Preparation of organoaluminum reagents from propargylic bromides and aluminum activated by PbCl2and their regio- And diastereoselective addition to carbonyl derivatives

Article abstract of DOI:10.1002/chem.201000523

Various propargylic and allenic aluminum reagents have been easily prepared by a direct insertion of aluminum into propargylic bromides in the presence of PbCl₂ (1 mol%). These organoaluminum reagents react with carbonyl compounds to afford the

Full text of DOI:10.1002/chem.201000523

FULL PAPER
DOI: 10.1002/chem.201000523
Preparation of Organoaluminum Reagents from Propargylic Bromides and
Aluminum Activated by PbCl2 and Their Regio- and Diastereoselective
Addition to Carbonyl Derivatives
Li-Na Guo, Hongjun Gao, Peter Mayer, and Paul Knochel*[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
Abstract: Various propargylic and allenic aluminum reagents have been easily pre-
pared by a direct insertion of aluminum into propargylic bromides in the presence
of PbCl2 (1 mol%). These organoaluminum reagents react with carbonyl com-
pounds to afford the corresponding allenic alcohols or homopropargylic alcohols
in good to excellent yields with high regio- and diastereoselectivity.
Keywords: aluminum · diastereose-
lectivity · lead chloride · organoalu-
minum · propargylic bromide
Introduction
as a propargylic organometallic species of type 3. Their ad-
dition to carbonyl compounds (aldehydes or ketones), which
proceeds via a six-membered cyclic transition state, gives
the corresponding homopropargylic alcohols of type 4 or al-
lenic alcohols of type 5 (Scheme 1).
The preparation of organometallics by the oxidative addi-
tion of a metal to an organic halide is an important method,
which has a good atom economy[1] and excellent generality.
The metal activation is crucial for performing a direct inser-
tion reaction of a metal to an organic halide. Rieke has
shown that activated magnesium and activated zinc can be
obtained by the reduction of magnesium or zinc halides with
lithium metal.[2] Alternatively, we have shown that the addi-
tion of LiCl considerably facilitates the oxidative addition of
Zn,[3] Mg,[4] and In[5] powder to various organic halides. Re-
cently, we have reported that although the direct activation
of Al with LiCl was not possible for reactions with unsatu-
rated iodides or bromides, we have found that additional
catalysis with small amounts of various salts such as SnCl4,
[6]
SnCl2, InCl3, BiCl3, or PbCl2 allows a smooth unprecedent-
ed direct insertion of Al powder to aryl bromides or io-
dides.[7] To our delight, we found that Al powder can also
easily insert into propargylic bromides of type 1 in the pres-
ence of a catalytic amount of PbCl2.[8] Depending on the
nature of the substituent R, the organoaluminum reagent
exists either as an allenic organometallic species of type 2 or
Scheme 1. Selective synthesis of homopropargylic alcohol 4 or allenic al-
cohol 5 from propargylic bromide 1a–e.
Thus, if R is a small group (R=H), the allenic aluminum
isomer 2 is preferred, whereas if R is more sterically hin-
dered (R¼H), a propargylic aluminum species of type 3 is
favored.[9] Herein, we wish to report a detailed study of the
regio- and diastereoselective addition of these organoalumi-
num species to carbonyl compounds such as aldehydes and
ketones.
[a] Dr. L.-N. Guo, Dr. H. Gao, Dr. P. Mayer, Prof. Dr. P. Knochel
Department Chemie and Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Gemany)
Fax : (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000523.
Chem. Eur. J. 2010, 16, 9829 – 9834
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9829

Table 1. Addition of allenyl aluminum bromide (2a) to aldehydes and
ketones leading to homopropargylic alcohols 4aa–4aj.[a]
Results and Discussion
According to Gaudemar[10] and Eiter et al.,[11] allyl and
propargyl aluminum derivatives are prepared by heating the
corresponding bromides in THF to reflux with aluminum
granules activated by a catalytic amount of HgCl2.[10–12]
Much milder conditions can be achieved by an appropriate
activation of the aluminum surface.[13,14] Thus, we have
found that the treatment of various propargylic bromides 1
with aluminum powder (1.2 equiv) in the presence of PbCl2
(1 mol%) in THF at 08C for 1 h readily produces the corre-
sponding organoaluminum reagents of type 2 or 3. This
practical preparation encouraged us to investigate their ad-
ditions to various aldehydes and ketones.
Entry
1
Aldehyde or Ketone
Product
Yield [%][b]
6a: R=H
6b: R=CO2Me
6c: R=CN
4aa: R1 =H
4ab: R=CO2Me
4ac: R=CN
0[c], 87
95
92
2
3
First, 3-bromo-1-propyne (1a, 2.0 mmol) was treated with
aluminum powder (2.4 mmol) in the presence of PbCl2
(0.02 mmol, 1 mol%) in THF (2 mL) at 08C for 1 h, leading
to the allenic aluminum reagent 2a. Owing to this allenic
structure, the addition to aldehydes and ketones via a six-
membered cyclic transition state afforded only the homo-
propargyl alcohols 4aa–4aj as sole products in 61–99%
yield (Table 1).[15] Whereas aliphatic or aromatic aldehydes
(6a–d) react with the allenyl-aluminum reagent 2a at
ꢀ788C (1–2 h; Table 1, entries 1–4), this addition reaction
requires 1–2 h at 08C for ketones (6e–j; Table 1, entries 5–
10). Remarkably, various functional groups such as ester, cy-
anide, or primary amino groups are well tolerated under
these reaction conditions (Table 1, entries 2, 3, 5, and 6).
Also, the presence of relatively acidic methylene groups
such as in a- or b-tetralone (6g and 6h) or 1,3-diphenyl-
propan-2-one (6i) are also tolerated. The addition reaction
proceeds smoothly and no competitive deprotonation is ob-
served. The desired homopropargylic alcohols 4ag–4ai were
obtained as sole products in 72–91% yield (Table 1, en-
tries 7–9).
4[d]
61
99
6d
4ad
5
6e: R=CO2Me
4ae: R=CO2Me
6
77
6 f
4af
7
8
91
72
6g
6h
4ag
4ah
Furthermore, 3-substituted propargylic bromides 1b–e
can also readily be converted to the corresponding organoa-
luminum reagents under the same conditions. In this case,
steric interactions disfavor the allenic form 2 and the prop-
9
91
95
6i
6j
4ai
4aj
argylic aluminum species of type
3
are preferred
10
(Scheme 1). Thus, after an addition reaction to carbonyl de-
rivatives, the allenic alcohols of type 5 are produced as
single products in most cases (Table 2). Thus, the organoalu-
minum species generated from 1-bromo-2-nonyne (1b; R=
hexyl (Hex)) and (trimethylsilyl)propargyl bromide (1c;
R=TMS)[9a] reacted with various aromatic and aliphatic ke-
tones affording the allenic alcohols 5 as single isomers
(Table 2, entries 1–4 and 6–11). No homopropargylic alco-
hols were observed in all of these cases. However, treatment
of the aluminum reagent derived from 1b with benzalde-
hyde (6a) gave a separable mixture of allenic alcohol 5ba
and homopropargyl alcohol 4ba in 91% yield (86:14 ratio
5ba:4ba; Table 2, entry 5). A similar mixture was obtained
for the reaction of acetophenone (6k) with the organoalumi-
num reagents derived from 1-bromo-6-chloro-2-hexyne (1d;
Table 2, entry 12) and (3-bromoprop-1-ynyl)cyclohexane
(1e; Scheme 2). We envisioned that by increasing the steric
[a] All reactions were performed with aldehydes (0.8 equiv) at ꢀ788C or
ketones (0.8 equiv) at 08C unless otherwise indicated. [b] Yield of isolat-
ed pure product. [c] Without PbCl2 (1 mol%). [d] 0.7 equiv of aldehyde
was used.
hindrance of the other substituents attached to the alumi-
num center, we would favor the propargylic organometallic
species (for example 3e over 2e; Scheme 2). Thus, we treat-
ed the aluminum reagent generated from 1b, 1d, and 1e
with
a
bulky
arylmagnesium
bromide
(2,4,6-
(iPr)3C6H2MgBr; 0.7 equiv) at 08C for 3 h, leading tentative-
ly to the new aluminum reagents such as 7e and 8e
(Scheme 2). Steric hindrance favors the regioisomeric organ-
ometallic species 8e. This change allowed improved isomeric
ratio. Thus, the product ratio between 4ek and 5ek went
9830
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Organoaluminum Reagents
FULL PAPER
Table 2. Additions of 3-substituted primary propargylic bromides to carbonyl compounds with catalytic PbCl2/
Al.[a]
Organoaluminum
reagents
derived from the secondary
propargylic bromides 1 f and 1g
could be prepared in a similar
fashion and their addition to al-
dehydes and ketones were also
examined under the previously
optimized conditions. A com-
plete regioselectivity is ob-
served for all these aluminum
reagents and only homopropar-
gylic alcohols of type 4 were
obtained (Table 3). The organo-
aluminum reagent generated
from 3-bromo-1-butyne (1 f) re-
acted with benzaldehyde (6a)
furnishing homopropargyl alco-
hol 4 fa in 91% yield with low
Entry
1
1
6
Product
Yield [%][b]
R=Hex (1b)
1b
1b
6k: R1 =H
5bk: R1 =H
80
73
77
2
3
6e: R1 =CO2Me
6l: R1 =CN
5be: R1 =CO2Me
5bl: R1 =CN
4
5
6
85
1b
1b
6j
5bj
diastereoselectivity
(Table 3,
entry 1). The use of various co-
solvents or additives (DME,
CH3CN, 2,6-dimethylpyridine,
and diethylene glycol diethyl
ether) did not improve the dia-
stereoselectivity. Also, changing
of the methyl substituent in the
a position of the propargyl bro-
mide to an isopropyl group had
no influence on the diastereose-
lectivities (Table 3, entries 1
and 8). However, good selectiv-
ity was observed when cyclo-
91 (14:86) 85 (6:94)[c]
6a
4ba
5ba
R=TMS (1c)
1c
1c
6k: R1 =H
5ck: R1 =H
80
83
76
7
8
6e: R1 =CO2Me
6l: R1 =CN
5ce: R1 =CO2Me
5cl: R1 =CN
9
83
hexanecarboxaldehyde
(6d)
1c
6j
5cj
was used. In this case, the anti
adduct is the major isomer
(Table 3, entry 2).[16] Note that
the addition of the allenylalu-
minum reagents 2 f and 2g to
various ketones always pro-
ceeds with high yields (85–
92%) and diastereoselectivities
(up to 97:3; Table 3, entries 3,
4, 6, and 9). There are very few
reports in the literature on the
preparation of tertiary homo-
propargylic alcohols with such
high diastereoselectivites.[17]
10
88
1c
1c
cyclohexanone 6m 5 cm
11
12
79
6a
5ca
R=(CH2)3Cl (1d) 6k
4dk
5dk
93 (20:80) 91 (10:90)[c]
To determine the relative ste-
reochemistry of these tertiary
[a] All reactions were performed with aldehydes (0.7 equiv) at ꢀ788C or ketones (0.7 equiv) at 08C unless oth-
erwise indicated. [b] Yield of isolated pure product. The numbers in parentheses are the ratio of 4 and 5 deter-
mined by crude 1H NMR or GC analysis. [c] 2,4,6-(iPr)3C6H2MgBr (0.7 equiv) was added. The numbers in pa- alcohols, the major isomer 4 fk
rentheses are the ratio of 4 and 5 determined by HPLC analysis.
was successfully converted to
the 1,4-disubstituted 1,2,3-tria-
zole 9 fk via a copper(I)-cata-
from 31:69 (94%) to 7:93 (89%). Similar changes can also
be observed for the propargylic bromides 1b and 1d
(Table 2, entries 5 and 12).
lyzed three-component [3+2] cycloaddition reaction in
85% yield.[18] The relative stereochemistry of compound 9 fk
was determined by its X-ray crystal structure (Scheme 3).
This indicated that the reaction of the allenylaluminum spe-
Chem. Eur. J. 2010, 16, 9829 – 9834
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9831

P. Knochel et al.
Table 3. Reactions of terminal secondary propargylic bromides with carbonyl
compounds with catalytic PbCl2/Al.[a]
Entry
1
1
6
Product
Yield [%][b]
91 (56:44)
1 f
PhCHO 6a
4 fa
2
3
4
91 (88:12)
85 (89:11)
87 (88:12)
1 f
1 f
c-C6H11CHO 6d
PhCOMe 6k
4 fd
4 fk
Scheme 2. Postulated reaction pathway.
1 f
1 f
4-NCC6H4COMe 6l 4 fl
5
87
cyclohexanone 6m
a-tetralone 6h
4 fm
6
7
1 f
1 f
4 fh
90 (94:6)
Scheme 3. Determination of the relative stereochemistry of the alcohol
4 fk.
1,3-diphenylpropan- 4 fj
2-one 6j
92
cies 2 f with acetophenone (6k) proceeded with syn selectiv-
ety. This syn selectivity may result from the transition state
11 depicted in Figure 1. This cyclic transition state is favored
compared to the alternative cyclic transition state 12 for
steric reasons. The preferential formation of syn-4 fk over
anti-4 fk is consistent with the rule proposed by Seebach and
Golinski.[19] Furthermore, the major isomer 4 fh was also
converted successfully into the 1,4-disubstituted 1,2,3-tri-
8
9
90 (56:44)
1g
1g
PhCHO 6a
4ga
4gk
92 (97:3)
ACHTUNGTRENNUNGazole 9 fh in 90% yield, which was further converted to the
PhCOMe 6k
[a] All reactions were performed with aldehydes (0.8 equiv) at ꢀ788C or ke-
tones (0.7 equiv) at 08C unless otherwise indicated. [b] Yield of isolated pure
product. The numbers in parentheses are the ratios of diastereoselectivies de-
1
termined by crude H NMR analysis.
corresponding benzoyl ester 10 fh in 88% isolated yield by
Vedejsꢃ method,[20] the stereochemistry of which was also de-
termined by X-ray analysis (Scheme 4).
Remarkably, by using the 3-substituted propargylic bro-
mides 1h–j as precursors, only the homopropargylic alcohols
of type 4 as single regioisomers in 68–98% yield (Table 4)
Figure 1. Possible transition state for addition of the allenylaluminum
species 2 f to acetophenone (6k).
9832
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Organoaluminum Reagents
FULL PAPER
Table 4. Reactions of internal secondary propargylic bromides with carbonyl
compounds with catalytic PbCl2/Al.[a]
Entry
1
1
6
Product
Yield [%][b]
R=nBu
6a
4ha
76 (60:40)
73 (94:6)
R1 =Me (1h)
2
3
Scheme 4. Determination of the relative stereochemistry of the alcohol
4 fh.
1h
1h
6k
6o
4hk
4ho
68 (99:1)[d]
were obtained. Propargylic bromide 1i (R=(CH2)2OMe;
R1 =Me) that has a methoxy group furnished better yields
than the propargylic bromide 1h (R=nBu; R1 =Me) under
the same conditions (Table 4, entries 1–3 versus entries 4, 5,
and 7). We propose that the oxygen atom of the methoxy
group stabilized the allenylaluminum species. These allenyl-
90 (55:45)
4
88 (50:50)[c]
R=(CH2)2OMe 6a
R1 =Me (1i)
4ia
ACHTUNGTRENNUNGaluminum reagents reacted with benzaldehyde (6a) afford-
ing the corresponding homopropargylic acohols 4ha, 4ia,
and 4ja in 76, 90, and 96% yields, respectively, but with low
diastereoselectivities (Table 4, entries 1, 4, and 8). No im-
provement was obtained by using the corresponding organo-
zinc reagent prepared from 1i (Table 4, entry 4). Much to
our delight, excellent diastereoselectivities were also ob-
tained for the addition of these allenylaluminum species to
various ketones (Table 4, entries 2–3, 5–7, and 11).[21] It is in-
teresting to note that syn selectivity is preferred for aromat-
ic ketones, whereas anti selectivity is predominant for a ster-
ically hindered aliphatic ketone such as tBuCOMe (Table 4,
entries 3 and 7).[22]
5
6
7
93 (92:8)
98 (91:9)
86 (99:1)[d]
1i
1i
6k
6p
4ik
4ip
1i
6o
4io
8
Conclusion
In summary, we have reported a new and efficient prepara-
tion of allenic- and propargylic aluminum reagents under
mild conditions. These organoaluminum species react with
carbonyl compounds (aldehydes or ketones) to give the ho-
mopropargylic or allenic alcohols in good to excellent yields
and in several cases with high diastereoselectivity. Various
functional groups such as ester, cyanide, primary amino
groups, and the relatively acidic methylene group are toler-
ated in this reaction.
R=(CH2)2OMe 6a: R2 =H
R1 =nBu (1j)
1j
1j
4ja: R2 =H
96 (55:45)
9
10
6q: R2 =OMe
6r: R2 =CF3
4jq: R2 =OMe
4jr: R2 =CF3
98 (54:46)
90 (31:69)
11
88 (92:8)
1j
6k
4jk
[a] All reactions were performed with aldehydes (0.7 equiv) at ꢀ788C or ke-
tones (0.7 equiv) at 08C unless otherwise noted. [b] Yield of isolated pure
product. The numbers in parentheses are the ratios of diastereoselectivies de-
termined by crude 1H NMR or GC analysis. [c] The organozinc reagent was
used. [d] The relative stereochemistry of the alcohol 4ho and 4io were deter-
mined by NOESY spectroscopy.
Chem. Eur. J. 2010, 16, 9829 – 9834
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P. Knochel et al.
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Experimental Section
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[8] The organoaluminum reagents are equimolar mixtures of RAlBr2
and R2AlBr, which is summarized by RAl2/3Br.
General methods: All reactions were carried out under a nitrogen atmos-
phere in flame-dried glassware by using Schlenk techniques. Syringes
were purged with nitrogen prior to use. THF was continuously heated to
reflux and was freshly distilled from sodium benzophenone ketyl under
nitrogen. Melting points are uncorrected and were measured on a Bꢁchi
B.540 apparatus. 1H and 13C NMR spectra were recorded on a Bruker
AC 300 or WH 400 instrument. Chemical shifts are given in ppm relative
to the residual solvent peak ([D1]chloroform: 7.26 ppm/77.0 ppm;
[D6]benzene 7.16 ppm/128.0 ppm). IR spectra were recorded on a Nicolet
510 FT-IR or a Perkin–Elmer 281 IR spectrometer. Mass spectra were re-
corded on a Finnigan MAT 95Q Finnigan MAT90 instrument. Column
chromatography purification was performed on Merck silica gel 60 (230–
400 mesh ASTM).
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General procedure for the preparation of the organoaluminum reagent:
A dry, argon-flushed Schlenk flask equipped with a magnetic stirrer and
a rubber septum was charged with anhydrous PbCl2 (5.6 mg, 0.02 mmol,
1 mol%) and the flask was dried with a heating gun for 3 min under high
vacuum. To this flask was added aluminum powder (65 mg, 2.4 mmol)
and the flask was evacuated and refilled with argon. After the addition
of freshly distilled THF (2 mL), propargyl bromide (2.0 mmol) was
added in one portion when the solution was cooled to 08C. After stirring
for 1 h at this temperature, the reaction mixture was then cannulated to a
new Schlenk flask for the reaction with an electrophile at ꢀ788C or 08C.
General procedure for addition reactions: A dry Schlenk flask equipped
with a magnetic stirrer and a rubber septum was charged with the corre-
sponding electrophile (1.4 or 1.6 mmol, 0.7 or 0.8 equiv). The flask was
thoroughly flushed with argon, and freshly distilled THF (0.5 mL) was
added to it through the rubber septum. The resultant mixture was stirred
at ꢀ788C or 08C for 2 min before the corresponding aluminum reagent
was slowly cannulated into the flask and the mixture was stirred at
ꢀ788C or 08C from 1 h to 2 h. Once the GC analysis of a standard ali-
quot had indicated the consumption of the electrophile, the reactions
were quenched with saturated aqueous NH4Cl. The mixture was extract-
ed with EtOAc (3ꢄ20 mL), washed with saturated aqueous NaHCO3,
water, and saturated NaCl solution. The combined organic layers were
dried over Na2SO4 and the solvents were removed under reduced pres-
sure to furnish the crude product, which was further purified by column
chromatography (silica gel) to obtain an analytically pure sample.
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X-ray crystallographic analysis: CCDC-766013 (9 fk), 766014 (10 fh), and
766015 (10ik) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
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Received: February 28, 2010
Published online: June 22, 2010
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