SHORT PAPER
An Improved Synthesis of N-Isocyanoiminotriphenylphosphorane
21
Hydrazidoyl Chloride 7
References
To a 500 mL 3-neck round bottom flask with mechanical stirrer was
added 6 (18.27 g, 33.5mmol) as a solution in 1,2-dichloroethane
(DCE; 183 mL). The solution was treated with of N,N-dimethyl-
formamide (500 mL) followed by oxalyl chloride (4.42 mL, 50.3
mmol) added via addition funnel over 5 min (Caution! Gas evolu-
tion). After 40 min the reaction was determined to be complete16
and the solution of acid chloride was concentrated in vacuo at 40 °C,
with simultaneous addition of DCE (360 mL), to 135 mL.17 The so-
lution of acid chloride was transferred to an addition funnel and
added drop-wise over 10 min to isonitrile 1 (15.2 g, 50.3 mmol) sus-
pended in DCE (80 mL). After 2 h, distilled water (36 mL) was add-
ed and the reaction stirred overnight. The mixture was transferred to
a separatory funnel and the phases were separated. The organic
phase was dried over MgSO4, filtered and concentrated to an oil.
HPLC assay showed hydrazidoyl chloride (18.4 g, 91%). The crude
oil can be used directly in the next step or chromatographed on silica
gel using toluene–EtOAc (95:5) as eluent. An analytical standard
was produced by crystallizing the chromatographed foam from 2-
PrOH; mp 36–137 °C.
(1) Arndt, F.; Eistert, B. Chem. Ber. 1935, 68, 200.
(2) (a) Aoyama, T.; Shioiro, T. Tetrahedron Lett. 1980, 21,
4461. (b) Aoyama, T.; Shioiro, T. Chem. Pharm. Bull. 1981,
29, 3249.
(3) Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6,
884; and references therein.
(4) Aller, E.; Molina, P.; Lorenzo, Á. Synlett 2000, 526.
(5) It should be noted that diazoketones themselves are often
unstable compounds, thus great care should be taken
whenever diazoketones or diazoalkanes are being formed.
(6) A further advantage of Aller’s procedure is that the isolation
of pure diazoketones from reaction is often simpler than
from reactions using TMSCHN2 or CH2N2. Diazoketones
formed from both diazo reagents invariably are
contaminated with a-chloroketones and, in the case of
TMSCHN2, the a-TMS ketone, both of which are difficult to
remove because they usually impart a polarity similar to that
of the diazoketone functionality. Using 1 to form
diazoketones gives none of these difficult to remove
impurities. In our experience in using 1, the overall yield of
diazoketone from acid is consistently higher than when
TMSCHN2 or CH2N2 is used.
(7) (a) Aller and co-workers reference the following paper for
the synthesis of 1: Weinberger, B.; Fehlhammer, W. P.
Chem. Ber. 1985, 118, 42. (b) To the best of our knowledge
no other syntheses of 1 have been reported.
(8) Appel has studied the reaction of tertiary phosphoranes and
CCl4 in detail and notes the acceleration of the reaction in
MeCN specifically: Appel, R. Angew. Chem., Int. Ed. Engl.
1975, 14, 801.
(9) Compound 1 showed no degradation by HPLC analysis after
more than 3 d in MeCN–H2O (1:1) or in MeCN–0.01%
K2HPO3 (1:1) aqueous solution.
(10) The addition of more water anti-solvent led to high isolated
yield but lower quality material.
(11) The synthesis of 6 will be published at a later date.
(12) A cursory cost calculation based on quotes obtained for bulk
quantities of formic hydrazide, PPh3, CCl4 and DBU give a
raw material cost of $0.54/gram N-isocyanotriphenyl-
iminophosphorane.
IR (CHCl3): 3446, 3306, 3214, 2985, 1728, 1558, 1371, 1324, 1165,
749 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.80 (d, JHF = 32.9 Hz, 1 H), 6.71
(s, 2 H), 4.35–4.26 (m, 4 H), 4.15 (d, J = 17.8 Hz, 1 H), 4.06 (d, J =
17.8 Hz, 1 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.29 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 185.9, 167.7, 162.9, 159.9 (d,
JCF = 35 Hz), 147.8 (d, JCF = 264 Hz), 140.8, 130.2, 127.1, 126.4,
116.4, 63.7, 62.6, 61.9, 41.3, 14.3, 14.0.
19F NMR (400 MHz, CDCl3): d = –132.2.
Diazoketone 8 Method A (Aller’s Conditions)
A solution of hydrazidoyl chloride (0.97 g, 1.60 mmol) in CH2Cl2
(10 mL) was treated with p-toluenesulfonyl chloride (0.09 g,
0.45mmol) and then with Et3N (0.332 mL, 2.4 mmol). The reaction
was stirred under N2 overnight. HPLC assay showed diazoketone
(0.26 g, 0.61 mmol, 29% yield) and unreacted hydrazidoyl chloride
(0.49 g, 0.81 mmol, 51%).
Diazoketone 8 Method B
To a solution of a-ketohydrazidoyl chloride 7 (18.38 g, 30.35
mmol) in CH2Cl2 (100 mL), anhyd ZnBr2 (1.4 g, 6.1 mmol, 20
mol%) was added, followed by diisopropylamine (5.5 mL, 39.5
mmol, 1.3 equiv). A mild exotherm ensued causing the reaction to
heat from 23°C to 29 °C. Thirty-five min after the addition of base,
TLC with toluene–EtOAc (4:1) showed the reaction to be complete.
The reaction was washed with an aq 1% ethylenediamine tetraacetic
acid tetrasodium salt (EDTA–Na; 50 mL) solution. The organic
phase was dried with MgSO4 and concentrated. Flash chromatogra-
phy on silica gel eluting with toluene–EtOAc (9:1) gave diazoke-
tone 8 as a crystalline solid (12.4 g, 28.8 mmol, 95% yield). The
diazoketone could be recrystallized from 10 volumes of methyl
t-butyl ether–heptane (1:1) to obtain analytical samples; mp 119–
120 °C.
(13) For a review see: Ye, T.; McKervey, A. Chem. Rev. 1994,
94, 1091.
(14) Aside from the papers mentioned in ref.,4,6 we have found
only a single additional mention of this compound in the
literature: Zinner, G.; Beck, G.; Fehlhammer, W. P.;
Wilberg, N. J. Organomet. Chem. 1989, 368, 23.
(15) Adding seed to the reaction is necessary only if no
crystalline material has precipitated upon cooling to 35 °C.
The initial seed may be obtained by removing a few
millilitres of the reaction solution and cooling it to r.t.
(16) After 40 min the reaction was complete by HPLC assay; a
reaction sample quenched into MeOH show ca 99%
conversion to the methyl ester.
IR (CHCl3): 3106, 2985, 2108, 1728, 1637, 1371, 1323 cm–1.
(17) Concentration and flush with fresh DCE removes excess
oxalyl chloride.
1H NMR (400 MHz, CDCl3): d = 6.84 (d, JHF = 33.4 Hz, 1 H), 5.43
(br s, 1 H), 4.35–4.28 (m, 4 H), 3.58 (d, J = 15.6 Hz, 1 H), 3.42 (d,
J = 15.6 Hz, 1 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): 189.5, 167.2, 162.9, 159.8 (d, JCF
=
35 Hz), 147.7 (d, JCF = 265 Hz), 140.2, 130.1, 127.1, 115.9, 63.5,
62.6, 62.3, 56.7, 42.8, 14.2, 14.0.
19F NMR (400 MHz, CDCl3): d = –123.1.
Synthesis 2005, No. 1, 19–21 © Thieme Stuttgart · New York