Direct, metal-free amination of heterocyclic amides/ureas with NH-heterocycles and N-substituted anilines in POCl3

Article abstract of DOI:10.1021/jo201425q

A POCl₃-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional

Full text of DOI:10.1021/jo201425q

ARTICLE
pubs.acs.org/joc
Direct, Metal-Free Amination of Heterocyclic Amides/Ureas with
NH-Heterocycles and N-Substituted Anilines in POCl3
Xiaohu Deng,*,† Armin Roessler,‡ Ivana Brdar,‡ Roger Faessler,‡ Jiejun Wu,† Zachary S. Sales,† and
Neelakandha S. Mani†
†Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States
‡PDMS API SM Development, Cilag AG, Hochstrasse 201, CH-8205 Schaffhausen, Switzerland
S Supporting Information
b
ABSTRACT: A POCl3-mediated, direct amination reaction of hetero-
cyclic amides/ureas with NH-heterocycles or N-substituted anilines is
described. Compared to the existing methods, this operationally
simple protocol provides unique reactivity and functional group
compatibility because of the metal-free, acidic reaction conditions.
The yields are generally excellent.
’ INTRODUCTION
2-Aminosubstituted heterocycles with generic structure 1 are
ubiquitous in biologically active compounds1 including the block-
buster drugs Tarceva, Avandia, Gleevec, Crestor, and Lunesta
(Figure 1).
Typical syntheses of 1 start from heterocyclic amides 2, which
often come from condensation reactions of appropriate precur-
sors (Scheme 1, a). Activation of the tautomerizable hydroxyl
group in 2 to halides is usually required for the subsequent SNAr
(nucleophilic aromatic substitution) reaction to occur with
nitrogen nucleophiles to afford 1.2 Highly dependent on the
nature of the coupling partner, the SNAr reactions are particularly
difficult for weak nucleophiles such as NH-heterocycles and
Figure 1. Blockbuster drugs containing the 2-aminoheterocycle motif
represented generically as 1.
anilines. In these cases, harsh conditions are usually necessary,
and diminished yields are often obtained.3 One of the solutions
to this problem is the employment of highly reactive phospho-
nium derivatives of heterocyclic amide 2 for the SNAr reaction.4
The reaction conditions are generally mild even for weak
nucleophiles such as NH-heterocycles and anilines. The down-
sides of this very useful method are cost of the expensive
phosphonium reagents such as BOP ((Benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate) or PyBroP
(Bromotripyrrolidinophosphonium hexafluorophosphate), poor
atom economy, and potentially carcinogenic byproducts. An-
other successful approach involves metal (either Pd5 or Cu6)-
catalyzed BuchwaldꢀHartwig cross-coupling amination reaction
of heteroaryl halides or triflates, which has significantly improved
the reactivity and versatility of this process. However, the use of
metal catalysts and expensive ligands renders the metal-catalyzed
processes less cost-effective. Very recently, direct, oxidative
amination of heteroarene through metal-catalyzed CꢀH activa-
tion has also been achieved, but the reaction scopes are fairly
narrow so far.7 Acids generated in the amination processes (HX,
TfOH, etc.) are generally believed to impede the desired
nucleophilic displacement, presumably by protonation of the
amine nucleophiles.8 Therefore, stoichiometric amounts of bases
are almost always employed in the above amination processes,
either to scavenge the acids or to promote the displacement
processes through deprotonation of the nucleophilic species.
That is probably the reason that SNAr amination reactions of
heteroaryl halides under acidic conditions are much rarer in the
literature and harsh reaction conditions are usually required.9
Despite this conventional wisdom, we reasoned that in certain
cases involving weak nitrogen nucleophiles, acids might as well
facilitate the displacement process of intermediate 3 through
coordination of the adjacent nitrogen atom (Scheme 1, b).
Furthermore, by choosing an appropriate acid-compatible
CꢀO bond activator, isolation of intermediate 3 might not be
necessary and direct amination of heterocyclic amides 2 might be
feasible (Scheme 1, c).10 We report that inexpensive POCl3 is
such an activator, promoting direct amination of a variety of
Received: July 11, 2011
Published: September 07, 2011
r
2011 American Chemical Society
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Scheme 1. Common and Alternative Strategies for Synthesis of 1
Scheme 2. Synthesis of 8 via 5 or through a Proposed Direct,
One-Step Amination
heterocyclic amides with NH-heterocycles or N-substituted
anilines. This operationally simple reaction requires no metal
catalyst and is usually high yielding. It offers clear advantages
over existing amination methods in terms of simplicity and
efficiency. It also provides complementary reactivity and func-
tional group compatibility because of the acidic reaction con-
ditions. We expect wide applicability of this method in organic
synthesis.
’ RESULTS AND DISCUSSION
In connection with one of our drug discovery programs,
we were interested in preparing 2-pyrrazolobenzimidazole 8
(Scheme 2).11 The BOP- or PyBrop-mediated direct amination
of compound 4 with pyrazole under basic conditions failed to
provide the desired compound.4 We then turned our attention to
the classic sequence through the chloride intermediate 5. It
turned out that preparation of compound 5 through a variety of
chlorination methods was rather difficult, especially on multi-
gram scales.12 Careful examination of the chlorination reaction of
compound 4 in POCl3 revealed that the major byproduct was
pseudodimeric 6. Yields of compound 6 ranged from 10% to as
high as 40%, depending on the reaction scales. We postulated
that there were two competing pathways a and b for the POCl3-
mediated reaction. On the same activated intermediate 7,13
either Clꢀ or another molecule of starting material 4 could serve
as the nucleophile, affording compounds 5 and 6, respectively. With
this insight, we reasoned that an in situ nitrogen nucleophile
(pyrazole) that was more nucleophilic than both starting material
4 and Clꢀ should react preferentially with 7 through pathway c.
Therefore, a direct, one-step amination method from compound 4
to produce compound 8 under acidic conditions might be feasible.
To test the above hypothesis, an equimolar mixture of
benzimidazol-2-one and pyrazole was heated at reflux in POCl3
(1.1 mol/L) for 16 h (Table 1, entry 1). Much to our pleasure,
the desired direct amination reaction went cleanly, and a simple
POCl3 quench with iceꢀwater followed by pH adjustment to
∼10 afforded compound 9 in 90% isolated yield. Compound 9
was collected as a white solid via filtration in >95% purity.
Interestingly, other chlorination reagents such as SOCl2 and
oxalyl chloride did not work for this reaction. Encouraged by this
result, we investigated a variety of nitrogen nucleophiles other
than pyrazole (Table 1). It appears that the POCl3-mediated,
direct amination reaction succeeds only in cases where the
following criteria are met: (1) The nitrogen nucleophile can
not react directly with POCl3 under the refluxing reaction conditions.
Strong nucleophiles such as dialkyl amines (morpholine and pyrro-
lidine, entry 6), alcohols (IPA and n-BuOH), phenol, or thio-
phenol were not suitable for this reaction. (2) The nucleophile has
to be more nucleophilic than benzimidazol-2-one itself to avoid
the formation of compound 6-type pseudodimer. Weak nucleo-
philes such as amides (PhCONHPh, pyrrolidin-2-one, indolin-2-
one)14 or sulfonamides (PhNHSO2Ph) were not suitable for
this reaction either. (3) The nucleophile must be acid-stable.
For this reason, 1,2,3-triazole (entry 4), pyrrole (entry 5),
indole (entry 7), and succinimide were also incompetent
partners. In contrast, nucleophiles that met these criteria such
as azoles (entries 1ꢀ3) and benzo-azoles (entries 8ꢀ10)
afforded excellent yields of the amination products. In addition,
secondary anilines proved to be good partners for this reaction
as well (entries 11ꢀ13). Higher temperature (140 °C for
2 days) in a sealed tube was usually required to drive the
reactions to completion, probably due to the lower nucleophili-
city of secondary anilines. It is worth noting that primary anilines
did participate in the reaction, however, affording a mixture of
mono and double amination products. An appropriate protecting
group might address this issue.
The reaction scope with respect to the heterocyclic amides was
investigated next. It was found that N-1 substitutions on the benz-
imidazol-2-one were tolerated (Table 1, entry 2; Table 2, entry 1).
4,5-Diphenyl imidazol-2-one also worked well in the reaction
(Table 2, entry 2). Replacement of NH of benzimidazol-2-one with
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Table 1. Reaction Scope with Respect to Nitrogen Nucleophiles
a 140 °C, sealed tube, 2 d.
Table 2. Reaction Scope with Respect to Heterocyclic Amides
* R = OH, 2 equiv of pyrazole was used.
sulfur did not affect the reaction (entry 3). The total lack of the
amination products for benzoxazol-2-one (entry 4) and indolin-
2-one (entry 5) might suggest the importance of the aromaticity of the
tautomerizable amides. Interestingly, benzoimidazol-2-thione
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afforded the desired product 9 as well, although in low yield
(entry 6).15 A wide range of six-membered heterocyclic
amides also afforded the desired amination products in excellent
yields (entries 7ꢀ13).
3,5-diisopropylpyrazole afforded the desired amination product
49, albeit at higher temperature (entry 10).
With respect to the mechanism of the reaction, we ob-
served two competing pathways, depending on the nucleophiles
(Scheme 3). Activation of the heterocyclic amide with POCl3 is
presumed to take place first, affording active species 51. From
there, either pathway a or b is feasible. Control experiments on a
representative reaction (Table 1, entry 1) showed that heating
pure isolated 2-chlorobenzimidazole and pyrazole in POCl3
provided compound 9, albeit in lower yield. However, with
pyrazole already present in the reaction solution, no detectable
formation of 2-chlorobenzimidazole was observed during the
reaction course based on HPLC and in situ NMR studies. The
same observation held true with all the reactions that went to
completion at reflux temperature (110 °C). In those cases,
pathway a is likely the dominant one.16 In comparison, in the
cases of N-substituted anilines and sterrically hindered pyrazole
as the nucleophiles (Table 1, entries 11ꢀ13 and Table 4, entry 10),
where the reaction was more sluggish and higher temperature was
required for the reaction to proceed, formation of chloride
intermediate 52 was observed prior to the amination product.
Apparently, in those cases, pathway b is the preferred one.
The electronic properties of the substituents at the phenyl ring
of benzimidazol-2-one had little effect on the reaction (Table 3).
As long as the substituents could survive the acidic reaction
conditions, excellent yields of the amination products were
obtained (entries 1ꢀ5).
A variety of substituted pyrazole nucleophiles were next
studied. Pyrazoles with either electron-donating (Table 4, entries
1, 4, and 6) or electron-withdrawing (entries 2, 3, and 5)
substituents all afforded excellent yields of the desired amination
products. The steric effects of the substituents on the regioselec-
tivity of the reaction were also studied. The results indicated that
the formation of sterically less hindered products was preferred.
For instance, in the case of 3-substituted pyrazoles (entries 2, 3,
6ꢀ8), only regioisomers with 3-substituents away from the
benzimidazole ring were observed. With a 3,5-disubstituted
pyrazole (entry 9), sterically less hindered product 47 was the
major product. It is notable that even highly sterically hindered
Table 3. Reaction Scope with Respect to Substituents on
Benzimidazol-2-one
Scheme 3. Two Plausible Pathways
entry
R
product
yield
1
2
3
4
5
-COOMe
-NO2
34
35
36
13
38
98%
95%
93%
92%
98%
-CF3
-CN
-OMe
Table 4. Reaction Scope with Respect to Substituents on Pyrazoles
a 110 °C, 4 d.b b 140 °C, 1 d.
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Scheme 4. Three-Component, One-Pot Synthesis of Com-
pound 9
1H), 7.59 (br s, 1H), 7.46 (br s, 1H), 7.20 (dd, J = 5.8, 2.3 Hz, 2H), 6.67
(dd, J = 2.6, 1.7 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 145.8, 142.6,
141.5, 133.4, 128.8, 122.1, 121.8, 118.1, 111.3, 108.8. HRMS-ESI (m/z):
[M + H]+ calcd for C10H9N4 185.0822; found 185.0826.
One-Pot Procedure. In a 100 mL round-bottom flask was
suspended a mixture of benzene-1,2-diamine (5.0 g, 46 mmol, 1.0
equiv) and pyrazole (3.1 g, 46 mmol, 1.0 equiv) in POCl3 (43 mL,
460 mmol, 10 equiv). Triphosgene (4.5 g, 15.3 mmol, 0.33 equiv) was
added as solid slowly at room temperature (exothermic reaction). After
stirring at room temperature for 30 min, the reaction mixture was heated
to reflux temperature (110 °C) for 16 h. The hot reaction solution was
carefully poured into an iceꢀwater solution with sufficient stirring.
Saturated aqueous NaOH solution was added to adjust the pH to ∼10.
After stirring at room temperature for 2 h, the precipitated white solid
was collected via filtration, washed with water, and dried to afford the
title compound (6.9 g, 37 mmol, 81%).
We also explored the feasibility of a one-pot synthesis of
compound 9 directly from phenylene-1,2-diamine without the
isolation of benzimidazol-2-one (Scheme 4). Acid-compatible
triphosgene was slowly added to the suspension mixture of
phenylene-1,2-diamine and pyrazole in POCl3 at room tempera-
ture. The mixture was stirred at room temperature for 30 min and
then at reflux for 16 h to afford compound 9 in 81% isolated yield
after the same acid quench/pH adjustment isolation proce-
dures. Apparently, the presence of pyrazole did not interfere
with the formation of benzimidazol-2-one from phenylene-1,2-
diamine and triphosgene. Subsequent direct amination reaction
of benzimidazol-2-one with pyrazole delivered compound 9 in a
one-pot fashion. This facile, one-pot protocol should be applic-
able to the synthesis of other 2-aminobenzimidazoles as well.
In summary, we have developed a simple, direct amination
method for heterocyclic amides/ureas via CꢀO activation in
POCl3. This reaction works best with weak, acid-stable nitrogen
nucleophiles such as azoles and N-substituted anilines. It has
broad substrate scope with respect to heterocyclic amides/ureas,
and the yields are usually excellent. Performed under metal-free,
acidic conditions, this highly economical method offers comple-
mentary reactivity and functional group compatibility to the
existing amination methods. A three-component, one-pot pro-
tocol to 2-pyrazolo-benzimidazole directly from phenylene-1,2-
diamine, triphosgene, and pyrazole is also demonstrated. It is
worth to note that the reaction is readily scalable to >100 g.
5,50,6,60-Tetrachloro-10H-[1,20-bibenzo[d]imidazol]-2(3H)-
one, Compound 6. 1H-Benzo[d]imidazol-2-ol (20 g, 1.0 mmol,
1.0 equiv) was heated in POCl3 (150 mL) for 24 h. After cooling to rt,
the reaction solution was carefully poured into iceꢀwater with stirring. The
precipitated solid was collected by filtration and dried. Compound 6 was
isolated as the major byproduct after column chromatography. The yield
varied from batch to batch, depending on quality of the reagents and the
scale of the reaction. 1H NMR (500 MHz, DMSO) δ 8.46 (s, 1H), 7.82
(s, 2H), 7.32 (s, 1H). 13C NMR (126 MHz, DMSO) δ 152.5, 145.5, 129.7,
126.5, 125. 6, 124.0, 123.2, 114.5, 111.0.* HRMS-ESI (m/z): [M + H]+
calcd for C14H6Cl4N4O 386.9368; found 386.9378.
2-(1H-Imidazol-1-yl)-1-methyl-1H-benzo[d]imidazole, Com-
pound 10. Following the general method described above, the title
compound was isolated in 75% yield. 1H NMR (600 MHz, DMSO) δ 8.28
(t, J = 1.3 Hz, 1H), 7.82 (t, J = 1.3 Hz, 1H), 7.68 (ddd, J = 5.4, 4.6, 2.4 Hz,
2H), 7.36 (ddd, J= 8.3, 7.3, 1.1 Hz, 1H), 7.31 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H),
7.25ꢀ7.21 (m, 1H), 3.78 (s, 3H). 13C NMR (151 MHz, DMSO) δ 143.7,
140.1, 137.8, 135.2, 129.5, 123.0, 122.6, 120.1, 119.0, 110.7, 30.5. HRMS-
ESI (m/z): [M + H]+ calcd for C11H11N4 199.0978; found 199.0972.
2-(1H-1,2,4-Triazol-1-yl)-1H-benzo[d]imidazole, Compound
11. Following the general method described above, the title compound was
isolated in 88% yield. 1H NMR (600 MHz, DMSO) δ 9.46 (s, 1H), 8.45
(s, 1H), 7.59 (dd, J = 5.2, 3.2 Hz, 2H), 7.33ꢀ7.23 (m, 2H). 13C NMR (151
MHz, DMSO) δ 153.1, 143.5, 143.1, 122.6.* HRMS-ESI (m/z): [M + H]+
calcd for C9H8N5 186.0744; found 186.0778.
’ EXPERIMENTAL SECTION
General Experimental Methods. Proton and carbon NMR
spectra were recorded at a 500 MHz or a 600 MHz NMR spectrometer.
One-dimension NOE experiments were performed by the method of
Stott et al. with a mixing time of 0.8 s.17 Flash column chromatography
was performed using Merck silica gel 60. The analytical HPLC condi-
tions were Agilent ZORBAX Eclipse XDB-C8, 5 μm, 4.6 mm ꢁ 150 mm,
flow rate 1 mL/min, gradient (acetonitrile/water with 0.05% trifluoro-
acetic acid) 1% acetonitrile/99% water to 99% acetonitrile/1% water
ramp over 8 min, then hold at 99% acetonitrile/1% water. HRMS (ESI)
was performed on a μTOF apparatus.
1-(1H-Benzo[d]imidazol-2-yl)-1H-benzo[d][1,2,3]triazole,
Compound 16. Following the general method described above, the
title compound was isolated in 89% yield. 1H NMR (600 MHz, DMSO)
δ 13.78 (s, 1H), 8.59 (dt, J = 8.3, 0.9 Hz, 1H), 8.28 (dt, J = 8.3, 0.9 Hz,
1H), 7.84 (ddd, J = 8.1, 7.0, 0.9 Hz, 1H), 7.80ꢀ7.50 (br m, 2H), 7.64
(ddd, J = 8.1, 7.0, 0.9 Hz, 1H), 7.37ꢀ7.24 (m, 2H). 13C NMR (151
MHz, DMSO) δ 145.6, 143.9, 130.8, 130.0, 125.8, 122.8, 119.8, 113.4.*
HRMS-ESI (m/z): [M + H]+ calcd for C13H10N5 236.0931; found
236.0930 .
Unless specified, all solvents and reagents were purchased from
commercial sources and used without further purification.
General Procedure for the Amination Reaction
1-(1H-Benzo[d]imidazol-2-yl)-1H-indazole, Compound 17.
Following the general method described above, the title compound was
isolated in 91% yield. 1H NMR (600 MHz, DMSO) δ 13.61 (s, 1H), 9.24
(d, J = 1.0 Hz, 1H), 7.85 (dt, J = 8.5, 0.9 Hz, 1H), 7.77 (dd, J = 8.8, 0.9 Hz,
1H), 7.74ꢀ7.64 (m, 1H), 7.57ꢀ7.50 (m, 1H), 7.42 (ddd, J = 8.8, 6.5,
2-(1H-Pyrazol-1-yl)-1H-benzo[d]imidazole, Compound 9.
In a sealed tube18 equipped with a magnetic stirring bar were suspended
1H-benzo[d]imidazol-2-ol (134 mg, 1.0 mmol, 1.0 equiv) and pyrazole
(82 mg, 1.2 mmol, 1.2 equiv) in POCl3 (0.92 mL, 10 mmol, 10 equiv).
The reaction mixture was heated to reflux temperature (110 °C) for
16 h. The hot reaction solution was carefully poured into an iceꢀwater
solution with sufficient stirring. Saturated aqueous NaOH solution was
added to adjust the pH to ∼10. After stirring at room temperature for
2 h, the precipitated white solid was collected via filtration, washed with
water, and dried to afford the title compound (165 mg, 0.9 mmol, 90%).
No further purification was performed. 1H NMR (600 MHz, DMSO) δ
13.10 (s, 1H), 8.60 (dd, J = 2.6, 0.5 Hz, 1H), 7.95 (dd, J = 1.6, 0.5 Hz,
1.0 Hz, 1H), 7.32ꢀ7.24 (m, 2H), 7.19 (ddd, J = 8.5, 6.5, 0.7 Hz, 1H). 13
C
NMR (151 MHz, DMSO) δ 149.6, 145.9, 141.6, 133.8, 128.2, 123.0,
122.9, 122.5, 122.2, 122.1, 121.5, 118.6, 117.3, 111.7. HRMS-ESI (m/z):
[M + H]+ calcd for C14H11N4 235.0978; found 235.0966.
10H-1,20-Bibenzo[d]imidazole, Compound 18. Following the
general method described above, the title compound was isolated in 82%
yield. 1H NMR (600 MHz, DMSO) δ 9.01 (s, 1H), 8.48 (d, J = 8.1 Hz,
1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 5.8, 3.2 Hz, 2H), 7.51 (t, J =
7.7 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 6.0, 3.1 Hz, 2H).
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13C NMR (151 MHz, DMSO) δ 143.6, 142.8, 141.3, 131.4, 124.6, 123.7,
122.3, 119.7, 114.0.* HRMS-ESI (m/z): [M + H]+ calcd for C14H11N4
235.0978; found 235.0975.
1.6 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 149.6, 145.8, 142.5, 139.8,
130.6, 128.0, 127.7, 127.1, 126.7, 126.1, 111.9, 108.7. HRMS-ESI (m/z):
[M + H]+ calcd for C12H10N3 196.0869; found 196.0874.
N-Methyl-N-phenyl-1H-benzo[d]imidazol-2-amine, Com-
pound 19. Following the general method described above except that
the reaction was heated at 140 °C for 3 days, the title compound was
2-(1H-Pyrazol-1-yl)quinoxaline, Compound 28. Following
the general method described above, the title compound was isolated in
98% yield. 1H NMR (600 MHz, DMSO) δ 9.61 (s, 1H), 8.82 (dd, J =
2.6, 0.6 Hz, 1H), 8.16 (dd, J = 8.3, 1.3 Hz, 1H), 8.06 (ddd, J = 8.3, 1.3,
0.5 Hz, 1H), 8.02 (dd, J = 1.6, 0.6 Hz, 1H), 7.92 (ddd, J = 8.4, 7.0, 1.4 Hz,
1H), 7.84 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 6.74 (dd, J = 2.6, 1.6 Hz, 1H).
13C NMR (151 MHz, DMSO) δ 144.5, 143.5, 140.5, 139.3, 137.7, 131.4,
129.2, 128.9, 127.9, 127.8, 109.5. HRMS-ESI (m/z): [M + H]+ calcd for
C11H9N4 197.0822; found 197.0824.
4-(1H-Pyrazol-1-yl)quinazoline, Compound 29a. Following
the general method described above, the title compound was isolated in
83% yield. 1H NMR (600 MHz, DMSO) δ 9.39 (dt, J = 8.7, 1.0 Hz, 1H),
9.17 (s, 1H), 8.90 (dd, J = 2.7, 0.7 Hz, 1H), 8.13 (dd, J = 1.6, 0.6 Hz, 1H),
8.10ꢀ8.06 (m, 2H), 7.83 (ddd, J = 8.4, 5.2, 3.0 Hz, 1H), 6.76 (dd, J = 2.7,
1.7 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 154.3, 153.4, 152.6, 144.7,
134.5, 131.1, 128.4, 128.1, 127.5, 115.9, 108.8. HRMS-ESI (m/z):
[M + H]+ calcd for C11H9N4 197.0822; found 197.0815.
1
isolated in 93% yield. H NMR (600 MHz, DMSO) δ 11.26 (s, 1H),
7.49ꢀ7.38 (m, 4H), 7.21 (dt, J = 8.7, 4.3 Hz, 3H), 6.95 (dd, J = 5.8, 3.2
Hz, 2H), 3.31 (br s, 3H). 13C NMR (151 MHz, DMSO) δ 154.0, 144.9,
129.4, 124.5, 123.5, 119.9, 38.9.* HRMS-ESI (m/z): [M + H]+ calcd for
C14H14N3 224.1182; found 224.1184.
1-(1H-Benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline,
Compound 20. Following the general method described above except
that the reaction was heated at 140 °C for 3 days, the title compound was
isolated in 61% yield after column chromatography with EtOAc/hexanes
as the eluents. 1H NMR (600 MHz, DMSO) δ 11.65 (s, 1H), 7.76 (d, J =
8.1 Hz, 1H), 7.30 (s, 2H), 7.16 (dd, J = 13.6, 7.1 Hz, 2H), 7.00 (dd, J = 5.7,
3.1 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 3.93ꢀ3.82 (t, J = 6.3 Hz, 2H), 2.79
(t, J = 6.3 Hz, 2H), 2.03ꢀ1.92 (m, 2H). 13C NMR (151 MHz, DMSO) δ
152.6, 139.6, 128.9, 127.8, 126.4, 121.5, 120.1, 119.6, 113.2, 109.5, 47.2,
26.8, 22.5. HRMS-ESI (m/z): [M + H]+ calcd for C16H16N3 250.1339;
found 250.1335.
2,4-Di(1H-pyrazol-1-yl)quinazoline, Compound 29b. Fol-
lowing the general method described above using 2 equiv of pyrazole,
1
the title compound was isolated in 80% yield. H NMR (600 MHz,
2-(2-Methylindolin-1-yl)-1H-benzo[d]imidazole, Compound
21. Following the general method described above except that the reac-
tion was heated at 140 °C for 3 days, the title compound was isolated
in 56% yield after column chromatography with EtOAc/hexanes as
DMSO) δ 9.47 (d, J = 8.7 Hz, 1H), 9.17 (d, J = 2.7 Hz, 1H), 8.99 (d, J =
2.6 Hz, 1H), 8.17 (d, J = 1.0 Hz, 1H), 8.09ꢀ8.00 (m, 2H), 7.94 (d, J =
0.9 Hz, 1H), 7.74 (ddd, J = 8.4, 6.6, 1.5 Hz, 1H), 6.81 (dd, J = 2.7, 1.6 Hz,
1H), 6.67 (dd, J = 2.6, 1.6 Hz, 1H). 13C NMR (151 MHz, DMSO) δ
155.8, 154.0, 150.5, 145.3, 143.4, 135.3, 131.9, 130.3, 128.2, 127.7, 127.3,
114.3, 109.1, 108.7. HRMS-ESI (m/z): [M + H]+ calcd for C14H11N6
263.1039; found 263.1035.
1
eluents. H NMR (600 MHz, MeOD) δ 7.76 (d, J = 7.9 Hz, 1H),
7.45ꢀ7.38 (m, 2H), 7.24 (t, J = 8.3 Hz, 2H), 7.17ꢀ7.11 (m, 2H),
7.01ꢀ6.95 (m, 1H), 4.79ꢀ4.63 (m, 1H), 3.55ꢀ3.46 (m, 1H), 2.81 (dd,
J = 15.7, 2.6 Hz, 1H), 1.39 (d, J = 6.3 Hz, 3H). 13C NMR (151 MHz,
MeOD) δ 150.6, 143.2, 137.4, 131.5, 128.6, 126.5, 123.5, 122.7, 113.7,
113.6, 59.3, 37.4, 20.5. HRMS-ESI (m/z): [M + H]+ calcd for C16H16N3
250.1339; found 250.1341.
4-(1H-Pyrazol-1-yl)pyrimidine, Compound 30. Following
the general method described above, the title compound was
1
isolated in 91% yield. H NMR (600 MHz, DMSO) δ 9.09 (d, J =
1.1 Hz, 1H), 8.89 (d, J = 5.6 Hz, 1H), 8.72 (dd, J = 2.7, 0.6 Hz, 1H),
7.98ꢀ7.96 (m, 1H), 7.94 (dd, J = 5.6, 1.3 Hz, 1H), 6.68 (dd, J = 2.7,
1.6 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 159.5, 158.4, 156.1,
144.1, 127.7, 109.6, 108.6. HRMS-ESI (m/z): [M + H]+ calcd for
C7H7N4 147.0665; found 147.0668.
2-(1H-Pyrazol-1-yl)pyrimidine, Compound 31. Following
the general method described above, the title compound was isolated
in 94% yield. 1H NMR (600 MHz, DMSO) δ 8.86 (d, J = 4.8 Hz, 2H),
8.65 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.47 (t, J = 4.8 Hz, 1H), 6.59
(s, 1H). 13C NMR (151 MHz, DMSO) δ 159.3 (2 C), 155.3, 143.2,
129.4, 119.5, 108.7.* HRMS-ESI (m/z): [M + H]+ calcd for C7H7N4
147.0665; found 147.0664.
2-(1H-Pyrazol-1-yl)pyrazine, Compound 32. Following the
general method described above, the title compound was isolated in 74%
yield. 1H NMR (600 MHz, CDCl3) δ 9.35 (d, J = 1.3 Hz, 1H), 8.52 (dd,
J = 2.6, 0.6 Hz, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.36 (dd, J = 2.5, 1.5 Hz,
1H), 7.80 (d, J = 1.1 Hz, 1H), 6.52 (dd, J = 2.6, 1.7 Hz, 1H). 13C NMR
(151 MHz, CDCl3) δ 147.5, 143.1, 141.8, 141.8, 135.7, 127.4, 108.6.
HRMS-ESI (m/z): [M + H]+ calcd for C7H7N4 147.0665; found
147.0663.
2-(1H-Pyrazol-1-yl)pyridine, Compound 33. Following the
general method described above, the title compound was isolated in 96%
yield. 1H NMR (600 MHz, CDCl3) δ 8.57 (dd, J = 2.6, 0.6 Hz, 1H), 8.42
(dd, J = 4.8, 1.0 Hz, 1H), 7.98 (dd, J = 4.9, 4.1 Hz, 1H), 7.82 (ddd, J = 8.3,
7.4, 1.9 Hz, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.19 (ddd, J = 7.3, 4.9, 1.0 Hz,
1H), 6.47 (dd, J = 2.5, 1.7 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
146.1, 140.1, 136.8, 125.1, 119.5, 110.5, 105.9.* HRMS-ESI (m/z): [M +
H]+ calcd for C8H8N3 146.0713; found 146.0708.
1-Methyl-2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole, Com-
pound 22. Following the general method described above, the title
compound was isolated in 93% yield. 1H NMR (600 MHz, DMSO) δ
8.52 (d, J = 2.5 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.73ꢀ7.55 (m, 2H),
7.41ꢀ7.21 (m, 2H), 6.78ꢀ6.55 (m, 1H), 4.01 (s, 3H). 13C NMR (151
MHz, DMSO) δ 145.2, 142.6, 139.9, 135.5, 131.8, 122.6, 122.4, 118.6,
110.5, 107.9, 31.7. HRMS-ESI (m/z): [M + H]+ calcd for C11H11N4
199.0978; found 199.0976.
1-(4,5-Diphenyl-1H-imidazol-2-yl)-1H-pyrazole, Compound
23. Following the general method described above, the title compound was
isolated in 98% yield. 1H NMR (600 MHz, DMSO) δ 8.44 (d, J = 2.2 Hz,
1H), 7.87 (d, J = 1.3 Hz, 1H), 7.53ꢀ7.47 (m, 4H), 7.39ꢀ7.33
(m, 4H), 7.33ꢀ7.29 (m, 2H), 6.61 (dd, J = 2.3, 1.3 Hz, 1H). 13C NMR
(151 MHz, DMSO) δ 141.7, 140.9, 132.1, 128.5, 128.4, 127.8, 127.4, 108.0.
* HRMS-ESI (m/z): [M + H]+ calcd for C18H15N4 287.1291; found
287.1288.
2-(1H-Pyrazol-1-yl)benzo[d]thiazole, Compound 24. Fol-
lowing the general method described above, the title compound was
isolated in 98% yield. 1H NMR (600 MHz, DMSO) δ 8.70 (dd, J = 2.7,
0.5 Hz, 1H), 8.11 (ddd, J = 8.0, 1.2, 0.6 Hz, 1H), 7.97 (dd, J = 1.6, 0.5 Hz,
1H), 7.93 (ddd, J = 8.2, 1.1, 0.6 Hz, 1H), 7.54 (ddd, J = 8.2, 7.3, 1.3 Hz,
1H), 7.48ꢀ7.39 (m, 1H), 6.73 (dd, J = 2.7, 1.7 Hz, 1H). 13C NMR
(151 MHz, DMSO) δ 160.0, 150.3, 143.9, 132.4, 128.5, 126.8, 125.0,
122.4, 121.9, 110.1. HRMS-ESI (m/z): [M + H]+ calcd for C10H8N3S
202.0433; found 202.0433.
2-(1H-Pyrazol-1-yl)quinoline, Compound 27. Following the
general method described above, the title compound was isolated in 90%
yield. 1H NMR (600 MHz, DMSO) δ 8.82 (dd, J = 2.6, 0.7 Hz, 1H), 8.58
(d, J = 8.7 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.04 (dd, J = 8.1, 1.3 Hz,
1H), 8.02ꢀ7.97 (m, 1H), 7.92 (dd, J = 1.6, 0.6 Hz, 1H), 7.82 (ddd, J =
8.4, 6.9, 1.5 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.67 (dd, J = 2.6,
Methyl 2-(1H-Pyrazol-1-yl)-1H-benzo[d]imidazole-6-car-
boxylate, Compound 34. Following the general method described
above, the title compound was isolated in 98% yield. 1H NMR
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ARTICLE
(600 MHz, DMSO) δ 8.64 (dd, J = 2.6, 0.5 Hz, 1H), 8.12 (s, 1H),
8.01ꢀ7.99 (m, 1H), 7.86 (dd, J = 8.4, 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz,
1H), 6.70 (dd, J = 2.6, 1.7 Hz, 1H), 3.88 (s, 4H). 13C NMR (151 MHz,
DMSO) δ 166.6, 147.8, 143.3, 129.2, 123.5, 123.4, 109.3, 52.0. HRMS-
ESI (m/z): [M + H]+ calcd for C12H11N4O2 243.0877; found 243.0875.
6-Nitro-2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole, Com-
pound 35. Following the general method described above, the title
compound was isolated in 95% yield. 1H NMR (600 MHz, DMSO) δ
13.83 (s, 1H), 8.66 (d, J = 2.6 Hz, 1H), 8.37 (s, 1H), 8.14 (dd, J = 8.8,
2.3 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.70 (s, 1H), 6.73 (dd, J = 2.6,
1.7 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 149.2, 143.8, 142.7, 129.5,
118.1, 109.7. HRMS-ESI (m/z): [M + H]+ calcd for C10H8N5O2
230.0673; found 230.0671.
MHz, DMSO) δ 8.53 (s, 1H), 7.91 (s, 1H), 7.56ꢀ7.50 (m, 2H),
7.26ꢀ7.19 (m, 2H), 3.88 (t, J = 6.9 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H). 13
C
NMR (151 MHz, DMSO) δ 145.6, 143.2, 127.5, 122.3, 120.9, 114.6,
109.5, 44.7, 27.1. HRMS-ESI (m/z): [M + H]+ calcd for C12H12N4Cl
247.0745; found 247.0747.
2-(4-Nitro-1H-pyrazol-1-yl)-1H-benzo[d]imidazole, Com-
pound 43. Following the general method described above, the title
compound was isolated in 84% yield. 1H NMR (600 MHz, DMSO) δ
9.54 (d, J = 0.36 Hz, 1H), 8.75 (d, J = 0.36 Hz, 1H), 7.60 (s, 2H),
7.34ꢀ7.19 (m, 2H). 13C NMR (151 MHz, DMSO) δ 144.2, 138.2,
137.3, 128.4, 122.9, 109.5. HRMS-ESI (m/z): [M + H]+ calcd for
C10H8N5O2 230.0673; found 230.0673.
1-Methyl-2-(3-methyl-1H-pyrazol-1-yl)-1H-benzo[d]imid-
azole, Compound 44. Following the general method described
2-(1H-Pyrazol-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imid-
azole, Compound 36. Following the general method described
1
above, the title compound was isolated in 98% yield. H NMR (600
1
above, the title compound was isolated in 93% yield. H NMR (600
MHz, CDCl3) δ 8.28 (d, J = 2.5 Hz, 1H), 7.70 (ddd, J = 3.9, 2.3, 0.5 Hz,
1H), 7.38ꢀ7.34 (m, 1H), 7.32ꢀ7.27 (m, 2H), 6.30 (d, J = 2.5 Hz, 1H),
4.11 (s, 3H), 2.40 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 152.3, 145.8,
140.6, 135.8, 131.8, 122.7, 122.6, 119.1, 109.4, 108.0, 32.1, 13.8. HRMS-
ESI (m/z): [M + H]+ calcd for C12H13N4 213.1135; found 213.1133 .
1-Methyl-2-(3-phenyl-1H-pyrazol-1-yl)-1H-benzo[d]imid-
azole, Compound 45. Following the general method described
MHz, DMSO) δ 8.64 (dd, J = 2.6, 0.5 Hz, 1H), 8.01 (dd, J = 1.6, 0.4 Hz,
1H), 7.85 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.4, 1.4 Hz, 1H),
6.71 (dd, J = 2.6, 1.7 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 147.9,
143.4, 129.2, 124.9 (q, J = 271.6 Hz, 1C), 122.7 (q, J = 31.8 Hz, 1C),
118.9 (q, J = 3.5 Hz, 1C), 109.4. HRMS-ESI (m/z): [M + H]+ calcd for
C11H8N4F3 253.0696; found 253.0698.
2-(1H-Pyrazol-1-yl)-1H-benzo[d]imidazole-6-carbonitrile,
Compound 37. Following the general method described above, the
title compound was isolated in 92% yield. 1H NMR (600 MHz, DMSO)
δ 13.66 (s, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 1.4 Hz, 2H), 7.67
(d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.3, 1.5 Hz, 1H), 6.71 (dd, J = 2.6, 1.7
Hz, 1H). 13C NMR (151 MHz, DMSO) δ 148.3, 143.5, 129.3, 125.9,
119.8, 109.5, 104.0. HRMS-ESI (m/z): [M + H]+ calcd for C11H8N5
210.0774; found 210.0779.
6-Methoxy-2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole,
Compound 38. Following the general method described above, the
title compound was isolated in 98% yield. 1H NMR (600 MHz, DMSO)
δ 8.55 (d, J = 2.6 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 8.7 Hz,
1H), 7.03 (s, 1H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 6.65 (dd, J = 2.5, 1.7 Hz,
1H), 3.79 (s, 3H). 13C NMR (151 MHz, DMSO) δ 155.7, 145.5, 142.5,
128.6, 111.1, 108.7, 55.4. HRMS-ESI (m/z): [M + H]+ calcd for
C11H11N4O 215.0927; found 215.0924.
2-(4-Chloro-1H-pyrazol-1-yl)-1H-benzo[d]imidazole, Com-
pound 39. Following the general method described above, the title
compound was isolated in 98% yield. 1H NMR (600 MHz, DMSO) δ
13.17 (s, 1H), 8.84 (d, J = 0.6 Hz, 1H), 8.10 (d, J = 0.6 Hz, 1H), 7.53 (br s,
2H), 7.29ꢀ7.15 (m, 2H). 13C NMR (151 MHz, DMSO) δ 145.2, 141.1,
126.9, 122.2, 112.4. HRMS-ESI (m/z): [M + H]+ calcd for C10H8N4Cl
219.0432; found 219.0433.
1
above, the title compound was isolated in 91% yield. H NMR (600
MHz, DMSO) δ 8.60 (s, 1H), 8.01 (d, J = 7.3 Hz, 2H), 7.67 (d, J =
7.8 Hz, 2H), 7.51 (t, J = 7.3 Hz, 2H), 7.43 (t, J = 7.0 Hz, 1H), 7.32 (dt, J =
24.9, 7.2 Hz, 2H), 7.19 (s, 1H), 4.14 (s, 3H). 13C NMR (151 MHz,
DMSO) δ 153.5, 145.1, 140.0, 135.6, 133.2, 131.8, 128.8, 128.6, 125.7,
122.5, 122.47, 118.5, 110.5, 105.6, 31.9. HRMS-ESI (m/z): [M + H]+
calcd for C17H15N4 275.1291; found 275.1290.
1-Methyl-2-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-1H-benzo-
[d]imidazole, Compound 46. Following the general method described
above, the title compound was isolated in 95% yield. 1H NMR (600 MHz,
DMSO) δ 8.70 (s, 1H), 7.67ꢀ7.63 (m, 2H), 7.63ꢀ7.60 (m, 2H),
7.49ꢀ7.44 (m, 2H), 7.37ꢀ7.27 (m, 3H), 4.08 (s, 3H), 2.49 (s, 3H). 13C
NMR (151 MHz, DMSO) δ 149.1, 145.0, 139.9, 135.6, 131.7, 129.9, 128.8,
127.4, 126.9, 122.7, 122.6, 122.5, 118.5, 110.5, 31.8, 13.5. HRMS-ESI (m/
z): [M + H]+ calcd for C18H17N4 289.1448; found 289.1447.
1-Methyl-2-(5-methyl-3-phenyl-1H-pyrazol-1-yl)-1H-benzo
[d]imidazole, Compound 47. Following the general method de-
scribed above except that it took 4 days for the reaction to complete, the
title compound was isolated in 60% yield after column chromatography
with EtOAc/hexanes as eluents. 1H NMR (600 MHz, CDCl3) δ
7.89ꢀ7.82 (m, 2H), 7.77 (dd, J = 6.7, 1.8 Hz, 1H), 7.44ꢀ7.37 (m, 2H),
7.37ꢀ7.27 (m, 4H), 6.55 (d, J = 0.7 Hz, 1H), 3.87 (s, 3H), 2.57 (d, J =
0.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 153.2, 145.1, 144.0, 140.8,
135.2, 132.7, 128.7, 128.4, 125.9, 123.3, 122.7, 119.9, 109.7, 105.0, 31.4,
12.5. HRMS-ESI (m/z): [M + H]+ calcd for C18H17N4 289.1448; found
289.1452.
1-Methyl-2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1H-benzo
[d]imidazole, Compound 48. The title compound was isolated as a
minor product in 6% yield after column chromatography with EtOAc/
hexanes as eluents. 1H NMR (600 MHz, DMSO) δ 7.62 (dd, J = 8.9, 8.2
Hz, 2H), 7.38ꢀ7.34 (m, 1H), 7.32ꢀ7.26 (m, 4H), 7.25ꢀ7.21 (m, 2H),
6.69 (s, 1H), 3.62 (s, 3H), 2.34 (s, 3H). 13C NMR (151 MHz, DMSO) δ
151.0, 146.5, 144.9, 139.9, 134.5, 128.9, 128.7, 128.6, 127.3, 123.3, 122.5,
119.6, 110.8, 107.4, 29.9, 13.3. HRMS-ESI (m/z): [M + H]+ calcd for
C18H17N4 289.1448; found 289.1451.
2-(3-(4-Methoxyphenyl)-1H-pyrazol-1-yl)-1H-benzo[d]imid-
azole, Compound 40. Following the general method described above,
the title compound was isolated in 96% yield. 1HNMR(600MHz, DMSO)
δ 8.67 (d, J = 2.7 Hz, 1H), 8.01ꢀ7.92 (m, 2H), 7.63ꢀ7.54 (m, 2H),
7.30ꢀ7.23 (m, 2H), 7.13 (d, J = 2.7 Hz, 1H), 7.12ꢀ7.05 (m, 2H), 3.83
(s, 3H). 13C NMR (151 MHz, DMSO) δ 159.9, 153.9, 145.3, 136.4, 130.7,
127.4, 124.2, 122.6, 114.5, 114.3, 106.6, 55.2. HRMS-ESI (m/z): [M + H]+
calcd for C17H15N4O 291.1240; found 291.1235.
2-(3-(Trifluoromethyl)-1H-pyrazol-1-yl)-1H-benzo[d]imid-
azole, Compound 41. Following the general method described
1
above, the title compound was isolated in 88% yield. H NMR (600
MHz, DMSO) δ 13.37 (s, 1H), 8.84 (dd, J = 2.6, 0.9 Hz, 1H), 7.58
(dd, J = 7.4, 1.6 Hz, 2H), 7.29ꢀ7.24 (m, 2H), 7.16 (d, J = 2.6 Hz, 1H).
13C NMR (151 MHz, DMSO) δ 144.6, 143.7 (q, JCꢀF = 38.0 Hz, 1C),
131.6, 122.7, 120.9 (q, JCꢀF = 269.1 Hz, 1C), 107.2. HRMS-ESI (m/z):
[M + H]+ calcd for C11H8N4F3 253.0696; found 253.0699.
2-(3,5-Diisopropyl-1H-pyrazol-1-yl)-1H-benzo[d]imidazole,
Compound 49. Following the general method described above except
that the reaction was performed at 140 °C for 1 d, the title compound was
isolated in 55% yield after column chromatography with EtOAc/hexanes
1
2-(4-(2-Chloroethyl)-1H-pyrazol-1-yl)-1H-benzo[d]imid-
azole, Compound 42. Following the general method described
as eluents. H NMR (600 MHz, CDCl3) δ 11.14 (s, 1H), 7.72 (d, J =
7.8 Hz, 1H), 7.36ꢀ7.10 (m, 3H), 6.19 (s, 1H), 4.42ꢀ4.18 (m, 1H),
1
above, the title compound was isolated in 89% yield. H NMR (600
3.13ꢀ2.90 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.31 (d, J = 7.0 Hz, 6H). 13C
8268
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The Journal of Organic Chemistry
ARTICLE
NMR (151 MHz, CDCl3) δ 161.4, 154.0, 146.7, 142.6, 132.0, 122.5, 122.1,
119.1, 110.3, 102.8, 28.0, 25.9, 22.5, 22.4. HRMS-ESI (m/z): [M + H]+
calcd for C16H21N4 269.1761; found 269.1763.
Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc.
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2-(3,5-Diisopropyl-1H-pyrazol-1-yl)-10H-1,20-bibenzo[d]-
imidazole, Compound 50. The title compound was isolated as a
byproduct in 18% yield after column chromatography with EtOAc/
1
hexanes as eluents. H NMR (600 MHz, CDCl3) δ 12.10 (s, 1H),
8.42ꢀ8.36 (m, 1H), 7.85ꢀ7.78 (m, 2H), 7.50 (ddd, J = 8.3, 7.3, 1.2 Hz,
1H), 7.43 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.40ꢀ7.35 (m, 1H), 7.33ꢀ7.26
(m, 2H), 6.14 (s, 1H), 3.49ꢀ3.30 (m, 1H), 3.13 (hept, J = 6.9 Hz, 1H),
1.43 (d, J = 7.0 Hz, 6H), 1.12 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz,
CDCl3) δ 162.2, 157.2, 142.6, 142.0, 141.7, 140.3, 133.7, 132.2, 125.7,
124.5, 123.4, 122.7, 120.2, 119.7, 114.5, 110.8, 102.8, 28.1, 25.6, 22.4,
22.2. HRMS-ESI (m/z): [M + H]+ calcd for C23H25N6 385.2135; found
385.2127.
* Denotes that some of the C signals do not show up even at very high
concentration.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra. This
S
b
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: xdeng@its.jnj.com.
’ ACKNOWLEDGMENT
We wish to thank Ms. Heather McAllister for analytical
support and Dr. Daniel J. Pippel for proofreading the manuscript.
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