Chiral β-iodoamines by urea-catalysed iodocyclization of trichloroacetimidates

Article abstract of DOI:10.1039/c3sc50410g

Highly enantioselective vicinal iodoamination of olefins is accomplished through the iodocyclization of alkenyl trichloroacetimidates catalysed by a new chiral Schiff-base urea derivative. The resulting products are converted readily to a variety of polyfunctional amine-containing chiral building blocks.

Full text of DOI:10.1039/c3sc50410g

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Chiral b-iodoamines by urea-catalysed iodocyclization
of trichloroacetimidates†
Cite this: DOI: 10.1039/c3sc50410g
*
Cheyenne S. Brindle,‡ Charles S. Yeung‡ and Eric N. Jacobsen
Received 11th February 2013
Accepted 12th March 2013
Highly enantioselective vicinal iodoamination of olefins is accomplished through the iodocyclization of
alkenyl trichloroacetimidates catalysed by a new chiral Schiff-base urea derivative. The resulting products
are converted readily to a variety of polyfunctional amine-containing chiral building blocks.
DOI: 10.1039/c3sc50410g
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as the optimal source of electrophilic iodine, and the presence of
trace amounts of water, light, radical scavengers, or catalytic I2
Introduction
Alkene halocyclizations provide a powerful pathway for the
preparation of sterically congested and stereochemically
dened heterocycles.1 Several recent studies have documented
catalytic asymmetric halolactonizations for the construction of
chiral lactones.2 Vicinal haloaminations, by comparison,
represent an underdeveloped class of alkene oxidations in
asymmetric catalysis,3,4 and this type of transformation could
provide useful access to valuable nitrogen-containing chiral
intermediates.5 Drawing on the recently demonstrated ability of
chiral ureas to promote stereoselective transformations of
iodonium intermediates,2g we describe here the intramolecular
vicinal iodoamination of alkenes catalysed with high enantio-
selectivity by new Schiff-base urea derivatives.
was found to have little effect on either the observed enantiose-
lectivity or efficiency of the reaction. The tertiary aminourea
4, which was the optimal catalyst in previously reported
Table 1 Catalyst optimization for intramolecular iodoamination of 2aa
Our selection of a target reaction for the development of
enantioselective iodoamination catalysts was guided by the goal
of accessing products that could serve as versatile chiral
building blocks. We chose alkene 1a (Table 1) as a model
substrate because the trichloroacetimidate group would be
delivered to the alkene in an iodoamination reaction through a
readily cleavable tether.6,7 The resulting product 2a is a synthetic
equivalent of a b-iodo-1,3-aminoalcohol with the nitrogen
residing on a newly formed tertiary stereogenic center.
Results and discussion
Entry
Catalyst
Temp. (ꢀC)
Time (d)
Yieldb (%)
ee (%)
Evaluation of a broad series of chiral H-bond donors as potential
catalysts8 led to promising lead results with the known Schiff-
base urea derivatives 3a and 3b (Table 1, entries 1 and 2).9
Commercially available N-iodosuccinimide (NIS) was identied
1c
2d
3d
4d
5d
6d
7d
8d
9c
3a
3b
3c
3d
3e
3e
3f
3f
4
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ30
ꢁ20
ꢁ40
ꢁ20
9
56
33
31
44
84
27
74
74
79
82
88
79
90
ꢁ15
1.5
1.5
1.5
1.5
3
1.5
1.5
9
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, USA. E-mail: jacobsen@chemistry.harvard.edu
87
100
100
91
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, additional discussion on catalyst optimization and
substrate scope, and crystallographic information (CIF) for compounds 2i, 2l, 5c
and 7a. CCDC 924031–924034. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3sc50410g
a
Conditions: 10 mol% catalyst, [2a] ¼ 0.05 M. b Crude yields based on
1H NMR integration against an internal quantitative standard. c 1.1 eq.
NIS. 5 eq. NIS.
d
‡ These authors contributed equally.
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iodolactonization reactions,2g induced iodocyclization of 1a with hydroxyl group plays a direct role in the iodoamination reaction
very poor enantioselectivity (entry 9). Other urea derivatives mechanism, not only by restricting the catalyst conformation
lacking the salicylaldimine functionality were ineffective in through an intramolecular H-bond, but perhaps also through
promoting iodoamination. Based on catalyst structure–enan- interaction with the basic imidate during the cyclization.
tioselectivity relationship studies,8 we identied the 3-(tert-
By modifying the tertiary amide component in our Schiff-
butyl)-5-formyl-4-hydroxyphenyl pivalate as the optimal Schiff- base urea catalysts, signicant improvements in enantiose-
base substituent; replacing the OH group with either a H or OMe lectivity were obtained (entries 2–8). Although product ee was
afforded less selective catalysts. Even minor variations of the only weakly responsive to the structure of the tertiary amide,
electronic properties of the aromatic substituent led to dimin- reactivity could be enhanced through the introduction of
ished enantioselectivities. Thus, it is likely that the phenolic appropriate arylpyrrolidine derivatives.10 The o-tolylpyrrolidino
Table 2 Substrate scope of intramolecular iodoaminationa
a
Reactions were performed on a 0.1 mmol scale unless otherwise indicated. Yields are of isolated product following purication. Enantiomeric
excesses (ee) were determined by HPLC analysis on commercial chiral columns. The absolute conguration of (S)-2i and (S)-2l was determined
by obtaining molecular structures by X-ray crystallography. The absolute conguration of (S)-2a and (S)-2c was determined by derivatization (see
b
Scheme 1). All other products are assigned by analogy. See ESI for full details.8 Reaction was conducted on a 1 mmol scale (432 mg 2c was
isolated). c ee following a single recrystallization from hexanes.
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derivative 3f was found to be optimal in this regard, allowing the
reaction to be carried out with improved enantioselectivity and
high yield at reduced temperatures (entry 8).
The scope of the enantioselective iodoamination reaction was
explored with the optimal catalyst 3f (Table 2). Most a-styrenyl
derivatives examined bearing homoallylic trichloroacetimidate
groups were found to be suitable substrates, undergoing iodocy-
clization to products 2b–n with enantioselectivities exceeding 90%
in most cases.11 The transformation is compatible with a variety of
functional groups including esters (2f–g), ketones (2h), acetals (2k),
and bystander alkenes (2j). In general, the cyclization products are
obtained cleanly: unreacted homoallylic trichloroacetimidate is
observed and can be recovered in cases where modest yields were
obtained. Substrates bearing electron-rich aromatic substituents
underwent cyclization with lower enantioselectivity, and most of
those bearing ortho substituents (with the exception of 1m) did not
provide iodoamination products.12 Aliphatic homoallylic tri-
chloroacetimidates were also found to undergo iodocyclization,
albeit with reduced enantioselectivity (e.g., 2o).
Scheme 2 Proposed role of 3f as a phase transfer catalyst. For spectroscopic
evidence and potential conformations for a related NIS$3b complex, see ESI.†
The utility of the chiral vicinal iodotrichloroacetimidates
produced in this reaction is readily demonstrated in a variety of
simple transformations (Scheme 1). Full deprotection of the tri-
chloroacetimidate could be inducedby treatment of2c with acid in
the presence of water to generate 6c. Under anhydrous conditions,
4-chloro-1-iodo-2-trichloroacetamide 5c was formed via selective
cleavage of the C–O bond and generation of a new C–Cl bond,
leaving the trichloroacetamide group intact. Reaction of 2a and 2c
with cyanide resulted in smooth conversion to products 7a and 7c,
respectively. Instead of direct SN2 displacement of the highly con-
gested iodide, cyanide addition to the trichloroacetimidate
occurred with subsequent iodide displacement to afford the
unusual aziridine N,O-acetals diastereoselectively.13,14 The absolute
and relative stereochemistry of aziridine 7a was established
unambiguously by X-ray crystallography.
The electrophilic iodinating agent, N-iodosuccinimide (NIS),
has no detectable solubility in the reaction medium used forꢀthe
ꢀ
catalytic iodoamination reaction (toluene, ꢁ40 C to ꢁ50 C).
However, a soluble complex is generated in the presence of the
urea catalyst, as evidenced by 1H NMR spectral shis of the
catalyst's urea N–H protons observed upon addition of one
equivalent of NIS (Scheme 2). Complexation is presumably
reversible since the active catalyst can be reisolated following a
reductive quench of the reaction mixture. Preliminary compu-
tational studies on substrate complexation reveal that the sali-
cylaldimine group is in close proximity to the bound molecule
of NIS.8 This suggests a basis for the high sensitivity of enan-
tioinduction on the substituents on the salicyaldimine. We
propose that the urea Schiff-base catalysts promote the iodo-
cyclization reaction by acting as a neutral phase transfer agent.
This pathway is reminiscent of the chiral phosphate anion
phase transfer catalysis that has recently been implicated in
related halocyclizations,15 although the solubilization mecha-
nism is clearly quite different in the present case.
Conclusions
We have achieved the enantioselective synthesis of chiral
iodoamines by
a urea-catalysed iodocyclization of easily
accessed alkenyl trichloroacetimidates. This approach to
enantioselective iodoamination represents a potentially general
platform for electrophilic alkene functionalizations that may be
readily extended to other onium ions.
Acknowledgements
This work was supported by the NIGMS CMLD program
(P50GM069721), a fellowship to C.S.B. from the American
Cancer Society, and a postdoctoral fellowship to C.S.Y. from
NSERC. We thank Dr. Shao-Liang Zheng for crystal structure
determination and Mr. Yongho Park for experimental
assistance.
Scheme 1 Transformations of chiral iodotrichloroacetimidates. (i) 4 M HCl
(dioxane), CH2Cl2, 12 h, 89%, 98% ee; (ii) 2 M HCl (aq.), MeOH, 13 h, 99%; (iii)
NaCN, DMF, 50 ꢀC, 12 h, 84%, 98% ee (7a), 16 h, 79%, 90% ee (7c). a ee following
b
a single recrystallization from hexanes/Et2O. ee determined via derivatization.
See ESI for full details.†
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