Dimethylzinc-mediated alkynylation of imines

Article abstract of DOI:10.1021/jo052273o

The treatment of various aromatic and aliphatic aldimines with a mixture of a terminal alkyne and a commercially available dimethylzinc solution in toluene yields the corresponding protected propargylic amines in moderate to excellent yields. The reaction

Full text of DOI:10.1021/jo052273o

Dimethylzinc-Mediated Alkynylation of Imines
Lorenzo Zani,† Silvia Alesi,‡ Pier Giorgio Cozzi,‡ and Carsten Bolm*,†
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1, D-52056 Aachen, Germany, and
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum, UniVersita` di Bologna, Via Selmi 2,
I-40126 Bologna, Italy
carsten.bolm@oc.rwth-aachen.de
ReceiVed NoVember 2, 2005
The treatment of various aromatic and aliphatic aldimines with a mixture of a terminal alkyne and a
commercially available dimethylzinc solution in toluene yields the corresponding protected propargylic
amines in moderate to excellent yields. The reaction proceeds in the absence of any activator. These
observations led to the development of a three-component synthesis of propargylic amines in which the
product was obtained upon mixing an aldehyde with ortho-methoxyaniline and phenylacetylene in the
presence of dimethylzinc, through in situ formation of the corresponding imine.
Introduction
actylenes to CdN double bonds, a general and an easy-to-
perform procedure for the alkynylation of simple imines is still
desirable.
The addition of carbon nucleophiles to reactive electrophilic
functions, such as CdO and CdN double bonds, is a process
of fundamental importance in the development of a chemical
synthesis.1 Among the various nucleophilic species available,
alkynes are excellent reagents for mild and selective CsC bond-
forming reactions.2
While the addition of acetylenes to carbonyl compounds, in
both a racemic and an enantioselective manner, has been the
subject of a large number of publications,3 1,2 additions of
alkynes to compounds with CdN double bonds by a direct
nucleophilic reaction have been much less developed, mostly a
result of the poor electrophilicity of the azomethine carbon.4
Moreover, to overcome the general low reactivity of imines,
often more activated substrates such as nitrones or iminium salts
are used. Recent protocols commonly employ metal salts or
complexes as promoters, used in either stoichiometric5 or
catalytic amounts.6-12 An excellent example is Knochel’s highly
enantioselective copper-catalyzed addition of alkynes to enam-
ines, further developed into a three-component reaction.12
Despite these substantial advances in the direct addition of
Recently, we found that mixtures of ZnMe2 and acetylenes
are able to promote the alkynylation of aldehydes and ketones
to furnish propargylic alcohols in good to excellent yields at
room temperature.13 These results were surprising, because a
mixture of phenylacetylene and dimethylzinc had previously
been reported to be rather unreactive toward aldehydes14 in the
absence of a proper activator.15 This suggested the possibility
that the carbonyl oxygen could behave in a “ligand-like” fashion,
activating ZnMe2 by the coordination of its lone pairs.
(3) For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095. For
more recent examples, see: (c) Cozzi, P. G.; Alesi, S. Chem. Commun.
2004, 2448. (d) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.;
Han, Z. Org. Lett. 2004, 6, 4147. (e) Kang, Y.-F.; Liu, L.; Wang, R.; Zhou,
Y.-F.; Yan, W.-J. AdV. Synth. Catal. 2005, 347, 243. (f) Liu, L.; Wang, R.;
Kang, Y.-F.; Chen, C.; Xu, Z.-Q.; Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong,
M.-Z. J. Org. Chem. 2005, 70, 1084. (g) Takita, R.; Fukuta, Y.; Tsuji, R.;
Ohshima, T.; Shibasaki, M. Org. Lett. 2005, 7, 1363. (h) Fang, T.; Du,
D.-M.; Lu, S.-F.; Xu, J. Org. Lett. 2005, 7, 2081. (i) Watts, C. C.; Thoniyot,
P.; Hirayama, L. C.; Romano, T.; Singaram, B. Tetrahedron: Asymmetry
2005, 16, 1829. (j) Weil, T.; Schreiner, P. R. Eur. J. Org. Chem. 2005,
2213. (k) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E.
Tetrahedron 2005, 61, 7219. (l) Lettan, R. B., II; Scheidt, K. A. Org. Lett.
2005, 7, 3227. (m) Pizzuti, M. G.; Superchi, S. Tetrahedron: Asymmetry
2005, 16, 2263. (n) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J.
Am. Chem. Soc. 2005, 127, 13760. (o) Trost, B. M.; Weiss, A. H.; Jacobi
von Wangelin, A. J. Am. Chem. Soc. 2006, 12, 8. (p) Emmerson, D. P. G.;
Hems, W. P.; Davis, B. G. Org. Lett. 2006, 8, 207.
* To whom correspondence should be addressed. Fax: +49-241-8092391.
Phone: +49-241-8094675.
† RWTH Aachen University.
‡ Universita` di Bologna.
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John
Wiley & Sons: New York, 1988.
(2) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.;
VCH: Weinheim, Germany, 1995.
10.1021/jo052273o CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/20/2006
1558
J. Org. Chem. 2006, 71, 1558-1562

Dimethylzinc-Mediated Alkynylation of Imines
SCHEME 1. Alkynylation of N-Tosylphenylimine (1a) with
Two Different Alkylzinc Reagents
Prompted by these observations, we decided to investigate
the reaction of N-substituted imines 1 with mixtures of alkylzinc
reagents and acetylenes 2. To our delight, we found that they
exhibited here a similar behavior. Although zinc-mediated
alkynylation reactions of CdN electrophiles have already been
reported,5b,c,e-g,6 our findings represent the first example of a
ZnMe2-promoted addition of acetylenes to activated imines. The
results obtained in these experiments, as well as the develop-
ment of an unprecedented Zn-mediated one-pot synthesis of
propargylic imines, are reported herein.
Results and Discussion
TABLE 1. Alkynylation of Different N-Substituted Phenylimines
in the Presence of ZnMe2
First, the reaction of N-tosylphenylimine (1a) with 3 equiv
of phenylacetylene (2a) in the presence of dimethylzinc (3.0
equiv, as a commercially available 2.0 M solution in toluene)
in anhydrous toluene at room temperature was examined. Under
those conditions, the conversion of 1a was limited to about 65%
entry
substrate
PG
product
yielda (%)
(4) For reviews on addition reactions to imines, see: (a) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (b) Bloch, R. Chem.
ReV. 1998, 98, 1407. (c) Alvaro, G.; Savoia, D. Synlett 2002, 651. (d)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (e) Denmark, S. E.;
Nicaise, O. J.-C. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 924.
(5) (a) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2003,
44, 4171. (b) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767. (c)
Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216. (d) Fischer, C.;
Carreira, E. M. Org. Lett. 2004, 6, 1497. (e) Lee, K. Y.; Lee, C. G.; Na, J.
E.; Kim, J. N. Tetrahedron Lett. 2005, 46, 69. (f) Fa¨ssler, R.; Frantz, D.
E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. (g)
Topic, D.; Aschwanden, P.; Fa¨ssler, R.; Carreira, E. M. Org. Lett. 2005, 7,
5329. (h) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15.
1
2
3b
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ts
Ms
3aa
3ba
3ca
3da
3ea
3fa
80
78
(82)c
91
69
0
SO2Mes
Ns
P(O)Ph2
Bn
4-(MeO)Ph
2-(MeO)Ph
1g
1h
3ga
3ha
0
76d
a After flash column chromatography (see Supporting Information for
details). b The reaction was carried out at 70 °C. c The product was only
about 90% pure (as determined by NMR). d The amount of 2.5 equiv each
of dimethylzinc and phenylacetylene was used.
(6) Zn: (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245. (b) Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.;
Vallee, Y. Org. Lett. 2002, 4, 1463.
after 48 h (as determined by the NMR analysis of the crude
reaction mixture).16 However, the reaction could easily be
accelerated by raising the temperature, and after a brief
optimization, we found that a mixture of 2a and ZnMe2 (1.5
equiv each) in toluene at 50 °C was able to convert 1a
quantitatively, affording the corresponding protected propargyl-
amine 3aa in 80% yield (Scheme 1 and Table 1, entry 1).
(7) Ir: Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319.
(8) Cu: (a) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268. (b) Wei, C.;
Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (c) Wei, C.; Mague, J. T.; Li,
C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749. (d) Wei, C.; Li, Z.; Li,
C.-J. Synlett 2004, 1472. (e) Benaglia, M.; Negri, D.; Dell’Anna, G.
Tetrahedron Lett. 2004, 45, 8705. (f) Orlandi, S.; Colombo, F.; Benaglia,
M. Synthesis 2005, 1689. (g) Park, S. B.; Alper, H. Chem. Commun. 2005,
1315. (h) Knoepfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 216. (i) Black, D. A.;
Arndtsen, B. A. Org. Lett. 2004, 6, 1107. (j) Black, D. A.; Arndtsen, B. A.
Tetrahedron 2005, 61, 11317. (k) Taylor, A. M.; Schreiber, S. L. Org. Lett.
2006, 8, 143.
(9) Zr: Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003,
5, 3273.
(10) Au: (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584. For
a heterogeneous gold catalyst, see: (b) Kantam, M. L.; Prakash, B. V.;
Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 2329.
Surprisingly, when ZnEt2 (as a commercially available 1.0
M solution in heptane) was used instead of ZnMe2 under the
same conditions, the substrate was completely transformed, but
benzylamine 4, stemming from the reduction of 1a, was found
to be the major product, in a ratio of 3:1 to 3aa (Scheme 1).
Compound 4 is probably formed directly by the reaction of
substrate 1a with diethylzinc through a â-hydride transfer
accompanied by the elimination of ethylene. This is in agreement
with the observations recently reported by Qian and co-workers,
who found that, in noncoordinating solvents such as toluene or
hexane, ZnEt2 can be efficiently used to reduce N-sulfonylimines
to the corresponding protected amines in high yields.17 It is
noteworthy that in none of these experiments, including those
described below, any trace of the product resulting from the
direct alkyl addition to the substrate was found.
(11) Ag: (a) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473. (b) Ji,
J.-X.; Au-Yeung, T. T. L.; Wu, J.; Yip, C. W.; Chan, A. S. C. AdV. Synth.
Catal. 2004, 346, 42.
(12) (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535. (b) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel,
P. Chem.sEur. J. 2003, 9, 2797. (c) Gommermann, N.; Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763. (d)
Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324. (e) Dube, H.;
Gommermann, N.; Knochel, P. Synthesis 2004, 2015. (f) Gommermann,
N.; Knochel, P. Tetrahedron 2005, 61, 11418. (g) Gommermann, N.; Gehrig,
A.; Knochel, P. Synlett 2005, 2796. (h) Gommermann, N.; Knochel, P.
Synlett 2005, 2799.
(13) Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomasini, C. J.
Org. Chem. 2005, 70, 5733.
(14) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J.
Synthesis 1999, 1453.
Having established the optimal reaction conditions for the
conversion of 1a, the effect of the nature of the nitrogen atom
protecting group was examined. Thus, various N-substituted
(15) The activation of alkyl-, aryl-, and alkynylzinc species is often
carried out using amino alcohols as ligands: (a) Rasmussen, T.; Norrby,
P.-O. J. Am. Chem. Soc. 2003, 125, 5130. (b) Rudolph, J.; Rasmussen, T.;
Bolm, C.; Norrby, P.-O. Angew. Chem., Int. Ed. 2003, 42, 3002. (c) Rudolph,
J.; Bolm, C.; Norrby, P.-O. J. Am. Chem. Soc. 2005, 127, 1548. (d) Frantz,
D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806.
(16) This conversion value is based on the integration of the signals of
the starting material (proton of the imino group, δ 8.98 ppm) and of the
product (proton on the N-bearing carbon atom, δ 4.91 ppm) in the 1H NMR
spectrum of the crude reaction mixture. Signals of other compounds were
not detected in the spectrum.
J. Org. Chem, Vol. 71, No. 4, 2006 1559

Zani et al.
TABLE 2. Substrate Scope of the Alkynylation Reaction
entry
substrate
PG
R
R′ (alkyne)
product
temp (°C)
yielda (%)
1
1a
1a
1a
1a
1d
1i
Ts
Ts
Ts
Ts
Ns
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ph
Ph
Ph
Ph
Ph
n-hexyl (2b)
TMS (2c)
TMS (2c)
4-CF3-Ph (2d)
n-hexyl (2b)
Ph (2a)
n-hexyl (2b)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-CF3-Ph (2d)
Ph (2a)
Ph (2a)
3ab
3ac
3ac
3ad
3db
3ia
70
70
70
50
70
60
70
60
50
50
50
50
70
70
67
52
60
87
79
77
60
85
85
93
80
95
84
15
2b
3b,c
4
5
6
7
8
4-Me-Ph
4-Me-Ph
4-MeO-Ph
2-naph
2-Br-Ph
2-furyl
2-furyl
c-hex
2-Me-propyl
1i
1j
3ib
3ja
9
1k
1l
1m
1m
1n
1o
3ka
3la
3ma
3md
3na
3oa
10
11
12
13
14
a After flash column chromatography (see Supporting Information for details). b The amount of 2.5 equiv each of dimethylzinc and trimethylsilylethyne
was used. c Commonly, the reaction was performed on a 0.5-mmol scale. In this case, however, 2.0 mmol of the imine were used.
aromatic imines 1a-h were treated with phenylacetylene in
the presence of dimethylzinc. The results obtained are listed in
Table 1.
lene in the imine addition reaction and of varying the residue
on the imines was examined (Table 2).
Acetylenes such as n-octyne (2b) and trimethylsilylethyne
(2c) were also applicable (Table 2, entries 1 and 2), though they
proved to be less reactive than 2a, probably a result of their
lower acidity. Consequently, a higher temperature was required
and, in the case of 2c, 2.5 equiv of the alkynylating mixture
were needed to reach a reasonable yield of the product. In
agreement with these observations, the yield of the correspond-
ing product was superior when the more acidic 4-(trifluoro-
methyl)phenylacetylene (2d) was used in the addition to 1a
compared to the same reaction with 2a (Table 2, entry 4 versus
Table 1, entry 1, respectively). More electron-rich imines such
as 1i-k could also be easily converted into the corresponding
propargylic amines (Table 2, entries 6-9), although the tem-
perature had to be raised to 60 °C to obtain full conversion. A
bulky halogen substituent in the ortho position was also tolerated
(Table 2, entry 10), with the product being obtained in re-
markably high yield (93%). Imines bearing heteroaryl substit-
uents were also found to be viable substrates for the reaction
(Table 2, entries 11 and 12). Thus, the combination of N-fur-
furylidene toluene-4-sulfonamide (1m) and alkyne 2d furnished
amine 3md in the highest yield observed in this study (95%,
entry 11). The latter transformation is particularly interesting,
because the furane ring can be easily oxidized to the carboxylic
acid,18 thus opening the way for a possible synthesis of alkynyl-
R-amino acids (eq 1).
Phenylimines bearing a sulfonyl group on the nitrogen atom
proved to be excellent substrates for the reaction (Table 1, entries
1-4), the best being N-benzylidene 4-nitrobenzensulfonamide
(1d). Probably the strong electron-withdrawing character of the
nosyl group led to an activation of the imine moiety, resulting
in a positive effect on the product yield (Table 1, entry 4). Only
in the case of substrate 1c bearing a mesitylsulfonyl (mesityl
) 2,4,6-trimethylphenyl) substituent, was it necessary to increase
the reaction temperature to 70 °C to obtain full conversion
(Table 1, entry 3). Although the NMR signals of the desired
product, 3ca, could clearly be observed, its purification proved
to be difficult, and an analytically pure sample could not be
obtained.
N-benzylidene diphenylphosphinamide (1e) also gave full
conversion to the corresponding product under the reaction
conditions, but in this case the yield of 3ea was slightly lower
than that with the sulfonyl protecting groups (Table 1, entry
5). Non-electron-withdrawing groups such as benzyl and
4-methoxyphenyl failed to sufficiently activate the imine for
the reaction with the alkynylating reagent (Table 1, entries 6
and 7). Surprisingly, however, the product could be obtained
in good yield when N-benzylidene 2-methoxyaniline (1h) was
used as the substrate (Table 1, entry 8). This result can be
explained by considering the possibility of substrate 1h acting
as a ligand, thus activating the alkynylzinc species formed in
the reaction mixture and facilitating the reaction. In contrast to
para-substituted 1g, the two donor atoms, N and O, present in
1h are placed in a perfect position to form a chelate complex
with a metal, in this case zinc. The strong activation furnished
by chelation would then allow the reaction to proceed, even if
1h is a far less reactive substrate than, for example, 1a-e.
Next, the possibility of using alkynes other than phenylacety-
Interestingly, when the reaction of 1a with trimethylsilyl-
ethyne (2c) was performed on a 2.0 mmol (instead of the
common 0.5 mmol) scale, the product yield was slightly higher
(Table 2, entry 4). The treatment of amine 3ac with tetrabutyl-
ammonium fluoride in THF for 30 min afforded the corre-
sponding desilylated product 5 in good yield (eq 2).
(17) (a) Gao, F.; Deng, M.; Qian, C. Tetrahedron 2005, 61, 12238. For
a related observation in the Cu-catalyzed alkylation of imines with ZnEt2,
see: (b) Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J.
Org. Chem. 2003, 68, 9723.
1560 J. Org. Chem., Vol. 71, No. 4, 2006

Dimethylzinc-Mediated Alkynylation of Imines
TABLE 3. Three-Component Synthesis of Propargylic Amines
time yieldb
entry
aldehyde
product methoda (h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
benzaldehyde (7a)
3ha
3pa
3qa
3ra
3sa
3ta
3ua
3va
3wa
3xa
3ya
3za
3za
3Aa
3Ba
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
48
48
48
48
48
48
60
48
48
48
48
48
48
96
96
48
76
73
73
92
30
66
79
65
63
65
22
85
67
45
4-chlorobenzaldehyde (7b)
3-bromobenzaldehyde (7c)
4-bromobenzaldehyde (7d)
2-naphthaldehyde (7e)
4-phenylbenzaldehyde (7f)
3-nitrobenzaldehyde (7g)
4-CF3-benzaldehyde (7h)
4-COOMe-benzaldehyde (7i)
pentafluorobenzaldehyde (7j)
3-carboxypyridine (7k)
cyclohexanecarbaldehyde (7l)
cyclohexanecarbaldehyde (7l)
pivalaldehyde (7m)
The results obtained with N-tosylimines derived from aliphatic
aldehydes were more complex. Substrate 1n, bearing a cyclo-
hexyl group, reacted smoothly with 2a at 70 °C, affording the
corresponding product 3na in remarkably high yield (84%, Table
2, entry 13). On the other hand, the reaction of compound 1o,
derived from isovaleraldehyde, with 2a was sluggish, and several
byproducts, probably stemming from enolization processes, were
present in the crude reaction mixture together with the expected
propargylic amine 3oa. The latter compound could, therefore,
be isolated only in very low yield (Table 2, entry 14). A
lowering of the temperature and a shortening of the reaction
time was not beneficial, and almost the same result was obtained
at room temperature after only 12 h. These findings suggest
that R-branched imines are suitable substrates for the present
transformation, whereas more appropriate conditions have to
be found for the efficient conversion of aliphatic aldehydes
lacking the R branching.
The observation that imine 1h, bearing an ortho-methoxy-
phenyl group on the nitrogen atom, gave rise to the expected
product in the reaction with 2a/ZnMe2, coupled with the
knowledge of already published protocols for the three-
component synthesis of propargylic amines,10-12 prompted us
to explore the possibility of preparing compounds 3 by means
of a three-component reaction of 2-methoxyaniline (6), an
aldehyde (7), and phenylacetylene (2a) in the presence of
dimethylzinc (eq 3).19
octanal (7n)
a Method A: reactions were carried out in toluene (ca. 0.1 M relative to
the aldehyde) at room temperature, employing ZnMe2 (2.0 M solution in
toluene, 3.5 equiv) and phenylacetylene (2a, 2.5 equiv). Method B: no
additional solvent was used (see Results and Discussion and Supporting
Information for details). b After flash column chromatography (see Sup-
porting Information for details).
withdrawing substituents on the ring, could also be transformed,
although in one case a longer reaction time was necessary (Table
3, entries 7-9). Interestingly, perfluorinated compound 7j and
heterocyclic aldehyde 7k were also suitable substrates for the
reaction (Table 3, entries 10 and 11). In the latter case, the
ligating properties of the pyridine ring, which are often a
problem in organozinc-mediated reactions,21 did not seem to
compromise the efficiency of the protocol.
Unfortunately, when cyclohexanecarbaldehyde (7l) was used
as the substrate under the usual reaction conditions, only a very
low yield of the product was obtained after 2 days (Table 3,
entry 12).
Recently, Walsh demonstrated that the efficiency and selec-
tivity of the enantioselective addition of alkylzinc reagents to
ketones can be greatly enhanced under solvent-free or “highly
concentrated” conditions.22 Inspired by these observations, we
performed the reaction using as the only solvent the toluene
present in the commercial ZnMe2 solution employed throughout
this study (method B, corresponds to ca. a 0.6 M concentration
relative to the aldehyde). Gratifingly, we found that propargyl-
amine 3za could now be obtained in a remarkable 85% yield
after 48 h at room temperature (Table 3, entry 13). The
application of the same conditions to pivaldehyde (7m) and
octanal (7n) led to the isolation of the corresponding alkyny-
lation products, albeit these reactions needed a longer time to
reach completeness (Table 3, entries 14 and 15). Although in
the latter case an R-unbranched substrate was used and side
products (presumably derived from enolization processes) were
detected, the desired product was isolated in an acceptable yield.
In conclusion, we have presented an efficient and facile
addition of acetylenes to imines, mediated by commercially
available ZnMe2 solution in toluene, without the employment
of specific ligands. The experimental procedure is easy and does
not require special precautions, except for the use of anhydrous
solvent under an inert atmosphere. Furthermore, a three-
First, the reaction of 4-chlorobenzaldehyde (7b) with 6 and
2a was examined. After optimization,20 we found that the
treatment of a mixture of 7b and 6 with dimethylzinc (3.5 equiv,
as a commercially available 2.0 M solution in toluene) and 2a
(2.5 equiv) in toluene at room temperature (method A) furnished
the desired product 3pa in 76% yield after 48 h. On the basis
of this result, the substrate scope of the reaction was subse-
quently examined. The results are summarized in Table 3.
While the reactions with benzaldehyde (7a) and 4-phenyl-
benzaldehyde (7f) furnished the corresponding products 3ha and
3ta, respectively, in only moderate yields (Table 3, entries 1
and 6), benzaldehydes 7b-d bearing halogen substituents on
the ring proved to be better substrates (Table 3, entries 2-4).
The best result, however, was obtained with 2-naphthaldehyde
(7e), which gave the corresponding amine in 92% yield after
48 h (Table 3, entry 5). Aldehydes 7g-i, having electron-
(18) (a) Demir, A. S. Pure Appl. Chem. 1997, 69, 105. (b) Alvaro, G.;
Martelli, G.; Savoia, D.; Zoffoli, A. Synthesis 1998, 1773. (c) Borg, G.;
Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001, 42, 1433. (d) Demir, A.
S.; Sesenoglu, O¨ .; U¨ lku¨, D.; Arici, C. HelV. Chim. Acta 2003, 86, 91.
(19) A related three-component, asymmetric, aza-Reformatzky reaction
has recently been reported: Cozzi, P. G.; Rivalta, E. Angew. Chem., Int.
Ed. 2005, 44, 3600.
(21) For an example in the asymmetric phenylation of aldehydes, see:
(a) Bolm, C.; Mun˜iz, K. Chem. Commun. 1999, 1295. (b) Bolm, C.;
Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew. Chem., Int. Ed. 2000,
39, 3465.
(20) See Supporting Information for details.
(22) Jeon, S.-J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416.
J. Org. Chem, Vol. 71, No. 4, 2006 1561

Zani et al.
Typical Procedure for the Three-Component Synthesis of
Propargylic Amines. Method A: In an oven-dried Schlenk flask
under an inert atmosphere of argon were placed the appropriate
aldehyde (7, 0.2 mmol) and 2-methoxyaniline (6, 0.2 mmol, 1.0
equiv), followed by anhydrous toluene (2.0 mL). After 30 min of
stirring, a 2.0 M solution of dimethylzinc in toluene (0.35 mL, 0.7
mmol, 3.5 equiv) was added. The reaction mixture was then stirred
for another 30 min before adding phenylacetylene (2a, 0.5 mmol,
2.5 equiv). The resulting solution was stirred at room temperature
for 48-60 h. The reaction mixture was diluted with diethyl ether
(5 mL) and quenched with water (10 mL). The resulting hetero-
geneous mixture was filtered over Celite. The aqueous phase was
separated and washed with diethyl ether (2 × 5 mL). The combined
organic layers were dried over Na2SO4 and evaporated under
reduced pressure to give the crude product, which was then purified
by flash column chromatography (see Supporting Information for
details).
Method B (Concentrated Conditions): In an oven-dried
Schlenk flask under an inert atmosphere of argon were placed the
appropriate aldehyde (7, 0.4 mmol) and 2-methoxyaniline (6, 0.4
mmol, 1.0 equiv). A 2.0 M solution of dimethylzinc in toluene (0.7
mL, 1.4 mmol, 3.5 equiv) was immediately added. The reaction
mixture was then stirred for 15 min before the addition of
phenylacetylene (1a, 1.0 mmol, 2.5 equiv). The resulting solution
was stirred at room temperature for 48-96 h. Subsequently, the
protocol followed the procedure reported above for method A.
component protocol has been developed that allows the prepara-
tion of protected propargylic amines in one step, thus circum-
venting a prior synthesis of the corresponding imines. Although
aromatic aldehydes were superior substrates for this reaction,
we demonstrated that simple modifications in the reaction
protocol allowed the transformation of aliphatic substrates with
a similar level of efficiency. Efforts to further expand the scope
of this novel three-component procedure with regard to the
alkyne moiety, as well as to develop an asymmetric version of
the same transformation, are currently underway in our labo-
ratories.
Experimental Section
N-sulfonyl imines 1a-d,i-m were prepared using a modified
version of the procedure described by Kim and co-workers,23
employing 1,2-dichloroethane as the solvent instead of CH2Cl2 and
heating at reflux for 48 h instead of 12 h. N-benzylidene diphen-
ylphosphinamide (1e) was prepared following the procedure
reported by Jennings and Lovely.24 N-tosyl imines derived from
aliphatic aldehydes (1n,o) were prepared following the procedure
reported by Chemla and co-workers.25
Typical Procedure for the Alkynylation of N-Protected
Imines. In an oven-dried Schlenk flask under an inert atmosphere
of argon, alkynes 2a-d (0.75-1.25 mmol, 1.5-2.5 equiv) were
dissolved in anhydrous toluene (4.5 mL). A 2.0 M solution of
dimethylzinc in toluene (0.38-0.63 mL, 0.75-1.25 mmol, 1.5-
2.5 equiv) was then carefully added, and the resulting mixture was
stirred at room temperature for 30 min. The appropriate imine 1
(0.5 mmol) was then added in one portion, and the temperature
was increased to the desired value (50-70 °C). The resulting
solution was stirred for 24 h, after which a white precipitate
appeared in some cases. The reaction was quenched with water
(10 mL). The aqueous phase was extracted with CH2Cl2 (3 × 15
mL), and the organic phase was washed with brine (25 mL) and
dried over MgSO4. The evaporation of the solvent under reduced
pressure furnished the crude product, typically as a solid, which
was purified by flash column chromatography and/or by recrys-
tallization (see Supporting Information for details).
N-(2-Methoxyphenyl)-1,3-diphenyl-1-aminoprop-2-yne (3ha).
1H NMR (CDCl3, 400 MHz) δ 3.83 (s, 3H), 4.78 (s, 1H), 5.50 (s,
1H), 6.71-6.91 (m, 4H), 7.23-7.44 (m, 8H), 7.64-7.70 (m, 2H).
13C NMR (CDCl3, 100 MHz) δ 50.4, 55.5, 84.9, 88.7, 109.6, 111.7,
117.7, 121.1, 122.9, 127.4, 128.0, 128.16, 128.2, 128.7, 131.8,
136.4, 139.9, 147.1. Anal. Calcd. for C22H19NO: C, 84.31; H, 6.11;
N, 4.47. Found: C, 84.43; H, 6.22; N, 4.20.
Acknowledgment. C.B. and L.Z. are grateful to the Fonds
der Chemischen Industrie and to the Deutsche Forschungsge-
meinschaft (DFG) within the Collaborative Research Center
(Sonderforschungsbereich) 380 for financial support. P.G.C. and
S.A. thank FIRB and MIUR (Rome) “Progetto Stereoselezione
in Chimica Organica Metodologie ed Applicazioni” and the
University of Bologna (funds for selected research topics) for
financial support of this research.
N-(p-Toluenesulfonyl)-1,3-diphenyl-1-aminoprop-2-yne (3aa).
1H NMR (CDCl3, 400 MHz) δ 2.24 (s, 3H), 4.91 (d, J ) 9.2 Hz,
1H), 5.48 (d, J ) 9.2 Hz, 1H), 7.01-7.08 (m, 2H), 7.11-7.34 (m,
8H), 7.44-7.52 (m, 2H), 7.70-7.79 (m, 2H). 13C NMR (CDCl3,
100 MHz) δ 21.4, 49.8, 85.4, 86.7, 121.9, 127.3, 127.5, 128.1,
128.4, 128.6, 128.7, 129.5, 129.7, 131.5, 137.4, 143.5. Anal. Calcd.
for C22H19NO2S: C, 73.31; H, 5.03; N, 3.88. Found: C, 73.09; H,
5.17; N, 3.75.
Supporting Information Available: General experimental
information and procedures, complete analytical data of all the
1
propargylic amines 3, and copies of the H and 13C NMR spectra
of these compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44, 1231.
(24) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5568.
(25) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
JO052273O
1562 J. Org. Chem., Vol. 71, No. 4, 2006