Intermolecular hydroaminations via strained (E)-cycloalkenes

Article abstract of DOI:10.1021/jo701985w

(Chemical Equation Presented) A photoinduced procedure for the intermolecular hydroamination of alkenes using azoles is described. This reaction occurs in modest to good yield for 6- and 7-membered cyclic alkenes. Upon irradiation at 254 nm in the presence of methyl benzoate and a small amount of triflic acid as an additive (20 mol %), imidazoles, pyrazoles, triazoles, and tetrazole can react with the alkene to afford complex Markovnikov adducts. The proposed mechanism involves photoisomerization to generate highly strained (E)-cycloalkene intermediates and (E)-cycloalkene protonation followed by reaction with the azole nucleophile. Alkene isomerization was found to be a competing side reaction under these conditions.

Full text of DOI:10.1021/jo701985w

Intermolecular Hydroaminations via Strained (E)-Cycloalkenes
Joseph Moran, Pamela H. Cebrowski, and Andre´ M. Beauchemin*
Department of Chemistry, Centre for Catalysis Research and InnoVation, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
andre.beauchemin@uottawa.ca
ReceiVed September 10, 2007
A photoinduced procedure for the intermolecular hydroamination of alkenes using azoles is described.
This reaction occurs in modest to good yield for 6- and 7-membered cyclic alkenes. Upon irradiation at
254 nm in the presence of methyl benzoate and a small amount of triflic acid as an additive (20 mol %),
imidazoles, pyrazoles, triazoles, and tetrazole can react with the alkene to afford complex Markovnikov
adducts. The proposed mechanism involves photoisomerization to generate highly strained (E)-cycloalkene
intermediates and (E)-cycloalkene protonation followed by reaction with the azole nucleophile. Alkene
isomerization was found to be a competing side reaction under these conditions.
Introduction
nucleophiles do not lead to hydroamination products due
to an acid-base reaction with the Brønsted acid. This buffer-
ing effect results in both inefficient alkene protonation and
in the deactivation of the nucleophile by the formation of the
conjugate acid. As such, most Brønsted acid-based approaches
are related to the Ritter reaction,3 in which nitriles are used as
the nitrogen nucleophiles (eq 1). Other weakly basic reagents
such as anilines,4 azoles,5 hydrazines,6 sulfonamides,7 and
amides7c can also add efficiently under strongly acidic condi-
tions. It was recently reported that the nature of the counterion
has a profound impact on the efficiency of these reactions
(eq 2).4a
Nitrogen-containing motifs are ubiquitous in natural products
and drug discovery. Given the widespread availability of
nitrogen nucleophiles and alkenes, there is substantial interest
in developing efficient C-N bond-forming reactions from
these simple starting materials. Considerable efforts have notably
been directed at hydroamination of electron-rich alkenes, both
in intra- and intermolecular systems.1 Various strategies are
used to overcome the high activation energy associated with
combining two electron-rich reactants, notably transition-
metal and Brønsted acid catalysis.2 While considerable pro-
gress has been made, intermolecular reactions remain limited,
notably with respect to substrate scope and functional group
compatibility. For example, various functionalities are not
compatible with the strength of the Brønsted acids required to
protonate the double bond. On the other hand, various nitrogen
(3) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. For
a review of the Ritter reaction, see: (b) Krimen, L. I.; Cota, D. J. Org.
React. 1969, 17, 213.
(4) (a) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 14542. (b) Lapis, A. A. M.; DaSilveira Neto, B. A.; Scholten,
J. D.; Nachtigall, F. M.; Eberlinb, M. N.; Duponta, J. Tetrahedron Lett.
2006, 47, 6775.
(5) (a) Katritzky, A. R.; Puschmann, I. B.; Stevens, C. V.; Wells, A. P.
J. Chem. Soc., Perkin Trans. 2 1995, 1645. (b) Katritzky, A. R.; Qi, M.;
Wells, A. P. Geterotsikl. Soedin. 1996, 1520. (c) Ostrovskii, V. A.; Koren,
A. O. Heterocycles 2000, 53, 1421 (and references cited therein). (d)
Gaponik, P. N.; Voitekhovich, S. V.; Klyaus, B. G. Zh. Org. Khim. 2004,
40, 624.
(1) For selected reviews, see: (a) Matsunaga, S. J. Synth. Org. Chem.
Jpn. 2006, 64, 778. (b) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367.
(c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (d)
Roesky, P. W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708. (e)
Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (f) Nobis, M.; Driessen-
Ho¨lscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983. (g) Brunet, J.-J.;
Neibecker, D. In Catalytic Heterofunctionalization; Togni, A., Gru¨tzmacher,
H., Eds.; VCH: Weinheim, 2001; pp 91-141. (h) Mu¨ller, T. E.; Beller,
M. Chem. ReV. 1998, 98, 675.
(6) (a) Kelly US Patent 4,954,655, filed 03/1989. (b) Eichinger; Fiege
US Patent 5,585,521, filed 09/1995.
(2) For selected alternatives, see: (radicals) (a) Guin, J.; Mu¨ck-
Lichtenfeld, C.; Grimme, S.; Studer, A. J. Am. Chem. Soc. 2007, 129, 4498-
4503. For a review on base-catalyzed hydroaminations, see: (b) Seayad,
J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth. Catal. 2002, 344,
795-813.
(7) (a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He,
C. Org. Lett. 2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya,
A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (c) Motokura,
K.; Nakagiri, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Jitsukawa, K.; Kaneda,
K. Org. Lett. 2006, 8, 4617.
10.1021/jo701985w CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/28/2007
1004
J. Org. Chem. 2008, 73, 1004-1007

Intermolecular Hydroaminations Via Strained (E)-Cycloalkenes
As highlighted in the example shown in eq 2, strained organic
molecules are typically more reactive due to a higher ground-
state energy.8 In hydroamination reactions, strained alkenes
could potentially allow reactions with more basic nitrogen
nucleophiles due to the increased ability of the olefin to undergo
protonation. In this context, we were inspired by the seminal
work of Kropp9 and Marshall,10 and recent contributions by
Inoue,11 who showed that intermolecular hydroetherification of
strained (E)-cycloalkenes occurs under acid-free conditions (eq
3).12 Under their conditions, sensitized photoisomerization leads
to the formation of short-lived, ground-state (E)-cycloalkenes
possessing approximately 30 kcal/mol of ring strain. These
highly strained intermediates react with the alcohol, typically
used as solvent, under acid-free conditions.13 Herein, we report
that this reactivity can be used to perform intermolecular
hydroaminations using azole nucleophiles (eq 4).
Results and Discussion
We embarked on our search for conditions to perform
intermolecular hydroaminations drawing precedence from the
work of Kropp and Marshall,9,10 in which xylenes (or p-xylene)
are used as a triplet sensitizer and the nucleophile, MeOH, is
used as a solvent (see eq 3). Our initial goal was to identify
conditions in which the nucleophile could be used in near
stoichiometric quantities. For these studies, 1-methyl-1-cyclo-
hexene was used and imidazole was selected as the azole
nucleophile; selected results from the initial screening are
presented in Table 1.
The data presented in Table 1 highlight the key findings of
our initial search for hydroamination reactivity. Initial attempts
to perform photoinduced, direct hydroamination in a variety of
solvents failed, as illustrated in entry 1. The addition of 20 mol
% of an acid additive (leading to the in situ formation of the
imidazolium conjugate acid) to facilitate protonation of the
putative (E)-cycloalkene intermediate provided our initial leads
(entries 2 and 3), and our results are consistent with the
counterion effects documented by Anderson, Arnold, and
Bergman (entry 3).4a While encouraging reactivity was observed
in various solvents (entries 3 and 4 are representative examples),
multiple products could be seen in the unpurified reaction
mixture. Inspired by the elegant work of Inoue using benzoates
as singlet sensitizers,11 methyl benzoate-sensitized photoisomer-
ization was explored and led to a similar conversion (entry 5)
but minimized the side reactions associated with the use of
p-xylene as triplet sensitizer. Importantly, irradiation of an
equimolar mixture of 1-methylcyclohexene and imidazole
using PhCO2Me as sensitizer led to a 26% conversion to the
desired product (entry 6) and served as the starting point
for the reaction optimization presented in Table 2. Control
experiments were routinely performed during this investi-
gation, and in all cases, no hydroamination could be
obserVed in the absence of UV irradiation, which is consistent
with the buffering effect of azoles (illustrated by Table 1,
entry 7).
Solvent and counterion effects were briefly reinvestigated
using methyl benzoate as sensitizer, and both the use of
imidazolium trifluoromethanesulfonate as a conjugate acid and
EtOAc as solvent were found to be optimal (Table 2, entry 2).
Surprisingly, increasing the ratio in favor of one of the reactants
had only a minimal impact on the reaction outcome (entries 5
and 6). Stimulated by a recent publication by Squillacote and
co-workers suggesting that the (E)-cycloalkene “thermal”
isomerization (i.e., their lability) arises from a bimolecular
pathway involving alkenes,14 we performed the reaction by
adding the excess alkene in five portions over the course of
Reported additions of azoles to electron-rich alkenes are
scarce.5 A representative, well-studied system involves the acid-
catalyzed addition of benzotriazole to various alkenes. Katritzky
and co-workers have shown that benzotriazole will form a
mixture of hydroamination products in the presence of a strong
acid additive and excess alkene.5a While styrene affords the
desired hydroamination products in the presence of catalytic
amounts of p-TsOH at 80 °C (eq 5), cyclohexene requires the
use of a stoichiometric amount of p-TsOH at 120 °C (eq 6).
Typically, alkene isomerization (if possible) also occurs under
the latter conditions.
(8) Liebman, J. F.; Greenberg, A. Chem. ReV. 1976, 76, 311.
(9) (a) Kropp, P. J. J. Am. Chem. Soc. 1966, 88, 4091. (b) Kropp, P. J.;
Krauss, H. J. J. Am. Chem. Soc. 1967, 89, 5199. (c) Kropp, P. J. J. Am.
Chem. Soc. 1969, 91, 5783. (d) Tise, F. P.; Kropp, P. J. Org. Synth. 1983,
61, 112.
(10) (a) Marshall, J. A.; Carroll, R. D. J. Am. Chem. Soc. 1966, 88, 4092.
(b) Marshall, J. A.; Wurth, M. J. J. Am. Chem. Soc. 1967, 89, 6788.
(11) (a) Inoue, Y.; Ueoka, T.; Kuroda, T.; Hakushi, T. J. Chem. Soc.,
Chem. Commun. 1981, 1031. (b) Inoue, Y.; Ueoka, T.; Kuroda, T.; Hakushi,
T. J. Chem. Soc., Perkin Trans. 2 1983, 983. (c) Inoue, Y.; Ueoka, T.;
Hakushi, T. J. Chem. Soc., Perkin Trans. 2 1984, 2053. (d) Shim, S. C.;
Kim, D. S.; Yoo, D. J.; Wada, T.; Inoue, Y. J. Org. Chem. 2002, 67, 5718.
(e) Hoffmann, R.; Inoue, Y. J. Am. Chem. Soc. 1999, 121, 10702. (f) Asaoka,
S.; Horiguchi, H.; Wada, T.; Inoue, Y. J. Chem. Soc., Perkin Trans. 2 2000,
737.
(12) For reviews, see: (a) Marshall, J. A. Science 1970, 170, 137. (b)
Kropp, P. J. Mol. Photochem. 1978, 9, 39.
(13) In some cases, trace amounts of acid (not sufficient to promote
hydroetherification) were found to be beneficial. See ref 9d.
(14) Squillacote, M. E.; DeFellipis, J.; Shu, Q. J. Am. Chem. Soc. 2005,
127, 15983.
J. Org. Chem, Vol. 73, No. 3, 2008 1005

Moran et al.
TABLE 1. Selected Optimization Data Highlighting the
Importance of Sensitizer and Additives to Achieve Intermolecular
Hydroaminationa
TABLE 3. Photoinduced Additions of Azoles to
1-Methyl-1-cyclohexenea
entry
additive
sensitizer
solvent
conversionb (%)
1
2
3
4
5
6
p-xylene
p-xylene
p-xylene
p-xylene
PhCO2Me
PhCO2Me
PhCO2Me
dioxane
dioxane
dioxane
EtOAc
dioxane
dioxane
dioxane
0
4
13
5
14
26c
0
AcOH
TfOH
TfOH
TfOH
TfOH
TfOH
7 (no hν)
a Conditions: 1a (1 equiv) was added to a solution of 2a (7.6 equiv),
additive (20 mol %), sensitizer (7% v/v for p-xylene or 1.8 equiv of
PhCO2Me), and solvent (0.05 M) in a quartz tube under N2 and then
irradiated with UVC lamps (254 nm) for 18 h. b Conversions were
1
determined by H NMR based on imidazole resonances. c Only 1.0 equiv
of imidazole was used.
TABLE 2. Optimization Using Methyl Benzoate as Sensitizera
a Conditions: 1a (0.41 mmol) was added to a solution of nitrogen
heterocycle (0.41 mmol), TfOH (20 mol %), PhCO2Me (1.8 equiv), and
EtOAc (8 mL) in a quartz tube under N2 and then irradiated with UVC
lamps (254 nm). Additional 1-methyl-1-cyclohexene was added portionwise
over time (1 equiv/6-12 h to a total of 5 equiv) with continued irradiation.
b Isolated yield.
conversionb
entry
solvent
additive
alkene/azole ratio
1:1
1:1
1:1
1:1
1:2
5:1
5:1
(%)
1
2
3
4
5
6
7
dioxane
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
TfOH
TfOH
AcOH
CF3CO2H
TfOH
26
22
0
method provides simple access to hindered nitrenium derivatives
such as 8.
7
18
23
72
TfOH
TfOH
(portionwise addition)
a Conditions: 1a was added to a solution of 2a (molar ratio shown),
additive (20 mol %), PhCO2Me (1.8 equiv), and solvent (0.05 M) in a
quartz tube under N2 and then irradiated with UVC lamps (254 nm) for 18
h. b Conversions were determined by 1H NMR based on imidazole
resonances.
With the azole scope explored, we turned our attention to
the reaction of other cyclic alkenes with imidazole. These results
are presented in Table 4.
As shown, the hydroamination reactivity observed with
1-methyl-1-cyclohexene and imidazole (Table 4, entry 1) could
also be extended to other alkenes. Variation of the alkene
substituent or of the ring size led to somewhat lower yields, as
shown by the reaction of 1-ethyl-1-cyclohexene (entry 2) and
1-methyl-1-cycloheptene (entry 3). Encouragingly, (-)-limonene
(1d) led to selective hydroamination of the cyclic alkene,17 with
a mixture of diastereoisomers isolated in good yield (entry 4).
The use of cyclohexene (1e) led to the hydroamination product
in modest yield (entry 5). In contrast, 1-methylcyclopentene and
cyclooctene did not lead to product formation under our reaction
conditions. This lack of reactivity suggests that the ring strain
present in (E)-cyclooctene, which is known to be stable at room
temperature, is not sufficient to allow the desired reaction.
approximately 30 h. This new procedure led to a significant
improvement: 72% conversion to the desired hydroamination
product was observed (entry 7 vs entry 6).
With optimized conditions in hand, we could examine the
reaction scope with respect to the azole reacting partner. These
studies were performed using 1-methyl-1-cyclohexene as sub-
strate and are presented in Table 3.
The hydroamination reactivity discovered with imidazole
(Table 3, entry 1) extended well to other azole nucleophiles.
For example, pyrazoles (entries 2 and 3) led to the formation
of the desired adducts, albeit in lower yield with the hindered
2,5-dimethylpyrazole (2c, entry 3). 1,2,4-Triazole (entry 4) and
tetrazole (entry 5) also afforded the desired products in good
yield. An unexpected result was obtained with 1,2,3-triazole,
which afforded the nitrenium salt 8 in an unoptimized 20% yield
(eq 7). Such nitrenium salts have been shown by Boche to have
remarkable properties,15 as expected based on their isoelectronic
nature with the related Arduango carbenes.16 Therefore, the
(16) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361.
(17) This selectivity for the cyclic alkene in limonene, as well as the
lack of reactivity observed with 1-methylcyclopentene, cyclooctene, and
in control experiments performed with other cyclic alkenes (R-pinene and
2-carene, for example) strongly suggest the intermediacy of highly strained
(E)-cycloalkene intermediates. We also prefer this rationale over other
possibilities, including reactivity arising from azole excited states being
more acidic, for example.
(15) Boche, G.; Andrews, P.; Harms, K.; Marsch, M.; Rangappa, K. S.;
Schimeczek, M.; Willeke, C. J. Am. Chem. Soc. 1996, 118, 4925.
1006 J. Org. Chem., Vol. 73, No. 3, 2008

Intermolecular Hydroaminations Via Strained (E)-Cycloalkenes
TABLE 4. Photoinduced Additions of Imidazole to Cyclic Alkenesa
Conclusion
A photoinduced procedure for intermolecular hydroamination
of cyclic alkenes using azoles has been developed. The presence
of a mild acid and sequential addition of the alkene over time
were found to be crucial to obtain good yields of the complex
N-alkylazole products. Highly strained trans-cycloalkenes,
formed in situ via sensitized photoisomerization using methyl
benzoate at 254 nm, are likely reaction intermediates.
Experimental Section
General Procedure for Photoinduced Hydroamination of
Cycloalkenes (Tables 3 and 4). A 10 mL quartz tube was
charged with a stir bar, methyl benzoate (0.10 g, 0.73 mmol),
nitrogen heterocycle (0.41 mmol), and 8.0 mL of EtOAc,
followed by trifluoromethanesulfonic acid (0.012 g, 0.081
mmol). The mixture was stirred for 10 s. Cycloalkene (0.41
mmol) was added, and the tube was capped with a rubber
septum and purged with a nitrogen balloon and an outlet for 5
min while stirring. The tube was then placed between two
Luzchem exposure panels, each equipped with four ultraviolet
lamps, for 6-12 h while stirring. The reaction was carried out
in a well-ventilated hood, and little, if any, sample warming
occurred. Irradiation was then stopped, a further equivalent of
cycloalkene (0.41 mmol) was added, and the tube was again
purged with nitrogen and subjected to irradiation. This was
continued until 5 equiv of the cycloalkene had been added. The
reaction was monitored by thin layer chromatography. The crude
reaction mixture was concentrated under reduced pressure and
purified by silica gel chromatography to give the N-substituted
heterocycle.
a Conditions: Cycloalkene (0.41 mmol) was added to a solution of
imidazole (0.41 mmol), TfOH (20 mol %), PhCO2Me (1.8 equiv), and
EtOAc (8 mL) in a quartz tube under N2, then irradiated with UVC lamps
(254 nm). Additional cycloalkene was added portion-wise over time (1
equiv/6-12 h to a total of 5 equiv) with continued irradiation. b Isolated
yield. c 1.3:1 mixture of diastereoisomers.
The variability observed with respect to the alkene structure
can be explained by looking at the efficiency of the hydroami-
nation step. The reaction conditions require the presence of an
excess of alkene to obtain high yields of the hydroamination
product. This excess is necessary due to an unproductive
isomerization step, which leads to the formation of the exocyclic
alkene. For example, if the reaction with (-)-limonene (1d) is
performed using equimolar amounts of alkene and imidazole,
the product distribution favors the isomerization product 13 over
the hydroamination product 11 (eq 8). This control experiment
suggests the formation of highly strained (E)-cycloalkenes under
our reaction conditions is efficient as shown by the total
conversion to 11 and 13. However, the tertiary carbocation
formed upon alkene protonation can either react with imidazole
to provide the desired hydroamination product or undergo
deprotonation, which either leads back to the starting material
(with erosion of ee)18 or leads to the formation of an exocyclic
alkene. The latter reaction is irreversible as it cannot lead to
the formation of hydroamination products; this reactivity of (E)-
cycloalkenes is well documented.19
Acknowledgment. We thank NSERC for generous support
through the discovery grants and research tools and instrumenta-
tion programs, the University of Ottawa for startup funds, the
Canadian Foundation for Innovation, and the Ontario Ministry
of Research and Innovation. J.M. also thanks NSERC for
CGS-M and PGS D postgraduate scholarships and the University
of Ottawa for a SAD award.
Supporting Information Available: Typical experimental
procedures, experimental details, and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(18) In agreement with this rationale, the limonene recovered from the
reaction shown in eq 8 was found to be racemic. See the experimental
details.
(19) See ref 12 for a discussion. For an example of application in total
synthesis, see: Marshall, J. A.; Pike, M. T. J. Org. Chem. 1968, 33, 435.
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J. Org. Chem, Vol. 73, No. 3, 2008 1007