Palladium-Catalyzed C-H Bond Functionalization Reactions Using Phosphate/Sulfonate Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.joc.9b01278

A new and operationally simple approach for palladium-catalyzed C-H functionalization reactions utilizing an organophosphorus/sulfonate hypervalent iodine reagent as both an oxidant and the source of a functional group has been developed. Through this method, the oxidative phosphorylation-, sulfonation-, and hydroxylation of unactivated benzyl C(sp³)-H bonds, along with the hydroxylation and arylation of aryl C(sp²)-H bonds, are successfully realized under mild conditions and with excellent site-selectivity. The versatile C-OSO₂R bond provides a platform for a wide array of subsequent diversification reactions.

Full text of DOI:10.1021/acs.joc.9b01278

Subscriber access provided by KEAN UNIV
Article
Palladium-Catalyzed C-H Bond Functionalization Reactions
Using Phosphate/Sulphonate Hypervalent Iodine Reagents
Yimiao He, Lilan Huang, Limei Xie, Peng Liu, Qiongmei Wei, Fangfang
Mao, Xuehong Zhang, Jun Huang, Sijing Chen, and Chusheng Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01278 • Publication Date (Web): 22 Jul 2019
Downloaded from pubs.acs.org on July 22, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Palladium-Catalyzed C-H Bond Functionalization Reactions Using
Phosphate/Sulfonate Hypervalent Iodine Reagents
8
9
Yimiao He,*a Lilan Huang,a + Limei Xie,a + Peng Liu,b Qiongmei Wei,c Fangfang Mao,a Xuehong
Zhang,a Jun Huang,a Sijing Chen,a Chusheng Huang*a
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
a. College of Chemistry and Materials, Guangxi Key Laboratory of Natural Polymer Chemistry and
Physics, Nanning Normal University, Nanning 530001, P. R. China.
b. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan
Avenue, Guangzhou 510530, P. R. China.
c. College of Tourism and Culture, Nanning Normal University, Nanning 530001, P. R. China.
+ L. Huang and L. Xie contributed equally to this work.
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
R'
R'
R'
N
N
N
or
OP(O)R2
25 examples
34%-88% yields
OSO2R
18 examples
22%-84% yields
OH
7 examples
35%-69% yields
DG
H
Ar
OH
I
X = OP(O)R2
+
R2
X = OSO2R
X
R2
Pd(II)
N
N
R1
OH
Ar
8 examples
36%-63% yields
6 examples
48%-67% yields
chemo and site-specific C-H functionalization
achieving multiple derivatization reactions
introduction of diverse valuble FGs
open flask and simple operation
ABSTRACT: A new and operationally simple approach for palladium-catalyzed C-H functionalization
reactions utilizing an organophosphorus/sulfonate hypervalent iodine reagent as both an oxidant and
the source of a functional group has been developed. Through this method, the oxidative
phosphorylation, sulfonation and hydroxylation unactivated benzyl C(sp3)-H bonds, along with the
hydroxylation and arylation of aryl C(sp2)-H bonds, are successfully realized under mild conditions and
with excellent site-selectivity. The versatile C-OSO2R bond provides a platform for a wide array of
subsequent diversification reactions.
INTRODUCTION
Phosphates and sulfonates, not only widely exist in a variety of important biologically active
molecules (e.g., nucleic acids, proteins, carbohydrates, lipids, coenzymes, and steroids),1 but
also have extensive applications in the fields of pharmaceutical chemistry2 and agrochemicals3
as well as analytical chemistry.4 In addition, these key structures are also useful in organic
synthesis,5 for example, sulfonates are often utilized as the synthons for SN2 reactions. For
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
5
6
7
8
9
these reasons, the development of simple and effective synthetic methods for their preparation
is of great importance. Historically, the primary means of introducing these important
functional groups involve P/S-O bond formation, which is typically accomplished by the
nucleophilic substitution of an appropriate phosphoryl/sulfonyl-GLG (GLG: good leaving
group) moiety with a suitable alcohol or phenol (Scheme 1, path a).6,7 However, this strategy
suffers from some drawbacks, including the use of tedious multistep procedures, harsh reaction
conditions and hazardous phosphoryl halides. A more convenient method to access these useful
structures involving the direct transformation of an unactivated C-H bond into a
C-OP(O)R2/OSO2R bond is highly desirable (Scheme 1, path b).8 While metal-free
α-phosphorylation and α-sulfonation reactions of carbonyl compounds mediated by the
corresponding phosphate and sulfonate hypervalent iodine reagents were successively reported
by Togo’s group and Wirth’s group in 2002 and 2005 (Scheme 1a),9 the substrate scopes were
limited to the ketones. Subsequently in 2015, Dong and co-workers described an elegant
approach for the synthesis of β-sulfonyloxylated alcohols through a palladium-catalyzed
regioselective C(sp3)-H bond functionalization of masked alcohols (Scheme 1b).10 However,
the reaction was performed under harsh reaction conditions. Hence, the realization of a broadly
applicable C-H bond phosphorylation and sulfonation in a mild and atom-economic manner is
still urgently needed.
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
Scheme 1 Synthetic strategies for accessing sulfonates/phosphates.
C-O bond
formation
P/S-O bond
formation
O
Z
O
Z
O
Z
R1
R1H
HOR1
+
+
R
O
R
OH
R
X
path a
path b
Z = PR2 or S O
Previous work
O
OH
I
O
(2)
R2
R2
Ph
Y
R1
R1
(a)
(b)
Y
H
no slovent
Y = OP(O)R2 or OSO2R
Pd(OAc)2 (cat.)
DG
O
DG
O
RSO2OH, NFSI
DCE, N2, 90 oC
R1
R1
R2
H
OSO2R
R2
This
Work
R'
R'
R'
or
N
N
N
OP(O)R2
OSO2R
18 examples
22%-84% yields
OH
25 examples
7 examples
DG
34%-88% yields
Ar
OH
35%-69% yields
I
X
X = OP(O)R2
+
R2
X = OSO2R
H
Pd(II)
R2
(c)
N
N
R1
OH
6 examples
48%-67% yields
Ar
8 examples
36%-63% yields
chemo and site-specific C-H functionalization
introduction of diverse valuble FGs
open flask and simple operation
achieving multiple derivatization reactions
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
On the other hand, in the past few decades, significant advances have been made in catalytic
C-H oxygenations, which have successfully introduced a series of valuable oxygen groups such
as OH,11 OCOR,12 and OR.13 In contrast to these strongly nucleophilic groups, however, the
installation of weakly nucleophilic and good leaving groups, such as OP(O)R2 and OSO2R, to a
specific position still faces a number of challenges. First, the complexity of such a catalytic
system and the exceedingly low nucleophilicity of OP(O)R2 and OSO2R anions, make the
proposed phosphorylation and sulfonation likely to suffer from competition from other
potential nucleophiles. Second, due to the high reactivity of the target phosphates and
sulfonates, product stability during the reaction must be considered and will necessitate
relatively mild and simple catalytic systems.
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
Herein, we reveal a new and efficient approach for the direct, palladium-catalyzed, benzyl C(sp3)-H
phosphorylation/sulfonation of 8-methylquinolines,14 in which an organophosphorus/sulfonate
hypervalent iodine reagent is used as both an oxidant and the source of a functional group. In addition,
pyridyl-directed aryl C(sp2)-H bond hydroxylation and arylation are also conveniently achieved via the
current method (Scheme 1c).
RESULTS AND DISCUSSION
The reaction was initially investigated by using 1a as the model substrate, Pd(OAc)2 as the catalyst,
PhI(OH)P(O)(OPh)2 (2a) as the oxidant and dioxane as the solvent at room temperature in air. To our
delight, desired product 3a was obtained in 58% yield (Table 1, entry 1). Among the catalysts that were
tested, Pd(OAc)2 displayed the best efficiency (entries 2-4). The presence of additives had an important
effect on the reaction. While the addition of 4Å MS could significantly increase the conversion of the
reaction (entry 5), other additives such as an acid (e.g. PivOH) or a base (e.g. K2CO3) did not improve
the yield of the reaction (entries 6-7). Moreover, increasing the amount of the oxidant increased the
yields of 3a (entries 8-10). When the amount of the oxidant reached 2.4 equiv, 3a was obtained in 87%
isolated yield. However, continuing to increase the amount of oxidant did not further increased the
yield of 3a (entry 11). In addition, lowering the catalyst loading to 5 mol% reduced the yield of 3a to
74% (entry 12). To verify the role of the molecular sieves, 5 equiv of H2O was added, and the yield of
3a significantly decreased (entry 13). Meanwhile, 3a was obtained in 85% yield when the reaction was
performed under Ar (entry 14). Consequently, the optimum reaction conditions were determined to be
1a (0.2 mmol) in the presence of Pd(OAc)2 (10 mol%), 2a (2.4 equiv), 4Å MS (175 mg) in dioxane (1
mL) at room temperature open to air.
Table 1. Optimization of the Reaction Conditions a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
OH
cat. (10 mol%)
+
I
N
Ph
OP(O)(OPh)2
dioxane, rt, air
N
OP(O)(OPh)2
1a
2a, X equiv
8
3a
9
Entry
1
Catalyst
X
Additive
Yield [%]b
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
Pd(OAc)2
1.5
-
-
3a, 58%
3a, 37%
3a, 32%
3a, <5%
3a, 68%
3a, 53%
3a, 59%
3a, 76%
3a, 81%
3a, 87%
3a, 84%
3a, 74%
3a, 78%
3a, 85%
2
Pd(OCOCF3)2
PdCl2
1.5
1.5
1.5
1.5
1.5
1.5
1.8
2.1
2.4
2.5
2.4
2.4
2.4
3
-
4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
5 c
6 d
7 e
8 c
9 c
10 c
11 c
12 c
4Å MS
PivOH
K2CO3
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS, H2O
-
13 c, g
14 h
a Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%), solvent (1 mL). b Isolated yields. c 4Å MS (175 mg) was
added. d 1 equiv. of acid was added. e 1 equiv. of base was added. f 5 mol% of catalyst was used. g 5 equiv of H2O
was added. h in Ar.
With the optimized conditions in hand, the reactions between substrates 1a-1m and phosphate
hypervalent iodine species were first tested. As shown in Table 2, the substrates bearing
electron-withdrawing substitutes such as F, Cl, Br, and NO2 at the 5-position were tolerated and
gave corresponding products 3c-3f in good yields. However, when the substrates possessed
electron-donating groups, the yields were sharply decreased (3b, 3g-3k). These results
indicated that the electronic properties of the substituents are crucial to the reaction. When the
7-position of the substrate was blocked by a substituent (e.g., methyl), the yield was obviously
reduced, possibly due to steric hinderance (3h). Moreover, when the oxidant was replaced by
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
dibenzyl or diethyl phosphate hypervalent iodine, corresponding products 3l and 3m were
isolated in 76% and 69% yields, respectively.
Table 2 Phosphate esterification of 8-methylquinolines a, b
7
8
9
5
4
Pd(OAc)2 (10 mol%)
PhI(OH)OP(O)(OR)2
(2.4 equiv)
6
R1
7
R1
R2
3
2
R2
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
N
N
1
8
4A MS (175 mg)
dioxane, rt, air
OP(O)(OR)2
1
3
F
Cl
Br
N
N
N
N
OP(O)(OPh)2
OP(O)(OPh)2
OP(O)(OPh)2
OP(O)(OPh)2
3b, 49%, 9h
3c, 79%, 9h
3d, 80%, 9h
3e, 82%, 9h
NO2
N
N
N
N
OP(O)(OPh)2
OP(O)(OPh)2
OP(O)(OPh)2
OP(O)(OPh)2
3h, 34%, 12h
3i, 54%, 11h
3f, 86%, 12h
3g, 69%, 9h
C2H5
Ph
N
N
N
N
OP(O)(OPh)2
3j, 59%, 9h
OP(O)(OBn)2
OP(O)(OPh)2
OP(O)(OEt)2
3m, 69%, 11h
3l, 76%, 11h
3k, 47%, 9h
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (0.02 mmol), oxidant (0.48 mmol), 4Å MS (175 mg), dioxane (1
mL) at rt for 9-12 h in air. b Isolated yields.
Table 3 Phosphinic esterification of 8-methylquinolines a, b
Pd(OAc)2 (10 mol%)
PhI(OH)OP(O)Ph2
(2.4 equiv)
5
4
R1
6
R1
7
R2
3
2
R2
N
N
1
8
4A MS (175 mg)
dioxane, rt, air
R3 OP(O)Ph2
R3
1
4
F
Cl
N
N
N
N
OP(O)Ph2
OP(O)Ph2
4a, 88% (80%)c, 8h
OP(O)Ph2
OP(O)Ph2
4b, 79%, 8h
4c, 68% , 8h
4d, 60%, 9h
Br
NO2
N
N
N
N
OP(O)Ph2
OP(O)Ph2
OP(O)Ph2
OP(O)Ph2
4f, 59%, 6h
4e, 66%, 8h
4g, 70%, 8h
4h, 52%, 10h
Ph
C2H5
N
N
N
N
OP(O)Ph2
4i, 60%, 7h
OP(O)Ph2
OP(O)Ph2
OP(O)Ph2
4l, 59%, 8h
4k, 50%, 8h
4j, 65%, 8h
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (0.02 mmol), oxidant (0.48 mmol), 4Å MS (175 mg),
dioxane (1 mL) at rt for 6-10 h in air. b Isolated yields. c 2.0 mmol scale.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
Phosphinic hypervalent-iodines were subsequently evaluated (Table 3). Regardless of if the
5
6
substrates possessed electron-donating groups such as
a
methyl substituent, or
electron-withdrawing substituents, such as F, Cl, Br, or NO2, the reaction proceeded smoothly
and afforded target products 4a-4k in moderate to good yields. However, the phosphate product
was not obtained when a strong electron-donating group such as OMe was present on the
substrate. To our delight, when the primary C-H bond was replaced with a secondary C-H bond
at the 8-position of the substrate, the reaction still occurred and gave product 4l in 59% yield.
However, when converting to more sterically hindered tertiary C-H bonds, the reaction did not
proceed. To prove the practicality of this approach, a 2.0 mmol scale reaction was carried out,
and product 4a was isolated in a yield of 80%, which was comparable to that of the small-scale
reaction.
7
8
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
Table 4 Hydroxylation of 2-phenylpyridines a, b
Pd(OAc)2 (10 mol%)
R
R
PhI(OH)OP(O)Ph2
(3.0 equiv.)
Cs2CO3 (1.5 equiv)
PivOH (0.3 equiv.)
DCE, 130 oC, air
N
OH
N
5
6
C2H5
F
N
OH
N
OH
N
OH
N
OH
6a, 56%, 10h
6b, 67%, 12h
6c, 54%, 10h
6d, 57%, 10h
OMe
Ph
N
OH
N
OH
6e, 48%, 10h
6f, 51%, 15h
Pd(OAc)2 (10 mol%)
PhI(OH)OP(O)Ph2
(3.0 equiv.)
Cs2CO3 (1.5 equiv)
+
18OH
[O18]-6a, 15%
PivOH (0.3 equiv.)
H218O (5 equiv.)
dioxane, 130 oC, Ar
46%
N
OH
N
N
H
5a
6a
, 85%
a Reaction conditions: 5 (0.2 mmol), Pd(OAc)2 (0.02 mmol), oxidant (0.6 mmol), Cs2CO3 (0.3 mmol),
PivOH (0.06 mmol), DCE (1 mL) at 130 oC for 10-15 h in air. b Isolated yields.
When 2-phenylpyridines 5 were utilized as substrates, an OH group other than the OP(O)Ph2
group was unexpectedly introduced (Table 4).15 Substrates bearing the electron-donating groups
such as Me, Et, OMe, and Ph substituents or the electron-withdrawing groups such as F
substituent at para-position of the benzene smoothly underwent the reaction and produced
18
target products 6a-6f in moderate to good yields. Moreover, when 5 equiv. of H2 O was added
to the reaction, products 6a and [O18]-6a were obtained in an approximate ratio of 5.7 (see SI),
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
indicating that the oxygen atom in the hydroxy product likely originated from the phosphinic
hypervalent iodine rather than adventitious H2O.
Table 5 Sulfonation of 8-methylquinolines a, b
7
8
9
Pd(OAc)2 (10 mol%)
PhI(OH)OSO2R (3.0 equiv)
R
R
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
N
N
7
OTs
1
dioxane, rt, air
Cl
R = halo, EWG
NO2
I
Br
F
N
N
N
N
N
OTs
OTs
OTs
OTs
OTs
7e, 84%, 16h
7c, 59%, 12h
7a, 79%, 12h
7b, 40%, 12h
7d, 61%, 13h
NO2
O2N
Br
F
Cl
N
N
N
N
N
OTs
OTs
OTs
OTs
ONs
7f, 72%, 12h
7i, 75%, 14h
7j, 42%, 16h
7h, 57%, 13h
7g, 66%, 13h
NO2
NO2
NO2
NO2
Br
N
N
N
N
N
OCls
OCs
OMs
7m, 54%, 16h
OBs
OBs
7o, 41%, 12h
7k, 68%, 16h
7l, 61%, 16h
7n, 65%, 16h
Br
Br
N
N
OMs
7p, 56%, 12h
OCs
7q, 57%, 12h
a
b
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (0.02 mmol), oxidant (0.60 mmol), dioxane (1 mL) for 12-16 h.
c
Isolated yields.
Ns, 4-NO2-C6H4SO2; Cls, 4-Cl-C6H4SO2; Bs, C6H5SO2; Ms, MeSO2; Cs,
(1R)-10-camphorylsulfonyl.
When sulfonate hypervalent iodine reagents were used as the oxidant, the reactions proceeded
smoothly, and the results are presented in Table 5. The OTs products were produced in
moderate to excellent yields from reactions with substrates bearing electron-withdrawing
substituents under similar conditions (7a-7i). Preliminary screenings indicated that more
strongly electron-withdrawing substituents (e.g., NO2 versus F, Cl, Br, and I) favored the
reaction. Other sulfonate hypervalent iodine species were examined, and various sulfonates
(e.g., ONs, OCls, OBs, OMs, and OCs) were expediently introduced in moderate to good yields
when using substrates bearing a NO2 group at the 5-position (7j-7n). However, when the
5-position of the substrate was taken up by a Br group, some changes had occurred. For alkyl or
phenyl sulfonates, the expected products were obtained (7o-7q); however, when the
para-position of the sulfonates were substituted with electron-withdrawing groups such Cl or
NO2, the OH product was obtained as the major or only product (Scheme 2a and 2b).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
Scheme 2 Competitive reactions.
5
6
Br
Br
Br
7
8
9
Standard conditions
+
+
+
PhI(OH)OCls
(a)
N
N
N
OCls
7r, 22%
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
OH
8a, 45%
1a
Br
Br
Standard conditions
(b)
PhI(OH)ONs
N
N
OH
8a, 66%
1a
When the substrates bearing electron-donating groups were subjected to the reaction,
surprisingly, OH other than OTs products were obtained (8a-8g). Interestingly, for substrate 1a,
OTs product 7a was isolated in 79% yield following purification with a more polar eluent (PE:
EA = 2:1), while hydroxy product 6a was obtained in 69% yield when using a less polar eluent
(PE: EA = 20:1). Thus, the reaction not only offered a new approach for hydroxylation, but also
revealed that the hydroxy source was OTs other than the OH of HTIB. To our delight, when the
primary C-H bond at 8-position of the substrate was replaced by secondary C-H bond, the
reaction still proceeded smoothly and gave product 6g in 51% yield. However, when moving to
more sterically hindered tertiary C-H bonds, the reaction did not occur.
Table 6 Hydroxylation of 8-methylquinolines a, b
Pd(OAc)2 (10 mol%)
R1
R2
R1
R2
PhI(OH)OTs (3.0 equiv)
N
N
R3
1'
dioxane, rt, air
8
R3 OH
R1, R2 = alkyl, Br
Br
N
N
N
N
OH
OH
8d, 68%,12h
OH
OH
8a, 69%c, 12h
8b, 46%,12h
8c, 49%,12h
C2H5
N
N
N
OH
OH
8f, 46%,12h
OH
8e, 35%, 14h
8g, 51%,16h
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (0.02 mmol), oxidant (0.60 mmol), dioxane (1 mL) for
b
c
12-16 h. Isolated yields. Less polar developing solvent (PE: EA = 20:1) was used during the column
chromatography.
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The reactions between 2-phenylpyridine analogues and sulfonate hypervalent iodine species
are also discussed (Table 7). In this process, an aryl group other than the OTs of the sulfonate
hypervalent iodine was unexpectedly introduced, thus affording an alternative method for
arylation.16
Table 7 Arylation of 2-phenylpyridines a, b
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
Pd(OAc)2 (10 mol%)
P(o-benzyl)3 (20 mol%)
R2
R2
ArI(OH)OTs (3 equiv.)
N
R1
N
R1
AgOAc (0.5 equiv.)
toluene, 100 oC, air
Ar
H
5
9
N
N
N
N
MeO
9d, 39%, 24h
9a, 63%, 18h
9b, 44%, 18h
9c, 50%, 18h
N
N
N
N
CF3
9e, 36%, 24h
9f, 40%, 18h
9g, 39%, 18h
9h, 40%, 18h
a Reaction conditions: 6 (0.2 mmol), Pd(OAc)2 (0.02 mmol), ligand (0.04 mmol), oxidant (0.60 mmol),
AgOAc (0.1 mmol), toluene (1 mL) for 18-24 h. b Isolated yields.
Scheme 3 Synthetic applications.a
NO2
N
NO2
NO2
11, 95%
Br
path C
7e
N
7e
path
N
7e
path
NO2/Br
B
Cl
D
I
10, 78%
12, 71%
N
NO2
Br
7a
path
7e
path
OTs
E
A
path F
7e
N
N
NO2
NO2
13, 51%
OH
8a, 87%
14, 94%
N
N3
a
Conditions: (a) 5a (0.2 mmol), SiO2 (0.6 mmol), PE : EA = 1mL : 0.05 mL, rt, 5 h; (b) 5e (0.2 mmol),
t-BuCl (0.24 mmol), [pmIm]Br (0.4 mmol), 60 oC, 4 h; (c) 5e (0.2 mmol), t-BuBr (0.24 mmol), [pmIm]Br
(0.4 mmol), sonication, 0.5 h; (d) 5e (0.2 mmol), t-BuI (0.24 mmol), [pmIm]Br (0.4 mmol), sonication,
0.5 h; (e) 5e (0.2 mmol), AgNO3 (0.4 mmol), t-AmOH, 120 oC, 6 h; (f) 5e (0.2 mmol), NaN3 (0.3 mmol),
THF/H2O, reflux, 3 h. b Isolated yields.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
5
6
7
8
9
The synthetic utility of the OTs products was exemplified by further transformations of
products 7a/7e (Scheme 3). Substrate 7a was hydrolyzed to product 8a in 87% yield under
reaction conditions similar to the column chromatography conditions. Given that OTs is a good
leaving group, several substitution reactions were conducted.17 tert-Butyl chloride, bromide and
iodide in combinations with the ionic liquid [pmIm]Br had been used to convert the OTs
derivative into the corresponding chloride, bromide and iodide products under sonication
conditions (or heating) in good yields. In addition, the NO2 and N3 products were also produced
by reacting the OTs derivatives with AgNO3 and NaN3, respectively.
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
CONCLUSIONS
In summary, by utilizing organophosphorus/sulfonate hypervalent iodine reagents as both an
oxidant and the source of a functional group, we have realized a convenient and efficient
approach for the direct, palladium-catalyzed C(sp3)-H phosphorylation/sulfonation of
8-methylquinolines. Various weakly nucleophilic and good leaving groups, such as phosphates,
phosphonates and sulfonates, were successfully introduced under mild conditions, providing a
new strategy for the preparation of such species. However, when using the current method for
2-phenylpyridine analogues, the hydroxyl or phenyl products are unexpectedly produced.
EXPERIMENTAL SECTION
General Information. Reactions were monitored by using thin-layer chromatography (TLC) on
commercial silica gel plates (GF254). Visualization of the developed plates was performed under UV
1
lights (254 nm). Flash column chromatography was performed on silica gel (200-300 mesh). H, 13C
and 31P NMR spectra were recorded on a Bruker AV300，400 or 500 spectrometer. Chemical shifts (δ)
were reported in ppm referenced to the CDCl3 residual peak (δ 7.26) or the DMSO-d6 residual peak (δ
2.50) for 1H NMR. Chemical shifts of 13C NMR were reported relative to CDCl3 (δ 77.0) or D6-DMSO
(δ 39.5). Chemical shifts of 31P NMR were reported relative to 85% H3PO4 (δ = 0). The following
abbreviations were used to describe peak splitting patterns when appropriate: br s = broad singlet, s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constant, J, was reported in Hertz
unit (Hz). Melting points (mp) were taken on a MEL-TEMP® apparatus and were uncorrected. High
resolution mass spectra (HRMS) were obtained on an ESI-LC-MS/MS spectrometer.
Genaral procedure: Preparation of the substrates
All substrates 1a-1l used in this work are known compounds. 8-Methylquinolines 1a, 1l and
2-phenylpyridines 5 are commercially available. The substrates 1b-1k were prepared as published
before, and the 1H NMR spectral data matched those of previous reported.18
General procedure for the synthesis of the substates 1b-1h18a-18c
Glycerin (5.6 g, 60 mmol) was added dropwise over a period of 0.5h to a solution of substituted
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
aniline (50 mmol) and NaI (0.1 g, 0.6 mmol) in 80% aqueous H2SO4 (27 g, 220 mmol) and stirred in a
140 ºC oil-bath. The mixture was then heated at 140-145 ºC for 3.5h while distilling the water formed
during this period. Upon cooling to room temperature, the dark solution was carefully poured into ice
(50 g) and then neutralized with 25% NaOH (55 g, 0.34 mol) to basic pH 8~11. The mixture was
extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with water (2×50
mL), brine (50 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 8:1)
to afford the corresponding substituted 8-methyl-quinoline 1b-1h.
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
General procedure for the synthesis of the substates 1i-1j18d-18e
Unsaturated aldehyde (5.6 g, 60 mmol) was added dropwise over a period of 0.5h to a solution of
substituted aniline (50 mmol) and NaI (0.1 g, 0.6 mmol) in 80% aqueous H2SO4 (27 g, 220 mmol) and
stirred in a 110 ºC oil-bath. The mixture was then heated at 110 ºC for 2h while distilling the water
formed during this period. Upon cooling to room temperature, the dark solution was carefully poured
into ice (50 g) and then neutralized with 25% NaOH (55 g, 0.34 mol) to basic pH 8~11. The mixture
was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with water
(2×50 mL), brine (50 mL), dried with anhydrous sodium sulfate, and concentrated under reduced
pressure. The crude product was purified by column chromatography on silica gel (petroleum
ether/EtOAc = 8:1) to give the corresponding substituted 8-methyl-quinoline 1i-1j.
General procedure for the synthesis of the substate 1k18f
Aniline (5.0 mmol) and styrene oxide (10.0 mmol) were added to a mixture of MeSO3H (1.5 mL) and
Al2O3 (0.5 g). The mixture was stirred at room temperature in solvent-free conditions for 0.5 h. After
completion of the reaction, the mixture was diluted with ethyl acetate, and filtered. The filtrate was
washed with a solution of NaHCO3 (5%; 3 x 30 mL) and then 150 mL deionized water. The solution
was dried over magnesium sulfate; the solvent was evaporated to give the crude product, which was
purified by silica gel column chromatography employing petroleum ether/ethyl acetate (8:1) as eluent.
Genaral procedure: Palladium-Catalyzed phosphorylation/sulfonation reactions
of 8-methylquinolines
[Caution] Since the hypervalent iodine reagents are generally explosive, so please operate them in a
fume hood.
Procedure A: A oven-dried 15 mL Schlenk tube was charged with a mixture of 1 (0.2 mmol),
Pd(OAc)2 (10 mol%), oxidant (0.48 mmol), 4Å MS (175 mg) in dioxane (1.0 mL) and was stirred at
room temperature for 6-12 h. After the reaction was complete (as determined by TLC analysis), the
reaction was cooled to room temperature and 10 mL of water was added. Then, the mixture was
extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
brine and dried by anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the
residue was purified on a silica gel column (petroleum ether/ethyl acetate = 4:1) to afford the targeted
products 3a-3m or 4a-4l.
7
8
9
Diphenyl (quinolin-8-ylmethyl) phosphate (3a)
1
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
Yield: 87% (68.1 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.92 (d, J = 4.2 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 8.1 Hz, 2H), 7.53 (t, J =
7.7 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.24 (m, 8H), 7.18 (t, J = 7.1 Hz, 2H), 6.09 (d, J = 8.1 Hz, 2H);
13C{1H} NMR (75 MHz, CDCl3): δ 150.6 (d, J = 7.1 Hz), 149.8, 145.5, 136.2, 133.5 (d, J = 7.4 Hz),
129.7, 128.2 (d, J = 16.1 Hz), 128.0, 126.3, 125.3, 121.4, 120.2 (d, J = 4.9 Hz), 67.3 (d, J = 5.6 Hz); 31
P
NMR (121 MHz, CDCl3): δ -11.69; IR (KBr): v 3070, 3015, 2952, 1594, 1487, 1290, 1215, 1187, 1163,
876, 823, 789, 764; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H18NO4PNa 414.0866, Found
414.0870.
(5-methylquinolin-8-yl)methyl diphenyl phosphate (3b)
1
Yield: 49% (39.7 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.92 (d, J = 4.2 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.49-7.45
(m, 1H), 7.37-7.14 (m, 11H), 6.04 (d, J = 8.1 Hz, 2H), 2.69 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
150.6 (d, J = 7.1 Hz), 149.3, 145.8, 135.3, 132.6, 131.5 (d, J = 7.1 Hz), 129.7, 128.1, 127.4, 126.6,
125.2, 121.0, 120.2 (d, J = 4.9 Hz), 67.5 (d, J = 5.6 Hz), 18.7; 31P NMR (121 MHz, CDCl3): δ -10.58;
IR (KBr): v 3065, 2922, 2853, 1594, 1491, 1412, 1240, 1203, 1160, 848, 771, 719; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C23H20NO4PNa 428.1022, Found 428.1025.
(5-fluoroquinolin-8-yl)methyl diphenyl phosphate (3c)
1
Yield: 79% (64.7 mg), Colorless oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.95 (d, J = 3.3 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.75 (t J = 6.6 Hz, 1H), 7.51-7.47
(m, 1H), 7.33-7.15 (m, 11H), 5.99 (d, J =8.4 Hz, 2H ); 13C{1H} NMR (125 MHz, CDCl3): δ 157.9 (d, J
CF = 254.9 Hz), 150.6 (t, J = 11.0 Hz), 146.2 (d, J = 3.1 Hz), 129.7, 129.4 (d, J = 4.5 Hz), 128.4 (d, J =
9.1 Hz), 125.2, 121.4 (d, J = 2.8 Hz), 120.1 (d, J = 4.9 Hz), 118.8 (d, J = 16.5 Hz), 109.7 (d, J = 19.4
Hz), 66.8 (d, J = 5.6 Hz); 31P NMR (121 MHz, CDCl3): δ -11.68; IR (KBr): v 3050, 2962, 2930, 1599,
1489, 1409, 1287, 1217, 1185, 1160, 898, 868, 776, 756; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H18FNO4P 410.0952, Found 410.0954.
(5-chloroquinolin-8-yl)methyl diphenyl phosphate (3d)
1
Yield: 80% (68.1 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.95 (d, J = 3.3 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.61-7.54
(m, 2H), 7.34-7.16 (m, 10H), 6.02 (d, J =8.4 Hz, 2H ); 13C{1H} NMR (125 MHz, CDCl3): δ 150.5 (d, J
= 6.9 Hz), 150.3, 146.0, 133.0, 131.6, 129.7, 127.8, 126.3, 126.0, 125.3, 122.1, 120.1 (d, J = 4.9 Hz),
66.9 (d, J = 5.5 Hz); 31P NMR (121 MHz, CDCl3): δ -11.72; IR (KBr): v 3047, 2932, 2848, 1587, 1489,
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
1444, 1282, 1220, 1187, 1162, 871, 848, 774, 754; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H18ClNO4P 426.0656, Found 426.0658.
(5-bromoquinolin-8-yl)methyl diphenyl phosphate (3e)
7
8
9
Yield: 82% (77.1 mg), Pale yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.72 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63 (d, J
= 7.8 Hz, 1H), 7.50-7.46 (m, 1H), 7.33-7.23 (m, 8H), 7.16 (t, J =7.1 Hz, 2H), 6.00 (d, J = 8.1 Hz, 2H);
13C{1H} NMR (75 MHz, CDCl3): δ 150.5 (t, J = 7.1 Hz), 145.9, 135.5, 133.7 (d, J = 7.3 Hz), 130.0,
129.8 (d, J = 0.5 Hz), 128.2, 127.2, 125.4 (d, J = 1.1 Hz), 122.5, 122.2, 120.1 (d, J = 5.0 Hz), 67.0 (d, J
= 5.4 Hz); 31P NMR (121 MHz, CDCl3): δ -11.71; IR (KBr): v 3097, 3057, 3042, 2942, 1589, 1482,
1452, 1295, 1215, 1187, 1145, 871, 828, 776, 761; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C22H17BrNO4PNa 491.9961, Found 491.9955.
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
(5-nitroquinolin-8-yl)methyl diphenyl phosphate (3f)
1
Yield: 86% (75.1 mg), Yellow oil, Rf = 0.35 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 9.01 (t, J = 7.7 Hz, 2H), 8.34 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.71-7.67
(m, 1H), 7.38-7.20 (m, 10H), 6.12 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 150.7, 150.4
(d, J = 7.1 Hz), 145.0 (d, J = 14.0 Hz), 141.6 (d, J = 7.7 Hz), 132.2, 129.9, 125.5, 124.8, 124.4, 124.2,
120.7, 120.1 (d, J = 4.9 Hz), 66.9 (d, J = 5.0 Hz); 31P NMR (121 MHz, CDCl3): δ -11.78; IR (KBr): v
3072, 3057, 3040, 2965, 1591, 1524, 1479, 1452, 1404, 1292, 1212, 1180, 1155, 871, 851, 834, 799,
774, 721; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H17N2O6PNa 459.0716, Found 459.0710.
(6-methylquinolin-8-yl)methyl diphenyl phosphate (3g)
1
Yield: 69% (55.9 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, DMSO): δ 8.87 (d, J = 4.1 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.57-7.53 (m, 2H),
7.44-7.39 (m, 4H), 7.27-7.22 (m, 6H), 5.92 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz,
DMSO): δ 152.1 (d, J = 6.9 Hz), 147.8, 141.3, 139.2, 138.2, 137.3, 130.6, 130.0, 128.6, 126.0, 124.4,
122.0, 120.4 (d, J = 5.0 Hz), 59.9, 21.8; 31P NMR (121 MHz, CDCl3): δ -12.34; IR (KBr): v 3072, 2918,
2853, 1589, 1489, 1439, 1290, 1160, 1122, 868, 776, 711; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C23H20NO4PNa 428.1027, Found 428.1034.
(7-methylquinolin-8-yl)methyl diphenyl phosphate (3h)
1
Yield: 34% (27.6 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.93 (d, J = 4.2 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.42-7.36
(m, 2H), 7.31-7.12 (m, 10H), 6.20 (d, J = 6.9 Hz, 2H), 2.61 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
150.7 (d, J = 7.1 Hz), 150.1, 146.8, 140.8, 135.9, 130.1, 129.8, 129.6, 128.8, 126.5, 125.0, 120.5, 120.2
(d, J = 5.0 Hz), 63.1 (d, J = 5.7 Hz), 19.7; 31P NMR (121 MHz, CDCl3): δ -11.88; IR (KBr): v 3050,
2920, 2850, 1594, 1482, 1437, 1285, 1220, 1190, 1163, 831, 776, 749; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C23H20NO4PNa 428.1022, Found 428.1023.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
4
(3-methylquinolin-8-yl)methyl diphenyl phosphate (3i)
1
5
6
7
8
Yield: 54% (43.8 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.75 (d, J = 1.5 Hz, 1H), 7.89 (s, 1H), 7.76-7.70 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H),
7.34-7.24 (m, 8H), 7.17 (t, J = 7.1 Hz, 2H), 6.07 (d, J = 8.1 Hz, 2H), 2.51 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 151.8, 150.6 (d, J = 7.1 Hz), 143.8, 134.8, 133.2 (d, J = 7.3 Hz), 130.9, 129.7, 127.8
(d, J = 10.3 Hz), 127.1, 126.3, 125.3 (d, J = 1.0 Hz), 120.2 (d, J = 5.0 Hz), 67.4 (d, J = 5.6 Hz), 18.7;
31P NMR (121 MHz, CDCl3): δ -11.74; IR (KBr): v 3065, 2922, 2850, 1586, 1544, 1489, 1439, 1290,
1217, 1187, 1165, 881, 768, 711; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H20NO4PNa 428.1022,
Found 428.1018.
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
(3-ethylquinolin-8-yl)methyl diphenyl phosphate (3j)
1
Yield: 59% (49.5 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.79 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.77-7.74 (m, 2H), 7.52-7.47 (m,
1H), 7.34-7.24 (m, 8H), 7.20-7.14 (m, 2H), 6.08 (d, J = 8.1 Hz, 2H), 2.89-2.81 (m, 2H), 1.36 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 151.3, 150.6 (d, J = 7.1 Hz), 144.0, 137.0, 133.6, 133.2 (d,
J = 7.3 Hz), 129.7, 127.9 (d, J = 6.1 Hz), 127.2, 126.3, 125.2 (d, J = 1.1 Hz,), 120.2 (d, J = 5.0 Hz),
67.4 (d, J = 5.6 Hz), 26.2, 15.2; 31P NMR (121 MHz, CDCl3): δ -11.72; IR (KBr): v 3072, 2967, 2925,
2870, 1589, 1489, 1457, 896, 876, 828, 776; HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C24H22NO4PK
458.0918, Found 458.0926.
Diphenyl ((3-phenylquinolin-8-yl)methyl) phosphate (3k)
1
Yield: 47% (43.9 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 9.15 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 10.2 Hz, 2H), 7.70 (t, J
= 3.6 Hz, 2H), 7.55-7.52 (m, 3H), 7.46-7.43 (m, 1H), 7.31-7.23 (m, 8H), 7.15 (t, J = 3.6 Hz, 2H), 6.09
(d, J = 4.2 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 150.6 (d, J = 7.1 Hz), 149.3, 144.6, 137.7,
134.1, 133.5 (d, J = 7.1 Hz), 133.3, 129.7, 129.3, 128.5, 128.3, 128.1, 127.8, 127.4, 126.8, 125.3, 120.2
(d, J = 4.9 Hz), 67.3 (d, J = 5.6 Hz); 31P NMR (121 MHz, CDCl3): δ -11.71; IR (KBr): v 3067, 2922,
2850, 1584, 1484, 1444, 1285, 1215, 1187, 1162, 898, 871, 826, 771; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C28H22NO4PNa 490.1179, Found 490.1187.
Dibenzyl (quinolin-8-ylmethyl) phosphate (3l)
Yield: 76% (63.7 mg), Pale yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.90 (t, J = 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.52 (t, J =
7.8 Hz, 1H), 7.45-7.33 (m, 11H), 5.85 (d, J = 7.5 Hz, 2H), 5.11 (d, J = 7.8 Hz, 4H); 13C{1H} NMR (75
MHz, CDCl3): δ 149.8, 145.6, 136.2, 135.9 (d, J = 7.1 Hz), 134.1 (d, J = 7.6 Hz), 128.5 (d, J = 7.6 Hz),
128.0 (d, J = 11.0 Hz), 126.3, 121.3, 69.3 (d, J = 5.5 Hz), 66.0 (d, J = 5.0 Hz); 31P NMR (121 MHz,
CDCl3): δ -0.73; IR (KBr): v 3032, 2920, 2853, 1596, 1502, 1454, 1275, 1215, 1187, 876, 821, 786,
736; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H22NO4PNa 442.1179, Found 442.1183.
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
Diethyl (quinolin-8-ylmethyl) phosphate (3m)
1
5
6
7
8
Yield: 69% (40.8 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.91 (d, J = 3.9 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 6.9 Hz, 1H), 7.79 (d, J
= 7.8 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.45-7.41 (m, 1H), 5.83 (d, J = 7.2 Hz, 2H), 4.21-4.11 (m, 4H),
1.32 (t, J = 6.9 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 149.7, 145.5, 136.2, 134.4 (d, J = 7.5 Hz),
127.9, 127.7, 126.3, 121.3, 65.7 (d, J = 5.0 Hz), 63.9 (d, J = 5.7 Hz), 16.1 (d, J = 6.8 Hz); 31P NMR
(121 MHz, CDCl3): δ -0.82; IR (KBr): v 2980, 2930, 2905, 1596, 1559, 1499, 1462, 1265, 1162, 876,
826, 791; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C14H18NO4PNa 318.0866, Found 318.0874.
Quinolin-8-ylmethyl diphenylphosphinate (4a)
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
Yield: 88% (63.3 mg), Pale yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.84 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 4.2 Hz, 1H), 7.95-7.88 (m, 5H), 7.75 (d, J = 3.9
Hz, 1H), 7.55-7.48 (m, 3H), 7.44-7.38 (m, 5H), 5.83 (d, J = 3.6 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3): δ 149.6, 145.6, 136.1, 134.9 (d, J = 7.0 Hz), 132.5, 132.1 (d, J = 2.8 Hz), 131.8 (d, J = 10.1
Hz), 130.7, 128.5 (d, J = 13.1 Hz), 127.8 (d, J = 10.4 Hz), 126.3, 121.2, 63.3 (d, J = 5.0 Hz); 31P NMR
(121 MHz, CDCl3): δ 32.42; IR (KBr): v 3049, 2930, 2863, 1589, 1576, 1496, 1437, 1222, 1160, 1125,
863, 833, 786, 749, 729; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H18NO2PNa 382.0967, Found
382.0970.
(5-methylquinolin-8-yl)methyl diphenylphosphinate (4b)
Yield: 79% (59.0 mg), Pink oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300 MHz,
CDCl3): δ 8.85 (d, J = 3.9 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.95-7.89 (m, 4H), 7.82 (d, J = 7.5 Hz,
1H), 7.53-7.35 (m, 8H), 5.82 (d, J = 7.5 Hz, 2H), 2.65 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
149.1, 146.0, 134.7, 132.8 (d, J = 7.1 Hz), 132.5 (d, J = 4.4 Hz), 132.1 (d, J = 2.8 Hz), 131.8 (d, J =
10.1 Hz), 130.8, 128.5 (d, J = 13.1 Hz), 127.8, 127.3, 126.7, 120.8, 63.5 (d, J = 5.1 Hz), 18.6; 31P NMR
(121 MHz, CDCl3): δ 32.16; IR (KBr): v 3069, 3015, 2927, 1596, 1501, 1434, 1227, 1175, 1128, 1113,
851, 826, 774, 746, 724; HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C23H20NO2PK 412.0863, Found
412.0865.
(5-fluoroquinolin-8-yl)methyl diphenylphosphinate (4c)
1
Yield: 68% (51.3 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.91 (d, J = 3.0 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.92-7.86 (m, 5H), 7.52-7.45 (m,
7H), 7.21 (t, J = 8.7 Hz, 1H), 5.78 (d, J = 7.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 157.6 (d,
JCF = 254.3 Hz), 150.4, 146.2, 132.1 (d, J = 2.8 Hz), 131.8 (d, J = 10.3 Hz), 131.0, 129.4 (d, J = 4.6 Hz),
128.5 (d, J = 13.1 Hz), 128.2 (d, J = 9.0 Hz), 121.3 (d, J = 2.8 Hz), 118.7 (d, J = 16.4 Hz), 109.8 (d, J =
19.3 Hz), 62.9 (d, J = 5.0 Hz); 31P NMR (121 MHz, CDCl3): δ 32.56; IR (KBr): v 3017, 2918, 2848,
1594, 1474, 1437, 1407, 1222, 1130, 863, 798, 751, 729; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H18FNO2P 378.1054, Found 378.1057.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
(5-chloroquinolin-8-yl)methyl diphenylphosphinate (4d)
1
5
6
7
8
Yield: 60% (47.3 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.90 (d, J = 3.3 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 7.94-7.87 (m, 5H), 7.63 (d, J = 7.5
Hz, 1H), 7.53-7.46 (m, 7H), 5.81 (d, J = 7.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 150.1,
146.1, 134.3 (d, J = 11.6 Hz), 133.0, 132.2 (d, J = 4.9 Hz), 131.8 (d, J = 17.0 Hz), 131.2, 130.5, 128.6
(d, J = 21.9 Hz), 127.7, 126.4, 125.9, 122.0, 63.0 (d, J = 8.1 Hz); 31P NMR (121 MHz, CDCl3): δ 32.69;
IR (KBr): v 3052, 2920, 2848, 1576, 1494, 1437, 1220, 1122, 1113, 853, 816, 749, 729; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C22H18ClNO2P 394.0758, Found 394.0760.
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
(5-bromoquinolin-8-yl)methyl diphenylphosphinate (4e)
Yield: 66% (57.9 mg), Pale yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.84 (d, J = 4.1 Hz, 1H), 8.48 (t, J = 7.5 Hz, 1H), 7.93-7.87 (m, 4H), 7.87 (s, 2H),
7.54-7.41 (m, 7H), 5.79 (d, J = 7.5 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 150.1, 146.1, 135.6,
135.0 (d, J = 7.0 Hz), 132.3 (d, J = 2.9 Hz), 131.8 (d, J = 10.2 Hz), 130.4, 130.1, 128.6 (d, J = 13.1 Hz),
128.1, 127.2, 122.3, 121.7, 63.0 (d, J = 5.0 Hz); 31P NMR (121 MHz, CDCl3): δ 32.81; IR (KBr): v
3052, 3012, 2940, 2865, 1589, 1571, 1491, 1437, 1220, 1125, 1110, 853, 771, 736, 724; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C22H17BrNO2PNa 460.0072, Found 460.0075.
(5-nitroquinolin-8-yl)methyl diphenylphosphinate (4f)
1
Yield: 59% (47.7 mg), Yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.98 (d, J = 8.9 Hz, 1H), 8.90 (d, J = 4.1 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.07 (d, J
= 7.8 Hz, 1H), 7.96-7.89 (m, 4H), 7.64-7.60 (m, 1H), 7.56-7.45 (m, 6H), 5.88 (d, J = 7.5 Hz, 2H);
13C{1H} NMR (75 MHz, CDCl3): δ 150.5, 144.9 (d, J = 10.7 Hz), 143.0 (d, J = 6.9 Hz), 132.5 (d, J =
2.8 Hz), 132.2, 131.8 (t, J = 6.9 Hz), 130.1, 128.7 (d, J = 13.1 Hz), 124.9, 124.6, 124.0, 120.6, 63.2 (d,
J = 4.7 Hz); 31P NMR (121 MHz, CDCl3): δ 33.38; IR (KBr): v 3104, 3052, 2945, 1589, 1506, 1439,
1404, 1230, 1192, 1130, 861, 833, 803, 721; HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C22H17N2O4PK
443.0558, Found 443.0564.
(6-methylquinolin-8-yl)methyl diphenylphosphinate (4g)
1
Yield: 70% (52.3 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.83 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.40-7.25
(m, 9H), 7.20-7.15 (m, 2H), 6.06 (d, J = 8.1 Hz, 2H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
150.6 (d, J = 7.1 Hz), 148.9, 144.1, 136.1, 135.5, 133.0 (d, J = 7.2 Hz), 130.2, 129.7, 128.1, 127.0,
125.3 (d, J = 1.1 Hz), 121.4, 120.2 (d, J = 5.0 Hz), 67.3 (d, J = 5.6 Hz), 21.7; 31P NMR (121 MHz,
CDCl3): δ 32.35; IR (KBr): v 3059, 2930, 2855, 1589, 1496, 1434, 1263, 1227, 1130, 1115, 861, 828,
768, 726, 701; HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C23H20NO2PK 412.0863, Found 412.0871.
(7-methylquinolin-8-yl)methyl diphenylphosphinate (4h)
1
Yield: 52% (38.8 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MHz, CDCl3): δ 8.92 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.40-7.34
(m, 2H), 7.31-7.22 (m, 8H), 7.15 (t, J = 6.9 Hz, 2H), 6.21 (d, J = 6.9 Hz, 2H), 2.60 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3): δ 150.7 (d, J = 7.1 Hz), 150.1, 149.9, 140.7, 135.9, 130.1 (d, J = 7.7 Hz),
129.7 (d, J = 9.8 Hz), 128.9, 126.5, 125.1, 120.6, 120.2 (d, J = 4.9 Hz), 63.1 (d, J = 5.9 Hz), 19.7; 31P
NMR (121 MHz, CDCl3): δ 31.79; IR (KBr): v 3055, 2922, 2850, 1501, 1464, 1437, 1222, 1130, 1110,
876, 833, 793, 729; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H21NO2P 374.1304, Found
374.1309.
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
Methyl 3-benzoylimidazo[1,2-a]pyridine-7-carboxylate (4i)
1
Yield: 60% (44.8 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.68 (s, 1H), 7.95-7.85 (m, 6H), 7.66 (d, J = 8.1 Hz, 1H), 7.51-7.42 (m, 7H), 5.83 (d, J
= 7.2 Hz, 2H), 2.45 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 151.5, 143.8, 134.8, 134.5 (d, J = 7.1
Hz), 132.4, 132.2 (d, J = 2.8 Hz), 131.8 (d, J = 10.2 Hz), 130.6 (d, J = 6.2 Hz), 128.5 (d, J = 13.1 Hz),
127.8, 127.2, 126.8, 126.3, 63.4 (d, J = 5.1 Hz), 18.7; 31P NMR (121 MHz, CDCl3): δ 32.46; IR (KBr):
v 3049, 2930, 2862, 1589, 1499, 1482, 1437, 1227, 1128, 1110, 896, 838, 821, 769, 729; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C23H21NO2P 374.1304, Found 374.1313.
(3-ethylquinolin-8-yl)methyl diphenylphosphinate (4j)
1
Yield: 65% (50.4 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.73 (d, J = 1.8 Hz, 1H), 7.95-7.87 (m, 6H), 7.70 (d, J = 8.1 Hz, 1H), 7.53-7.40 (m,
7H), 5.85 (d, J = 6.9 Hz, 2H), 2.84-2.77 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3): δ 151.0, 144.1, 136.8, 134.5 (d, J = 7.1 Hz), 133.5, 132.4, 132.2 (d, J = 2.8 Hz), 131.8 (d, J =
10.1 Hz), 130.6, 128.5 (d, J = 13.1 Hz), 127.9, 127.4, 126.9, 126.3, 63.4 (d, J = 5.1 Hz), 26.2, 15.2; 31P
NMR (121 MHz, CDCl3): δ 32.27; IR (KBr): v 3050, 2957, 2895, 1589, 1486, 1444, 1215, 1130, 1113,
868, 729, 701; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H23NO2P 388.1461, Found 388.1469.
(3-phenylquinolin-8-yl)methyl diphenylphosphinate (4k)
1
Yield: 50% (43.6 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 9.14 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.98-7.92 (m, 5H), 7.85 (d, J = 8.1
Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.63-7.44 (m, 10H), 5.90 (d, J = 7.2 Hz, 2H); 13C{1H} NMR (75
MHz, CDCl3): δ 149.1, 144.7, 137.8, 134.8 (d, J = 7.1 Hz), 133.9, 133.3, 132.5, 132.2 (d, J = 2.8 Hz),
131.8 (d, J = 10.1 Hz), 130.7, 129.2, 128.6 (d, J = 13.1 Hz), 128.1 (d, J = 11.9 Hz), 127.8 (d, J = 10.2
Hz), 127.4, 126.8, 63.3 (d, J = 5.0 Hz); 31P NMR (121 MHz, CDCl3): δ 32.44; IR (KBr): v 3054, 2922,
2865, 1584, 1484, 1437, 1275, 1222, 1128, 1110, 866, 769, 729; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C28H23NO2P 436.1461, Found 436.1470.
1-(quinolin-8-yl)ethyl diphenylphosphinate (4l)
1
Yield: 59% (44.1 mg), Colorless oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.75 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 4.2 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.91-7.88
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
6
7
8
9
(m, 2H), 7.73-7.70 (m, 3H), 7.56 (t, J = 3.9 Hz, 1H), 7.51 (t, J = 3.6 Hz, 1H), 7.46-7.43 (m, 2H),
7.36-7.31 (m, 2H), 7.26-7.23 (m, 2H), 6.81-6.76 (m, 1H), 1.79 (d, J = 3.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 149.3, 144.5, 141.1 (d, J = 4.6 Hz), 136.0, 133.3, 132.7, 132.0 (d, J = 2.8 Hz), 131.8
(d, J = 2.6 Hz), 131.7 (d, J = 2.6 Hz), 131.5, 130.9, 128.5, 128.3 (d, J = 6.2 Hz), 128.1, 128.0, 127.4,
126.4, 125.7, 121.0, 70.9 (d, J = 5.3 Hz), 25.2; 31P NMR (121 MHz, CDCl3): δ 30.57; IR (KBr): v 3060,
2972, 2855, 1594, 1576, 1499, 1437, 1250, 1160, 1127, 826, 811, 754, 724; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C23H20NO2PNa 396.1124, Found 396.1121.
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
General Procedure for the Synthesis of 4a in a 2.0 mmol Scale.
A oven-dried 100 mL Schlenk tube was charged with a mixture of 1a (2.0 mmol), Pd(OAc)2 (10 mol%),
oxidant (4.8 mmol), 4Å MS (1750 mg) in dioxane (10.0 mL) and was stirred at room temperature for 8
h. After the reaction was complete (as determined by TLC analysis), the reaction was cooled to room
temperature and 100 mL of water was added. Then, the mixture was extracted with ethyl acetate (30
mL × 3). The combined organic layers were washed with saturated brine and dried by anhydrous
Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified on a silica
gel column (petroleum ether/ethyl acetate = 4:1) to afford the targeted product 4a in 80% yield (573
mg).
Procedure B: A 15 mL Schlenk tube was charged with a mixture of 5 (0.2 mmol), Pd(OAc)2 (10
mol%), oxidant (0.60 mmol), C2CO3 (0.3 mmol), PivOH (0.06 mmol) in DCE (1.0 mL) and was stirred
in a 130 oC oil-bath for 10-15 h. After the reaction was complete (as determined by TLC analysis), the
reaction was cooled to room temperature and 10 mL of water was added. Then, the mixture was
extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated
brine and dried by anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the
residue was purified on a silica gel column (petroleum ether/ethyl acetate = 2:1) to afford the targeted
products 6a-6f.
2-(pyridin-2-yl)phenol (6a)15
1
Yield: 56% (19.2 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); H NMR (300
MHz, CDCl3): δ 14.40 (br s, 1H), 8.53 (d, J = 4.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88-7.81 (m, 2H),
7.36-7.25 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 6.9 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 160.0, 157.9, 145.9, 137.7, 131.5, 126.1, 121.5, 119.1, 118.8, 118.7, 118.6.
5-fluoro-2-(pyridin-2-yl)phenol (6b)15
o
Yield: 67% (25.4 mg), Mp 102-103 C, Yellow solid, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1);
1H NMR (300 MHz, CDCl3): δ 14.84 (br s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 7.86-7.75 (m, 3H), 7.26 (t, J
= 3.3 Hz, 1H), 6.74 (d, J = 10.5 Hz, 1H), 6.68-6.61 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
165.7, 163.7, 162.1, 162.0, 157.3, 145.7, 137.9, 127.6, 127.5, 121.4, 118.8, 115.4, 106.4, 106.2, 105.3,
105.1.
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5-methyl-2-(pyridin-2-yl)phenol (6c)15
1
5
6
7
8
Yield: 54% (20.0 mg), Colorless oil, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); H NMR (300
MHz, CDCl3): δ 14.36 (br s, 1H), 8.50 (d, J = 3.9 Hz, 1H), 7.91-7.80 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H),
7.22 (t, J = 6.0 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 7.8 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 159.9, 158.0, 145.8, 142.1, 137.6, 125.9, 121.0, 119.9, 118.9, 118.7, 116.3, 21.4.
5-ethyl-2-(pyridin-2-yl)phenol (6d)15
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
Yield: 57% (22.7 mg), Yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); 1H NMR (300 MHz,
CDCl3): δ 14.35 (br s, 1H), 8.51 (d, J = 3.3 Hz, 1H), 7.91-7.80 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.23
(t, J = 5.1 Hz, 1H), 6.90 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 2.70-2.63 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 160.0, 158.0, 148.4, 145.8, 137.6, 126.0, 121.0, 118.7, 117.6,
116.5, 28.7, 15.1.
5-methoxy-2-(pyridin-2-yl)phenol (6e)15
1
Yield: 48% (19.3 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); H NMR (300
MHz, CDCl3): δ 14.76 (br s, 1H), 8.46 (d, J = 3.6 Hz, 1H), 7.80 (t, J =3.3 Hz, 2H), 7.72 (d, J = 9.0 Hz,
1H), 7.20-7.16 (m, 1H), 6.57-6.50 (m, 2H), 3.85 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 162.4,
161.9, 157.9, 145.6, 137.6, 127.1, 120.5, 118.2, 112.1, 106.6, 102.2, 55.3.
4-(pyridin-2-yl)-[1,1'-biphenyl]-3-ol (6f)15
Yield: 51% (25.2 mg), Mp 144-145 oC, White solid, Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); 1H
NMR (300 MHz, CDCl3): δ 14.51 (br s, 1H), 8.55 (d, J = 3.9 Hz, 1H), 7.97 (d, J =8.4 Hz, 1H), 7.89 (d,
J = 8.4 Hz, 2H), 7.69 (d, J =7.5 Hz, 2H), 7.48 (t, J = 6.9 Hz, 2H), 7.40 (d, J = 6.6 Hz, 1H), 7.30 (d, J
=9.9 Hz, 2H), 7.20 (d, J = 8.1 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 160.3, 157.7, 145.9, 144.2,
140.3, 137.8, 128.8, 127.7, 127.0, 126.5, 121.4, 119.0, 117.8, 117.7, 116.9.
Procedure C: A oven-dried 15 mL Schlenk tube was charged with a mixture of 1 (0.2 mmol),
Pd(OAc)2 (10 mol%), oxidant (0.60 mmol) in dioxane (1.0 mL) and was stirred at room temperature
for 12-16 h. After the reaction was complete (as determined by TLC analysis), the reaction was cooled
to room temperature and 10 mL of water was added. Then, the mixture was extracted with ethyl acetate
(10 mL × 3). The combined organic layers were washed with saturated brine and dried by anhydrous
Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified on a silica
gel column (petroleum ether/ethyl acetate = 4:1) to afford the targeted products 7a-7r.
(5-bromoquinolin-8-yl)methyl 4-methylbenzenesulfonate (7a)
o
Yield: 79% (62.0 mg), Mp 114-116 C, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 8.85 (d, J = 4.2 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 8.4 Hz,
3H), 7.67 (d, J = 7.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.31 (d, J = 8.1 Hz, 2H), 5.78 (s, 2H), 2.44 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 150.4, 146.1, 144.7, 135.6, 133.2, 132.2, 130.0, 129.7, 128.9, 128.1,
127.3, 122.6, 122.5, 68.2, 21.6; IR (KBr): v 3087, 2920, 2853, 1586, 1491, 1459, 1439, 1295, 1200,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
1120, 871, 813, 778, 759; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C17H14BrNO3SNa 413.9770,
Found 413.9766.
(5-fluoroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7b)
7
8
9
1
Yield: 40% (26.5 mg), Colorless oil, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); H NMR (300
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
MHz, CDCl3): δ 8.88 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.75 (t, J = 6.9 Hz,
1H), 7.50-7.46 (m, 1H), 7.30 (t, J = 4.8 Hz, 2H), 7.20 (t, J = 8.7 Hz, 1H), 5.76 (s, 2H), 2.44 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 158.1 (d, JCF = 255.8 Hz), 150.7, 146.2, 144.6, 133.5, 129.6,
129.5, 129.2, 129.1, 128.1, 121.5, 118.9, 109.8, 109.7, 68.1, 21.6; IR (KBr): v 2922, 2850, 1556, 1491,
1477, 1409, 1205, 1180, 1122, 871, 843, 816, 786; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H15FNO3S 332.0751, Found 332.0745.
(5-chloroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7c)
Yield: 59% (41.0 mg), Pale yellow oil, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.87 (t, J = 2.7 Hz, 1H), 8.55 (t, J = 7.2 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.73 (d, J =
7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.31 (d, J = 8.1 Hz, 2H), 5.78 (s, 2H), 2.44 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 150.3, 146.0, 144.7, 133.3, 133.0, 132.0, 131.4, 129.7, 128.5,
128.1, 126.2, 126.0, 122.2, 68.2, 21.6; IR (KBr): v 3092, 2920, 2853, 1591, 1571, 1496, 1449, 1290,
1172, 1120, 858, 826, 778, 731; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15ClNO3S 348.0456,
Found 348.0452.
(5-iodoquinolin-8-yl)methyl 4-methylbenzenesulfonate (7d)
Yield: 61% (53.6 mg), Pale yellow oil, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.84 (d, J = 2.7 Hz, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.83 (d, J
= 8.1 Hz, 2H), 7.55-7.49 (m, 2H), 7.29 (d, J = 7.5 Hz, 2H), 5.78 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 150.3, 144.7, 141.2, 137.6, 133.3, 133.0, 129.9, 129.7, 128.9, 128.0, 126.1, 123.0,
99.1, 68.0, 21.6; IR (KBr): v 3090, 2918, 2850, 1594, 1559, 1494, 1447, 1290, 1165, 1120, 861, 811,
778, 719; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15INO3S 439.9812, Found 439.9808.
(5-nitroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7e)
Yield: 84% (60.2 mg), Mp 94-96 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); 1H
NMR (300 MHz, CDCl3): δ 9.00-8.94 (m, 2H), 8.36 (d, J = 8.1 Hz, 1H), 7.94-7.88 (m, 3H), 7.69-7.64
(m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 5.86 (s, 2H), 2.46 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 150.7,
145.2, 144.9, 140.1, 132.8, 132.2, 129.9, 128.1, 125.4, 124.3, 124.2, 120.7, 67.9, 21.7; IR (KBr): v
3104, 2922, 2853, 1594, 1521, 1504, 1442, 1245, 1192, 1170, 1157, 858, 811, 778, 731; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H15N2O5S 359.0696, Found 359.0699.
(6-fluoroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7f)
o
Yield: 72% (47.7 mg), Mp 103-104 C, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 8.79 (t, J = 2.1 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.1 Hz,
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 7.60 (d, J = 8.1 Hz, 1H), 7.45-7.33 (m, 4H), 5.81 (s, 2H), 2.45 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 160.0 (d, JCF = 247.3 Hz), 148.9, 144.9, 142.5, 135.5, 135.4, 133.1, 129.8, 128.8, 128.7,
128.1, 122.2, 118.4, 118.2, 110.9, 110.8, 67.7, 21.6; IR (KBr): v 3065, 2925, 2853, 1594, 1561, 1499,
1447, 1290, 1172, 1127, 878, 813, 783, 761; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15FNO3S
332.0751, Found 332.0750.
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
(6-chloroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7g)
o
Yield: 66% (45.9 mg), Mp 123-124 C, Pale yellow solid, Rf = 0.50 (petroleum ether / ethyl acetate =
4:1); 1H NMR (300 MHz, CDCl3): δ 8.83 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1
Hz, 2H), 7.74 (d, J =12.9 Hz, 2H), 7.47-7.42 (m, 1H), 7.34 (d, J = 7.8 Hz, 2H), 5.79 (s, 2H), 2.45 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 149.9, 144.8, 143.8, 135.2, 134.3, 133.2, 132.2, 129.8, 128.9,
128.6, 128.1, 126.7, 122.3, 67.7, 21.6; IR (KBr): v 3060, 2925, 2853, 1591, 1559, 1491, 1442, 1240,
1212, 1120, 873, 816, 783, 751; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H14ClNO3S 348.0456,
Found 348.0459.
(6-bromoquinolin-8-yl)methyl 4-methylbenzenesulfonate (7h)
o
Yield: 57% (44.7 mg), Mp 137-138 C, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 8.84 (t, J = 2.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.85 (t, J
= 10.2 Hz, 3H), 7.46-7.42 (m, 1H), 7.33 (d, J = 8.1 Hz, 2H), 5.79 (s, 2H), 2.45 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 150.0, 144.8, 144.1, 135.1, 134.3, 133.2, 131.4, 130.2, 129.8, 129.1, 128.1, 122.3,
120.2, 67.6, 21.6; IR (KBr): v 3065, 2918, 2848, 1596, 1584, 1494, 1449, 1292, 1232, 1182, 1135, 861,
811, 783, 749; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15BrNO3S 391.9951, Found 391.9947.
(6-nitroquinolin-8-yl)methyl 4-methylbenzenesulfonate (7i)
Yield: 75% (53.8 mg), Mp 140-141 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 9.04 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.37 (d,
J = 8.1 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.64-7.59 (m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 5.86 (s, 2H),
2.46 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 153.1, 147.3, 145.2, 145.1, 138.0, 135.2, 133.0,
129.9, 128.1, 126.9, 124.6, 123.2, 121.3, 67.3, 21.6; IR (KBr): v 3097, 2922, 2848, 1591, 1534, 1491,
1444, 1240, 1210, 1180, 1137, 881, 846, 788, 741; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H15N2O5S 359.0696, Found 359.0702.
(5-nitroquinolin-8-yl)methyl 4-nitrobenzenesulfonate (7j)
Yield: 42% (32.7 mg), Mp 130-132 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 9.00 (d, J = 8.7 Hz, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 9.0 Hz,
3H), 8.22 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.71-7.67 (m, 1H), 5.96 (s, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ 150.9, 145.8, 145.1, 141.6, 138.8, 132.4, 129.5, 126.1, 124.5, 124.4, 124.1, 120.8,
68.9; IR (KBr): v 3104, 2920, 2850, 1546, 1519, 1496, 1437, 1240, 1177, 1152, 1108, 871, 856, 811,
739; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12N3O7S 390.0390, Found 390.0394.
(5-nitroquinolin-8-yl)methyl 4-chlorobenzenesulfonate (7k)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
o
Yield: 68% (51.5 mg), Mp 98-100 C, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 9.01 (d, J = 8.7 Hz, 1H), 8.94 (d, J = 3.6 Hz, 1H), 8.38 (d, J = 7.8 Hz,
1H), 7.95 (d, J = 8.4 Hz, 3H), 7.70-7.66 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 5.89 (s, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ 150.8, 145.5, 145.0, 140.8, 139.5, 134.3, 132.3, 125.7, 124.3, 124.2, 120.8, 68.3;
IR (KBr): v 3095, 2925, 2853, 1589, 1531, 1496, 1439, 1280, 1185, 1160, 1115, 861, 831, 801, 756;
5
6
7
8
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
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12ClN2O5S 379.0150, Found 379.0150.
(5-nitroquinolin-8-yl)methyl benzenesulfonate (7l)
1
Yield: 61% (42.0 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 9.01 (d, J = 8.7 Hz, 1H), 8.94 (t, J = 2.4 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.02 (d, J =
7.5 Hz, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 6.0 Hz, 2H), 7.58 (t, J = 7.8 Hz, 2H), 5.90 (s, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 150.7, 145.3, 145.0, 139.9, 135.9, 134.0, 132.3, 129.3, 128.1,
125.5, 124.3, 124.2, 120.7, 68.1; IR (KBr): v 3107, 2920, 2848, 1589, 1519, 1501, 1447, 1245, 1185,
1157, 848, 801, 759, 734; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H13N2O5S 345.0540, Found
345.0540.
(5-nitroquinolin-8-yl)methyl methanesulfonate (7m)
Yield: 54% (30.5 mg), Mp 130-132 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 9.05 (t, J = 8.7 Hz, 2H), 8.42 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.5 Hz,
1H), 7.75-7.70 (m, 1H), 6.05 (s, 2H), 3.20 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 151.0, 145.6,
145.3, 139.7, 132.4, 126.1, 124.3, 120.9, 67.6, 37.8; IR (KBr): v 3012, 2920, 2848, 1591, 1516, 1464,
1409, 1260, 1160, 866, 803, 776, 724; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H11N2O5S
283.0383, Found 283.0383.
(5-nitroquinolin-8-yl)methyl (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (7n)
Yield: 65% (54.4 mg), Mp 116-118 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 9.05 (t, J = 5.4 Hz, 2H), 8.43 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.1 Hz,
1H), 7.74-7.70 (m, 1H), 6.13 (s, 2H), 3.85 (d, J = 15.0 Hz, 1H), 3.19 (d, J = 15.0 Hz, 1H), 2.61-2.52 (m,
1H), 2.43 (d, J = 18.6 Hz, 1H), 2.17-2.07 (m, 2H), 1.99 (d, J = 18.6 Hz, 1H), 1.80-1.71 (m, 1H),
1.53-1.44 (m, 1H), 1.16 (s, 3H), 0.93 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 214.5, 150.9, 145.4,
145.2, 140.3, 132.3, 125.9, 124.4, 124.3, 120.8, 68.2, 58.1, 48.1, 47.4, 42.8, 42.5, 26.9, 25.0, 19.8, 19.7;
IR (KBr): v 3102, 2947, 2918, 2848, 1587, 1519, 1452, 1409, 1245, 1167, 1152, 1130, 836, 813, 793,
741; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H23N2O6S 419.1271, Found 419.1284.
(5-bromoquinolin-8-yl)methyl benzenesulfonate (7o)
Yield: 41% (31.0 mg), Mp 98-99 oC, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); 1H
NMR (300 MHz, CDCl3): δ 8.84 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H),
7.82 (d, J = 7.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.55-7.50 (m, 3H), 5.81 (s, 2H); 13C{1H} NMR (125 MHz,
CDCl3): δ 150.4, 146.1, 136.3, 135.7, 133.7, 132.0, 129.9, 129.1, 129.0, 128.0, 127.4, 122.8, 122.6,
68.4; IR (KBr): v 3060, 2922, 2848, 1586, 1571, 1491, 1444, 1230, 1192, 1175, 853, 826, 759, 736;
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H13BrNO3S 377.9794, Found 377.9791.
(5-bromoquinolin-8-yl)methyl methanesulfonate (7p)
6
7
Yield: 56% (35.4 mg), Mp 94-96 oC, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); 1H
8
9
NMR (300 MHz, CDCl3): δ 8.97 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H),
7.75 (d, J = 7.5 Hz, 1H), 7.61-7.57 (m, 1H), 5.94 (s, 2H), 3.15 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 150.7, 146.4, 135.9, 131.9, 130.1, 129.9, 127.6, 123.3, 122.7, 68.1, 37.8; IR (KBr): v 3007,
2930, 2850, 1569, 1491, 1444, 1422, 1262, 1197, 1165, 866, 821, 776, 721; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C11H11BrNO3S 315.9638, Found 315.9642.
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
(5-bromoquinolin-8-yl)methyl
(7q)
(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate
o
Yield: 57% (51.6 mg), Mp 108-110 C, White solid, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1);
1H NMR (300 MHz, CDCl3): δ 8.97 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.75 (d,
J = 6.9 Hz, 1H), 7.58 (d, J = 4.2 Hz, 1H), 6.00 (t, J = 12.3 Hz, 2H), 3.85 (d, J = 15.0 Hz, 1H), 3.16 (d, J
= 15.0 Hz, 1H), 2.57-2.38 (m, 2H), 2.13-1.93 (m, 3H), 1.80-1.71 (m, 1H), 1.46 (d, J = 8.7 Hz, 1H),
1.13 (s, 3H), 0.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 214.5, 150.7, 146.4, 135.8, 132.3,
130.1, 129.7, 127.6, 123.1, 122.7, 68.3, 58.1, 48.0, 47.3, 42.8, 42.5, 26.9, 25.0, 19.9, 19.7; IR (KBr): v
3080, 2952, 2915, 1571, 1494, 1452, 1407, 1227, 1170, 1147, 1113, 846, 788, 754; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C20H23BrNO4S 452.0526, Found 452.0521.
(5-bromoquinolin-8-yl)methyl 4-chlorobenzenesulfonate (7r)
1
Yield: 22% (18.2 mg), Colorless oil, Rf = 0.50 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.84 (d, J = 3.3 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.89-7.82 (m, 3H), 7.67 (d, J = 7.5
Hz, 1H), 7.56-7.52 (m, 1H), 7.48 (d, J = 8.1 Hz, 2H), 5.81 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ
150.5, 140.3, 135.8, 134.8, 131.6, 129.9, 129.4, 129.3, 127.4, 123.1, 122.6, 68.7; IR (KBr): v 3090,
2922, 2848, 1586, 1559, 1494, 1474, 1297, 1227, 1170, 1120, 828, 778, 754, 706; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C16H12BrClNO3S 411.9404, Found 411.9406.
Procedure D: A oven-dried 15 mL Schlenk tube was charged with a mixture of 1 (0.2 mmol),
Pd(OAc)2 (10 mol%), oxidant (0.60 mmol) in dioxane (1.0 mL) and was stirred at room temperature
for 12-16 h. After the reaction was complete (as determined by TLC analysis), the reaction was cooled
to room temperature and 10 mL of water was added. Then, the mixture was extracted with ethyl acetate
(10 mL × 3). The combined organic layers were washed with saturated brine and dried by anhydrous
Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified on a silica
gel column (petroleum ether/ethyl acetate = 4:1) to afford the targeted products 8a-8g.
(5-bromoquinolin-8-yl)methanol (8a)
o
Yield: 69% (32.9 mg), Mp 113-115 C, Pale yellow solid, Rf = 0.30 (petroleum ether / ethyl acetate =
4:1); 1H NMR (300 MHz, CDCl3): δ 8.91 (d, J = 4.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.59-7.55 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 5.17 (s, 2H), 4.76 (br s, 1H); 13C{1H} NMR (75
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
5
6
7
8
9
MHz, CDCl3): δ 149.7, 147.7, 138.3, 136.3, 130.1, 128.1, 127.8, 122.3, 121.3, 64.2; IR (KBr): v 3361,
3055, 2920, 2850, 1559, 1494, 1467, 1429, 1287, 1247, 1147, 1113, 876, 831, 778, 729; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C10H9BrNO 237.9862, Found 237.9872.
Quinolin-8-ylmethanol (8b)
Yield: 46% (14.6 mg), Mp 68-70 oC, Yellow solid, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); 1H
NMR (300 MHz, DMSO): δ 8.89 (d, J = 4.2 Hz, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.84 (t, J = 7.5 Hz, 2H),
7.63-7.53 (m, 2H), 5.17 (s, 2H); 13C{1H} NMR (75 MHz, DMSO): δ 149.9, 145.3, 140.3, 136.9, 127.9,
126.9, 126.8, 126.6, 121.8, 60.0; IR (KBr): v 3299, 2920, 2868, 1594, 1576, 1499, 1447, 1295, 1232,
1757, 1127, 866, 821, 783, 759; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H10NO 160.0757, Found
160.0754.
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
(5-methylquinolin-8-yl)methanol (8c)
Yield: 49% (17.0 mg), Pale yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.88 (d, J = 4.2 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.32 (d, J = 7.2
Hz, 1H), 5.17 (s, 2H), 2.68 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 148.5, 147.4, 136.1, 134.2,
133.3, 127.9, 127.5, 126.7, 120.7, 64.8, 18.5; IR (KBr): v 3366, 3207, 2963, 2918, 2850, 1599, 1501,
1457, 1409, 1292, 1235, 1210, 1152, 838, 811, 776, 709; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C11H12NO 174.0913, Found 174.0915.
(6-methylquinolin-8-yl)methanol (8d)
Yield: 68% (23.6 mg), Pale yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3): δ 8.81 (d, J = 4.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.44-7.40 (m, 2H),
5.19 (s, 2H), 2.53 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 148.1, 145.8, 137.7, 136.3, 136.1, 130.1,
128.7, 126.0, 121.2, 64.8, 21.5; IR (KBr): v 3361, 3259, 2920, 2848, 1584, 1494, 1467, 1439, 1247,
1205, 1120, 881, 856, 776, 701; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H12NO 174.0913, Found
174.0912.
(7-methylquinolin-8-yl)methanol (8e)
1
Yield: 35% (12.1 mg), Yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.82 (d, J = 3.9 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.39-7.35
(m, 2H), 5.28 (s, 2H), 2.56 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 148.6, 147.6, 136.8, 136.5,
134.8, 130.2, 127.0, 126.6, 120.2, 60.5, 19.6; IR (KBr): v 3426, 2957, 2918, 2850, 1596, 1556, 1504,
1457, 1270, 1180, 1122, 896, 873, 836, 798; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H12NO
174.0913, Found 174.0911.
(3-ethylquinolin-8-yl)methanol (8f)
1
Yield: 46% (17.2 mg), Yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.76 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.54-7.44
(m, 2H), 5.21 (s, 2H), 2.90-2.83 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
150.4, 145.6, 137.8, 136.8, 134.2, 128.5, 127.0, 126.8, 126.4, 64.8, 26.3, 15.2; IR (KBr): v 3414, 2965,
2922, 2850, 1584, 1494, 1457, 1419, 1247, 1177, 1155, 893, 871, 768, 716; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C12H14NO 188.1070, Found 188.1066.
7
8
9
1-(quinolin-8-yl)ethan-1-ol (8g)
1
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
Yield: 51% (17.7 mg), Yellow oil, Rf = 0.30 (petroleum ether / ethyl acetate = 4:1); H NMR (300
MHz, CDCl3): δ 8.87 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.60 (d, J
= 6.3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.47-7.42 (m, 1H), 6.20 (br s, 1H), 5.52-5.45 (m, 1H), 1.76 (d, J
= 6.6 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 148.4, 146.5, 141.8, 137.1, 128.7, 127.1, 126.4,
120.9, 70.2, 24.1; IR (KBr): v 3416, 2967, 2922, 2848, 1596, 1576, 1496, 1447, 1277, 1237, 1162,
1113, 876, 826, 791, 761; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H12NO 174.0913, Found
174.0916.
Procedure E: A 15 mL Schlenk tube was charged with a mixture of 5 (0.2 mmol), Pd(OAc)2 (10
mol%), ligand (0.04 mmol), sulphonate hypervalent-iodine (0.6 mmol), AgOAc (0.1 mmol) in toluene
o
(1.0 mL) and was stirred in a 100 C oil-bath for 12-18 h. After the reaction was complete (as
determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of water was
added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers
were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified on a silica gel column (petroleum ether/ethyl acetate =
8:1) to afford the targeted product 9a-9h.
2-([1,1'-biphenyl]-2-yl)pyridine (9a) 16
Yield: 63% (29.1 mg), Mp 73-75 oC, Yellow solid, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); 1H
NMR (300 MHz, DMSO): δ 8.55 (d, J = 4.8 Hz, 1H), 7.61-7.48 (m, 4H), 7.44-7.41 (m, 1H), 7.26-7.20
(m, 4H), 7.09 (t, J = 4.8 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO): δ 159.1,
149.7, 141.3, 140.6, 139.7, 136.1, 130.9, 130.8, 129.7, 129.0, 128.6, 128.0, 127.2, 125.3, 122.2; HRMS
(ESI): Exact mass calcd for C17H13N [M+H]+, 232.1121; Found: 232.1127.
2-(4-methyl-[1,1'-biphenyl]-2-yl)pyridine (9b) 16
1
Yield: 44% (21.6 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 8.66 (d, J = 4.5 Hz, 1H), 7.55 (s, 1H), 7.41-7.34 (m, 2H), 7.31-7.23 (m, 4H), 7.17-7.09
(m, 3H), 6.88 (d, J = 7.8 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 159.4, 149.4, 141.3,
139.2, 137.8, 137.4, 135.2, 131.1, 130.5, 129.7, 129.3, 128.0, 126.5, 125.5, 121.3, 21.1; HRMS (ESI):
Exact mass calcd for C18H15N [M+H]+, 246.1277; Found: 246.1280.
2-(5-methyl-[1,1'-biphenyl]-2-yl)pyridine (9c) 16
1
Yield: 50% (24.5 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 8.65-8.63 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.32-7.24 (m, 5H),
7.20-7.16 (m, 2H), 7.12-7.07 (m, 1H), 6.88 (t, J = 8.4 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
CDCl3): δ 159.2, 149.4, 141.5, 140.5, 138.4, 136.7, 135.1, 131.3, 130.5, 129.7, 129.6, 128.4, 128.0,
127.6, 126.6, 125.4, 121.1, 21.2; HRMS (ESI): Exact mass calcd for C18H15N [M+H]+, 246.1277;
Found: 246.1286.
7
8
9
2-(5-methoxy-[1,1'-biphenyl]-2-yl)pyridine (9d) 16
1
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
Yield: 39% (20.4 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 8.63-8.61 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.39-7.33 (m, 1H), 7.28-7.25 (m, 3H),
7.21-7.16 (m, 2H), 7.10-7.02 (m, 2H), 6.98 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.90 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 159.7, 158.9, 149.3, 142.0, 141.4, 135.1, 132.3, 131.9, 129.6, 129.5,
128.1, 127.6, 126.9, 125.4, 120.9, 115.7, 113.3, 55.4; HRMS (ESI): Exact mass calcd for C18H15NO
[M+H]+, 262.1236; Found: 262.1238.
2-([1,1'-biphenyl]-2-yl)-3-methylpyridine (9e) 16
Yield: 36% (17.7 mg), Yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); 1H NMR (300 MHz,
CDCl3): δ 8.51 (d, J = 4.5 Hz, 1H), 7.50-7.40 (m, 4H), 7.33-7.30 (m, 1H), 7.19-7.10 (m, 6H), 1.77 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3): δ 159.5, 146.5, 141.1, 140.7, 139.4, 137.5, 131.7, 129.9, 129.7,
129.3, 128.4, 127.8, 127.4, 126.6, 122.1, 18.8; HRMS (ESI): Exact mass calcd for C18H15N [M+H]+,
246.1277; Found: 246.1282.
2-(4'-methyl-[1,1'-biphenyl]-2-yl)pyridine (9f) 16
1
Yield: 40% (19.6 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 8.66 (d, J = 5.1 Hz, 1H), 7.72-7.69 (m, 1H), 7.49-7.38 (m, 4H), 7.15-7.07 (m, 5H),
6.92 (d, J = 8.4 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 149.4, 140.6, 139.4, 138.4,
136.4, 135.2, 130.5, 130.5, 129.6, 129.5, 128.8, 128.5, 128.4, 127.4, 125.4, 121.3, 21.1; HRMS (ESI):
Exact mass calcd for C18H15N [M+H]+, 246.1277; Found: 246.1286.
2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)pyridine (9g) 16
1
Yield: 39% (23.3 mg), Pale yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 8.64-8.62 (m, 1H), 7.73-7.70 (m, 1H), 7.54-7.43 (m, 6H), 7.28 (t, J = 5.7 Hz, 2H),
7.18-7.13 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.8, 149.5, 145.1,
139.6, 139.2, 135.6, 130.6, 130.4, 129.9, 128.7, 128.3, 125.2, 125.0, 125.0, 121.7; HRMS (ESI): Exact
mass calcd for C18H12F3N [M+H]+, 300.0995; Found: 300.0999.
10-phenylbenzo[h]quinoline (9h) 16
Yield: 40% (20.4 mg), Yellow oil, Rf = 0.40 (petroleum ether/ethyl acetate = 8:1); 1H NMR (300 MHz,
CDCl3): δ 8.46-8.43 (m, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.7 Hz,
1H), 7.73-7.68 (m, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.43-7.32 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3):
δ 146.9, 146.8, 146.4, 141.7, 135.2, 135.0, 131.5, 129.0, 128.3, 127.9, 127.4, 127.2, 127.0, 125.9, 125.7,
121.1, 29.7; HRMS (ESI): Exact mass calcd for C19H13N [M+H]+, 256.1121; Found: 256.1124.
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
Genaral procedure: Synthetic applications
5
6
7
8
Path A: A oven-dried 15 mL Schlenk tube was charged with 7a (0.2 mmol), SiO2 (0.6 mmol) in a
mixture of PE (1 mL) and EA (0.05 mL), which was stirred at room temperature for 5 h. After the
reaction was complete (as determined by TLC analysis), the reaction was cooled to room temperature
and 10 mL of water was added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The
combined organic layers were washed with saturated brine and dried by anhydrous Na2SO4. The
solvent was evaporated under reduced pressure, and the residue was purified on a silica gel column
(petroleum ether/ethyl acetate = 2:1) to afford the corresponding product 8a.
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
o
Yield: 87% (41.4 mg), Mp 113-115 C, Pale yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate =
2:1); 1H NMR (300 MHz, CDCl3): δ 8.91 (d, J = 4.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.59-7.55 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 5.17 (s, 2H), 4.76 (br s, 1H); 13C{1H} NMR (75
MHz, CDCl3): δ 149.7, 147.7, 138.3, 136.3, 130.1, 128.1, 127.8, 122.3, 121.3, 64.2; IR (KBr): v 3361,
3055, 2920, 2850, 1559, 1494, 1467, 1429, 1287, 1247, 1147, 1113, 876, 831, 778, 729; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C10H9BrNO 237.9862, Found 237.9872.
Path B: A oven-dried 15 mL Schlenk tube was charged with a mixture of 7e (0.2 mmol), t-BuCl (0.24
o
mmol), [pmIm]Br (0.4 mmol) and was stirred in a 60 C oil-bath for 4 h. After the reaction was
complete (as determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of
water was added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined
organic layers were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified on a silica gel column (petroleum
ether/ethyl acetate = 8:1) to afford the targeted product 10.
o
Yield: 78% (34.7 mg), Mp 99-100 C, Pale yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate =
8:1); 1H NMR (300 MHz, CDCl3): δ 9.11 (t, J = 3.9 Hz, 1H), 9.03 (d, J = 8.7 Hz, 1H), 8.35 (d, J = 7.8
Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.72-7.68 (m, 1H), 5.25 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ
151.1, 145.5, 143.7, 132.3, 128.5, 127.6, 124.3, 124.2, 121.3, 27.9; IR (KBr): v 3047, 2922, 2853, 1594,
1516, 1496, 1404, 1237, 1212, 1155, 1122, 873, 831, 791, 739; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C10H8ClN2O2 223.0269, Found 223.0269.
Path C: A oven-dried 15 mL Schlenk tube was charged with a mixture of 7e (0.2 mmol), t-BuBr (0.24
mmol), [pmIm]Br (0.4 mmol) and was sonicated in an ultrasonic bath for 0.5 h. After the reaction was
complete (as determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of
water was added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined
organic layers were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified on a silica gel column (petroleum
ether/ethyl acetate = 8:1) to afford the corresponding product 11.
o
Yield: 95% (50.7 mg), Mp 106-107 C, Pale yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
4
5
6
7
8
9
8:1); 1H NMR (300 MHz, CDCl3): δ 9.12 (d, J = 2.1 Hz, 1H), 9.03 (d, J = 8.7 Hz, 1H), 8.36 (d, J = 7.8
Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.73-7.69 (m, 1H), 5.26 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ
151.1, 145.5, 143.7, 132.3, 128.5, 124.3, 124.2, 121.3, 27.9; IR (KBr): v 2965, 2920, 2853, 1591, 1511,
1496, 1404, 1250, 1217, 1160, 876, 831, 791, 714; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C10H8BrN2O2 266.9764, Found 266.9756.
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
Path D: A oven-dried 15 mL Schlenk tube was charged with a mixture of 7e (0.2 mmol), t-BuI (0.24
mmol), [pmIm]Br (0.4 mmol) and was sonicated in an ultrasonic bath for 0.5 h. After the reaction was
complete (as determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of
water was added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined
organic layers were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified on a silica gel column (petroleum
ether/ethyl acetate = 8:1) to afford the corresponding product 12.
o
Yield: 71% (44.6 mg), Mp 126-127 C, Pale yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate =
8:1); 1H NMR (300 MHz, CDCl3): δ 9.13 (d, J = 2.4 Hz, 1H), 9.06 (d, J = 8.7 Hz, 1H), 8.31 (d, J = 7.8
Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.72-7.68 (m, 1H), 5.21 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ
150.6, 145.9, 145.2, 132.2, 127.6, 124.6, 124.4, 121.6, 0.87; IR (KBr): v 3037, 2922, 2853, 1561, 1511,
1494, 1402, 1235, 1165, 876, 851, 833, 793; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H8IN2O2
314.9625, Found 314.9627.
Path E: A oven-dried 15 mL Schlenk tube was charged with a mixture of 7e (0.2 mmol), AgNO3 (0.4
mmol) in t-AmOH (1 mL) and was stirred in a 120 oC oil-bath for 6 h. After the reaction was complete
(as determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of water was
added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers
were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified on a silica gel column (petroleum ether/ethyl acetate =
8:1) to afford the corresponding product 13.
1
Yield: 51% (23.8 mg), Yellow oil, Rf = 0.40 (petroleum ether / ethyl acetate = 8:1); H NMR (300
MHz, CDCl3): δ 9.05 (d, J = 9.0 Hz, 2H), 8.40 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.75-7.71
(m, 1H), 6.28 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 151.2, 145.6, 138.7, 132.3, 126.1, 124.4,
124.1, 121.1, 70.2; IR (KBr): v 3104, 2913, 2850, 1594, 1516, 1499, 1402, 1277, 1232, 1190, 1157,
858, 833, 806, 778, 736; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H8N3O4 234.0509, Found
234.0511.
Path F: To a solution of sodium azide (0.30 mmol) in water (1 mL) in a two necked round bottom
flask equipped with a stirring bar and reflux condenser was added a solution of 7e (0.20 mmol) in THF
(0.2 mL) and the mixture was heated to reflux in an oil-bath for 3 h. After the reaction was complete
(as determined by TLC analysis), the reaction was cooled to room temperature and 10 mL of water was
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers
were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified on a silica gel column (petroleum ether/ethyl acetate =
8:1) to afford the corresponding product 14.
Yield: 94% (43.1 mg), Mp 93-94 oC, Yellow solid, Rf = 0.40 (petroleum ether / ethyl acetate = 8:1); 1H
NMR (300 MHz, CDCl3): δ 9.05 (t, J = 5.1 Hz, 2H), 8.40 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
7.72-7.68 (m, 1H), 5.19 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 150.9, 145.8, 145.2, 142.1, 132.3,
126.3, 124.4, 124.2, 121.1, 51.1; IR (KBr): v 3047, 2922, 2853, 1594, 1519, 1501, 1432, 1282, 1195,
1162, 1130, 878, 846, 803, 776; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H8N5O2 230.0673,
Found 230.0676.
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
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.xxxxxx.
1H and 13C spectra for 3a-3m, 4a-4l, 6a-6f, 7a-7r, 8a-8g, 9a-9h, 10-14 and 31P spectra for 3a-3m, 4a-4l
(pdf)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: heyimiao@gxtc.edu.cn (Y. M. H.).
*E-mail: huangcs@gxtc.edu.cn (C. S. H.).
ORCID
Yimiao He: 0000-0003-0530-7426
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by National Natural Science Foundation of China (21702034,
21861007), Natural Science Foundation of Guangxi Province (2017GXNSFBA198089), “BAGUI
Scholar” Program of Guangxi Province of China.
REFERENCES
(1) Corbridge, D. E. C. Phosphorus 2000. Chemistry, Biochemistry & Technology; Elsevier:
Oxford, 2000; Chapters 10 and 11.
(2) (a) Hecker, S. J.; Erion, M. D. Prodrugs of Phosphates and Phosphonates. J. Med. Chem. 2008,
51, 2328; (b) Pisani, L.; Barletta, M.; Soto-Otero, R.; Nicolotti, O.; Mendez-Alvarez, E.; Catto,
ACS Paragon Plus Environment