filtration with DABCO HCl salt as a 1:1 mixture (10) in
3
quantitative yield.5 A number of multi-kilogram scale batches
of 10 were prepared according to this procedure. Reagent 10
has been kept at ambient temperatures (20ꢀ23 °C) up to one
year without detectable decomposition by NMR or loss of
reactivity when used in test reactions.
Figure 1. MLN4924.
Scheme 1. Preparation of Sulfamoylation Reagent 10
As part of our effort to improve the synthesis of
MLN4924 (Figure 1), an investigational small molecule
inhibitor of Nedd-8 activating enzyme currently in phase I
clinical trials, novel sulfamoylating reagents were investi-
gated.5 The key properties of a desirable reagent were
defined to include solid-state stability, safety, and reactivity.
Selectivity for 1° vs 2° in a diol system was also con-
sidered. The approach to the process friendly sulfamoyla-
tion reagent wasbasedon Burgess-type reagent 2 (Figure 2)
reported by Winum.3a A derivative of the original Burgess
reagent 3,6bꢀg 2 reacts with various amines and anilines to
afford sulfamides at rt. However, 2 is not reactive toward
alcohols. Structural modification of 2 led to the develop-
ment of Burgess-type reagent 1, an ambient temperature
stable solid, suitable for large scale selective sulfamoylation
of a 1,3 diol intermediate in the synthesis of MLN4924.5b
This paper describes the general reactivity and utility of the
novel sulfamoylating reagent 1 toward various alcohols.
In order to establish an optimal protocol for screening
the reactivity of 10 with various alcohols, the reaction of 10
with 3-hydroxypropylbenzene (7a) was investigated under
various conditions (Table 1). The rate of conversion from
7a to 7b was evaluated as a function of solvent, amounts
of 10, and acid catalyst added.
Since Burgess-type reagents are known to be unstable in
solution,7 a group of minimally nucleophilic solvents were
selected and the sulfamoylation reaction was run at ambi-
ent temperature with 2.0 equiv of 10. Low reaction rates
were observed for a number of common solvents, such as
MTBE, 1,4-dioxane, and THF, due to the poor solubility
of reagent 10 (Table 1, entries 1ꢀ3). Among the solvents
showing promising reaction rates, sulfolane and NMP
gave the slowest conversions (Table 1, entries 4 and 5).
The reaction was much faster in MeCN (Table 1, entry 6).
A combination of MeCN and NMP showed no improve-
ment compared with using MeCN alone (Table 1, entry 7).
The best conversion rate was observed when DCM was
used as the reaction solvent (Table 1, entry 8). However,
DCM was not selected as the standard solvent in this study
because of its environmental concerns.8 All the solvents
tested failed to provide a complete conversion of 7a to 7b
with 2.0 equiv of 10. In most of the solvents, the reaction
stalled after 17 h at 70ꢀ80% conversion. Increasing the
initial amount of 10 to 4.0 equiv showed minimal impact
(Table 1, entry 9) presumably due to the solution stability
issue combined with poor solubility of 1. Subsequent addi-
tion of more reagent 10, however, successfully drove the
reaction to completion (Table 1, entry 10). It was later
discovered that this reaction could also be accelerated
with a small amount of anhydrous HCl (Table 1, entries
11 and 12). This result was likely due to protonation of
the nitrogen anion in reagent 1to provide a quaternary salt 100
(Scheme 2) which should be more reactive toward nucleophiles.
Figure 2. Previous Burgess-type reagents.
Similar to the preparation of 2,6e an optimized proce-
dure to make reagent 1 was developed with an efficient iso-
lation process. Chlorosulfonylisocyanate (4) and tert-butyl
alcohol (5) react together in toluene to give N-(tert-
butoxycarbonyl)sulfamoyl chloride (6), which reacts
further with 2.0 equiv of 1,4-diazabicyclo[2.2.2]octane
(DABCO) to afford the desired sulfamoylation reagent 1
plus an equiv of DABCO HCl salt (Scheme 1). Due to the
rapid decomposition of 1 in water, the product is collected by
3
(5) (a) Armitage, I.; Elliott, E. L.; Langston, M.; Langston, S. P.;
McCubbin, Q. J.; Mizutani, H.; Stirling, M.; Zhu, L. Process for the
synthesis of 4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl) cy-
clopentanol derivatives as E1 activating enzyme inhibitors. U.S. Patent
Application US2009/0036678, Feb 5, 2009. (b) Manuscript for the develop-
ment of sulfamoylating reagents is under preparation.
(6) (a) Winum, J. Y.; Toupet, L.; Barragan, V.; Dewynter, G.; Montero,
J. L. Org. Lett. 2001, 3, 2241–2243. (b) Atkins, G. M.; Burgess, E. M. J. Am.
Chem. Soc. 1968, 90, 4744–4745. (c) Burgess, E. M.; Penton, H. R.; Taylor,
E. A. J. Org. Chem. 1973, 38, 26–31. (d) Wood, R. W.; Kim, J. Y.; Books,
K. M. Tetrahedron Lett. 2002, 43, 3887–3890. (e) Nicolaou, K. C.; Snyder,
S. A.; Huang, X. Synthesis of sulfamidates. WO Pat. 03/066549 A2. (f)
Masui, Y.; Watanabe, H.; Masui, T. Tetrahedron Lett. 2004, 45, 1853–1856.
(g) Borghese, A.; Antoine, L.; Van Hoeck, J. P.; Mockel, A.; Merschaert, A.
Org. Process Res. Dev. 2006, 10, 770–775.
(7) Okada, M.; Iwashita, S.; Koizumi, N. Tetrahedron Lett. 2000, 41,
7047–7051.
(8) Quantification of toxicological effects for dichloromethane. Re-
port Order No. PB92-173335 (1992) United States Environmental Protec-
tion Agency, Off. Assist Adm. Water, Washington, DC, USA.
B
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