Fenster et al.
SCHEME 1. Ambident Electrophilicity of Iminium Ethers
SCHEME 2. Preparation of Iminium Ethers
of a second hydride equivalent completes the reaction. This
conversion was achievable either under hydrogenation (Table
1, entries 1 and 2) conditions or with sodium borohydride
(entries 3 and 4). These mild conditions stand in contrast to the
usual reduction of lactams with lithium aluminum hydride or
borane reagents. One particularly useful application of this
reaction would be the synthesis of D- or T-labeled amines under
very mild conditions (entry 5).
of the ambident iminium ether, the temperature and duration
of the reaction, and the solvent. Similar regioselectivity issues
arise in the ring-opening chemistry of oxazolines, which is often
carried out through N-protonated intermediates.1d-h
Path a adducts can also lead to alternative products when
ring opening successfully competes with the ejection of the
nucleophile. Two examples are shown in Scheme 3. Thus, when
disodium sulfide is added to the iminium ether, the resulting
thiolate directly undergoes ring opening to afford the thioamide
product in modest yield (Table 1, entry 6). A similar situation
was observed with amines (entries 7-10) as well as hydrazines
(entry 11), which were found to yield amidines and hydrazones,
respectively. The products resulting from amine nucleophiles
were found to be unstable to aqueous workup and SiO2
purification, such that hydrolysis to the corresponding amide
occurred when a standard aqueous workup was used. In contrast,
immediate silylation of the side chain alkoxy resulted in stable
amidines (entries 9-10), suggesting that the hydrolysis step
involved intramolecular addition of the terminal hydroxy group
to the amidine (Scheme 4). In our preliminary report, we
misassigned the product of hydrazine addition as taking place
via path b to afford a 3′-(dimethylhydrazino)propyl lactam.4
Resynthesis and spectroscopic examination of the product of
this reaction suggested that it afforded an N-guanidinyl lactam
6h; this compound was isolable by recrystallization from the
reaction mixture. Its structure was further supported by O-
silylation under standard conditions to afford 6i, which was only
consistent with the presence of a hydroxy group (Scheme 4).
Reactions That Proceed via Reversible Nucleophilic Ad-
dition (Path b). Some nucleophiles that add to iminium ether
3 via path b are shown in Table 2. In each case, the nucleophile
was able to undergo elimination from the first-formed adduct
and ultimately attack at the terminal carbon atom (i.e., path b).
A number of diverse N-alkylated lactams were produced in this
way, including azides (entry 1), ethers (entry 2), sulfides (entry
3), and halides (entries 4-5). In a carbon-carbon forming step,
cyanide could also be added to yield nitrile derived N-alkylated
lactams (entry 6).
In a preliminary report, we described the preparation of two
isolated iminium ethers and their reaction with several nucleo-
philes.4 We have recently had occasion to re-examine this
chemistry as a tool for library generation. Here, we present a
full account that addresses (1) the expansion of the scope of
the reaction to encompass a series of substrates related to a
recently reported series of γ-turn mimics,5 (2) the determination
of the regiochemistry of hydroxide addition to the iminium
ethers, and (3) the development of a one-pot iminium ether
synthesis/nucleophilic addition sequence.
Results and Discussion
Survey of the Ambident Electrophilicity of Iminium
Ethers. Our initial experiments were carried out with isolated
iminium ethers 3 and 4, which were prepared from cyclohex-
anone as previously reported.3a This involved the treatment of
cyclohexanone with the hydroxyethyl or hydroxypropyl azide
in the presence of boron trifluoride followed by crystallization
of the resulting iminium ether as its tetrafluoroborate salt
(Scheme 2). First, reactions that unambiguously arise from either
mechanism, as judged by the products formed, were surveyed.
We then considered special cases that are either mechanistically
ambiguous (hydroxide addition, which would afford the same
product by either mechanism) or have a more complex
dependency on nucleophilic structure (a related series of
stabilized carbon nucleophiles).
Reactions That Proceed via Irreversible Nucleophilic
Addition (Path a). Nucleophiles that provide product via path
a do so because the initial addition of nucleophile is either
irreversible or the initial adduct has another pathway open to
it. Examples of these reactions are shown in Scheme 3 and Table
1. Treatment with reducing agents leads to the fully reduced
tertiary amine because the addition of hydride to the iminium
ether is obviously irreversible. Furthermore, the reduced het-
erocycle is in equilibrium with the corresponding N-hydrox-
ypropyliminium N-hydroxybutyliminium ion and so the addition
The applicability of this reaction to peptidomimetic synthesis
was demonstrated in the construction of 1,4-diazepin-5-ones.6
Compounds containing this ring system have recently been
shown to exhibit effective inhibition of the lymphocyte function-
associate antigen-1 LFA-1 in inflammation and autoimmune
(6) (a) Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith, A. B., III;
Hirschmann, R. Org. Lett. 2001, 3, 1089-1092. (b) Han, Y.; Mierke, D.
F.; Chorev, M. Biopolymers 2002, 64, 1-15. (c) Vasudevan, A.; Villamil,
C. I.; Djuric, S. W. Org. Lett. 2004, 6, 3361-3364. (d) Alajar´ın, M.; Vidal,
A.; Tovar, F. Tetrahedron 2005, 61, 1531-1537. (e) Iden, H. S.; Lubell,
W. D. Org. Lett. 2006, 8, 3425-3428.
(4) Gracias, V.; Milligan, G. L.; Aube´, J. J. Org. Chem. 1996, 61, 10-
11.
(5) Ramanathan, S. K.; Keeler, J.; Lee, H.-L.; Reddy, D. S.; Lushington,
G.; Aube´, J. Org. Lett. 2005, 7, 1059-1062.
202 J. Org. Chem., Vol. 73, No. 1, 2008