Hydrogen bonding directed intermolecular cope-type hydroamination of alkenes

Article abstract of DOI:10.1021/ol3023177

Intermolecular hydroamination of unactivated alkenes represents a significant synthetic challenge. An efficient Cope-type hydroamination is achieved under mild conditions for reactions of N-alkylhydroxylamines with allylic amines, using hydrogen bonding t

Full text of DOI:10.1021/ol3023177

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Hydrogen Bonding Directed
Intermolecular Cope-Type
Hydroamination of Alkenes
ꢀ
Shu-Bin Zhao, Eric Bilodeau, Valerie Lemieux, and Andre M. Beauchemin*
ꢀ
Center for Catalysis Research and Innovation, Department of Chemistry, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
andre.beauchemin@uottawa.ca
Received August 21, 2012
ABSTRACT
Intermolecular hydroamination of unactivated alkenes represents a significant synthetic challenge. An efficient Cope-type hydroamination is
achieved under mild conditions for reactions of N-alkylhydroxylamines with allylic amines, using hydrogen bonding to achieve increased
reactivity and high regioselectivity. This approach provides a number of highly functionalized vicinal diamine motifs as Markovnikov addition
products.
Amine derivatives pervade fine chemicals, pharmaceu-
ticals, and natural products.1 Millions of tons of amine
products are used annually worldwide. Consequently there
is much interest in the conversion of simple precursors
into nitrogen-containing molecules. Hydroamination is
a highly atom-economical transformationthat can provide
access tovariousaminesby directly adding a NÀH bond to
an unsaturated CÀC bond.2,3 However achieving inter-
molecular alkene hydroamination remains very challeng-
ing.2,4 Besides suffering from a high activation energy due
to electrostatic repulsion between the π-electrons and the
lone pair of the nitrogen atom, the process is also typically
only slightly exothermic or even thermoneutral.5 The effi-
ciency of intermolecular alkene hydroaminations, which
display a negative reaction entropy, can thus be negatively
impacted if the reaction is performed at high tempera-
tures or if more stable alkenes (e.g., polysubstituted or
conjugated) are used.
Catalysis based on Brønsted/Lewis acids, strong bases,
and transition metals (e.g., actinides, lanthanides, early
and late transition metals) has been exploited to enable
hydroamination reactions.2À4 Approaches based on elec-
trophilic nitrogen sources6 and radical routes7 have also
been developed as useful alternatives. Strategically, the
catalysis of hydroamination reactions usually involves
activation of either the alkene π-bond or the amine nu-
cleophile. While significant progress has been achieved,2,3
issues such as limited reaction scope, functional group
(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications.
Cambridge University Press; Cambridge, U.K: 2004.
€
€
(2) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b) Muller,
T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795(and reviews cited therein).
(3) (a) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (b)
Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367. (c) Hultzsch, K. C.;
Gribkov, D. V.; Hampel, K. J. Organomet. Chem. 2005, 690, 4441. (d)
Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. (e) Andrea,
T.; Eisen, M. S. Chem. Soc. Rev. 2008, 37, 550. (f) Hesp, K. D.;
Stradiotto, M. Chem. Cat. Chem. 2010, 2, 1192.
(4) For recent examples with unbiased alkenes, see: (a) Zhang, J.;
Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (b) Zhang, Z.;
Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. (c)
Reznichenko, A. L.; Nguyen, H. N.; Hultzsch, K. C. Angew. Chem., Int.
Ed. 2010, 49, 8984. (d) Sevov, C. S.; Zhou, J.; Hartwig, J. F. J. Am. Chem.
Soc. 2012, 134, 11960. (and cited references). See also: (e) Hartung,
C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157.
(5) (a) Johns, A. M.; Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 9306. For an approach to this thermoneutrality
problem, see: (b) Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.;
(6) (a) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676.
(b) Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4099. (c)
Kemper, J.; Studer, A. Angew. Chem., Int. Ed. 2005, 44, 4914. (d) Guin,
€
J.; Muck-Lichtenfeld, C.; Grimme, S.; Studer, A. J. Am. Chem. Soc.
€
2007, 129, 4498. Guin, J.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed.
2008, 47, 779.
(7) (a) Kemper, J.; Studer, A. Angew.Chem., Int. Ed. 2005, 44, 4914.
€
(b) Guin, J.; Muck-Lichtenfeld, C.; Grimme, S.; Studer, A. J. Am. Chem.
€
Soc. 2007, 129, 4498. (c) Guin, J.; Frohlich, R.; Studer, A. Angew. Chem.,
ꢀ
Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874.
Int. Ed. 2008, 47, 779.
r
10.1021/ol3023177
XXXX American Chemical Society

compatibility, and in particular challenges linked to un-
favorable thermodynamics continue to stimulate efforts
toward the hydroamination of unactivated alkenes.4
The Cope-type hydroamination reactivity of hydroxyl-
amines and hydrazines constitutes a conceptually different
yet efficient thermal alternative that operates under metal-
free conditions.8 Intramolecular Cope-type hydroamina-
tions are mild and synthetically versatile and proceed
through a concerted five-membered transition state.9
In contrast, intermolecular variants are limited and typi-
cally require the use of biased substrates at high tempera-
tures (e.g., norbornene: 110 °C; vinylarenes: 140 °C).10
To address this limitation, we have been exploring pre-
association-based strategies (i.e., catalysis via temporary
intramolecularity11) to achieve increased reactivity. Re-
cently, we reported that aldehydes catalyze the addition
of N-alkylhydroxylamines to allylic amines (Scheme 1).12
In this system, efficient catalysis occurs by inducing tem-
porary intramolecularity via in situ formation of a mixed
aminal intermediate. A highly stereoselective variant
of this reaction is also possible using chiral aldehydes.
The current limitations associated with this reactivity (high
catalyst loadings and applicability limited to terminal
allylic amines) and the importance of the vicinal diamine
motif13 led us to explore other approaches.14 Herein we
report a complementary mode of activation and show that
hydrogen bonding allows for mild directed intermolecular
hydroaminations and enables the synthesis of complex
diamine motifs from allylic amines (Scheme 1).
Scheme 1. Approaches to Directed Hydroaminations
embarked on improving this reactivity, which appeared
to be promoted by hydrogen bonding.15 Selected results of
reaction optimization efforts are shown in Table 1.
Table 1. Optimization of Reaction of 1a with 2aa
time
(h)
NMR yield
(%)b
entry
solvent
neat
temp
1
rt
24 (170)
2 (24)
96
2
neat
70 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
17
6
6
6
6
6
6
6
6
6
6
In our previous studies on tethered hydroaminations,12
we observed that a slow background reaction is present
for some allylic amines and hydroxylamines. We thus
3
neat
99
4
C6H6
41
5
EtOAc
DMF
42
6
72
7
EtOH
94
(8) For an excellent review on the Cope-type hydroamination, see: (a)
Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243. Such reactions
are also often called reverse Cope eliminations or reverse Cope cycliza-
tions in the literature. For early examples, see: (b) House, H. O.;
Manning, D. T.; Melillo, D. G.; Lee, L. F.; Haynes, O. R.; Wilkes,
B. E. J. Org. Chem. 1976, 41, 855. (c) House, H. O.; Lee, L. F. J. Org.
Chem. 1976, 41, 863. (d) Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker,
B. H.; Petrzilka, M. Tetrahedron 1985, 41, 3497.
8
i-PrOH
t-BuOH
CF3CH2OH
(CF3)2CHOH
Et3N
93
9
98
10
11
12
11
trace
79
a Conditions: 1a (2 equiv), 2a (1 equiv), neat or 1.0 M in solution, rt or
heated in a sealed tube. b NMR yield using 1,4-dimethoxybenzene as an
internal standard.
(9) (a) Ciganek, E. J. Org. Chem. 1990, 55, 3007. (b) Oppolzer, W.;
Spivey, A. C.; Bochet, C. G. J. Am. Chem. Soc. 1994, 116, 3139. (c)
Ciganek, E.; Read, J. M., Jr. J. Org. Chem. 1995, 60, 5795.
ꢀ
(10) (a) Beauchemin, A.; Moran, J.; Lebrun, M.; Seguin, C.; Dimi-
trijevic, E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008, 47,
1410. (b) Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.;
Previously we noticed that N-allylbenzylamine (1a)
slowly reacts with N-benzylhydroxylamine (2a) at room
temperature yielding ∼2% of 3a within 24 h or ∼24% after
a week (Table 1, entry 1).15 Fortunately, temperature
exhibited a pronounced effect on the reaction (Table 1):
2a underwent an essentially quantitative reaction with 1a
when heated at 80 °C under neat conditions. Similar
reactivity was also observed in various aprotic and protic
solvents, with more polar solvents generally giving better
yields (entries 4À9). However the use of protic solvent with
increased acidity leads to poor reactivity (entries 10À11).
Despite its basicity, Et3N was compatible with the reactiv-
ity (entry 12). The relative loading between 1a and 2a also
considerably affected the reaction. To probe the effect,
reactions varying the relative loading of 1a to 2a were
performed (neat, 80 °C, 2 h). 1H NMR analyses revealed
ꢀ
ꢀ
Bedard, A.-C.; Seguin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008,
130, 17893. (c) Moran, J.; Pfeiffer, J. Y.; Gorelsky, S. I.; Beauchemin,
A. M. Org. Lett. 2009, 11, 1895. (d) Loiseau, F.; Clavette, C.; Raymond,
M.; Roveda, J.-G.; Burrell, A.; Beauchemin, A. M. Chem. Commun.
2011, 47, 562.
(11) For an excellent recent review on temporary intramolecularity in
catalysis, see: Tan, K. L. ACS Catal. 2011, 1, 877.
(12) (a) MacDonald, M. J.; Schipper, D. J.; Ng, P. J.; Moran, J.;
Beauchemin, A. M. J. Am. Chem. Soc. 2011, 133, 20100. (b) Guimond,
N.; MacDonald, M. C.; Lemieux, V.; Beauchemin, A. M. J. Am. Chem.
Soc. 201210.1021/ja303320x.
(13) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
(14) For a review on substrate-directable chemical reactions, see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(15) See supporting information of reference 12a. In comparison
1-decene failed to react with 2a even after prolonged heating (>24 h) at
100 °C. These observations provided initial support for a possible
hydrogen-bonding promoted pathway. For intermolecular Cope-type
hydroamination reactivity of unactivated alkenes, see: Laughlin, R.
J. Am. Chem. Soc. 1973, 95, 3295.
B
Org. Lett., Vol. XX, No. XX, XXXX

that the conversion of hydroxylamine 2a increased rapidly
with increased loadings of allylic amine 1a, as indicated
by the plot in Figure 1. In contrast, the conversion of 1a
responded negatively to increased loadings of 2a.16,17
Table 2. Scope of H-Bonding Directed Hydroaminationa
Figure 1. Conversion of hydroxylamine 2a on varying the
relative loading of allylic amine 1a (neat, 80 °C, 2 h).
Under the optimized conditions shown in Table 2,
a variety of hydroxylamine and allylamine derivatives
efficiently underwent this transformation. Excellent yields
were typically obtained with substrates bearing pri-
mary alkyl groups. Amides and various functional groups
(MeO, F, CF3, NO2) were well-tolerated, even if electron-
withdrawing ones generally slowed down the reaction
(e.g., entries 5 and 10). However extension of this method
to substrates bearing bulky substituents seemed more
challenging (e.g., entries 7 and 15). Allylamine itself
also showed reduced reactivity in comparison with its
N-alkyl derivatives (entries 1À4 vs 8). In general, the use
of different solvents failed to improve the most challenging
reactions (e.g., t-BuOH, entry 6).
Given that aldehyde-catalyzed intermolecular Cope-
type hydroaminations were limited to unsubstituted allylic
amines,12 we explored the scope of this hydrogen bonding
reactivity to access more complex vicinal diamine motifs.
Several disubstituted derivatives were examined (Table 3).
Substrates with distal alkene substituents worked well but
more slowly, and surprisingly the cis- and trans-isomers
displayed no reactivitydifference(entries1À2). The hydro-
amination of N-benzylcinnamylamine was much slower;
however increasing the temperature to 100 °C reduced
the reaction time and led to an efficient hydroamina-
tion process (entries 3 vs 4). The more sterically congested
isobutenylamine derivative reacted slowly to afford a
modest yield of product 3q (entry 5). Nevertheless, these
conditions lead to an unprecedented substrate scope for
a Reaction conditions: 1 (2.0 equiv), 2 (1.0 equiv), neat, 80 °C. b Yield
of isolated products. c NMR yield. d To simplify purification, only
1.0 equiv of 2-(allylamino)-N,N-diethylacetamide was used. e t-BuOH
as the solvent (1 M). f With 5.0 equiv of 1a.
the intermolecular hydroamination reactivity. It is also
worth noting that the diamine products are stable
toward Cope elimination: 3q remained intact even after
prolonged heating at 80 °C (72 h, in C6D6). Given the
thermoneutral nature of intermolecular alkene hydro-
aminations (vide supra),5 stabilization of the products
via hydrogen bonding could also be critical to the out-
come shown in Table 3.
We then turned our attention to allylamines substituted
at the allylic position. Unexpectedly, excellent diastereo-
control was observed in the hydroamination of benzyl sec-
butenylamine. A single diastereomer (3r) was obtained in
57% isolated yield (eq 1), and its structure was confirmed
by X-ray diffraction analysis.16 This stereochemical out-
come is consistent with a H-bonding directed reaction with
the favored Cope hydroamination transition state being
(16) See Supporting Information for details.
(17) This likely reflects competitive formation of different H-bonding
species. A possible explanation is that hydroxylamine 2a prefers to
dimerize (or aggregate) via intermolecular hydrogen bonding. A high
loading of allylic amine 1a could shift the equilibrium towards the mixed
H-bonding pair, and subsequently lead to the desired product.
Org. Lett., Vol. XX, No. XX, XXXX
C

N-substitution, the relative reactivity between 1a and
several benzylic allylamines (p-OMe, p-F, and p-NO2)
was assessed by performing competition reactions with
hydroxylamine 2a.16,20 Fitting the obtained data to a
Hammett plot afforded a linear progression with a nega-
tive F of À0.33 (R2 ∼0.96).16 When the para-methoxy-
benzyl or 3-phenylpropyl hydroxylamine derivatives
competed with the parent hydroxylamine 2a to react
with 1a, relative rates of 1.14 and 1.42 were obtained,
respectively.16 These experiments suggest a transition state
with the buildup of positive charges at both N-atoms.
These data and the reactivity trends shown in Table 2
support the proposed transition state model illustrated
in Figure 2. The exclusive formation of vicinal diamines
3 thus likely originates from the synergy between the
H-bonding effect and the propensity of Cope-type hydro-
aminations to favor Markovnikov addition products.8,10
Table 3. Scope of H-Bonding Directed Hydroaminationa
a Conditions: allylic amine (2.0 equiv), hydroxylamine (1.0 equiv),
neat, 80 °C. b Yield of isolated products; NMR yields in parentheses.
c Reaction was carried out at 100 °C.
positioned trans to the methyl group to minimize non-
bonding interactions.
Figure 2. Proposed transition state model for the H-bonding
directed Cope-type hydroamination.
In conclusion, a hydrogen bonding promoted Cope-type
hydroamination process was developed, which allows
the conversion of allylic amines into functionalized
vicinal diamine motifs. Further studies building on
preassociation to enable difficult intermolecular hydro-
aminations are underway and will be reported in due
course.
We also speculated that more complex substrates might
be subject to a cascade hydroamination sequence.18 To
test this hypothesis, N-benzyl hexa-1,5-dien-3-amine was
synthesized.16 A hydroamination cascade indeed took
place with this substrate, directly providing the pyrrolidine
N-oxide 4 in ∼60% yield, again as a single diastereomer
(eq 2). Detailed NMR analysis including NOE studies
supports a structure with all-cis substituents on the pyrro-
lidine ring.16 This stereochemical outcome is expected,
building on the diastereoselectivity observed in the forma-
tion of 3r, as well as on the propensity of Cope-type
cyclizations to be stereospecific.19
Acknowledgment. Support from NSERC (Discovery
Grant and Discovery Accelerator Supplement to A.M.B.),
the University of Ottawa, the Canadian Foundation
for Innovation and the Ontario Ministry of Research
and Innovation is gratefully acknowledged. Acknowl-
edgment is also made to the donors of The American
Chemical Society Petroleum Research Fund and to
Boehringer Ingelheim (Canada) Ltd. for support of
related research efforts. We also thank Dr. Ilia Korobkov
(University of Ottawa) for X-ray crystallographic analysis of
compound 3r.
Supporting Information Available. Complete experi-
mental procedures, characterization data, X-ray crystall
structure of 3r and NMR spectra.This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
To gain further support for a hydrogen bonding directed
hydroamination and additional insight on the impact of
(18) For pioneering work in intramolecular systems (bicyclizations),
see: (a) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 4391. (b) Jiang, T.;
Livinghouse, T. Org. Lett. 2010, 12, 4271. (c) Jiang, T.; Livinghouse, T.;
Lovick, H. M. Chem. Commun. 2011, 47, 12861.
(20) Competition reactions were performed to minimize potential
differences in solvation behaviors.
(19) (a) See references in ref 9. (b) Hanrahan, J. R.; Knight, D. W.
Chem. Commun. 1998, 2231.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX