Copper-catalyzed allylic hydroxyamination and amination of alkenes with Boc-hydroxylamine

Article abstract of DOI:10.1016/j.tetlet.2005.01.024

Olefins react regioselectively with Boc-NHOH in the presence of Cu(I,II) salts to produce allyl-N(OH)(Boc) derivatives, apparently via the intermediacy of Boc-NO; yields and rates are dramatically improved by the addition of H ₂O₂. The corresponding allylamine derivatives, allyl-NH(Boc), are formed selectively from Boc-NHOH/olefin with CuBr/P(OEt) ₃.

Full text of DOI:10.1016/j.tetlet.2005.01.024

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1451–1453
Copper-catalyzed allylic hydroxyamination and amination
of alkenes with Boc-hydroxylamine
Biswajit Kalita and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Received 15 December 2004; revised 27December 2004; accepted 7January 2005
Available online 22 January 2005
Abstract—Olefins react regioselectively with Boc-NHOH in the presence of Cu(I,II) salts to produce allyl-N(OH)(Boc) derivatives,
apparently via the intermediacy of Boc-N@O; yields and rates are dramatically improved by the addition of H2O2. The correspond-
ing allylamine derivatives, allyl-NH(Boc), are formed selectively from Boc-NHOH/olefin with CuBr/P(OEt)3.
Ó 2005 Elsevier Ltd. All rights reserved.
The direct N-functionalization of unsaturated hydrocar-
bons is an attractive, but underdeveloped synthetic
methodology.1 Additions to C–C unsaturation such as
hydroxyamination,2 aziridination3 and, most recently,
hydroamination,4 have received the most attention.
Allylic N-functionalization reactions have also been
emerging, which employ S/Se-imido reagents,5 azo-
derivatives,6 nitro-aryls7 and hydroxylamines8–10 as
nitrogen sources. Our prior contributions in the latter
area have included the development of Mo(VI)-,8
Fe(II/III)-9 and Cu(I/II)-10 catalyzed allylic aminations
of olefins by aryl hydroxylamines (Scheme 1), all of
which proceed with excellent ene reaction-like regio-
selectivity11 (i.e., with C@C transposition). In search
of a convenient reagent to access primary allyl amines
we have now examined copper-catalyzed reactions of
olefins with the readily available12 and deprotectable13
Boc-NHOH (Boc = tBuO2C–). Presented here is the
unexpected outcome of such reactions: (1) that N-Boc-
N-hydroxy-N-allyl amines are the major products
(Scheme 1); and (2) that Boc-N-allyl amines are formed
selectively in the presence of suitable ligands (Scheme 1).
Initial reactivity studies were conducted between a-
methyl styrene (AMS, R = Ph) and Boc-NHOH with
various Cu(I) and Cu(II) salts (10 mol%) in 1,2-dichloro-
ethane/acetonitrile (2:1) at reflux. Several of the salts
catalyzed the slow consumption of the hydroxylamine,14
with CuBrÆMe2S showing the highest activity and prod-
uct selectivity (by TLC). Employing a 3:1 Boc-NHOH/
AMS ratio and the latter catalyst, two products were
isolated (Scheme 2) the Boc-N-OH allyl derivative 1a
(48%) and the known (Boc)2NOH15 (3%). The identity
of 1a was established spectroscopically and by conver-
sion to the corresponding O-acetate (1b; Ac2O/pyridine)
and Boc-amine derivatives (1c; TiCl3/MeOH).16
Z
R
R
Z = Ar
HN
(1)
(2)
Mo(VI), Fe(III), Cu(I,II)
The formation of hydroxylamine 1a contrasts with the
corresponding Cu-catalyzed reactions of AMS with aryl
hydroxylamines, which afford the reduced N-aryl-N-
allyl amines (e.g., 1c).10 Since the present conversion
R
Z = tBuO2C
H
Z
+
Z
N
HON
Cu(I,II)
(H2O2)
OH
Z = tBuO2C
Z
R
(3)
HN
Cu(I), P(OEt)3
Ph
CuBr.Me2S
BOC Ph
ZN
H
+
N
BOC
Scheme 1.
(CH2Cl)2/CH3CN
OH
1a (Z=OH)
1b (Z=OAc)
1c (Z=H)
(excess)
Keywords: Allylic amination; Hydroxyamination; Copper-catalyzed.
*
Corresponding author. Tel.: +1 405 325 3696; fax: +1 405 325
4811; e-mail: knicholas@ou.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.024

1452
B. Kalita, K. M. Nicholas / Tetrahedron Letters 46 (2005) 1451–1453
CuBr.SMe2
Ph
H
BOC Ph
HN
+
H
BOC
BOC N
(CH2Cl)2/CH3CN
N
O
+
BOC
N
Cu(I), P(OEt)3
Ph
OH
OH
1a
H2O2 , CuCl
(CH2Cl)2/CH3CN
2
TFA
H2N
Scheme 3.
5
constitutes a net oxidation of the two reactants, it
seemed possible that the oxidizing equivalents were
derived from Cu-catalyzed disproportionation of Boc-
NHOH,17 with the intermediate Boc-NO undergoing
an ene reaction with the olefin. Support for this notion
was provided by the finding that when Boc-NHOH
and 1,3-cyclohexadiene were heated together with
10 mol% CuBrÆMe2S, the Diels–Alder adduct 2 derived
from Boc-NO (65 h, 41%) was isolated (Scheme 3).12c,18
Scheme 5.
established that both CuX and the phosphite are
required for the reduction. The Boc-N-allyl amines
are convenient precursors to primary allyl amines by
efficient removal of the Boc group under standard
conditions, for example, 1a ! 5 (TFA/CH2Cl2,
68%; Scheme 5).
As to the origin of the differing outcomes of the Cu-cat-
alyzed Boc-NHOH and Ar-NHOH reactions with ole-
fins, we found that the CuBr-promoted reaction of
AMS with MeO2C–NHOH also gives the corresponding
N-hydroxy allyl derivative as the main product. This
suggests that the uniqueness of RO2C–NHOH as ami-
nating agents is electronic (rather than steric) in origin
and that Cu(I)-catalysts modified with donor ligands
are needed to convert the intermediate Boc-N-hydroxy
allylamine to the corresponding Boc-allylamine. A
possible catalytic pathway is outlined in Scheme 6,
beginning with Cu-induced disproportionation of Boc-
NHOH (or Cu(I) oxidation if H2O2 is present). The
resulting Boc-NO (free or coordinated) can undergo
an ene-reaction with the olefin to give the N-Boc allyl
hydroxylamine. In the presence of P(OEt)3 the Cu(I)Ln
complex formed can reduce the hydroxylamine to the
allylamine (regenerating Cu(II) for catalytic recycle).
Mechanistic details not withstanding, the combination
of efficient hydroxyamination by Cu(I)/H2O2 with sub-
sequent reduction or the direct amination with Boc-
NHOH catalyzed by Cu(I)/P(OR)3 provides convenient
access to the synthetically valuable Boc-and primary
allyl amines.
Accordingly, a dramatic improvement in the facility and
the efficiency of both the Diels–Alder reaction (quantita-
tive) and the AMS hydroxamination (73% of 1a) could
be achieved if these reactions were conducted using a
stoichiometric oxidant, for example, 30% H2O2, for
the Boc-NHOH (Schemes 3 and 4), proceeding at
20 °C within a few hours with CuCl as the catalyst.19
Under these conditions, reactions of Boc-NHOH/H2O2
with b-pinene and 1-octene also afforded moderate
yields of the corresponding N-hydroxallyl amine deriva-
tives 3 (43%) and 4 (24%), displaying the regioselectivity
typical of ene-type reactions.11 Although [2 + 4]-cyclo-
additions of transient Boc-NO are well established, the
CuCl–H2O2 system offers the most economical method
for generating this species.12c,18,20,21 Furthermore, the
novel function of Boc-NO as an enophile,20a illustrated
by these examples, is firmly established here.
Since it was apparent that Cu(I)X salts were ineffective
at reducing Boc-N-hydroxy amines to the desirable
Boc-N-allyl amines directly, we investigated the effects
of added ligands which could enhance the Cu(I) reduc-
tion potential. Indeed, among several representative N-
and P-based ligands surveyed,22 the reaction between
Boc-NHOH and AMS in the presence of CuBr/
P(OEt)3 (10 mol%:100 mol%; 85 °C) afforded the allyl
amine derivative 5 as the major product (37%). Simi-
larly, amination of b-pinene afforded the corresponding
Boc-N-pinyl amine regioselectively in modest yield
(13%). Control experiments, involving heating N-hydro-
xy derivative 1a and P(OEt)3, with and without CuBr,
Experimental procedures and characterizational data
for all new compounds (IR, NMR, MS) are provided
in the Supplementary data that is available online with
the paper in ScienceDirect.
R
BOC
Ph
OH Ph
BOCN
1a
(H2O2)
R
N
(73%)
BOC
HO
Cu(I)Ln
BOC-NHOH
O
N
Cu(I)
N-BOC
BOC-NHOH
H2O2/CuCl
(L = P(OR)3)
(43%)
OH
Cu(II)Ln
+
3
BOC-NH2
(H2O)
Cu(II)
BOC-NHOH
OH
BOCN
H
C5H11
BOC-N
(24%)
C5H11
4
R
Scheme 4.
Scheme 6.

B. Kalita, K. M. Nicholas / Tetrahedron Letters 46 (2005) 1451–1453
1453
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Acknowledgements
We thank the National Science Foundation for support
of this project.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
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