A 1,3-amino group migration route to form acrylamidines

Article abstract of DOI:10.1039/c3cc47182a

A novel 1,3-amino group migration strategy for the synthesis of acrylamidines is presented. Cu(i) catalyzed reaction of N,N-disubstituted propargylamine with tosylazide generates a highly reactive ketenimine intermediate which is trapped by a tethered amino group leading to the rearrangement reaction.

Full text of DOI:10.1039/c3cc47182a

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A 1,3-amino group migration route to form
acrylamidines†
Cite this: Chem. Commun., 2014,
50, 323
Dinesh Pratapsinh Chauhan, Sreejith Jayasree Varma, Arjun Vijeta, Pallavi Banerjee
and Pinaki Talukdar*
Received 19th September 2013,
Accepted 30th October 2013
DOI: 10.1039/c3cc47182a
www.rsc.org/chemcomm
A novel 1,3-amino group migration strategy for the synthesis of acryl-
Herein, we report the reaction of the in situ generated
amidines is presented. Cu(I) catalyzed reaction of N,N-disubstituted ketenimine with a tethered amino nucleophile to form acrylamidine
propargylamine with tosylazide generates a highly reactive ketenimine via the 1,3-migration of the amino group (Scheme 1B). Acrylamidine17
intermediate which is trapped by a tethered amino group leading to the is an important skeleton for atropisomerism studies.18 It is also a
rearrangement reaction.
synthetic precursor of amidine which is present in various bioactive
compounds,19 e.g. selective muscarinic agonists,20 NR2B subtype-
Click chemistry,1 primarily known for the synthesis of triazoles via the selective antagonists,21 etc. Considering the wide synthetic appli-
copper-catalyzed cycloaddition reaction between alkyl or aryl azides cability of amidine,19,22 the a,b-unsaturation can be viewed as a
and terminal alkynes,1a,2,3 has provided colossal applications in the handle for various chemical transformations e.g. epoxidation, hydrox-
fields of bioconjugation,4 materials science,5 and drug discovery.2a,6 ylation, CQC cleavage, Michael addition, etc. In 2005, Chang and
Soon after its discovery, a novel feature of triazole as a N2 releasing coworkers reported nucleophilic addition of water to ketenimine
source was disclosed.7 In particular, either sulfonyl azides7b or bearing a tethered –NHBoc group to form the corresponding
phosphoryl azides8 were demonstrated to react with terminal alkynes b-amino sulfonamide.10 We envisaged the potential of the tethered
under mild Cu(I)-catalytic conditions to form a highly reactive amino group to undergo 1,3-shift if it is made sufficiently nucleophilic
ketenimine intermediate which instantaneously participates in because Wentrup et al. have reported a ketenimine–ketene rearrange-
nucleophilic addition reactions9 with amines,7b water,10 alcohols,11 ment mediated by a flanking amino group under flash vacuum
pyrroles,12 indoles,12,13 ammonium salts,14 etc. (Scheme 1A). This thermolysis conditions.23 However, Cu(I)-catalytic formation of kete-
three-component approach was further extended to the four- nimine is advantageous to investigate the 1,3-shift under milder
component version by the introduction of either strong electrophiles reaction conditions.
e.g. aldehyde15 or Michael acceptors e.g. nitro olefins.16
The results are shown in Table 1. When N,N-dibenzyl-
propargylamine 1 was treated with 1.1 equivalents of tosylazide in
CHCl3 under open air conditions in the presence of a CuI catalyst
(10 mol%) and Et3N base at room temperature, the reaction
proceeded up to 30 minutes, forming acrylamidine 2 in 84% yield
(entry 1). The structure of 2 was confirmed by NMR (Fig. S50 and
S51, ESI†) and single crystal X-ray diffraction studies (Fig. S1, ESI†).
Table 1 Cu(I)-catalyzed formation of acrylamidine 2
Scheme 1 Participation of ketenimine in addition reaction with an external
nucleophile (A) and 1,3-migration of a tethered nucleophile (B).
Entry
Catalyst
Solvent
Base
Time (min)
Yield (%)
Department of Chemistry, Mendeleev Block, Indian Institute of Science Education
and Research, Pune, India. E-mail: ptalukdar@iiserpune.ac.in;
1
2
3
4
5
6
CuI
CuBr
CuCl
—
CuCl
—
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Et3N
Et3N
Et3N
—
—
Et3N
30
3
3
30
30
30
84
95
96
0
60
0
Fax: +91 20 2589 9790; Tel: +91 20 2590 8001
† Electronic supplementary information (ESI) available: Experimental proce-
dures, supplementary data, and the 1H-, 13C-NMR spectra. CCDC 932111–
932113 and 933156. For ESI and crystallographic data in CIF or other electronic
format, see DOI: 10.1039/c3cc47182a
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Table 2 Scope of the 1,3-amino group migration strategy
Introduction of a CuBr catalyst (10 mol%) facilitated the reaction
within 3 minutes and improving the yield to 95% (entry 2). A further
alteration of the catalyst to CuCl (10 mol%) resulted in 96% yield of 2
(entry 3). Formation of 2 was not favored in the absence of CuCl
confirming the importance of the catalyst (entries 4 and 6). The
catalytic reaction when carried out in the absence of Et3N proceeded
for 30 minutes and furnished 2 with only 60% yield (entry 5).
To establish the scope of methodology, the optimized conditions
were applied to a wide range of propargylamines 3a–3j having alkyl
substitution (R = alkyl) at the C1-position and acyclic amino groups
(–NR0R00) to deliver corresponding acrylamidines 4a–4j (Table 2,
entries 1–10). The effect of different R groups was studied by keeping
fixed –NR0R00 = –NBn2 and no significant difference was observed
upon variation of the group through ethyl (entry 1, yield = 96%),
butyl (entry 2, yield = 91%), cyclohexyl (entry 3, yield = 91%) and
(S)-2,2-dimethyl-1,3-dioxolane (entry 4, yield = 95%). A subsequent
modification of the amino group (–NR0R00 = –NEt2) did not affect the
time and yields of reactions. Excellent yields of 95%, 96%, 96% and
89% for R = Et (entry 5), Bu (entry 6), cyclohexyl (entry 7) and
(S)-2,2-dimethyl-1,3-dioxolane (entry 8), respectively, were observed.
Introduction of an unsymmetrical amino group (–NR0R00 = –NMeBn)
also did not affect the yield of the acrylamidine 4i (entry 9, yield =
93%). When the effect of neighboring nucleophilic groups was
evaluated by introducing a di-hydroxy containing R-group, the
desired product 4j was obtained in moderate 60% yield (entry 10).
However, no byproduct that corresponds to the attack of an alcohol
nucleophile on a ketenimine intermediate was isolated.
On the basis of these findings, we explored the effect of cyclic
amino groups such as pyrrolidine, piperidine and morpholine in the
formation of acrylamidines. It was found that reactions of propargyl-
amines 3k–3r with tosylazide were relatively slow (reaction time =
15–20 min) under the optimized conditions using CuCl (Table 2,
entries 11–18). When pyrrolidine containing propargylamines, 3k and
3l were used, moderate yields of 4k (58%) and 4l (70%), respectively,
were observed (entries 11 and 12). For piperidine ring containing
propargylamines 3m, 3n and 3o isolated yields were significantly low,
i.e. 48%, 51% and 63%, respectively, (entries 13–15). When propargyl-
amines 3p, 3q and 3r having a morpholine ring were treated with
Entry
3
4
Yield (%)
1
2
3a
3b
4a
4b
96
91
3
3c
4c
91
4
3d
4d
95
5
6
7
3e
3f
4e
4f
95
96
96
3g
4g
8
3h
3i
4h
4i
89
93
60
9
10
3j
4j
11
12
13
14
15
16
17
18
3k
3l
4k
4l
58
70
48
51
63
83
85
83
3m
3n
3o
3p
3q
3r
4m
4n
4o
4p
4q
4r
19
20
21
22
23
24
25
3s
4s
4t
96
93
89
96
95
80
75
71
3t
3u
3v
4u
4v
4w
4x
4y
4z
4a0
3w
3x
3y
tosylazide a significant improvement in yields, i.e. 83% for 4p, 85% 26
3z
3a0
3b0
3c0
for 4q and 83% for 4r was observed (entries 16–18).
27
28
29
96
96
98
4b0
4c0
To expand the scope of the methodology, we evaluated the effect
of aromatic groups at the C1-position by introducing propargylamines
3s–3z and 3a0–3c0 (Table 2, entries 19–29). In these cases, reactions
were completed within 3 minutes. For substrates 3s (Ar = Ph) and 3t
(Ar = C6H4-p-Me), reactions provided 96% and 93% yields of 4s and Variable temperature 1H- (Fig. 1, Fig. S110, ESI†) and 13C-NMR
4t, respectively, (entries 19 and 20). For aryl groups consisting of an (Fig. S111, ESI†) experiments were carried out for 4t to resolve the
electron donating –OMe substituent at ortho-, meta- and para- slow rotamer interconversion and thus broadening of peaks was
positions, reactions proceeded smoothly with excellent yields of 4u observed at room temperature.
(89%), 4v (96%), and 4w (95%), respectively (entries 21–23). On the
A plausible mechanism for the formation of acrylamidine from
other hand, introduction of strong electron withdrawing substituents N,N-disubstituted propargylamine is depicted in Scheme 2.
e.g. ortho-NO2, meta-NO2 and para-CN resulted in slightly lower yields N-Sulfonyl triazolyl copper intermediate I, formed upon reaction of
of 4x (80%), 4y (75%) and 4z (71%), respectively, (entries 24–26). propargylamine with tosylazide, releases one molecule of N2 and
However, a weak electron withdrawing meta-Br substituent did not undergoes protonation to generate ketenimine II.7a,c Subsequent
affect the yield of 4a0 (entry 27, yield = 96%). When extended aromatic transformation of II to IV occurs in two steps. At first a 4-exo-dig
groups (Ar = a-naphthyl and 1-pyrenyl) were introduced reactions cyclization of II generates the intermediate III. The tethered nitrogen
provided excellent yields of 4b0 (96%) and 4c0 (98%), respectively. (N1) due to its available lone pair facilitates the attack on the highly
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propargylamines with an alkyl/aryl substituent at the C1-
position, products were isolated in moderate to excellent yields.
However, for N,N-cyclic substituted propargylamines, reactions
were slower and isolated yields were also affected. The 1,3-
migration of amine was predicted via a 4-exo-dig cyclization
followed by an E1cB elimination type ring opening step. With a
pyrene chromophore at the C1-position, the formation of a
more conjugated product was demonstrated by 22 nm red shift
of lmax and change in fluorescence from cyan to green.
We are grateful to the Director, IISER Pune and DST-SERB
(SR/S1/OC-65/2012) for financial support. D.P.C. thanks CSIR
for the fellowship.
Fig. 1 Variable temperature 1H-NMR (400 MHz) of 4t in CDCl3.
Notes and references
1 For various types of click reactions, see: (a) H. C. Kolb, M. G. Finn and
K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004; (b) N. J. Agard,
J. A. Prescher and C. R. Bertozzi, J. Am. Chem. Soc., 2004, 126, 15046;
(c) J. C. Jewett and C. R. Bertozzi, Chem. Soc. Rev., 2010, 39, 1272.
2 For click reactions involving alkynes and azides, see: (a) W. G. Lewis,
L. G. Green, F. Grynszpan, Z. Radic, P. R. Carlier, P. Taylor, M. G. Finn
and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 1053;
(b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596; (c) J. Lahann, Click Chemistry
for Biotechnology and Materials Science, John Wiely & Sons, Chichester,
West Sussex, 2009.
3 C. Le Droumaguet, C. Wang and Q. Wang, Chem. Soc. Rev., 2010,
39, 1233.
4 (a) R. Breinbauer and M. Koehn, ChemBioChem, 2003, 4, 1147;
(b) A. H. El-Sagheer and T. Brown, Chem. Soc. Rev., 2010, 39, 1388.
5 P. Wu, A. K. Feldman, A. K. Nugent, C. J. Hawker, A. Scheel, B. Voit,
J. Pyun, J. M. J. Frechet, K. B. Sharpless and V. V. Fokin, Angew.
Chem., Int. Ed., 2004, 43, 3928.
6 (a) H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128;
(b) J. M. Holub and K. Kirshenbaum, Chem. Soc. Rev., 2010, 39, 1325.
7 (a) E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin,
K. B. Sharpless and S. Chang, Angew. Chem., Int. Ed., 2007,
46, 1730; (b) I. Bae, H. Han and S. Chang, J. Am. Chem. Soc., 2005,
127, 2038; (c) E. J. Yoo, M. Ahlquist, I. Bae, K. B. Sharpless,
V. V. Fokin and S. Chang, J. Org. Chem., 2008, 73, 5520.
8 S. H. Kim, D. Y. Jung and S. Chang, J. Org. Chem., 2007, 72, 9769.
9 E. J. Yoo and S. Chang, Curr. Org. Chem., 2009, 13, 1766.
10 S. H. Cho, E. J. Yoo, I. Bae and S. Chang, J. Am. Chem. Soc., 2005,
127, 16046.
11 E. J. Yoo, I. Bae, S. H. Cho, H. Han and S. Chang, Org. Lett., 2006,
8, 1347.
12 S. H. Cho and S. Chang, Angew. Chem., Int. Ed., 2008, 47, 2836.
13 J. Wang, J.-J. Wang, Y.-X. Zhu, P. Lu and Y.-G. Wang, Chem.
Commun., 2011, 47, 3275.
14 J. Kim, S. Y. Lee, J. Lee, Y. Do and S. Chang, J. Org. Chem., 2008,
73, 9454.
15 E. J. Yoo, S. H. Park, S. H. Lee and S. Chang, Org. Lett., 2009, 11, 1155.
16 W. Song, W. Lu, J. Wang, P. Lu and Y. Wang, J. Org. Chem., 2010,
75, 3481.
17 (a) K. K. R. Tetala, R. J. Whitby, M. E. Light and M. B. Hurtshouse,
Tetrahedron Lett., 2004, 45, 6991; (b) N. Shindoh, K. Kitaura, Y. Takemoto
and K. Takasu, J. Am. Chem. Soc., 2011, 133, 8470; (c) X. Yan, J. Liao,
Y. Lu, J. Liu, Y. Zeng and Q. Cai, Org. Lett., 2013, 15, 2478.
18 N. Shindoh, Y. Takemoto and K. Takasu, Chem.–Eur. J., 2009, 15, 7026.
19 G. V. Boyd, in The Chemistry of Amidines and Imidates, ed. S. Patai
and Z. Rappoport, Wiley, New York, 1991, ch. 8, vol. 2.
20 B. Ojo, P. G. Dunbar, G. J. Durant, P. I. Nagy, J. J. Huzl III,
S. Periasamy, D. O. Ngur, A. A. El-Assadi, W. P. Hoss and
W. S. Messer Jr., Bioorg. Med. Chem., 1996, 4, 1605.
Scheme 2 Plausible mechanism for the formation of acrylamidine.
electrophilic C4-center. The formation of III is also favored due to
delocalization of the negative charge on the N5-center by a sulfonyl
group. A subsequent E1cB elimination type ring opening process
results in the formation of IV. Generation of III from II is considered
as the rate determining step due to formation of a strained
4-membered ring from an acyclic system. This prediction was
supported by longer reaction times of cyclic amino group containing
propargylamines 3k–3r and poorer yields of the corresponding
products 4k–4r. In these cases, formation of spiro-transition
states contributes to the slower reaction rates. The preferential
E-stereochemistry around the CQC bond as predicted by the
mechanism was confirmed by NMR and single crystal X-ray
diffraction studies of 4d (Fig. S2, ESI†) and 4w (Fig. S4, ESI†).
Pyrene-based propargylamine 3c0 (10 mM) displayed a lmax
=
353 nm. When an aliquot from the completed reaction mixture
of 3c0 and TsN3 (Table 2, entry 29) was diluted suitably (to
obtain B10 mM concentration of 4c0) in HEPES buffer (10 mM,
pH = 7.4), the resulting solution exhibited a lmax = 375 nm (i.e.
22 nm red shift) due to the formation of more conjugated 4c0
(Fig. 2A). Formation of more conjugated 4c0 was also marked by
the change in fluorescence from cyan to green (Fig. 2B).
In conclusion, we have demonstrated a new reaction of
ketenimine bearing a tethered amino group facilitating its
1,3-migration. The methodology portrays rapid reactions of
N,N-disubstituted propargylamines with tosylazide under CuCl
catalytic, open air conditions to synthesize acrylamidines. For
21 C. Thominiaux, B. de Bruin, Y. Bramoulle, F. Hinnen, S. Demphel,
H. Valette, M. Bottlaender, L. Besret, M. Kassiou and F. Dolle, Appl.
Radiat. Isot., 2006, 64, 348.
22 T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev., 2012, 41, 2463.
23 C. Wentrup, V. V. R. Rao, W. Frank, B. E. Fulloon, D. W. J. Moloney
and T. Mosandl, J. Org. Chem., 1999, 64, 3608.
Fig. 2 UV-visible spectra of 3c0 (10 mM) in the absence and in the presence
of 10 mM TsN3 (A); images of cuvettes containing either 3c0 (50 mM) or [3c0 +
TsN3] taken under the hand-held UV (lex = 365 nm) lamp (B).
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Chem. Commun., 2014, 50, 323--325 | 325