Metal-free metathesis reaction of C-chiral allylic sulfilimines with aryl isocyanates: Construction of chiral nonracemic allylic isocyanates

Article abstract of DOI:10.1021/ja504631v

We report the facile and efficient metal-free metathesis reaction of C-chiral allylic sulfilimines with aryl isocyanates. This process facilitates the room temperature construction of an array of chiral nonracemic allylic isocyanates, which are versatile

Full text of DOI:10.1021/ja504631v

Communication
pubs.acs.org/JACS
Metal-Free Metathesis Reaction of C‑Chiral Allylic Sulfilimines with
Aryl Isocyanates: Construction of Chiral Nonracemic Allylic
Isocyanates
Rebecca L. Grange and P. Andrew Evans*
Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
Scheme 1. Inspiration for the Development of the Metal-
Free Sulfilimine/Isocyanate Metathesis for the
Construction of Allylic Isocyanates
ABSTRACT: We report the facile and efficient metal-free
metathesis reaction of C-chiral allylic sulfilimines with aryl
isocyanates. This process facilitates the room temperature
construction of an array of chiral nonracemic allylic
isocyanates, which are versatile intermediates for the
construction of unsymmetrical ureas, carbamates, thio-
carbamates and amides. Furthermore, the sulfilimine/
isocyanate metathesis reaction with 4,4′-methylene
diphenyl diisocyanate (4,4′-MDI) circumvents harsh
reaction conditions and/or hazardous reagents employed
with more classical methods for the preparation of this
important functional group.
socyanates are important synthetic intermediates in organic
chemistry since they provide a convenient precursor to
I
motifs present in materials and bioactive agents, namely,
ureas, carbamates, thiocarbamates and amides.1 For instance,
enantiomerically enriched isocyanates have featured in the
preparation of drugs for the treatment of cystic fibrosis,
Alzheimer’s disease and influenza.2 Nevertheless, despite the
importance of this functionality, the asymmetric synthesis of
allylic isocyanates has not been well developed and relies on
classical methods that have a number of inherent
limitations.3−5 For example, the stereoselective [3,3]-rear-
rangement of an allylic cyanate derived from the correspond-
ing primary allylic carbamate provides an excellent method for
the preparation of chiral nonracemic allylic isocyanates, albeit
this approach tends to rely on chiral auxiliaries and chiral pool
intermediates.3 Alternatively, the stereospecific Curtius re-
arrangement of allylic β,γ-unsaturated carboxylic acids, which
are themselves preparatively challenging intermediates,
provides the allylic isocyanates via the acyl azide intermediate
without the concomitant [3,3]-rearrangement.4 Nevertheless,
the most direct method for the construction of allylic
isocyanates is the treatment of the corresponding allylic
amine with phosgene or a suitable equivalent, which requires
the use of toxic and expensive reagents, respectively.5 Hence,
the inherent utility of enantiomerically enriched allylic
isocyanates coupled with the challenges associated with their
preparation makes the development of a more practical
method both important and timely.6
iridium-catalyzed allylic amination (Scheme 1A), would permit
the development of a metal-free metathesis reaction with an
aryl isocyanate to afford the corresponding chiral nonracemic
allylic isocyanates.8,9 Although Franz and Martin described the
sulfilimine/isocyanate metathesis reaction of N-methyl sulfili-
mine with phenyl isocyanate, the methyl isocyanate adduct
central to our hypothesis was not isolated and characterized
(Scheme 1B).10−12 We recognized that the ability to control
the fragmentation of the putative four-centered intermediate A
would be a key component to the efficient synthesis of allylic
isocyanates via this type of process (Scheme 1C). For
example, there are two modes of fragmentation of A, which
can either generate the desired allylic isocyanate 3 or
regenerate the allylic sulfilimine 1. Notwithstanding this
challenge, we envisioned the ability to utilize commercially
available and inexpensive aryl isocyanates, which are generally
less toxic and expensive than phosgene and the various
phosgene equivalents, would provide an attractive approach to
this important functionality. Herein, we now describe the
Recent advances in the metal-catalyzed asymmetric allylic
amination reaction with aza-ylides provided the impetus for
the following study.7 We reasoned that C-chiral N-allylic
sulfilimines, which are readily available via the asymmetric
Received: May 8, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja504631v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
sulfilimine/isocyanate metathesis reaction of enantiomerically
enriched allylic sulfilimines 1 with aryl isocyanates 2 for the
construction of chiral nonracemic allylic isocyanates 3
(Scheme 1C).
isocyanates, in which 4,4′-methylene diphenyl diisocyanate
(4,4′-MDI) (2d) proved superior to 1,4-phenylene diisocya-
nate (1,4-PDI) (2c) and the polymeric aryl isocyanate
(PMDI) 2e (entry 4 vs 3/5). Importantly, 4,4′-MDI (2d) is
inexpensive and one of the least toxic commercially available
aryl isocyanates.15,16 Nevertheless, the allylic isocyanate 3a is
particularly sensitive, since exposure to the aryl isocyanate 2d
for an extended time led to a significantly lower recovery of
the urea 4a (entry 6). Further studies focused on the effect of
solvent, in which 1,2-dichloroethane provided a modest
improvement in the yield (entry 9 vs 7/8). At this juncture,
we envisioned that improving the overall efficiency would
require increasing the amount of the aryl isocyanate to drive
the equilibrium in an analogous manner to the metal-catalyzed
crossed metathesis reaction of alkenes.17 Gratifyingly, treat-
ment of the allylic sulfilimine 1a with excess 4,4′-MDI (2d)
provided the allylic urea 4a in 89% overall yield with complete
transfer of chirality (100% cee).
Table 2 outlines the application of the optimized reaction
conditions to a range of enantiomerically enriched allylic
sulfilimines 1. Interestingly, the reaction is tolerant of a range
of straight chain and branched alkyl derivatives (entries 1−7).
Another striking feature with this process is the ability to
interchange the aryl isocyanate 2 to assist in the isolation of
the allylic urea 4 (entry 1 vs 2) and thereby illustrate the
versatility of the metathesis reaction. Moreover, this opera-
tionally simple process can be conducted on gram scale with
similar efficiency (entry 1) and a solution of the allylic
isocyanate 3b was readily isolated in moderate yield via
distillation (entry 2). Further studies demonstrated that tert-
butyldimethylsilyl and benzyl protected hydroxyethyl groups,
in addition to the tethered N-Boc and N-Cbz derivatives,
provide suitable substrates for this process to afford the
formally differentially protected amino alcohols and diamines
(entries 8−11). Finally, the chloro-substituted allylic sulfili-
mine 1l also provides the allylic urea 4l to illustrate the mild
nature of this process. Overall, this study highlights the
synthetic versatility of the metal-free metathesis of allylic
sulfilimines to provide allylic ureas 4 in excellent yield without
significant racemization of the inherent stereogenic center.
Having established general reaction conditions for the
construction of unsymmetrical chiral nonracemic N,N′-
disubstituted allylic ureas 4, we elected to examine a range
of other useful pronucleophiles, as outlined in Table 3. In this
context, we explored primary, secondary and aryl amines to
provide the corresponding allylic ureas 4ab−4ad, albeit the
aryl amine is slightly less efficient (entries 1−3). Additionally,
we also demonstrated alcohols and thiols provide the
carbamates and thiocarbamates 4ae−4ah in 78−84% yield
without epimerization (entries 4−7). The formation of the
carbamate 4ae is particularly significant, since trapping with
aliphatic alcohols proved particularly challenging. Finally, the
examination of carbon nucleophiles provided the alkyl and
aryl amides in 70−83% yield to illustrate the generality of this
approach (entries 8 and 9).
Table 1. Optimization of the Metal-Free Metathesis of C-
Chiral Allylic Sulfilimines with Aryl Isocyanates for the
Construction of N,N′-Disubstituted Ureas (R′ = 2-
a
MeOC6H4CH2)
equiv
of 2
yield of 4a
cee of 4a
b
c
entry aryl isocyanate 2
solvent
(%)
(%)
1
2
PIC
1-NIC
1,4-PDI
4,4′-MDI
PMDI
4,4′-MDI
“
a
b
c
d
e
d
“
1.0
“
CHCl3
57
61
37
67
57
97
100
99
100
“
“
3
0.5
“
“
“
4
5
0.37
0.5
“
“
d
6
“
11
“
7
PhMe
THF
DCE
DCE
53
54
72
89e
100
“
8
“
“
“
9
“
“
“
“
10
4,4′-MDI
d
1.5
100
a
All reactions were performed on a 0.175 mmol reaction scale at room
temperature for ca. 1 h and then quenched with 2-methoxybenzyl-
b
amine (1 equiv). Isolated yields of the N-2-methoxybenzyl urea
c
adduct. The enantiomeric excess was determined by chiral HPLC on
d
the N-2-methoxybenzyl urea derivative. Reaction stirred for ca. 24 h.
e
Quenched with 2-methoxybenzylamine (3 equiv).
Figure 1. Classes of aryl isocyanates screened in the metal-free
metathesis reaction of chiral nonracemic allylic sulfilimines.
Table 1 outlines the optimization of the metal-free
metathesis reaction of enantiomerically enriched allylic
sulfilimines with aryl isocyanates. Treatment of the sulfilimine
1a with phenyl isocyanate (PIC) (2a) (Figure 1) in
chloroform at room temperature furnished the allylic
isocyanate 3a, which was trapped in situ with 2-methoxy-
benzylamine to afford the allylic urea 4a in 57% yield with
excellent chirality transfer but incomplete conversion (entry
1).13 In order to investigate the influence of the relative
stabilities of the isocyanate components (2 vs 3), 1-naphthyl
isocyanate (1-NIC) (2b) (ΔH°form = −2.3 kcal/mol) which is
considerably less stable than the corresponding PIC (2a)
(ΔH°form = −16.1 kcal/mol),14 was examined. Interestingly,
this provided only a very minor improvement in the
conversion (entry 2), which we attribute to the concomitant
destabilization of the aryl sulfilimine product. Additional
studies focused on the examination of polysubstituted aryl
In an effort to extend the synthetic utility of this process,
we envisioned the ability to convert the achiral allylic
benzoate 5a directly to the enantioenriched allylic urea 4ab
would provide an attractive synthetic method (Scheme 2). A
key and striking feature with this process is the ability to form
the reactive allylic isocyanate in the presence of the
byproducts from the initial allylic amination to facilitate a
challenging one-pot process. Gratifyingly, treatment of the
B
dx.doi.org/10.1021/ja504631v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Scope of the Metal-Free Metathesis of C-Chiral
Allylic Sulfilimines with Aryl Isocyanates for the
Table 3. Scope of the Nucleophilic Trapping of the
Enantiomerically Enriched Allylic Isocyanates Formed via
Construction of N,N′-Disubstituted Chiral Nonracemic
the Metal-Free Metathesis of C-Chiral Allylic Sulfilimines
a b c
, ,
ab c
, ,
Allylic Ureas (R′ = 2-MeOC6H4CH2)
with Aryl Isocyanates
a
All reactions were carried out on a 0.175 mmol reaction scale in DCE
(0.6 M) with 4,4′-MDI (2d) at room temperature and then quenched
b
c
with the respective nucleophile. Isolated yields. Enantiomeric excess
d
was determined by chiral HPLC. Quenched with amine (3 equiv).
Enantiomeric excess was determined by chiral HPLC analysis of the
N-benzyl derivative. Quenched with aliphatic alcohol (6 equiv).
Quenched with phenol (3.3 equiv). Enantioselectivity was
e
f
a
All reactions were carried out on a 0.175 mmol reaction scale in DCE
(0.6 M) with the aryl isocyanate 2a or 2d at room temperature and
then quenched with 2-methoxybenzylamine (3 equiv). AMethod A: 1.5
g
h
determined by chiral HPLC analysis of the N-2-methoxybenzyl urea
i
j
b
B
derivative. Quenched with thiol (3 equiv). Quenched with Me3Al (12
equiv of 4,4′-MDI (2d). Method B: 3.0 equiv. PIC (2a). Isolated
yields of the N-2-methoxybenzyl urea derivative. Enantioselectivity
k
c
equiv). Quenched with PhMgBr (3.3 equiv).
was determined by chiral HPLC on the N-2-methoxybenzyl urea
d
e
Scheme 2. One-Pot Enantioselective Construction of a
N,N′-Disubstituted Urea via the Chiral Nonracemic Allylic
Isocyanate Derived from the Allylic Substitution/
Sulfilimine-Isocyanate Metathesis Reaction
derivative. 93% Yield with 100% cee on 1 g scale. The intermediary
allylic isocyanate 3a was also distilled and trapped with 1.05 equiv of 2-
methoxybenzylamine (see Supporting Information for details).
allylic benzoate 5a with S,S-diphenylsulfilimine and the chiral
iridium complex derived from [Ir(cod)Cl]2 and the
phosphoramidite ligand 618 in chloroform at 35 °C furnished
the sulfilimine 2a, which was treated in situ with 4,4′-MDI
(2d) followed by 4-methoxybenzylamine to afford the
enantiomerically enriched allylic urea 4ab in 71% overall
yield with excellent regio- and enantioselectivity (rs ≥19:1,
91% ee).
In conclusion, we have developed a facile and efficient
metal-free metathesis reaction of C-chiral allylic sulfilimines
for the construction of chiral nonracemic allylic isocyanates,
which can be trapped with an array of pronucleophiles to
facilitate the construction of unsymmetrical ureas, carbamates,
thiocarbamates and amides. Furthermore, the sulfilimine/
isocyanate metathesis reaction with 4,4′-methylene diphenyl
diisocyanate (4,4′-MDI) circumvents harsh reaction con-
ditions and/or hazardous reagents employed with more
classical methods for the preparation of this important
motif. Finally, the direct conversion of an achiral allylic
alcohol derivative to the corresponding chiral nonracemic
allylic urea avoids the challenges associated with the direct
allylic alkylation with sodium isocyanate.8 Hence, we fully
anticipate that this transformation will provide a useful
alternative to more classical methods for the construction of
chiral nonracemic allylic isocyanates, which are important
intermediates for materials and medicinal chemistry.
C
dx.doi.org/10.1021/ja504631v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
isocyanates, see: Tsui, G. C.; Ninnemann, N. M.; Hosotani, A.;
Lautens, M. Org. Lett. 2013, 15, 1064.
(9) For the first report of an isocyanate metathesis reaction, see:
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectral data and copies of the
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Case, L. C. Nature 1959, 183, 675.
(10) Franz, J. A.; Martin, J. C. J. Am. Chem. Soc. 1975, 97, 583.
(11) For examples of the metathesis reaction between nitrogen-
phosphorus ylides and carbon dioxide, see: (a) Molina, P.; Alajarin,
M.; Arques, A. Synthesis 1982, 596. (b) Tsuge, O.; Kanemasa, S.;
Matsuda, K. J. Org. Chem. 1984, 49, 2688. (c) Charbonnier, F.;
AUTHOR INFORMATION
■
Corresponding Author
Andrew.Evans@chem.queensu.ca
Marsura, A.; Roussel, K.; Kovac
84, 535.
́ ́
s, J.; Pinter, I. Helv. Chim. Acta 2001,
(12) Interestingly, attempts to utilize phosphonium ylides in the
metal-catalyzed allylic substitution reaction were unsuccessful thereby
making the sulfilimine critical for this process.
Notes
The authors declare no competing financial interest.
(13) For the definition of conservation of enantiomeric excess (cee),
see: Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc.
1999, 121, 6761.
(14) For enthalpies of formation of various isocyanates, see:
Selivanov, V. D.; Konstantinov, I. I. Russ. J. Phys. Ch. 1975, 49, 620.
Unfortunately, the corresponding enthalpies of formation of aryl
sulfilimines are not available.
(15) Toxicity: LC50 (inhalation) in male rats for phosgene = 49
mg/m3 and MDI = 369 mg/m3. Alternatively, the amount that is
immediately dangerous to life or health for phosgene = 8.1 mg/m3
and MDI = 75 mg/m3. See: Hazardous Substances Data Bank
(http://toxnet.nlm.nih.gov/).
(16) Cost: Selected prices for Phosgene = 2.26; Diphosgene = 5.91;
PIC = 0.19; 4,4′-MDI = 0.07 ($/g, USD, Aldrich).
(17) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
ACKNOWLEDGMENTS
■
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant and
Queen’s University for generous financial support. NSERC
is also thanked for supporting a Tier 1 Canada Research Chair
(P.A.E.). Additionally, we acknowledge the Royal Society for a
Wolfson Research Merit Award (P.A.E.).
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D
dx.doi.org/10.1021/ja504631v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX