Organic Letters
Letter
Scheme 2. Synthesis of N-Methoxy-N-
methylcyanoformamide (4)
Table 1. Screening of N-Methoxy-N-methylcarbamoyl
Reagents 3, 4, and 7 with Lithium Enolates
1
2
Padiya’s “In Water” imidazole carbonylation procedure
(
Scheme 2, pathway b), thus generating the required urea
conveniently, rapidly, and in high yield.
The synthesis of 4 from 7 required a cyanide source, and the
restrictions imposed on access to inorganic cyanides
encouraged the use of readily available trimethylsilyl cyanide
(
TMSCN). A number of conditions were screened for the
condensation of 7 with TMSCN in various solvents, but
excellent yields were only obtained using a “green”, anhydrous,
solvent-free mixture. This reaction is amenable to scale-up and
can be performed with only 1.05 equiv of TMSCN at 18 °C for
a
Reaction conditions: 8 (1.0 mmol), LiHMDS (1.1 mmol), THF, −78
b
°C, 1 h, then 3 or 7 (1.1 mmol), −78 °C → 18 °C, 20 h. Reaction
conditions: 8 (1.0 mmol), LiHMDS (1.1 mmol), THF, −78 °C, 1 h,
then 4 (1.1 mmol), −78 °C, 0.25 h.
1
8 h or similarly for 10 min at 100 °C in 93% yield. Efforts to
isolate 4 directly from the reaction flask by fractional distillation
were unfortunately hampered by contamination of 1-
trimethylsilylimidazole, which shares a similar boiling point.
To avoid this issue, the reaction was quenched with an aqueous
workup prior to isolation. N-Methoxy-N-methylcyanoforma-
mide is a colorless oil after distillation (bp 81−84 °C, 19
mmHg) and should be stored under an inert atmosphere.
While we did not notice appreciable degeneration of the
reagent after storage in a Schlenk flask under inert, anhydrous
conditions for 2 months at room temperature, we recommend
storage below 0 °C. Care must be taken to avoid exposure to 4,
especially via inhalation and skin contact, and it should be
treated as highly toxic, as the reagent decomposes slowly in
efficient reactions to afford the product β-carbonylamides in
excellent yields at low temperature. Surprisingly, the major
product derived from the reaction of 4 with cyclohexanone, 9j,
was initially found to be the cyanohydrin−product adduct.
However, it was discovered that the cyanohydrin could be easily
transformed directly into the required β-keto Weinreb amide
simply by quenching the reaction with aqueous NaOH and
stirring at room temperature for 1 h. Unfortunately, under our
standard conditions the quaternary products 9l and 9m were
not observed. In the case of 9l, deprotonation at 0 °C and
addition of 4 at −78 °C allowed efficient product formation.
Under our standard conditions, 9m was not observed, but
instead, only the O-carbamoylated product was isolated.
Extended reaction times at higher temperatures (−40 to 18
°C) resulted in complex reaction mixtures. To alleviate this
problem, the reaction was conducted in diethyl ether with the
addition of HMPA, which provided good yields of the
quaternary product 9m. The less toxic additive DMPU gave
similar results.
13
water/moist air, presumably to liberate HCN, CO , and N,O-
2
dimethylhydroxylamine, the last of which can react slowly with
14
4
to form the symmetrical urea 1.
With an efficient synthesis of 4 in hand, we initiated a
comparison study of this reagent with the recently reported N-
5
methoxy-N-methylcarbamoylpyrrole (3) and imidazole re-
agent 7 in regard to their ability to react with lithium enolates
to directly synthesize β-keto Weinreb amides (Table 1). All of
the carbamoylating reagents were successful in converting 6-
methoxy-1-tetralone to 9a (entry 1), but the reactions involving
reagents 3 and 7 both required extended reaction times and
warming to room temperature. In contrast, reactions with 4
were complete within 15 min at −78 °C. In the case of
hindered ketones (entries 2 and 3) only cyanoformamide 4
efficiently formed the product Weinreb amides (9b and 9c) in
We next investigated the ability of 4 to act as a general means
to install the Weinreb amide functionality through reaction with
various organometallic species. Lithiated species (Table 2,
entries 1−3) were highly reactive toward 4 and selective for the
single one-carbon-homologated Weinreb amide addition
products (10a−c). No reaction of 4 with Grignard reagents
was observed at −78 °C in THF; however, when the reaction
was conducted at 0 °C and with 1 equiv of nucleophile, only
the single-addition products (10a, 10d, and 10e) were observed
1
5
high yields.
5
We next turned to an investigation of the substrate scope of
cyanoformamide 4 for the formation of β-carbonyl Weinreb
amides. We subjected the reagent to a variety of lithium
enolates (Scheme 3) and discovered that enones (8c−f), aryl
ketones and lactones (8a, 8g, 8h, 8i, and 8l), and saturated
cyclic and aliphatic ketones (8j and 8k) were all suitable
(entries 4−6). Surprisingly, and in contrast with reagent 3, the
2
reaction of sp -hybridized Grignard reagents with reagent 4
allowed the selective formation of the monoaddition products
(10d and 10e).
We predicted that 4 could act as a carbonyl dication
3a,5
synthon in the one-pot formation of unsymmetrical ketones,
1
6
substrates. These compounds all underwent clean and
hence, we subjected 4 to various organometallics in a sequential
B
Org. Lett. XXXX, XXX, XXX−XXX