Synthetic utility of ammonium salts in a Cu-catalyzed three-component reaction as a facile coupling partner

Article abstract of DOI:10.1021/jo802014g

(Chemical Equation Presented) Ammonium salts were found to be a convenient and inexpensive reagent in the Cu-catalyzed three-component reaction with terminal alkynes and sulfonyl or phosphoryl azides leading to N-unprotected amidines. Thus obtained amidines bearing 2-bromobenzenesulfonyl moiety were efficiently cyclized by the Cu-catalyzed intramolecular N-arylation to give an important pharmacophore skeleton of 2H-1,2,4-benzothiadiazine 1,1-dioxides. Conveniently, two tandem catalytic procedures could be readily operated in one pot.

Full text of DOI:10.1021/jo802014g

arylamines in high yields. One of the attractive features of using
ammonium salts turned out to be excellent functional group
tolerance presumably due to the low nucleophilicity of the
reagent. On the basis of the N-arylation results, we envisioned
that ammonium salts could also be employed as an ammonia
surrogate in the Cu-catalyzed three-component reaction to make
N-unprotected amidines.
Synthetic Utility of Ammonium Salts in a
Cu-Catalyzed Three-Component Reaction as a
Facile Coupling Partner
Jinho Kim, S. Yunmi Lee, Junseung Lee, Youngkyu Do, and
Sukbok Chang*
Department of Chemistry and School of Molecular Science
(BK21), Korea AdVanced Institute of Science and
Recently, we have developed the Cu-catalyzed three-
component reaction of terminal alkynes, sulfonyl azides, and
primary or secondary amines, leading to amidines under mild
conditions.5 This reaction is revealed to proceed via a ketenimine
intermediate, generated in situ by the Cu-catalyzed coupling of
1-alkynes and sulfonyl azides upon release of N2.6 The
mechanistic description is further evidenced by the successful
incorporation of diverse nucleophiles such as alcohol,7 water,8
or pyrrole.9 Synthetically interesting applications have been also
achieved on the basis of the same approach.10,11 Herein, we
disclose the fruitful utilization of ammonium salts in the
coupling reactions and its application in the synthesis of a
biologically important pharmacophore of 2H-1,2,4-benzothia-
diazine 1,1-dioxides.
Technology (KAIST), Daejeon 305-701, Republic of Korea
sbchang@kaist.ac.kr
ReceiVed September 12, 2008
Using ammonium salts, we first investigated the Cu-catalyzed
three-component reaction with phenylacetylene and p-toluene-
sulfonyl azide (Table 1). To our delight, the reaction with NH4Cl
took place smoothly at room temperature to give 2-phenyl-N-
(p-toluenesulfonyl) acetamidine, and it was found that its yields
varied depending on the conditions employed. While CH2Cl2
turned out to be the most effective solvent, the equivalent of
Et3N additive was also important for the reaction efficiency.
The reaction could be carried out under ambient conditions, thus
not requiring inert atmosphere and dried solvents (compare
entries 3 and 7). As in our recent example in the Cu-catalyzed
N-arylation of aryl halides,4 aqueous ammonia solution (28%
aqueous NH3) was also a highly effective nitrogen source in
this case. In fact, reaction efficiency was even higher with
aqueous NH3 solution compared to that with NH4Cl, and side
products such as amides were not observed.8
Ammonium salts were found to be a convenient and
inexpensive reagent in the Cu-catalyzed three-component
reaction with terminal alkynes and sulfonyl or phosphoryl
azides leading to N-unprotected amidines. Thus obtained
amidines bearing 2-bromobenzenesulfonyl moiety were ef-
ficiently cyclized by the Cu-catalyzed intramolecular N-
arylation to give an important pharmacophore skeleton of
2H-1,2,4-benzothiadiazine 1,1-dioxides. Conveniently, two
tandem catalytic procedures could be readily operated in one
pot.
Although gaseous ammonia is the simplest nitrogen source
in chemical processes,1 it is less frequently used as an efficient
reagent in organic syntheses compared to substituted amines,2
mainly owing to practical problems with respect to safety and
convenience. On the other hand, ammonium salts (e.g., NH4Cl,
NH4OH, NH4OAc, or NH4BF4) are employed in some synthetic
procedures as a facile and inexpensive equivalent to ammonia
because of their ease of handling.3
In this context, we recently reported an example of utilizing
ammonium salts in Cu-catalyzed N-arylation.4 We found that,
by the action of CuI/proline catalyst, NH4Cl or NH4OH react
readily with aryl halides under mild conditions to afford primary
It was interesting to compare the relative initial reaction rates
among various nucleophiles in the Cu-catalyzed three-compo-
(5) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038–2039.
(6) (a) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I. H.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730–1733. (b)
Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. J.
Org. Chem. 2008, 73, 5520–5528.
(7) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8,
1347–1350.
(8) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046–16047. (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1897–1900. (c) Cho, S. H.; Hwang, S. J.; Chang, S. Org. Synth. 2008, 85, 131–
137. (d) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed. 2006,
45, 3154–3157.
(9) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836–2839.
(10) (a) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K.
J. Am. Chem. Soc. 2006, 128, 12366–12367. (b) Kim, S. H.; Jung, D. Y.; Chang,
S. J. Org. Chem. 2007, 72, 9769–9771. (c) Kim, J. Y.; Kim, S. H.; Chang, S.
Tetrahedron Lett. 2008, 49, 1745–1749. (d) Yoo, E. J.; Chang, S. Org. Lett.
2008, 10, 1163–1166.
(1) LeBlanc, J. R. J.; Madhavan, S.; Porter, R. E.; Kellogg, P. Encyclopedia
of Chemical Technology, 2nd ed.; Wiley: New York, 1963; Vol. 2.
(2) (a) Roundhill, D. M. Chem. ReV. 1992, 92, 1–27. (b) Lang, F.; Zewge,
D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett. 2001, 42, 3251–3254. (c)
Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028–10029.
(3) (a) Capdevielle, P.; Lavigne, A.; Maumy, M. Synthesis 1989, 451–452.
(b) Ogo, S.; Uehara, K.; Abura, T.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126,
3020–3021. (c) Willis, M. C. Angew. Chem., Int. Ed. 2007, 46, 3402–3404. (d)
Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K.-I. Org. Lett. 2008, 10, 181–
184, and references cited therein.
(11) (a) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517–4520.
(b) Cui, S.-L.; Wang, J.; Wang, Y.-G. Org. Lett. 2007, 9, 5023–5025. (c) Cui,
S.-L.; Wang, J.; Wang, Y.-G. Tetrahedron 2008, 64, 487–492. (d) Kita, Y.; Toma,
T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251–3253.
(4) Kim, J.; Chang, S. Chem. Commun. 2008, 3052–3054.
9454 J. Org. Chem. 2008, 73, 9454–9457
10.1021/jo802014g CCC: $40.75 2008 American Chemical Society
Published on Web 10/29/2008

TABLE 1. Screen of Reaction Conditions in the Cu-Catalyzed
Three-Component Couplings with Ammonium Saltsa
TABLE 2. Three-Component Reactions of Various Alkynes with
p-Toluenesulfonyl Azide and Ammonium Saltsa
entry
NH4X
Et3N (equiv)
solvent
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
THF
DMSO
CH2Cl2
CH2Cl2
ClCH2CH2Cl
THF
yield (%)b
1
2
3
4
5
6
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
2.0
2.0
1.5
0.5
2.0
2.0
1.5
1.5
2.0
2.0
68
85
84
62
58
25
87
89
88
63
7c
8c
9c
10c
NH4Cl
NH3 (aq)d
NH3 (aq)d
NH3 (aq)d
a Phenylacetylene (0.5 mmol), p-toluenesulfonyl azide (0.5 mmol),
Et3N, NH4X (0.5 mmol), and CuI (0.05 mmol) in the indicated solvent
b
(1.0 mL) at 25 °C under N2. 1H NMR yield (internal standard
1,1,2,2-tetrachloroethane). c Run open to the air. d Aqueous 28%
solution.
a Alkyne (0.5 mmol), p-toluenesulfonyl azide (0.5 mmol), Et3N (0.75
mmol), NH4Cl (0.5 mmol), and CuI (0.05 mmol) in CH2Cl2 (1.0 mL) at
25 °C for 1 h. b Isolated yield. c NH3 (28% aqueous, 0.5 mmol) was
employed instead of NH4Cl.
FIGURE 1. Reaction profile in the Cu-catalyzed three-component
couplings of phenylacetylene and p-toluenesulfonyl azide with NH3
(aq), benzylamine, NH4Cl, water, or benzyl alcohol.
nent reactions (Figure 1).12 It was revealed that aqueous
ammonia solution displayed the highest initial rates followed
by benzylamine and NH4Cl. On the other hand, reactions with
water or benzyl alcohol proceeded with much slower initial rates.
Under the optimized reaction conditions with ammonium
salts, the scope of terminal alkynes was next investigated using
p-toluenesulfonyl azide as a representative coupling partner
(Table 2). We were pleased to see that a wide range of aromatic
alkynes underwent the reaction with excellent efficiency ir-
respective of their electronic and steric properties (entries 1-6).
It should be noted that employment of aqueous ammonia
solution, in general, provides similar or slightly higher yields
of amidine products compared to those with NH4Cl. Aliphatic
alkynes were also readily utilized to provide the corresponding
amidines with satisfactory yields (entries 7-9). Heteroaromatic
alkynes underwent the three-component reaction without dif-
ficulty (entry 10).
FIGURE 2. Selected bond lengths (Å) of an amidine 2: C7-C8,
1.515(8); C8-N1, 1.295(7); C8-N2, 1.306(7); N2-S1, 1.590(5);
S1-O2, 1.432(4); S1-O1, 1.446(4); S1-C9, 1.756(6).
(Table 3). Not only arene- but also alkanesulfonyl azides were
found to be facile reactants, giving amidines in high yields under
the optimized conditions (entries 1 and 2). However, phosphoryl
azides were less effective for the coupling reaction (entry 3).
With the subsequent intramolecular N-arylation in mind (vide
infra), when 2-bromobenzenesulfonyl azide was allowed to react
with a range of 1-alkynes, the corresponding amidines could
be obtained in satisfactory yields (entries 4-6).
The synthetic utility of N-unsubstituted amidines was then
investigated in the subsequent conversion to interesting hetero-
cycles. 2H-1,2,4-Benzothiadiazine 1,1-dioxide is a biologically
important pharmacophore, and various derivatives bearing the
It is interesting to note that double bond character in the
generated amidines is delocalized over two C-N bonds as
evidenced by the solid state structure analysis of an isolated
amidine 2 (Figure 2).12 We then examined the scope of azides
substituted with various sulfonyl or phosphoryl groups in the
Cu-catalyzed three-component coupling with ammonium salts
(12) See Supporting Infomation for the reaction profile and X-ray crystal-
lographic data.
J. Org. Chem. Vol. 73, No. 23, 2008 9455

TABLE 3. Three-Component Reactions with Ammonium Saltsa
SCHEME 1. Synthetic Strategy to 2H-1,2,4-
Benzothiadiazine 1,1-Dioxide
TABLE 4. Intramolecular Catalytic N-Arylation of Amidinesa
a Alkyne (0.5 mmol), azide (0.5 mmol), Et3N (0.75 mmol), NH4Cl
(0.5 mmol), and CuI (0.05 mmol) in CH2Cl2 (1.0 mL) at 25 °C.
b Isolated yield. c NH3 (28% aqueous, 0.5 mmol) was employed. d For
12 h.
a Amidine (0.3 mmol), CuI (0.03 mmol), Cs2CO3 (0.6 mmol), and
1,10-phenanthroline (0.06 mmol) in DMF (4.0 mL) at 80 °C for 16 h.
b Recrystallization yield.
key moiety are known to show antihypertensive or antimicrobial
activities.13 For instance, 1-butyl-3-(1,1-dioxido-2H-1,2,4-ben-
zothia-diazin-3-yl)-4-hydroxy-(1H)-quinolinone and its deriva-
tives were revealed to be potent HCV polymerase inhibitors.14
Therefore, a range of efficient synthetic routes to the pharma-
cophore have been developed.15 Since we queried that the key
molecular skeleton of 2H-1,2,4-benzothiadiazine 1,1-dioxides
could be prepared by the intramolecular N-arylation of the
precursors that are obtainable based on our approach, we
envisioned to develop a straightforward and convenient route
to the important pharmacophore by employing two tandem Cu-
catalytic reactions (Scheme 1). The Cu-catalyzed intramolecular
C-N cross-coupling16 of 2-bromobenzenesulfonyl amidines,
which were obtained from the above three-component reactions
(Table 3, entries 4-6), was readily achieved by a slight
modification of the known catalytic protocol of 1,10-phenan-
throline, CuI, and Cs2CO3 in DMF (Table 4).17 Under the
employed conditions, a range of 3-substituted 2H-1,2,4-ben-
zothiadiazine 1,1-dioxides were obtained in respectable yields
after recrystallization. Interestingly, a TMS group was desily-
lated in situ under the reaction conditions (entry 3).
Due to the fact that CuI catalyst was employed commonly
in both amidine formation and N-arylation reaction, we tried
to carry out the two operations in one pot. After the initial three-
component coupling reaction, volatile species were removed,
and then the intramolecular N-arylation was next attempted by
simply adding 1,10-phenanthroline and Cs2CO3 in DMF in the
same flask. As expected, the one-pot operation of the two
catalytic procedures was successfully carried out leading to
3-benzyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (5) in good
overall yield (Scheme 2).
(13) (a) Topliss, J. G.; Yudis, M. D. J. Med. Chem. 1972, 15, 394–400. (b)
Tait, A.; Luppi, A.; Franchini, S.; Preziosi, E.; Parenti, C.; Buccioni, M.; Marucci,
G.; Leonardi, A.; Poggesi, E.; Brasili, L. Bioorg. Med. Chem. Lett. 2005, 15,
1185–1188.
(14) (a) Zhou, Y.; Webber, S. E.; Murphy, D. E.; Li, L.-S.; Dragovich, P. S.;
Tran, C. V.; Sun, Z.; Ruebsam, F.; Shah, A. M.; Tsan, M.; Showalter, R. E.;
Patel, R.; Li, B.; Zhao, Q.; Han, Q.; Hermann, T.; Kissinger, C. R.; LeBrun, L.;
Sergeeva, M. V.; Kirkovsky, L. Bioorg. Med. Chem. Lett. 2008, 18, 1413–1418.
(b) Tedesco, R.; Shaw, A. N.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy,
M. G.; Dhanak, D.; Fitch, D. M.; Gates, A.; Gerhardt, W. G.; Halegoua, D. L.;
Han, C.; Hofmann, G. A.; Johnston, V. K.; Kaura, A. C.; Liu, N.; Keenan, R. M.;
Lin-Goerke, J.; Sarisky, R. T.; Wiggall, K. J.; Zimmerman, M. N.; Duffy, K. J.
J. Med. Chem. 2006, 49, 971–983.
(15) (a) Bosse, T. D.; Larson, D. P.; Wagner, R.; Hutchinson, D. K.;
Rockway, T. W.; Kati, W. M.; Liu, Y.; Masse, S.; Middleton, T.; Mo, H.;
Montgomery, D.; Jiang, W.; Koev, G.; Kempf, D. J.; Molla, A. Bioorg. Med.
Chem. Lett. 2008, 18, 568–570. (b) Rockway, T. W.; Zhang, R.; Liu, D.;
Betebenner, D. A.; McDaniel, K. F.; Pratt, J. K.; Beno, D.; Montgomery, D.;
Jiang, W. W.; Masse, S.; Kati, W. M.; Middleton, T.; Molla, A.; Maring, C. J.;
Kempf, D. J. Bioorg. Med. Chem. Lett. 2006, 16, 3833–3838. (c) Imai, Y.;
Mochizuki, A.; Kakimoto, M. Synthesis 1983, 851. (d) Imai, Y.; Sato, S.;
Takasawa, R.; Ueda, M. Synthesis 1981, 35–36. (e) Su, W.; Cai, H.; Yang, B.
J. Chem. Res. 2004, 87–88.
In summary, we have demonstrated that ammonium salts can
be readily utilized as a convenient and cheap reagent in a Cu-
catalyzed three-component reaction to afford amidines, which
were further manipulated to give 2H-1,2,4-benzothiadiazine 1,1-
dioxides, a biologically important pharmacophore.
(16) For recent reviews on this topic, see: (a) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (b) Yang, B. H.; Buchwald, S. L.
J. Organomet. Chem. 1999, 576 (1-2), 125–146. (c) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818. (d) Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
(17) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133–136.
9456 J. Org. Chem. Vol. 73, No. 23, 2008

SCHEME 2. One-Pot Synthesis of 3-Benzyl-2H-1,2,4-
benzothiadiazine 1,1-Dioxide (5)
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 mL × 3). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude residue was purified
by flash column chromatograph on silica gel (ethyl acetate/hexane,
1:1) to afford 2-phenyl-N-(p-toluenesulfonyl)acetamidine as a white
1
solid (129.8 mg, 90%): mp 115-116 °C; H NMR (400 MHz,
CDCl3) δ 8.02 (br, 1H), 7.75 (d, J ) 8.2 Hz, 2H), 7.30-7.16 (m,
7H), 5.97 (br, 1H), 3.58 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.5, 143.0, 139.0, 133.4, 129.5, 129.3, 129.1, 127.9,
126.3, 43.6, 21.4; IR (NaCl) ν 3327, 3328, 3238, 1654, 1545, 1449,
1414, 1277, 1103, 801 cm-1; HRMS(FAB) m/z calcd for
C15H17O2N2S [M + H]+ 289.1011, found 289.1001.
Experimental Section
Acknowledgment. This research was supported by the
KOSEF (R01-2007-000-10618-0). We also acknowledge the
Korea Basic Science Institute for the mass analysis.
Representative Procedure for the Cu-Catalyzed Three-Com-
ponent Coupling Reaction with Ammonium Salts. To a stirred
mixture of NH4Cl (26.7 mg, 0.5 mmol), CuI (9.5 mg, 0.05 mmol),
and phenylacetylene (51.1 mg, 0.5 mmol) in CH2Cl2 (1 mL) was
slowly added triethylamine (0.14 mL, 0.75 mmol) at room
temperature. After color changed to yellow, p-toluenesulfonyl azide
(98.6 mg, 0.5 mmol) was added dropwise. After the reaction was
completed, which was monitored with TLC, the reaction mixture
was diluted by adding CH2Cl2 (2 mL) and aqueous NH4Cl solution
(3 mL). The mixture was stirred for an additional 30 min, and two
Supporting Information Available: Detailed experimental
procedures, characterization data, copies of 1H and 13C-spectra
of new compounds, and a CIF file of 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO802014G
J. Org. Chem. Vol. 73, No. 23, 2008 9457