Gold-catalyzed intermolecular markovnikov hydroamination of allenes with secondary amines

Article abstract of DOI:10.1021/ol901418c

A cationic (CAAC)gold(I) complex promotes the addition of all types of nontertiary amines to a variety of alienes, affording allylic amines in good to excellent yields; the amino fragment always adds to the less substituted terminus of the CCC skeleton.

Full text of DOI:10.1021/ol901418c

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3166-3169
Gold-Catalyzed Intermolecular
Markovnikov Hydroamination of Allenes
with Secondary Amines
Xiaoming Zeng,† Michele Soleilhavoup, and Guy Bertrand*
UCR-CNRS Joint Research Chemistry Laboratory (UMI 2957), Department of
Chemistry, UniVersity of California, RiVerside, California 92521-0403
guy.bertrand@ucr.edu
Received March 9, 2009
ABSTRACT
A cationic (CAAC)gold(I) complex promotes the addition of all types of nontertiary amines to a variety of allenes, affording allylic amines in
good to excellent yields; the amino fragment always adds to the less substituted terminus of the CCC skeleton.
The most widely used chemical reaction for the functional-
ization of alkenes, alkynes, and allenes is the addition of an
A-B bond across a carbon-carbon π-bond.1 Since nitrogen-
carbon bonds are ubiquitous in molecules and of significant
importance in human life, as well as for the chemical
industry,2 the so-called hydroamination reaction has attracted
considerable interest.3 However, a close look at the literature
reveals that although the intramolecular hydroamination of
allenes4 has been widely studied,5 the intermolecular version
has received limited attention. Depending on the regiochem-
istry, this reaction can lead to imines, enamines, or ally-
lamines. The allylamines (Markovnikov adducts) are espe-
cially interesting since they are among the most versatile
intermediates in synthesis, components of many naturally
occurring and biologically active molecules, and of industrial
importance.6 In 1992, Bergman reported that zirconium
bis(amides) were efficient catalysts to promote the addition
of primary arylamines to 1,2-propadiene giving the corre-
† Present address: Key Laboratory of Green Chemistry & Technology
of Ministry of Education at Sichuan University, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China.
(1) For recent general reviews, see: (a) Beller, M.; Seayad, J.; Tillack,
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Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079–3159. (c) Chianese,
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10.1021/ol901418c CCC: $40.75
Published on Web 07/13/2009
 2009 American Chemical Society

sponding imines,7 and more recent papers confirm that early-
transition-metal catalysts lead to the anti-Markovnikov
adducts (Scheme 1, top).8 The Markovnikov addition has
(Scheme 1, bottom).15 Interestingly, an opposite regioselec-
tivity was observed when compared with Yamamoto’s
results.14b Recently, we have shown that cationic gold(I)
complexes (Cat) (Figure 1),16 featuring a bulky cyclic
Scheme 1. Previous Results for the Hydroamination of Allenes
Figure 1. Cationic gold(I) complexes promoting the addition of
NH3 to nonactivated alkynes and allenes.
(alkyl)(amino)carbene (CAAC)17 as ancillary ligand, ef-
ficiently promoted the addition of NH3 to nonactivated
alkynes and allenes.18 These first examples of hydroamina-
tion reaction with ammonia prompted us to investigate the
scope of application of our catalytic system. Here, we show
that Cat1 [a 1/1 mixture of (CAAC)AuCl and KB(C6F5)4]
efficiently promotes the intermolecular Markovnikov hy-
droamination of allenes A-C (scheme 2) with a variety of
primary and, more importantly, secondary amines.
first been achieved in the presence of equimolar amounts of
mercury(II), palladium(II), and platinum(II) salts9 and then
used a palladium(0) catalyst in the presence of triethylam-
monium iodide10 or acetic acid11 as cocatalysts. Gold
catalysts12 have more recently been developed.13 Yamamoto
et al. first demonstrated that 10 mol % of AuBr3 allowed
the room-temperature addition of primary arylamines to
allene to afford allylic amines14a and then described the
addition of morpholine to mono- and disubstituted allenes
at 80 °C, using 10 mol % of a 1/1 mixture of (Ar3P)AuCl
and AgOTf (Scheme 1, middle).14b In 2008, Widenhoefer
reported the Markovnikov hydroamination with N-unsub-
stituted carbamates using catalytic amounts of an equimolar
mixture of LAuCl and AgOTf (L ) NHC, phosphine)
Scheme 2. Allenes A-C Used in This Study
Since, as mentioned above, several catalytic systems are
known to promote the hydroamination of allenes with
primary amines, we briefly investigated if Cat1 was efficient
as well (Table 1, entries 1-3). In the presence of 5 mol %
of Cat1, we were pleased to observe that after 12 h at 70
°C, aniline reacted with 1,1-dimethylallene A to afford a 60/
40 mixture of N-allyl- and N,N′-diallylaniline in 95% yield
(entry 1). Clearly, the N,N′-diallylaniline results from the
addition of the primarily formed N-allylaniline on allene A,
which gives a clear indication that secondary arylamines are
suitable substrates for our catalytic system. Mesitylamine and
even the strongly basic and bulky tert-butylamine react with
A, although under more drastic conditions, giving the
secondary allylamines in 74 and 54% yield, respectively
(entries 2 and 3).
(7) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.
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108, 3266–3325. (c) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV.
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We then turned our attention to secondary (aryl)(alkyl)-
amines using again 5 mol % of Cat1 (Table 1, entries 4-9).
(13) For a recent review on gold-catalyzed hydroamination of allenes,
see: Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555–4563.
(14) (a) Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45,
3314–3317. (b) Nishina, N.; Yamamoto, Y. Synlett 2007, 1767–1770.
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Org. Lett., Vol. 11, No. 15, 2009
3167

secondary (aryl)(alkyl)amines is not limited to 1,1-disubsti-
tuted allenes. The parent allene B can also be used as shown
in entry 9.
Based on these positive results, we investigated the
catalytic activity of Cat1 for the hydroamination of allenes
with more basic secondary amines (Table 2). By analogy
Table 1. Hydroamination of Allenes with Primary Amines and
Secondary (Alkyl)(aryl)aminesa
Table 2. Hydroamination of Allenes with Secondary
Alkylaminesa
a Cat1 (5 mol %), amine (0.5 mmol), allene (0.5 mmol), and C6D6 (0.4
b
1
mL). Yields are determined by H NMR using benzylmethyl ether as an
internal standard. c Yield based on allene. d Excess allene was used.
In an initial experiment, 1,1-dimethylallene A was treated
with N-methylaniline, and after 12 h at only 70 °C, the
desired hydroamination product was obtained in 98% yield
(entry 4). Para substitution of the aniline by a chlorine or
methoxy group is well tolerated, the corresponding adducts
being formed in 97% yields (entries 5 and 6). 1,2,3,4-
Tetrahydroquinoline and indoline have been recognized as
important synthetic intermediates19 and exhibit extensive
biological activities and potential pharmaceutical applica-
tions. Using allene A, their allylic amine derivatives have
been prepared using our catalytic procedure with up to 99%
yield (entries 7 and 8). The hydroamination reaction with
a Cat1 (5 mol %), amine (0.5 mmol), allene (0.5 mmol), and C6D6 (0.4
b
1
mL). Yields are determined by H NMR using benzylmethyl ether as an
internal standard. c Excess allene was used; yield based on amine. d E/Z )
2.2. e Two equivalents of allene was used; yield based on amine. f E/Z )
3.4.
with the work of Yamamoto, we first reacted morpholine
with allenes A-C, and in all cases, the Markovnikov adduct
was obtained in good to excellent yields (entries 1-3).
Benzylic and benzocyclic amines also smoothly react with
allenes A and B at temperatures between 70 and 90 °C
affording the hydroamination products in 93 to 99% yields
after only 8-12 h (entries 4-7). Lastly, we used diethy-
(19) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446. (b) Higashio,
Y.; Shoji, T. Appl. Cat. A: Gen. 2004, 260, 251–259.
3168
Org. Lett., Vol. 11, No. 15, 2009

lamine as the prototypical secondary alkylamine. Although
drastic conditions are required (130-165 °C, 24-36 h), the
addition occurred to yield the Markovnikov adduct in 61 to
98% yields (entries 8-10). These results emphasize the
robustness of the catalyst.
To gain insight into the mechanism of the gold(I)-catalyzed
hydroamination of allenes, the following experiments were
performed (Scheme 3). Addition of excess allene A to
tion of allenes and alkynes, respectively, with arylamines.
Moreover, it seems quite likely that the amine complex I is
the resting state of the catalyst, just as Cat3 is in the case of
the hydroamination with ammonia.18
Since we have already shown that Cat1 promotes the
addition of ammonia to allenes,18 it appears that the catalytic
system described here has a broad scope of application; many
types of nontertiary amines can be used, as well as a variety
allenes. Importantly, the regioselectivity observed (Mark-
ovnikov addition) is opposite to that obtained with early
transition metal catalysts (anti-Markovnikov addition).7,8 The
regioselectivity is also different from that reported by
Windehoefer;15 using unsubstituted carbamates and a cationic
gold(I) complex bearing an NHC or a phosphine ligand, the
Markovnikov adduct was formed but at the more substituted
terminus of the allene (Scheme 1). This striking difference
has not yet been rationalized, and mechanistic studies are
under active investigation. Moreover, the hydroamination of
1,3-disubstituted allenes allows for the formation of a chiral
center, and we are investigating the possibility of using
gold(I) complexes bearing an optically active CAAC ligand
for the preparation of enantiomerically enriched allylic
amines.22
Scheme 3. Experiments To Approach the Reaction Mechanism
complex Cat2 did not give the desired allene gold complex
at room temperature or even upon heating at 50 °C. This is
in marked contrast with the case of alkynes, for which an
η2-alkyne complex was readily formed and isolated.18,20 On
the other hand, upon exposure at room temperature of a
solution of Cat2 in deuterated benzene to 1 equiv of
diethylamine, the amine complex I was spontaneously and
quantitatively obtained. Then, addition of excess allene A
to a C6D6 solution of I gave after 16 h at 70 °C complex II,
which was isolated in 95% yield. These observations call
into question an outer-sphere mechanism involving the attack
of the amine to an initially formed gold π-allene complex15
and rather suggest an inner sphere mechanism with transient
formation of a tricoordinated gold complex, as proposed by
Yamamoto14 and Tanaka21 for gold-catalyzed hydroamina-
Acknowledgment. Financial support from the NIH (R01
GM 68825) is gratefully acknowledged. Thanks are also due
to the China Scholarship Council for a Graduate Fellowship
(X.Z.).
Supporting Information Available: General catalytic
procedure, experimental details, and characterization of
1
complexes I and II, as well as H, 13C, and MS spectra for
new catalytic products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL901418C
(22) A few examples of intramolecular asymmetric hydroamination of
allenes have been reported. See refs 5f,,5g and 12g and: (a) Aillaud, I.;
Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105–5118.
(b) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317,
496–499. (c) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R.
Organometallics 2004, 23, 4614–4620. (d) Roesky, P. W.; Muller, T. E.
Angew. Chem., Int. Ed. 2003, 42, 2708–2710.
(20) Shapiro, N. D.; Toste, F. D. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 2779–2782
.
(21) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349–
3352.
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