Iron-catalyzed [3 + 2] annulation of aminocyclopropanes with aldehydes: Stereoselective synthesis of aminotetrahydrofurans

Article abstract of DOI:10.1021/ol203144v

The first method for the [3 + 2] annulation of donor-acceptor aminocyclopropanes with aldehydes is reported. The reaction is catalyzed by iron trichloride on alumina in yields up to 99% and with excellent cis selectivities (up to >20:1) and represents a stereoselective and atom economic access to valuable 2-aminotetrahydrofurans, which constitute the core of DNA and RNA.

Full text of DOI:10.1021/ol203144v

ORGANIC
LETTERS
2012
Vol. 14, No. 1
386–389
Iron-Catalyzed [3 þ 2] Annulation of
Aminocyclopropanes with Aldehydes:
Stereoselective Synthesis of
Aminotetrahydrofurans
ꢀ ^
Fides Benfatti, Florian de Nanteuil, and Jerome Waser*
ꢀ ꢀ
Laboratory of Catalysis and Organic Synthesis Ecole Polytechnique Federale de
Lausanne EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received November 24, 2011
ABSTRACT
The first method for the [3 þ 2] annulation of donorꢀacceptor aminocyclopropanes with aldehydes is reported. The reaction is catalyzed by iron
trichloride on alumina in yields up to 99% and with excellent cis selectivities (up to >20:1) and represents a stereoselective and atom economic
access to valuable 2-aminotetrahydrofurans, which constitute the core of DNA and RNA.
Donorꢀacceptor (DꢀA) cyclopropanes represent
versatile three-carbon zwitterionic synthons1 and are
widely used to assemble carbocycles and heterocycles
by means of [3 þ n] annulation reactions.2 Among them,
the [3 þ 2] reaction with olefins,3 carbonyls,4 and imines5
represents a valuable tool for the convergent synthesis
of cyclopentanes, tetrahydrofurans,6 and pyrrolidines,
respectively.
The annulation of DꢀA cyclopropanes with carbonyl
compounds in particularhasbeen hampered for a long time
by modest diastereoselectivity and the need for stoichio-
metric amounts of a strong Lewis acid (i.e., TiX4, SnX4).7
Inthe past decade, this transformation has been the focus of
a renewed research effort. In particular, Johnson et al.
developed catalytic methods for the highly stereoselective
synthesis of tetrahydrofurans (THFs) using Lewis acids
(i.e., Sn(OTf)2, Hf(OTf)4) under mild conditions.8
In the [3 þ 2] annulation with aldehydes and ketones,
(1) For reviews on DꢀA cyclopropanes, see: (a) Reissig, H.-U.;
Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L.
Tetrahedron 2005, 61, 321. (c) Rubin, M.; Rubina, M.; Gevorgyan, V.
Chem. Rev. 2007, 107, 3117. (d) De Simone, F.; Waser, J. Synthesis 2009,
3353. Theoretical study: (e) Schneider, T. F.; Werz, D. B. Org. Lett.
2011, 13, 1848.
(2) (a) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051.
(b) Lebold, T. P.; Kerr, M. A. Pure Appl. Chem. 2010, 82, 1797.
(c) Agrawal, D.; Yadav, V. K. Chem. Commun. 2008, 6471. (d) Ivanova,
O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Trushkov, I. V.; Melnikov,
M. Y. J. Org. Chem. 2011, 76, 8852.
(3) Selected examples with silyl enol ethers: (a) Komatsu, M.
Suehiro, I.; Horiguchi, Y.; Kuwajima, I. Synlett 1991, 771. (b) Qu
J.-P.; Deng, C.; Zhou, J.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2009, 74,
7684. With enamines: (c) Dolfini, J. E.; Menich, K.; Corliss, P.
Tetrahedron Lett. 1966, 4421. (d) Berkowitz, W. F.; Grenetz, S. C.
J. Org. Chem. 1976, 41, 10. With indoles: (e) England, D. B.; Kuss,
T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704. (f)
Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007,
129, 9631. With allyl silanes: (g) Sugita, Y.; Yamadoi, S.; Hosoya, H.;
Yokoe, I. Chem. Pharm. Bull. 2001, 49, 657. (h) Sapeta, K.; Kerr, M. A.
Org. Lett. 2009, 11, 2081.
DꢀA cyclopropanes bearing oxygen donor group(s) were
(4) Perspective article: (a) Campbell, M. J.; Johnson, J. S.; Parsons,
A. T.; Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. 2010, 75, 6317.
Pioneering examples: (b) Reissig, H.-U. Tetrahedron Lett. 1981, 22, 2981.
(c) Shimada, S.; Hashimoto, Y.; Sudo, A.; Hasegawa, M.; Saigo, K. J. Org.
Chem. 1992, 57, 7126. (d) Shimada, S.; Hashimoto, Y.; Nagashima, T.;
Hasegawa, M.; Saigo, K. Tetrahedron 1993, 49, 1589. (e) Shimada, S.;
Hashimoto, Y.; Saigo, K. J. Org. Chem. 1993, 58, 5226. (f) Sugita, Y.;
Kawai, K.; Yokoe, I. Heterocycles 2000, 53, 657. (g) Sugita, Y.; Kawai, K.;
Yokoe, I. Heterocycles 2001, 55, 135. (h) Han, Z.; Uehira, S.; Tsuritani, T.;
Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987.
(5) Selected examples: (a) Alper, P. B.; Meyers, C.; Lerchner, A.;
Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186.
(b) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242. (c) Kang,
Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4, 299. (d) Parsons,
A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010,
132, 9688.
(6) For a review on the synthesis of tetrahydrofurans, see: Wolfe,
J. P.; Hay, M. B. Tetrahedron 2007, 63, 261.
r
10.1021/ol203144v
Published on Web 12/21/2011
2011 American Chemical Society

most frequently exploited,4bꢀg,8e but the use of aryl,4a,8a,c
alkenyl,8b,d alkyl,4a,8d and silylmethyl2c donors has also
beendocumented. To the bestofour knowledge, thistrans-
formation has never been reported using DꢀA cyclopro-
panes substituted with a nitrogen-containing donor group
instead.9 In fact, aminocyclopropanes are generally under-
represented in annulation and cyclization reactions,10 despite
the abundance of synthetic methods for their preparation.11
The development of [3 þ 2] annulations of aminocyclo-
propanes with aldehydes would constitute important
progress in the field, as this reaction allows the one-pot,
atom-economic assembly of 2-aminotetrahydrofurans,
a common motif in “evolutionarily selected” molecules
such as nucleosides, as well as in synthetic drugs such as
AZT (1)12 (Figure 1).
aldehydes affording 2-aminotetrahydrofurans with excel-
lent diastereoselectivity (Scheme 1).
Our group has been interested in the use of DꢀA
cyclopropanes (D = NPg or aryl, Pg = protecting group)
as precursors of reactive intermediates in cyclization reac-
tions onto electron-rich olefins or heterocycles.14 In partic-
ular, we made use of aminocyclopropanes as acyl iminium
precursors in the synthesis of natural alkaloids.14b
Scheme 1. [3 þ 2] Annulation of DꢀA Aminocyclopropanes
with Aldehydes
In 2011, we decided to investigate the use of more
convergent annulation reactions of aminocyclopropanes
for the efficient synthesis of carbo- and heterocycles. As a
result of these efforts, we reported the first catalytic,
enantiospecific [3 þ 2] annulation between silyl enol ethers
and DꢀA aminocyclopropane 2a to give cyclopentyl-
amines (eq 1).15
Figure 1. Bioactive natural and synthetic compounds containing
an aminotetrahydrofuran core.
It is well-known that nucleosides and their mimetics13
are widespread as therapeutic agents for the treatment
of cancer, infections, and viral diseases. Therefore the
2-aminotetrahydrofuran core may be rightly considered
as a privileged scaffold for drug discovery.
Herein, we describe the first catalytic method for the [3 þ 2]
annulation of donorꢀacceptor aminocyclopropanes with
(7) Only two catalytic methods were reported before 2005: References
4fꢀ4g.
The fine-tuning of the DꢀA substituents on 2a was
required to reach an optimal compromise between stability
and reactivity. We found that the combination of phthal-
imide as a weak donor group and a gem-diester as an
acceptor to be ideal. As an extension to our work, we
wondered if phthaloyl aminocyclopropane 2a could be
exploitedin the [3 þ 2] reaction withother partners, suchas
carbonyls.
We decided to examine first the reaction of 2a with
benzaldehyde (3a). In contrast to the results obtained with
enol ethers, the use of tin tetrachloride (eq 1) was not ideal,
since a low yield was observed at rt, while irreproducible
results were obtained at ꢀ78 °C (Table 1, entries 1ꢀ2). We
consequently decided to screen a more extended selection
of Lewis acids. Pleasingly, all Lewis acids tested, except
Yb(OTf)3 (entry 3, Table 1), were competent catalysts for
(8) Enantiospecific annulation: (a) Pohlhaus, P. D.; Johnson, J. S.
J. Am. Chem. Soc. 2005, 127, 16014. (b) Pohlhaus, P. D.; Sanders, S. D.;
Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642.
DyKAT: (c) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131,
3122. With quaternary stereocenters: (d) Smith, A. G.; Slade, M. C.;
Johnson, J. S. Org. Lett. 2011, 13, 1996. Recently, an example of
intramolecular annulation was also reported by Wang and co-workers:
(e) Xing, S.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int.
Ed. 201110.1002/anie.201106368.
(9) For reviews on aminocyclopropanes, see: (a) Gnad, F.; Reiser, O.
Chem. Rev. 2003, 103, 1603. (b) Brackmann, F.; de Meijere, A. Chem.
Rev. 2007, 107, 4493.
(10) Intermolecular: (a) Wimalasena, K.; Wickman, H. B.;
Mahindaratne, M. P. D. Eur. J. Org. Chem. 2001, 2001, 3811. (b) Tanguy,
C.; Bertus, P.; Szymoniak, J.; Larionov, O. V.; de Meijere, A. Synlett 2006,
2006, 2339. Intramolecular: (c) Lee, H. B.; Sung, M. J.; Blackstock, S. C.;
Cha, J. K. J. Am. Chem. Soc. 2001, 123, 11322. (d) Larquetoux, L.;
Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 2005, 4654.
(e) Mangelinckx, S.; De Kimpe, N. Synlett 2006, 2006, 0369. Applications in
total synthesis: (f) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44,
447. (g) De Simone, F.; Waser, J. Synlett 2011, 2011, 589.
ꢀ
(11) Recent examples: (a) Faler, C. A.; Joullie, M. M. Org. Lett. 2007,
9, 1987. (b) Song, Z. L.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko,
C. H.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069. (c) Valenta, P.;
Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132, 14179 and
references therein.
ꢁ
(14) (a) De Simone, F.; Andres, J.; Torosantucci, R.; Waser, J. Org.
Lett. 2009, 11, 1023. (b) De Simone, F.; Gertsch, J.; Waser, J. Angew.
Chem., Int. Ed. 2010, 49, 5767.
(12) (a) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249,
1533. (b) Basavapathruni, A.; Anderson, K. S. FASEB J. 2007, 21, 3795.
(13) Herdewijn, P. Modified Nucleosides: in Biochemistry, Biotech-
nology and Medicine; Wiley-VCH: Weinheim, 2008.
(15) De Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50,
12075. Aminocyclopropane 2a can be synthesized in multigram scale
via rhodium-catalysed cyclopropanation of commercially available
vinylphthalimide with diethyl diazomalonate.
Org. Lett., Vol. 14, No. 1, 2012
387

the activation of 2a, affording 2-aminotetrahydrofuran
4aa in excellent diastereoselectivity in favor of the cis
isomer (entries 4ꢀ11). Employing In(OTf)3, a trace of
the trans isomer could be identified in the crude 1H
NMR spectrum (dr = 19:1, entry 4); otherwise only the
2,5-cis-tetrahydrofuran16 was detected. Cyclopropane 2a
was completely consumed after 90 min in all cases, except
for Cu(OTf)2 (entry 5).
Next, the scope of the reaction with 2a and 2b was
explored, using 5 mol % of iron(III) chloride on alumina
and 1.5 equiv of aldehydes 3aꢀm at rt (Table 2).
Table 2. Scope of Aldehydes 3aꢀm in the [3 þ 2] Annulation
with Aminocyclopropanes 2aꢀba
Table 1. Screening of Lewis Acidsa
a Reaction conditions: 1.0 equiv of 2a, 1.5 equiv of 3a, 20 mol % of
Lewis acid, 0.1 M in dichloromethane. b Yield was determined via 1H
NMR spectroscopy using hexamethyldisiloxane as internal standard.
1
c Determined by H NMR spectroscopy on the crude raction mixture.
a Standard reaction conditions: 0.2 mmol of 2aꢀb, 1.5 equiv of 3aꢀm,
5 mol % of FeCl3ꢀAl2O3, 0.1 M in dichloromethane. b Expressed as
cis/trans. c Determined by 1H NMR spectroscopy on the crude raction
mixture. d Obtained after one single recrystallization (see Supporting
Informations). e Reaction run at ꢀ10 °C.
d Performed at ꢀ78 °C. e Only 50% conversion of 2a was observed.
The effect of the counteranion was studied in the case
of indium salts, and it provednegligible(triflatevschloride,
entry 4 vs 6). When the formation of 5-membered ring 4aa
was not quantitative (entries 1ꢀ2, 4ꢀ8), the crude 1H NMR
spectrum showed the presence of a byproduct, most likely
derived from decomposition of the Lewis acid activated 2a.
The cleanest reactions were observed with Hf(OTf)4, Sc-
(OTf)3, and FeCl3ꢀAl2O3 (entries 9ꢀ11).17 We selected the
latter as a catalyst to continue our studies due to its low cost
and toxicity.18 Although the efficiency of Fe catalysts in
promoting cycloaddition and ring expansion is well estab-
lished,19 this represents the first example of an Fe-catalyzed
[3 þ 2] annulation of DꢀA cyclopropanes.
In general, excellent yields were obtained in a short
reaction time (2 h),20 while employing aldehydes with
diverse steric and electronic properties. No difference in
reactivity/selectivity was observed between the ethyl
diester 2a and the methyl diester 2b in the reaction with
benzaldehyde (3a) (entry 1 vs 2). The electron-rich para-
and ortho- anisaldehydes (3bꢀc) and thiophene-2-carbox-
aldehyde (3d) displayed modest stereoselectivities at rt(up
to 6:1 cis/trans; entries 3ꢀ5); nevertheless increased dr’s
were obtained at a lower temperature (up to >20:1
cis/trans, entries 6ꢀ8). Interestingly, no detrimental effect
onyield and stereoselectivity of anortho vsparasubstituent
was observed with anisaldehyde 3c vs 3b (entries 6ꢀ7).
In all cases, the two isomers could not be separated by flash
chromatography. However, the pure cis isomer could be
obtained by means of a single recrystallization, except for
products 4ak and 4al. The X-ray diffraction analysis
performed on aminotetrahydrofuran 4ab allowed the un-
ambiguous attribution of the 2,5-cis relative stereochem-
istry (Figure 2).
(16) 2,5-Relative stereochemistry was assigned on the basis of X-ray
diffraction analysis performed on compound 4ab and extended to the
other compounds of the series on the basis of the regularityin their NMR
spectra (see Figure 3 and Supporting Information for details).
(17) Iron trichloride gave comparable results, but the alumina-
supported reagent was preferred because it is easier to handle and
known to be a scavenger of adventitious traces of water and acid. For
examples on the use of FeCl3ꢀAl2O3, see: (a) Tietze, L. F.; Beifuss, U.
Synthesis 1988, 5, 359. (b) Tietze, L. F.; Beifuss, U.; Antel, J.; Sheldrick,
G. M. Angew. Chem., Int. Ed. 1988, 27, 703.
(18) In the past decade, a revival of iron catalysis in organic synthesis
was observed, due to the abundance and versatility of this environmen-
tally benign metal. See for example: Iron Catalysis Fundamentals and
Applications; Plietker, B., Ed.; Topics in Organometallic Chemistry; Springer-
Verlag: Berlin Heidelberg, 2011; Vol. 33.
(19) (a) Hilt, G.; Janikowski, J. Iron Catalysis in Organic Chemistry:
Reactions and Applications; Wiley-VCH: Weinheim, 2008; Chapter 9. (b) Bolm,
C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev 2004, 104, 6217.
(20) 2 h was the chosen standard time for full conversion. When
completion was reached in a shorter time, the prolonged stirring with the
catalyst at rt caused no erosion in yield or dr.
388
Org. Lett., Vol. 14, No. 1, 2012

with 3a under the standard reaction conditions (eq 3).
We had found in our previous work that the reaction of
enantiopure aminocyclopropane 2a with silyl enol ethers
was enantiospecific with all the olefins tested,15 indicating
most probably the formation of a tight, configurationally
stable ion pair between the cyclopropane and the tin
catalyst. In contrast, the iron-catalyzed annulation of 2a
with benzaldehyde (3a) at rt resulted in a complete loss of
the stereochemical information, as tetrahydrofuran 4aa was
isolated in a racemic form.8b,22 This evidence suggests that,
upon Lewis acid activation, the aminocyclopropane under-
goes fast racemization via an open, zwitterionic species.
While the result hampers the synthesis of enantioenriched
amino THFs, it is a potential starting point for the devel-
opment of a dynamic kinetic asymmetric transformation
(DyKAT).8c,23
Figure 2. X-ray structure of aminotetrahydrofuran 4ab.
The annulation reaction was not limited to aromatic
aldehydes, and a good yield was alsoobtainedinthe case of
cinnamyl aldehyde (4bg), albeit with a low diastereoselec-
tivity (entry 11). Once again, the cis-selectivity could be
increased by lowering the temperature to ꢀ10 °C (entry
12). The reaction was also successful for unsaturated
aldehyde 3h, with both 2a and 2b (entries 13 and 14).
Aliphatic aldehydes are generally challenging substrates
for Lewis acid catalyzed reactions, as they are prone to
undergo aldol side reactions. Gratifyingly, this was not an
issue under our mild reaction conditions, and aliphatic
aldehydes with linear (entries 15ꢀ16) or branched (entries
17ꢀ19) substituents afforded the corresponding aminotet-
rahydrofurans in outstanding yields (89ꢀ99%) and good
diastereoselectivities (up to >20:1 cis/trans).
In summary, we have developed the first iron(III) cata-
lyzed [3 þ 2] annulation of aminocyclopropanes with
aldehydes, affording aminotetrahydrofurans in excellent
yields (71ꢀ99%) and diasteroselectivities (upto>20:1 dr).
This protocol represents an atom-economic, stereoselective
route to unprecedented structures that share an aminotetra-
hydrofuran motif of utmost value, due to its presence in
DNA and RNA. The exploration of the synthetic potential
of the aminotetrahydrofurans,24 the development of an
asymmetric version of the reaction, and its extension to
ketones are currently under investigation in our laboratories.
As further evidence of the efficiency of our methodol-
ogy, the reaction of 2a with an equimolar amount of
benzaldehyde (3a) in the presence of a 1 mol % loading
of Fe catalyst afforded compound 4aa in 88% yield and
excellent dr on a 1 mmol scale (eq 2).
Acknowledgment. We thank the European Commission
(Marie Curie IEF fellowship to F.B., Grant No. 253274)
and the Swiss National Science Foundation (SFN, Grant
No. 200021_129874) for financial support. Dr. Rosario
Scopelliti (EPFL) is acknowledged for the X-ray studies.
Supporting Information Available. Experimental de-
tails, characterization data, and X-rays diffraction anal-
ysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
To gain more knowledge on the mechanism of our [3 þ 2]
annulation, enantioenriched 2a (er = 99:1)21 was reacted
(21) Obtained by preparative HPLC separation on chiral stationary
phase (see Supporting Information for details).
(22) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
(23) (a) Pellissier, H. Chirality from dynamic kinetic resolution; RSC
Publishing: Cambridge, 2011. (b) Steinreiber, J.; Faber, K.; Griengl, H.
Chem.;Eur. J. 2008, 14, 8060.
(24) The ring opening of phthalimide with amines was accomplished,
but cleavage of the second CꢀN bond could not yet be achieved due to
the instability of the resulting free aminotetrahydrofuran. As alternative
strategies, the use of modified aminocyclopropanes or the substitution
of the phthalimide with nucleophiles will be investigated in the future for
the synthesis of nucleoside analogues.
Org. Lett., Vol. 14, No. 1, 2012
389