Direct, intermodular, enantioselective, iridium-catalyzed allylation of carbamates to form carbamate-protected, branched allylic amines

Article abstract of DOI:10.1021/ol901151u

The direct reaction between carbamates and achiral allylic carbonates to form branched, conveniently protected primary allylic amines with high regioseiectivity and enantioselectivity Is reported. This process occurs without base or with 0.5 equiv K₃PO₄ In the presence of a metalacyclic iridium catalyst containing a labile ethylene ligand. The reactions of aryl-, heteroaryl-, and alkyl-substituted allylic carbonates with BocNH ₂, FmocNH₂, CbZNH₂, TrocNH₂, TeocNH₂, and 2-oxazolidinone occur In good yields, with high selectivity for the branched isomer and high enantioselectivities (98% average ee).

Full text of DOI:10.1021/ol901151u

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2944-2947
Direct, Intermolecular, Enantioselective,
Iridium-Catalyzed Allylation of
Carbamates to Form
Carbamate-Protected, Branched Allylic
Amines
Daniel J. Weix, Dean Markovic´, Mitsuhiro Ueda, and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue,
Urbana, Illinois 61801
jhartwig@illinois.edu
Received May 24, 2009
ABSTRACT
The direct reaction between carbamates and achiral allylic carbonates to form branched, conveniently protected primary allylic amines with
high regioselectivity and enantioselectivity is reported. This process occurs without base or with 0.5 equiv K3PO4 in the presence of a metalacyclic
iridium catalyst containing a labile ethylene ligand. The reactions of aryl-, heteroaryl-, and alkyl-substituted allylic carbonates with BocNH2,
FmocNH2, CbzNH2, TrocNH2, TeocNH2, and 2-oxazolidinone occur in good yields, with high selectivity for the branched isomer and high
enantioselectivities (98% average ee).
Chiral, nonracemic N-allyl carbamates are versatile inter-
mediates for the synthesis of a variety of products,1 including
R-, ꢀ-, and γ- amino acids and amino alcohols. One of the
most direct methods for the synthesis of these materials
would be a simple intermolecular, catalytic, enantioselective
allylic substitution with carbamate nucleophiles (eq 1).2
However, this process has been reported to lead to little or
no conversion in the presence of Pd3 or Ir4 catalysts. Related
intermolecular Pd-catalyzed allylations of primary amides
have been accomplished with O-allyl isoureas, but mixtures
of mono- and diallylation products were obtained.5
To overcome this limitation, alternate protocols involving
the use of alkali iminodicarboxylate3,4,6,7 nucleophiles, in
situ generated benzyl N-carboxycarbamate nucleophiles,8 or
the rearrangement of O-allylic trichloroimidates9 have been
developed. However, these Ir- and Pd-catalyzed routes to
(5) Inoue, Y.; Taguchi, M.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1985,
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Lett. 2007, 9, 3949–3952
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(2) For an alternate disconnection see: Lee, A.; Ellman, J. A. Org. Lett.
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(8) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774–775.
(9) Overman, L. E.; Carpenter, N. E. Org. React. (N.Y.) 2005, 66, 1–
(4) Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 7094–7098.
107.
10.1021/ol901151u CCC: $40.75
Published on Web 06/10/2009
 2009 American Chemical Society

N-allyl carbamates require manipulation of the products to
generate primary amines with conventional protective groups
or more extensive substrate synthesis than would be required
for a direct addition.10 Here, we report the discovery and
development of a direct, enantioselective, iridium-catalyzed
substitution of a series of allylic carbonates with carbamate
nucleophiles to form branched N-allyl carbamates in high
yields, branched-to-linear ratios, and enantioselectivities. The
reactions occur with Boc, Cbz, Troc, Fmoc, and Teoc
carbamates to form conveniently protected primary allylic
amines.
reactions conducted with the ethylene catalyst 1d derived
from ligand L2 occurred with somewhat higher b:l selectivi-
ties and faster rates than those conducted with the analogous
catalyst 1c derived from ligand L1. For example, the
branched-to-linear regioselectivity of reactions of linear
aliphatic carbonates improved from 75:25 to 85:15. More-
over, the allylation reactions conducted with catalyst 1d
occurred without the need for additional base or with only
0.5 equiv of K3PO4 as base.
Studies on the reactions of allylic acetates and a series of
allylic carbonates with tert-butylcarbamate showed that
reactions conducted with allylic tert-butyl carbonates gave
the highest yields of branched products among the carbonates
tested (eq 1, C(O)R2 ) Ac, CO2Me, CO2Et, CO2t-Bu,
C(O)CH2OMe). Lower yields were observed when the
reaction was conducted with allylic ethyl or methyl carbon-
ates. These lower yields were due to the formation of ether
side products from decarboxylation.17 Reactions with allylic
acetates were much slower (OAc) or low yielding
(MeOCH2C(O)). Using a modified combination of two
literature procedures,18,19 we realized a more convenient
synthesis of pure allylic tert-butyoxy carbonates (eq 2, see
Supporting Information).
To assess the feasibility of preparing nonracemic, R-chiral,
N-allyl carbamates by direct asymmetric allylic substitution,
we investigated the reactions of BocNHM (M ) Li, Na, K)
with tert-butyl cinnamyl and tert-butyl dodecenyl carbonates.
We conducted these reactions in the presence of the catalyst
formed from a mixture of L1 (Figure 1) and [Ir(cod)Cl]2
Figure 1. Phosphoramidite ligands and cyclometalated Ir catalysts.
activated in situ, as we have previously reported,11 by
addition of propylamine. However, reactions of these car-
bamate salts led to modest yields of the desired product
(e25%).3-5 Reactions of the neutral carbamate in the
presence of weak bases12 provided the desired products in
higher yields, but even the highest yielding reactions, which
occurred with K3PO4 (100 mol %) as base, occurred in only
38% yield with tert-butyl dodecenyl carbonate and 64% yield
with tert-butyl cinnamyl carbonate.
Studies on the effect of solvent (THF, 2-methyl-THF,
CH2Cl2, toluene, ether, dioxane, and DME were tested)
showed that reactions performed in THF or ether formed
the highest yields of branched product. Although reactions
in CH2Cl2 occurred with the highest regioselectivity, the yield
of branched allylic carbamate remained low (40-60%). The
yield, regioselectivity, and enantioselectivity were generally
similar for reactions conducted in THF and ether, but the
reactions in ether were typically faster.
The optimized conditions were then applied to the reac-
tions of a variety of allylic tert-butyl carbonates, and the
results of these experiments are summarized in Table 1. High
yields of the desired product, and, with one exception,
acceptable branched-to-linear ratios were obtained. In all
cases, the branched and linear products were separable using
standard flash chromatography on silica gel. All reactions
occurred with exceptional enantioselectivity.
A pronounced electronic effect was seen in the reactions
of substituted cinnamyl carbonates (entries 1-5). The
reactions of more electron-rich carbonates occurred with
higher b:l selectivity and faster rates than reactions of more
electron-poor carbonates. Reactions of allylic carbonates
containing heteroaromatic (furan, entry 6), dienyl (entry 7),
and straight-chain aliphatic (entry 8) moieties also yielded
the desired products in good yield and excellent enantiose-
To improve this process further, we investigated a series
of catalyst precursors (Figure 1). These studies showed that
the most effective catalysts for the asymmetric allylation of
tert-butyl carbamate are 1a-d. Complex 1c has been used
for mechanistic analysis, and complexes 1c and 1d (derived
from ligand L213-15 ) have recently been used for asym-
metric allylation of azoles.16 The reactions conducted with
1d provided the desired branched products with the highest
yields and branched-to-linear (b:l) selectivities. In general,
(10) For preliminary results on the direct synthesis of primary allylic
amines using NH2SO3H as the nucleophile source see: Defieber, C.; Ariger,
M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139–
3143.
(11) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093–1096.
(12) Many bases were tested, and only reactions conducted with K3PO4,
Cs2CO3 and CsF resulted in high yields of the desired product. See
Supporting Information for details.
(13) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353
(14) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529–3532
(15) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem.
.
.
(17) Ueno, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 1928–
1931.
Soc. 2005, 127, 15506–15514
.
(18) Basel, Y.; Hassner, A. Synthesis 2001, 550–552.
(16) Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, ASAP,
(19) Houlihan, F.; Bouchard, F.; Fre´chet, J. M. J.; Willson, C. G. Can.
J. Chem. 1985, 63, 153–162
DOI: 10.1021/ja902243s.
.
Org. Lett., Vol. 11, No. 13, 2009
2945

Table 1. Reaction of a Variety of Allylic Carbonates with
Table 2. Synthesis of a Variety of Different N-Allyl Carbamates
BocNH2
entrya
Nu-H
time (h)
b:lb
yield (%)c ee (%)d
1
FmocNH2
CbzNH2
TrocNH2
TeocNH2
2-oxazolidinone
21
9
10
10
12
83:17
80:20
96:4
80:20
99:1
57
74
80
73
72
94
97
95
98
99
2
3e
4
5e
a General conditions: 0.7 mmol BocNH2, 0.5 mmol tert-butyl cinnamyl
carbonate, 0.02 mmol 1d, 0.25 mmol K3PO4, and 10 µL dodecane in 0.5
mL ether. Reactions were heated to 30 °C. Results are an average of two
runs. b Determined by NMR analysis of the crude reaction mixture or by
isolation. c Isolated yield of branched product. d Determined by chiral HPLC
analysis, see Supporting Information for details. e DBU (0.1 mmol) was
used in place of K3PO4.
with Zn0, H2, base, or F-, respectively, all afforded acceptable
yields of the branched product.
In some cases, the reactions of the carbamates were
accelerated by the addition of DBU. For example, the
allylation of TrocNH2 and a secondary carbamate, 2-oxazo-
lidinone (Table 2, entry 5) occurred in high yield, branched-
to-linear selectivity and enantioselectivity when 20 mol %
DBU was used in place of K3PO4 as the base. However, the
use of DBU as base did not affect reactions of BocNH2 or
CbzNH2.
To determine if these conditions could be transferred to
palladium-catalyzed, intermolecular allylation of carbamates,
we tested the N-allylation of tert-butyl carbamate with tert-
butyl cinnamyl carbonate in the presence of both achiral and
chiral catalysts (Table 3). Of catalysts containing PPh3,
a General conditions: 0.7 mmol BocNH2, 0.5 mmol carbonate, 0.02 mmol
1d, and 10 µL dodecane in 0.5 mL ether. Results are an average of two
runs. b Determined by NMR analysis of the crude reaction mixture or by
isolation. c Isolated yield of branched product. d Determined by chiral HPLC
analysis, see Supporting Information for details. e THF was used as solvent.
f K3PO4 (0.25 mmol) was added. g Reaction was run at 30 °C.
lectivity. The reaction of a benzyloxy-substituted allylic
carbonate (entry 9) yielded results similar to the unfunc-
tionalized straight-chain aliphatic carbonate. In contrast to a
previously reported Ir-catalyzed reaction utilizing a benzyl
carboxycarbamate nucleophile,20 the aminoalcohol derivative
was formed with high enantioselectivity under our new
conditions. Reaction of an aliphatic substrate with branching
R-to the allyl unit (R1 ) Cy, entry 10) occurred in a low
isolated yield due to low reactivity (reactions required 48 h
to consume starting material) and poor b:l selectivity. The
enantioselectivity of the reaction, however, remained high.
Although Boc is among the most common protecting
groups for primary amines, sometimes the acidic deprotection
conditions are incompatible with other functionality in the
molecule. In these cases, other carbamate protecting groups
are required. The reactivity of a representative sample of
these carbamates toward the iridium-catalyzed asymmetric
allylation is summarized in Table 2. The reactions with 2,2,2-
trichloroethoxycarbamate (TrocNH2), benzyloxycarbamate
(CbzNH2), fluorenyloxycarbamate (FmocNH2), and 2-trim-
ethylsilylethoxycarbamate (TeocNH2) that are deprotected
Table 3. Conditions Tested for Palladium-Catalyzed
N-Allylation of tert-Butyl Carbamate
entry
R1, R2, R3
ligand (X mol %)
yield (%)
b:l
1a
2a
3a
4a
5
6
7
8
Ph, H, H
Ph, H, H
Ph, H, H
Ph, H, H
Ph, H, Ph
H, -C3H6-
H, -C3H6-
H, -C3H6-
Xantphos (8)
Trost’s ligand (8)
PPh3 (16)
93
1:>99b
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
-
-
-
-
-
-
-
(R,R,R)-L2 (16)
PPh3 (8)
Xantphos (4)d
Trost’s ligand (4)d
Trost’s ligand (2)e
a 1.2 equiv K3PO4 was used. b Determined by 1H NMR analysis of the
crude reaction mixture. c N.R.: No Reaction. d 2 mol % [Pd(allyl)Cl]2 was
used as catalyst precursor. e 2 mol % Pd(dba)2 was used as precursor.
Trost’s ligand,21 L2, and Xantphos (9,9-dimethyl-4,5-bis-
(diphenylphosphino)-xanthene), only 4 mol % [{(η3-
(20) Singh, O. V.; Han, H. Org. Lett. 2007, 9, 4801–4804.
2946
Org. Lett., Vol. 11, No. 13, 2009

C3H5)PdCl}2] and 8 mol % Xantphos formed the substitution
product in good yield (93% isolated yield). In this case,
however, the allylic substitution formed exclusively the linear
isomer (entry 1).22
are easily obtained by chromatrography on silica gel. Work
to extend this method to the allylation of amides is ongoing.
Acknowledgment. We acknowledge financial support
from the NIH (GM-55382 to J.F.H. and GM075703 to
D.J.W.) and a gift of [Ir(cod)Cl]2 from Johnson-Matthey.
We thank Sanjeev Dalavoy of the Univerity of Illinois for
the synthesis of several allylic alcohols and Levi Stanley of
the University of Illinois for assistance with NMR charac-
terization.
In summary, we have identified conditions for Ir- and Pd-
catalyzed intermolecular direct monoallylation of carbamates,
a process that has fallen outside the scope of allylic
substitution chemistry. The simplicity and availability of the
reagents, the mild conditions, and the broad scopesincluding
the scope of carbamate nucleophilesare particular attributes
of this protocol. Moreover, the Ir-catalyzed procedure is
highly enantioselective. Although the regioselectivity is not
as high as was observed for decarboxylative processes,8 the
substrates are more available and the pure branched products
Supporting Information Available: Experimental pro-
cedures and spectral data for the synthesis of the allylic
carbonates, catalyst 1d, and allylated carbamate products as
well as two additional tables of reaction optimization
experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
(21) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. Engl.
1992, 31, 228–230. See Supporting Informationfor the structures.
(22) Initial attempts to conduct enantioselective Pd-catalyzed carbamate
allylation reactions have been unsuccessful.
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