Synthesis of N-styrenyl amidines from α,β-unsaturated nitrones and isocyanates through CO2 elimination and styrenyl migration

Article abstract of DOI:10.1021/ol501503a

A mild, metal-free, and modular route for the preparation of N-styrenyl amidines from N-aryl-α,β-unsaturated nitrones and isocyanates has been developed that accesses an initial oxadiazolidinone intermediate that can undergo CO₂ elimination and styrenyl migration. The use of a migration event to install N-styrenyl amidine substituents circumvents a limitation of traditional Pinner-type methods for amidine synthesis that require the use of amine nucleophiles. The modularity of the nitrone and isocyanate reagents provides access to a variety of differentially substituted N-styrenyl amidines. The scope and tolerance of the method are presented, and preliminary mechanistic data for the transformation are discussed.

Full text of DOI:10.1021/ol501503a

Letter
pubs.acs.org/OrgLett
Synthesis of N‑Styrenyl Amidines from α,β-Unsaturated Nitrones and
Isocyanates through CO2 Elimination and Styrenyl Migration
Dong-Liang Mo, Wiktoria H. Pecak, Meng Zhao, Donald J. Wink, and Laura L. Anderson*
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: A mild, metal-free, and modular route for the
preparation of N-styrenyl amidines from N-aryl-α,β-unsatu-
rated nitrones and isocyanates has been developed that
accesses an initial oxadiazolidinone intermediate that can
undergo CO2 elimination and styrenyl migration. The use of a
migration event to install N-styrenyl amidine substituents
circumvents a limitation of traditional Pinner-type methods for
amidine synthesis that require the use of amine nucleophiles. The modularity of the nitrone and isocyanate reagents provides
access to a variety of differentially substituted N-styrenyl amidines. The scope and tolerance of the method are presented, and
preliminary mechanistic data for the transformation are discussed.
further synthetic manipulation of amidine 2 to result in the
midines are important functional groups that are present
Ain a variety of biologically active molecules and are synthesis of barrenazine alkaloids 3. Recently, Ashfeld and co-
commonly used as precursors to heterocyclic compounds.1−3
workers discovered a novel Staudinger ligation and Beckmann
rearrangement cascade process for the synthesis of phosphor-
amidic acid ester-substituted amidines, which can be used to
access N-alkenyl amidines such as 5 through a Beckman-like
migration event.7 As part of our program aimed at exploiting
the reactivity of α,β-unsaturated-N-aryl nitrones, we have
discovered that N-styrenyl amidines 9 can be generated from
nitrone 6 via an oxadiazolidinone intermediate 8 that
undergoes CO2 elimination and styrenyl migration.8 This
transformation can be used to synthesize a variety of N-aryl-N-
styrenyl amidines with a range of N′-substitution patterns due
to the modularity of the nitrone and isocyanate reagents.
Herein we discuss the scope and tolerance of this new method
for the rapid generation of N-styrenyl amidines from simple
reagents under mild and metal-free conditions.
Amidines are traditionally prepared by transformations related
to the Pinner reaction that involve the addition of an amine to
an activated nitrile or imidate moiety.4,5 Due to the
requirement of an amine nucleophile, these strategies make
N-alkenyl amidines challenging to prepare; however, access to
N-alkenyl amidines is synthetically appealing due to their
potential for further functionalization. For example, Charette
and co-workers previously showed that amidine 2 could be
generated from pyridinium 1 through a Grignard addition
(Scheme 1a).6 This vinylogous amide functionality allowed for
Scheme 1. Synthesis of N-Alkenyl Amidines
The synthesis of oxadiazolidinone 8a was initially observed
upon treatment of nitrone 6a with isocyanate 7a at 80 °C in
THF (Table 1, entry 1).9 Surprisingly, when the same reagents
were mixed in toluene and heated to 80 °C, amidine 9a was
isolated as the sole product in 90% yield (Table 1, entry 2).10
Further screening of solvents showed that DCE also favored
the exclusive formation of 9a in slightly attenuated yield and
mixtures of 8a and 9a could be isolated from reactions run in
MeCN or DMSO (Table 1, entries 3−5). Increased reaction
times in MeCN or DMSO led to the exclusive formation of
9a.11 Variation of reaction temperature affected both the
chemoselectivity and efficiency of the process. While only 9a
was observed for reactions run in toluene from 60−100 °C,
mixtures of 8a and 9a were observed at lower temperatures
(Table 1, entries 2 and 6−9). The yield for the amidine
Received: May 24, 2014
Published: July 8, 2014
© 2014 American Chemical Society
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Table 1. Optimization of Amidine Synthesis
Table 2. Scope of Nitrone Reagent for Amidine Synthesis
a
a
entry
solvent
t (°C)
yield (%)
8a/9a
1
2
3
4
5
6
7
8
9
THF
80
80
80
80
80
100
60
40
25
80
90
83
only 8a
only 9a
only 9a
PhMe
DCE
b
b
MeCN
DMSO
PhMe
PhMe
PhMe
81
3:1
c
c
40
3:1
77
88
74
49
only 9a
only 9a
1:2
PhMe
1:2
a
1
Determined by H NMR spectroscopy using CH2Br2 as a reference:
b
c
6a (1 equiv), 7a (2 equiv), 0.1 M, 18 h. 36 h, 75%, only 9a. 36 h,
59%, only 9a.
synthesis was optimal for reaction temperatures between 60
and 80 °C but decreased at both higher and lower
temperatures. When oxadiazolidinone 8a was dissolved in
toluene and heated to 80 °C, amidine 9a was isolated in almost
quantitative yield (eq 1). This experiment correlated with the
longer reaction time results determined for MeCN and DMSO,
as well as the reaction temperature data for toluene, and
suggested that 8a is an intermediate along the pathway for
conversion of 6a to 9a. With optimal conditions for the
preparation of N-styrenyl amidine 9a in hand, the scope of the
method was further examined.
The synthesis of N-styrenyl amidines 9 from N-aryl-α,β-
unsaturated nitrones 6 and phenylisocyanate 7a was shown to
tolerate a variety of different substitution patterns on the
nitrone component of the reaction mixture.12,13 As shown in
Table 1, nitrones with both electron-rich and electron-deficient
aryl groups at the R3-position gave the corresponding amidines
in high yield (Table 2, entries 1−7). Tolerance for
functionalizable groups such as nitro and halogen substituents,
as well as substitution at the 2-, 3-, and 4-positions of the arene,
broadened the synthetic applicability of the method. In addition
to arenes, furanyl and styrenyl groups were also tolerated at the
R3-position and were smoothly converted to the corresponding
N-(2-vinylfuranyl) and N-dienyl amidines 9h and 9i,
respectively (Table 2, entries 8−9). Arene substitution at the
R1-position was shown to be more sensitive to electronic effects
than the R3-position. p-Tolyl substituted nitrone 6j gave
amidine 9j in an attentuated yield, while p-CF3-substituted 6k
proceeded smoothly to give 9k (Table 2, entries 10−11). When
a p-OMe-substituted arene was tested at the R1-position only a
trace amount of product was observed.14 In contrast to these
limitations, H, Me, and styrenyl groups were well-tolerated at
the R1-position and gave amidines 9l−9n in good yields (Table
2, entries 12−14). The R2-position of the nitrone can be
substituted with a methyl group as illustrated for 9o and
indicated that the scope of the amidine synthesis also includes
β-substituted styrenyl groups (Table 2, entry 15). In addition to
a
% Isolated yield. Conditions: 6 (1 equiv), isocyanate 7a (2 equiv), 0.1
M in PhMe, 80 °C, 18 h.
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changing the substituents on the carbon chain of the nitrone,
the N-aryl substituents were also varied. This functionality
tolerated halogen, 3-OMe, 3,5-Me2, vinyl, and naphthyl
substitution patterns all in good yield (Table 2, entries 16−
22).15 The results described in Table 2 showcase the generality
of the method for the synthesis of a range of N-styrenyl
amidines from a variety of α,β-unsaturated nitrones.
Scheme 2. Proposed Mechanism and Mechanistic
Experiments
Table 3. Scope of Isocyanate Reagent for Amidine Synthesis
a
b
entry
R
conditions
no.
yield (%)
1
2
7b, p-OMe(C6H4)
7c, p-CF3(C6H4)
7d, p-I(C6H4)
7e, p-F(C6H4)
7f, 1-naphthyl
7g, 2-Br(C6H4)
7h, p-Cl(C6H4)SO2
7i, Fmoc
A
A
A
A
A
A
A
B
C
C
10
11
12
13
14
15
16
17
18
19
51
45
75
72
83
66
61
64
75
84
3
4
5
6
7
8
9
7j, Bn
10
7k, allyl
a
Conditions A: 6a (1 equiv), 7b−7g, 7i (2−4 equiv), 0.1 M in PhMe,
addition and rearrangement of 6b with 7a was run in the
presence of 6p. This experiment suggests that solvent-separated
intermediates are not involved in the CO2 elimination and
migration process. A competition experiment was also designed
to probe whether the geometry of the nitrone or the electronic
nature of the styrenyl group affected the migratory aptitude of
the substrate. As shown in Scheme 2c, a distinct electronic
effect was observed when dibenzylidene acetone derived
nitrones 6w and 6x were treated with 7a. The p-OMe-
substituted styrenyl group of 6w migrated in preference to the
unsubstituted styrenyl group, while the unsubstituted styrenyl
group of 6x migrated in preference to the p-CF3-substituted
styrenyl group. These results indicate that the reactive
intermediate that precedes the migration must exhibit electro-
philic character at the N-atom derived from the nitrone and
that the styrenyl group migrates as a nucleophilic species. Since
both 6w and 6x were subjected to the reaction conditions as 1:1
mixtures of E/Z isomers, these results further suggest that the
geometry of the nitrone does not affect the migratory
preference of the nitrone substituents. This result is in contrast
to the Beckman-type rearrangement, observed by Ashfeld and
co-workers for the synthesis of N-phosphoramide-substituted
amidines from oximes, sulfonyl azides, and chlorophosphites.7
To test the synthetic utility of the enamine functionality of
the N-alkenyl amidines, we decided to use dienyl amidine 9i as
a cycloaddition substrate. As shown in Scheme 3, this
compound smoothly undergoes a [4 + 2] cycloaddition
reaction with dimethylacetylene dicarboxylate (DMAD) to
give the cycloadduct 20. This experiment illustrates the use of
80 °C, 18 h. Conditions B: 6a (1 equiv), 7h (4 equiv), 0.1 M in DCE,
80 °C, 18 h. Conditions C: 6a (1 equiv), 7j−7k (4 equiv), 0.1 M in
b
PhMe, 80 °C, 18 h, then AlCl3 (10 mol %), 25 °C, 4−18 h.
%
Isolated yield.
In addition to exploring the scope of the nitrone component
of the amidine synthesis, the tolerance for the isocyanate
reagent was also investigated. As shown in Table 3, several aryl
isocyanates smoothly underwent the addition and rearrange-
ment with 6a to give N-styrenyl amidines 10−15 (Table 3,
entries 1−6). These transformations were more efficient for
halogen-substituted aryl and naphthyl isocyanates 7d−7f than
4-OMe- and 4-CF3-substituted aryl isocyanate reagents 7b−7c.
To our delight, the scope of the amidine synthesis included not
only aryl isocyanates but also sulfonyl-, carbamate-, and alkyl-
substituted reagents (Table 3, entries 7−10). While sulfonyli-
socyanate 7h underwent the amidine synthesis when subjected
to standard reaction conditions, improved yields were observed
for Fmoc isocyanate 7i when the transformation was run in
DCE. Benzyl and allyl isocyanate reagents required the addition
of 10 mol % AlCl3 to facilitate CO2 elimination and styrenyl
migration from the corresponding oxadiazolidinones. Addition
of this Lewis acid rapidly provided the desired products 18 and
19 in good yield. Having determined the generality of the
method for the preparation of N-styrenyl amidines, we next
examined the mechanism of the transformation.
A proposed mechanism for the synthesis of N-styrenyl
amidine 9a from N-aryl nitrone 6a is illustrated in Scheme 2.
The addition of nitrone 6a to isocyanate 7a gives heterocycle
8a, which can then undergo a subsequent CO2 elimination and
styrenyl migration to give 9a. The intermediacy of
oxadiazolidinone 8a in the synthesis of 9a is supported by
the independent conversion of 8a to 9a as illustrated in eq 1. In
order to gain a better understanding of the CO2 elimination
and styrenyl group migration steps, we decided to test two
other product-based mechanistic experiments. As shown in
Scheme 2b, no crossover products were observed when the
Scheme 3. Functionalization of N-Dienyl Amidine 9i
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Y. Chem.Eur. J. 2013, 19, 1496. (c) Alla, S. K.; Kumar, R. K.; Sadhu,
P.; Punniyamurthy, T. Org. Lett. 2013, 15, 1334. (d) McGowan, M. A.;
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(g) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48,
348. (h) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932.
(4) For examples of amidine syntheses related to the Pinner reaction,
see: (a) Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; Wiley: New York, 1991. (b) Dunn, P. J.
Amidines and N-Substituted Amidines. In Comprehensive Organic
Functional Group Transformations II; Katritzky, A. R., Taylor, R. J. K.,
Eds.; Elsevier: New York, 2005; Vol. 5, pp 655−699. (c) Wang, J.; Xu,
F.; Cai, T.; Shen, Q. Org. Lett. 2008, 10, 445. (d) Katritzky, A. R.; Cai,
C.; Singh, S. K. J. Org. Chem. 2006, 71, 3375.
(5) For other examples of amidine syntheses that require the use of
nucleophilic amines, see: (a) DeKorver, K. A.; Johnson, W. L.; Zhang,
Y.; Hsung, R. P.; Dai, H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org.
Chem. 2011, 76, 5092. (b) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc.
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A.; Hoerter, J. M.; Guzei, I. A.; Cui, Q.; Gellman, S. H.; Stahl, S. S. J.
Am. Chem. Soc. 2007, 129, 1776.
the amidine synthesis described above as a simple method for
accessing functionalizable amidines that can be easily converted
to more complicated compounds through the reactivity of the
enamine functionality. The fact that compound 20 is
structurally similar to cyclohexene nucleoside analogues
suggests that these transformations may be applicable to a
variety of medicinal targets.16
In summary, we have discovered a new method for the
synthesis of N-styrenyl amidines by the addition of α,β-
unsaturated nitrones to isocyanates. This transformation
provides a new route to N-alkenyl amidines which are
challenging to access by traditional methods for amidine
synthesis. Preliminary mechanistic studies suggest that this
transformation proceeds through an initial cycloaddition of a
nitrone to an isocyanate to form an oxadiazolidinone followed
by a subsequent CO2 elimination and styrenyl migration.
Ongoing studies in our lab are aimed at expanding the scope of
the migratory alkenyl group through a better understanding of
the mechanism for CO2 elimination and migration, as well as
developing synthetic applications that exploit N-styrenyl
amidines as synthetic intermediates.
(6) Focken, T.; Charette, A. B. Org. Lett. 2006, 8, 2985.
(7) Fleury, L. M.; Wilson, E. E.; Vogt, M.; Fan, T. J.; Oliver, A. G.;
Ashfeld, B. L. Angew. Chem., Int. Ed. 2013, 52, 11589.
ASSOCIATED CONTENT
* Supporting Information
■
S
(8) (a) Mo, D.-L.; Wink, D. A.; Anderson, L. L. Org. Lett. 2012, 14,
5180. (b) Mo, D.-L.; Anderson, L. L. Angew. Chem., Int. Ed. 2013, 52,
6722.
(9) For examples of [3 + 2] cycloaddition of nitrones and isocyanates
to form oxadiazolidinones, see: (a) Ritter, T.; Carreira, E. M. Angew.
Chem., Int. Ed. 2005, 44, 936. (b) Bell, A. M. T.; Bridges, J.; Cross, R.;
Falshaw, C. P.; Taylor, B. F.; Taylor, G. A.; Whittaker, I. C.; Begley, M.
J. J. Chem. Soc., Perkin Trans. 1 1987, 2593.
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lauralin@uic.edu.
Notes
(10) Structural assignment of 9a was verified by X-ray crystallog-
raphy: CCDC 1004695.
(11) When the transformation was run in THF for 36 h, only 8a was
observed. The THF did not contain an inhibitor.
The authors declare no competing financial interest.
(12) Nitrones 6a−6m and 6o−6v were prepared as a >95:5 mixture
of E/Z isomers and separated by chromatography to give only the E-
isomer. See ref 8b and the Supporting Information for details. Nitrone
6n was prepared as a 4:1 mixture of E/Z isomers as described in:
Hood, T. S.; Huels, C. B.; Yang, J. Tetrahedron Lett. 2012, 53, 4679.
(13) Diagnostic styrenyl 1H NMR resonances match spectral data for
N-aryl-N-electron-withdrawing group substituted enamines. See:
Nocquet-Thibault, S.; Retailleau, P.; Cariou, K.; Dodd, R. H. Org.
Lett. 2013, 15, 1842.
ACKNOWLEDGMENTS
■
We acknowledge generous funding from ACS-PRF (DNI-
50491), NSF (NSF-CHE 1212895), and the University of
Illinois at Chicago. We also thank Prof. T. Driver (UIC) for
insightful discussions and Mr. Furong Sun (UIUC) for mass
spectrometry data.
REFERENCES
■
(14) No starting material was recovered, no evidence of aryl
migration was observed, and only decomposition products were
isolated.
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