Can the Crabbé homologation be successfully applied to the synthesis of 1,3-disubstituted allenes?

Article abstract of DOI:10.1055/s-0030-1259936

The Crabbé homologation of terminal alkynes could be applied to the synthesis of 1,3-disubstituted allenes using aldehydes, N,N-dicyclohexylamine, and a catalytic amount of copper(I) iodide. The key to this success was the employment of an excess of aldeh

Full text of DOI:10.1055/s-0030-1259936

LETTER
1129
Can the Crabbé Homologation Be Successfully Applied to the Synthesis of
1,3-Disubstituted Allenes?
C
rabbé Homo
h
ilied to
n
the Synthesis
j
of 1,3
i
-
Disubstituted
K
A
llenes itagaki,* Mika Komizu, Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Fax +81(76)2344410; E-mail: kitagaki@p.kanazawa-u.ac.jp
Received 31 January 2011
the transformation of propargylamines, a plausible inter-
mediate of the Crabbé homologation, into the correspond-
ing 1,3-disubstituted allenes. In addition, zinc was shown
to promote the one-pot synthesis6 of 1,3-disubstituted al-
Abstract: The Crabbé homologation of terminal alkynes could be
applied to the synthesis of 1,3-disubstituted allenes using alde-
hydes, N,N-dicyclohexylamine, and a catalytic amount of copper(I)
iodide. The key to this success was the employment of an excess of
aldehyde and amine, and performing the reaction under microwave lenes by the reaction of alkynes with aldehydes in the
presence of morpholine.9 In this letter, we report our pre-
irradiation conditions.
liminary results that the copper-mediated alkyne homolo-
gation (Crabbé reaction) is still effective for the
preparation of 1,3-disubstituted allenes under the modi-
fied conditions.
Key words: allenes, copper, microwave, multicomponent reaction,
propargylamines
In the late 1970s, Crabbé and co-workers reported the
copper(I) bromide mediated alkyne homologation to al-
lenes by the reaction with formaldehyde (2a) and N,N-
diisopropylamine (3a, R2 = i-Pr) in refluxing dioxane
(Equation 1).1 While a variety of allene forming reactions
have already been developed,2 this traditional method is
still widely used in the synthesis of monosubstituted al-
lenes because of its simplicity, efficiency, versatility, and
the use of an inexpensive copper salt. Recently, the im-
proved Crabbé homologation was independently reported
by two groups. Nakamura and co-workers found that the
microwave (MW) irradiation accelerated the reaction,3
whereas Ma and co-workers found that replacing 3a and
copper(I) bromide with N,N-dicyclohexylamine (3b,
R2 = Cy) and copper(I) iodide, respectively, led to an in-
crease in the chemical yields of the allenes.4
R1
R3
R3
O
CuX
R1
•
N
H
+
+
R2
R2
H
Scheme 1
The Crabbé homologation could be rationalized in terms
of the intermediacy of the propargylamine intermediate (4
in Equation 1), which should be formed by the Mannich-
type reaction of copper acetylide with an iminium salt
(first step). The second step involves the copper-mediated
1,5-hydride transfer to produce the allene 5. The a-
branched dialkylamine component, like N,N-dicyclohex-
ylamine or N,N-diisopropylamine, is more suitable for
this hydride shift than the di-n-alkylamines or unsubstitut-
ed cyclic amines. Copper salts, such as copper(I) bromide
and copper(I) iodide, have already been found to be effec-
tive for the three-component coupling reactions of various
aldehydes, alkynes, and amines (A3 coupling) to produce
the corresponding propargylamines, although the use of
a-branched dialkylamines is prone to lead to slightly low-
er product yields.7,10,11 Therefore, the first step in the
Crabbé homologation using alkyl or aryl aldehydes would
safely proceed under the influence of the copper catalyst.
Thus, our initial investigation focused on the transforma-
tion of the propargylamines into the 1,3-disubstituted al-
lenes by the copper-mediated 1,5-hydride transfer (second
step in the Crabbé homologation), which has not yet been
reported. N,N-Dicyclohexyl-8-phenyl-5-octyn-4-ylamine
(4ab) was selected as a substrate and prepared by the A3-
coupling of 4-phenylbut-1-yne (1a), n-butyraldehyde
(2b), and dicyclohexylamine (3b) under modified Knoch-
el’s conditions11a using 5 mol% of copper(I) bromide in
refluxing toluene (4ab, 56%, allene 5ab, 5% yield). How-
ever, the reaction of 4ab with 1 equivalent of copper(I)
bromide in refluxing dioxane (0.1 M) for 24 hours (almost
R1
Cu
R2
R2
R2
O
CuX
R1
+
N
+
+
R2
N+
dioxane
reflux
H
3
H
H
1
2a
H
H
R1
Mannich-type
reaction
R1
1,5-H shift
N
R2
second step
first step
H
R3
H
R3
4
5
Equation 1
The Crabbé homologation has long been believed not to
be used for the synthesis of 1,3-disubstituted allenes
(Scheme 1).5,6 Alternatively, palladium,7 gold,8a and
silver8b recently emerged as useful transition metals for
SYNLETT 2011, No. 8, pp 1129–1132
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259936; Art ID: U01111ST
© Georg Thieme Verlag Stuttgart · New York

1130
S. Kitagaki et al.
LETTER
usual Crabbé conditions) gave the desired allene 5ab only tions (entry 6). The propargylamines with a phenyl group
in 4% yield (Table 1, entry 1). When copper(I) iodide was at R1 and/or R2 were not suitable substrates for this trans-
used, the yield of the allene 5ab increased to 10% (entry formation (Table 2, entries 4, 7, and 8). When using 4ad
2). Small amounts of the alkyne 1a was observed in both (R2 = Ph) or 4db (R1 = Ph) as a substrate, the MW irradi-
reactions, indicating that the retro-Mannich reaction must ation at temperatures lower than 200 °C resulted in a high-
have competitively occurred under the stated reaction er yield of the corresponding allene 5ad or 5db, indicating
conditions.1d,12 Thus, the use of an aldehyde 2b and amine the instability of 4 or 5 under the reaction conditions at
3b as additives in order to suppress the retro-Mannich re- higher temperatures [Table 2, entries 4 and 7, cf. 5ad
action was examined and actually found to improve the (MW, 200 °C, 1 h, 16%) and 5db (MW, 200 °C, 45 min,
product yield (entry 3). Adding 2b and 3b might shift an 12%)].
equilibrium between propargylamine 4ab and Csp–Csp3-
cleaved compounds to the direction that produce 4ab, and
Table 2 Copper-Catalyzed Synthesis of 5 from 4
accelerate the 1,5-hydride transfer. Further improvement
in yield and reaction rate was realized by MW irradiation
of the toluene solution. Thus, exposure of a mixture of
propargylamine 4ab, aldehyde 2b, amine 3b, and cop-
per(I) iodide in the ratio of 1:3:3:0.1 in toluene to sealed-
vessel MW irradiation conditions (200 °C, 3 h) led to a
68% yield of the allene (Table 1, entry 4). In addition to
these conditions, the higher concentration (0.5 M) enabled
us to reduce the amount of not only copper(I) iodide, but
also the aldehyde and amine (Table 1, entry 5).
CuI (0.1 equiv)
R2CHO (2) (3 equiv)
Cy2NH (3b) (3 equiv)
R2
R2
•
NCy2
toluene (0.1 M), MW, 200 °C
R1
R1
5
4
Entry
1
4
R1
R2
Time (h) Yield of 5 (%)
4ab
4ac
4ac
4ad
4bb
4cb
4db
4dd
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me(CH2)5
n-Pr
i-Pr
i-Pr
Ph
3
5ab 68
5ac 67
5ac 69
5ad 32
5bb 47
5cb 62
5db 15
5dd 2
2a
5.5
2
Table 1 Copper-Mediated Synthesis of 5ab from 4ab
3a,b
4b,c
5
3
Ph
5ab
CuX, additive
solvent (0.1 M)
n-Pr
2
reflux
6
TBSO(CH2)5 n-Pr
4
NCy2
Cu
+
7a,b,d
8b,d
Ph
Ph
n-Pr
2.5
3.5
Ph
4ab
Ph
Ph
+
H+
NCy2
a CuI (0.2 equiv) was used.
b The reaction was performed in 0.5 M solution.
c The reaction was performed at 150 °C.
d The reaction was performed at 165 °C.
Ph
1a
Entry CuX
(equiv)
Additive
(equiv)
Solvent
Time Yield of
(h)
24a
24a
21
3a
5ab (%)
Having identified the conditions to convert propargyl-
amines into allenes using a copper salt, we examined the
one-pot allene formation reaction of an alkyne, aldehyde,
and amine (Crabbé homologation). The exposure of a
mixture of 4-phenylbut-1-yne (1a), n-butyraldehyde (2b),
dicyclohexylamine (3b), and copper(I) iodide in the ratio
of 1:1:1:0.1 in toluene (0.5 M) to the sealed-vessel MW ir-
radiation conditions (200 °C, 2 h) led to the production of
the allene 5ab in 40% yield (Table 3, entry 1). An increase
in the amount of 2b and 3b (each 1.5 equiv) improved the
yield of 5ab to 50% (Table 3, entry 2). When the reaction
was conducted using 1 equivalent of copper(I) iodide un-
der conventional heating for 15 hours, the desired 5ab was
obtained in 38% yield (Table 3, entry 3). Thus, the condi-
tions shown in entry 2 (Table 3) were used for the forma-
tion of various 1,3-dialkyl-substituted allenes.13 For the
reaction of acetylenes 1a–c, the product yields remained
moderate to good with a slight decrease compared to the
yields from the corresponding propargylamines, irrespec-
tive of the partner aldehyde (Table 3, entries 4–6). The re-
spective slight increase in the amount of the aldehyde,
amine, and copper(I) iodide improved the product yield in
1
CuBr (1)
CuI (1)
–
–
dioxane
dioxane
4b
2
10b
44
3
CuI (1)
2b (3) + 3b (3) dioxane
2b (3) + 3b (3) toluene
2b (1) + 3b (1) toluene
4c
5c,d
CuI (0.1)
CuI (0.1)
68
2a
62
a Reaction did not go to completion.
b Acetylene 1a was detected on TLC.
c The reaction was performed under MW irradiation conditions at
200 °C.
d The reaction was performed in 0.5 M solution.
The conversion of various propargylamines into the cor-
responding allenes was next examined under the condi-
tions in entry 4 (Table 1). The a-branched alkyl group on
the propargylic position (R2 group) slightly retarded the
reaction, but did not influence the chemical yield
(Table 2, entry 2). A shorter reaction time was achieved at
the higher concentration (0.5 M, Table 2, entry 3). The si-
loxy functionality could be tolerated under these condi-
Synlett 2011, No. 8, 1129–1132 © Thieme Stuttgart · New York

LETTER
Crabbé Homologation Applied to the Synthesis of 1,3-Disubstituted Allenes
1131
O
the case of entry 4 (1a/2c/3b/CuI = 1:2.3:1.8:0.2, 64%
yield; cf. 1:1.5:1.5:0.1, 43% yield, Table 3). The acety-
lenes having a siloxy or tosylamido group at the propar-
gylic position also reacted with aldehydes 2b or 2c to give
the corresponding allenes in 35–64% yields (Table 3, en-
tries 7–10). The reactions including phenylacetylene or
benzaldehyde as the reaction component furnished the de-
sired products in lower yields (Table 3, entries 11 and 12),
which might be predictable based on the results shown in
Table 2. The results of the reaction using other amines
than dicyclohexylamine were in good agreement with the
previously reported tendency in the original Crabbé reac-
tion.1,3,4 Thus, the use of diisopropylamine resulted in a
lower yield of the allene, and both reactions using mor-
pholine and dibenzylamine afforded only a trace amount
of the desired product (Scheme 2).
+
+
R2NH
H
Ph
1a
2b
3a,c,d
CuI (0.1 equiv)
Ph
toluene
MW, 200 °C
5ab
3a R = i-Pr2NH
3c R = morpholine
3d R = Bn2NH
37%
trace
trace
Scheme 2 One-pot preparation of 5ab using various amines 3
the inexpensive copper(I) iodide in high yields similar to
the already reported methods,6–8 especially when the pro-
pargylamines have aliphatic substituents on the acetylene
terminus and the propargylic position.
In conclusion, we have shown that the transformation of
propargylamines into 1,3-disubstituted allenes as well as
the one-pot reaction from alkynes, aldehydes, and amines
(Crabbé homologation) nicely proceeded by applying the
MW irradiation conditions. The presence of excess alde-
hydes and amines versus the alkynes is crucial for the
allene-forming reaction. The newly developed methods
can provide allenes using only 0.1 or 0.2 equivalents of
References and Notes
(1) (a) Crabbé, P.; Fillion, H.; André, D.; Luche, J.-L. J. Chem.
Soc., Chem. Commun. 1979, 859. (b) Crabbé, P.; André, D.;
Fillion, H. Tetrahedron Lett. 1979, 893. (c) Fillion, H.;
André, D.; Luche, J.-L. Tetrahedron Lett. 1980, 929.
(d) Searles, S.; Li, Y.; Lopes, M.-T. R.; Tran, P. T.; Crabbé,
P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
(2) For recent reviews, see: (a) Ogasawara, M. Tetrahedron:
Asymmetry 2009, 20, 259. (b) Brummond, K. M.;
DeForrest, J. E. Synthesis 2007, 795. (c) Modern Allene
Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004.
(3) Nakamura, H.; Sugiishi, T.; Tanaka, Y. Tetrahedron Lett.
2008, 49, 7230.
(4) Kuang, J.; Ma, S. J. Org. Chem. 2009, 74, 1763.
(5) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.;
Bertrand, G. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 13569.
(6) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786.
(7) Nakamura, H.; Ishikura, M.; Sugiishi, T.; Kamakura, T.;
Biellmann, J.-F. Org. Biomol. Chem. 2008, 6, 1471.
(8) (a) Lo, V. K.-Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2008,
10, 517. (b) Lo, V. K.-Y.; Zhou, C.-Y.; Wong, M.-K.; Che,
C.-M. Chem. Commun. 2010, 46, 213. (c) Melchionna, M.;
Nieger, M.; Helaja, J. Chem. Eur. J. 2010, 16, 8262.
(9) For the synthesis of substituted allenes from propargyl
ethers, see: Bolte, B.; Odabachian, Y.; Gagosz, F. J. Am.
Chem. Soc. 2010, 132, 7294.
Table 3 One-Pot Preparation of 5 from 1, 2, and 3ba
R1
CuI (0.1 equiv)
O
R1
+
+
Cy2NH
toluene (0.5 M)
MW, 200 °C
R2
H
R2
1
2
3b
5
Entry
1
R1
2
R2
Time Yield of 5
(h)
(%)
1b
2
1a PhCH2CH2
1a PhCH2CH2
1a PhCH2CH2
2b n-Pr
2b n-Pr
2b n-Pr
2
5ab 40
5ab 50
5ab 38
5ac 64
5bb 43
5cb 50
5eb 60
5ec 61
5fb 35
5fc 64
5ad 31
5db 14
2
3c
15
3.5
2.5
1.5
2
4d,e 1a PhCH2CH2
2c
i-Pr
5
1b Me(CH2)5
2b n-Pr
2b n-Pr
6
1c
1e
1e
1f
TBSO(CH2)5
(10) For reviews of catalytic three-component coupling of
alkyne, aldehyde, and amine, see: (a) Kouznetsov, V. V.;
Méndez, L. Y. V. Synthesis 2008, 491. (b) Zani, L.; Bolm,
C. Chem. Commun. 2006, 4263. (c) Wei, C.; Li, Z.; Li, C.-J.
Synlett 2004, 1472.
7
n-C7H15CH(OTBS) 2b n-Pr
n-C7H15CH(OTBS) 2c i-Pr
n-C7H15CH(NHTs) 2b n-Pr
n-C7H15CH(NHTs) 2c i-Pr
1a PhCH2CH2 2d Ph
1d Ph 2b n-Pr
8d
9
3.5
1
(11) For selected examples of Cu(I)-catalyzed three-component
10d,e 1f
1.25
2.5
5
coupling of alkyne, aldehyde, and amine, see:
11e,f
12g
(a) Gommermann, N.; Koradin, C.; Knochel, P. Angew.
Chem. Int. Ed. 2003, 42, 5763. (b) Gommermann, N.;
Knochel, P. Chem. Eur. J. 2006, 12, 4380. (c) Shi, L.; Tu,
Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A. Org. Lett. 2004,
6, 1001. (d) Sreedhar, B.; Reddy, P. S.; Prakash, B. V.;
Ravindra, A. Tetrahedron Lett. 2005, 46, 7019. (e) Sasaki,
N.; Uchida, N.; Konakahara, T. Synlett 2008, 1515.
(f) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2009, 74, 7052. (g) Bariwal, J. B.; Ermolat’ev, D. S.;
Glasnov, T. N.; Van Hecke, K.; Mehta, V. P.; Van Meervelt,
L.; Kappe, C. O.; Van der Eycken, E. V. Org. Lett. 2010, 12,
2774.
a Aldehyde 2 and amine 3b (each 1.5 equiv) were used.
b Aldehyde 2b and amine 3b (each 1 equiv) were used.
c Reaction was performed using CuI (1 equiv) in refluxing toluene
without MW heating.
d Aldehyde 2c (2.3 equiv) and amine 3b (1.8 equiv) were used.
e CuI (0.2 equiv) was used.
f The reaction was performed at 150 °C.
g The reaction was performed at 150 °C for 3 h and at 165 °C for 2 h.
Synlett 2011, No. 8, 1129–1132 © Thieme Stuttgart · New York

1132
S. Kitagaki et al.
LETTER
(12) Sugiishi, T.; Kimura, A.; Nakamura, H. J. Am. Chem. Soc.
2010, 132, 5332.
(13) Typical Procedure for the Microwave-Assisted Crabbé
Homologation
residue was purified by column chromatography on silica
gel(hexane) to afford 5ab (46.8 mg, 50%) as a colorless oil.
IR (CHCl3): 1961 cm–1. 1H NMR (600 MHz, CDCl3, TMS):
d = 7.27 (t, J = 7.6 Hz, 2 H), 7.20–7.16 (m, 3 H), 5.14–5.06
(m, 2 H), 2.72 (t, J = 7.6 Hz, 2 H), 2.32–2.27 (m, 2 H), 1.97–
1.87 (m, 2 H), 1.38 (sext, J = 7.6 Hz, 2 H), 0.90 (t, J = 7.6
Hz, 3 H). 13C NMR (150 MHz, CDCl3): d = 204.1, 141.9,
128.5, 128.2, 125.8, 91.3, 90.2, 35.5, 31.0, 30.7, 22.4, 13.6.
MS (EI): m/z (%) = 186 (3.1) [M+]. HRMS: m/z calcd for
C14H18: 186.1409; found: 186.1407.
Alkyne 1a (65.0 mg, 0.500 mmol), aldehyde 2b (68 mL, 0.75
mmol), amine 3b (150 mL, 0.754 mmol), CuI (9.6 mg, 0.050
mmol), and toluene (1.0 mL) were mixed in a 2 mL process
vial. The vial was sealed, and the reaction mixture was
heated with microwaves to 200 °C for 2 h. After cooling, the
mixture was filtered, and the filtrate was concentrated. The
Synlett 2011, No. 8, 1129–1132 © Thieme Stuttgart · New York

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