Thermally induced and silver-salt-catalyzed [2+2] cycloadditions of imines to (Alkoxymethylene)cyclopropanes

Article abstract of DOI:10.1002/anie.200600961

(Chemical Equation Presented) A silver lining: [2+2] Cycloadditions of imines 2 to (alkoxymethylene)cyclopropanes 1 proceed readily at 80°C and ambient pressure to furnish spirocyclopropanated 2-alkoxyazetidines 3 in good to excellent yields. The same rea

Full text of DOI:10.1002/anie.200600961

Communications
Cycloadditions
DOI: 10.1002/anie.200600961
Thermally Induced and Silver-Salt-Catalyzed
[2+2] Cycloadditions of Imines to
(Alkoxymethylene)cyclopropanes**
Itaru Nakamura,* Tetsuya Nemoto,
Yoshinori Yamamoto, and Armin de Meijere
[2+2] Cycloadditions of imines to carbon–carbon multiple
bonds have been widely applied in organic synthesis, as they
produce highly useful azetidine derivatives in a single step.[1]
[2+2] Cycloadditions of imines to ketenes, originally discov-
ered by Staudinger,[2] provide azetidin-2-ones (b-lactams)
(Scheme 1, type a). Recently, allenes[3] and enones[4] were
Scheme 1. [2+2] Cycloadditions of imines to a) ketenes[2] and b) enol
ethers.[5]
utilized as substrates for [2+2] cycloadditions with imines.
However, cycloadditions of imines to enol ethers (Scheme 1,
type b) have rarely been employed; Scheeren and co-workers
reported that [2+2] cycloadditions of imines to enol ethers
require high pressure (12 kbar).[5] Owing to their ring strain,
(alkoxymethylene)cyclopropanes, which are easily accessible
and stable at room temperature, ought to be particularly
favorable substrates for various cycloadditions;[6] de Meijere
et al. reported high-pressure-promoted [4+2] cycloadditions
of (alkoxymethylene)cyclopropanes to b,g-unsaturated a-
[*] Dr. I. Nakamura, T. Nemoto, Prof. Dr. Y. Yamamoto
Department of Chemistry
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Fax: (+81)22-795-6784
E-mail: itaru-n@mail.tains.tohoku.ac.jp
Prof. Dr. A. de Meijere
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
[**] For one of us (A.d.M.) this is to be counted as Part 129 in the series
“Cyclopropyl Building Blocks for Organic Synthesis”. Part 128: V. S.
Korotkov, O. V. Larionov, A. de Meijere, Synthesis 2006, in press.
Part 127: C. Tanguy, A. de Meijere, P. Bertus, J. Szymoniak, O. V.
Larionov, A. de Meijere, Synlett 2006, in press.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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ketoesters.[7] Herein we report our first results concerning
[2+2] cycloadditions of imines to (alkoxymethylene)cyclo-
propanes 1 at ambient pressure.
When (benzyloxymethylene)cyclopropane (1a; 1.5 equiv)
was heated with N-tosylbenzaldimine (2c; 1.0 equiv) in
acetonitrile at 808C for 40 h, the [2+2] cycloadduct 4-
benzyloxy-6-phenyl-5-tosyl-5-azaspiro[2.3]hexane (3ac) was
isolated in 97% yield, predominantly as the cis diastereomer
(51:1) (Table 1). The same reaction, but with 1 equivalent of
Table 1: Thermal [2+2] cycloadditions of 2 to (alkoxymethylene)cyclo-
propanes 1.
1[a] R1
2
R2
R3
Ts
t [h]
3
Yield [%][b] cis/trans[c]
1a Bn 2c Ph
1a Bn 2d p-MeOC6H4 Ts
1a Bn 2e p-CF3C6H4 Ts
1a Bn 2 f tBu
1a Bn 2g Ph
1a Bn 2h Ph
1b nBu 2c Ph
40 3ac 97[d]
46 3ad 82
51:1
24:1
18:1
29:1
28:1
28:1
8:1
6
3ae 91
61 3af 80
3ag 92
Ts
Ns
4
SO2Ph 32 3ah 71
Ts 24 3bc 80
[a] In general, 1 (0.3 mmol) was treated with 2 (0.2 mmol). [b] Yields of
isolated products. [c] The diastereomeric ratio was determined by
1H NMR spectroscopy. [d] Scale: 1a (3.0 mmol), 2c (2.0 mmol); product
3ac obtained in 68% yield. Ns=nosyl=p-nitrobenzenesulfonyl; Ts=p-
toluenesulfonic acid.
1a, gave 3ac in 65% yield along with recovered 2c (14%).
The reaction of 1a with other N-tosylarylaldimines 2d and 2e
produced 3ad and 3ae in 82 and 91% yield, respectively. The
N-tosylimine of pivaldehyde 2 f also reacted with 1a to give
the corresponding [2+2] cycloadduct 3af in 80% yield. With
N-nosylbenzaldimine (2g) and N-benzenesulfonylbenzaldi-
mine (2h), the corresponding N-nosylazetidine 3ag and N-
benzenesulfonylazetidine 3ah were obtained in 92 and 71%
yield, respectively. (n-Butoxymethylene)cyclopropane (1b)
reacted with 2c smoothly to give 3bc. The constitutions of the
spirocyclopropanated azetidines 3 were confirmed by spec-
troscopic methods. Furthermore, the structures of both the cis
and the trans isomers of 3ac were established unambiguously
by X-ray crystallographic analyses (Figure 1).[8]
To test the possibility of performing this cycloaddition
more efficiently and at lower temperature, several Lewis
acidic transition-metal compounds were screened. Among the
Lewis acids tested (AuBr3, [Cu(acac)], Pd(OAc)2, Zn(OTf)2,
Sc(OTf)3, Yb(OTf)3, AgOTf, [Ag(acac)]), only [Ag(fod)]
(fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedio-
nato) exhibited the desired catalytic activity. Thus, the
reaction of 1a (1 equiv) with 2c (1 equiv) in the presence of
[Ag(fod)] (10 mol%) in ethyl acetate at 308C proceeded
smoothly to give 3ac in 94% yield (Table 2, entry 1). At 308C
in the absence of the silver catalyst, no reaction was observed,
and only the starting materials were recovered quantitatively.
The choice of solvent turned out to be very important; the
reaction proceeded almost equally well in acetone, THF, and
CH2Cl2, but sluggishly in acetonitrile, toluene, and hexane.
Figure 1. Crystal structures of a) cis-3ac and b) trans-3ac. ORTEP
representations with thermal ellipsoids set at 50% probability.[8]
Table 2: Catalyzed versus thermally induced [2+2] cycloadditions of 2 to
1a.
Entry
2
R2
R3
3
Catalytic[a]
Yield cis/ Yield cis/
[%][c] trans[d] [%][c] trans[d]
Thermal[b]
1
2
3
4
2c Ph
Ts
Ts
3ac 94
3ai 45
135:1 97
35:1 57[e]
46:1 93
48:1 84
51:1
1.2:1
5:1
2i
2j
CO2Et
Ph
Ms 3aj 77
2k 4-CF3C6H4 Ms 3ak 76
4:1
[a] The reaction of 1 (0.3 mmol) and 2 (0.3 mmol) was carried out in the
presence of [Ag(fod)] (10 mol%) in ethyl acetate (0.3 mL) at 308C.
[b] The reaction of 1 (0.3 mmol) and 2 (0.2 mmol) was carried out in
acetonitrile (0.1 mL) at 808C. [c] Yields of isolated products. [d] The
1
diastereomeric ratio was determined by H NMR spectroscopy. [e] The
reaction was carried out at 308C. Ms=methanesulfonyl.
The catalyzed reaction of the N-tosylimine 2i derived from
ethyl glyoxylate produced 3ai with higher cis selectivity than
that of the thermal reaction (Table 2, entry 2). The reaction of
N-mesylbenzaldimines 2j and 2k also proceeded with higher
cis selectivity under the catalytic conditions (Table 2, entries 3
and 4).[9]
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This [2+2] cycloaddition is proposed to proceed in two
steps via the well-stabilized 1,4-zwitterion 4. Initially, nucle-
ophilic attack of the carbon–carbon double bond in 1 on the
electrophilic center in the imine 2 would most probably lead
to the anti-oriented zwitterion anti-4, which after internal
rotation cyclizes to the azetidine cis-3 or trans-3 (Scheme 2).
Scheme 3. Mechanism of the silver-catalyzed [2+2] cycloaddition of
1+2.
and subsequent removal of the nosyl group of 9 gave 10
(Scheme 4).
Scheme 4. Synthesis of a-cyclopropane-modified b-phenylalanine 9.
Several catalyzed cycloadditions of methylenecyclopro-
panes to imines have been reported in recent years; [3+2]
cycloadditions occur upon palladium-catalyzed reactions of
alkylidenecyclopropanes with sulfonylimines[11] and upon
Lewis acid catalyzed reactions of arylidenecyclopropanes
with tosylimines.[12] Under scandium catalysis, arylidenecy-
clopropanes react with N-phenylimines in a [4+2] cyclo-
addition.[13] The reactions presented herein are the first
examples of [2+2] cycloadditions of imines to methylenecy-
clopropane derivatives. The readily available 2-alkoxyazeti-
dines offer themselves as versatile building blocks for the
synthesis of various other compounds. One such application is
preparation of a-cyclopropanated b-amino acids such as 10,
some of which are found in biologically active compounds.[14]
It has also been shown that oligopeptides derived from a-
cyclopropanated b-amino acids may have interesting secon-
dary structures.[15]
Scheme 2. Mechanism of the thermally induced [2+2] cycloaddition of 1+2.
EWG=electron-withdrawing group.
Apparently, this ring closure is reversible, and cis-3 is the
thermodynamically more stable isomer, as isolated trans-3ac,
when heated in acetonitrile at 808C for 16 h, isomerized
virtually completely to cis-3ac. Under the same conditions,
cis-3ac remained unchanged. The greater stability of cis-3ac
most likely stems from a smaller repulsion between the
toluenesulfonyl and the benzyloxy group in the cis isomer (see
Figure 1). According to DFT calculations at the B3LYP/6-
311G level of theory, cis-3ac is 2.1 kcalmolÀ1 more stable than
trans-3ac. The stabilization of the zwitterionic intermediate 4
by the cyclopropyl group adjacent to the cationic center is
essential, as the enol ether 5, which does not contain a
cyclopropane ring, did not react with the N-tosylimine 2c,
neither under purely thermal nor under catalytic condi-
tions.[10]
Experimental Section
General procedure: a) Thermal conditions: Substrate 1 (0.3 mmol)
was added to a solution of the imine 2 (0.2 mmol) in acetonitrile
(0.1 mL) under argon in a Wheaton microreactor. The mixture was
stirred at 808C for 4–61 h, and the product 3 was purified by column
chromatography through silica gel (Fuji Silysia) with hexane/EtOAc/
The silver complex certainly acts as a Lewis acid and
enhances the electrophilicity of the imine as in 6 (Scheme 3),
Et3N (20:1:2) as eluent. b) Catalytic conditions: Substrate
1
(0.3 mmol) was added to mixture of [Ag(fod)] (12.1 mg,
a
À
and C N bond formation would occur through the silver
amide intermediate syn-7, leading predominantly to the cis-3
isomer.
0.030 mmol) and the imine 2 (0.3 mmol) in ethyl acetate (0.3 mL)
under argon in a Wheaton microreactor. The mixture was stirred for
37–42 h and then filtered through a short silica gel (Fuji Silysia)
column with EtOAc/Et3N (10:1) eluent. Purification of the crude
product by chromatography through silica gel (Fuji Silysia) with
hexane/EtOAc/Et3N (20:1:2) afforded 3.
3ac: H NMR (400 MHz, CDCl3): d = 0.05–0.08 (m, 1H), 0.55–
0.60 (m, 2H), 0.78–0.82 (m, 1H), 2.39 (s, 3H), 4.84 (dd, J = 84,
12.4 Hz, 2H), 4.85 (s, 1H), 5.50 (s, 1H), 7.20–7.37 (m, 12H), 7.65 ppm
One of the potential applications of these newly accessible
spirocyclopropanated azetidines was demonstrated by the
facile three-step conversion of the [2+2] cycloadduct cis-3ag
into the b-phenylalanine analogue 10. Hydrolysis of cis-3ag
afforded the aldehyde 8 in 90% yield. Jones oxidation of 8
1
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(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 4.4, 8.3, 21.6,
29.7, 65.4, 70.6, 92.3, 127.4, 127.6, 127.7, 127.7, 127.9, 128.2, 128.3,
129.4, 135.2, 137.3, 137.7, 143.6 ppm; IR (neat): n˜ = 3062–2953, 2902,
1596, 1338, 1250, 1115 cmÀ1; elemental analysis: calcd for C25H25NO3S
(419.54): C 71.57, H 6.01, N 3.34, S 7.64; found: C 71.40, H 6.14, N
3.34, S 7.56; HRMS(EI): m/z calcd for C25H25NO3S: 419.1555; found:
419.1550.
Received: March 11, 2006
Revised: May 1, 2006
Published online: July 6, 2006
Keywords: amino acids · cycloaddition · cyclopropanes ·
.
homogeneous catalysis · silver
[1] For a review, see: S. France, A. Weatherwax, A. E. Taggi, T.
Lectka, Acc. Chem. Res. 2004, 37, 592 – 600.
[2] a) H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51 – 123;
for recent reports concerning the Staudinger reaction, see: b) C.
Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Eur. J. Org.
Chem. 1999, 3223 – 3235; c) S. France, H. Wack, A. M. Hafez,
A. E. Taggi, D. R. Witsil, T. Lectka, Org. Lett. 2002, 4, 1603 –
1605; d) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124,
1578-1579; e) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, D.
Ferraris, T. Lectka, J. Am. Chem. Soc. 2002, 124, 6626 – 6635.
[3] T. Akiyama, K. Daidouji, K. Fuchibe, Org. Lett. 2003, 5, 3691 –
3693.
[4] J. A. Townes, M. A. Evans, J. Queffelec, S. J. Taylor, J. P.
Morken, Org. Lett. 2002, 4, 2537 – 2540.
[5] R. W. M. Aben, R. Smit, J. W. Scheeren, J. Org. Chem. 1987, 52,
365 – 370.
[6] a) A. T. Bottini, L. J. Cabral, Tetrahedron 1978, 34, 3187 – 3194;
b) N. A. Petasis, E. I. Bzowej, Tetrahedron Lett. 1993, 34, 943 –
946.
[7] A. de Meijere, A. Leonov, T. Heiner, M. Noltemeyer, M. T. Bes,
Eur. J. Org. Chem. 2003, 3, 472 – 478.
[8] CCDC-284945 (trans-3ac) and CCDC-284946 (cis-3ac) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[9] In a preliminary attempt to induce an asymmetric reaction of 1a
with 2c with Ag(OTf) and (S)-binap as a chiral catalyst system,
the product 3ac was not obtained all.
[10] a) H. Hart, J. M. Sandri, J. Am. Chem. Soc. 1959, 81, 320; b) N. C.
Deno, H. G. Richey, Jr., J. S. Liu, J. D. Hodge, J. J. Houser, M. J.
Wisotsky, J. Am. Chem. Soc. 1962, 84, 2016; c) D. D. Roberts,
R. C. Snyder, Jr., J. Org. Chem. 1979, 44, 2860 – 2863; d) For a
review see: A. de Meijere, Angew. Chem. 1979, 91, 867 – 884;
Angew. Chem. Int. Ed. Engl. 1979, 18, 809 – 826.
[11] B. H. Oh, I. Nakamura, S. Saito, Y. Yamamoto, Tetrahedron Lett.
2001, 42, 6203 – 6205.
[12] M. Shi, B. Xu, J.-W. Huang, Org. Lett. 2004, 6, 1175 – 1178.
[13] a) M. Shi, L.-X. Shao, B. Xu, Org. Lett. 2003, 5, 579 – 582; b) L.
Patient, M. B. Berry, S. J. Coles, M. B. Hursthouse, J. D. Kilburn,
Chem. Commun. 2003, 2552 – 2553; c) S. Rajamaki, J. D. Kil-
burn, Chem. Commun. 2005, 1637 – 1639.
[14] Cf. D. L. Varie, C. Shih, D. A. Hay, S. L. Andis, T. H. Corbett,
L. S. Gossett, S. K. Janisse, M. J. Martinelli, E. D. Moher, R. M.
Schultz, J. E. Toth, Bioorg. Med. Chem. Lett. 1999, 9, 369 – 374.
[15] a) D. Seebach, S. Abele, T. Sifferlen, M. Hꢀnggi, S. Gruner, P.
Seiler, Helv. Chim. Acta 1998, 81, 2218 – 2241; b) S. Abele, P.
Seiler, D. Seebach, Helv. Chim. Acta 1999, 82, 1559 – 1571; c) S.
Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1 – 15.
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www.angewandte.org
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