Arylphosphonate-Directed Ortho C-H Borylation: Rapid Entry into Highly-Substituted Phosphoarenes

Article abstract of DOI:10.1021/jacs.0c04159

Phosphonate-directed ortho C-H borylation of aromatic phosphonates is reported. Using simple starting materials and commercially accessible catalysts, this method provides steady access to o-phosphonate arylboronic esters bearing pendant functionality and flexible substitution patterns. These products serve as flexible precursors for a variety of highly substituted phosphoarenes, and in situ downstream functionalization of the products is described.

Full text of DOI:10.1021/jacs.0c04159

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Communication
Aryl Phosphonate-Directed Ortho C–H Borylation:
Rapid Entry into Highly-Substituted Phosphoarenes
Feiyang Xu, Olivia Duke, Daniel Rojas, Hanka Eichelberger,
Raphael S. Kim, Timothy Bryan Clark, and Donald A. Watson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04159 • Publication Date (Web): 27 Jun 2020
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Aryl Phosphonate-Directed Ortho C–H Borylation: Rapid Entry into
Highly-Substituted Phosphoarenes
Feiyang Xu,†‡ Olivia M. Duke,† Daniel Rojas,† Hanka M. Eichelberger,†‡ Raphael S. Kim,† Timothy B.
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Clark,*‡ and Donald A. Watson*†
†Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716 (USA)
‡Department of Chemistry and Biochemistry, University of San Diego, San Diego, CA 92110 (USA)
ABSTRACT: Phosphonate-directed ortho C–H borylation of aromatic phosphonates is reported. Using simple starting materials and
commercially accessible catalysts, this method provides steady access to ortho-phosphonate aryl boronic esters bearing pendant func-
tionality and flexible substitution patterns. These products serve as flexible precursors for a variety of highly-substituted phos-
phoarenes, and in situ downstream functionalization of the products is described.
Aryl phosphonates are useful motifs in organic synthesis as
their versatility allows for transformation into a number of func-
tional groups, including phosphines, phosphoramidates, and
phosphorus oxides.1-2 Additionally, some aryl phosphonates
and related compounds have also shown interesting bioactivi-
ties,3-5 including in the clinical treatment of various cancers.6
Over the last couple decades, directed C–H borylation has
emerged as a powerful tool to prepare ortho-substituted aryl bo-
ronic esters from simple starting materials.20-22 A variety of di-
recting groups have been demonstrated in this field, including a
number of carbonyls,23-27 Lewis basic nitrogens,23, 26-32 phe-
nols,33 silanes,34-35 thianes,36-39 ethers,23, 26, 40 and halides.23 We
envisioned phosphonate-directed ortho-borylation as an attrac-
tive platform for the preparation of a variety of ortho-function-
alized aryl phosphonates (Figure 1). A general method to con-
vert widely accessible simple aryl phosphonates into ortho-
boryl phosphonates, when combined with the vast chemistry of
aryl boronates, would allow for the facile preparation of a wide
variety of ortho-functionalized aryl phosphonates and their
downstream derivatives.
Due to their value, several strategies have been reported to
prepare aryl phosphonates. However, current methods to gener-
ate functionalized aryl phosphonates typically involve the con-
struction of the C–P bond via pre-functionalized starting mate-
rials such as organolithium or Grignard reagents,7 (pseudo)hal-
ides,8-12 boronic acids,13-15 carboxylic acids,16 or hypervalent io-
dine compounds.17-18 These methods are often limited by the
availability of the starting materials, and thus only aryl phos-
phonates with simple structures can be synthesized readily.
More complex aryl phosphonates, such as the ones bearing or-
tho-substitutions, are often very challenging to access for this
reason. One attractive route to the synthesis of highly-substi-
tuted phosphonates is via ortho-boryl aryl phosphonates, as
these products are readily diversified and are able to be con-
verted into a range of phosphoarenes. However, like the other
methods mentioned above, current routes to these intermediates
require multiple steps to access (Figure 1).19
Previously, we have shown that benzyl phosphines can be
used as directing groups for C–H borylation, which provides
access to ortho-borylated benzylic phosphines.41-42 Later, Shi
and Takaya independently reported C–H borylation conditions
to prepare ortho-borylated phosphines via the use of an aryl
phosphine as a directing group.43-44 However, these latter meth-
ods are limited to phosphines bearing a single type of aromatic
group. Moreover, no reactivity was observed with substrates
bearing pre-existing ortho-substitutions. Thus, there is a clear
need to have an alternative way to prepare these ortho-borylated
phosphoryl aromatic compounds that can overcome these limi-
tations. In this paper, we describe the successful realization of
that goal, and report conditions for the preparation of ortho-
phosphonate aryl boronic esters via a C–H borylation strategy
using phosphonate as a directing group. Using easily accessed
starting materials and commercially available catalytic compo-
nents, we show that the reaction enjoys broad functional group
tolerance and is highly flexible in regard to substitution pat-
terns.
Previous Ortho-Boryl Aryl Phosphonate Synthesis: multi-step route required
Br
Br
O
P
Bpin O
P
I
OEt
OEt
OEt
OEt
R
R
R
H
H
H
59-63%
This Work: aryl phosphonate-directed C−H borylation
R2
R2
H
O
P
Bpin O
P
R
P
O
P
R2X
cat. Ir
OEt
OEt
OEt
OEt
OEt
OEt
R
B2pin2
R1
R1
R1
R1
● simple catalytic components & easily acessible starting materials
● broad functional group tolerance & flexible substitution pattern
● versatible functionalization of products
Our studies began with the borylation of commercially avail-
able diethyl phenylphosphonate, and the preliminary screen of
iridium catalysts revealed (COD)Ir(acac) as the optimal iridium
source (see Supporting Information). The use of [(COD)2Ir]BF4
provided comparable results, but the selection of (COD)Ir(acac)
is advantageous because it is bench stable and less expensive.
Figure 1. Previous Synthesis of Ortho-Boryl Aryl Phosphonates
and Our Design.
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We then examined the effects of ligand with the model substrate
isomer is in itself notable. This result suggests that the primary
selectivity is steric in nature, but the fact that borylation para to
the phosphonate is not observed also suggests a strong elec-
tronic differentiation between the methyl and phosphonate
groups.
1
2
3
4
1, an aryl phosphonate substituted at the ortho position (Table
1). The ortho-borylation of 1 would produce the highly-substi-
tuted phosphonate 2, whose substitution pattern would be diffi-
cult to access using other methods.
5
6
7
8
Table 1. Reaction Optimization.
Excitingly, however, when the phosphine/silane-based bi-
dentate ligand previously reported by Smith, Maleczka, and
Krska was used, we observed 31% yield of 2 (entry 5).26 Despite
the encouraging result using this ligand, we continued to ex-
plore other options as we recognized that use of a commercially
available ligand would make the method more broadly useful.
Therefore, we explored simple phosphine ligands as an alterna-
tive. Although PPh3 did not provide any of the ortho-borylation
product (entry 6), with more electron-deficient triaryl phos-
phines we started to observe the desired ortho selectivity (entry
7-8). Following this trend, we finally identified the use of P[3,5-
(CF3)2-C6H3]3 in this reaction, which has the optimal balance of
electronic and steric properties, affording 2 in 84% yield (entry
9).24,45
5 mol % (COD)Ir(acac)
5 mol % ligand
Bpin
O
P
O
P
O
P
OEt
OEt
Me
OEt
pinB
OEt
OEt
Me
+
OEt
2 equiv B2pin2
THF/dioxane, 100 °C, 24 h
Me
2
9
1
3
10
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23
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entry
ligand
no ligand
2-picolylamine
dtbpy
yield of 2 yield of 3
1
2
3
4
5
6
7
8
9
0%
0%
7%
4%
0%
41%
38%
0%
tmphen
P[2-Si-(iPr)2H-C6H4](o-tol)2
0%
31%
0%
PPh3
7%
With optimized reaction conditions developed, the scope of
this reaction was then investigated (Scheme 1). The borylated
phosphonate 2 was isolated in 78% yield on 1 mmol scale. Dur-
ing purification, we observed some loss of product due to the
unstable nature of boronic esters, but such an effect can be min-
imized by running the reaction at larger scales. For example,
scaling the same reaction up to gram scale provided 87% iso-
lated yield of 2.
P(4-F-C6H4)3
4%
0%
P(4-CF3-C6H4)3
P[3,5-(CF3)2-C6H3]3
4%
0%
84%
0%
a Yield determined by 1H NMR analysis with 1,3,5-trimethoxyben-
zene as internal standard.
Various ligands were examined in conjunction with
(COD)Ir(acac) as catalyst. We began by investigating condi-
tions without added external ligand, such as those that had
shown success in our previous work on benzyl phosphine-di-
rected C–H borylation.41 However, with this catalyst system we
did not observe any ortho-borylation; instead, the borylation
took place at the meta position to give 3 (Table 1, entry 1).
Substrates without ortho-substitution next to the phosphonate
require somewhat more stringent conditions, including use of a
higher catalyst loading, use of iridium pre-catalyst with a less
coordinating counter-ion [(COD)2Ir]BF4, and elevated reaction
temperature (4). Under these conditions, however, we observed
a significant amount of bis-borylation at both ortho positions.46
To avoid the bis-borylation, we hypothesized that the use of
larger directing group could restrict the conformational rotation
of the phosphonate group in the mono-borylated product and
prevent the second C–H activation at the other ortho position.
This idea is supported by the use of diisopropyl phosphonate,
only mono-borylated product is produced (5).
Moving forward, very little reactivity was observed with 2-
picolylamine as ligand, the ligand used in our benzyl amine-
directed C–H borylation (entry 2).30 Although we found that the
borylation was more efficient with bipyridine ligands, such as
dtbpy and tmphen that have often been used in aryl borylation,
there was still no formation of the desired ortho-borylated prod-
uct (entry 3-4). The selective formation of the meta-borylation
5 mol % (COD)Ir(acac)
5 mol % P[3,5-(CF3)2-C6H3]3
O
Bpin
O
P
P
OR
OR
OR
OR
2-5 equiv B2pin2
THF/dioxane, 100 °C, 3-24 h
Bpin O
Bpin
O
Bpin O
P
Bpin
O
P
Bpin
O
P
Bpin O
P
Bpin O
P
Bpin O
P
Bpin O
P
P
OEt
OEt
P
OEt
OEt
NMe2
OEt
OEt
OiPr
OiPr
OEt
OEt
Me
OEt
OEt
OMe
a6, 74%a
OEt
OEt
Cl
10, 85%e
OEt
OEt
Br
11, 58%a,b,c
OEt
OEt
CF3
OCF3
4, 44%a,b,c
5, 51%a,b,c
Bpin O
a7, 90%a
a8, 60%a
a2, 78%a
87% (gram scale)
9, (99%)d
Bpin O
P
Bpin O
Bpin O
P
Bpin O
P
Bpin O
Bpin O
Bpin
O
P
Bpin
O
P
OEt
OEt
P
OEt
OEt
P
OEt
OEt
OEt
OEt
OEt
P
OMe
OMe
Br
P
OPh
OPh
OEt
OEt
OMe
OEt
OEt
OMe
OEt
Cl
F
F
F
MeO
Br
CO2Me
15, (65%)a,b,d
Me
14, 61%a,b,c
OMe
16, 33%a,b,c
OMe
OMe
12, 80%a
13, (75%)d
a17, 72%a
a18, 63%a
19, 70%e
20, 76%a,e
Bpin O
Bpin
O
P
Bpin
O
Bpin O
P
Bpin
O
P
Bpin
O
P
Bpin O
P
P
OEt
OEt
OEt
OEt
OMe
P
OEt
OEt
OEt
OEt
Me
OEt
OEt
Me
F
OEt
OEt
OMe
OEt
OEt
Cl
O
Bpin
MeO
MeO
F
N
EtO
EtO
a27, 86%a
P
Cl
N
O
OMe
21, 61%a,e (91%)d
a Run with [(COD)
F
22, 38%a,e (98%)d
a23, 0%a
a24, 91%a
a25, 90% (X-ray)a
26, (9%)a,b,c,d
a28, 84%a
2Ir]BF4.
b 120 °C. c 7.5 mol % catalyst loading. d Parenthetical yields calculated by 1H NMR with 1,3,5-trimethoxybenzene as internal standard. e 110 °C.
Scheme 1. Scope of Phosphonate-Directed C–H Borylation
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In contrast, substrates bearing varied substitutions at the pre-
(30),49 bromides (31),49 and nitriles (32)50 by applying known
methods from the literature (Scheme 2). It is noteworthy that
the purification of the boronic esters is not required prior to
many downstream functionalizations. This is particularly im-
portant because the purification of some borylated products can
cause significant material loss due to their instabilities.
1
2
3
4
5
6
7
8
existing ortho position participate in this reaction under stand-
ard conditions and result in borylated products efficiently (6-
13), including ethers (6, 9), trifluoromethyl (7), aniline (8), and
halogens (10-13). With a bulky substitution at the ortho posi-
tion, such as bromine, we found that the reaction requires higher
catalyst loading and temperature to proceed (11), presumably
due to the limitation of conformational rotation of phosphonate
by steric congestion. We found, however, that simply switching
to the smaller dimethyl phosphonate group overcomes this lim-
itation and higher yield is observed under milder conditions
(12). Phosphonates with aromatic substitutions were also easily
borylated under the standard conditions (13); however, product
instability precluded isolation.
In addition, aryl boronic esters are reliable precursors for sub-
stituted biaryl compounds. Previously, Westcott and co-work-
ers reported conditions for Suzuki coupling to transform ortho-
boryl aryl phosphonates into biarylphosphonate substrates, such
as 33.19 The further functionalization of 33 led to the synthesis
of a dialkyl biarylphosphine ligand 34, showing the utility of
ortho-borylated aryl phosphonate products in ligand synthesis
(Scheme 3).51
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With meta-substituted aryl phosphonates, the borylation only
occurs at the less sterically hindered site (14). These reactions
are most efficient with weakly donating or electron-withdraw-
ing groups at the meta position (15). With a strong electron-
donating group at the meta position, yield of the borylated prod-
uct is lower (16).47 However, these electronic effects appear to
be very sensitive. Simple inclusion of a weak electron-with-
drawing group in the substrate mitigates the effects of the meta
donor group (17-18).
Me
Br
O
OMe
P
Bpin
O
P
OEt
2 steps
Ref. 19
P
OEt
OEt
OEt
BH
·
3
Me
OMe
Pd/L
base
OMe
4
34
Known Ref. 19
33, 56%
Scheme 3. Biaryl Phosphonate Synthesis and Their Utility in
Ligand Synthesis
Finally, we wished to compare the relative directing group
ability of phosphonates to esters (Scheme 4).24 Under the stand-
ard and related conditions (see Supporting Information), boryla-
tion ortho to the ester (36) is preferred and mono-borylation or-
tho to the phosphonate was not observed. Interestingly, how-
ever, subsequent borylation at that site appears to be competi-
tive (37).
Aryl phosphonates bearing di-substitutions at other positions
can also participate in this reaction (19-20), and even highly-
substituted substrates could be converted to the borylated prod-
ucts with good efficiencies (21-22). As with other directed C–
H borylation reactions, this reaction is sensitive to steric effects.
We did not observe reactivity with alkyl substitution next to the
reactive C–H bond (23). However, with a smaller substitution,
such as fluorine, high yields of the desired product are observed
(24). A naphthyl substrate also works well under these reaction
conditions and can be borylated in 90% isolated yield (25). One
limitation that we have found with this reaction is that Lewis
basic heterocycles, such as pyridine, were not tolerated and re-
sulted in only minimal conversion (26). However, less-basic
heterocycles are tolerated (27-28).
MeO
O
MeO
O
MeO
O
O
P
O
P
O
P
a
pinB
OEt
OEt
pinB
OEt
+
OEt
Bpin
37, 42%
OEt
OEt
35
36, 38%
a 5 mol % (COD)Ir(acac), 5 mol % P[3,5-(CF3)2-C6H3]3, 5 equiv B2pin2, THF/dioxane, 100
°C, 24 h; yields calculated by 1H NMR with 1,3,5-trimethoxybenzene as internal standard.
Scheme 4. Comparison Between Phosphonate and Ester
OH
O
Cl
O
P
P
OEt
OEt
OEt
In conclusion, we developed conditions for C–H borylation
using phosphonate as a directing group, which allows the prep-
aration of ortho-phosphonate aryl boronic esters from simple
starting materials. This reaction uses commercially available
catalytic components and has a broad functional group toler-
ance. Using this method, highly-substituted aryl phosphonates
can be prepared, which is a known synthetic challenge in this
field.
OEt
Cl
MeO
F
F
O
OMe
29, 51%
30, 61%
a
b
O
P
Bpin
O
P
cat. Ir
OEt
OEt
OEt
OEt
R
B2pin2
R
d
c
ASSOCIATED CONTENT
CN
O
P
Br
O
P
OEt
OEt
OEt
OMe
Supporting Information
OEt
MeO
The Supporting Information is available free of charge on the ACS
Publications website.
OMe
31, 65%
32, 61%
a NaOH, H2O2, 0 °C to rt. b CuCl2, acetone/H2O, 90 °C. c CuBr2, acetone/H2O, 90
°C. d Zn(CN)
, Cu(NO3)2•3H2O, CsF, MeOH/H2O, 100 °C.
Experimental procedures and spectra data (PDF)
Crystallographic data for compound 25 (CIF)
AUTHOR INFORMATION
2
Scheme 2. In Situ Downstream Functionalization
As one of the most versatile functional groups in organic syn-
thesis, boronic esters can be readily converted into a range of
other structures. For example, we were rapidly able to prepare
aryl phosphonates containing ortho phenols (29),48 chlorides
Corresponding Author
*E-mail: dawatson@udel.edu
3
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15.
Hu, G.; Chen, W.; Fu, T.; Peng, Z.; Qiao, H.; Gao, Y.; Zhao, Y.,
*E-mail: clarkt@sandiego.edu
Nickel-Catalyzed C–P Cross-Coupling of Arylboronic Acids with P(O)H
1
2
3
4
5
6
7
8
Compounds. Org. Lett. 2013, 15, 5362−5365, 10.1021/ol402672e.
ACKNOWLEDGMENT
16.
Decarbonylative Phosphorylation of Carboxylic Acids via Redox-Neutral
Palladium Catalysis. Org. Lett. 2019, 21, 9256−9261,
10.1021/acs.orglett.9b03678.
17. Xu, J.; Zhang, P.; Gao, Y.; Chen, Y.; Tang, G.; Zhao, Y.,
Liu, C.; Ji, C.-L.; Zhou, T.; Hong, X.; Szostak, M.,
The University of Delaware (UD), the University of San Diego
(USD), the Camille and Henry Dreyfus Foundation, the National
Science Foundation (CHE-1800011, CHE-1764307) are gratefully
acknowledged for support. Dr. Glenn P. A. Yap (UD) and Maxwell
I. Martin (UD) are thanked for X-ray crystallography. Data was ac-
quired at UD on instruments obtained with the assistance of NSF
and NIH funding (NSF CHE-0421224, CHE-1048367, and CHE-
0840401; NIH P20GM104316, P30GM110758, S10RR02692, and
S10OD016267).
Copper-Catalyzed P-Arylation via Direct Coupling of Diaryliodonium Salts
with Phosphorus Nucleophiles at Room Temperature. J. Org. Chem. 2013,
78, 8176−8183, 10.1021/jo4012199.
18.
Lecroq, W.; Bazille, P.; Morlet-Savary, F.; Breugst, M.;
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Lalevée, J.; Gaumont, A.-C.; Lakhdar, S., Visible-Light-Mediated Metal-
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25 examples, yields up to 91%
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! broad functional group tolerance & flexible substitution pattern
! versatible product functionalization
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