Rhodium-catalyzed regio- and stereoselective oxyamination of dienes via tandem aziridination/ring-opening of dienyl carbamates

Article abstract of DOI:10.1039/c4cc01312c

The reaction of dienyl carbamates with PhI(OR)₂ in the presence of rhodium catalysts affords vinyl aziridines which are in situ regio- and stereoselectively opened to afford oxyamination products resulting from a selective S_N2 (Rh₂(OAc)₄/PhI(OPiv)₂) or S_N2′ (Rh₂(OPiv)₄/PhI(OAc) ₂) opening. The scope and limitations of this tandem process are described.

Full text of DOI:10.1039/c4cc01312c

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Rhodium-catalyzed regio- and stereoselective
oxyamination of dienes via tandem aziridination/
ring-opening of dienyl carbamates†
Cite this: Chem. Commun., 2014,
50, 7344
Received 19th February 2014,
Accepted 16th May 2014
Joan Guasch, Yolanda Dıaz, M. Isabel Matheu* and Sergio Castillon*
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DOI: 10.1039/c4cc01312c
www.rsc.org/chemcomm
The reaction of dienyl carbamates with PhI(OR)2 in the presence of
Ring-opening reactions of vinylaziridines with oxygen nucleo-
rhodium catalysts affords vinyl aziridines which are in situ regio- and philes constitute a useful pathway for the stereoselective synthesis
stereoselectively opened to afford oxyamination products resulting from of unsaturated aminoalcohols.5,5d,9 We recently developed an efficient
a selective SN2 (Rh2(OAc)4/PhI(OPiv)2) or SN20 (Rh2(OPiv)4/PhI(OAc)2) silver-catalyzed regio- and stereospecific aziridination of dienols that
opening. The scope and limitations of this tandem process are described. allowed an easy access to sphingosine.10 The regioselectivity obtained
in the aziridination reaction (9 : 1) was remarkable. However, we
Vinyl aziridines are key starting intermediates for the synthesis of a considered that it could be improved by performing an intra-
diversity of functionalized nitrogen-containing products through molecular version of the reaction. Intramolecular aziridination using
nucleophilic ring opening processes.1 Thus, the nucleophilic ring sulfamates,11 sulfonamides,12 sulfonimidamides,13 carbamates14 and
opening of vinylaziridines could proceed through either SN2 (B) or tosylcarbamates15 as nitrene precursors catalyzed by copper or
SN20 (A) processes (Scheme 1).2 They also undergo isomerization rhodium complexes has been reported. However, there are no
and cycloaddition reactions affording a wide range of heterocycles examples of their application in the synthesis of vinylaziridines.
through tandem opening/cyclization processes usually catalyzed by
transition metal complexes.1
In this communication we report the first tandem transition
metal-catalyzed intramolecular aziridination of dienes followed
In vinylaziridine ring opening, the selective weakening of by a regiocontrolled ring-opening with oxygen nucleophiles.
the allylic C–N bond by the pCQC–s*C–N overlap3 intrinsically The metal catalyst plays a double role, as a nitrene stabilizing
directs the nucleophilic addition through A and B pathways. An agent in the aziridination reaction and eventually as a Lewis
SN20 pathway is observed with organocopper reagents,4 whereas acid in the nucleophilic ring opening process (Scheme 2).
oxygen-centered nucleophiles,5 halogens6 and sulfur-stabilized
At the outset of this study we focused on the intramolecular
carbanions3,7 preferentially lead to SN2 products. The latter aziridination of carbamate 1 (Table 1). Initially, Cu, Ag and Rh were
examples suggest that the regioselectivity of the ring opening tested as catalysts in the presence of iodobenzene diacetate
reactions of vinylaziridines is governed mainly by the type of (PhI(OAc)2) and MgO at 20 1C.16 In all cases the formation of acetates
nucleophile. However, vinylaziridine substitution, catalysts8 3a and 3b was observed. These compounds arise from the transient
and solvents also play a role in controlling the regioselective vinylaziridine 2 and subsequent SN2 and SN20 ring opening, respec-
opening. In this sense, controlling the regioselective opening of tively, by the acetate group resulted in the formation of the nitrene
vinylaziridines remains an unachieved challenge.
transfer reagent.14a,b Both reactions were stereoselective, affording a
single diastereomer (see Scheme 3 and the ESI† for the determina-
tion of relative configuration of compound 3b). The best results were
Scheme 1 Pathways for the ring-opening of vinylaziridines.
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Department of Quımica Analıtica i Quımica Organica, Universitat Rovira i Virgili,
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C/Marcelꢀlı Domingo s/n, 43007 Tarragona, Spain. E-mail: sergio.castillon@urv.cat,
maribel.matheu@urv.cat
† Electronic supplementary information (ESI) available: Characterization data of main
products prepared and 1H and 13C NMR data, as well as the procedure for determining
the relative configuration of SN20 products. See DOI: 10.1039/c4cc01312c
Scheme 2 Tandem intramolecular aziridination-ring opening.
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Table 1 Tandem intramolecular aziridination/ring opening of 1 with
different nitrene sources using Rh(II)carboxylate as catalysts. Optimization
of the reaction conditionsa
Scheme 4 Proposed mechanism for the SN2 and syn SN20 processes.
Conv.b
Regiosel. a,b
Entry
R
L
Products
(Yield)c (%)
ratiob (%)
regioselectivity, which could be initially explained considering
that the metal complex remains linked to nitrogen after the
aziridination17 activating the opening process. The effect of the
temperature was then evaluated, and when the reaction was
carried out at 5 1C, a remarkable SN2/SN20 = o5 : 495 of
compounds 3a,b was obtained (Table 1, entries 9 and 10).
When trifluoroacetate iodobenzene was used, no reaction was
observed regardless of the catalyst (Table 1, entries 4 and 8).
For determining the relative configuration of stereocentres
in the SN20 products, compound 3b was transformed into the
bicyclic compound 7 following a modified reported procedure18
(see Scheme 3 and ESI†). From NOE experiments on 7 it can be
inferred that the proton on the bridge and the methyl group
were anti, involving a syn orientation of amino and acetate
groups in compound 3b. This fact is not consistent with the
classical anti stereochemical outcome of an intermolecular SN20
process. An explanation is proposed in Scheme 4.
1
2
3
4
5
6
7
Ac
Piv
Bz
CF3CO
Ac
Piv
Bz
CF3CO
Ac
Ac
OAc
OAc
OAc
OAc
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
3a,b
4a,b
5a,b
6a,b
3a,b
4a,b
5a,b
6a,b
3a,b
3a,b
95 (87)
499 (89)d
499 (91)
499 (0)
499 (82)
499 (61)
499 (82)
499 (0)
499
75 : 25
91 : 9
66 : 34
—
10 : 90
15 : 85
14 : 86
—
18 : 82
o5 : 495
8
9e
10 f
499 (74)
a
All reactions were performed using a catalyst/1/PhI(OR)2/MgO molar
ratio of 0.1 : 1 : 2 : 3.3 in a 0.05 M substrate solution in CH2Cl2, T = 20 1C,
b
t = 48 h for Rh2(OAc)4 and 24 h for Rh2(OPiv)4. Determined by
1H NMR. Isolated yields (combination of regioisomers). Compounds
c
d
e
f
3a,b were also obtained in 8% yield. Temperature 45 1C. Temperature
5 1C.
To explore the scope and the limitations of this methodology, we
applied it to a variety of differently configured and functionalized
dienyl carbamates (Fig. 1, Table 2). Carbamates were easily synthe-
sized from the corresponding dienols through the carbamoylation
process described by Kocovsky.19 Tandem aziridination/opening of
substrates 8 and 9 with a trans/trans configuration of the double
bonds (Table 2, entries 1–4) provided an excellent regiocontrol with
both catalytic systems affording products resulting from an SN2
attack under conditions A (14a, 16a), and from an SN20 attack under
conditions B (15b, 17b). When the diene was substituted by a phenyl
group (10) (Table 2, entries 5 and 6), selectivity with both catalytic
systems decreased probably due to the high reactivity of the transient
phenyl-substituted vinylaziridine. The unexpected effect of the
methyl substituent at C-4 in the regioselective outcome is worth
mentioning. Thus, unexpectedly, when the reaction was conducted
with carbamate 11, employing Rh2(OAc)4, and especially Rh2(OPiv)4,
the SN20 attack was preferred over the SN2 attack (Table 2, entries 7
and 8). Next, we explored the reaction of trans–cis and cis–cis dienyl
carbamates 12 and 13, related to carbamate 1 but with different
configurations in the double bonds (Table 2, entries 9–12). The
regioisomers resulting from an SN2 attack were obtained in
Scheme 3 Determination of relative configuration of 3b.
obtained using catalytic amounts of dirhodium tetraacetate which
afforded acetates 3a and 3b in good yield with a regioisomeric ratio
of 75 : 25 (Table 1, entry 1).
Replacing PhI(OAc)2 by PhI(OPiv)2 (Table 1, entry 2), products 4a
and 4b were obtained with a significant increase in the regioisomeric
ratio up to 91 : 9. In this case, minor amounts of the acetate
derivatives 3 were also obtained. The acetate groups in products 3
come from the rhodium acetate complex. In order to avoid their
formation we decided to test the corresponding rhodium pivalate
complex. To our delight, using Rh2(OPiv)4 as the catalyst, a reversion
of the regioselectivity was obtained with a 4a/4b (SN2/SN20) ratio of
15 : 85 (Table 1, entry 6). The effect of the nucleophile and the
catalyst on the regioselectivity was then evaluated by modifying the
iodine(III) oxidant and the carboxylate group in the catalyst (Table 1).
When the reaction was carried out using different iodine(III) reagents
catalyzed by Rh2(OAc)4 (Table 1, entries 1–4), the regioselectivity
appeared to arise mainly from the properties of the nucleophile.
Thus, the preferences towards the SN2 attack of three carboxylates
can be related to their respective nucleophilicity. On the other hand,
when the reaction was catalyzed by the more sterically demanding
Rh2(OPiv)4 (Table 1, entries 5–10) the SN20 attack was preferentially
produced, and the character of the O-nucleophile did not have any
influence on the regioselectivity. Comparing entries 2 and 6 it is
evident that the catalyst is responsible for the control of the
Fig. 1 Substrate scope.
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Table 2 Tandem intramolecular aziridination/ring opening. Scopea
(Scheme 3), an anti-relative configuration was attributed to com-
pound 22b.2,4
Yieldb a,b ratioc
Compounds 3b, 4b and 14b–22b resulted from a syn-SN20
process. Scheme 4 shows a plausible mechanism to explain both
the regioselectivity and the syn-nature of this process. The syn process
can be justified by a directed transfer of carboxylate from the metal
coordinated to the carbamate function. In fact, the coordination of
rhodium to the aziridinic nitrogen,11c or the directing effect of
cations in the opening of aziridines has already been reported.20
Looking for information about this process we carried out the
reaction of 1 using Rh2(OPiv)4 as a catalyst, under the optimized
reaction conditions using sodium, potassium and cesium carbonate
as bases, and observed 3a/3b ratios (SN2/SN20) of 9 : 91, 37 : 63 and
86 : 14, respectively. These results clearly show the role of cations in
the control of regio- and stereoselectivity, which suggest that
magnesium plays a determining role in the SN20 process.
In this context, the strong preference for the SN2 attack in the
Rh2(OAc)4-catalysed process can be rationalized considering that
rhodium remains coordinated to nitrogen, and Mg(OCOR)2
opens the activated aziridine through an SN2 process. On the
other hand, the sterically more demanding Rh2(OPiv)4 can be
easily released from the coordination to nitrogen, which enables
Mg(OCOR)2 to coordinate the carbamate function and direct the
attack of the carboxylate through a syn-SN20 manner.
Entry SM Cond.a
(%)
(%)
Products
1
8
A
B
A
B
A
B
A
72
86 : 14
2
8
65
71
76
54
60
71
10 : 90
91 : 9
3
9
4
9
13 : 87
70/30
28/72
25 : 75
5
10
10
11
6
7d
8
11
12
12
Bd
A
68
56
64
10 : 90
90/10
39/61
The procedure developed can provide a straightforward access to
sphingosine and derivatives. For this purpose, diene 25 was treated
with Rh2(OAc)4/PhI(OPiv)2 under the optimized reaction conditions
to afford 26a in a 79% yield. When the catalytic system Rh2(OPiv)4/
PhI(OAc)2 was used, compound 27b was obtained in 66% yield,
together with minor amounts of 27a (10%) (Scheme 5). Treatment of
compound 26a in a basic medium afforded sphingosine.21 Thus,
sphingosine was synthesized in two steps from the dienyl carbamate
25 in a 56% overall yield.
9
10
11
B
13
13
A
B
74
71
90 : 10
36 : 64
12
In conclusion, tandem intramolecular aziridination/ring
opening of dienol carbamates was regioselectively performed
by selecting the rhodium catalyst and the iodine(III) oxidizing
reagent. The carboxylate present in the iodine(III) reagent
released during the reaction behaves as a nucleophile opening the
aziridine intermediate. The use of Rh2(OAc)4 affords products
resulting from an SN2 attack and the rhodium catalyst plays a double
role, first in promoting the metalonitrene formation and second as a
a
Conditions A: Rh2(OAc)4/substrate/PhI(OPiv)2/MgO (0.1 : 1 : 2 : 3.3) in a
0.05 M solution in CH2Cl2, T = 20 1C, t = 48 h. Conditions B: Rh2(OPiv)4/
substrate/PhI(OAc)2/MgO (0.1 : 1 : 2 : 3.3) in a 0.05 M solution in CH2Cl2,
b
T = 5 1C, t = 24 h. Isolated yields (combination of regioisomers).
c
d
Determined by 1H NMR. PhI(OAc)2 was used instead of PhI(OPiv)2
since yields were better and selectivity similar.
selectivities similar to those obtained with the trans–trans Lewis acid in the SN2 opening process. On the contrary, when
dienes, while those resulting from the SN20 attack suffered a Rh2(OPiv)4 was used as the catalyst, products resulting from an
moderate drop. Compounds obtained from carbamate 13 by SN20 attack were selectively obtained. The bulkiness of Rh2(OPiv)4
aziridination and SN20 opening proved to be identical to 3b might favor the de-coordination from the aziridinic nitrogen, leaving
(entry 12) and 4b (entry 11), which indicates that the reaction place for coordination of magnesium, which would direct the
follows a similar stereochemical pathway regardless of the
double bond configuration. Products 21b and 22b, obtained
from 12, showed very similar 1H and 13C NMR spectra com-
pared to 4b and 3b, respectively. To elucidate whether related
products were configurationally identical, compounds 22b and 3b
were hydrolyzed and the resulting products were treated with
Mosher acid chloride to selectively give the esters. The NMR spectra
of the obtained products showed significant differences, proving
that both compounds were different. Since a syn-relative configu-
Scheme 5 Preparation of (ꢁ)-sphingosine.
ration was confirmed for product 3b by NOE experiments
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carboxylate attack in a syn SN20 fashion. The efficiency of the
reaction is strongly affected by the presence of substituents in
the intermediate framework of the diene system, and the product
resulting from the SN20 attack is obtained with both catalytic
systems if a methyl group is present at C-4. The synthetic procedure
developed in this work has allowed the synthesis of sphingosine in
only two steps from the starting dienyl carbamate.
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