Org. Synth. 2002, 79, 59
DOI: 10.15227/orgsyn.079.0059
SYNTHESIS AND UTILIZATION OF INDIUM (I) IODIDE FOR IN
SITU FORMATION OF ENANTIOENRICHED ALLENYLINDIUM REAGENTS AND THEIR ADDITION TO ALDEHYDES:
(2R,3S,4S)-1-(tert-BUTYLDIPHENYLSILYLOXY)-2,4-DIMETHYL-5-HEXYN-3-OL
[
5-Hexyn-3-ol, 1-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2,4-dimethyl-,
(2R,3S,4S)-
]
Submitted by Brian A. Johns, Charsetta M. Grant, and James A. Marshall
1
.
Checked by Edward B. Holson and William R. Roush.
1. Procedure
A.
Indium(III) iodide
.
To a 1-L, oven-dried, round-bottomed flask flushed with argon
and equipped with a magnetic stirrer is added xylenes
(500 mL). The solvent is degassed (Note 1)
and the flask is equipped with a reflux condenser.
Indium powder (5.00 g, 43.6
mmol)
(Note 2) is added to the vigorously
stirring solution, followed by
iodine
(I2, 16.57 g, 65.32 mmol). The mixture
is stirred vigorously (Note 3) and heated at reflux (bath temp.
≈160-170°C) under argon for 1-1.5 hr or until the
indium metal is consumed. When the
metal is consumed, a crystal of
iodine
is added and stirring at reflux is resumed. The reaction is complete when the added
iodine
is not consumed after
15 min at reflux. The solution is filtered hot and allowed to cool to room temperature
(Note 4). The resulting bright yellow crystals are filtered under
nitrogen using a Schlenk filtration system
(Note 5) and washed with two
10-mL
portions of cold benzene
to remove traces of I2.
The filtrate is concentrated to 1/4-1/3 volume (Note 6) and cooled
to 0°C. The yellow precipitate is Schlenk-filtered under nitrogen
and washed with cold benzene (10
mL). The product is dried under reduced pressure to yield 18.3 g (85%)
of
indium(III) iodide [In(III)I]
(Note 7).
B.
Indium(I) iodide
.
To a 1-L, oven-dried, round-bottomed flask flushed with argon
and equipped with a magnetic stirrer is added xylenes
(400 mL). The solvent is degassed (Note 1)
and the flask is equipped with a reflux condenser.
Indium(III) iodide (18.30 g, 36.93
mmol) is added to the flask, and the mixture is stirred vigorously
while
indium powder (2.12 g,
18.46 mmol)
(Note 2) is added. The
mixture is stirred vigorously (Note 3) at reflux under argon
for 18 hr. The resulting yellow suspension is allowed to cool to room temperature,
diluted with ether (400-500 mL)
and stirred for 1 hr. The resulting burgundy precipitate is filtered under air and
washed with ether (100 mL). The
product is dried under reduced pressure to yield 6.14
g (92%) of
indium(I) iodide
. The filtrate is concentrated
to dryness on a rotary evaporator, venting with nitrogen,
to yield 14.4 g (105% based on eq B.) (Note 8) of recovered
indium(III) iodide
(Note 9).
C.
(R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropanal
.
A 500-mL, oven-dried, round-bottomed flask equipped with a
magnetic stirrer is charged with
10.00
g (84.67 mmol) of methyl (R)-(−)-3-hydroxy-2-methylpropionate
(Note 10), and
100 mL
of N,N-dimethylformamide
(Note 11).
The solution is cooled to 0°C and
14.4 g
(211 mmol) of imidazole
is added. Upon
dissolution of the imidazole,
23.1
mL (88.9 mmol) of tert-butyldiphenylchlorosilane
(DPSCl)
(Note 12) is added dropwise via syringe. After
10 min, the cooling bath is removed and the solution is allowed to warm to room temperature
for 2 hr. The reaction is quenched by the addition of
200
mL of pentane
and 40 mL of water (H2O).
The layers are separated and the pentane layer is washed with
brine (75 mL). The aqueous layer
is extracted with
pentane (3
× 75 mL), and the combined extracts are dried over anhydrous sodium sulfate (Na2SO4).
Filtration and concentration under reduced pressure followed by purification by flash
chromatography (Note 13) yield 29.9
g (99%) of
methyl (R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropionate
as a clear oil (Note 14).
A 1-L, oven-dried, round-bottomed flask equipped with a
magnetic stirrer is charged with
9.92
g (27.9 mmol) of methyl (R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropionate
and
200 mL of dry hexanes
(Note 15). The solution is cooled to −78°C, and
31.5
mL (31.5 mmol) of 1 M diisobutylaluminum hydride
(in
hexane
) (DIBAL-H) (Note 16) is added dropwise over 15 min via a syringe pump.
After the addition is complete, the resultant solution is stirred at −78°C
for 2 hr. The reaction is quenched by pouring the cold solution into
250
mL of saturated aqueous Rochelle's salt. Ether
(300 mL) and H2O (75 mL) are added and the
biphasic mixture is stirred vigorously for 1 hr (Note 17). The
layers are separated and the ether layer is washed with brine.
The aqueous layer is extracted with ether (2 ×
50 mL) and the combined extracts are dried over Na2SO4
.
Filtration of the solution and concentration of the filtrate under reduced pressure
followed by purification of the crude product by flash chromatography (Note 18)
yields 7.85 g (86%) of
(R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropanal
as a white solid (Note 19).
D.
(R)-3-Butyn-2-yl
methanesulfonate
.
To a 1-L, oven-dried, round-bottomed flask flushed with argon
and equipped with a magnetic stirrer is added
dichloromethane
(CH2Cl2, 713 mL) and
(R)-(+)-3-butyn-2-ol
(10.00 g, 143 mmol)
(Note 20).
The mixture is cooled to −78°C and
triethylamine
(Et3N, 39.7 mL, 285 mmol) and
methanesulfonyl chloride (16.6
mL, 214 mmol) are added. The resulting mixture
is stirred at −78°C for 1 hr, then quenched with aqueous saturated
sodium bicarbonate (NaHCO3)
solution and allowed to warm to room temperature. The layers are separated and the
organic layer is washed with brine and concentrated under aspirator pressure (Note 21). The residue is diluted with
500
mL of ether and washed with water (20 mL) followed by brine (20 mL). The aqueous layer is extracted
with ether (50 mL). The combined
extracts are dried over anhydrous Na2SO4
and concentrated under aspirator pressure to yield 20.13
g (95%) of the methanesulfonate
(Note 22). The material is used without further purification
(Note 23).
E.
(2R,3S,4S)-1-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-5-hexyn-3-ol
.
An oven-dried, 100-mL, one-necked flask, equipped with a magnetic
stirring bar is purged with argon. The flask is charged
with
(R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropanal
(3.00 g, 9.19 mmol) and the (R)-methanesulfonate
(1.50 g, 10.1 mmol).
Tetrahydrofuran
(THF, 29.4 mL) and
hexamethylphosphoramide
(HMPA, 7.4 mL) are added via syringe. To the solution
is added PdCl2(dppf) (335 mg, 0.46
mmol)
(Note 24), immediately followed by
indium(I) iodide (2.66 g, 11.0
mmol). The resultant dark suspension is stirred vigorously for
1 hr at which time the reaction is judged complete by TLC (Note 25).
The reaction mixture is quenched by the addition of H2O (30 mL), and ether (20 mL) is added. After being stirred
for 2 min the layers are separated and the ether layer is washed with brine.
The aqueous layer is extracted with ether (3 ×
25 mL) and the combined extracts are dried over anhydrous
Na2SO4
. Filtration of the solution and concentration
of the filtrate under reduced pressure followed by purification of the crude product
by flash chromatography on silica gel
(Note 26) provide 2.64 g
(76%) of
(2R,3S,4S)-1-(tert-butyldiphenylsilyloxy)-2,4-dimethyl-5-hexyn-3-ol
(Note 27) as a clear oil and 201 mg of the (2R,3R,4R) diastereomer
(Note 28).
2. Notes
1.
The commercial mixture of xylenes was used as received without
further purification. Degassing was accomplished by bubbling
argon
through the solvent for 30 min.
2.
Indium powder,
−100 mesh, 99.99%, was purchased from Aldrich Chemical
Company, Inc.
3.
Vigorous stirring is very important. Use of a large stir bar for
this reaction is crucial. During the course of the reaction the powdered
indium metal may adhere to the sides
of the flask. On occasion it was necessary to dislodge this powder from the walls
of the flask. The flask was removed from the heat source, allowed to cool below reflux,
and the walls of the flask were scraped with a
metal spatula.
Caution should be exercised when performing this operation to avoid burns
and the flask should be blanketed with argon to prevent solvent
flash. On a larger scale the submitters recommend use of a
mechanical
stirrer.
4.
A
coarse, 150-mL, fritted glass filter
was used for the hot filtration. This filtration should be performed quickly, as precipitates
form rapidly upon cooling. This filtration may be performed in the air without complication.
5.
The product is very hygroscopic and should be handled under an
inert atmosphere. The checkers found that inactive material was produced if the filtration
was performed using a
150-mL fritted funnel under a blanket
of
nitrogen. The checkers subsequently performed this filtration
under
nitrogen using a
Schlenk filtration system
consisting of a
2-L, 24/40 three-necked flask, a
24/40
double male adapter, and a
400-mL 24/40 coarse fritted Schlenk
filter. The reaction vessel is connected to one end of the double male
adapter and the other end is quickly attached to the Schlenk filter system under a
positive flow of nitrogen. The solution is poured onto the filter, and filtered into
the three-necked flask via a vacuum system that is connected to one of the ports on
the three-necked flask.
6.
This step may be performed by using a
rotary evaporator
connected to a
water aspirator, with a drying column inserted
between the aspirator and the evaporator. The rotary evaporator is vented with
nitrogen
once the desired final volume is reached.
7.
The checkers obtained
74-85%
yields of
indium(III) iodide
.
8.
The checkers obtained
86-93%
yields of
indium(I) iodide
,
and
98-113% yields of recovered
indium(III) iodide etherate
.
The latter material was successfully recycled as described by the submitters
(Note 9).
9.
The recovered InI
3 can be used without further purification
to generate additional InI. Procedure B was repeated with recovered
InI3
(14.4 g, 29.1 mmol),
indium
powder (1.7 g, 14.8 mmol) and degassed
xylenes (320 mL) to yield
5.0 g (
95%)
of
indium(I) iodide
and
10.0 g (
93%) of recovered
indium(III)
iodide
.
10.
Methyl (R)-(−)-3-hydroxy-2-methylpropionate
was purchased from Sigma Chemical Company
and refrigerated
until used.
11.
Anhydrous N,N-dimethylformamide
was purchased from Aldrich Chemical Company, Inc.
12.
tert-Butyldiphenylchlorosilane
was purchased from United Chemical Technologies Inc.
13.
The separation is achieved on a column of
silica
gel with
pentane:ether (gradient
18:1 to 9:1) as the eluent.
14.
The physical properties are as follows:
[α]D
20−16.4° (CHCl3, c
2.8);
1H
NMR (300 MHz, CDCl
3) δ: 1.04 (s, 9 H), 1.16 (d,
3 H, J = 6.9), 2.72 (m, 1 H), 3.70 (s, 3 H), 3.73
(dd, 1 H, J = 9.9, 5.7)
3.84 (dd, 1 H, J = 9.9, 6.9), 7.36-7.46
(m, 6 H), 7.65-7.68 (m, 4 H)
; IR (film) cm
−1: 3071, 3050,
2955, 1746, 1111
. Anal. Calcd for
C
21H
28O
3Si; C, 70.74; H, 7.92. Found: C, 70.73; H,
7.80.
15.
Hexane
was dried by storage over activated
4 Å molecular sieves.
16.
The submitters indicated that 1.1 equiv of DIBAL-H was the optimal
stoichiometry to ensure complete consumption of the starting methyl ester. If less
was used, the aldehyde was not readily obtained in pure form. Excess DIBAL-H results
in ≈5-10% overreduction to afford a small amount of the alcohol. However, the
checkers found that the reaction did not go to completion under these conditions,
and that it was very difficult to separate the aldehyde product from the ester starting
material. Therefore, the checkers used 1.13-1.15 equivalents of DIBAL-H for complete
reaction, and obtained the product aldehyde in 85-86% yield along with 12-13% yields
of alcohol from overreduction. The checkers also obtained small amounts of ester
1
(2-5%, depending on the batch of DIBAL-H used). Ester
1 can be visualized by
TLC (R
f 0.65,
5% ether/
pentane
), versus Rf's = 0.40 for the
starting ester and product aldehyde (which do not separate under these conditions).
17.
The biphasic mixture should be stirred until both layers are
clear upon settling.
18.
The separation is achieved on a column of
silica
gel with
pentane:ether (gradient
18:1 to 9:1) as the eluent. If any methyl ester remains, the aldehyde can
be further purified by recrystallization from hexanes.
19.
The physical properties are as follows:
[α]D
20−24.7° (CHCl3, c
1.5);
mp 63-64°C;
1H NMR (300 MHz,
CDCl
3) δ: 1.04 (s, 9 H), 1.10 (d, 3 H, J = 6.9),
2.57 (m, 1 H), 3.84 (dd, 1 H, J = 10.5, 6.3), 3.91
(dd, 1 H, J = 10.5, 5.4), 7.37-7.47 (m, 6 H), 7.63-7.66
(m, 4 H), 9.77 (d, 1 H, J = 1.2)
. Anal. Calcd for C
20H
26O
2Si:
C, 73.57; H, 8.03. Found: C, 73.30; H, 7.93.
20.
(R)-(+)-3-Butyn-2-ol
was purchased from Aldrich Chemical Company, Inc., or DMS
Fine Chemicals Inc.
21.
Concentration of the crude mesylate under reduced pressure must
be done with care to avoid loss of product due to volatility.
22.
The physical properties are as follows:
[α]D
20+108.4° (CHCl3, c
2.39);
1H
NMR (300 MHz, CDCl
3) δ: 1.66 (d, 3 H, J = 6.8), 2.70
(d, 1 H, J = 2.0), 3.12 (s, 3 H), 5.29 (qd, 1 H, J = 6.8,
2.0)
;
13C
NMR (75 MHz, CDCl
3) δ: 22.3, 39.0, 67.4,
76.6, 80.1
.
23.
The checkers found that the mesylate is unstable to storage and
gave best results in the subsequent reaction with In(I)I if used immediately after
preparation.
24.
PdCl2(dppf) was
prepared according to the published procedure
2
from
PdCl2(NCPh)2 and dppf ligand
purchased from Aldrich Chemical Company, Inc.
The
commercially available
PdCl2(dppf)
catalyst was also used, but the freshly prepared catalyst proved superior.
25.
TLC analysis was performed on
silica
gel plates developed with
hexanes:ether (3:1),
R
f = 0.47, and visualized with
ceric(IV)
sulfate
/
ammonium molybdate
stain.
26.
The separation is achieved on a column of
silica
gel (34 cm × 16 cm) with
hexanes:ether (9:1)
as the eluent.
27.
The physical properties are as follows:
[α]D
20−17.0° (CHCl3, c
1.51);
1H
NMR (300 MHz, CDCl
3) δ: 0.86 (d, 3 H, J = 6.9), 1.07
(s, 9 H), 1.33 (d, 3 H, J = 7.5), 2.06 (m, 1 H),
2.15 (d, 1 H, J = 2.4), 2.71 (m, 1 H), 3.42 (m, 1
H), 3.44 (d, 1 H, J = 1.5), 3.71 (dd, 1 H, J = 10.2, 6.9),
3.78 (dd, 1 H, J = 10.2, 4.2), 7.37-7.46 (m, 6 H), 7.72-7.67
(m, 4 H)
; IR (film) cm
−1:
3493, 3305, 2931
;
13C NMR (75 MHz, CDCl
3) δ:
13.5, 17.9, 19.1, 26.8, 30.2,
38.9, 68.6, 70.2, 78.1, 85.0,
127.8, 129.8, 132.9, 135.6
.
Anal. Calcd for C
24H
32O
2Si: C, 75.74; H, 8.47. Found:
C, 75.74; H, 8.43.
28.
The (2R,3R,4R) diastereomer results from partial racemization
of one or both of the allenylmetal intermediates. This point was confirmed by comparison
to authentic material as the (S)-MPA (
(S)-(2-methoxy)phenylacetic acid-Mosher's
acid) derivative. The optical rotations of these compounds are small, and thus correlation
by comparison of [α]
D
20 values is unreliable.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Chiral allenylmetal compounds provide convenient access to enantioenriched homopropargylic
alcohols through S
E2' additions to aldehydes.
3 The syn
adducts can be obtained through addition of allenyl tributylstannanes in the presence
of stoichiometric
boron trifluoride etherate
(BF3·OEt2). The use of allenylmetal halides
derivatives of Sn, Zn, and In lead to the anti diastereomers. The former additions
proceed through an acyclic transition state whereas the latter are thought to involve
a cyclic transition state, thus accounting for the difference in diastereoselectivity.
The present method is practical and efficient as it employs readily available enantioenriched
propargylic alcohols
4
as precursors to the allenylindium reagents. With achiral aldehydes the diastereoselectivity
is high for branched aldehydes, moderate for unbranched aldehydes, and low for
benzaldehyde
(Table I).
5 With chiral α-methyl
aldehydes
6 the
additions proceed under effective reagent control to afford anti adducts of high ee
and with excellent diastereoselectivity (eq. 1 and 2). Comparable results were obtained
with 3:1
dimethyl sulfoxide
-
tetrahydrofuran
(DMSO-THF) as the solvent.
Table I
The described preparation of InI is a modification of a 3-step literature procedure
in which
indium shot is hammered into
indium foil and heated with
iodine
to form InI
3.
7 The InI
3 is then heated with excess
indium foil to form In
2I
4
(as a complex of InI[InI
3]).In a third step, the In
2I
4
is treated with
diethyl ether
whereupon it disproportionates to insoluble InI and soluble InI
3 etherate
that are separated by filtration.
The present procedure combines the second and third steps, thus avoiding handling
of the hygroscopic intermediate In2I4 complex. It also demonstrates
efficient recycling of the recovered InI3 etherate. Commercial InI, available
from Aldrich Chemical Company, Inc., can be used in the allenylindium procedure with
comparable results but at greater expense. The InI prepared as described is an easily
handled free-flowing powder, whereas the commercial product consists of small beads
that must be crushed before use.
An alternative preparation of enantioenriched anti-homopropargylic alcohols along
similar lines uses Et
2Zn to effect in situ transmetallation of an allenylpalladium
intermediate from a
propargyl mesylate
and
2.5 mol % of Pd(OAc)2·PPh3
in the presence of an aldehyde (Table II).
8
The two methods are comparable.
Table II
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Indium (I) iodide:
Indium iodide
(8);
Indium iodide (InI) (9); (13966-94-4)
(2R,3S,4S)-1-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-5-hexyn-3-ol:
5-Hexyn-3-ol, 1-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2,4-dimethyl-, (2R,3S,4S)-
(14); (220634-80-0)
Indium (III) iodide:
Indium iodide
(8);
Indium iodide (InI3) (9); (13510-35-5)
Indium (8, 9); (7440-74-6)
Iodine (8, 9); (7553-56-2)
(R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropanal:
Propanal, 3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-, (2R)-
(12); (112897-04-8)
Methyl (R)-(−)-3-hydroxy-2-methylpropionate:
Propanoic acid, 3-hydroxy-2-methyl-, methyl ester, (R)- (10);
(72657-23-9)
N,N-Dimethylformanide: CANCER SUSPECT AGENT:
Formanide,
N,N-dimethyl- (8, 9); (68-12-2)
Imidazole (8);
1H-Imidazole (9);
(288-32-4)
tert-Butyldiphenylchlorosilane:
Silane, chloro(1,1-dimethylethyl)diphenyl-
(9); (58479-61-1)
Methyl (R)-3-(tert-butyldiphenylsilyloxy)-2-methylpropionate:
Propanoic acid, [[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-, methyl
ester, (2R)- (13); (153775-90-7)
Diisobutylaluminum hydride: DIBAL-H:
Aluminum,
hydrodiisobutyl- (8);
Aluminum, hydrobis(2-methylpropyl)-
(9); (1191-15-7)
(R)-3-Butyn-2-yl methanesulfonate:
3-Butyn-2-ol,
methanesulfonate, (2R)- (12); (121887-95-4)
(R)-(+)-3-Butyn-2-ol:
3-Butyn-2-ol, (+)-
(9); (42969-65-3)
Triethylamine (8);
Ethanamine, N,N-diethyl-
(9); (121-44-8)
Methanesulfonyl chloride (8, 9); (124-63-0)
Hexamethylphosphoramide: HIGHLY TOXIC; CANCER SUSPECT
AGENT:
Phosphoric triamide, hexamethyl- (8, 9); (680-31-9)
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium:
Palladium, [1,1'-bis(diphenylphosphino)ferrocene-P,P']dichloro-
(10); (72287-26-4)
Bis(benzonitrile)dichloropalladium(II):
Palladium,
bis(benzonitrile)dichloro- (8, 9); (14220-64-5)
1,1'-Bis(diphenylphosphino)ferrocene (dppf):
Phosphine, 1,1'-ferrocenediylbis[diphenyl- (8);
Ferrocene,
1,1'-bis(diphenylphosphino)- (9); (12150-46-8)
(2R,3R,4R)-1-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-5-hexyn-3-ol:
5-Hexyn-3-ol, 1-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2,4-dimethyl-, (2R,3R,4R)-
(14); (220634-81-1)
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