Facile formation of cyclic aminals through a Br?nsted acid-promoted redox process

Article abstract of DOI:10.1021/jo802325x

(Chemical Equation Presented) Cyclic aminals were prepared through a Br?nsted acid-promoted reaction. This redox neutral process involves iminium ion formation, 1,5 H-transfer, followed by ring closure.

Full text of DOI:10.1021/jo802325x

products 2 are typically unstable and known to readily undergo
oxidation to the corresponding benzimidazolium salts.4 We have
recently reported a new process in which aminobenzaldehydes
react with cyclic amines under thermal conditions to produce
aminals such as 3 (eq 2).5 The formation of both 2 and 3 is
thought to involve a 1,6-hydride shift process as the initial step
preceding ring closure. Interestingly, only one report has
appeared for the mechanistically distinct transformation of imine
4 to aminal 5 (eq 3) that is initiated by a 1,5-hydride shift.6,7
Heating of 4 in n-butanol under reflux for 5 days was reported
to provide 5 in 66% yield as a single diastereomer.6
Facile Formation of Cyclic Aminals through a
Brønsted Acid-Promoted Redox Process
Chen Zhang, Sandip Murarka, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The
State UniVersity of New Jersey, Piscataway, New Jersey 08854
seidel@rutchem.rutgers.edu
ReceiVed October 15, 2008
Cyclic aminals were prepared through a Brønsted acid-
promoted reaction. This redox neutral process involves
iminium ion formation, 1,5 H-transfer, followed by ring
closure.
We reasoned that this transformation should be readily
realized as a single-flask acid-catalyzed procedure that does not
require the isolation of the intermediate imine (Scheme 1). Thus,
the reaction of o-aminobenzaldehydes such as 6 with amines is
expected to provide access to potentially useful heterocyclic
scaffolds 7.8-10
The term “tert-amino effect” has been used to describe a
diverse number of reactions that proceed via intramolecular,
C-C, or C-X bond-forming redox processes within conjugated
systems.1 These reactions involve the functionalization of a
C-H bond R to a tertiary amine nitrogen and have also been
referred to as “R-cyclization of tertiary amines”.2,3 In the vast
majority of cases, these reactions are promoted thermally and
relatively little effort has been devoted to developing catalytic
approaches.1 To ultimately expand the scope and applicability
of these intriguing transformations, it is desirable to identify
catalysts that would allow for milder reaction conditions as well
as shorter reaction times. Here we report Brønsted acid-promoted
syntheses of aminals from o-aminobenzaldehydes and aromatic
or aliphatic amines that proceed in a simple single-flask
procedure.
Brønsted and Lewis acids were evaluated as catalysts for the
reaction of aminobenzaldehyde 6 with aniline (Table 1, entries
(4) (a) Meth-Cohn, O.; Naqui, M. A. Chem. Commun. 1967, 1157–1158.
(b) Grantham, R. K.; Meth-Cohn, O. Chem. Commun. 1968, 500–502. (c)
Grantham, R. K.; Meth-Cohn, O.; Naqui, M. A. J. Chem. Soc., C 1969, 1438–
1443. (d) Grantham, R. K.; Meth-Cohn, O. J. Chem. Soc., C 1969, 1444–1448.
(e) Clark-Lewis, J. W.; Moody, K.; Thompson, M. J. Aust. J. Chem. 1970, 23,
1249–1273. (f) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Shivanyuk,
A. N.; Tolmachev, A. A. J. Org. Chem. 2007, 72, 7417–7419. (g) Che, X.; Zheng,
L.; Dang, Q.; Bai, X. Synlett 2008, 2373–2375.
(5) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
416–417.
A number of aminal forming reactions have been reported
that involve R-functionalizations of tertiary amines (eqs 1-3).
The acid-catalyzed reaction outlined in eq 1 is an early example
of the tert-amino effect and is known to occur in the presence
of acid, often at room temperature.4 The initially formed
(6) Verboom, W.; Hamzink, M. R. J.; Reinhoudt, D. N.; Visser, R.
Tetrahedron Lett. 1984, 25, 4309–4312.
(7) In related reactions that involve attempted Vilsmeier formylations of
4-substituted, tertiary anilines, the intermediate iminium salts undergo a number
of different rearrangements: (a) Meth-Cohn, O.; Taylor, D. L. J. Chem. Soc.,
Chem. Commun. 1995, 1463–1464. (b) Meth-Cohn, O.; Cheng, Y. Tetrahedron
Lett. 1996, 37, 2679–2682. (c) Cheng, Y.; Meth-Cohn, O.; Taylor, D. J. Chem.
Soc., Perkin Trans. 1 1998, 1257–1262. (d) Patsenker, L. D.; Ermolenko, I. G.;
Artyukhova, E. E.; Krasovitskii, B. M. Chem. Heterocycl. Compd. 2000, 36,
611–612. (e) Patsenker, L. D.; Ermolenko, I. G.; Fedyunyaeva, I. A.; Popova,
N. A.; Krasovitskii, B. M. Chem. Heterocycl. Compd. 2000, 36, 623–625. (f)
Patsenker, L. D.; Yermolenko, I. G.; Artyukhova, Y. Y.; Baumer, V. N.;
Krasovitskii, B. M. Tetrahedron 2000, 56, 7319–7323. (g) Cheng, Y.; Liu, Q.-
X.; Meth-Cohn, O. Synthesis 2000, 640–642. (h) Cheng, Y.; Liu, Q.-X.; Meth-
Cohn, O. Tetrahedron Lett. 2000, 41, 3475–3478. (i) Cheng, Y.; Jiao, P.;
Williams, D. J.; Cohn, O.-M. J. Chem. Soc., Perkin Trans. 1 2001, 44–46. (j)
Cheng, Y.; Yang, H.-B.; Liu, B.; Meth-Cohn, O.; Watkin, D.; Humphries, S.
Synthesis 2002, 906–910. (k) Cheng, Y.; Wang, B.; Meth-Cohn, O. Synthesis
2003, 2839–2843. (l) Semenova, O. N.; Kudryavtseva, Y. A.; Ermolenko, I. G.;
Patsenker, L. D. Russ. J. Org. Chem. 2005, 41, 1100–1101. (m) Ryabtsova, O. V.;
Pozharskii, A. F.; Degtyarev, A. V.; Ozeryanskii, V. A. MendeleeV Commun.
2006, 313–316.
(1) For reviews, see: (a) Meth-Cohn, O.; Suschitzky, H. AdV. Heterocycl.
Chem. 1972, 14, 211–278. (b) Verboom, W.; Reinhoudt, D. N. Recl. TraV. Chim.
Pays-Bas 1990, 109, 311–324. (c) Meth-Cohn, O. AdV. Heterocycl. Chem. 1996,
65, 1–37. (d) Quintela, J. M. Recent Res. DeV. Org. Chem. 2003, 7, 259–278.
(e) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-Dajka, B.
Synthesis 2006, 2625–2639.
(2) (a) Jiang, S.; Janousek, Z.; Viehe, H. G. Bull. Soc. Chim. Belg. 1993,
102, 663–668. (b) Jiang, S.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett. 1994,
35, 1185–1188. (c) De Boeck, B.; Jiang, S.; Janousek, Z.; Viehe, H. G.
Tetrahedron 1994, 50, 7075–7092. (d) De Boeck, B.; Janousek, Z.; Viehe, H. G.
Tetrahedron 1995, 51, 13239–13246.
(3) These reactions are mechanistically distinct from other oxidative ap-
proaches that lead to R-functionalization of tertiary amines. For an excellent
review on this topic, see: Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069–1084.
10.1021/jo802325x CCC: $40.75
Published on Web 11/21/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 419–422 419

TABLE 1. Evaluation of Potential Catalystsa
SCHEME 1. Proposed Brønsted Acid-Promoted Process
entry
R
catalyst (equiv)
solvent time [h] yield [%]
1b
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph CF3COOH (0.2)
Ph CF3COOH (0.2)
Ph CF3COOH (0.2)
Ph CF3COOH (0.2)
Ph CF3COOH (0.2)
Ph CF3COOH (0.2)
Ph CF3COOH (1.2)
Ph CF3SO3H (0.2)
Ph 4-Me-C6H4SO3H (0.2)
Ph 2,4-(NO2)2-C6H3SO3H (0.2) EtOH
Ph CH3COOH (0.2)
Ph HCl (1.2)
Ph Zn(OTf)2 (0.1)
Ph Yb(OTf)3 (0.1)
EtOH
EtOH
MeCN
THF
CH2Cl2
PhH
EtOH
EtOH
EtOH
48
12
5
12
36
7
38c
66
57
38c
30c
60
12
3
53
71
53
12
12
24
12
12
12
24
24
24
24
24
24
12
24
24
24
12
24
24
1-14). No formation of 7a was observed in the absence of acid
for a reaction performed in ethanol. The addition of trifluoro-
acetic acid (20 mol %) to a reaction run at room temperature
led to product formation, but the reaction remained incomplete
after 48 h (Table 1, entry 1). Under the same conditions but at
reflux temperature, the reaction was complete after 12 h and
7a was isolated in 66% yield (Table 1, entry 2). Addition of
excess trifluoroacetic acid (Table 1, entry 7) did not lead to a
shortened reaction time but instead resulted in a reduced yield
of product 7a. Other acids are viable catalysts, including Lewis
acids such as zinc triflate and ytterbium triflate. Ultimately, triflic
acid (20 mol%) was identified as the optimal catalyst with 7a
being isolated in 71% yield (Table 1, entry 8). Ethanol was
shown to be the best solvent among those tested.
66
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
THF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
50c
71
52
45
NR
54
57
NR
53c
48c
75
NR
31c
60
15b Bn CF3COOH (0.2)
16
17
18
19
20
21
22
23
24
25
26
27
Bn CF3COOH (0.2)
Bn CF3COOH (0.2)
Bn CF3COOH (0.2)
Bn MeSO3H (0.2)
Bn 4-Me-C6H4SO3H (0.2)
Bn CF3COOH (1.2)
Bn H3PO4 (0.2)
Bn CH3COOH (0.2)
Bn CF3SO3H (0.2)
Bn HCl (1.2)
47
53
53
Bn Zn(OTf)2 (0.1)
Bn Yb(OTf)3 (0.1)
A different reactivity pattern was seen for the reaction of
aminobenzaldehyde 6 with benzylamine (Table 1, entries
15-27). No reaction was observed in the absence or presence
of trifluoroacetic acid (20 mol %) at room temperature (Table
1, entry 15). Performing the reaction in the presence of
trifluoroacetic acid (20 mol %) under reflux conditions led to
full conversion and formation of 7b in 54% yield (Table 1, entry
16). The maximum yield for 7b (75%) was obtained when
excess trifluoroacetic acid (1.2 equiv) was used (Table 1, entry
21). Other Brønsted and Lewis acids are viable catalysts/
promoters of this reaction, but proved less efficient in terms of
reaction time and/or yield.
In cases where less than 1 equiv of acid is used to facilitate
rearrangement, the actual acid catalyst is presumed to be an
ammonium salt. Of course, the nature of the counteranion is
expected to have a drastic, if nonobvious role, as complex
counterion effects are well-documented in the context of
iminium catalysis.11
a Reactions were performed in a given solvent (0.1 M) under reflux
on a 0.25 mmol scale and were run to full conversion as judged by TLC
analysis. b Performed at room temperature. c Reaction did not go to full
conversion.
to good yields. Bulky substituents on both ortho-positions of
the aniline moiety were readily accommodated (Table 2, entry
3). Interestingly, the reaction of 6 with 4-cyanoaniline proceeded
readily at room temperature to provide the corresponding
product 7f in 50% yield (Table 2, entry 5). The use of
heterocyclic amines such as 2-aminopyridine or aminopyrimi-
dine (Table 2, entries 8 and 9) gave rise to products 7i and 7j
in lower yields, presumably due to the availability of multiple
protonation sites that might interfere with the catalytic process.
Aliphatic amines were also evaluated in the reaction with
aminobenzaldehyde 6 and gave rise to products 7 in good yields
(Table 2, entries 10-13), using reaction conditions previously
optimized for benzylamine.
The scope of the reaction with regard to the aminobenzal-
dehyde component is summarized in Table 3. A number of
structurally diverse aminobenzaldehydes gave rise to products
9 upon reaction with primary amines in the presence of acid.
The required starting materials were readily obtained from
2-fluorobenzaldehyde and the corresponding secondary
amines.12 Aminobenzaldehydes derived from cyclic amines
bearing benzylic R C-H bonds were particularly reactive (Table
The scope of the reaction of aminobenzaldehyde 6 with
different aromatic amines was subsequently evaluated (Table
2, entries 1-9). Electronically diverse anilines with various
substitution patterns provided access to products 7 in moderate
(8) For related, Lewis acid-catalyzed reactions in nonconjugated systems,
see: (a) Woelfling, J.; Frank, E.; Schneider, G.; Tietze, L. F. Eur. J. Org. Chem.
2004, 90–100. (b) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc.
2005, 127, 12180–12181. (c) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7, 5429–
5431.
(9) For selected publications on the chemistry of aminals and alternate
methods for their preparation, see: (a) Campi, E. M.; Jackson, W. R.; McCubbin,
Q. J.; Trnacek, A. E. Aust. J. Chem. 1994, 47, 1061–1070. (b) Alexakis, A.;
Mangeney, P. AdV. Asym. Synth. 1996, 93–110. (c) Simon, C.; Peyronel, J.-F.;
Rodriguez, J. Org. Lett. 2001, 3, 2145–2148. (d) Sinha, N.; Jain, S.; Anand, N.
Tetrahedron Lett. 2004, 46, 153–156. (e) Hiersemann, M. Functions bearing
two nitrogens. In ComprehensiVe Organic Functional Group Transformations
II; Katritzky, A. R. T., RichardJ. K., Ed.; Elsevier Ltd.: Oxford, UK, 2005; Vol.
4, pp 411-441. (f) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennama-
dhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696–
15697. (g) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813–
3816.
(10) Aminals are found in a number of natural products. For selected
examples, see: (a) Braekman, J. C.; Daloze, D.; Pasteels, J. M.; Van Hecke, P.;
Declercq, J. P.; Sinnwell, V.; Francke, W. Z. Naturforsch., C: J. Biosci. 1987,
42, 627–630. (b) Hino, T.; Nakagawa, M. Chemistry and reactions of cyclic
tautomers of tryptamines and tryptophans. In Alkaloids; Academic Press: New
York, 1988; Vol. 34, pp 1-75. (c) Hajicek, J.; Taimr, J.; Budesinsky, M.
Tetrahedron Lett. 1998, 39, 505–508. (d) Crich, D.; Banerjee, A. Acc. Chem.
Res. 2007, 40, 151–161.
(11) For a recent review on iminium catalysis, see: Erkkilae, A.; Majander,
I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416–5470.
420 J. Org. Chem. Vol. 74, No. 1, 2009

TABLE 2. Variation of the Amine Componenta
TABLE 3. Variation of the Aminobenzaldehyde Componenta
a Reactions were performed on a 1 mmol scale in EtOH (0.1 M) and
were run to full conversion as judged by TLC analysis. Method A:
CF3SO3H (0.2 equiv), reflux. Method B: CF3COOH (1.2 equiv), reflux.
Method C: CF3SO3H (0.2 equiv), room temperature. b dr ) 59:41. c dr
) 66:34.
the increased hydride donor capability of a tertiary over a
secondary C-H bond. Reaction of 6 with R-methylbenzylamine
gave rise to products 9ias a 59:41 mixture of diastereomers
(Table 3, entry 9). Similarly, reaction of 2-pyrrolidinyl ac-
etophenone with 4-bromoaniline resulted in the formation of
9j as a 66:34 mixture of diastereomers (Table 3, entry 10),
illustrating that aminoacetophenones are also viable substrates
a Reactions were performed on a 1 mmol scale in EtOH (0.1 M) and
were run to full conversion as judged by TLC analysis. Method A:
CF3SO3H (0.2 equiv), reflux. Method B: CF3COOH (1.2 equiv), reflux.
Method C: CF3SO3H (0.2 equiv), room temperature.
(12) (a) Nijhuis, W. H. N.; Verboom, W.; Abu El-Fadl, A.; Harkema, S.;
Reinhoudt, D. N. J. Org. Chem. 1989, 54, 199–209. (b) Nijhuis, W. H. N.; Leus,
G. R. B.; Egberink, R. J. M.; Verboom, W.; Reinhoudt, D. N. Recl. TraV. Chim.
Pays-Bas 1989, 108, 172–178. (c) D’yachenko, E. V.; Glukhareva, T. V.;
Nikolaenko, E. F.; Tkachev, A. V.; Morzherin, Y. Y. Russ. Chem. Bull. 2004,
53, 1240–1247.
2, entries 5-7), presumably due to the increased hydride donor
capabilities of these substrates. Compound 9h was isolated as
a single regioisomer resulting from functionalization at the more
hindered position (Table 3, entry 8). This finding likely reflects
J. Org. Chem. Vol. 74, No. 1, 2009 421

SCHEME 2. Competing Reaction Pathways
The reaction mixture was monitored by TLC. After the completion
of the reaction, 1.0 mL of triethylamine was added. The reaction
mixture was worked up according to procedure A.
General Procedure C for the Reaction between Amino-
aldehydes and Amines. To a stirred solution of aminoaldehyde (1
mmol) in 10 mL of EtOH was added the primary amine (1.2 mmol)
and triflic acid (0.2 mmol), followed by stirring at room temperature.
The reaction mixture was monitored by TLC. After the completion
of the reaction, 0.3 mL of triethylamine was added. The reaction
mixture was worked up according to procedure A.
in this transformation. The low isolated yield of product 9k is
likely a reflection of product instability rather than reactivity
of the starting material (Table 3, entry 11) as full conversion of
the aminobenzaldehyde was observed.
7a: The reaction was carried out according to general procedure
A (3 h). The product was obtained as a white solid in 71% yield
(Rf 0.34 in 8% EtOAc/Hex); mp 82 - 84 °C; IR (KBr) 3031, 2970,
2937, 2835, 1606, 1596, 1510, 1494, 1477, 1461, 1398, 1363, 1323,
1
1308, 1256, 1207, 1193, 774, 702 cm-1; H NMR (500 MHz,
The reaction of 6 with tryptamine was investigated in order
to compare the title reaction to a potentially competing
Pictet-Spengler pathway. (Scheme 2).4g Interestingly, a mixture
of both products was obtained with the product resulting from
the Pictet-Spengler reaction (11) being the predominantly
formed species. Although the overall yields of this nonoptimized
process are low, the findings demonstrate the relative ease with
which acid-catalyzed hydride shift reactions can occur.
In summary, we have shown that reactions involving the “tert-
amino effect” can be accelerated by Brønsted acids. This allowed
for the synthesis of potentially useful and previously unknown
aminals under mild conditions, species that are not readily
obtainable by other means. The exploration of catalytic ap-
proaches to related reactions is ongoing and results will be
reported in due course.
CDCl3) δ 7.32 (app tt, J ) 2.0, 3.9 Hz, 2H), 7.22-7.10 (m, 4H),
6.97 (d, J ) 7.4 Hz, 1H), 6.69-6.63 (m, 1H), 6.54 (d, J ) 8.0 Hz,
1H), 4.65 (dd, J ) 5.3, 8.3 Hz, 1H), 4.40 (d, J ) 14.9 Hz, 1H),
4.12 (d, J ) 14.9 Hz, 1H), 3.47 (app td, J ) 3.1, 8.7 Hz, 1H), 3.39
(dd, J ) 8.6, 16.2 Hz, 1H), 2.14-1.85 (comp, 3H), 1.80-1.68 (m,
1H); 13C NMR (125 MHz, CDCl3) 150.3, 143.5, 128.9, 127.8, 125.9,
125.2, 124.7, 120.8, 116.2, 111.3, 76.7, 57.3, 47.1, 31.9, 22.2; m/z
(ESIMS) 251.2 [M + H]+.
7b: The reaction was carried out according to general procedure
B (24 h). The product was obtained as a colorless oil in 75% yield
(Rf 0.24 in 2% EtOAc/DCM); IR (film) 3066, 3025, 2968, 2834,
1606, 1578, 1509, 1483, 1462, 1395, 1369, 1321, 1304, 1160, 1130,
1
741, 698 cm-1; H NMR (500 MHz, CDCl3) 7.45-7.26 (comp,
5H), 7.11 (app t, J ) 7.5 Hz, 1H), 6.83 (d, J ) 7.2 Hz, 1H), 6.59
(app td, J ) 0.9, 7.4 Hz, 1H), 6.47 (d, J ) 8.0 Hz, 1H), 4.17 (dd,
J ) 5.3, 8.3 Hz, 1H), 3.95 (d, J ) 13.1 Hz, 1H), 3.69 (d, J ) 14.8
Hz, 1H), 3.57 (d, J ) 14.8 Hz, 1H), 3.50-3.30 (comp, 3H),
2.35-2.25 (m, 1H), 2.19-2.09 (m, 1H), 2.07-1.86 (comp, 2H);
13C NMR (125 MHz, CDCl3) 143.2, 138.3, 129.0, 128.3, 127.6,
127.1, 126.4, 119.4, 115.7, 110.3, 78.4, 56.5, 54.4, 46.6, 31.8, 22.4;
m/z (ESIMS) 265.2 [M + H]+.
Experimental Section
General Procedure A for the Reaction between Amino-
aldehydes and Amines. To a stirred solution of aminoaldehyde (1
mmol) in 10 mL of EtOH was added the primary amine (1.2 mmol)
and triflic acid (0.2 mmol), followed by heating at reflux. The
reaction mixture was monitored by TLC. After the completion of
the reaction, 0.3 mL of triethylamine was added. The solution was
concentrated in vacuo and the crude product was dissolved in ethyl
acetate (20 mL) and washed with 25 mL of 1 M NaOH. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine (25 mL) and dried
with sodium sulfate. The solvent was removed in vacuo and the
crude product was purified by column chromatography.
Acknowledgment. The authors thank the Donors of the
American Chemical Society Petroleum Research Fund for
support of this research. Financial support from Rutgers, The
State University of New Jersey is gratefully acknowledged. We
thank Dr. Tom Emge for crystallographic analysis.
Supporting Information Available: Detailed experimental
procedures and characterization data for all new compounds
including X-ray structures of 7d, 9e, 9f, and 11. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure B for the Reaction between Amino-
aldehydes and Amines. To a stirred solution of aminoaldehyde (1
mmol) in 10 mL of EtOH was added the primary amine (1.2 mmol)
and trifluoroacetic acid (1.2 mmol), followed by heating at reflux.
JO802325X
422 J. Org. Chem. Vol. 74, No. 1, 2009