Organic Syntheses, Vol. 81, p.14 (2005).
] must be used in pure form rather than as a solution in hexane
. Titanium tetraisopropoxide (95%) was obtained from ABCR, Karlsruhe by the submitters and from Aldrich Chemical Company
by the checkers and was distilled under nitrogen before use. Titanium tetrachloride (>99%) was purchased from VWR by the submitters and from Aldrich Chemical Company
by the checkers and was used without further purification. The submitters obtained a solution of methyllithium
in ether (1.6M, 5 wt%) from Fluka
. The amount of titanium tetrachloride was incorrectly given as 6.48 mL and the concentration of methylithium solution was incorrectly given as 1.0 M in the original published version of this Organic Syntheses procedure due to typographical errors.
The product is air and moisture sensitive, and the checkers used it immediately after preparation. The submitters report that MeTi(OiPr)3
can be stored for several months in a freezer under an inert atmosphere.
was prepared as follows. A 250-mL, round-bottomed flask
equipped with reflux condenser
fitted with an argon inlet
was charged with 100 mL of DMF
, 40.4 mL (210 mmol) of dibenzylamine
, and 12.8 mL (300 mmol) of formic acid
. The solution was heated at reflux overnight, allowed to cool to room temperature, and then quenched by carefully adding 40 mL of saturated Na2CO3
solution. The aqueous phase was separated and extracted with four 50-mL portions of ether
, and the combined organic layers were washed with two 20-mL portions of brine
, dried over MgSO4
, and concentrated by rotary evaporation at reduced pressure. The crude product was crystallized from 100 mL of 70:30 ether/pentane
to yield 40.2 g
) of N,N-dibenzylformamide
, mp 50-51°C;
it is hygroscopic and must be dried before use under reduced pressure (0.007 mm) overnight.
The submitters used THF that was freshly distilled from sodium
, while the checkers used THF that was dried by pressure filtration through activated alumina
is prepared as follows. A 250-mL, three-necked, round-bottomed flask
containing a magnetic stirbar
and equipped with two rubber septa
and an addition funnel
fitted with an argon inlet
was charged with 4.8 g (200 mmol) of magnesium turnings (Aldrich)
suspended in 70 mL of anhydrous THF
. A solution of 18.3 mL (180 mmol) of 4-bromo-1-butene (Aldrich)
in 60 mL of anhydrous THF
was added by dropping funnel at a rate adjusted to maintain a gentle reflux (total addition time, ca. 3 hr). The reaction mixture was then stirred for an additional hour. To determine the concentration of product, a 1-mL aliquot of the mixture was quenched with 0.1N HCl
and then back-titrated with 0.1N NaOH
(phenolphthalein indicator) which indicated a concentration of 1.5M.
The concentration of the Grignard reagent should not be higher than 1.5M. The use of more concentrated solutions leads to lower yields. Because of the rather high concentration of the reagents, it is important to stir the reaction mixture vigorously during and after the addition of the Grignard reagent. If the reaction is carried out on a larger scale than that described here, then the use of a mechanical stirrer is recommended.
The submitters used a syringe pump
to add the Grignard solution. However, the checkers experienced problems with precipitation of the Grignard reagent and recommend the use of an addition funnel. If the reagent begins to precipitate in the funnel during the addition period, then gentle
warming with a heat gun accomplishes redissolution.
The reductive cyclopropanation reaction proceeds very rapidly. For example, the submitters report that hydrolysis of the reaction mixture after only 1 min gives the product in 75%
yield. However, stirring for an additional 1 hr is recommended, and this should be sufficient for analogous transformations with other Grignard reagents and formamides as well. Higher N,N
-dialkylcarboxamides may require longer reaction times (up to 5 hr).
The hydrolysis should be carried out with access of air so that the black titanium(II) derivatives are oxidized rapidly and completely to colorless titanium(IV) compounds.
The solvents are removed within 1 hr at a bath temperature of 50°C at 15 mm.
diastereomeric ratio is determined by integration of resonances in the 1
H NMR spectrum of the crude mixture and is usually found in the range of 1/6.0 to 1/7.5.
TLC analysis of the crude product (elution with 50:1 pentane:ether
, visualization with iodine
) showed three non-baseline spots: Rf
0.52 (unknown impurity), and Rf
isomer). The unknown impurity is intensely sensitive to iodine
and largely coelutes with the cis
-isomer in the subsequent column chromatography. However, the 1
H NMR spectrum of this isomer shows excellent purity despite the presence of this spot on TLC. In 100:1 pentane:ether
values of the cis
isomers are about 0.50 and 0.15, respectively.
It is important to wet-pack the column with the eluting solvent. Dry packing results in strong retention of the sample and poor separation, possibly because the small amount of ether
in the eluting solvent is adsorbed by the dry silica gel.
If separation of the diastereomers is not required, then filtration of the crude product through a pad of 50 g of silica eluting with dichloromethane
followed by concentration affords a mixture of diastereomers separated from baseline materials.
The submitters report obtaining 1.29
) of the cis
-diastereoisomer and 8.39 g
) of the trans
-diastereoisomer. The submitters recommend that the purified diastereomers be stored in the freezer (-18°C). Both pure isomers slowly equilibrate to a 21:79 mixture of cis/trans
isomers upon standing at ambient temperature for several weeks.
The products exhibit the following spectroscopic properties: trans
H NMR pdf
(300 MHz, CDCl3
) δ 0.60 (ddd, J = 6.7, 5.5, 4.9 Hz, 1 H), 0.76 (ddd, J = 9.0, 4.6, 4.6 Hz, 1 H), 1.35-1.26 (m, 1 H), 1.79 (ddd, J = 7.1, 4.2, 3.0 Hz, 1 H), 3.60 (d, J = 13.5 Hz, 2 H), 3.70 (d, J = 13.5 Hz, 2 H), 4.83-4.76 (m, 2 H), 5.33 (ddd, J = 17.0, 10.3, 8.5 Hz, 1H), 7.34-7.20 (m, 10H); 13
C NMR (75 MHz, CDCl3
) 15.9, 25.5, 45.1, 58.2, 112.2, 126.8, 128.0, 129.4, 138.4, 139.6; IR cm−1
: 3062, 3027, 2921, 2809, 1635, 1493, 1453, 1364. cis
H NMR pdf
(300 MHz, CDCl3
) δ 0.45 (ddd, J = 4.8, 4.8, 4.8 Hz, 1 H), 0.87 (ddd, J = 8.6, 6.8, 4.9 Hz, 1 H), 1.57-1.51 (m, 1 H), 2.06 (ddd, J = 6.8, 6.8, 4.6 Hz, 1H), 7.34-7.22 (m, 10 H), 3.51 (d, J = 13.7 Hz, 2 H), 3.74 (d, J = 13.7 Hz, 2 H), 4.97 (dd, J = 10.3, 2.0 Hz, 1 H), 5.14 (dd, J = 17.3, 2.0 Hz, 1 H), 5.88 (ddd, J = 17.3, 10.3, 9.5 Hz, 1 H); 13
C NMR (75 MHz, CDCl3
) 15.6, 23.3, 42.4, 57.2, 113.60, 126.8, 128.0, 129.5, 138.3, 138.4; IR cm−1
: 3062, 3026, 2922, 2807, 1634, 1493, 1453, 1364.
The transformation of N,N
-dialkylcarboxamides with low valent titanium compounds formed in situ from Grignard reagents and titanium alkoxides of the type XTi(Oi
(X = Oi
Pr, Cl, Me) to correspondingly substituted N,N
-dialkylcyclopropylamines has been thoroughly examined in recent years since it was first discovered.3
Related to the conversion of esters to cyclopropanols,5
this new and reasonably general access to this important class of compounds4
is now easily carried out and generally furnishes high yields.6
For example, unsubstituted N,N
-dialkylcyclopropylamines are obtained from N,N
-dialkylformamides and ethylmagnesium bromide
following this protocol in up to 98% yield.
A wide range of alkenyl-, aryl-, alkyl-, and dialkyl-substituted cyclopropylamines can be made by reaction of an N,N
-dialkylformamide (or higher N,N
-dialkylcarboxamide) with cyclohexylmagnesium halide in the presence of methyltitanium triisopropoxide
(or titanium tetraisopropoxide
) and a 1,3-diene, a styrene, a terminal or an internal alkene following this protocol with some minor modifications.9
In these cases the reacting low valent titanium intermediate is generated by ligand exchange,10
and the overall transformation corresponds to an aminocyclopropanation of the added alkene. For example, a solution of N-Boc-protected pyrroline (4.36 g, 25.8 mmol)
and Ti(OiPr)4 (9.06 mL, 30.9 mmol)
in THF (100 mL)
is treated with MeMgCl (10.3 mL of a 3M solution in THF, 30.9 mmol, added within 10 min)
at 0°C and the mixture is warmed to ambient temperature. N,N-Dibenzylformamide (6.95 g, 30.9 mmol)
is added in one portion, then dropwise with stirring a solution of cyclohexylmagnesium bromide (28.1 mL of a 2.2M solution in diethyl ether, 61.9 mmol)
within 2 hr. The mixture is heated under reflux for an additional 1 hr, then cooled to ambient temperature. Addition of 100 mL of water and 100 mL of pentane
, filtration and further workup with filtration through a pad of 10 g of basic aluminum oxide
and subsequent crystallization from pentane
yields 8.75 g
) of crystalline N-Boc-protected exo-6-N,N-dibenzylamino-3-azabicyclo[3.1.0]hexane
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