While there have been many intermolecular versions with a
variety of dipoles such as nitrones,5 imines,6 aldehydes,7
aromatic azomethine imines,8 diazenes,9 nitriles,10 isocya-
nides,11 isocyanates,12 isothiocyanates,13 R,ꢀ-unsaturated
ketones,14 allenes, acetylenes,15 allylsilanes,16 and indoles,17
there have been limited reports on intramolecular versions.18
Intramolecularity would in principle allow for increased
reactivity as well as control of diastereoselectivity.19 This
idea was shown to have merit in our recently reported
stereodivergent synthesis of pyrrolidines18a via an intramo-
lecular annulation of oxime ether-tethered cyclopropanes, and
the extension of this methodology was successfully employed
in the total synthesis of allosecurinine.20
benzaldehyde in the presence of 5 mol % Yb(OTf)3. After
complete conversion to the corresponding hydrazone, the
reaction was brought to reflux to induce cyclization, provid-
ing 2,5-trans-pyrazolidine 10 in 85% yield. This sequence
of events was then repeated with a variety of aldehydes, the
results of which are shown in Scheme 2. The reaction is
Scheme 2.
Synthesis of 2,5-trans-Pyrazolidinesa
Synthesis of our desired cyclopropane began with readily
available cyclopropane 421 which was converted to its iodo
derivative 5 by treatment with PPh3, imidazole, and iodine
in a 78% yield. Displacement of the iodo leaving group with
unsymmetrically protected hydrazines 6a and 6b yielded
cyclopropanes 7a (94%) and 7b (96%), respectively. Re-
moval of the phthalimide protecting group was then achieved
by treatment with methylhydrazine to afford the unprotected
cyclopropanes 8a (97%) and 8b (91%) in excellent yields.
Scheme 1. Synthesis of Hydrazinoethylcyclopropane 8a and 8b
a Reagents employed: cyclopropane (1 equiv), aldehyde (1.2 equiv),
Yb(OTf)3 (0.05 equiv), and CH2Cl2 (4 mL). b Product obtained in >99%
ee. c 17% of cis isomer was also obtained. d 22% of cis isomer was also
obtained. e 14% of cis isomer was also obtained.
robust in its generality with respect to the aldehyde employed.
The electronic nature of substituents on the aldehyde seems
inconsequential and other aromatic and heteroaromatic
aldehydes perform with equal aplomb. It is also of note that
even sterically demanding aldehydes such as isobutyralde-
hyde and pivaldehyde work well. In each case, the adducts
were formed as the 2,5-trans diastereomers (pyrrolidine
numbering) with insignificant amounts of the 2,5-cis adducts
present in most cases. Furthermore, when enantiomerically
pure (S)-cyclopropane 4 was employed in the reaction the
With our desired hydrazinoethyl 1,1-cyclopropanediester
8a in hand, we next investigated the scope of the reaction.
Our initial reaction involved stirring cyclopropane 8a with
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