Direct imine acylation: Rapid access to diverse heterocyclic scaffolds

Article abstract of DOI:10.1021/ol303073b

A simple and efficient procedure to prepare a range of diverse heterocycles by the direct acylation of imines using a variety of functionalized benzoic acids is described. The methodology features a novel method for N-acyliminium ion generation followed by in situ intramolecular trapping by oxygen-, nitrogen-, sulfur-and carbon-based nucleophiles. Preliminary mechanistic studies, using ReactIR, are also reported.

Full text of DOI:10.1021/ol303073b

ORGANIC
LETTERS
2013
Vol. 15, No. 2
258–261
Direct Imine Acylation: Rapid Access to
Diverse Heterocyclic Scaffolds
William P. Unsworth, Christiana Kitsiou, and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U. K.
richard.taylor@york.ac.uk
Received November 8, 2012
ABSTRACT
A simple and efficient procedure to prepare a range of diverse heterocycles by the direct acylation of imines using a variety of functionalized
benzoic acids is described. The methodology features a novel method for N-acyliminium ion generation followed by in situ intramolecular trapping
by oxygen-, nitrogen-, sulfur- and carbon-based nucleophiles. Preliminary mechanistic studies, using ReactIR, are also reported.
New methods for the synthesis of polycyclic heterocycles
are invaluable in the pharmaceutical and agrochemical
industries.1 The potential of such methodology is at its
greatest when it facilitates the synthesis of a diverse range
of substrate classes, is high yielding and operationally
simple, and results in a rapid increase in molecular com-
plexity from simple readily available starting materials.2,3
We report a novel scaffold diversity approach built
around the concept of direct imine acylation (DIA) as
illustrated in Scheme 1. It was planned that acylation of an
imine (1) with a suitably functionalized carboxylic acid (2)
would generate an N-acyliminium ion (3) in anticipation
that a nucleophile or pronucleophile built into the acid
coupling partner would initiate in situ cyclization. We now
report the successful implementation of the DIA approach
using functionalized benzoic acids to generate a range of
diverse heterocycles (4).
Scheme 1. Direct Imine Acylation
The use of N-acyliminium ions in heterocycle synthesis is
well documented,4 but in the vast majority of examples, the
N-acyliminium species are generated from preformed sys-
tems, usually by a regioselective partial imide reduction or
a regioselective amide oxidation.4 The key advantage to
our convergent approach is the direct use of a carboxylic
acid (rather than activated derivatives)5,6 in N-acylimi-
nium generation allowing a range of ortho-functional
groups to be tolerated. The ready availability of starting
materials and the convergent nature of the process gives
DIA great potential, particularly with regards to diversity-
oriented synthesis.2
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (b) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford,
2008 and references therein.
(2) (a) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A.
Angew. Chem., Int. Ed. 2009, 48, 104. (b) Spandl, R. J.; Bender, A.;
Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149. (c) Lipkus., A. R.;
Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F., III; Schenck, R. J;
Trippe, A. J. J. Org. Chem. 2008, 73, 4443.
(3) (a) Taylor, R. J. K.; Reid, M.; Foot, J. S.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851. (b) Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc.
2004, 126, 12260. (c) Klein, J. E. M. N.; Perry, A.; Pugh., D. S.; Taylor,
R. J. K. Org. Lett. 2010, 12, 3446 and references therein.
(4) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 1985.
4367. (b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817. (c) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431.
(5) For early examples using acid chlorides, acyl fluorides, anhy-
drides, etc., see (a) Ziegler, E.; Hanus, H. D. Monatsh. Chem. 1965, 96,
411. (b) Ziegler, E.; Kollenz, G.; Kappe, T. Monatsh. Chem. 1968, 99,
804. (c) Kametani, T.; Higa, T.; Van Loc, C.; Ihara, M.; Koizumi, M.;
Fukumoto, K. J. Am. Chem. Soc. 1976, 98, 6186. (d) Castagnioli, N., Jr.
J. Org. Chem. 1969, 34, 3187.
r
10.1021/ol303073b
Published on Web 12/24/2012
2012 American Chemical Society

The viability of the DIA concept was established
using the novel cyclic imine 1a and the benzoic acid 2a
(Scheme 2). Propylphosphonic acid anhydride (T3P, 5)7 in
toluene was chosen to effect the direct coupling, as it is
nontoxic and the byproducts are easily removed by aque-
ous extraction.8
Table 1. Acid Scope in Direct Imine Acylation/Cyclizationa
Scheme 2. Reaction of Imine 1a with Acid 2a
We were delighted to observe the efficient formation of
tricyclic lactam 4a in 84% yield after chromatography.
Additional experiments in which the same coupling was
attempted in the absence of either DIPEA or T3P led only
to the recovery of the starting materials, with no evidence
of the cyclized product 4a.
We then went on to explore DIA using a range of
substituted benzoic acid derivatives (2bÀ2h, Table 1). As
can be seen, salicylic acid derivatives are extremely well
tolerated, affording products in excellent yields (Table 1,
entries iÀvi).9 The DIA methodology is not restricted to
the trapping of the intermediate N-acyliminium salt with
carbon and oxygen nucleophiles. For example, under the
standard T3P conditions, treatment of imine 1a with
thiosalicylic acid 2g gave thiazinone 4g (entry vii), and
N-methyl anthranilic acid 2h underwent cyclization to the
diazine 4h (entry viii), both in near quantitative yields. The
final example in Table 1 (entry ix) illustrates that the DIA
concept need not be limited to acylation, as demonstrated
by the formation of sulfonamide-containing dioxo(dihydro)-
benzoxathiazine 7 from reaction of imine 1a with commer-
cially available sulfonyl chloride 6.
We next went on to confirm that the scope of this meth-
odology is equally versatile in terms of the imine substrate
(Table 2). First, 3,4-dihydroisoquinoline (1b) gave adducts
4i and 4j in reasonable and excellent yields, respectively
(entries i and ii); this substructure features heavily in
natural products and in pharmaceutically important com-
pounds,10 and applications of this DIA sequence in target
synthesis are anticipated. Further diversity can be achieved
a Unless stated, reactions were performed on a 0.1À0.3 mmol scale
using T3P, DIPEA in PhMe at 90 °C for 20 h. b Isolated yields after
purification by column chromatography. c Reaction performed in the
absence of T3P gave 0% yield of product. d Reaction performed in the
absence of DIPEA gave 0% yield of product. e Reaction performed on a
3 mmol scale under the standard conditions. f Reaction performed in the
absence of T3P gave 20% yield of product. g Compound 6 was stirred
with imine 1a and DIPEA in PhMe at 90 °C for 20 h.
(6) For more recent examples using acid chlorides, acyl fluorides,
anhydrides, etc., see (a) Strumberg, D.; Pommier, Y.; Paull, K.; Jayara-
man, M.; Nagafuji, P.; Cushman, M. J. Med. Chem. 1999, 42, 446. (b)
Sieck, O.; Ehwald, M.; Liebscher, J. Eur. J. Org. Chem. 2005, 4, 663. (c)
Chen, Z.; Hu, G.; Chen, J.; Li, D.; Chen, J.; Li, Y.; Zhou, H.; Xie, Y.
Bioorg. Med. Chem. 2009, 17, 2351. (d) Johannes, K.; Martens, J.
Tetrahedron 2010, 66, 242 and references therein.
by varying the ring size of the imine, as demonstrated
by the DIA reaction of the disubstituted 1-pyrroline 1c
affording adduct 4k in excellent yield (entry iii).
Synthetic applications of acyclic N-acyliminium salts
are limited as they are much less stable than their cyclic
analogues, particularly with respect to hydrolysis.4,11
(7) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. 1980, 19, 133.
(8) Successful coupling was also achievedusing T3P, HATU or DCC,
each with DIPEA, in refluxing CHCl3 or toluene at 90 °C.
(9) After the completion of this work, a single example of N-acyliminium
ion formation by direct carboxylic acid coupling to imines was reported using
DCC/DMAP to couple a substituted benzoic acid to dihydrocarboline: Pin,
.
F.; Comesse, S.; Daιch, A. Tetrahedron 2011, 67, 5564.
(10) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341 and references therein.
€
(11) Bohme, H.; Hartke, K. Chem. Ber. 1963, 96, 600.
Org. Lett., Vol. 15, No. 2, 2013
259

coupling with anthranilic acid 2h, overcoming loss of
aromaticity,13 toaffordthe tetracyclic nitrogen heterocycle
4o in 94% yield. This example indicates that DIA will not
be limited tosimple imines. It should also be noted that, for
comparison purposes, all reactions were carried out using
the standard conditions and that optimization should lead
to an increase in yield in the majority of cases.
Table 2. Imine Scope in Direct Imine Acylation/Cyclizationa
Two extreme mechanistic pathways could be envisaged
for these processes: (i) N-acylation takes place first and is
followed by an intramolecular cyclization (as we have
assumed, Scheme 1), or (ii) nucleophilic addition of the
ortho-substituent onto the imine occurs first, followed by
intramolecular acylation. An added complication is that
imino-ketene intermediates have been proposed for the
acylation step in related anthranilic acid processes.5c,6d Of
course, it is not unreasonable that the exact mechanism is
substrate-dependent, or that more than one mechanism
may operate in competition. However, the fact that no
reaction occurs with most examples in the absence of the
T3P coupling agent provides corroboration for the theory
that the initial step involves N-acylation of the imine.14 To
shed more light on the process, an in situ ReactIR study
was carried out to study the DIA reaction of imine 1a with
5-nitro-salicylic acid 2c.15 A more detailed analysis is
included in the Supporting Information, but this ReactIR
study rules out a ketene intermediate and is consistent with
a process involving (i) rapid carboxylic acid activation, (ii)
imine N-acylation generating a short-lived N-acyliminium
ion 3c (Peak 1, Figures 1 and 2), (iii) reversible trapping of
the iminium intermediate by excess DIPEA in the reaction
mixture, affording an ammonium salt 8 (Peak 2, Figures 1
and 2), and (iv) regeneration of the N-acyliminium inter-
mediate 3c and cyclization to give the product 4c (Peak 3,
Figures 1 and 2).
a Reactions were performed on a 0.1À0.3 mmol scale using T3P,
DIPEA in PhMe at 90 °C for 20 h. b Isolated yields after purification by
column chromatography. c Imine 1f was generated by deoligomerization
of dodecahydro-4a,8a,12a-triazatriphenylene in situ.
DIA technology overcomes this problem by forming and
trapping the unstable N-acyliminium ions in situ, and so acylic
imines 1d and 1e undergo DIA reactions giving adducts 4l
and 4m (entries iv and v). Dodecahydro-4a,8a,12a-triaza-
triphenylene, the trimericformof imine1f,12 wasemployed
directly in a DIA procedure with anthranilic acid 2h to
produce diazine 4n (entry vi), demonstrating that even
unstable imines, which are prone to oligomerization and
enamine formation, can be compatible with the DIA
protocol. Finally (entry vii), we demonstrated that isoqui-
noline (1g) could be successfully employed in a DIA
Figure 1. 3D ReactIR plot of atomic absorption against wave-
number and time.
(13) Sieck, O.; Ehwald, M.; Liebscher, J. Tetrahedron Lett. 2000, 29,
5479.
€
(12) (a) Schopf, C.; Komzak, A.; Braun, F.; Jacobi, E.; Bormuth,
M.-L.; Bullnheimer, M.; Hagel, I. Liebigs Ann. 1948, 559, 1. (b) Barker,
G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.;
O’Brien, P. J. Org. Chem. 2011, 76, 5936.
(14) With thiosalicylic acid 2g (Table 1, entry vi) a small amount
(20%) of coupled product 4g was observed in the absence of T3P, and so
some intermolecular imine addition may be taking place in this system.
260
Org. Lett., Vol. 15, No. 2, 2013

Scheme 3. Application of DIA to Prepare Evodiamine
for the N-acylation is important in this regard, as they have
been shown to be compatible with unprotected nucleo-
philes, which may not survive the typically much harsher
conditions used in most of the existing procedures for
N-acyliminium ion generation. The potential substrate
scope is very large, and in most cases the isolated yields
were found to be very high under identical conditions,
suggesting that diverse targeted libraries of compounds
should be readily synthesized using DIA, requiring little or
no optimization. It is also worth noting that while for the
purpose of the publication, column chromatography was
used to ensure analytically pure products were obtained,
in the majority of cases no discernible byproducts from
the reagents, or reaction side-products, were observable
Figure 2. 2D ReactIR plot of atomic absorption units of the
wavenumbers 1786, 1668 and 1684 cmÀ1 against time.
Finally, the value of DIA has been illustrated by the
rapid and efficient synthesis of evodiamine (9), a natural
product isolated from Evodiae fructus.16 Evodiamine has
been shown to reduce fat uptake in animal studies16b and
has been included in some dietary preparations, particularly
in the Chinese herbal weight loss supplement, Wu-Chu-Yu.
More recently, it has been demonstrated that evodiamine is
a novel inhibitor of human DNA topoisomerase I.16c Start-
ing from dihydrocarboline 1h,17 treatment with N-methyl
anthranilic acid 2h and T3P under standard DIA conditions
produced evodiamine (9) in a one-pot process in 95% yield
as a crystalline product (Scheme 3).
In summary, DIA methodology has been shown to be a
reliable and versatile tool for the synthesis of a range of
polycyclic heterocyclic scaffolds. The procedure uses read-
ily available nontoxic reagents, is operationally simple and
is relatively insensitive to both water and air. Crucially, the
in situ generation and trapping of the transient N-acylimi-
nium ion avoids the need to isolate unstable N-acylimi-
nium ion precursors. The mild nature of the reagents used
1
in the H NMR spectra of the unpurified products. We
are confident that in time the reactions described will be
further optimized and augmented with new variants, as
well as finding use in target synthesis.18
Acknowledgment. The authors thank the EPSRC for
postdoctoral support (W.P.U., EP/G068313/1), the Uni-
versity of York Wild Fund for a PhD bursary (C.K.), the
University Strategic Equipment Fund for the ReactIR
purchase, James. D. Firth (University of York) for assis-
tance with the IR studies and Prof. Peter O’Brien
(University of York) for helpful advice.
Supporting Information Available. Synthetic proce-
dures, ReactIR details and spectral data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(15) Acid 2c was chosen, as this substrate was found to be particularly
reactive; a lower temperature was needed to be compatible with the
ReactIR probe, and this reaction proceeded efficiently in 1 h at 50 °C.
(16) (a)Nakasato, T.;Asada., S.;Murai., K.J. Pharm. Soc. Jpn. 1962, 82,
619. (b) Kobayashi, Y.; Nakano, Y.; Kizaki, M.; Hoshikuma, K.; Yokoo, Y.;
Kamiya, T. Planta Med. 2001, 67, 628. (c) Dong, G.; Sheng, C. S.; Wang, S.;
Miao, Z.; Yao, J.; Zhang, W. J. Med. Chem. 2010, 53, 7521.
(18) Unsworth, W. P.; Gallagher, K. A.; Jean, M.; Schmidt, J. P.;
Diorazio, L. J.; Taylor, R. J. K. Org. Lett. 2012, DOI: dx.doi.org/10.1021/
ol3030764.
(17) Nicolaou, K. C.; Mathison, C. J. N.; Maonagnon., T. Angew.
Chem., Int. Ed. 2003, 42, 4077.
The authors declare no competing financial interest.
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