Cu-catalyzed carbon-heteroatom coupling reactions under mild conditions promoted by resin-bound organic ionic bases

Article abstract of DOI:10.1021/jo101917x

Resin-bound organic ionic bases (RBOIBs) were developed in which tetraalkyl-ammonium or phosphonium cations are covalently attached to solid resins. The application tests showed that the performance of the tetraalkyl-ammonium-type RBOIBs is slightly better than that of the corresponding Cs salts in Cu-catalyzed C-N cross-couplings, while the tetraalkylphosphonium-type RBOIBs are significantly better than all the inorganic bases. With these newly developed RBOIBs, room-temperature Cu-catalyzed C-Ncoupling with various nonactivated aryl iodides and even aryl bromides can be readily accomplished. Moreover, RBOIBs can be easily recycled and reused for a number of times without much drop of activity. The good performances of RBOIBs are proposed to arise from the relatively weak binding forces between the cationic polymer backbone and basic anions, as opposed to the strong metal-anion interactions in the inorganic bases. Further applications of RBOIBs in Ni-catalyzed Suzuki-type couplings at room temperature, Cu-catalyzed C-N couplings at -30 °C, a Pd-catalyzed Heck reaction at 60 °C, and Cu-catalyzed C-S couplings at room temperature demonstrate that RBOIBs are generally applicable bases with improved performance for many other types of organic transformations.

Full text of DOI:10.1021/jo101917x

pubs.acs.org/joc
Cu-Catalyzed Carbon-Heteroatom Coupling Reactions under Mild
Conditions Promoted by Resin-Bound Organic Ionic Bases
Yao-Bing Huang,† Chu-Ting Yang,† Jun Yi,† Xiao-Jian Deng,† Yao Fu,*,† and Lei Liu‡
†Department of Chemistry, Joint Laboratory of Green Synthetic Chemistry, University of Science and
Technology of China, Hefei 230026, and ‡Department of Chemistry, Tsinghua University, Beijing 100084, China
fuyao@ustc.edu.cn
Received October 3, 2010
Resin-bound organic ionic bases (RBOIBs) were developed in which tetraalkyl-ammonium or
phosphonium cations are covalently attached to solid resins. The application tests showed that the
performance of the tetraalkyl-ammonium-type RBOIBs is slightly better than that of the corre-
sponding Cs salts in Cu-catalyzed C-N cross-couplings, while the tetraalkylphosphonium-type
RBOIBs are significantly better than all the inorganic bases. With these newly developed RBOIBs,
room-temperature Cu-catalyzed C-N coupling with various nonactivated aryl iodides and even aryl
bromides can be readily accomplished. Moreover, RBOIBs can be easily recycled and reused for a
number of times without much drop of activity. The good performances of RBOIBs are proposed to
arise from the relatively weak binding forces between the cationic polymer backbone and basic
anions, as opposed to the strong metal-anion interactions in the inorganic bases. Further applica-
tions of RBOIBs in Ni-catalyzed Suzuki-type couplings at room temperature, Cu-catalyzed C-N
couplings at -30 °C, a Pd-catalyzed Heck reaction at 60 °C, and Cu-catalyzed C-S couplings at
room temperature demonstrate that RBOIBs are generally applicable bases with improved perfor-
mance for many other types of organic transformations.
1. Introduction
quantities of the copper salts.2 Recently, by the use of
chelating ligands such as β-diketones,3 1,2-diamines,4 phen-
anthrolines,5 amino acids,6 and others,7 milder and selec-
tive carbon-heteroatom coupling reactions have been devel-
oped with Cu as catalyst. With certain tailor-made ligands,
even room-temperature (rt) couplings have been accomplished
Copper-catalyzed carbon-heteroatom cross-coupling re-
actions have been established as important tools for synth-
esis of medicinally active compounds and agrochemicals.1
These reactions were originally carried out under harsh con-
ditions that required high temperatures and stoichiometric
(3) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(b) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3490.
(4) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Antilla, J. C.; Baskin, J. M.; Barder,
T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578. (d) Yuen, J.; Fang,
Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (e) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem.;Eur. J. 2004, 10, 5607.
(1) Reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400. (b) Deng, W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004, 24, 150.
(c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
(d) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(e) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 2. (f) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(2) (a) Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174.
(b) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
800 J. Org. Chem. 2011, 76, 800–810
Published on Web 12/31/2010
DOI: 10.1021/jo101917x
r
2010 American Chemical Society

Huang et al.
JOCArticle
for aryl iodides with aliphatic amines,8 amides,9 malonates,10
and alkoxy diboron reagents.11 By contrast, there have been
scant experimental reports for Cu-catalyzed cross-coupling
reactions at room temperature for nonactivated aryl
bromides.12
In a recent study we showed that the selection of base
has an important effect on Cu-catalyzed C-N coupling
reactions.12 This phenomenon can be explained by a mecha-
nism in which the amine group coordinated to (Ligand)CuI
must be deprotonated before the oxidation addition step13
(or before the single-electron transfer step14). The commonly
used bases in Cu catalysis are inorganic ionic salts (e.g.,
K3PO4, Cs2CO3) that are poorly ionized in organic solvents
and therefore, impede the necessary deprotonation step. To
overcome this problem, we designed new organic ionic bases
composed of tetraalkyl-ammonium or phosphonium cations
and basic anions (e.g., (nBu4Pþ)2CO32-).12 These organic
ionic bases were found to enable Cu-catalyzed C-N cross-
coupling reactions of nonactivated aryl bromides at room
temperature.
FIGURE 1. Methods for preparing RBOIBs.
The organic ionic bases are not without disadvantages.
First, these bases are relatively expensive to obtain. Second,
the organic ionic bases are found to be fairly hygroscopic and
have to be stored and used under strictly dry conditions.
These disadvantages may hamper the utility of the organic
ionic bases in both Cu-catalyzed couplings and other base-
mediated organic reactions. To overcome these disadvan-
tages, we now describe resin-bound organic ionic bases
(abbreviated as RBOIB below) in which the cations are
replaced by tetraalkyl-ammonium or phosphonium cations
covalently bound to hydrophobic polymers. Though various
tests, we found that the new RBOIBs are stable in the air.
They are easily prepared and inexpensive, and these bases
can promote Cu-catalyzed C-N coupling reactions of non-
activated aryl bromides at room temperature and other
organic transformations. More interestingly, unlike the tra-
ditional inorganic bases, RBOIBs can be easily recycled and
reused.
2. Results and Discussion
2.1. Synthesis of RBOIBs. Figure 1 shows the RBOIBs
synthesized in the present study. They can be prepared
through the ion exchange reaction of commercially available
Amberlite IRA-400 resins with Na2CO3, Na3PO4, or NaOAc
(Method A). Alternatively, they can be prepared by Method
(5) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973. (b) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 4978. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera,
E. L. Org. Lett. 2004, 6, 1151. (d) Altman, R. A.; Koval, E. D.; Buchwald,
S. L. J. Org. Chem. 2007, 72, 6190. (e) Altman, R. A.; Shafir, A.; Choi, A.;
Lichtor, P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73, 284. (f) Tye, J. W.;
Weng, Z.; Giri, R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 2185.
(6) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. (b) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(c) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799. (d) Pan, X.; Cai, Q.; Ma, D. Org.
Lett. 2004, 6, 1809. (e) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164. (f) Cai, Q.; He, G.; Ma, D. J. Org. Chem. 2006, 71, 5268. (g) Deng, W.;
Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311.
(h) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X. Tetrahedron Lett.
2005, 46, 7295.
(7) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695. (b) Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler,
J.-F.; Taillefer, M. Org. Lett. 2004, 6, 913. (c) Xia, N.; Taillefer, M. Chem.;
Eur. J. 2008, 14, 6037. (d) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem.;Eur. J. 2006, 3636. (e) Ouali, A.; Laurent, R.; Caminade, A.-M.;
Majoral, J.-P.; Taillefer, M. J. Am. Chem. Soc. 2006, 128, 15990. (g) Kawano,
T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900.
(8) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(b) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3490. (c) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672.
(d) Kim, J.; Chang, S. Chem. Commun. 2008, 3052.
B
15 that involves the reaction of Merrifield resin with nBu3N
or nBu3P followed by ion exchange. These new RBOIBs
resemble traditional basic anion exchange resins. However,
two features are unique for the new materials. First, the
anions in the new RBOIBs are not OH- but weaker and less
nucleophilic basic anions. The OH-type anion exchange
resin does not have much utility in Cu-catalyzed coupling
reactions. Second, and more importantly, the tetraalkylphos-
phonium cations, which have seldom been used for the
anion exchange resins, are found to be crucial for RBOIBs
to exhibit good performances in mediating organic reactions.
Note that in addition to Amberlite or Merrifield resins, some
other types of solid supports such as silica or polyacrylic
materials can also be considered to make RBOIBs. Compar-
ison of the properties of RBOIBs made from different solid
supports is beyond the scope of the present study and will be
studied in our following research.
(9) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421. (b) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863. (c) Phillips, D. P.;
Zhu, X.-F.; Lau, T. L.; He, X.-H.; Yang, K.; Liu, H. Tetrahedron Lett. 2009,
50, 7293.
2.2. Solvent Effects on RBOIB-Mediated rt C-N Cou-
plings. To test the performance of the newly developed
RBOIBs in comparison to traditional inorganic bases, we have
examined the room temperature coupling of benzylamine with
(10) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9,
3469.
(11) Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem., Int. Ed.
2009, 48, 5350.
(12) Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew.
Chem., Int. Ed. 2009, 48, 7398.
(13) (a) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 9971. (b) Strieter, E. R.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78. (c) Zhang, S.-L.; Liu, L.;
Fu, Y.; Guo, Q.-X. Organometallics 2007, 26, 4546.
(14) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 6205.
(15) For previous wok on polystyrene-supported ammonium and phos-
phonium salts, see: (a) Regen, S. L. J. Am. Chem. Soc. 1975, 97, 5956.
(b) Molinari, H.; Montanari, F.; Quici, S.; Tundo, P. J. Am. Chem. Soc. 1979,
101, 3920. (c) Regen, S. L.; Bolikal, D.; Barcelon, C. J. Org. Chem. 1981, 46,
2511. (d) Montanari, F. Nouv. J. Chim. 1982, 6, 635.
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FIGURE 3. RBOIB (RB-TBPA) (a) before and (b) after the Cu-
catalyzed C-N cross-coupling reaction.
types of RBOIBs were not active enough to promote the re-
action. The most powerful base was found to be RB-TBPA,
which afforded a yield of 82% in DMSO (Figure 2b). On the
other hand, the yields with the OAc- salts of the tetraalk-
ylammonium type polymers (RB-TBAA and RB-TMAA)
were around 65%. The performance of CsOAc was similar
to that of the tetraalkylammonium type polymers, but the
yields with KOAc and NaOAc were significantly lower.16
Again, the reaction yield was strongly dependent on the
solvent polarity, and RBOIBs always afforded significantly
higher yields than the inorganic bases.
2.3. Recycling of RBOIBs. Note that in our previous work
the yield for the room temperature coupling of benzylamine
with bromobenzene was 92%, where the base was tetra-
butylphosphonium malonate. This observation may indicate
that the performance of free organic ionic bases is slightly
better than that of RBOIBs, presumably because the free
organic ionic bases are fully soluble in the organic solvents
whereas RBOIBs are insoluble resins (Figure 3). Nonethe-
less, it is important to aware that most inorganic bases are
not soluble in the organic solvents either. Therefore, the use
of RBOIBs does not bring about more operation problems
than the inorganic bases. On the other hand, three major
advantages can be identified for the RBOIBs: (1) RBOIBs
exhibit significantly improved performances than the Cs, K,
and Na salts (Figure 2). (2) RBOIBs are made from inexpen-
sive resins and cheap Na salts (e.g., NaOAc or Na2CO3). The
estimated cost of a RBOIB is much lower than that of the
corresponding Cs salt. (3) The resin can be readily recycled
and reused for a number of times (Table 1). This property
may allow the RBOIB to be applied to some large scale
syntheses where the inorganic bases are not effective enough.
The successful recycle of RBOIBs also indicates that
RBOIBs do not decompose when mediating the reaction.
2.4. Scope of rt C-N Coupling. As to the generality of the
RBOIB-promoted C-N couplings at room temperature, a
number of aryl iodides and bromides were examined with a
variety of amine nucleophiles (Tables 2 and 3). Both electron-
rich and electron-poor aryl iodides or bromides can be
successfully converted bearing a range of functional groups.
Heterocycle-containing substrates can also be tolerated in
the coupling. The amine nucleophiles include primary and
secondary amines, N-heterocycles, and even anilines. The
coupling yields were mostly good to excellent. Note that Cu-
catalyzed C-N cross-coupling of nonactivated aryl bro-
mides at room temperature12 has been achieved only recently
by use of organic ionic bases, whereas the traditional inorganic
FIGURE 2. Effect of bases on rt C-N coupling of benzylamine
with (a) iodobenzene and (b) bromobenzene.
aryl halides. When iodobenzene was tested, RBOIBs with
PO43-, CO32-, and OAc- anions could all promote the room
temperature coupling (Figure 2a). For instance, the coupling
yield with the CO32- salt of the tetrabutylphosphonium type
polymer (RB-TBPC) was 78% in DMSO, whereas the yields
with the CO32- salts of the tetraalkylammonium type poly-
mers (RB-TBAC and RB-TMAC) were ca. 65%. By compar-
ison, the yield with Cs2CO3 was 58%, and the yields with
K2CO3 and Na2CO3 were significantly lower. Note that the
above reaction was achieved with L-proline, whereas ligands
such as 2-isobutyrylcyclohexanone were required in the
previous protocols for Cu-catalyzed C-N coupling at room
temperature.8 Also note that the reaction yield was strongly
dependent on the solvent polarity. From DMSO to toluene,
the yield decreased considerably from 78% to <10% with
RB-TBPC. This observation may be attributed to the fact
that DMSO is a better ion pair separating solvent with
respect to toluene and other employed solvents. Besides,
DMSO can well swell the solid support and enhance acces-
sibility to its inner site. All the other bases showed similar
trends, but the use of RBOIBs always afforded significantly
higher yields than with inorganic bases.
As to the more challenging substrate (i.e., bromobenzene),
2-
(16) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K; Tokuyama, H.;
Fukuyama, T. Tetrahedron 2008, 64, 11230.
the OAc- salt must be used, because the PO43- and CO3
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TABLE 1. Yields after Several Rounds of Recycle When using RBOIBsa
X
base
1
2
3
4
5
6
7
8
9
10
X = I
X = Br
RB-TBPA
RB-TBPA
95%
81%
92%
80%
90%
73%
93%
71%
94%
85%
92%
78%
91%
76%
85%
71%
85%
74%
79%
68%
aRecycle method: After each round of cross-coupling reaction, the resin was collected by filtration. The resin was washed three times with DMSO and
then three times with EtOH. Next the resin was treated with 1 mol/L NaOAc aqueous solution for 24 h. The final material was washed with pure water
and EtOH, and then dried at 40 °C under vacuum for 24 h before the next use. Note that due to the magnetic stirring, the resins were pulverized after
several rounds of recycling. However, this does not make filtration or recycling difficult in our hands. GC yield. b
TABLE 2. Yields for Cu-Catalyzed C-N Couplings of Aryl Iodides
TABLE 3. Yields for Cu-Catalyzed C-N Couplings of Aryl Bromides
with Amines at rta
with Amines at rta
aConditions: ArI (0.5 mmol), amine (0.75 mmol), ligand (20 mol %),
RB-TBPA (0.34 g, 1.5 equiv), DMSO (1.0 mL).
bases (except for CsOAc that can give ca. 60% yields) cannot
afford acceptable yields at room temperature. These results
show again that the RBOIBs can be more powerful than
inorganic bases. Note that with our current catalyst systems,
more challenging substrates (such as acyclic secondary
amines) cannot undergo the C-N cross-coupling even at
elevated temperatures, presumably because these substrates
require the use of more sophisticated ligands instead of
L-proline and DMEDA. We will study these more difficult
substrates with other ligands in our following research.
The above protocols of room temperature C-N cross-
coupling reactions may find applications in organic synthe-
sis. By changing ligands, sequential amination reactions can
be achieved at the C-I bond and then at the C-Br bond both
aConditions: ArBr (0.5 mmol), amine (0.75 mmol), ligand (20 mol %),
RB-TBPA (0.34 g, 1.5 equiv), DMSO (1.0 mL).
under very mild conditions at room temperature (Scheme 1).
With RB-TBPA it is even possible to achieve C-N cross-
coupling of an aryl chloride at room temperature (Scheme 2).
Previously the same C-Cl activation reaction had to be
accomplished at 60-70 °C by using Cs2CO3 or K2CO3 as
base.17 Interestingly, for the chlorinated substrate the course
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SCHEME 1. Selective Amination Reactions
SCHEME 2. Intra- and Intermolecular Amination
FIGURE 4. (a) Catalytic cycle of the C-N cross-coupling reaction.
(b) Compare the surfaces of RBOIBs and inorganic bases.
of the reaction could be diverted toward intermolecular
amination in the presence of an aryl iodide, whereas for the
brominated substrate the intramolecular cyclization is still
favored.
TABLE 4. Ni-Catalyzed Suzuki-Type Cross-Coupling at rta
2.5. Mechanistic Considerations. To understand why
RBOIBs are more active than the inorganic bases, we need
to point out that deprotonation of the N-H group and/or
coordination of the deprotonated nucleophile to Cu could be
a rate-limiting step in C-N couplings (Figure 4a). This
proposal was supported by our previous experiments with
free organic ionic bases showing that variation of the base
could dramatically change the reaction rate of the cross
coupling.12 Therefore, optimization of the base is as impor-
tant as optimization of the ligand for the cross-coupling
reaction. As for RBOIBs, our experiments showed that they
are not soluble. Thus, the deprotonation step can only take
place at the surface of the RBOIBs (and also in the case of
inorganic bases). Because of the large size of the tetraalk-
ylammonium or phosphonium cations, it is understandable
that the basic anions on the surface of RBOIBs are only
loosely bound to the polymer backbone (Figure 4b). By
contrast, the basic anions are tightly coordinated by the metal
cations on the surface of an inorganic base. The outcome is
that the surface of RBOIBs is much more active than that of
the inorganic bases, so that RBOIBs can mediate the depro-
tonation step more efficiently than inorganic bases. Further-
more, some other factors may also explain the advantages
of RBOIBs over inorganic bases including the accessibility of
the inner sites of RBOIBS.
aConditions: ArBr (0.25 mmol), boronic acid (0.5 mmol), RB-TBPP
(0.15 g, 2 equiv), THF (1.0 mL).
improve performance for many other types of organic
transformations in general. Table 4 shows that the phos-
phate salt of tetrabutyl-phosphonium-type resin (i.e., RB-
TBPP) can promote the Ni-catalyzed Suzuki-type cross-
coupling at room temperature. Previous protocols for the
same cross-coupling used K3PO4 as base and required the
reaction to proceed at elevated temperatures (e.g., 80 °C).18
To achieve room temperature Ni-catalyzed Suzuki-type
reactions, previous studies used either air-sensitive Ni(COD)2
as catalyst or n-BuLi as reductant.19 These conditions are
less favorable as compared to the present room temperature
protocol that uses inexpensive and air-stable Ni(PPh3)2Cl2 as
catalyst and Zn as reductant.
2.6. Applications to Other Transition Metal-Catalyzed
Reactions. More experiments indicate that RBOIBs can
(18) (a) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024.
(b) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org. Chem.
2004, 69, 3447.
(17) (a) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
(b) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(19) Tang, Z.-Y.; Hu, Q.-S. J. Org. Chem. 2006, 71, 2167.
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TABLE 5. Cu-Catalyzed C-N Couplings at a Very Low Temperaturea
carried out at fairly high temperatures ranging from 60 to
120 °C22 even when some special ligands such as β-keto
ester23 and 1,1,1-tris(hydroxymethyl)ethane24 were used.
The fact that in the presence of RB-TBPP, a common ligand
(i.e., 1,10-phenanthroline) can already promote room tem-
perature C-S couplings provides an additional example for
the advantageous effect of using RBOIBs. Note that in the
control experiments with K2CO3, K3PO4, Cs2CO3, and
t-BuOK as the base under the same conditions in Table 6,
the C-S coupling yields were lower than 10%.
aConditions: ArI (0.5 mmol), amine (0.75 mmol), RB-TBPA (0.34 g,
1.5 equiv), DMSO/DMF (0.5:0.5 mL).
3. Conclusion
In summary, recent studies showed that organic ionic bases
oftetraalkyl-ammoniumorphosphonium saltsare better than
the traditional inorganic bases in some Cu-catalyzed cross-
coupling reactions.25 However, their high synthetic costs and
hygroscopic property may limit their application. To solve
these problems we developed in this study resin-bound or-
ganic ionic bases (RBOIBs) that are inexpensive to prepare
and very easy to use. The following conclusions can be made
on the basis of our experimental examinations:
SCHEME 3. Use of RBOIBs in Pd-Catalyzed Heck Reaction
First, the performance of the tetraalkyl-ammonium-type
RBOIBs is slightly better than that of the corresponding Cs
salts in Cu-catalyzed C-N cross-couplings, whereas the
tetraalkylphosphonium-type RBOIBs are significantly bet-
ter than all the inorganic bases.
TABLE 6. Cu-Catalyzed C-S Cross-Coupling at rta
Second, room-temperature Cu-catalyzed C-N coupling
with various nonactivated aryl bromides can be readily
accomplished with the RBOIBs, and RBOIBs can be easily
recycled and reused for a number of times without much
drop of activity.
Finally, RBOIBs can be used to improve the performance
of other types of organic transformations as demonstrated
by Ni-catalyzed Suzuki-type couplings at room temperature,
Cu-catalyzed C-N couplings at -30 °C, a Pd-catalyzed
Heck reaction at 60 °C, and Cu-catalyzed C-S couplings
at room temperature.
aConditions: ArI (1.0 mmol), thiol (0.5 mmol), RB-TBPP (0.34 g, 1.5
equiv), NMP/MeOH (0.5:0.5 mL).
4. Experimental Section
It is important to note that the RBOIBs can mediate
chemical reactions at various temperatures. For instance,
Table 5 shows that RB-TBPA can promote Cu-catalyzed
C-N cross-coupling reactions with common aryl iodides
at -30 °C. Compared to the previous protocols that required
at least room temperature to achieve the same reactions,20
these results demonstrated that RBOIBs not only are bases
with better performance, but also can be used at low tem-
peratures. Moreover, Scheme 3 shows a Pd-catalyzed Heck
cross-coupling at 60 °C, indicating that RBOIBs are stable
and can be used for Pd-catalyzed transformations as well as
reactions at elevated temperatures.21
General Procedure for Preparation of RBOIB (A). The Am-
berlite IRA-400 resin purchased commercially contains the
functional group of -Nþ(CH3)3Cl-. Its average moisture con-
tent is 42-48% and its complete exchange capacity is >3.6
mmol/g (dry). The particle diameter is 0.40-0.70 mm. The resin
was packed in an exchange-column and flushed with 1 mol/L
HCl. Then, the resin was washed with water. A solution of
1 mol/L inorganic base was used to exchange with the anion in
the resin until all the Cl- was exchanged. The flow rate was
about 2-3 mL min-1. Finally, the resin was washed by water.
(22) For examples of Cu-catalyzed C-S bond formation, see: (a) Bates,
C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
(b) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004,
1254. (c) Rout, L.; Sen, T.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007,
46, 5583. (d) Carril, M.; SanMartin, R.; Dominguez, E.; Tellitu, I. Chem.;
Eur. J. 2007, 13, 5100.
Finally, Table 6 shows an interesting discovery that the
Cu-catalyzed C-S cross-coupling reaction can now be ac-
complished at room temperature when a RBOIB is used as
the base. Previously, Cu-catalyzed C-S couplings had to be
(23) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
(24) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609.
(25) The selection of base has also been known to be very important in
many previous studies on organic transformations. For examples, see:
(a) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463.
(b) Rodriguez, A. L.; Christopher, K.; Wolfgang, D.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488. (c) Alcazar-Roman, L. M.; Hartwig, J. F.
J. Am. Chem. Soc. 2001, 123, 12905. (d) Taillefer, M.; Rahier, N.; Hameau,
A. Chem. Commun. 2006, 3238. (e) Shekhar, S.; Hartwig, J. F. Organome-
tallics 2007, 26, 340.
(20) Previous Cu-catalyzed cross-couplings below r.t. required special
substrates that could involve an ortho-substituent effect. See: Xie, X.; Chen,
Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
(21) For recent examples of Pd-catalyzed Heck reaction, see: (a) Littke,
A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (b) Littke, A. F.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 6989. (c) Cui, X.; Li, Z.; Tao, C.-Z.; Xu, Y.; Li, J.; Liu,
L.; Guo, Q.-X. Org. Lett. 2006, 8, 2467.
J. Org. Chem. Vol. 76, No. 3, 2011 805

Huang et al.
JOCArticle
RB-TMAC (1). Following procedure A, the anion of the resin
was exchanged by CO32- from Na2CO3 solution. A small puce
resin was obtained.
RB-TMAP (2). Following procedure A, the anion of the resin
was exchanged by PO43- from Na3 PO4 solution. A small puce
resin was obtained.
RB-TMAA (3). Following procedure A, the anion of the resin
was exchanged by OAc- from NaOAc solution. A small puce
resin was obtained.
General Procedure for Preparation of RBOIB (B). The Merri-
field resin was swelled in DMF for 24 h. An overdried three-neck
round-bottom flask with a reflux condensing tube, a constant
pressure funnel and a stir bar was charged with the Merrifield
resin. The device was evacuated and backfilled with argon.
Under a counter flow of argon, DMF was added by syringe
and alkylamine was added to the constant pressure funnel. The
flask was heated to 80-110 °C. Then alkylamine or alkylphos-
phine was added dropwise. The reaction was allowed to stir for
48 h. After the reaction, the resin was filtered, and washed with
water and ethanol three times.
RB-TBAA (4). Following procedure B, tributylamine (80 mL)
was allowed to react with Merrifield resin (20 g, 50-100 mesh) at
80 °C for 48 h. After exchanged with OAc- from NaOAc
solution, a small buff resin was obtained. The average moisture
content is 43.8%. The loading value is 2.1 mmol/g (dry) and the
particle diameter is 0.40-0.70 mm. Elemental analysis: C/N =
27.8 (w/w), N: 2.756%.
added by syringe. The tube was sealed and the mixture was
allowed to stir under argon at room temperature (25 ( 3 °C) for
24 h. Upon completion of the reaction, the mixture was diluted
with ethyl acetate, and the solvent was removed with the aid of a
rotary evaporator. The residue was purified by column chro-
matography on silica gel and the product was dried under high
vacuum for at least 0.5 h.
N-Benzylaniline (1a):12 Following procedure A (B), iodoben-
zene (bromobenzene) (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was isolated
as a light yellow solid (92% (82%) yield). 1H NMR (400 MHz,
CDCl3): δ = 7.37-7.28 (m, 5H), 7.22-7.15 (m, 2H), 6.75-6.69
(m, 1H), 6.65-6.62 (m, 2H), 4.33 (d, 2H), 4.03 (br, 1H).13C
NMR (100 MHz, CDCl3, δ ppm): 148.1, 139.4, 129.2, 128.6,
127.5, 127.2, 117.5, 112.8, 48.3.
N-Benzyl-4-chloroaniline (1b):26 Following procedure A,
1-chloro-4-iodobenzene (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was isolated as a
yellow solid (101 mg, 93% yield). 1H NMR (400 MHz, CDCl3):
δ = 7.34-7.23 (m, 5H), 7.09 (d, 2H, J = 8.6 Hz), 6.53 (d, 2H,
J = 8.6 Hz), 4.28 (s, 2H), 4.10 (br, 1H). 13C NMR (100 MHz,
CDCl3, δ ppm): 146.6, 138.9, 128.7, 127.4, 127.3, 122.1, 133.9,
113.9, 48.3.
N-Benzyl-4-nitroaniline (1c):27 Following procedure A,
1-iodo-4-nitrobenzene (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was isolated as a
yellow solid (103 mg, 90% yield). 1H NMR (400 MHz, CDCl3):
δ = 8.07 (d, 2H, J = 8.4 Hz), 7.37-7.26 (m, 5H), 6.57 (d, 2H,
J = 8.4 Hz), 4.60-4.26 (br, 1H), 4.43 (s, 2H). 13C NMR (100
MHz, CDCl3, δ ppm): 153.0, 138.4, 137.4, 128.9, 127.8, 127.3,
126.4, 111.3, 47.6.
RB-TBPC (5). Following procedure B, tributylphosphine
(80 mL) was allowed to react with Merrifield resin (20 g,
2-
50-100 mesh) at 100 °C for 48 h. After exchanged with CO3
from Na2CO3 solution, a small buff resin was obtained. The average
moisture content is 42.5%. The loading value is 2.2 mmol/g (dry)
and the particle diameter is 0.20-0.60 mm.
Methyl 4-(benzylamino)benzoate (1d):28 Following procedure
A, methyl 4-iodobenzoate (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was iso-
lated as a white solid (110 mg, 92% yield). 1H NMR (400
MHz, CDCl3): δ = 7.85 (d, 2H, J = 8.7 Hz), 7.33-7.25 (m,
5H), 6.58 (d, 2H, J = 8.7 Hz), 4.51 (br, 1H), 4.37 (s, 2H), 3.83 (s,
3H). 13C NMR (100 MHz, CDCl3, δ ppm): 167.3, 151.8, 138.4,
131.6, 128.8, 127.5, 127.4, 118.7, 111.7, 51.5, 47.7.
RB-TBPP (6). Following procedure B, tributylphosphine
(80 mL) was allowed to react with Merrifield resin (20 g,
3-
50-100 mesh) at 100 °C for 48 h. After exchanged with PO4
from Na3PO4 solution, a small buff resin was obtained. The
average moisture content is 44.6%. The loading value is 2.2
mmol/g (dry) and the particle diameter is 0.20-0.60 mm.
RB-TBPA (7). Following procedure B, tributylphosphine
(80 mL) was allowed to react with Merrifield resin (20 g,
50-100 mesh) at 100 °C for 48 h. After exchanged with OAc-
from NaOAc solution, a small yellow resin was obtained. The
average moisture content is 43.2%. The loading value is ap-
proximately equal 2.2 mmol/g (dry) and the particle diameter is
0.20-0.60 mm. Elemental analysis: C/P = 9.87 (w/w), P:
7.275%.
N-Benzyl-3, 5-dimethylaniline (1e):26 Following procedure A,
1-iodo-3,5-dimethylbenzene (0.5 mmol) was allowed to react
with benzylamine (0.75 mmol) for 24 h. The product was
1
isolated as a light-yellow solid (100 mg, 95% yield). H NMR
(400 MHz, CDCl3): δ = 7.35-7.16 (m, 5H), 6.37 (s, 1H), 6.26 (s,
2H), 4.27 (s, 2H), 3.83 (br, 1H), 2.21 (s, 6H). 13C NMR (100
MHz, CDCl3, δ ppm): 148.3, 139.6, 138.8, 128.5, 127.5, 127.1,
119.6, 110.7, 48.4, 21.5.
General Procedure for C-N Coupling (A). CuI (9.5 mg,
0.05 mmol, 10 mol %), L-proline (11.5 mg, 0.1 mmol, 20 mol %),
RB-TBPA (0.34 g, 0.75 mmol, 1.5 equiv) and any remaining
solids (aryl iodide) were added to a vacuum tube filled with
argon. The tube was evacuated and backfilled with argon (this
procedure was repeated three times). Under a counter flow of
argon, amine, aryl iodide (if liquid) and DMSO (1.0 mL) were
added by syringe. The tube was sealed and the mixture was
allowed to stir under argon at room temperature (25 ( 3 °C)
for 24 h. Upon completion of the reaction, the mixture was
diluted with ethyl acetate, and the solvent was removed with
the aid of a rotary evaporator. The residue was purified by
column chromatography on silica gel and the product was dried
under high vacuum for at least 0.5 h.
General Procedure for C-N Coupling (B). CuI (9.5 mg,
0.05 mmol, 10 mol %), RB-TBPA (0.34 g, 0.75 mmol, 1.5 equiv)
and any remaining solids (aryl bromide) were added to a
vacuum tube filled with argon. The tube was evacuated and
backfilled with argon (this procedure was repeated three times).
Under a counter flow of argon, DMEDA (12 μL, 0.10 mmol,
20%), amine, aryl iodides (if liquid) and DMSO (1.0 mL) were
3-(Benzylamino)benzonitrile (1f):26 Following procedure A,
3-iodobenzonitrile (0.5 mmol) was allowed to react with ben-
zylamine (0.75 mmol) for 24 h. The product was isolated as a
yellow solid (94 mg, 90% yield). 1H NMR (400 MHz, CDCl3): δ
= 7.37-7.27 (m, 5H), 7.21-7.17 (m, 1H), 6.94 (d, 1H, J = 7.5
Hz), 6.79 (d, 2H, J = 6.9 Hz), 4.36 (br, 1H), 4.31 (s, 2H). 13C
NMR (100 MHz, CDCl3, δ ppm): 148.2, 138.1, 128.8, 127.6,
127.3, 120.9, 119.4, 117.2, 115.0, 112.9, 47.8.
Ethyl 3-(Venzylamino)benzoate (1g) Following procedure A,
ethyl 3-iodobenzoate (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was isolated
as a white solid (123 mg, 97% yield). 1H NMR (400 MHz,
CDCl3): δ = 7.35-7.18 (m, 8H), 6.77 (s, 1H), 4.35-4.30 (m, 4H),
4.19 (br, 1H), 1.36 (t, 3H, J = 7.1 Hz). 13C NMR (100 MHz,
CDCl3, δ ppm): 166.9, 148.1, 138.9, 129.2, 128.7, 127.5, 127.4,
118.6, 117.0, 113.6, 60.8, 48.2, 14.3. HRMS (ESI) Calcd for
C16H17NO2, 255.1259; Found, 255.1260.
(26) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(27) Katritzky, A. R.; Laurenzo, K. S. J. Org. Chem. 1988, 53, 3978.
(28) Baelen, G. V.; Maes, B. U. W. Tetrahedron 2008, 64, 5604.
806 J. Org. Chem. Vol. 76, No. 3, 2011

Huang et al.
JOCArticle
N-Phenethylpyridin-3-amine (1h). Following procedure A
(or B), 3-iodopyridine (or 3-bromopyridine) (0.5 mmol) was
allowed to react with 2-phenylethanamine (0.75 mmol) for 24 h.
The product was isolated as a white solid (I, 70%; Br, 76% yield).
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, 1H, J = 2.1 Hz), 7.95
(d, 1H, J = 4.5 Hz), 7.32 (t, 2H, J = 7.3 Hz), 7.23 (dd, 3H, J =
15.5, 7.3 Hz), 7.07 (dd, 1H, J = 8.2, 4.7 Hz), 6.90-6.82 (m, 1H),
3.78 (br, 1H), 3.41 (t, 2H, J = 6.9 Hz), 2.92 (t, 2H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3, δ ppm): 143.9, 138.8, 138.7, 136.1,
128.7, 128.6, 126.6, 123.7, 118.6, 44.5, 35.3. HRMS (ESI) calcd
for C13H14N2, 198.1157; Found, 198.1156.
4-Chloro-N-(4-methoxyphenyl)aniline (1o):34 Following pro-
cedure A, 1-chloro-4-iodobenzene (0.5 mmol) was allowed to
react with 4-methoxyaniline (0.75 mmol) for 24 h. The prod-
uct was isolated as a white solid (91 mg, 78% yield). 1H NMR
(400 MHz, CDCl3): δ = 7.13 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H,
J = 8.1 Hz), 6.85 (d, 2H, J = 8.4 Hz), 6.79 (d, 2H, J = 8.1 Hz),
5.45 (br, 1H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm):
155.6, 143.9, 135.2, 129.1, 123.9, 122.5, 116.6, 114.7, 55.5.
N-Benzyl-4-methoxyaniline (2a):35 Following procedure B,
1-bromo-4-methoxybenzene (0.5 mmol) was allowed to react
with benzylamine (0.75 mmol) for 24 h. The product was
isolated as a colorless liquid (70 mg, 66% yield). 1H NMR
(400 MHz, CDCl3): δ = 7.37-7.27 (m, 4H), 7.26-7.24 (m, 1H),
6.78-6.76 (m, 2H), 6.61-6.59 (m, 2H), 4.27 (s, 2H), 3.38 (br,
1H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm): 152.2,
142.3, 139.6, 128.6, 127.5, 127.1, 114.9, 114.2, 55.8, 49.3.
4-(Benzylamino)phenyl 4-methylbenzenesulfonate (2b). Fol-
lowing procedure B, 4-bromophenyl 4-methylbenzene sulfonate
(0.5 mmol) was allowed to react with benzylamine (0.75 mmol)
for 24 h. The product was isolated as a white solid (148 mg, 84%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, 2H, J = 7.7 Hz),
7.32-7.25 (m, 7H), 6.75 (d, 2H, J = 8.1 Hz), 6.47 (d, 2H,
J = 8.1 Hz), 4.26 (s, 2H), 4.09 (br, 1H), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3, δ ppm): 146.7, 144.9, 141.1, 138.7, 132.6,
129.6, 128.7, 128.6, 127.5, 127.4, 123.2, 113.1, 48.4, 21.7. HRMS
(ESI) calcd for C20H19NO3S, 353.1086; found, 353.1084.
Ethyl 4-(Benzylamino)benzoate (2c):26 Following procedure
B, ethyl 4-bromobenzoate (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 24 h. The product was isolated as a
N-phenethylpyridin-2-amine (1i):29 Following procedure A (or
B), 2-iodopyridine (or 2-bromopyridine) (0.5 mmol) was al-
lowed to react with 2-phenylethanamine (0.75 mmol) for 24 h.
The product was isolated as a white solid (I, 88%; Br, 49%
yield). 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, 1H, J = 5.0
Hz), 7.42-7.30 (m, 1H), 7.25-7.22 (m, 2H), 7.21-7.20 (m, 3H),
6.58-6.54 (m, 1H), 6.36 (d, 1H, J = 8.4 Hz), 4.51 (br, 1H),
3.58-3.53 (dd, 2H, J = 12.9, 7.0 Hz), 2.94-2.90 (d, 2H, J =
7.0 Hz). 13C NMR (100 MHz, CDCl3, δ ppm): 158.6, 148.2,
139.2, 137.4, 128.8, 128.6, 126.4, 112.9, 106.8, 43.3, 35.7.
1-(4-Chlorophenyl)-1H-imidazole (1j):30 Following proce-
dure A, 1-chloro-4-iodobenzene (0.5 mmol) was allowed to
react with imidazole (0.75 mmol) for 24 h. The product
1
was isolated as a yellow solid (66 mg, 74% yield). H NMR
(400 MHz, CDCl3): δ = 7.85 (s, 1H), 7.46 (d, 2H, J = 8.0 Hz),
7.34 (d, 2H, J = 8.0 Hz), 7.28-7.27 (m, 2H). 13C NMR (100
MHz, CDCl3, δ ppm): 135.9, 135.5, 133.2, 130.7, 130.0, 122.7,
118.3.
1-(4-Chlorophenyl)-1H-pyrazole (1k):31 Following procedure
A, 1-chloro-4-iodobenzene (0.5 mmol) was allowed to react with
pyrazole (0.75 mmol) for 24 h. The product was isolated as a
yellow solid (63 mg, 71% yield). 1H NMR (400 MHz, CDCl3):
δ = 7.88 (d, 1H, J = 1.9 Hz), 7.71 (s, 1H), 7.63 (d, 2H, J = 8.7 Hz),
7.40 (d, 2H, J = 8.7 Hz), 6.46 (s, 1H). 13C NMR (100 MHz,
CDCl3, δ ppm): 141.3, 138.7, 131.8, 129.5, 126.6, 120.3, 107.9.
N-Sec-butyl-4-chloroaniline (1l). Following procedure A,
1-chloro-4-iodobenzene (0.5 mmol) was allowed to react with
butan-2-amine (0.75 mmol) for 24 h. The product was isolated as
a yellow liquid (68 mg, 74% yield). 1H NMR (400 MHz, CDCl3):
δ = 7.08 (d, 2H, J = 8.2 Hz), 6.47 (d, 2H, J = 8.2 Hz), 3.42 (br,
1H), 3.33 (dq, 1H, J = 12.1, 6.3 Hz), 1.62-1.53 (m, 1H),
1.51-1.40 (m, 1H), 1.14 (d, 3H, J = 6.3 Hz), 0.93 (t, 3H, J =
7.4 Hz). 13C NMR (100 MHz, CDCl3, δ ppm): 146.3, 129.0,
121.1, 114.1, 50.0, 29.5, 20.1, 10.3. HRMS (ESI) calcd for
white solid (95 mg, 75% yield). H NMR (400 MHz, CDCl3):
1
δ = 7.87 (d, 2H, J = 8.8 Hz), 7.35-7.27 (m, 5H), 6.59 (d, 2H, J =
8.8 Hz), 4.49 (br, 1H), 4.38 (s, 2H), 4.30 (q, 2H, J = 7.1 Hz), 1.35
(t, 3H, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3, δ ppm): 166.8,
151.7, 138.4, 131.5, 128.8, 127.5, 127.4, 119.1, 111.6, 60.2, 47.7,
14.5.
(4-(Benzylamino)phenyl)(phenyl)methanone (2d):36 Following
procedure B, (4-bromophenyl)(phenyl)methanone (0.5 mmol) was
allowed to react with benzylamine (0.75 mmol) for 24 h. The
1
product was isolated as a white solid (96 mg, 67% yield). H
NMR (400 MHz, CDCl3): δ = 7.74 (m, 4H), 7.51-7.49 (m, 1H),
7.45-7.41 (m, 2H), 7.34-7.25 (m, 5H), 6.61 (d, 2H, J = 8.3 Hz),
4.67 (br, 1H), 4.40 (s, 2H). 13C NMR (100 MHz, CDCl3, δ ppm):
195.1, 151.8, 139.1, 138.2, 132.9, 131.2, 129.4, 128.8, 128.0,
127.5, 127.3, 126.4, 111.5, 47.6.
N0-Benzyl-N00,N00-dimethylbenzene-1,4-diamine (2e):12 Fol-
lowing procedure B, 4-bromo-N,N-dimethylaniline (0.5 mmol)
was allowed to react with benzylamine (0.75 mmol) for 24 h. The
C
10H14ClN, 183.0815; found, 183.0810.
4-(4-Chlorophenyl)morpholine (1m):32 Following procedure
1
A, 1-chloro-4-iodobenzene (0.5 mmol) was allowed to react
with morpholine (0.75 mmol) for 24 h. The product was isolated
as a white solid (85 mg, 86% yield). 1H NMR (400 MHz,
CDCl3): δ = 7.22 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H, J = 8.5
Hz), 3.85 (s, 4H), 3.11 (s, 4H). 13C NMR (100 MHz, CDCl3, δ
ppm): 149.9, 129.0, 124.9, 116.9, 66.8, 49.3.
product was isolated as a yellow solid (80 mg, 71% yield). H
NMR (400 MHz, CDCl3): δ = 7.37-7.30 (m, 4H), 7.24 (t, 1H,
J = 8.0 Hz), 6.73 (d, 2H, J = 7.6 Hz), 6.61 (d, 2H, J = 7.6 Hz),
4.26 (s, 2H), 3.51 (br, 1H), 2.80 (s, 6H). 13C NMR (100 MHz,
CDCl3, δ ppm): 144.1, 140.8, 139.9, 128.5, 127.5, 127.0, 115.8,
114.3, 49.4, 42.2.
3-(Benzylamino)benzaldehyde (2f). Following procedure B,
3-bromobenzaldehyde (0.5 mmol) was allowed to react with
benzylamine (0.75 mmol) for 36 h. The product was isolated as a
yellow liquid (68 mg, 66% yield). 1H NMR (400 MHz, CDCl3):
δ = 9.90 (s, 1H), 7.36-7.29 (m, 6H), 7.20 (d, 1H, J = 7.3 Hz),
7.12 (s, 1H), 6.86 (d, 1H, J = 8.0 Hz), 4.37 (s, 2H), 4.27 (br, 1H).
13C NMR (100 MHz, CDCl3, δ ppm): 192.8, 148.6, 143.4, 138.6,
137.5, 129.7, 128.7, 127.5, 120.2, 119.2, 111.6, 48.1. HRMS
(ESI) calcd for C14H13NO, 211.0907; found, 211.0902.
4-Methyl-N-phenylaniline (1n):33 Following procedure A,
iodobenzene (0.5 mmol) was allowed to react with p -toluidine
(0.75 mmol) for 24 h. The product was isolated as a white solid
1
(68 mg, 74% yield). H NMR (400 MHz, CDCl3): δ = 7.22
(d, 2H, J = 8.2 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.00-6.99 (m, 4H),
6.87 (t, 1H, J = 7.3 Hz), 5.59 (br, 1H), 2.30 (s, 3H). 13C NMR
(100 MHz, CDCl3, δ ppm): 143.9, 140.3, 130.9, 129.8, 129.3,
120.3, 118.9, 116.9, 20.6.
(29) Helmut, V.; Konrad, K. Chem. Ber. 1984, 117, 1523.
(30) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J. Org.
Chem. 2005, 70, 3997.
(34) Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2008, 73, 5167.
(31) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F; Taillefer, M. Eur. J. Org.
Chem. 2004, 4, 695.
(35) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
(32) Xu, G.; Wang, Y.-G. Org. Lett. 2004, 6, 985.
(33) Gary, C. H. C.; Thomas, O. Org. Lett. 2004, 6, 3079.
(36) Hayat, S.; Atta-ur-Rahman; Choudhary, M. I.; Mohammed, K. K.;
Wilhelm, S.; Ernst, B. Tetrahedron 2001, 57, 9951.
J. Org. Chem. Vol. 76, No. 3, 2011 807

Huang et al.
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1-(3-(Benzylamino)phenyl)ethanone (2g):37 Following proce-
dure B, 1-(3-bromophenyl)ethanone (0.5 mmol) was allowed
to react with benzylamine (0.75 mmol) for 24 h. The product
(br, 1H), 3.13 (t, 2H, J = 7.0 Hz), 1.64-1.59 (m, 2H), 1.47-1.32
(m, 6H), 0.9 (m, 3H). 13C NMR (100 MHz, CDCl3, δ ppm):
147.9, 141.3, 129.9, 128.6, 127.9, 126.5, 125.9, 112.9, 44.0, 31.6,
29.5, 26.8, 22.6, 14.0. HRMS (ESI) Calcd for C18H23N,
253.1830; Found, 253.1824.
2-(Biphenyl-4-ylamino)ethanol (2n). Following procedure B,
4-bromobiphenyl (0.5 mmol) was allowed to react with 2-amino-
ethanol (0.75 mmol) for 24 h. The product was isolated as a
white solid (85 mg, 80% yield). 1H NMR (400 MHz, d-DMSO):
δ = 7.54 (d, 2H, J = 7.7 Hz), 7.41 (d, 2H, J = 8.3 Hz), 7.37
(t, 2H, J = 7.7 Hz), 7.21(t, 1H, J = 7.3 Hz), 6.67 (d, 2H, J =
8.3 Hz), 5.67 (t, 1H, J = 5.4 Hz), 4.71 (t, 1H, J = 5.4 Hz), 3.59 (q,
2H, J = 5.7 Hz), 3.14 (q, 2H, J = 5.7 Hz). 13C NMR (100 MHz,
d-DMSO, δ ppm): 134.9, 127.0, 115.1, 113.7, 113.5, 112.0, 111.7,
98.8, 46.0, 31.9. HRMS (ESI) calcd for C14H15NO, 213.1154;
found, 213.1148.
1
was isolated as a yellow liquid (81 mg, 72% yield). H NMR
(400 MHz, CDCl3): δ = 7.36-7.31 (m, 4H), 7.28-7.20 (m, 4H),
6.78 (m, 1H), 4.34 (s, 2H), 4.24 (br, 1H), 2.52 (s, 3H). 13C NMR
(100 MHz, CDCl3, δ ppm): 166.9, 148.1, 138.9, 129.1, 128.6,
127.5, 127.3, 118.6, 117.0,113.6, 60.8, 48.2, 14.3.
N-Butylnaphthalen-2-amine (2h). Following procedure B,
2-Bromonaphthalene (0.5 mmol) was allowed to react with
butan-1-amine (0.75 mmol) for 24 h. The product was isolated
1
as a colorless liquid (81 mg, 82% yield). H NMR (400 MHz,
CDCl3): δ = 7.65 (d, 1H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.5 Hz),
7.33 (t, 1H, J = 7.5 Hz), 7.16 (t, 1H, J = 8.0 Hz), 6.86 (d, 1H,
J = 8.5 Hz), 6.81 (s, 1H), 3.97 (br, 1H), 3.21 (t, 2H, J = 7.1 Hz),
1.70-1.67 (m, 2H), 1.50-1.42 (m, 2H), 0.98(t, 3H, J = 7.7 Hz).
13C NMR (100 MHz, CDCl3, δ ppm): 146.0, 135.3, 128.8, 127.6,
127.5, 126.3, 125.9, 121.8, 118.0, 104.4, 43.8, 31.5, 20.3, 13.9.
HRMS (ESI) calcd for C14H17N, 199.1361; found, 199.1355.
N-Phenethylthiophen-3-amine (2i). Following procedure B,
3-bromothiophene (0.5 mmol) was allowed to react with 2-phenyl-
ethanamine (0.75 mmol) for 24 h. The product was isolated as a
4-(4-Bromophenyl)morpholine (3a):40 Following procedure A,
1-bromo-4-iodobenzene (0.5 mmol) was allowed to react with
morpholine (0.75 mmol) for 24 h. The product was isolated as a
white solid (89 mg, 88% yield). 1H NMR (400 MHz, CDCl3): δ
= 7.36 (d, 2H, J = 8.7 Hz), 6.81 (d, 2H, J = 8.7 Hz), 3.92-3.82 (t,
4H, J = 4.7 Hz), 3.20-3.04 (t, 4H, J = 4.7 Hz). 13C NMR (100
MHz, CDCl3, δ ppm): 151.0, 132.0, 117.5, 112.5, 66.6, 49.3.
N-Butyl-4-morpholinoaniline (3b). Following procedure B,
4-(4-bromophenyl)morpholine (0.44 mmol) was allowed to
react with butan-1-amine (0.66 mmol) for 24 h. The product
was isolated as a white solid (73 mg, 67% yield after two steps).
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 2H), 6.59 (s, 2H), 3.84
(m, 4H), 3.01 (m, 7H), 1.59-1.47 (m, 2H), 1.43-1.37 (m, 2H),
0.95 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz, CDCl3, δ ppm):
143.4, 118.4, 113.8, 67.1, 51.3, 44.5, 41.0, 31.8, 20.3, 13.9. HRMS
(ESI) calcd for C14H22N2O, 234.1732; found, 234.1726.
Indoline (3c):6e Following procedure B, 2-(2-chlorophenyl)-
ethanamine or 2-(2-bromophenyl)ethan-amine (0.5 mmol) was
reacted for 48 h or 24 h. The product was isolated as a colorless
1
white solid (62 mg, 61% yield). H NMR (400 MHz, CDCl3):
δ = 7.32-7.28 (m, 2H), 7.21 (m, 2H), 7.12-7.10 (dd, 1H, J =
5.1, 3.0 Hz), 6.56-6.54 (d, 1H, J = 5.1 Hz), 5.97-5.95 (d, 1H,
J = 3.0 Hz), 3.56-3.20 (br, 1H), 3.34-3.31 (t, 2H, J = 7.0 Hz),
2.92-2.88 (t, 2H, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3,
δ ppm): 148.3, 139.3, 128.7, 128.6, 126.4, 125.1, 119.9, 95.8, 47.3,
35.5. HRMS (ESI) calcd for C12H13NS, 203.0769; found,
203.0762.
4-Chloro-N-(cyclopropylmethyl)aniline (2j):38 Following pro-
cedure B, 1-bromo-4-chlorobenzene (0.5 mmol) was allowed to
react with cyclopropylmethanamine (0.75 mmol) for 24 h. The
product was isolated as a white solid (63 mg, 70% yield).
1H NMR (400 MHz, CDCl3): δ = 7.10 (d, 2H, J = 8.4 Hz),
6.51 (d, 2H, J = 8.4 Hz), 3.77 (br, 1H), 2.91 (d, 2H, J = 6.8 Hz),
1.07 (m, 1H), 0.54 (m, 2H), 0.23-0.22 (m, 2H). 13C NMR (100
MHz, CDCl3, δ ppm): 147.0, 129.0, 121.7, 113.8, 49.1, 10.8, 3.4.
N-(Cyclopropylmethyl)-4-(trifluoromethy)aniline (2k). Fol-
lowing procedure B, 1-bromo-4-(trifluoromethyl)benzene
(0.5 mmol) was allowed to react with cycloproylmethanamine
(0.75 mmol) for 24 h. The product was isolated as a yellow solid
1
liquid (76% or 88%). H NMR (400 MHz, CDCl3): δ = 7.10
(d, 1H, J = 7.3 Hz), 7.00 (t, 1H, J = 7.7 Hz), 6.69 (t, 1H, J =
7.3 Hz), 6.62(d, 1H, J = 7.7 Hz), 3.58 (br, 1H). 3.51 (t, 2H, J =
8.4 Hz), 3.00 (t, 2H, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3,
δ ppm): 151.5, 129.2, 127.1, 124.6, 118.6, 109.4, 47.3, 29.8.
N-(2-Chlorophenethyl)aniline (3d). Following procedure B,
2-(2-chlorophenyl)-ethanamine (0.5 mmol) was allowed to react
with iodobenzene for 24 h. The product was isolated as a
1
(71 mg, 71% yield). H NMR (400 MHz, CDCl3): δ = 7.38
1
(d, 2H, J = 8.2 Hz), 6.58 (d, 2H, J = 8.2 Hz), 4.11 (br, 1H), 2.98
(d, 2H, J = 6.9 Hz), 1.10-1.07 (m, 1H), 0.57 (d, 2H, J = 7.2 Hz),
0.25 (s, 2H). 13C NMR (100 MHz, CDCl3, δ ppm): 158.8, 126.6,
126.5, 118.4(q), 111.7, 48.5, 10.7, 3.5. HRMS (ESI) calcd for
C11H12F3N, 215.0922; found, 215.0927.
colorless liquid (92 mg, 80%). H NMR (400 MHz, CDCl3):
δ = 7.36 (d, 1H, J = 7.3 Hz), 7.19-7.15 (m, 5H), 6.70 (t, 1H,
J = 7.3 Hz), 6.62 (d, 2H, J = 7.9 Hz), 3.72 (br, 1H), 3.41
(m, 2H), 3.03 (t, 2H, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3,
δ ppm): 146.8, 135.9, 133.1, 129.8, 128.6, 128.2, 126.8, 125.8,
116.4, 111.8, 42.3, 32.4. HRMS (ESI) calcd for C14H14ClN,
231.0815; found, 231.0823.
Experimental Procedures for Ni-Catalyzed Suzuki reaction.
Ni(PPh3)2Cl2 (5 mol %), PPh3 (10 mol %), boronic acid
(0.5 mmol), Zn (1.2 e.q), RB-TBPP (1.5 equiv) and any remain-
ing solids (aryl bromide) were added to a vacuum tube filled with
argon. The tube was evacuated and backfilled with argon
(this procedure was repeated three times). Under a counter flow
of argon, THF and aryl bromide (if liquid) were added to the
tube by syringe. The tube was sealed and the mixture was
allowed to stir under argon at room temperature for 24 h. Upon
completion of the reaction, the mixture was diluted with ethyl
acetate, the solvent was removed with the aid of a rotary
evaporator. The residue was purified by column chromatogra-
phy on silica gel and the product was dried under high vacuum
for at least 0.5 h.
N-Hexylbenzo[d][1,3]dioxol-5-amine (2l):39 Following proce-
dure B, 5-bromobenzo[d][1,3]dioxole (0.5 mmol) was allowed to
react with hexan-1-amine (0.75 mmol) for 24 h. The product was
isolated as a white solid (72 mg, 65% yield). 1H NMR (400 MHz,
CDCl3): δ = 6.64 (d, 1H, J = 8.3 Hz), 6.23 (s, 1H), 6.02 (d, 1H,
J = 8.3 Hz), 5.85 (s, 2H), 3.27 (br, 1H), 3.02 (t, 2H, J = 7.1 Hz),
1.57 (dd, 2H, J = 8.3, 7.1 Hz), 1.38-1.31 (m, 6H), 0.89 (t, 3H,
J = 6.3 Hz). 13C NMR (100 MHz, CDCl3, δ ppm): 148.3, 144.3,
139.4, 108.6, 104.3, 100.5, 95.8, 45.1, 31.6, 29.5, 26.8, 22.6, 14.0.
N-Hexylbiphenyl-4-amine (2m). Following procedure B,
4-bromobiphenyl (0.5 mmol) was allowed to react with hexan-
1-amine (0.75 mmol) for 24 h. The product was isolated as a
white solid (105 mg, 83% yield). 1H NMR (400 MHz, CDCl3):
δ = 7.53 (d, 2H, J = 7.6 Hz), 7.43 (d, 2H, J = 7.8 Hz), 7.37 (t, 2H,
J = 7.6 Hz), 7.23 (m, 1H), 6.65 (d, 2H, J = 7.8 Hz), 3.67
(37) Taichi, S.; Teruaki, M. J. Am. Chem. Soc. 2004, 126, 7359.
(38) Yamamoto, M. Chem. Pharm. Bull. 1978, 26, 1633.
(39) Hollmann, D.; Baehn, S.; Tillack, A.; Beller, M. Angew. Chem., Int.
Ed. 2007, 46, 8291.
(40) Bennett, S. M.; Tang, Y.; McMaster, D.; Bright, F. V.; Detty, M. R.
J. Org. Chem. 2008, 73, 6849.
808 J. Org. Chem. Vol. 76, No. 3, 2011

Huang et al.
JOCArticle
3-Methoxybiphenyl (4a):41 Following procedure, bromoben-
zene (0.25 mol) was allowed to react with 3-methoxyphenyl-
boronic acid (0.50 mmol) for 24 h. The product was isolated as a
colorless liquid (36 mg, 78% yield). 1H NMR (400 MHz,
CDCl3): δ = 7.58 (d, 2H, J = 7.5 Hz), 7.43 (t, 2H, J = 7.4 Hz),
7.37-7.33 (m, 2H), 7.18 (d, 1H, J = 7.5 Hz), 7.13 (s, 1H), 6.90
(d, 1H, J = 8.0 Hz), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3,
δ ppm): 158.9, 141.7, 140.1, 128.7, 127.7, 126.4, 126.2, 118.6, 111.9,
111.6, 54.3.
4-Chloro-N-cyclohexylaniline (5b):8c 1-chloro-4-iodobenzene
(0.5 mmol) was allowed to react with cyclohexanamine (0.75
mmol) for 24 h. The product was isolated as a white solid (79 mg,
76% yield). 1H NMR (400 MHz, CDCl3): δ = 7.08 (d, 2H, J =
8.3 Hz), 6.49 (d, 2H, J = 8.3 Hz), 3.52 (br, 1H), 3.22-3.17 (m,
1H), 2.04-2.01 (m, 2H), 1.74 (m, 2H), 1.63 (m, 1H),
1.23-1.09(m, 5H). 13C NMR (100 MHz, CDCl3, δ ppm):
145.9, 129.0, 121.2, 114.1, 51.8, 33.3, 25.8, 24.9.
Ethyl 3-(Sec-butylamino)benzoate (5c). ethyl 3-iodobenzoate
(0.5 mmol) was allowed to react with butan-2-amine (0.75 mmol)
for 24 h. The product was isolated as a white solid (77 mg, 70%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, 1H, J = 7.6 Hz),
7.25 (s, 1H), 7.19 (t, 1H, J = 7.8 Hz), 6.73 (d, 1H, J = 7.9 Hz),
4.34 (q, 2H, J = 7.1 Hz), 3.63 (br, 1H), 3.44 (m, 1H), 1.62-1.43
(m, 2H), 1.37 (t, 3H, J = 7.1 Hz), 1.16 (d, 3H, J = 6.3 Hz), 0.95
(t, 3H, J = 7.4 Hz). 13C NMR (100 MHz, CDCl3, δ ppm):167.1,
147.7, 131.4, 129.1, 117.8, 117.3, 113.7, 60.7, 49.7, 29.6, 20.1, 14.3,
10.3. HRMS (ESI) calcd for C13H19NO2, 221.1416; found,
221.1414.
Experimental Procedures for Pd-Catalyzed Heck Reaction. A
oven-dried vacuum tube with a glass cap and a stir was charged
with Pd(OAc)2 (5 mol %), Davephos (10 mol %) and RB-TBAA
(1.5 equiv). The tube was evacuated and backfilled with argon or
nitrogen (this sequence was repeated three times). Under a
counter flow of argon, 1-chloro-4-trifluoromethyl- benzene
(0.5 mmol), styrene (0.75 mmol) along with 1,4-dioxane (1.0 mL)
was added to the tube. The mixture was allowed to stir at 60 °C for
24 h. After reaction, the mixture was cooled to room temperature
and diluted with ethyl acetate, and the solvent was removed with
the aid of a rotary evaporator. The residue was purified by column
chromatography on silica gel and the product was dried under high
vacuum for at least 0.5 h.
4-Methoxybiphenyl (4b):42 Following procedure, 4-bromoa-
nisole (0.25 mol) was allowed to react with phenylboronic acid
(0.50 mmol) for 24 h. The product was isolated as a white solid
1
(39 mg, 85% yield). H NMR (400 MHz, CDCl3): δ = 7.53
(m, 4H), 7.41 (d, 2H, J = 7.6 Hz), 7.30 (m, 1H), 6.97 (d, 2H, J =
8.5 Hz), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm):
159.1, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6, 114.2, 55.3.
Methyl 40-Cyanobiphenyl-4-carboxylate (4c):43 Following
procedure, methyl 4-bromobenzoate (0.25 mol) was allowed
to react with 4-cyanophenylboronic acid (0.50 mmol) for 24 h.
The product was isolated as a white solid (43 mg, 73% yield). 1H
NMR (400 MHz, CDCl3): δ = 8.15 (d, 2H, J = 8.0 Hz),
7.78-7.70 (m, 4H), 7.66 (d, 2H, J = 8.0 Hz), 3.96(s, 3H). 13C
NMR (100 MHz, CDCl3, δ ppm): 166.6, 144.5, 143.4, 132.7,
130.3, 130.2, 127.9, 127.2, 118.6, 111.8, 52.3.
1-(40-Methoxybiphenyl-4-yl)ethanone (4d):44 Following proce-
dure, 1-(4-bromophenyl)ethanone (0.25 mol) was allowed to react
with 4-methoxyphenylboronic acid (0.50 mmol) for 24 h. The
product was isolated as a white solid (45 mg, 80% yield). 1H NMR
(400 MHz, CDCl3): δ = 8.00 (d, 2H, J = 8.2 Hz), 7.64 (d, 2H, J =
8.2 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.00 (d, 2H, J = 8.5 Hz), 3.86 (s,
3H), 2.63 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm): 197.7,
159.9, 145.4, 135.3, 132.3, 128.9, 128.4, 126.6, 114.4, 55.4, 26.6.
General Procedure for C-N Coupling at Low Temperature.
CuI (9.5 mg, 0.05 mmol, 10 mol %), L-proline (11.5 mg,
0.1 mmol, 20 mol %), RB-TBPA (0.34 g, 0.75 mmol, 1.5 equiv)
and any remaining solids (aryl iodide) were added to a vacuum
tube filled with argon. The tube was evacuated and backfilled
with argon (this procedure was repeated three times). Under a
counter flow of argon, amine, aryl iodide (if liquid) and DMSO/
DMF (0.5:0.5 mL) were added by syringe. The tube was sealed
and the mixture was allowed to stir under argon at -30 °C for 24
h. Upon completion of the reaction, the mixture was diluted
with ethyl acetate, and the solvent was removed with the aid of a
rotary evaporator. The residue was purified by column chro-
matography on silica gel and the product was dried under high
vacuum for at least 0.5 h.
(E)-1-Styryl-4-(trifluoromethyl)benzene (6a):46 1-chloro-4-tri-
fluoromethyl- benzene (0.50 mmol) was allowed to react with
styrene (1.0 mmol) for 24 h. The product was isolated as a white
solid (99 mg, 80% yield). 1H NMR (300 MHz, CDCl3): δ
7.60-7.57 (m, 4H), 7.53 (d, 2H, J = 7.8 Hz), 7.38 (t, 2H, J =
7.5 Hz), 7.32-7.28 (t, 1H, J = 7.3 Hz), 7.19 (d, 1H, J = 16.4
Hz), 7.11 (d, 1H, J = 16.4 Hz). 13C NMR (75 MHz, CDCl3, δ
ppm): 140.8, 136.6, 131.2, 128.3, 127.1, 129.2 (q, 2J(C,F) = 32.4
Hz), 128.8, 126.8, 126.5, 125.5 (q, 3J(C,F) = 3.8 Hz), 124.2 (q,
1J(C,F) = 272 Hz).
Experimental Procedure for C-S coupling. CuI (19 mg,
20 mol %), 1,10-phenanthroline (23 mg, 40 mol %), RB-TBPP
(1.5 equiv) and any remaining solids (aryl iodides) were added to
a vacuum tube filled with argon. The tube was evacuated and
backfilled with argon (this procedure was repeated three times).
Under a counter flow of argon, amine, aryl iodides (if liquid) and
NMP/MeOH (0.5:0.5 mL) were added by syringe. The tube was
sealed and the mixture was allowed to stir under argon at room
temperature (25 ( 3 °C) for 36 h. Upon completion of the
reaction, the mixture was diluted with ethyl acetate, and the
solvent was removed with the aid of a rotary evaporator. The
residue was purified by column chromatography on silica gel
and the product was dried under high vacuum for at least 0.5 h.
4-Methylphenyl Phenyl Sulfide (7a):47 4-methylbenzenethiol
(0.50 mmol) was allowed to react with iodobenzene (1.0 mmol)
for 36 h. The product was isolated as a colorless liquid (65%
yield). 1H NMR (300 MHz, CDCl3): δ 2.31 (s, 3H), 7.09-7.18
(m, 3H), 7.20-7.29 (m, 6H). 13C NMR (75 MHz, CDCl3,
δ ppm): 21.2, 126.4, 129.0, 129.7, 130.0, 131.4, 132.3, 137.2, 137.5.
4-Chlorophenyl Phenyl Sulfide (7b):24 4-chlorobenzenethiol
(0.50 mmol) was allowed to react with iodobenzene (1.0 mmol) for
36 h. The product was isolated as a pale yellow liquid (66% yield).
N-Benzyl-4-methoxyaniline (2a):35 Following general proce-
dure, 1-iodo-4-methoxybenzene (0.5 mmol) was allowed to react
with benzylamine (0.75 mmol) for 24 h. The product was
isolated as a colorless liquid (85 mg, 80% yield). 1H NMR
(400 MHz, CDCl3): δ = 7.37-7.27 (m, 4H), 7.26-7.24 (m, 1H),
6.78-6.76 (m, 2H), 6.61-6.59 (m, 2H), 4.27 (s, 2H), 3.38 (br,
1H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3, δ ppm): 152.2,
142.3, 139.6, 128.6, 127.5, 127.1, 114.9, 114.2, 55.8, 49.3.
N-Butyl-4-nitroaniline (5a):45 1-iodo-4-nitrobenzene (0.5
mmol) was allowed to react with butan-1-amine (0.75 mmol)
for 24 h. The product was isolated as a yellow liquid (87 mg, 90%
yield). 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, 2H, J = 8.0 Hz),
6.51 (d, 2H, J = 8.0 Hz), 4.57 (s, 1H), 3.21 (t, 2H, J = 8.0 Hz),
1.66-1.60 (m, 2H), 1.49-1.39 (m, 2H), 0.97 (t, 3H, J = 8.0 Hz).
13C NMR (100 MHz, CDCl3, δ ppm):153.5, 137.7, 126.5, 110.9,
43.1, 31.2, 20.1, 13.8.
(41) Li, G. Y. J. Org. Chem. 2002, 67, 3643.
(42) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058.
(43) Papoian, V.; Minehan, T. J. Org. Chem. 2008, 73, 7376.
(44) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122.
(45) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987.
(46) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031.
(47) Fernandez-Rodriguez, M.; Shen, Q.; Hartwig, J. F. Chem.;Eur. J.
2006, 12, 7782.
J. Org. Chem. Vol. 76, No. 3, 2011 809

Huang et al.
JOCArticle
1H NMR (300 MHz, CDCl3): δ 7.24-7.28 (m, 4H), 7.28-7.35
(m, 5H). 13C NMR (75 MHz, CDCl3, δ ppm): 127.3, 129.2, 129.3,
131.3, 131.9, 132.9, 134.6, 135.1.
(1.0 mmol) for 36 h. The product was isolated as a pale yellow
liquid (50% yield). 1H NMR (300 MHz, CDCl3): δ 2.25 (s, 6H),
2.34 (s, 3H), 6.84 (s, 1H), 6.92 (d, 2H, J=2.0 Hz), 7.12(d, 2H, J =
2.0 Hz), 7.26 (d, 2H). 13C NMR (75 MHz, CDCl3, δ ppm): 21.3,
21.3, 128.1, 128.7, 130.1, 131.9, 132.0, 136.3, 137.3, 138.9. HRMS
(ESI) calcd for C15H16S, 228.0973; found, 228.0964.
3-Methylphenyl Phenyl Sulfide (7c):47 3-methylbenzenethiol
(0.50 mmol) was allowed to react with iodobenzene (1.0 mmol) for
36 h. The product was isolatedas a colorless liquid(69% yield). 1H
NMR (300 MHz, CDCl3): δ 2.29 (s, 1H), 7.15-7.24 (m, 4H),
7.27-7.33 (m, 4H). 13C NMR (75 MHz, CDCl3, δ ppm): 21.4,
126.9, 128.0, 128.4, 129.1, 129.2, 130.8, 131.9, 135.3, 136.2, 139.1.
1-Naphthalenyl Phenyl Sulfide (7d):47 naphthalene-1-thiol
(0.50 mmol) was allowed to react with iodobenzene (1.0 mmol)
for 36 h. The product was isolated as a pale yellow liquid (65%
yield). 1H NMR (300 MHz, CDCl3): δ 7.10-7.20 (m, 5H),
7.37-7.42 (m, 1H), 7.46-7.50 (m, 2H), 7.63-7.65(m, 1H),
7.81-7.86 (m, 2H), 8.35-8.39 (m, 1H). 13C NMR (75 MHz,
CDCl3, δ ppm): 125.6, 125.8, 126.1, 126.4, 126.9, 128.6, 129.0,
129.1, 129.2, 131.2, 132.5, 133.6, 134.2, 136.9.
(3,5-Bis(trifluoromethyl)phenyl)(p-tolyl)sulfane (7g). 4-meth-
ylbenzenethiol (0.50 mmol) was allowed to react with 1-iodo-
3,5-bis(trifluoromethyl)benzene (1.0 mmol) for 36 h. The pro-
1
duct was isolated as a colorless liquid (54% yield). H NMR
(400 MHz, CDCl3): δ 2.40 (s, 3H), 7.24 (d, 2H, J = 8.0 Hz), 7.40
(m, d, 2H, J = 8.0 Hz), 7.52 (s, 2H), 7.59 (s, 1H). 13C NMR
(100 MHz, CDCl3, δ ppm): 21.4, 119.3 (m), 123.0 (q, J = 272.0 Hz),
127.18 (m), 129.0, 131.0, 132.3 (q, J = 33 Hz), 134.5, 140.1,
142.8. HRMS (ESI) calcd for C15H10F6S, 366.0407; found,
366.0406.
(4-Chlorophenyl)(p-tolyl)sulfane (7e):48 4-methylbenzenethio
(0.50 mmol) was allowed to react with 1-chloro-4-iodobenzene
(1.0 mmol) for 36 h. The product was isolated as a white solid
(42% yield). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H),
7.13-7.18 (m, 4H), 7.22 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J =
8.0 Hz). 13C NMR (75 MHz, CDCl3, δ ppm): 21.3, 129.3, 130.4,
130.8, 131.0, 132.5, 132.6, 136.1, 138.2.
Acknowledgment. This study was supported by the Na-
tional Natural Science Foundation of China (Grant No.
20932006, 20972148) , Chinese Universities Scientific Fund
and Program for New Century Excellent Talents in University
(080519).
(3,5-Dimethylphenyl)(p-tolyl)sulfane (7f). naphthalene-1-thiol
(0.50 mmol) was allowed to react with 1-iodo-3,5-dimethylbenzene
Supporting Information Available: Experimental details and
compound spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(48) Wong, Y.; Jayanth, T.; Cheng, C. Org. Lett. 2006, 8, 5613.
810 J. Org. Chem. Vol. 76, No. 3, 2011