An efficient catalytic method for the Friedl?nder annulation mediated by peptide coupling agent propylphosphonic anhydride (T3P)

Article abstract of DOI:10.1016/j.tetlet.2011.10.048

We have demonstrated the utilization of T3P, a mild and low toxic peptide coupling agent, as a promoter and water scavenger in the Friedl?nder annulation, and thus introduced a highly efficient catalytic process to access carbocyclic and heterocyclic fused quinolines under microwave irradiation or a conventional heating technique. The reaction conditions are sufficiently mild to tolerate the acid and base sensitive functional groups that can serve as levers for further extension of the quinoline products.

Full text of DOI:10.1016/j.tetlet.2011.10.048

Tetrahedron Letters 52 (2011) 6814–6818
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Tetrahedron Letters
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An efficient catalytic method for the Friedländer annulation mediated
by peptide coupling agent propylphosphonic anhydride (T3PÒ)
John Kallikat Augustine a, , Agnes Bombrun b, Srinivasa Venkatachaliah a
⇑
a Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
b Merck Serono SA, 9 Chemin des Mines, 1202 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have demonstrated the utilization of T3P, a mild and low toxic peptide coupling agent, as a promoter
and water scavenger in the Friedländer annulation, and thus introduced a highly efficient catalytic pro-
cess to access carbocyclic and heterocyclic fused quinolines under microwave irradiation or a conven-
tional heating technique. The reaction conditions are sufficiently mild to tolerate the acid and base
sensitive functional groups that can serve as levers for further extension of the quinoline products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 September 2011
Revised 6 October 2011
Accepted 9 October 2011
Available online 15 October 2011
Keywords:
Friedländer annulation
Propylphosphonic anhydride
Quinolines
Catalytic
Microwave irradiation
Quinolines and their derivatives are very significant structural
motifs that occur widely in natural1 and synthetic products, often
displaying a broad range of biological activity. Members of this
family have wide applications in medicinal chemistry, being used
as antimalarial,2 antituberculosis,3 antibacterial,4 anti-inflamma-
tory,5 antiviral,6 antihypertensive,7 and as tyrosine kinase inhibit-
ing agents.8 In addition to the medicinal applications, quinolines
have been employed in the study of bioorganic and bioorganome-
tallic processes.9 Due to their broad range of applicability in medic-
inal, industrial, bioorganic as well as in the fields of synthetic
organic chemistry, there has been an increasing interest in devel-
oping efficient methods for quinoline synthesis.
carboxylate functionality was not tolerated under basic condi-
tions.13 In an attempt to improve on these procedures, Lewis acid
catalyzed methods for quinoline synthesis have recently been re-
ported.14 Yet, some of these procedures suffered from harsh reac-
tion conditions, low yields, and the use of stoichiometric and/or
expensive reagents. And in some cases, high catalyst loading had
to be employed in order to attain respectable yields. Thus, the
development of highly efficient catalytic methods having broad
substrate and functional group tolerance for the synthesis of quin-
olines is still vital.
Propylphosphonic anhydride (T3PÒ) is an efficient and mild
peptide coupling reagent having low toxicity and low allergenic
potential.15 Its water scavenging and coupling capabilities have
generated innovative uses for this reagent beyond peptide synthe-
sis.16 There are quite a few examples, wherein, T3P is utilized in
dehydration chemistry,17 and molecular rearrangements.18 Of late,
T3P has been used as a reagent in the preparation of various func-
tionalized heterocycles.19 Herein, we report our results on the
highly effective T3P catalyzed Friedländer annulation of quinolines
and polycyclic quinolines under microwave irradiation and a con-
ventional heating technique.
The preparation of 3a from 2-acetylaniline (1a) was chosen as a
model reaction to assess the competency of T3P in promoting the
Friedländer reaction (Table 1). The initial experiments were carried
out with equimolar amounts of 1a, cyclohexanone (2a) in solution
in DMF with T3P (50% solution in EtOAc) at room temperature. As
these conditions led to a slightly lower yield of 3a (Table 1, entry
1), the mixture was heated to 90 °C. We were interested to find
The Friedländer quinoline synthesis10 is one of the simplest and
powerful tools for the synthesis of quinolines. In its most classical
and general form, the Friedländer reaction involves condensation
between 2-aminoaryl carbonyl compound (aldehyde or ketone)
and a second carbonyl compound containing a reactive
a-methy-
lene group followed by cyclodehydration. The reaction can be pro-
moted by acid or base catalysis, or by heating a mixture of the
reactants at 150–220 °C in the absence of a catalyst.11 Many of
these procedures, however, have drawbacks such as poor func-
tional group tolerance, limited substrate scope, and difficulties in
the work-up procedures. For instance, under thermal or basic con-
ditions, ortho-aminobenzophenones failed to react with simple ke-
tones such as cyclohexanone and b-keto esters.12 Likewise, a
⇑
Corresponding author. Tel.: +91 80 2808 3131; fax: +91 80 2808 3150.
E-mail address: john.kallikat@syngeneintl.com (J.K. Augustine).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.048

J. K. Augustine et al. / Tetrahedron Letters 52 (2011) 6814–6818
6815
Table 1
Table 2
Screening optimal conditions
T3P catalyzed quinoline synthesis: scope of ketones
O
R2
R1
O
T3P (50% soln in EtOAc)
DMF
O
T3P (20 mol%)
O
R2
+
R1
+
N
NH2
NH2
DMF, 90 °C, 4-6 h
N
1a
2a-p
3a-p
1a
2a
3a
Entry
Substrate
Product
Yielda (%)
Entry
T3P (mol %)
Time (h)
Temp (°C)
Yield (%) 3a
O
1
2
3
4
5
6
7
8
9
100
100
50
25
20
15
20
10
—
12
4
4
6
6
11
0.5
1
25
90
90
90
90
90
90
100
120
21
98
98
98
1
2
98
98
N
3a
2a
O
98
94
97a
88a
0a,b
N
3b
2b
1
O
a
Reaction was performed under MW irradiation.
Intermediate Schiff base was observed in trace.
b
3
4
96
97
N
2c
O
3c
that complete consumption of the starting material occurred in 4 h
to provide tetrahydroacridine 3a in 98% yield (Table 1, entry 2).
Upon reinvestigation (see Table 1), it was found that 20 mol % of
T3P at 90 °C was also efficient to afford 3a in respectable yield (Ta-
ble 1, entry 5). Decreasing the amount of T3P from 20 to 15 mol %
prolonged the duration of reaction in addition to lowering the yield
of quinoline to some extent (Table 1, entry 6). Moreover, it is note-
worthy that this reaction could be run under microwave irradia-
tion without loss of efficiency in a much shorter duration (Table
1, entry 7). As observed from Table 1 (entries 7 and 8), it was essen-
tial to use 20 mol % of T3P under microwave irradiation to obtain
optimum conversion of 1a. Further, there was no product when
the reactants were irradiated under microwave conditions at
120 °C in DMF in the absence of T3P (Table 1, entry 9), but the
intermediate Schiff base was observed in trace.
N
3d
O
2d
O
O
O
O
O
5
6
94
95
N
2e
3e
N
O
N
O
O
O
N
O
2f
3f
O
7
98
Among the solvents screened (THF, DMF, dioxane, toluene,
MeCN, EtOAc, and NMP), most of them supported the reaction,
DMF and NMP were demonstrated as the best solvents. The high
efficiency of T3P catalyzed quinoline synthesis was then estab-
lished by reacting 1a with structurally diverse carbonyl com-
N
3g
O
2g
O
S
8
9
96
97
90
N
3h
S
pounds containing
a reactive a-methylene group under the
2h
optimized thermal conditions (DMF, 20 mol % of T3P, 90 °C, con-
ventional heating) and the results are summarized in Table 2. As
shown in Table 2, this method was equally effective for both cyclic
and acyclic ketones to generate a variety of quinoline derivatives.
The present protocol was free from side reactions, such as self-con-
densation of ketones, which were normally observed under basic
conditions and excellent isolated yields were observed for all sub-
strates employed. It is noteworthy that the reaction tolerated both
an acid sensitive (Table 2, entries 5 and 6) and base sensitive (Table
2, entries 9 and 10) functional groups to provide the respective
quinolines in good yields.
The Friedländer reaction, depending upon the nature of catalyst,
with unsymmetrical ketones such as ethyl methyl ketone is known
to undergo two possible modes of cyclization producing distinct
regioisomers viz., 2-ethylquinoline and 2,3-dimethylquinoline,
respectively.11 While under acidic conditions, 2,3-dimethylquino-
line was reported as the major product along with minor amounts
of 2-ethylquinoline, under basic conditions, 2-ethylquinoline was
reported as the major isomer along with minor amounts of 2,3-
dimethylquinoline. Surprisingly, the T3P catalyzed Friedländer
reaction with unsymmetrical ketones afforded regiospecifically
the 2,3-dialkylquinolines as exclusive products in excellent yields
(Table 2, entries 13 and 14). No trace of the isomeric 2-alkylquin-
O
COOEt
COOEt
N
3i
2i
O
COOEt
Ph
COOEt
Ph
10
N
3j
2j
O
O
O
11
98
N
3k
2k
O
12
13
96
98
N
3l
2l
O
N
3m
2m
(continued on next page)

6816
J. K. Augustine et al. / Tetrahedron Letters 52 (2011) 6814–6818
Table 3
Table 2 (continued)
T3P catalyzed quinoline synthesis: scope of 2-aminoaryl carbonyls
Entry
Substrate
Product
Yielda (%)
R
O
R
O
O
T3P (20 mol%)
N
O
O
N
O
R1
R1
+
NH2
O
N
14
99
N
3n
DMF, MW, 90 °C
15-45 min
2q
1a-j
3q-z
2n
Entry
Substrate
Product
Yielda (%)
96
O
CN
Ph
NC
O
Ph
O
15
16
95
79
boc
N
3o
N
2o
1
2
N
NH2
O
3q
1a
O
boc
N
O
O
N
N
O
O
2p
3p
94
89
N
NH2
a
3r
Isolated yields.
1b
O
boc
S
N
3
4
NH2
S
oline could be identified in 1H NMR of the crude product before
purification by crystallization. A related trend was observed in
the case of an unsymmetrical cyclic ketone 2f which gave rise
exclusively to polycyclic quinoline 3f (Table 2, entry 6). This phe-
nomenon could be attributed to relatively mild reaction conditions
and the absence of a Brönsted or Lewis acid catalyst. Under essen-
tially the same conditions, the ketone bearing a terminal alkyne
(2p) gave exclusively the unexpected quinoline 3p in 79% yield
(Table 2, entry 16).
The substrate scope of the reaction was further explored by per-
forming the reaction between a fairly acid sensitive N-Boc keto
derivative 2q with a variety of 2-aminoaryl carbonyls (1a–j) under
the optimized MW conditions20 (DMF, 20 mol % of T3P, 90 °C) and
the results are depicted in Table 3. As observed from Table 3, var-
ious substituted aromatic/heteroaromatic aldehydes and ketones
reacted smoothly with 2q to produce a range of quinoline deriva-
tives. The reactions were quick (15–45 min) and good to excellent
isolated yields were observed for all substrates employed. How-
ever, the reaction did not tolerate an ortho-aminoaryl aldehyde
bearing an activated halogen on the ring (Table 3, entry 10), but
gave the hydrolyzed product 3z. In most cases (Tables 2 and 3),
the solid products were isolated by simple aqueous work-up, and
finally crystallized.
The enhanced catalytic activity of T3P in promoting the Fried-
länder annulation could be explained by the transformations
shown in Scheme 1. A possible participation of T3P (4) during
the commencement of reaction between 1 and 2 enhances the rate
of formation of Schiff base (7) via the intermediate 5. The ‘open’
hydrated T3P (6) produced during the process cyclizes to regener-
ate the catalyst 4 (T3P), which in turn, promotes an intramolecular
aldol-type reaction to produce the intermediate 9. Subsequent
expulsion of quinoline 3 from the intermediate 9 produces 6, and
the catalytic cycle then continues by the regeneration of T3P in
the process.
3s
1c
O
Ph
NH2
Ph
O2N
Cl
O2N
boc
N
98
95
N
1d
3t
F
boc
Cl
N
5
F
O
NH2
N
1e
3u
CHO
NH2
boc
N
N
6
7
97b
96b
3v
1f
CHO
NH2
boc
boc
Br
Cl
Br
Cl
N
N
N
Br
Br
1g
3w
CHO
NH2
8
9
98b
94b
N
3x
1h
CHO
NH2
boc
MeOOC
Cl
MeOOC
O
N
N
3y
1i
boc
CHO
N
10
73b
N
H
N
3z
NH2
N
1j
a
Isolated yields.
Reaction was completed in 15 min.
b
In conclusion we have demonstrated the utilization of T3P, a
mild and low toxic peptide coupling agent, as a promoter and
water scavenger in the Friedländer annulation, thus introduced a
highly efficient catalytic method to access carbocyclic and hetero-
cyclic fused quinolines under microwave irradiation21 and a con-
ventional heating technique.22 The method, which uses cheap
and readily available T3P, not only provides an excellent comple-
ment to quinoline synthesis, but also avoids the use of hazardous
acids or bases. Further, the reaction conditions are sufficiently mild
to tolerate acid or base sensitive functional groups that can serve
as levers for further extension of the quinoline products. The high
yields of products, easy workup procedure, broad functional group
tolerance and use of only a catalytic amount of T3P make this pro-
cess a complementary and/or superior method for the Friedländer
quinoline synthesis.

J. K. Augustine et al. / Tetrahedron Letters 52 (2011) 6814–6818
6817
OH
Pr
P
O
O
P
O
O
P
R1
O
R2
H
N
Pr
O
Pr
HO
O
O
R3
P
P
P
Pr
O
5
O
Pr
R1
R1
O
6
HO
O
O
O
1
Pr
NH2
N
O
P
Pr
R2
7
R3
- H2O
R3
O
O
P
4
O
Pr
O
2
P
O
O
Pr
R2
O
Pr
R2
P
R1
O
O
P
R3
H
P
- H2O
O
O
O
Pr
O
Pr
N
4
OH
P
O
OH
Pr
Pr
P
P
O
O
O
O
8
Pr
6
Pr
P
Pr
O
O
O
O
N
P
P
Pr
R1
O
OH
O
R2
H
R3
R3
R2
9
N
R1
3
Scheme 1. Proposed mechanism of the T3P catalyzed quinoline synthesis.
8. (a) Chen, Y. L.; Fang, K. C.; Sheu, J. Y. S.; Hsu, L.; Tzeng, C. C. J. Med. Chem. 2001,
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1998, 120, 2501.
Supplementary data
Supplementary data (copies of 1H NMR, 13C NMR and LCMS re-
port for 3a–z) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.10.048.
10. Cheng, C.-C.; Yan, S.-J. In Organic Reactions; Dauben, W. G., Ed.; John Wiley &
Sons: New York, 1982; Vol. 28,. Chapter 2 (b) Friedländer, P. Berichte 1882, 15,
2572.
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the solvent was removed under vacuum and the residue was diluted with
water (20 mL). The solid product which separated out was filtered, washed
with water, and dried to afford the desired quinolines in good purity. The oily
quinolines were extracted with ethyl acetate (2 Â 15 mL) and the combined
organic phase was washed with saturated NaHCO3 solution (1 Â 10 mL) and
brine. The organic phase was dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the crude product was passed through a
small plug of silica to afford the quinolines in good purity and yield.
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20. The microwave chemistry was performed on a single-mode microwave reactor
Emrys™ Optimiser from Personal Chemistry in sealed reaction vessels.
21. T3P catalyzed synthesis of quinolines under MW irradiation: To a mixture of 2-
aminoaryl ketone/aldehyde (1, 0.01 mol) and ketone (2, 0.01 mol) in DMF
(8 mL) in a 20 mL microwave reaction vessel was added T3P (20 mol %, 50%
soln in EtOAc). The resulting reaction mixture was irradiated with stirring in a
microwave reactor (Emrys™ Optimiser from Personal Chemistry, 300 W) at
90 °C for 15–45 min. When the reaction was completed (monitored by TLC),
22. T3P catalyzed synthesis of quinolines under conventional heating: To a mixture of
2-aminoaryl ketone/aldehyde (1, 0.01 mol) and ketone (2, 0.01 mol) in DMF
(10 mL) was added T3P (20 mol %, 50% soln in EtOAc). The resulting reaction
mixture was stirred at 90 °C for 4–6 h under conventional heating. When the
reaction was completed (monitored by TLC), the solvent was removed under
vacuum and the residue was diluted with water (20 mL). The solid product
which separated out was filtered, washed with water, and dried to afford the
desired quinolines in good purity. The oily quinolines were extracted with
ethyl acetate (2 Â 15 mL) and the combined organic phase was washed with
saturated NaHCO3 solution (1 Â 10 mL) and brine. The organic phase was dried
over anhydrous Na2SO4. The solvent was removed under reduced pressure and
the crude product was passed through a small plug of silica to afford the
quinolines in good purity and yield.