Chemoselective C-H bond activation: Ligand and solvent free iron-catalyzed oxidative C-C cross-coupling of tertiary amines with terminal alkynes. Reaction scope and mechanism

Article abstract of DOI:10.1021/ol9002509

FeCI₂ catalyzes the oxidative C-C cross-coupling of tertiary amines with terminal alkynes Into propargylamlnes using (t-BuO)₂ as oxidant. The reaction can be applied to aromatic and aliphatic amines and alkynes without solvent. High chemoselectlvlty for amlnomethyl groups Is due to a steric factor.

Full text of DOI:10.1021/ol9002509

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1701-1704
Chemoselective C-H Bond Activation:
Ligand and Solvent Free Iron-Catalyzed
Oxidative C-C Cross-Coupling of
Tertiary Amines with Terminal Alkynes.
Reaction Scope and Mechanism
Chandra M. Rao Volla and Pierre Vogel*
Laboratoire de glycochimie et de synthe`se asyme´trique (LGSA), Swiss Federal Institute
of Technology of Lausanne (EPFL), CH 1015 Lausanne, Switzerland
pierre.Vogel@epfl.ch
Received February 5, 2009
ABSTRACT
FeCl2 catalyzes the oxidative C-C cross-coupling of tertiary amines with terminal alkynes into propargylamines using (t-BuO)2 as oxidant. The
reaction can be applied to aromatic and aliphatic amines and alkynes without solvent. High chemoselectivity for aminomethyl groups is due
to a steric factor.
The direct C-H activation for C-C bond-forming reaction
is of fundamental interest for preparative chemistry.1 In 1932,
de Paolini2 reported the dealkylation of tertiary amines with
benzoyl peroxide. In 1946, Horner et al.3 explained that
benzoyl peroxide polymerization of styrene is accelerated
by N,N-dimethylaniline. They later proposed the mechanism
shown in Scheme 1 (X ) Bz) for the amine dealkylation.4
Hydrogen transfer from the oxidant can occur in one step
(direct hydrogen transfer, 1 f 3) or in two steps via the
radical-cation intermediate 2 giving aminoalkyl radical
intermediates 3. The latter induce polymerization of alkenes;
they can be quenched by O2.5 Collapse of 3 with BzO•
generates the aminal derivatives 5 (X ) Bz) or, by electron
transfer, iminium salts of type 4. The latter react with
H2O to produce the secondary amines 6 and aldehydes
R′CHO.
(1) (a) Dyker, G. Handbook of C-H Transformations; Wiley-VCH:
Weinheim, 2005. (b) Li, C. J.; Li, Z. P. Pure Appl. Chem. 2006, 78, 935–
945. (c) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed.
2006, 45, 2619–2622. (d) Company, A.; Go´mez, L.; Gu¨ell, M.; Ribas, X.;
Luis, J. M.; Que, L., Jr.; Costas, M. J. Am. Chem. Soc. 2007, 129, 15766–
15767. (e) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069–1084. (f) Lewis,
J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013–
1025. (g) Li, B. J.; Yang, S. D.; Shi, Z. J. Synlett 2008, 949–957. (h) Park,
Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222–234. (i)
Herrerias, C. I.; Yao, X. Q.; Li, Z. P.; Li, C. J. Chem. ReV. 2007, 107,
2546–2562.
Oxidative dealkylations of tertiary amines with H2O2 cata-
lyzed by horseradish peroxidase,6 lignin peroxidase,7 and other
cytochrome P450 enzymes follow a similar mechanism in which
(4) (a) Horner, L.; Junkermann, H. Ann. Chem. Justus Liebig 1955, 591,
53–68. (b) Horner, L.; Kirmse, W. Ann. Chem. Justus Liebig 1955, 597,
48–65.
(2) de Paolini, I.; Ribet, G. Gazz. Chim. Ital. 1932, 62, 1041–1048.
(3) Horner, L.; Schwenk, E. Ann. Chem. Justus Liebig 1950, 566, 69–
84.
(5) Lalevee, J.; Allonas, X.; Fouassier, J. P.; Ingold, K. U. J. Org. Chem.
2008, 73, 6489–6496.
10.1021/ol9002509 CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

C-C coupling with aliphatic tertiary amines and/or with
acetylenes that are not arylethynes, we have searched for a
better method. Iron salts are inexpensive and benign to the
environment, especially when they do not require coordina-
tion to expensive or/and toxic ligands; they are now the
catalysts of choice.20 We are pleased to report the FeCl2
catalyzes the chemoselective oxidative C-C cross-coupling
of a large variety of tertiary amines and terminal alkynes,
using (t-BuO)2 as oxidant and no solvent.
Scheme 1. Oxidative Dealkylation of Tertiary Amines and
Quenching of Iminium Ion Intermediates with Nucleophiles
(Horner’s Mechanism)
With (t-BuO)2 as oxidant we found that Fe(acac)2, FeCl3,
Fe2(CO)9, Fe(CO)5, and FeCl2 (10 mol%) catalyze the
coupling reaction (24 h, 100 °C, Ar atm) giving 9aa in 12%,
56%, 12%, 13%, and 69% yield, respectively (4 mmol of 7a,
2 mmol of 8a, no solvent) (Table 1). Fe(OAc)2, Fe(ClO4)2, and
Fe(acac)3 did not catalyze the reaction. Interestingly, we found
that the yield of the FeCl2/(t-BuO)2-induced coupling reaction
was higher under air atmosphere (88%) than under Ar atmo-
sphere (69%). We cannot explain yet this observation. Under
1 atm of pure O2, decrease of yield (65%) was observed,
probably because of the known4,5 O2 quenching of short-lived
R-aminoalkyl radical of type 3 (Scheme 1).
In the presence of 1 equiv of H2O, the reaction was slower
and R-aminoether 4-Me-C6H4N(Me)CH2O-t-Bu (12, this
product could not be isolated; see below) was present in the
crude reaction mixture after 24 h at 100 °C. More water
inhibited the reaction completely, thus demonstrating that
anhydrous conditions must be chosen for success. The
reaction occurs already at 20 °C but in much lower yield
(7%, 24 h, no solvent).
We then explored the scope of our reaction conditions
(Table 2) and found that various aryl substituted N,N-
dimethylanilines (7) can be coupled with arylacetylenes
(8a,b,c), heteroarylacetylenes (8d,e), and nonaromatic
terminal alkynes (8f-k) including a conjugated enyne
(8h), a silylethyne (8g), ethyl propynoate (8i), 5-chloro-
pent-1-yne (8j), and phenyl propargyl ether (8k). Oxidative
coupling of bromoaniline 7d is particularly interesting as
MdO species oxidize the amines as X-O•.8 In 1988, Murahashi
et al. found that ruthenium salts and complexes catalyze the
oxidation of tertiary amines with t-BuOOH to give the corre-
sponding R-aminoalkyl tert-butyl ethers (5, X ) O-t-Bu) that
are hydrolyzed into 6 + R′CHO.9 Nucleophiles other than H2O
can be reacted with the immonium intermediates 4, including
carbon nucleophiles such as allylsilanes and HCN.10,11 Interest-
ingly, with RuCl3 catalyst the oxidant can be H2O2 or O2.10
In 1989, Miura and co-workers reported the O2 oxidation of
N,N-dimethylaniline (60 °C, MeCN) catalyzed by iron salts
to give N-methylformanilide and several other products
arising from the reactions of radical intermediates of type
3.12 Using CuCl2/O2 and terminal alkynes, they managed to
obtain (27-43% yield) the corresponding products of oxida-
tive C-C cross-coupling, N-methyl-N-propargylanilines.13
This was an important discovery as propargyl amines are
key synthetic intermediates in the preparation of a large
variety of biologically active compounds.14 More recently,
Li and co-workers, using t-BuOOH as oxidant and CuBr as
catalyst, have realized better yielding oxidative coupling of
tertiary amines with arylacetylenes,15 nitromethane,16 in-
doles,17 malonates, naphthols, and other carbon nucleo-
philes.18 An alternative method using NBS as oxidant and
CuBr as catalyst has been proposed by Fu and co-workers.19
As these methods give only moderate yields of oxidative
(14) See e. g.: (a) Likhar, P. R.; Subhas, M. S.; Roy, S.; Kantam, M. L.;
Sridhar, B.; Seth, R. K.; Biswas, S. Org. Biomol. Chem. 2009, 7, 85–93.
(b) Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.; Snyder,
J. K. J. Comb. Chem. 2008, 10, 534–540. (c) Boulton, A. A.; Davis, B. A.;
Durden, D. A.; Dyck, L. E.; Juorio, A. V.; Li, X. M.; Paterson, I. A.; Yu,
P. H. Drug DeV. Res. 1997, 42, 150–156. (d) Miura, M.; Enna, M.; Okuro,
K.; Nomura, M. J. Org. Chem. 1995, 60, 4999–5004.
(6) (a) Galliani, G.; Rindone, B.; Marchesini, A. J. Chem. Soc., Perkin
Trans. 1 1978, 456–460. (b) Galliani, G.; Rindone, B. J. Chem. Soc., Perkin
Trans. 2 1980, 1–3.
(7) (a) Guengerich, F. P.; MacDonald, T. L. Acc. Chem. Res. 1984, 17,
9–16. (b) Baciocchi, E.; Gerini, M. F.; Lapi, A. Chem. Commun. 2002,
946–947. (c) Baciocchi, E.; Gerini, M. F.; Lanzalunga, O.; Lapi, A.; Lo
Piparo, M. G.; Mancinelli, S. Eur. J. Org. Chem. 2001, 230, 5–2310.
(8) (a) Cytochrome P-450, 2nd ed.; Plenum: New York, 1995; (b)
Cuppoletti, A.; Galli, C.; Gentili, P.; Petride, H. J. Phys. Org. Chem. 2002,
15, 672–675. (c) Urlacher, V. B.; Bell, S. G.; Wong, L. L. Mod. Biooxid.
2007, 99–122. (d) Chiavarino, B.; Cipollini, R.; Crestoni, M. E.; Fornarini,
S.; Lanucara, F.; Lapi, A. J. Am. Chem. Soc. 2008, 130, 3208–3217.
(9) Murahashi, S.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988,
110, 8256–8258.
(15) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 11810–11811.
(16) (a) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 3672–3673.
See also the CuBr/O2-promoted oxidative R-(nitroalkylation) of tertiary
amines: (b) Basle´, O.; Li, C. J. Green Chem. 2007, 9, 1047–1050.
(17) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 6968–6969.
(18) Li, Z. P.; Bohle, D. S.; Li, C. J. Proc. Nat. Acad. Sci. U.S.A. 2006,
103, 8928–8933.
(19) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008,
73, 3961–3963.
(10) Murahashi, S. I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005–11012, and references therein
.
(20) (a) Fu¨rstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787, and references
therein. (b) Sherry, B. D.; Fu¨rstner, A. Acc. Chem. Res. 2008, 41, 1500–
1511. (c) Plietker, B. Iron Catalysis in Organic Chemistry; Wiley-VCH:
Weinheim, 2008. (d) Bauer, E. B. Curr. Org. Chem. 2008, 12, 1341–1369.
(e) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 5858–5859. (f) Enthaler, S.; Junge, K.; Beller, M. Angew.
Chem., Int. Ed. 2008, 47, 3317–3321. (g) Carril, M.; Correa, A.; Bolm, C.
Angew. Chem., Int. Ed. 2008, 47, 4862–4865. (h) Volla, C. M. R.; Vogel,
P. Angew. Chem., Int. Ed. 2008, 47, 1305–1307. (i) Loska, R.; Volla,
C. M. R. AdV. Synth. Catal 2008, 350, 2859–2864. (j) Reymond, S.; Ferrie´,
L.; Guerinot, A.; Capdevielle, P.; Cossy, J. Pure Appl. Chem. 2008, 80,
1683–1691. (k) Volla, C. M. R.; Vogel, P. Tetrahedron Lett. 2008, 49,
5961–5964.
(11) For other metal-catalyzed R-C-H activation of tertiary amines, see:
(a) Wilson, R. B., Jr.; Laine, R. M. J. Am. Chem. Soc. 1985, 107, 361–369.
(b) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935–10941. (c) DeBoef, B.; Pastine,
S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556–6557. (d) Pastine,
S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220–
14221. (e) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648–5649
.
(12) (a) Murata, S.; Miura, M.; Nomura, M. J. Org. Chem. 1989, 54,
4700–4702. (b) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Chem.
Commun. 1989, 116–118.
(13) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. J. Chem. Res.,
Synop. 1993, 434.
1702
Org. Lett., Vol. 11, No. 8, 2009

Table 1. Iron-Catalyzed Coupling of 4,N,N-Trimethylaniline
(7a) with Phenylacetylene (8a)a
Table 3. Chemoselective FeCl2-Catalyzed Oxidative Couplings
yield (%)b
time
(h)
yield
(%)
entry
Fe catalyst
oxidant (equiv)
atmosphere
entry
amine
R
1
2
FeCl2
t-BuOOH (3)
(t-BuO)2 (3)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
H2O2 (2)
O2 (1 atm)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
(BzO)2 (2)
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
tr
42
69
56
12
0
1
2
3
4
5
R′ ) Bn, R′′ ) Me (10a)
R′ ) Bn, R′′ ) Ph (10b)
R′ ) n-octyl, R′′ ) Me (10c)
R′ ) c-hexyl, R′′ ) Me (10d)
R′ ) n-octyl, R′′ ) Me (10c)
Ph (8a)
Ph (8a)
Ph (8a)
Ph (8a)
24
24
24
18
42 (11a)
13 (11b)
74 (11c)
89 (11d)
65 (11e)
FeCl2
3
FeCl2
FeCl3
4
5
Fe(acac)2
Fe(acac)3
Fe(OAc)2
Fe(ClO4)2
Fe2(CO)9
Fe(CO)5
FeCl2
3-pyridyl (8e) 18
6
7
0
8
0
9
12
13
7c
We have found also that tertiary amines that are not
anilines can be coupled with terminal alkynes under our
conditions (Table 3). Interestingly, N,N-dimethylbenzylamine
(10a) gave a major product 11a resulting from the chemose-
lective coupling with the methyl group rather than with its
benzyl group. The moderate yield (42%) after 24 h can be
improved to 75% if the reaction is run over 3 days. Reaction
8a + 10a f 11a is somewhat slower than reaction 8a + 7a
f 9aa.
10
11
12
13
14
15
16
17
18
19
20
21
FeCl2
FeCl2
FeCl2
air
air
O2
air
air
air
air
air
85
FeCl2
88d
65
FeCl2
FeCl2
tr
e
(BzO)2 (2)
(t-BuO)2 (2)
(t-BuO)2 (2)
FeCl2
FeCl2
trf
g
Desilylation of propargyl amine 9ag provides terminal alkyne
8l that can be coupled with N,N-dimethyloctylamine under the
same conditions to give 11f in 67% yield (Scheme 2).
a Reaction conditions: 1 equiv of phenylacetylene (2 mmol) and 2
equiv of 4,N,N-trimethylaniline (4 mmol) with iron catalyst (0.2 mmol)
and oxidant. b Yield of isolated product after column flash chromatography
on silica gel. c Reaction was done at room temperature. d 1.5 equiv of 4,N,N-
trimethylaniline was used. e Decomposition of tert-amine was observed.
f 1 equiv of H2O was added. g 20 equiv of H2O was added.
Scheme 2. Chemoselective FeCl2-Catalyzed Oxidative
Couplings with Two Different tert-Amines
it generates propargyl amine 9da that can, in principle,
undergo further transition-metal-catalyzed C-C or C-
hetero coupling reactions.21
Table 2. Oxidative Iron-Catalyzed C-C Cross-Coupling of
N,N-Dimethyl Anilines (7) with Terminal Alkynes (8) Giving
Propargylamines (9)a
The product resulting from the oxidation of the benzylic
C-H of 10a could not be detected, thus showing the high
chemoselectivity of our oxidative C-C coupling reaction,
the least sterically hindered R-C-H bonds of the amine being
oxidized preferentially. This can be explained by the known
chemoselectivity of hydrogen transfer from tertiary amines
to t-BuO• radical, which is faster for PhNMe2 and Et3N than
for (allyl)3N and PhN(CH2Ph)2.22 Although the hydrogen
transfer from a benzylic C-H bond to t-BuO• is more
exothermic (by ca. 12 kcal/mol) than the hydrogen transfer
from a methyl group, entropy effects (due to steric require-
ments) make this reaction chemoselective in favor of the least
sterically hindered R-C-H bond. According to Horner’s
mechanism (Scheme 1), proton transfer from 2 could be
responsible for the chemoselectivity. The low yield of
entry
Ar
R
time (h) yield (%)b
1
2
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
4-MeC6H4 (7a)
2-MeC6H4 (7b)
Ph (7c)
Ph (8a)
24
24
24
24
24
30
30
24
24
30
24
24
24
24
24
24
88 (9aa)
76 (9ab)
57 (9ac)
79 (9ad)
93 (9ae)
66 (9af)
82 (9ag)
47 (9ah)
61 (9ai)
69 (9aj)
71 (9ak)
71 (9ba)
24 (9ca)c
32 (9cb)d
79 (9bb)
54 (9da)
4-MeC6H4 (8b)
4-MeOC6H4 (8c)
2-pyridyl (8d)
3-pyridyl (8e)
n-hexyl (8f)
Et3Si (8g)
1-cyclohexenyl (8h)
COOEt (8i)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
ClCH2CH2CH2 (8j)
PhOCH2 (8k)
Ph (8a)
Ph (8a)
Ph (7c)
2-MeC6H4 (7b)
4-BrC6H4 (7d)
4-MeC6H4 (8b)
4-MeC6H4 (8b)
Ph (8a)
(21) See e. g.: (a) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008,
41, 59–72. (b) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440–
1449. (c) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338–6361. (d) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. (e)
Buchwald, S. L.; Martin, R. Acc. Chem. Res. 2008, 41, 1461–1473. (f)
Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486–1499.
a Reaction conditions: 1 equiv (2 mmol) of 8, 1.5 equiv (3 mmol) of
7, FeCl2 (0.2 mmol), (t-BuO)2 (4 mmol). b Yield of isolated product after
column flash chromatography on silica gel, not optimized. c 48% of
recovered 8a. d 39% of recovered 8b.
Org. Lett., Vol. 11, No. 8, 2009
1703

reaction 8a + 10b f 11b (13%, 24 h) is the manifestation
of a retardation of the hydrogen atom or proton transfer
because of the bulk introduced by the phenyl and benzyl
groups.22 The importance of this steric factor is evidenced
also with the reaction of aliphatic tertiary amines 10c,d. They
require only 18 h (instead of 24 h) to give good yields of
propargyl amines under our conditions.
Horner’s mechanism (Scheme 1) interprets all of our
observations. The role of FeCl2 is to catalyze the formation
formation of intermediates of type 5.23 In the absence of alkyne
the reaction 7a + (t-BuO)2/FeCl2 produces the R-aminoether
4-MeC6H4N(Me)CH2-O-t-Bu (12).24 The later does not react
with phenylacetylene (8a) in the absence of FeCl2, showing
that FeCl2, which acts as Lewis acid promoter, induces the SN1
cleavage of the R-aminoethers of type 5 into iminium ion
intermediates of type 4 (Scheme 3).25 In the absence of FeCl2,
formation of alkenyl cation intermediates) can be ruled out
because one does not observe significant differences in the
initial reaction rates as a function of the nature of the alkyne
(electron-rich (R ) 4-MeOC6H4, alkyl, silyl) or electron-
poor (R ) COOEt)). If the reaction should involve ami-
noalkyl radical addition to the alkynes in the rate-determining
step (with formation of alkenyl radical intermediates),
significant differences in rates should be observed for the
various alkynes studied, which is not the case. For instance,
when a 1:1:1 mixture of 8a, 8f, and 8i was reacted with 7a
and (t-BuO)2 + FeCl2 for 5 h at 100 °C (ca. 30% conversion),
a 1:0.6:1.5 mixture of 9aa, 9af, and 9ai was formed (similar
rate constant for phenyl-, hexyl-, and ester-substituted ethyne;
see Supporting Information for detailed scheme). Using
PhCONH2, 7a reacted to give the corresponding product of
oxidative coupling 4-MeC6H4N(Me)CH2NHCOPh (13, Scheme
4), in agreement with Horner’s mechanism (Scheme 1).27
Scheme 3. Formation of tert-Butyl Aminomethyl Ether and
Subsequent Coupling with Phenylacetylene
Scheme 4. Iron-Catalyzed Oxidative Coupling of
4,N,N-Trimethylaniline with Benzamide
In summary, the first iron-catalyzed oxidative C-C cross-
coupling of tertiary amines with terminal alkynes to give
propargylamines is presented. The conditions can be applied
to aromatic and nonaromatic amines and alkynes. The
reaction is chemoselective: for steric reasons the methylamino
group reacts faster than other alkylamino groups. Our
discovery should find applications in medicinal chemistry28
and material sciences.
(t-BuO)2 + 7a did not react to produce 12 (12 h, 100 °C). This
demonstrates that FeCl2 catalyzes the formation of 12, even
though it was reported that dialkyl peroxides are unreactive with
FeCl2.26 Reaction 1 + (t-BuO)2/FeCl2 f 5 might not involve
homolysis, (t-BuO)2 f 2 t-BuO•. The C-C bond-forming step
involves reaction of iminium ions of type 4 with acetylide
anions. When 1:1 mixture of Ph-C2-D and n-C6H13C2-H was
heated to 100 °C for 12 h in the presence of 2 equiv of Et3N,
a 0.5:0.5:0.5:0.5 mixture of Ph-C2-H, Ph-C2-D, n-hex-C2-D, and
n-hex-C2-H was formed. The same experiment run with 10%
FeCl2 and the absence of Et3N also led to H/D exchange
between the two terminal acetylenes, but the reaction was not
complete after 12 h at 100 °C. When using FeCl2 and Et3N the
exchange was complete at 100 °C after 12 h. These experiments
showed not only that tertiary amines are able to deprotonate
the alkynes but that FeCl2 itself can generate iron acetylide
intermediates, but more slowly than deprotonation by Et3N.
Any mechanism involving addition of iminium ion inter-
mediates to the alkynes in the rate-determining step (with
Acknowledgment. We are grateful to the Swiss National
Science Foundation and to the Roche Research Foundation
for financial support. We would like to thank Ms. Aswani
Yella (University of Mainz, Germany) for helpful discussions
and the referees for very helpful comments.
Supporting Information Available: Experimental pro-
cedures, characterization of compounds and further refer-
ences. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL9002509
(27) After submission of this manuscript, Li and co-workers reported
the FeCl3 catalyzes conversion of terminal alkynes, aldehydes, and secondary
amines into aminoalkynes, reactions that probably imply iminium ion
intermediates reacting with acetylide intermediates: Li, P.; Zhang, Y.; Wang,
L. Chem. Eur. J. 2009, 15, 2045–2049.
(22) Tanko, J. M.; Friedline, R.; Suleman, N. K.; Castagnoli, N., Jr.
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