New opportunities with the Duff reaction

Article abstract of DOI:10.1021/jo800700b

(Chemical Equation Presented) The Duff reaction (HMTA, AcOH or TFA) was studied on substituted [6 + 5] heterocyclic compounds. This reaction provides a useful route to aldehydes for compounds bearing sensitive amide functions. It gives also access to tric

Full text of DOI:10.1021/jo800700b

various heterocyclic systems, e.g., furan,2b,3d pyrrole,2c
pyrimidine,2e indole,1a–e,h,2g,4a–c benzothiophene,4e etc.
In ongoing work to develop new antiproliferative drugs and
melanoma tracers,5 we set out to explore the formylation of
imidazo[1,2-a]pyridinic compounds (IPs), substituted by an
amidic chain at various core positions. Scheme 1 describes the
synthesis of imidazopyridinic derivatives substituted on the C-2
or C-5-C-8 positions. Briefly, 2-aminopyridine compounds 1-5
reacted with the appropriate halo ketones to give ester-
substituted IPs 6a-e (50-63% isolated yields) by Tschitschiba-
bin cyclization. Amides 7a-e were then easily obtained with
high yields (>90%) by direct amidification using trimethyla-
luminum as activator (Scheme 1).
New Opportunities with the Duff Reaction
Nicolas Masurier,† Emmanuel Moreau,*,† Claire Lartigue,†
Vincent Gaumet,† Jean-Michel Chezal,† Annie Heitz,‡
Jean-Claude Teulade,† and Olivier Chavignon†
E.A.4231, Faculte´ de Pharmacie, 28 place Henri Dunant,
B.P. 38, 63001 Clermont-Ferrand Cedex 1, France, and
CBS, CNRS, INSERM, 29, rue de NaVacelles,
34060 Montpellier, France
emmanuel.moreau@u-clermont1.fr
ReceiVed March 28, 2008
SCHEME 1a
The Duff reaction (HMTA, AcOH or TFA) was studied on
substituted [6 + 5] heterocyclic compounds. This reaction
provides a useful route to aldehydes for compounds bearing
sensitive amide functions. It gives also access to tricyclic
lactams of potential biological interest. The formation of an
aminomethyl intermediate in the Duff reaction mechanism
is unequivocally demonstrated.
a Reagents and conditions: (i) BrCH2COCO2Et, EtOH, ∆; (ii)
NH2(CH2)2NEt2, AlMe3, THF, ∆; (iii) HMTA, AcOH, 90 °C; (iv)
CH3COCH2Cl, EtOH, ∆.
Position 3 of the imidazo[1,2-a]pyridine ring is the most
preferred position for electrophilic aromatic substitutions.6 This
position can be easily functionalized with a formyl group. The
Vilsmeier-Haack reaction was generally considered to offer
the best yields of formyl IP derivatives (around 30%),6e and
this reaction is largely used in this series.7 However, for amidic
IPcompounds7a-e,theseconditions(likethoseofRiemer-Tiemann)
Formylation is a useful reaction in heterocyclic chemistry
where it is widely used to gain access to multifunctional
compounds. Several methods can be used to prepare heterocyclic
formyl compounds. The Vilsmeier-Haack,1 Reimer-Tiemann,2
Gattermann,3 and Rieche4 reactions are commonly used in
* To whom correspondence should be addressed. Phone: +33(0)473178013.
Fax: +33(0) 473178012.
(3) (a) Scammells, P. J.; Baker, S. P.; Beauglehole, A. R. Bioorg. Med. Chem.
1998, 6, 1517. (b) Yang, Z.; Biao Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong,
H. N. C. J. Org. Chem. 1992, 57, 7248. (c) Wong, H. N. C.; Niu, C. R.; Yang,
Z.; Hon, P. M.; Chang, H. M.; Lee, C. M. Tetrahedron 1992, 48, 10339. (d)
Kutney, J. P.; Hanssen, H. W.; Vijayakumaran Nair, G. Tetrahedron 1971, 27,
3323.
† E.A.4231, Faculte´ de Pharmacie.
‡ CBS, CNRS.
(1) (a) Faust, R.; Garratt, P. J.; Trujillo Perez, M. A.; Piccio, V. J. D.; Madsen,
C.; Stenstrom, A.; Frolund, B.; Davidson, K.; Teh, M. T.; Sugden, D. Bioorg.
Med. Chem. 2007, 15, 4543. (b) Prueger, B.; Bach, T. Synthesis 2007, 7, 1103.
(c) Kaufmann, D.; Pojarova, M.; Vogel, S.; Liebl, R.; Gastpar, R.; Gross, D.;
Nishino, T.; Pfaller, T.; von Angerer, E. Bioorg. Med. Chem. 2007, 15, 5122.
(d) Coldham, I.; Dobson, B. C.; Fletcher, S. R.; Franklin, A. I. Eur. J. Org.
Chem. 2007, 16, 2676. (e) Coldham, I.; Dobson, B. C.; Franklin, A. I.; Fletcher,
S. R. Tetrahedron Lett. 2007, 48, 873. (f) Nandhakumar, R.; Suresh, T.; Calistus
Jude, A. L.; Rajesh Kannan, V.; Mohan, P. S. Eur. J. Med. Chem. 2007, 42,
1128. (g) Kolavi, G.; Hegde, V.; Khazia, I. A.; Gadadb, P. Bioorg. Med. Chem.
2006, 14, 3069. (h) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287. (i) Broggini,
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Owczarczyk, Z. Tetrahedron Lett. 1987, 28, 3021. (c) Smith, K. M.; Bobe, F. W.;
Minnetian, O. M.; Hope, H.; Yanuck, M. D. J. Org. Chem. 1985, 50, 790. (d)
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10.1021/jo800700b CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5989–5992 5989

TABLE 1. Duff Reaction applied to IP Derivatives 7a-e
entry substrate chain position reaction time isolated yieldsa (%)
TABLE 2. Synthesis of Lactam Tricycles 9 and 10
entry
solvent
reaction time
pH
9a (%)
10a (%)
b
1
2
3
4
5
7a
7b
7c
7d
7e
2
8
7
6
5
2 h 30 min
24 h
24 h
24 h
2 h
8a (20)
8b (41)
8c (54)b
8d (34)c
9 (44)
1
2
3
4
5
6
7
TFA
AcOH
–
2 h 30 min
2 h 30 min
2 h 30 min
2 h 30 min
2 h 30 min
18 h
2.51
3.35
3.82
4.21
4.73
6.65
44
43
37
29
22
8
AcOH 70%
AcOH 30%
AcOH 15%
AcOH 5%
H2O
24
28
28
19
a Based on consumed starting material. b 40% of 7c was recovered at
the end of the reaction. c 30% of 7d was recovered at the end of the
reaction.
a Isolated yields. b Starting material was recovered.
proved inefficient or offered only low yields of formyl com-
pounds (degradation or yields below 10%, data not shown).
Given these disappointing results, we decided to explore Duff
formylation (hexamethylenetetramine (HMTA) in acetic acid8
or TFA9), already used on several heterocyclic systems10 and
found to be efficient in IP series (18%10a to 29%10b isolated
yield of formyl compounds).
Under TFA conditions, no reaction was observed and only
starting material was recovered. In the presence of acetic acid,
the Duff reaction led to acceptable yields (in IP series) of formyl
compounds 8a-d (Table 1, entries 1-4).
Unexpectedly, the Duff reaction conditions applied to 7e
afforded the peri-annulated compound 9. This product was the
result of an intramolecular peri-annelation reaction between the
positions 3 and 5 of the IP nucleus. Reactions of peri-annelation
had already been observed by ring closure using 3,5-bifunc-
tionalized IP compounds10a,11 and also directly obtained starting
from 5-monofunctionalized IPs.12
FIGURE 1. Proposed mechanisms for the formation of tricyclic
lactams 9 and 10.
To our knowledge, this is the first report of a Duff reaction
without acid catalysis.
Various concentrations of aqueous acetic acid were then
studied. When acetic acid was concentrated (70% and above,
Table 2, entries 2 and 3), only compound 9 was obtained in
around 40% yield. With lower acid concentrations (Table 2,
entries 4-6), N-alkylated compound 10 was also obtained. The
overall reaction yield was highest in 30% aqueous acetic acid
(Table 2, entry 4). Also, an increase in the pH of the medium
lowered the yield of compound 9. In water (Table 2, entry 7),
the reaction was slower, as already observed,13 but offered the
highest ratio in favor of compound 10 (70% of compound 10).
It has been assumed that the mechanism of the Duff reaction
involves an aminomethylation (generated from HMTA) of the
substrate,13,14 followed by the dehydrogenation of the amine to
the corresponding imine, which is hydrolyzed to give the formyl
group.8c,13,14 To investigate the formation of compound 9,
compound 10 was placed in the Duff conditions, but even after
prolonged reaction time, no traces of compound 9 were detected
and 10 was recovered. As 10 was not a precursor of 9, two
mechanisms seem to operate during the reaction (Figure 1).
In the more acidic conditions (Table 2, entries 2 and 3), the
N-1 of the IP nucleus was largely protonated (pKa ) 3.89),15
decreasing the electronic density of the amide carbonyl group
and favoring attack by the aminomethyl group in position 3 to
form the lactam cycle of compound 9 (Figure 1, path I). Faster
attack of the amidic carbonyl by the nitrogen of the aminomethyl
group than formation of the imine intermediate could explain
this result.
In another run in AcOH, with an ethyl ester instead of the
amidic chain in C-5 (compound 6e), tricycle 9 was also obtained
in 16% isolated yield (Scheme 2). This result unequivocally
demonstrated the mechanism of formation of 9: the nitrogen
atom of the lactam cycle could only come from the aminomethyl
group. Another run, with 30% AcOH, which offered best overall
yields of lactams starting from 7e, raised the yield of compound
9 (54% from 6e).
(7) (a) Gudmundsson, K. S.; Johns, B. A. Bioorg. Med. Chem. Lett. 2007,
17, 2735. (b) Anaflous, A.; Benchat, N.; Mimouni, M.; Abouricha, S.; Ben-
Hadda, T.; El-Bali, B.; Hakkou, A.; Hacht, B. Lett. Drug. Des. DiscoV. 2004, 1,
224. (c) Gudmundsson, K. S.; Johns, B. A. Org. Lett. 2003, 5, 1369. (d) Ollis,
W. D.; Stanforth, S. P.; Ramsden, C. A. J. Chem. Soc., Perkin Trans. 1 1989,
5, 961.
(8) (a) Duff, J. C. J. Chem. Soc. 1941, 547. (b) Duff, J. C. J. Chem. Soc.
1945, 276. (c) Duff, J. C.; Furness, V. J. J. Chem. Soc. 1951, 1512.
(9) Smith, W. E. J. Org. Chem. 1972, 37, 3972.
(10) (a) Ikemoto, T.; Kawamoto, T.; Wada, H.; Ishida, T.; Ito, T.; Isogami,
Y.; Miyano, Y.; Mizuno, Y.; Tomimastsu, K.; Hamamura, K.; Takatani, M.;
Wakimasu, M. Tetrahedron 2002, 58, 489. (b) Ikemoto, T.; Wakimasu, M.
Heterocycles 2001, 55, 99. (c) van Niel, M. B.; Collins, I.; Beer, M. S.;
Broughton, H. B.; Cheng, S. K.; Goodacre, S. C.; Heald, A.; Locker, K. L.;
McLeod, A. M.; Morrison, D.; Moyes, C. R.; O’Connor, D.; Pike, A.; Rowley,
M.; Russell, M. G.; Sohal, B.; Stanton, J. A.; Thomas, S.; Verrier, H.; Watt,
A. P.; Castro, J. L. J. Med. Chem. 1999, 42, 2087. (d) Chatterjee, A.; Biswas,
J. J. Org. Chem. 1973, 38, 4002. (e) Verbiscar, A. J. J. Med. Chem. 1972, 15,
149. (f) Snyder, H. R.; Swaminathan, S.; Sims, H. J. J. Am. Chem. Soc. 1952,
74, 5110.
(11) (a) Kawamoto, T.; Tomimatsu, K.; Ikemoto, T.; Abe, H.; Hamamura,
K.; Takatani, M. Tetrahedron Lett. 2000, 41, 3447. (b) Ikemoto, T.; Kawamoto,
T.; Tomimastsu, K.; Takatani, M.; Wakimasu, M. Tetrahedron 2000, 56, 7915.
(c) Moreau, E.; Chezal, J.-M.; Dechambre, C.; Canitrot, D.; Blache, Y.; Lartigue,
C.; Chavignon, O.; Teulade, J.-C. Heterocycles 2002, 57, 21.
ˇ
(14) (a) Blazˇevic´, N.; Kolbah, D.; Belin, B.; Sunjic´, V.; Kajfezˇ, F. Synthesis
1979, 161. (b) Marzaro, G.; Chilin, A.; Pastorini, G.; Guitto, A. Org. Lett. 2006,
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Manzini, P.; Guitto, A. Tetrahedron 2006, 62, 12351.
(12) (a) Chezal, J.-M.; Moreau, E.; Chavignon, O.; Gaumet, V.; Me´tin, J.;
Blache, Y.; Diez, A.; Fradera, X.; Luque, J.; Teulade, J.-C. Tetrahedron 2002,
58, 295. (b) Chezal, J.-M.; Moreau, E.; Delmas, G.; Gueiffier, A.; Blache, Y.;
Grassy, G.; Lartigue, C.; Chavignon, O.; Teulade, J.-C. J. Org. Chem. 2001, 66,
6576.
(15) The pKa value was determined experimentaly by HCl (20 mM) titration
of compound 7e. The titration curve showed two pH jumps, the first one attributed
to the tertiary amine protonation (pKa ) 11.16)16 and the second one attributed
to the protonation of the IP N-117 (pKa ) 3.89).
(16) March, J. AdVanced Organic Chemistry: Reactions, mechanisms and
structure, 3rd ed.; John Wiley & Sons: New York, 1985; Chapter 8.
(13) Ogata, Y.; Kawasaki, A.; Suguria, F. Tetrahedron 1968, 24, 5001.
5990 J. Org. Chem. Vol. 73, No. 15, 2008

SCHEME 2
In less acidic media (30% aqueous acetic acid or lower, Table
2, entries 4-7), the pH of the medium entailed a lower degree
of protonation of the IP nucleus N-1 and the nitrogen of the
amide chain was thus less electron-depleted. The attack of the
imine carbon (or the aldehyde carbon) by the amide nitrogen
could then take place, giving tricyclic compound 10 (Figure 1,
path II). When the pH was greater than about 3.5, a competition
between the two routes was observed. The highest pH favored
path II.
To study the scope of peri-annelation reactions, the Duff
conditions (HMTA/AcOH) were extended to several compounds
presenting different carbonyl groups in position 5 of the IP core.
While the peri-annelation was observed with good yield with
compounds 6e and 7e, the presence of a deactivating group (ester
or amide) in position 2 of the IP nucleus (compounds 11 or 12,
Table 3, entry 1) opposed the electrophilic substitution in
position 3 of the IP nucleus and the starting material was
recovered. In the case of the aldehyde derivative 13 (Table 3,
entry 2), marked degradation occurred. However, two com-
pounds were isolated: tricyclic compound 9 and the 2-methyl-
FIGURE 2. Structural assignment of compound 18. Connectivities
(bold lines) deduced from the COSY spectrum by key HMBC
correlations and by selected NOESY (arrows).
3-formylimidazo[1,2-a]pyridine 17.6e,18 This result can be
explained by the oxidative conditions of the reaction.19 The
aldehyde group on position 5 can be converted into the acid
intermediate, which gives tricyclic compound 9 by peri-
annelation. Also, the acid can be decarboxylated and then
followed the “classic” formylation reaction, leading to 17.
In the case of the acetyl derivative 14 (Table 3, entry 3), the
reaction led not to the expected formyl or lactam derivative but
to compound 18, which presented a more complex structure.
The electronic impact mass spectrum of 18 presented a
1
molecular ion at m/z 267. The analysis of the H, 13C NMR
J-modulated and HSQC spectra indicated the presence of one
methyl, four methylene, three aromatic, three nonaromatic
1
methine, and four quaternary carbons. The H-13C HMBC
analysis allowed the assignment of H-7 (5.73 ppm) and H-13
(4.76 ppm), Figure 2A. Also, the 1H-15N HMBC analysis
allowed the assignment of the linkage of the carbon C-7 (70.8
ppm) with two nonaromatic nitrogens at δ -374 ppm and -365
ppm. In the same way, the carbon C-13 (59.8 ppm) was linked
to the nitrogen at δ -374 ppm. Finally, the total assignment of
the structure was achieved and the analysis of the 1H-1H
NOESY analysis confirmed structure 18 (Figure 2B).
TABLE 3. Duff Reaction Applied to Compounds 11-16
With this substrate, it seems that the presence of an enolizable
function in position 5 of the IP nucleus completely modified
reactivity toward HMTA. This novel reactivity requires a
separate study.
The Duff reaction was also studied on 4-substituted indole
or benzofuran nuclei. In the case of benzofuranic ester 15, no
Duff reaction occurred in AcOH. However, at TFA reflux, the
corresponding formyl compound 19 was isolated, with 32%
yield (Table 3, entry 4). This reaction also led to the formation
of the aminomethyl derivative 20 (16% isolated yield). With
the indole derivative 16, formyl and aminomethyl derivatives
(21 and 22 respectively) were isolated (Table 3, entry 5). Once
again, these results prove unequivocally that the aminomethyl
derivative was an intermediate in the Duff mechanism. It seems
that the cyclization of these two aminomethyl derivatives is
inhibited by steric congestion around position 3 and no peri-
(17) (a) Catalan, J. J. Heterocycl. Chem. 1984, 21, 269. (b) Boulton, B. E.;
Coller, A. W. Aust. J. Chem. 1974, 27, 2349. (c) Armarego, W. L. F. J. Chem.
Soc. 1964, 4226. (d) Paudler, W. W.; Blewitt, H. L. J. Org. Chem. 1966, 31,
1295.
a Compound 11 was synthesized according to the literature
procedure.11c New compounds 12-16 were synthesized using classical
methods (see the Supporting Information). b Starting material was
recovered. c TFA was used instead of AcOH.
(18) Hand, E. S.; Paudler, W. W.; Zachow, S. J. Org. Chem. 1977, 42, 3377.
(19) Potassium iodide was rapidly oxidized into iodine under the reaction
conditions (HMTA, AcOH, 90 °C). Further addition of sodium thiosulfate
decolorized the reaction medium.
J. Org. Chem. Vol. 73, No. 15, 2008 5991

added. The solution was basified with Na2CO3 to pH 8 and extracted
twice with 25 mL of CHCl3. The solution was dried on Na2SO4,
filtered, and concentrated to dryness under reduced pressure and
then purified by column chromatography.
annelation occurred. However, these compounds were tricyclic
lactam precursors and could easily lead to the corresponding
lactam derivatives, as described by Demerson et al.20
In summary, we studied the Duff reaction, to gain access to
formyl amido-IP compounds. While Vilsmeier-Haack and
Riemer-Tiemann conditions were not readily compatible with
the amide chain, the Duff conditions were found to provide
useful yields of formyl compounds. However, when the IP
nucleus was substituted on position 5, no formylation was
obtained, but a peri-annelation reaction occurred. This result
proved unequivocally that the Duff reaction proceeded Via an
aminomethyl intermediate, isolated with compounds 20 and 22.
This peri-annelation reaction offers a new route to synthesize
novel peri-fused tricyclic lactams, which have already been
found to possess useful biological activities (anti-PDGFR,21
polyADP(ribose) polymerase-1 inhibition,22 central nervous
system and antihypertensive activities).20
2-Methyl-3,4-dihydro-1,4,8b-triazaacenaphthylen-5-one (9): pu-
rified on alumina, eluted by CH2Cl2/EtOH 98/2 (v/v); yield, see
1
Table 2; yellow powder; mp 178-180 °C; H NMR (200 MHz,
CD3OD) δ 2.34 (s, 3H), 5.00 (s, 2H), 7.21 (t, 1H, J ) 7.0 Hz),
7.36 (dd, 1H, J ) 7.0 Hz, J ) 1.0 Hz), 7.46 (dd, 1H, J ) 7.0 Hz,
J ) 1.0 Hz); 13C NMR (50 MHz, CD3OD) δ 12.7 (CH3), 39.9
(CH2), 111.3 (C), 113.5 (CH), 120.0 (CH), 125.6 (CH), 126.8 (C),
138.3 (C), 143.4 (C), 160.4 (C); MS (EI, 70 eV) m/z (rel int) 187
(M+, 51), 186 (100), 172 (11), 156 (8), 131 (8), 118 (8), 78 (19),
51 (22); HRMS m/z calcd for C10H10N3O (M + H+) 188.0824,
found 188.0806.
4-[2-(Diethylamino)ethyl)]-2-methyl-3,4-dihydro-1,4,8b-triaz-
aacenaphthylen-5-one (10): purified on alumina, eluted by CH2Cl2/
1
EtOH 98/2 (v/v); yield, see Table 2; yellow oil; H NMR (200
MHz, CDCl3) δ 0.99 (t, 6H, J ) 7.0 Hz), 2.32 (s, 3H), 2.54 (q,
4H, J ) 7.0 Hz), 2.72 (t, 2H, J ) 6.5 Hz), 3.60 (t, 2H, J ) 6.5
Hz), 5.09 (s, 2H), 7.06 (dd, 1H, J ) 7.0 Hz, J ) 9.0 Hz), 7.43 (d,
1H, J ) 9.0 Hz), 7.37 (d, 1H, J ) 7.0 Hz); 13C NMR (50 MHz,
CDCl3) δ 11.9 (CH3), 13.3 (CH3), 46.1 (CH2), 46.5 (CH2), 47.3
(CH2), 50.0 (CH2), 108.6 (C), 112.2 (CH), 119.4 (CH), 123.7 (CH),
125.2 (C), 137.8 (C), 142.3 (C), 157.3 (C); MS (EI, 70 eV) m/z
(rel int): 286 (M+, 13), 187 (10), 186 (10), 86 (100), 58 (21); HRMS
m/z calcd for C16H23N4O (M + H+) 287.1872, found 287.1868.
Experimental Section
General Procedure for the Duff Reaction. To a solution of
0.73 mmol of the appropriate compound in 5 mL of solvent (see
Table 2) was added 200 mg of hexamethylenetetramine (1.43 mmol,
2 equiv). The solution was heated at 90 °C for the appropriate time
(see Tables 1 and 2). After being cooled to rt, the solution was
concentrated to around 2/3 volume and then 3 mL of water was
Acknowledgment. We sincerely thank Dr. Bruno Combou-
rieu for 15N NMR experiments, Dr. Bernadette Bouchon for
performing ESI mass spectral analysis, and Damien Canitrot
for excellent technical assistance.
(20) Demerson, C. A.; Philipp, A. H.; Humber, L. G.; Kraml, M. J.; Charest,
M. P.; Tom, H.; Va´vra, I. J. Med. Chem. 1974, 17, 1140.
(21) (a) Kawamoto, T.; Shibouta, Y.; Takatani, M.; Noda, M. Patent EP
826686, 1998. (b) Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T.
Patent WO 9602542, 1996.
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Almassy, R. J.; Li, J.; Yu, X. H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki,
T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.;
Kyle, S.; Thomas, H. D.; Wang, L. Z.; Calvert, A. H.; Golding, B. T.; Griffin,
R. J.; Newell, D. R.; Webber, S. E.; Hostomsky, Z. J. Med. Chem. 2002, 45,
4961. (b) Li, J. H.; Zhang, J.; Kalish, V. J. Patent WO 02/006240 A1, 2002. (c)
Webber, S. E.; Canan-Koch, S. S.; Tikhe, J.; Thoresen, L. H. Patent WO
00042040, 2000.
Supporting Information Available: Experimental details,
characterizations, and a copy of 1H and 13C spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO800700B
5992 J. Org. Chem. Vol. 73, No. 15, 2008