Suzuki-Miyaura cross-coupling reactions of unprotected haloimidazoles

Article abstract of DOI:10.1021/jo501326r

An efficient protocol for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of unprotected haloimidazoles is reported. The relatively mild reaction conditions allow for ready access to a wide array of functionalized imidazole derivatives in good to excellent yields. The synthetic utility of this method is demonstrated by the total synthesis of nortopsentin D.

Full text of DOI:10.1021/jo501326r

Subscriber access provided by NATIONAL SUN YAT SEN UNIV
Note
Suzuki-Miyaura Cross-coupling Reactions of Unprotected Haloimidazoles
Jiajing Tan, Yonggang Chen, Hongmei Li, and Nobuyoshi Yasuda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501326r • Publication Date (Web): 20 Aug 2014
Downloaded from http://pubs.acs.org on August 21, 2014
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Suzuki-Miyaura Cross-coupling Reactions of Unprotected
Haloimidazoles
8
9
Jiajing Tan,* Yonggang Chen,* Hongmei Li, Nobuyoshi Yasuda
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
Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065,
United States.
E-mail: jiajing.tan@merck.com, yonggang.chen@merck.com
ABSTRACT: An efficient protocol for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of
unprotected haloimidazoles is reported. The relatively mild reaction conditions allow for ready access to
a wide array of functionalized imidazole derivatives in good to excellent yields. The synthetic utility of
this method is demonstrated by the total synthesis of Nortopsentin D.
The Suzuki-Miyaura cross-coupling (SMC) reaction is one of the most widely utilized coupling reactions
in the pharmaceutical industry due to the mild reaction conditions, functional group compatibility and
accessibility of the organoboron reagents.1-3 The SMC reaction of heteroaryl halides is particularly useful
as heterocycles are ubiquitous in natural products and active pharmaceutical ingredients;4,5 however,
catalysis is sometimes inefficient due to competitive substrate and/or product inhibition, often requiring
laborious protecting group strategies to recover reactivity.6 In principle, SMC methods that can tolerate
the Lewis-basic functionality manifest in many heterocyclic motifs would be highly valued in parallel
synthesis in endeavors.4 To this end, our laboratories have been focusing on the development of SMC
reactions of heterocyclic moieties.7
Figure 1 Imidazole-containing bioactive molecules.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
1
2
3
4
5
6
7
8
Imidazoles are an important class of structural motifs in many bioactive natural products and medicines.
Based upon extensive research by medicinal chemists, many imidazole-containing molecules have
displayed promising pharmacological activities,8 which makes them compelling targets for the synthetic
community.1,4,9 For instance, Nortopsentin, a bis-indole alkaloids family isolated from the deep sea
sponge Spongosorites ruetzleri, possesses potent antitumor, antiviral and antiproliferative activities,10
whereas the antiviral reagent BMS-790052 is used to treat chronic Hepatitis C infections (Figure 1).11
Conventionally, imidazole derivatives can be synthesized from suitably functionalized acyclic
precursors.9 While such de novo synthetic strategies are attractive for manufacturing route
development, they are sub-optimal for fast exploration of structure-activity relationships where time
cycle concerns are paramount.1,4 With these considerations in mind, we devised a SMC-based strategy
where installation of the pre-constructed imidazole ring could be accomplished in a single operation. At
the onset of this work, only a limited number of examples of SMC reactions with haloimidazoles had
been reported, many of which suffered from moderate yields, limited substrate scope, and in most
cases, required protection of the imidazole NH group.7c,12 To date, the unprotected haloimidazoles are
recognized as a class of challenging substrates for transition metal-catalyzed coupling reactions.13
Undoubtedly, the lack of an efficient Pd-based catalyst has limited the employment of divergent SMC-
strategies towards functionalized imidazoles.12 This apparent methodological gap prompted us to search
for a more generalized active catalyst. Herein, we report our efforts toward an efficient palladium-
catalyzed SMC protocol, which is amenable to unprotected haloimidazoles.
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
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
Chart 1. Phosphine Ligands Screena-c
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
a2a/2b (10 μmol), 1a/1b (1.25 equiv.), Pd(OAc)2 (2.5 mol%), ligand (6 mol%),
biphenyl (internal standard, 0.25 equiv.), aq. K2CO3 solution (0.025 ml, 1.2 M)
b
c
and organic solvent (0.075 ml). Solution yields. Select ligands shown. For
details, see Supporting Information.
Our studies commenced with the evaluation of the SMC reactions of 3-pyridylboronic acid 1a and
phenylboronic acid 1b versus two imidazole halides viz. (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-
yl)pyrrolidine-1-carboxylate 2a12f (Chart 1, equation 1) and 2-methyl-4-iodoimidazole 2b, respectively
(equation 2). High-throughput experimentation protocols developed within our catalysis and
automation group were used to rapidly evaluate a series of electronically and sterically diverse
phosphine ligands.14 Interestingly, XPhos, a highly efficient and general ligand for the SMC
reactions,2a,2d,13a,15 gave moderate yields in both cases. In fact, of the 24 phosphine ligands evaluated,14
only A-taPhos16 and CataCXium A17 provided the desired coupling products in excellent yields. The ligand
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 18
1
2
3
4
5
6
7
8
1,1’-bis(diphenylphosphino)ferrocene (DPPF), which has been reported by Bellina et al. to catalyze the
reaction of bromoimidazole exclusively with aromatic boronic acids,12c gave lower yield than A-taPhos or
CataCXium A.
9
Table 1 Reaction condition optimizationa
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
entry
solvent
base
yield(%)b
98(95)c
1
2
DME
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Na2CO3
Cs2CO3
K2CO3
94
3
PhMe
CPMe
2-MeTHF
dioxane
DME
3
4
21
5
88
6
97
7
93
8
DME
90
9
10d
DME
85
DME
99
a2a (10 μmol), 1a (1.25 equiv.), Pd(OAc)2 (2.5 mol%), A-taPhos (6 mol%),
base (3 equiv.), biphenyl (internal standard, 0.25 equiv.), aq. K2CO3 (0.025
ml, 1.2M) and organic solvent (0.075 ml). bSolution yields. Yield in
c
d
parentheses is the isolated yield after column chromatography. Catalyst
loading: 1 mol%.
After identifying the most active ligand system for the SMC reaction of haloimidazoles, an extensive
survey of solvents and bases was conducted (Table 1). First, the reaction conditions for 1a and 2a were
validated at 0.2 mmol scale, giving the desired product P1 with 95% isolated yield (entry 1). Other
solvents, including toluene (PhMe), dimethylformamide (DMF), cyclopentyl methyl ether (CPME), 2-
methyltetrahydrofuran (2-MeTHF) and dioxane were investigated under otherwise identical reaction
conditions with only dioxane offering comparable results (entries 2-6). Evaluation of a series of inorganic
bases also failed to further improve the yield (entries 7-9). Notably, when the catalyst loading was
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
reduced to 1.0 mol%, the reaction still performed comparably, providing the desired coupling product in
essentially the same yield (entry 10).14
7
8
Table 2 Substrate scopea,b
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
1
2
1
aReaction performed on a 0.2 mmol scale. Yield determined by H NMR analysis of
3
4
5
6
7
8
unpurified reaction mixture using an IS. bNumbers in parentheses refer to isolated yields
c
d
after supercritical fluid chromatography. Vinyl MIDA boronate used. Reaction run in
dioxane at 115˚C. eCataCXium A used instead.
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
A wide range of haloimidazoles and organoboron reagents were then examined to evaluate the scope
of the reaction (Table 2). In all reactions of aryl- and vinyl-boron reagents with 2a, the coupling products
(P2-P5) were obtained in good yield (Table 2, part a). It is notable that boronic acids with attenuated
nucleophilicity such as 1a and 4-(ethoxycarbonyl)phenylboronic acid 1c also provided the coupling
products P1 and P3 in 97 and 98% yields respectively. Subjection of Molander’s potassium
organotrifluoroborates (R-BF3K) to identical reaction conditions also led to the desired coupling products
(P1, P2, P5) in similar yields, highlighting the versatility of this methodology with respect to the
nucleophilic component.18 The utility of this methodology for medicinal chemistry applications was
further showcased by the coupling of various heteroaryl boronic acids.4 Under the optimized reaction
conditions, the resultant products (P6-P8) were all obtained with good yields. Next, both 2-
methylimidazole bromides and iodides were examined with various organoboronic acids, all of which
underwent the SMC reaction to afford the desired products (P9-P11) in good yields albeit a higher
reaction temperature was required.13a
Since the 2,4(5)-di-arylimidazoles had recently been identified as potential human sodium channel
inhibitors, we next focused our attention on the SMC reaction of 2-phenyl-5-bromoimidazoles (part b).19
The reactions proceeded in good yield (P12-P15) for both aryl- and heteroaryl-boronic acids. In addition,
4-bromo-2H-imidazoles were coupled with a variety of aryl and heteroaryl boronic acids under the
optimized reaction conditions to afford the corresponding SMC adducts (P16-P18) in good yields (part c).
Products such as these are suitable for further functionalization at the 2-position via direct arylation,12c,20
thus providing orthogonal access to the 2,4(5)-di-substituted imidazoles. Although our initial studies
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
focused on the arylation reaction of imidazoles, we next wondered whether other unprotected
nitrogen-rich heterocycles would be suitable substrates. In fact, the coupling reactions of
bromoindazoles and bromopyrazoles under similar reaction conditions also furnished the resultant
products (P19-P21) in good yields, increasing the substrate scope of our method (part d).
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 SMC reaction of multibromo-imidazoles.
aReaction performed on a 0.3 mmol scale. bYield determined
by 1H NMR of unpurified reaction mixture using an IS.
To further demonstrate the synthetic value of this protocol, we next sought to extend the reaction
scope to di- and tri-bromoimidazoles (Scheme 1). To our delight, the double- and triple-SMC reactions
proceeded efficiently to give the chemiluminescent molecule Lophine P22 in 96 and 92% yield from 4,5-
di- and 2,4,5-tri-bromoimidazole respectively.21 Next, we investigated the double-SMC reaction of 2,4-
di-bromoimidazole (2j) with 1b. In this case, a higher reaction temperature was required, resulting in a
slightly diminished yield (88% yield) of the desired coupling product P12.22
Finally, we implemented this methodology in a total synthesis of Nortopsentin D (Scheme 2).23 The
desired bis-indole alkaloid P23 was prepared from commercially available 2j and N-Boc-indole-3-boronic
acid 1l, using the conditions outlined in Scheme 2. Double-SMC reaction followed by in situ thermolysis
of the Boc group afforded P23 in 68% yield.24 This concise synthesis represents the shortest route to
Nortopsentin D published to date, further underscoring the synthetic power of our protocol.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
1
2
3
4
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
a
Scheme 2 Total synthesis of Nortopsentin D. Reaction performed on a
b
1
0.3 mmol scale. Yield determined by H NMR of unpurified reaction
mixture using an IS.
In conclusion, we have developed an efficient Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of
unprotected haloimidazoles. The broad substrate scope with respect to various aryl and heteroaryl
boronic acids together with the mild reaction conditions enabled the rapid synthesis of a wide array of
functionalized imidazoles. The synthetic utility of this protocol was demonstrated by synthesizing
Nortopsentin D from commercially available reagents in a two-step, one-pot process. Compared to the
classical approaches for imidazole synthesis, we anticipate that our methodology will provide an
efficient alternative for divergent parallel synthesis efforts.
EXPERIMENTAL SECTION
General Methods. All reactions were carried out under nitrogen atmosphere in a glove box or using
standard Schlenk techniques. The reactions were monitored by either analytical thin-layer
chromatography using pre-coated silica gel plates with F254 indicator or reversed-phase UPLC MS.
Visualization was accomplished by UV light (254 nm). The crude product could be purified either using a
preparative thin layer chromatography (TLC) plate or preparative supercritical fluid chromatography
(SFC). The SFC conditions are optimized for purity consideration. Room temperature means 20±1 ºC. 1H
NMR spectra was recorded on a 400/500 MHz spectrometer at ambient temperature. Data is reported
as follows: 1) chemical shift in parts per million (δ, ppm) from CDCl3 (7.26 ppm), MeOH-d4 (3.31 ppm),
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
DMSO-d6 (2.50 ppm) and acetone-d6 (2.05 ppm); 2) multiplicity (s = singlet, bs = broad singlet, d =
doublet, t = triplet, q = quartet, and m = multiplet); 3) coupling constants (Hz). 13C NMR spectra was
recorded on a 100/125 MHz spectrometer at ambient temperature. Chemical shifts are reported in ppm
from CDCl3 (77.16 ppm), MeOH-d4 (49.15 ppm), DMSO-d6 (39.51 ppm) and acetone-d6 (29.92 ppm).
Trifluroacetic acid (TFA) was occasionally used as the additive for NMR experiments. HRMS data was
obtained on a Q-TOF mass spectrometer. All commercial materials were used as received unless
otherwise noted.14
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 Procedures for SMC Reactions in Table 2.
To an oven-dried microwave vial was added heteroaryl halide (0.2 mmol, 1.00 equiv.), boronic acid (0.25
mmol, 1.25 equiv.) and 1.0 ml solvent (DME or dioxane) in a glove box. The pre-mixed solution of
Palladium(II) acetate (0.0075 mmol, 2.5 mol%.) and ligand (A-taPhos or CataCXium A (0.0018 mmol, 6
mol%)) in 0.50 ml Dioxane or DME was then added followed by the final addition of the aqueous K2CO3
solution (0.50 ml, 1.2 M). At this point, the microwave vial was sealed and might bring out of the glove
box. The mixture was then heated to certain reaction temperature and stirred vigorously for 18-24 h.
After the UPLC-MS analysis indicated the complete consumption of starting materials, the reaction was
then cooled to room temperature and subsequently filtered through a short plug of Celite, the filter
cake was washed with ethyl acetate (25 mL), and the combined organic solvent was removed in vacuo.
The NMR yield was then determined using 1,3,5-trimethoxybenzene as internal standard (D1 needs to
be set as 10 or 30). The crude product could be purified by either preparative SFC (MeOH/CO2 or
MeOH+diethylamine/CO2) or preparative TLC plates (DCM/MeOH or EtOAc/MeOH). Compound P9, P12,
P16, P17, P18, P20 and P21 are known compounds.14
General Procedures for Reactions in Scheme 1 and 2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
1
2
3
4
5
6
7
8
9
To a microwave vial was added with the heteroaryl halide (0.3 mmol, 1.00 eq.), boronic acid (0.75 mmol,
2.5 equiv. or 1.5 mmol, 5 equiv.) in 1.5 ml dioxane or DME. A solution of Palladium(II) acetate (0.0075
mmol, 2.5 mol%.) and ligand (A-taPhos or CataCXium A, 0.0018 mmol, 6 mol%) in 0.75 ml 1,4-dioxane or
DME was then added followed by the final addition of the aqueous K2CO3 solution (0.75ml, 2.4 or 4.8 M).
The microwave vial was then sealed using a biotag cap equipped with a septum and might bring out of
the glove box. The reaction mixture was heated to certain reaction temperature and stirred vigorously.
After the UPLC-MS analysis indicated the complete consumption of starting materials, the reaction was
then cooled to room temperature and subsequently filtered through a short plug of Celite, the filter
cake was washed with ethyl acetate (25 mL), and the combined organic solvent was removed in vacuo.
The NMR yield was then determined using 1,3,5-trimethoxybenzene as internal standard (D1 needs to
be set as 10 or 30). The crude products could be purified by either preparative SFC (MeOH/CO2 or
MeOH+diethylamine/CO2) or preparative TLC plates (DCM/MeOH or EtOAc/MeOH). Compound P22 and
P23 are known compounds.14
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
(S)-tert-butyl 2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P1). For reaction with
boronic acids, 98% yield (62 mg). For reaction with potassium organotrifluoroborates, 97% yield (61 mg).
White solid. mp: 86-88 ˚C . 1H NMR (400 MHz, CDCl ): 8.95 (s, 1H), 8.47 (s, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.31
3
(s, 2H) 4.99-4.98 (m, 2H), 3.44-3.43 (m, 1H), 2.99-2.96 (m, 1H), 2.34-1.95 (m, 3H), 1.49-1.37 (m, 9H); 13C NMR
(100 MHz, CDCl ): 156.5, 150.2, 147.2, 146.1, 145.1, 132.2, 130.0, 123.7, 115.0, 80.5, 54.2,
3
47.4, 32.9, 28.5, 28.3, 24.8; Calculated for C17H22N4O2 [M-H]+ 315.1816 found (ES+) 315.1826.
(S)-tert-butyl 2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P2). Yield: 99% (61 mg). Light
1
yellow oil. H NMR (400 MHz, MeOH-d4): 7.67 (d, 7.32 Hz, 2H), 7.36-7.19 (m, 4H), 4.98-4.85 (m, 1H), 3.69-
3.65 (m, 1H), 3.52-3.46 (m, 1H), 2.36-1.88 (m, 4H), 1.46-1.22 (m, 9H); 13C NMR (100 MHz, MeOH-d4):
156.6, 156.2, 152.6, 152.1, 139.9, 134.7, 134.4, 129.8, 134.7, 134.4, 129.8, 128.7, 127.9, 125.9,
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
116.9, 81.3, 57.2, 56.7, 48.4, 47.9, 35.1, 33.8, 28.9, 28.6, 25.3, 24.8; Calculated for C18H23N3O2 [M-H]+
314.1863 found (ES+) 314.1860.
7
8
(S)-tert-butyl 2-(5-(4-(ethoxycarbonyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P3). NMR
9
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: 98% (75 mg); isolated yield: 78% (60 mg). Yellow oil. H NMR (500 MHz, DMSO-d6): 12.18 (s, 1H),
7.93-7.86 (m, 3H), 7.65 (m, 1H), 4.85-4.79 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.55 (s, 1H), 3.36 (s, 1H),
2.25-2.18 (m, 1H), 1.98-1.84 (m, 3H), 1.39-1.15 (m, 12H); 13C NMR (100 MHz, DMSO): 165.6, 153.8,
153.3, 151.3, 150.6, 138.8, 137.1, 134.2, 129.5, 127.8, 127.0, 123.9, 115.8, 78.6, 78.2, 60.4, 55.1, 54.6,
46.5, 46.3, 33.2, 31.8, 28.1, 27.8, 23.8, 23.1, 14.2; Calculated for C21H27N3O4 [M-H]+ 386.2074 found (ES+)
386.2061.
(S)-tert-butyl 2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P4). Yield: 98% (67
mg). Yellow oil. 1H NMR (400 MHz, MeOH-d4): 7.59 (d, J = 8.2 Hz, 2H), 7.16-7.12 (m, 1H), 6.92 (d, J = 8.6
Hz, 2H), 4.86-4.83 (m, 1H), 3.79 (s, 1H), 3.70-3.64 (m, 1H), 3.52-3.46 (m, 1H), 2.37-2.27 (m, 1H), 2.02-
1.88 (m, 3H), 1.46-1.23 (m, 9H); 13C NMR (100 MHz, MeOH-d4): 160.3, 156.6, 156.2, 152.2, 151.7,
127.2, 115.2, 81.3, 57.2, 56.7, 55.8, 48.4, 47.9, 35.1, 33.8, 28.9, 28.6, 25.3, 24.8; Calculated for
C19H25N3O3 [M-H]+ 344.1969 found (ES+) 344.1970.
(S)-tert-butyl 2-(5-vinyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P5). For reaction with
organoboronate, yield: 93% (49 mg). For reaction with potassium organotrifluoroborates, NMR yield:
91% (48 mg); isolated yield: 66% (35 mg). Light brown oil. 1H NMR (400 MHz, CDCl3): 9.59 (s, 1H), 7.02-6.89
(m 1H), 6.55 (dd, J = 17.6, 11.2 Hz, 1H), 5.52 (d, J = 17.6 Hz, 1H), 5.10 (d, J = 11.2 Hz, 1H), 4.95-4.94 (m,
1H), 3.58-3.36 (m, 2H), 3.81 (m, 1H), 2.17-1.92 (m, 3H), 1.48-1.36 (m, 9H); 13C NMR (100 MHz, CDCl ):
3
156.3, 149.4, 133.8, 125.9, 120.3, 111.8, 80.5, 54.0, 47.3, 32.7, 28.4, 24.8; Calculated for C14H21N3O2
[M-H]+ 264.1707 found (ES+) 264.1696.
(S)-tert-butyl 2-(5-(1H-indol-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P6). Yield: 97% (68 mg).
1
Yellow amorphous solid. H NMR (400 MHz, MeOH-d4): 7.85 (s, 1H), 7.44-7.37 (m, 2H), 7.21-7.13 (m, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
1
2
3
4
5
6
7
8
9
6.45 (d, J = 2.9 Hz, 2H), 4.98-4.83 (m, 1H), 3.70-3.64 (m, 1H), 3.49-3.41 (m, 1H), 2.31-2.22 (m, 1H), 2.05-
1.85 (m, 3H), 1.44-1.21 (m, 9H); 13C NMR (100 MHz, MeOH-d4): 156.7, 156.3, 151.8, 151.2, 139.3,
137.1, 129.9, 126.4, 125.0, 120.4, 117.6, 117.0, 112.5, 102.7, 81.3, 57.2, 56.6, 48.3, 47.9, 35.1,
33.6, 28.9, 28.7, 25.3, 24.8; Calculated for C20H24N4O2 [M-H]+ 353.1972 found (ES+) 353.1975.
(S)-tert-butyl 2-(5-(furan-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P7). NMR Yield: 98% (59
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
1
mg); isolated yield: 87% (52 mg). Yellow oil. H NMR (400 MHz, MeOH-d4): 7.79 (s, 1H), 7.49 (s, 1H), 7.09-
7.06 (m, 1H), 6.69 (s, 1H), 4.84-4.81 (m, 1H), 3.69-3.64 (m, 1H), 3.52-3.46 (m, 1H), 2.37-2.27 (m, 1H), 2.05-1.90 (m,
3H), 1.46-1.23 (m, 9H); 13C NMR (100 MHz, MeOH-d4): 156.6, 156.2, 152.3, 151.7, 144.7, 139.3, 120.5,
109.7, 81.3, 57.2, 56.7, 48.4, 47.9, 35.1, 33.8, 28.9, 28.6, 25.3, 24.8; Calculated for C16H21N3O3 [M-H]+
304.1656 found (ES+) 304.1664.
(S)-tert-butyl 2-(5-(quinolin-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (P8). Yield: 99% (72 mg).
1
White Solid. mp:158-160 ˚C; H NMR (400 MHz, MeOH-d4): 8.73, (s, 1H), 8.31-7.95 (m, 4H), 7.55-7.46 (m,
2H), 5.01-4.91 (m, 2H), 3.68 (s, 1H), 3.52-3.48 (m, 1H), 2.37-2.31 (m, 1H), 2.04-1.93 (m, 3H), 1.45-1.23 (m,
9H); 13C NMR (100 MHz, MeOH-d4): 156.6, 156.1, 153.4, 152.9, 150.6, 148.0, 138.3, 134.5, 130.4,
129.5, 129.1, 123.5, 123.0, 114.7, 81.3, 57.3, 56.8, 48.4, 48.0, 35.1, 33.8, 28.9, 28.6, 27.5, 25.4, 24.8;
Calculated for C21H24N4O2 [M-H]+ 365.1972 found (ES+) 365.1973.
6-(2-methyl-1H-imidazol-5-yl)quinoline (P10). For bromoimidazole, yield: 96% (40 mg). For
1
iodoimidazole, NMR yield: 95% (40 mg); isolated yield: 70% (29 mg). Yellow oil. H NMR (500 MHz,
MeOH-d4): 8.74 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.97 (d, J =
9.0 Hz, 1H), 7.49-7.47 (m, 2H), 2.44 (s, 1H); 13C NMR (125 MHz, MeOH-d4+TFA): 151.0, 148.1, 147.5,
138.4, 137.5, 131.9, 130.3, 129.7, 128.7, 123.8, 123.2, 117.2, 13.2; Calculated for C13H11N3 [M-H]+
210.1026 found (ES+) 210.1027.
5-(2-methyl-1H-imidazol-4-yl)-1H-indole (P11). For bromoimidazole, yield: 94% (37 mg). For
1
iodoimidazole, yield: 92% (36 mg). White solid. mp: 111-114 ˚C; H NMR (400 MHz, MeOH-d4): 7.832-
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.827 (dd, J = 2.4, 0.7 Hz 1H), 7.43-7.37 (m, 2H), 7.23 (d, J = 4.0 Hz, 1H), 7.12 (s, 1H), 6.46 (dd, J = 4.0, 0.5
Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, MeOH-d4+TFA): 146.0, 139.2, 137.1, 129.9, 126.3, 125.0,
120.2, 117.3, 116.7, 112.5, 102.7, 13.2; Calculated for C12H11N3 [M-H]+ 198.1026 found (ES+) 198.1025.
3-(2-phenyl-1H-imidazol-5-yl)pyridine (P13). Yield: 97% (43 mg). Yellow solid. mp: 146-148 ˚C; 1H NMR
(500 MHz, MeOH-d4): 8.98 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.0 Hz, 2H),
7.70 (s, 1H), 7.48-7.39 (m, 4H); 13C NMR (100 MHz, MeOH-d4+TFA): 149.3, 147.5, 145.7, 136.5,
136.0, 131.3, 130.8, 130.4, 129.4, 127.3, 126.1, 118.8; Calculated for C14H11N3 [M-H]+ 222.1026 found
(ES+) 222.1031.
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-(2-phenyl-1H-imidazol-5-yl)quinoline (P14). NMR Yield: 98% (53 mg); isolated yield: 77% (42 mg).
1
Yellow amorphous solid. H NMR (400 MHz, MeOH-d4): 8.73 (dd, J = 4.3, 2.0 Hz, 1H), 8.32-8.27 (m, 2H),
8.16 (dd, J = 8.8, 1.9 Hz, 1H), 8.00-7.94 (m, 3H), 7.65 (s, 1H), 7.48-7.45 (m, 3H), 7.42-7.39 (m, 1H); 13C
NMR (100 MHz, MeOH-d4+TFA): 151.0, 148.8, 147.8, 138.9, 138.3, 131.5, 131.0, 130.4, 130.2, 129.5,
129.1, 128.8, 127.4, 124.7, 123.3, 119.2; Calculated for C18H13N3 [M-H]+ 272.1182 found (ES+) 272.1186.
5-(2-phenyl-1H-imidazol-5-yl)-1H-indole (P15). Yield: 95% (49 mg). Colorless oil.1H NMR (400 MHz,
MeOH-d4): 7.96-7.94 (m, 3H), 7.52-7.50 (m, 13H), 7.47-7.34 (m, 5H), 7.24 (d, J = 3.1 Hz, 1H), 6.49 (dd, J =
3.2, 0.6 Hz, 1H); 13C NMR (100 MHz, MeOH-d4): 148.2, 140.6, 137.3, 131.8, 130.0, 129.9, 129.7,
126.7, 126.5, 124.5, 120.7, 119.8, 118.1, 112.6, 102.8; Calculated for C17H13N3 [M-H]+ 260.1182 found
(ES+) 260.1191.
3-(5-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine (P19). Yield: 99% (46 mg). Brown oil. 1H NMR (500 MHz,
MeOH-d4): 8.42 (dd, J = 4.8, 1.0 Hz, 1H), 8.32 (d, J = 1.2 Hz, 1H), 7.67-7.65 (dt, J = 7.9, 1.9 Hz,1H); 7.40
(dd, J = 7.9, 4.7 Hz, 1H), 7.300-7.297 (m, 4H), 2.30 (s, 3H); 13C NMR (100 MHz, MeOH-d4+TFA): 148.5,
145.8, 143.8, 142.2, 133.3, 129.9, 129.6, 129.5, 126.4, 114.1, 10.9; Calculated for C15H13N3 [M-H]+
236.1182 found (ES+) 236.1177.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
1
2
3
4
5
6
ASSOCIATED CONTENT
Supporting Information
7
8
1
Optimization details and copies of H and 13C NMR spectra for all new compounds. This material is
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
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: jiajing.tan@merck.com
* E-mail: yonggang.chen@merck.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
J.J.T. is grateful to Merck Postdoctoral Research Fellows Program for financial support and the MRL
Catalysis and Automation Group for making available the use of the instrumentation for this study. We
thank Dr. Matthew Tudge for advices on manuscript preparation, Rong-Sheng Yang for obtaining HRMS
data, Dr. Dan DiRocco and Dr. Peter Dormer for assistance with LCMS and NMR experiments
respectively.
REFERENCES
(1) (a) Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments, Molnár, A.,
Ed.; Wiley-VCH: Weinheim, 2013. (b) Applications of Transition Metal Catalysis in Drug Discovery and
Development, Crawley, M. L.; Trost, B. M., Eds.; Wiley: New York. 2012. (c) Torborg, C.; Beller, M. Adv.
Synth. Catal. 2009, 351, 3027.
(2) (a) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916. (b) Valente, C.; Çalimsiz, S.; Hoi,
K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314. (c) Suzuki, A. Angew.
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Chem. Int. Ed. 2011, 50, 6722. (d) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (e) Fu, G. C.
Acc. Chem. Res. 2008, 41, 1555. (f) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(3) (a) Wong, S. M.; So, C. M.; Kwong, F. Y. Synlett 2012, 1132. (b) Touchet, S.; Carreaux, F.; Carboni, B.;
Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev. 2011, 40, 3895. (c) Miyaura, N. Top. Curr. Chem. 2002, 219,
11.
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
(4) (a) Heterocyclic Chemistry in Drug Discovery, Li, J. J., Ed.; John Wiley & Sons, 2013. (b) Bansal, Y.;
Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208. (c) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54,
3451. (d) Dua, R.; Shrivastava, S.; Sonwane, S. K.; Srivastava, S. K. Adv. Biol. Res. 2011, 5, 120. (e)
Broughton, H. B.; Watson, I. A. J. Mol. Graph. Mod. 2004, 23, 51. (f) Cerecetto, H.; Gerpe, A.; Gonzalez,
M.; Aran, V. J.; Ocariz, C. O. Mini-Rev. Med. Chem. 2005, 5, 869.
(5) (a) Heterocycles from Transition Metal Catalysis: Formation and Functionalization, Kotschy, A.;
Timári, T., Eds.; Springer: Dordrecht, 2005. (b) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245. (c) Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd ed.; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(6) (a) Knochel, P.; Schade, M. A.; Bernhardt, S.; Manolikakes, G.; Metzger, A.; Piller, F. M.; Rohbogner, C.
J.; Mosrin, M. Beilstein J. Org.Chem. 2011, 7, 1261. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007,
36, 1173. (c) Oberli, M. A.; Buchwald, S. L. Org. Lett. 2012, 14, 4606. (d) Billingsley, K.; Anderson, K. W.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 3484. (e) Kudo, N.; Perseghini, M.; Fu, G. C. Angew.
Chem. Int. Ed. 2006, 45, 1282.
(7) (a) Dai, X.; Chen, Y. G.; Garrell, S.; Liu, H.; Zhang, L.-K.; Palani, A.; Hughes, G.; Nargund, R. J. Org. Chem.
2013, 78, 7758. (b) Schmink, J. R.; Tudge, M. T. Tetrahedron Lett. 2013, 54, 15. (c) Strotman, N. A.;
Chobanian, H. R.; He, J.; Guo, Y.; Dormer, P. G.; Jones, C. M.; Steves, J. E. J. Org. Chem. 2010, 75, 1733. (d)
Kuethe, J. T.; Childers, K. G. Adv. Synth. Catal. 2008, 350, 1577. (e) Cai, C.; Chung, J. Y. L.; McWilliams, J.
C.; Sun, Y.; Shultz, C. S.; Palucki, M. Org. Process Res. Dev. 2007, 11, 328. (f) McLaughlin, M. Org. Lett.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
1
2
3
4
5
6
7
8
2005, 7, 4875. (g) Chen, C.-Y.; Dagneau, P.; Grabowski, E. J. J.; Oballa, R.; O’Shea, P.; Prasit, P.; Robichaud,
J.; Tillyer, R.; Wang, X. J. Org. Chem. 2003, 68, 2633. (h) Yasuda, N. J. Organomet. Chem. 2002, 653, 279.
and reference therein.
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
(8) (a) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (b) Shalini, K.; Sharma, P. K.; Jumar, N. Chem. Sin. 2010, 1,
36. (c) Baroniya, S.; Anwer, Z.; Sharma, P. K.; Dudhe, R.; Kumar, N. Pharm. Sin. 2010, 1, 172. (d) De, L. L.
Curr. Med. Chem. 2006, 13, 1. (e) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931.
(9) Grimmett, M. R. Imidazole and Benzimidazole Synthesis; Academic: San Diego, 1997.
(10) (a) Carbone, A.; Pennati, M.; Parrino, B.; Lopergolo, A.; Barraja, P.; Montalbano, A.; Spanò, V.;
Sbarra, S.; Doldi, V.; De Cesare, M.; Cirrincione, G.; Diana, P.; Zaffaroni, N. J. Med. Chem. 2013, 56, 7060.
(b) Carbone, A.; Parrino, B.; Spanò, V.; Barraja, P.; Cirrincione, G.; Diana, P.; Maier, A.; Kelter, G.; Fiebig,
H.-H. Mar. Drugs 2013, 11, 643. (c) Diana, P.; Carbone, A.; Barraja, P.; Kelter, H. H.; Fiebig, G.; Cirrincione,
G. Bioorg. Med. Chem. 2010, 18, 4524.
(11) Fridell, R. A.; Qiu, D.; Valera, L.; Wang, C. F.; Rose, R. E.; Gao, M. J. Virol. 2011, 85, 7312.
(12) (a) Sandtorv, A. H.; Bjørsvik, H. Adv. Syn. Catal. 2013, 355, 3231. (b) Bellina, F.; Cauteruccio, S.; Fiore,
A. D.; Rossi, R. Eur. J. Org. Chem. 2008, 5436. (c) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007,
72, 8543. (d) Langhammer, I.; Erker, T. Heterocycles 2005, 65, 1975. (e) Zhong, Y.-L.; Lee, J.; Reamer, R.
A.; Askin, D. Org. Lett. 2004, 6, 929. (f) Mangion, I. K.; Chen, C.-Y.; Li, H. M.; Maligres, P.; Chen, Y. G.;
Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry. B.; Zavialov,
I. Org. lett. 2014, 16, 2310.
(13) (a) Düfert, M. A.; Billingsley, K. L.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 12877. (b) Yang, Y.;
Oldenhius, N. J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 615. (c) Maiti, D.; Fors, B. P.; Henderson,
J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 57. (d) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina,
M.; Mihovilovic, M. D.; Stanetty P. Eur. J. Org. Chem. 2006, 3283.
(14) For details, see Supporting Information.
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(15) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 6653. (b) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818.
(16) (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.;
Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787. (b) Guram, A. S.; Wang, X.; Bunel, E.
E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J. Org. Chem., 2007, 72, 5104.
(17) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem. Int. Ed. 2000, 39, 4153. (b) Köllhofer, A.;
Pullmann, T.; Plenio, H. Angew. Chem. Int. Ed. 2003, 42, 1056.
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
(18) (a) Molander, G. A.; Jean-Gérard, L. Organic React. 2013, 79, 1. (b) Molander, G. A.; Canturk, B.
Angew. Chem. Int. Ed. 2009, 48, 9240. and reference therein.
(19) (a) Fantini, M.; Rivara, M.; Zuliani, V.; Kalmar, C. L.; Vacondio, F.; Silva, C.; Baheti, A. R.; Singh, N.;
Merrick, E. C.; Katari, R. S.; Cocconcelli, G.; Ghiron, C.; Patel, M. K. Bioorg. Med. Chem. 2009, 17, 3642. (b)
Rivara, M.; Baheti, A. R.; Fantini, M.; Cocconcelli, G.; Ghiron, C.; Kalmar, C. L.; Singh, N.; Merrick, E. C.;
Patel, M. K.; Zuliani, V. Bioorg. Med. Chem. Lett. 2008, 18, 5460.
(20) (a) Joo, J. M.; Tourré, B. B.; Sames, D. J. Org. Chem. 2010, 75, 4911. (b) Yang, X.-D.; Li, L.; Zhang, H.-B.
Helv. Chim. Acta 2008, 91, 1435.
(21) White, E. H.; Harding, M. J. C. J. Am. Chem. Soc. 1964, 86, 5686.
(22) The major by-products were from homo-couping reactions. For reference, see: Cliff, M. D.; Pyne, S.
G. Synthesis 1994, 681.
(23) (a) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2, 2121. (b) Kaswasaki, I.; Yamashita, M.;
Ohta, S. J. Chem. Soc. Chem. Commun. 1994, 2085. (c) Kawasaki, I.; Yamashita, M.; Ohta, S. Chem. Pharm.
Bull. 1994, 44, 1831.
(24) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141.
Graphic Abstract
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
1
2
3
4
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
ACS Paragon Plus Environment