aa + 4aa under different equivalents of AgOAc.
55
Based on the above analysis, we proposed a plausible pathway
involving a free phosphorus radical species (Scheme 4). Initially,
diphenylphosphine oxide 2a reacts with AgOAc to form the
complex 9.10 In the presence of a small amount of AgOAc,
hydrophosphination becomes the main reaction to form 4aa. Our
60 previous experiments have further proved this result (Figure 1, C-
B). The reactive species A is then generated from 9.10, 11 Next, the
addition of P-radical A to 1a gives the allyl radical intermediate
B. Subsequently, an allyl-cation type C is formed via a single-
electron transfer (SET) process. Finally, coordinated by base,
65 selective deprotonation of C results in the desired product 3aa
and the isomers 5aa, 6aa. In this pathway, the pH value which
was regulated by the base and the loading of AgOAc may be the
decisive factor in the composition of products. However, the
exact role of the base is still unclear.
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55
60
Scheme 4 Plausible Mechanistic Pathway
65
Conclusions
In summary, we have developed an efficient and selective
copper-catalyzed oxidative phosphonation reaction. In this
transformation, the formation of C (sp3)-P bond is achieved.
Under mild conditions, a variety of allylic phosphinylated
products were obtained in high regioselectivity and
stereoselectivity. Further investigations to clarify the reaction
5
70
10 mechanism are currently underway in our laboratory.
75
Acknowledgements
We are grateful for the NSFC (Nos. 21272100) and, FRFCU
(lzujbky-2013-ct02, PCSIRT (IRT1138), and Program for New
Century Excellent Talents in University (NCET-11-0215 and
15 lzujbky-2013-k07) financial support. We thank S. F. Reichard,
MA for editing the manuscript.
80
85
Notes and references
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China. Fax: (+)86-931-8912859; Tel: (+)86-931-
20 8912859; E-mail: yangshd@lzu.edu.cn
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, 730000, P. R. China.
† Electronic Supplementary Information (ESI) available: See
25 DOI: 10.1039/b000000x/
‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
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