Copper-catalyzed allylation of alkyl halides with allylic grignard reagents

Article abstract of DOI:10.1246/bcsj.82.1194

Treatment of alkyl halides, including secondary and tertiary alkyl bromides, with allylic Grignard reagents in the presence of a catalytic amount of copper(II) triflate in diisopropyl ether at 25 °C yielded the corresponding allylated products in high yie

Full text of DOI:10.1246/bcsj.82.1194

1194 Bull. Chem. Soc. Jpn. Vol. 82, No. 9, 1194–1196 (2009)
Short Articles
Table 1. Scope of Alkyl Halides and Pseudohalides
5 mol% Cu(OTf)2
R2 R3
Et2O/ -Pr2O
R2 R3
Copper-Catalyzed Allylation of
Alkyl Halides with Allylic
Grignard Reagents
MgBr
(2 equiv)
+
R1
25 °C, time
R1
X
i
Entry
1
Alkyl halides
Time/h
2
Yield/%
3
3
2a
2b
92
88
n
-C8H17
Br
1a
1b
Masahiro Sai, Hideki Yorimitsu,* and
Koichiro Oshima*
2
Br
n
-C3H7
n
-C3H7
Department of Material Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto-daigaku
Katsura, Nishikyo-ku, Kyoto 615-8510
3
4
5
3
6
6
2c
2a
2b
49
n
n
-C4H9
Br
1c
54a)
69a)
-C8H17
Cl
1a-Cl
Received May 7, 2009
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp, oshima@
orgrxn.mbox.media.kyoto-u.ac.jp
Cl
I
1b-Cl
6
7
0.5
6
2b
2d
78
68
1b-I
Treatment of alkyl halides, including secondary and
tertiary alkyl bromides, with allylic Grignard reagents in
the presence of a catalytic amount of copper(II) triflate in
diisopropyl ether at 25 °C yielded the corresponding allylated
products in high yields. The coupling reactions of tertiary
alkyl halides lead to construction of allylated quaternary
carbon centers. The active species is likely to be allylcuprate.
n
-C6H13
Br
1d
8
6
2e
89
1e
1f
Br
9
3
4
2f
86a)
64
n
-C10H21 Br
10
2g
1g-Ms
1g-Ts
Br
Ph
OMs
OTs
Recently, we have been interested in the metal-catalyzed
reactions of alkyl halides, including secondary and tertiary
substrates, with allylic Grignard reagents.1 Cobalt1a,1b and
silver1c proved to be effective for the reactions. However,
the cobalt-catalyzed reaction requires fine tuning of reaction
conditions in accordance with substrates used. Very recently,
we found that copper(II) triflate (=trifluoromethanesulfonate)
[Cu(OTf)2] catalyzes the reaction of secondary and tertiary
alkyl halides with an allylic metal reagent, a cyclopentadi-
enylmagnesium reagent.2,3 Here we report that similar
reaction conditions are applicable to the reactions with
other allylic magnesium reagents. The efficiency and gen-
erality of the copper catalysis proved to be comparable to
those of silver catalysis.1c Notably, copper-catalyzed reac-
tions of secondary and tertiary alkyl halides have been rarely
reported.2,3e,4
Treatment of 2-bromo-2-methyldecane (1a) with 2 equiv
of allylmagnesium bromide in the presence of 5 mol % of
Cu(OTf)2 in diisopropyl ether at 25 °C provided the corre-
sponding allylated product 2a in high yield (Table 1, Entry 1).
1-Bromoadamantane (1b) also underwent allylation smoothly
(Entry 2). The reaction of sterically congested 1c was less
efficient probably because of limited accessibility to the tertiary
carbon (Entry 3). Tertiary alkyl chlorides 1a-Cl and 1b-Cl
were less reactive and required an elevated temperature and
a prolonged reaction time (Entries 4 and 5). In contrast, 1-
iodoadamantane (1b-I) reacted more smoothly within 30 min
(Entry 6).
11
12
13
14
4
3
3
3
2g
2h
2i
77
75
98
63
Ph
MeO
1h
1i
PhS
Br
2j
THPO
1j
Br
a) Reflux. b) THP: Tetrahydropyranyl.
alkyl bromide, 1-bromodecane (1f), should be performed in
refluxing diisopropyl ether to achieve full conversion (Entry 9).
Secondary alkyl mesylate 1g-Ms and tosylate 1g-Ts reacted to
yield the corresponding allylated product 2g in good yields
(Entries 10 and 11). It is worth noting that secondary alkyl
mesylates and tosylates resisted allylation under cobalt or silver
catalysis.1 Functional groups including a strongly coordinating
sulfide moiety were tolerant under the reaction conditions
(Entries 12-14).
The reaction of 1a with methallylmagnesium bromide
proceeded efficiently (eq 1). Unfortunately, the reaction with
2-butenyl- or prenylmagnesium chloride resulted in formation
of regioisomeric mixtures as well as moderate yields (eqs 2
and 3). The reaction of 1a with butyl- or phenylmagnesium
bromide led to the recovery of 1a.
5 mol% Cu(OTf)2
+
1a
MgBr
ð1Þ
n
-C8H17
Et2O/
i-Pr2O
Secondary alkyl bromides 1d and 1e also participated in the
allylation reaction (Entries 7 and 8). The reaction of primary
(2 equiv)
3
25 °C, 3 h, 92%
Published on the web September 9, 2009; doi:10.1246/bcsj.82.1194

M. Sai et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009) 1195
were commercially available or prepared from the corresponding
alcohol in concentrated hydrobromic or -chloric acid.
n
n
n
n
-C8H17
-C8H17
-C8H17
-C8H17
5 mol% Cu(OTf)2
Et2O/ -Pr2O
α
γ
4
Typical Procedure for Copper-Catalyzed Reactions. The
reaction of 1a with allylmagnesium bromide (Table 1, Entry 1) is
described as a representative procedure. Copper(II) triflate (9.0 mg,
0.025 mmol) was placed in a 30-mL reaction flask under argon.
Substrate 1a (118 mg, 0.50 mmol) in diisopropyl ether (3.0 mL)
was added to the flask. A solution of allylmagnesium bromide
(0.70 M in diethyl ether, 1.43 mL, 1.0 mmol) was then added. After
being stirred for 3 h at 25 °C, the reaction mixture was poured into
a saturated ammonium chloride solution (10 mL). The products
were extracted with hexane (10 mL © 3). The combined organic
layer was dried over Na2SO4 and concentrated. Silica gel column
purification (hexane) of the crude product provided the corre-
sponding allylated product 2a (90.5 mg, 0.46 mmol) in 92%
isolated yield.
+
+
MgCl
(2 equiv)
1a
1a
ð2Þ
ð3Þ
i
25 °C, 3 h, 58%
α
γ
4 /4 = 65:35
4
5 mol% Cu(OTf)2
α
5
5
MgCl
(2 equiv)
Et2O/i-Pr2O
25 °C, 3 h, 53%
α
γ
5 /5 = 72:28
γ
The reaction proceeds in the presence of copper(I) catalyst as
well as copper(II). The reaction of 1a with allylmagnesium
bromide in the presence of Cu(OTf) afforded 2a in 80% yield.
This suggests that reduction of Cu(OTf)2 would take place in
situ upon addition of allylic Grignard reagent.5,6 To investigate
the reaction mechanism, the reaction of 1a with a stoichio-
metric copper reagent was examined with varying amounts of
allylmagnesium bromide (Table 2). Treatment of 1a (0.50
mmol) with a copper reagent that was prepared from 0.50 mmol
of Cu(OTf)2 and 0.50 mmol of CH2=CHCH2MgBr led to
no conversion of 1a. A copper reagent obtained by mixing
0.50 mmol of Cu(OTf)2 and 1.0 mmol of CH2=CHCH2MgBr
effected allylation in 24% yield. Use of three equivalents of
CH2=CHCH2MgBr gave 2a in 63% yield. This implies that the
actual copper species would be magnesium diallylcuprate(I).7
The exact reaction mechanism is not clear.
Characterization of New Compounds: Compounds 1a,1b 1a-
Cl,1b 2a,1b 2b,1c 2d,1c 3,1b 4,1b and 51b showed spectra identical
with those reported in the literature.
4-Bromo-4-propyloctane (1c): IR (neat): 2961, 2874, 2360,
¹1
1684, 1559, 1457, 1128, 668 cm
;
1H NMR (CDCl3): ¤ 0.92
(t, J = 7.0 Hz, 3H), 0.93 (t, J = 7.3 Hz, 6H), 1.28-1.49 (m, 8H),
1.79-1.84 (m, 6H); 13C NMR (CDCl3): ¤ 14.22, 14.37, 18.78,
23.02, 27.63, 42.48, 45.02, 79.91. Found: C, 56.45; H, 10.04%.
Calcd for C11H23Br: C, 56.17; H, 9.86%.
1-Methyl-3-phenylpropyl Methanesulfonate (1g-Ms):
IR
(neat): 3028, 2983, 2939, 1456, 1340, 1174, 972, 910, 751,
701 cm¹1; 1H NMR (CDCl3): ¤ 1.46 (d, J = 6.0 Hz, 3H), 1.89-1.96
(m, 1H), 2.02-2.10 (m, 1H), 2.67-2.80 (m, 2H), 2.99 (s, 3H), 4.81-
4.87 (m, 1H), 7.19-7.21 (m, 3H), 7.28-7.32 (m, 2H); 13C NMR
(CDCl3): ¤ 21.43, 31.59, 38.45, 38.88, 79.68, 126.36, 128.51,
128.73, 140.89. Found: C, 58.06; H, 6.83%. Calcd for C11H16O3S:
C, 57.87; H, 7.06%.
In summary, we have developed an additional protocol for
the efficient reaction of secondary and tertiary alkyl halides
with allylic Grignard reagents by using a copper catalyst.
1-Methyl-3-phenylpropyl p-Toluenesulfonate (1g-Ts):
IR
Experimental
(neat): 3028, 2937, 1599, 1456, 1363, 1189, 1176, 893, 816, 750,
664 cm¹1; 1H NMR (CDCl3): ¤ 1.30 (d, J = 6.5 Hz, 3H), 1.77-1.84
(m, 1H), 1.89-1.97 (m, 1H), 2.45 (s, 3H), 2.47-2.51 (m, 1H), 2.58-
2.64 (m, 1H), 4.62-4.68 (m, 1H), 7.05-7.07 (m, 2H), 7.16-7.19
(m, 1H), 7.23-7.27 (m, 2H), 7.32-7.34 (m, 2H), 7.78-7.81 (m,
2H); 13C NMR (CDCl3): ¤ 21.03, 21.82, 31.34, 38.33, 80.06,
126.23, 127.92, 128.44, 128.62, 129.96, 134.64, 141.01, 144.69.
Found: C, 67.20; H, 6.47%. Calcd for C17H20O3S: C, 67.08; H,
6.62%.
Instrumentation and Chemicals. 1H NMR (300 MHz) and
13C NMR (75 MHz) spectra were taken on a Varian Mercury 300
spectrometer and were obtained in CDCl3 with tetramethylsilane as
an internal standard. IR spectra were determined on a SHIMADZU
FTIR-8200PC spectrometer. Elemental analyses were carried out at
the Elemental Analysis Center of Kyoto University. TLC analyses
were performed on commercial glass plates bearing a 0.25-mm
layer of Merck Silica gel 60F254. Silica gel (Wakogel 200 mesh)
was used for column chromatography.
Unless otherwise noted, materials obtained from commercial
suppliers were used without further purification. Cu(OTf)2 was
purchased from Aldrich. Allylic Grignard reagents were prepared
from magnesium turnings (Nacalai Tesque, Inc.) and the corre-
sponding allylic halides in ether. Ether was purchased from Kanto
Chemical Co., stored under nitrogen, and used as is. Diisopropyl
ether was purchased from Nacalai Tesque. Tertiary alkyl halides
6-Bromo-1-methoxy-6-methylheptane (1h): IR (neat): 2939,
1
2862, 1653, 1558, 1507, 1457, 1387, 1369, 1121 cm¹1; H NMR
(CDCl3): ¤ 1.35-1.42 (m, 2H), 1.50-1.63 (m, 4H), 1.75 (s, 6H),
1.78-1.81 (m, 2H), 3.34 (s, 3H), 3.38 (t, J = 6.8 Hz, 2H);
13C NMR (CDCl3): ¤ 26.32, 26.34, 29.71, 34.43, 47.69, 58.76,
68.64, 72.91. Found: C, 48.71; H, 8.62%. Calcd for C9H19BrO: C,
48.44; H, 8.58%.
6-Bromo-6-methyl-1-phenylsulfanylheptane (1i): IR (neat):
2936, 2859, 1700, 1653, 1559, 1507, 1481, 1437, 1369, 1093,
1025 cm¹1; 1H NMR (CDCl3): ¤ 1.43-1.57 (m, 4H), 1.65-1.72 (m,
2H), 1.75 (s, 6H), 1.75-1.80 (m, 2H), 2.93 (t, J = 7.3 Hz, 2H),
7.15-7.19 (m, 1H), 7.26-7.34 (m, 4H); 13C NMR (CDCl3): ¤
26.04, 28.86, 29.19, 33.69, 34.42, 47.52, 68.50, 125.92, 129.03,
129.15, 137.00. Found: C, 56.05; H, 6.87%. Calcd for C14H21BrS:
C, 55.81; H, 7.03%.
Table 2. Allylation by Means of a Stoichiometric Amount
of Cu(OTf)2
1.0 equiv Cu(OTf)2
MgBr
(X equiv)
1a
+
2a
Et2O/
i
-Pr2O, 25 °C, 3 h
X/equiv
Yield/%
2-(4-Bromopentyloxy)-1-oxacyclohexane (1j, Mixture of
1.0
2.0
3.0
0
24
63
Diastereomers):
IR (neat): 2924, 2869, 1442, 1379, 1353,
1201, 1121, 1078, 1034, 979, 869, 816 cm¹1; 1H NMR (CDCl3) for
a mixture of isomers: ¤ 1.40-1.93 (m, 10H), 1.72 (d, J = 6.5 Hz,

1196 Bull. Chem. Soc. Jpn. Vol. 82, No. 9 (2009)
© 2009 The Chemical Society of Japan
3H), 3.38-3.45 (m, 1H), 3.46-3.52 (m, 1H), 3.72-3.79 (m, 1H),
3.82-3.86 (m, 1H), 4.14-4.21 (m, 1H), 4.54-4.59 (m, 1H);
13C NMR (CDCl3) for a mixture of isomers: ¤ 19.82, 19.84, 25.64
(two signals merged), 26.68 (two signals merged), 28.24, 28.29,
30.90 (two signals merged), 38.13, 38.21, 51.77, 51.82, 62.56,
62.60, 66.85, 66.92, 99.05, 99.07. Found: C, 47.65; H, 7.53%.
Calcd for C10H19BrO2: C, 47.82; H, 7.62%.
of Diastereomers): IR (neat): 2940, 2871, 1558, 1507, 1457,
1201, 1121, 1079, 1027, 992, 909, 870 cm¹1; 1H NMR (CDCl3) for
a mixture of isomers: ¤ 0.88 (d, J = 6.5 Hz, 3H), 1.14-2.10 (m,
13H), 3.34-3.40 (m, 1H), 3.47-3.52 (m, 1H), 3.69-3.74 (m, 1H),
3.85-3.89 (m, 1H), 4.56-4.58 (m, 1H), 4.96-5.01 (m, 2H), 5.73-
5.82 (m, 1H); 13C NMR (CDCl3) for a mixture of isomers: ¤ 19.56
(two signals merged), 19.89 (two signals merged), 25.69 (two
signals merged), 27.46, 27.48, 30.97 (two signals merged), 32.85
(two signals merged), 33.07 (two signals merged), 41.50 (two
signals merged), 62.56 (two signals merged), 68.08, 68.11, 99.02,
99.06, 115.74 (two signals merged), 137.75 (two signals merged).
Found: C, 73.29; H, 11.66%. Calcd for C13H24O2: C, 73.54; H,
11.39%.
4,4-Dipropyl-1-octene (2c):
IR (neat): 3075, 2958, 2932,
2862, 1639, 1456, 1378, 994, 911, 745 cm¹1; 1H NMR (CDCl3): ¤
0.85-0.91 (m, 9H), 1.10-1.28 (m, 14H), 1.94 (dt, J = 7.5, 1.3 Hz,
2H), 4.96-5.00 (m, 2H), 5.72-5.80 (m, 1H); 13C NMR (CDCl3): ¤
14.39, 15.19, 16.41, 23.80, 25.43, 36.48, 38.01, 39.34, 41.37,
116.46, 135.85. Found: C, 85.89; H, 14.42%. Calcd for C14H28: C,
85.63; H, 14.37%.
Allylcyclododecane (2e): IR (neat): 2931, 2862, 1640, 1471,
This work is supported by Grants-in-Aid for Scientific
Research and GCOE Research. M.S. acknowledges JSPS for
financial support.
1
1446, 1346, 992, 909, 719 cm¹1; H NMR (CDCl3): ¤ 1.20-1.42
(m, 22H), 1.49-1.55 (m, 1H), 1.96-1.99 (m, 2H), 4.95-5.01 (m,
2H), 5.74-5.83 (m, 1H); 13C NMR (CDCl3): ¤ 21.91, 23.54, 23.59,
24.28, 24.90, 28.95, 34.13, 39.77, 115.40, 138.49. Found: C,
86.62; H, 13.61%. Calcd for C15H28: C, 86.46; H, 13.54%.
References
(3-Methyl-5-hexenyl)benzene (2g): IR (neat): 3027, 2917,
1
a) T. Tsuji, H. Yorimitsu, K. Oshima, Angew. Chem., Int.
¹1
2858, 1640, 1497, 1454, 994, 911, 745, 698 cm
;
1H NMR
Ed. 2002, 41, 4137. b) H. Ohmiya, T. Tsuji, H. Yorimitsu, K.
Oshima, Chem.®Eur. J. 2004, 10, 5640. c) H. Someya, H.
Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett. 2008, 10, 969. d) K.
Oshima, Bull. Chem. Soc. Jpn. 2008, 81, 1.
(CDCl3): ¤ 0.94 (d, J = 7.0 Hz, 3H), 1.41-1.48 (m, 1H), 1.51-1.61
(m, 1H), 1.63-1.70 (m, 1H), 1.92-1.98 (m, 1H), 2.09-2.14
(m, 1H), 2.55-2.61 (m, 1H), 2.63-2.69 (m, 1H), 4.98-5.03 (m,
2H), 5.74-5.82 (m, 1H), 7.16-7.19 (m, 3H), 7.25-7.29 (m, 2H);
13C NMR (CDCl3): ¤ 19.55, 32.58, 33.63, 38.57, 41.45, 115.90,
125.76, 128.46, 128.53, 137.57, 143.14. Found: C, 89.36; H,
10.22%. Calcd for C13H18: C, 89.59; H, 10.41%.
2
M. Sai, H. Someya, H. Yorimitsu, K. Oshima, Org. Lett.
2008, 10, 2545.
3
Reviews and representative recent examples of copper-
catalyzed cross-coupling reactions of alkyl halides: a) B. H.
Lipshutz, S. Sengupta, Org. React. 1992, 41, 149. b) H.-Q. Do, O.
Daugulis, J. Am. Chem. Soc. 2007, 129, 12404. c) J. Terao, A.
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9-Methoxy-4,4-dimethyl-1-nonene (2h):
IR (neat): 2934,
2862, 2827, 1473, 1457, 1387, 1122, 912 cm¹1; 1H NMR (CDCl3):
¤ 0.84 (s, 6H), 1.15-1.33 (m, 6H), 1.55-1.60 (m, 2H), 1.93 (dt,
J = 7.5, 1.1 Hz, 2H), 3.33 (s, 3H), 3.36 (t, J = 6.5 Hz, 2H), 4.96-
5.01 (m, 2H), 5.76-5.84 (m, 1H); 13C NMR (CDCl3): ¤ 24.00,
27.16, 27.20, 29.88, 33.22, 42.03, 46.64, 58.74, 73.15, 116.66,
126.10. Found: C, 77.98; H, 13.38%. Calcd for C12H24O: C, 78.20;
H, 13.12%.
9-Phenylsulfanyl-4,4-dimethyl-1-nonene (2i):
2931, 2859, 1586, 1471, 1439, 1365, 1026, 912, 737, 690 cm
IR (neat):
¹1
;
4
The reaction of secondary alkyl halides with stoichiometric
1H NMR (CDCl3): ¤ 0.83 (s, 6H), 1.14-1.42 (m, 6H), 1.63-1.70
(m, 2H), 1.92 (dt, J = 7.0, 1.3 Hz, 2H), 2.91 (t, J = 7.3 Hz, 2H),
4.95-5.02 (m, 2H), 5.75-5.83 (m, 1H), 7.14-7.18 (m, 1H), 7.25-
7.33 (m, 4H); 13C NMR (CDCl3): ¤ 23.70, 27.14, 29.37, 29.90,
33.22, 33.77, 41.92, 46.63, 116.72, 125.82, 129.00, 129.03,
136.03, 137.21. Found: C, 78.02; H, 10.18%. Calcd for C17H26S:
C, 77.80; H, 9.99%.
organocuprate was reported: E. C. Ashby, J. J. Lin, J. Org. Chem.
1977, 42, 2805.
5
H. O. House, W. L. Respess, G. M. Whitesides, J. Org.
Chem. 1966, 31, 3128.
6
Other copper salts were also effective: CuF2 (64%), CuCl2
(84%), CuBr (91%), and CuCN (85%).
7
A. S. E. Karlström, J.-E. Bäckvall, Chem.®Eur. J. 2001, 7,
2-(4-Methyl-6-heptenyloxy)-1-oxacyclohexane (2j, Mixture
1981.