Synthesis of differentially substituted 1,2-diamines through advances in C-H amination technology

Article abstract of DOI:10.1021/ol302895f

A general, high yielding method for the synthesis of 1,2-diamine derivatives is described that capitalizes on selective, rhodium-catalyzed C-H insertion of hydroxylamine-based sulfamate esters. The resulting Troc-protected oxathiadiazinane heterocycles are easily modified and can be reduced under the mild action of NaI to afford differentially substituted diamine products. This technology offers a number of salient improvements over related C-H and π-bond amination tactics for diamine synthesis.

Full text of DOI:10.1021/ol302895f

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6174–6177
Synthesis of Differentially Substituted
1,2-Diamines through Advances in CꢀH
Amination Technology
David E. Olson, D. Allen Roberts, and J. Du Bois*
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
jdubois@stanford.edu
Received October 19, 2012
ABSTRACT
A general, high yielding method for the synthesis of 1,2-diamine derivatives is described that capitalizes on selective, rhodium-catalyzed CꢀH
insertion of hydroxylamine-based sulfamate esters. The resulting Troc-protected oxathiadiazinane heterocycles are easily modified and can be
reduced under the mild action of NaI to afford differentially substituted diamine products. This technology offers a number of salient
improvements over related CꢀH and π-bond amination tactics for diamine synthesis.
Vicinal diamines, particularly those with non-equivalent
nitrogen substitution, appear as ubiquitous structural
elements in designed molecules and natural products
(Figure 1).1 Such compounds enjoy far-ranging applica-
tion in areas that include materials science,2 catalysis and
coordination chemistry,3 and medicinal chemistry.4 The
lack of convenient methods for the preparation of 1,2-diamine
derivatives, however, remains a problem in synthesis,5
complicated by an unavoidable reliance on serial functional
group interconversion. The application of CꢀH amination
technology for 1,2-diamine assembly can, in principle,
streamline access to such structures.6,7 Our efforts to
delineate a general solution for preparing differentially
substituted 1,2-diamines have led to the identification of a
novel family of N-protected hydroxylamine sulfamates
that react under the action of a dirhodium catalyst to give
(1) For examples of differentially substituted diamines, see: (a)
Sakai, R.; Oiwa, C.; Takaishi, K.; Kamiya, H.; Tagawa, M. Tetrahedron
Lett. 1999, 40, 6941–6944. (b) Roszkowski, P.; Maurin, J.; Czarnocki, Z.
Tetrahedron: Asymmetry 2006, 17, 1415–1419. (c) Garah, F. B. E.;
ꢀ
Stigliani, J. L.; Cosledan, F.; Meunier, B.; Robert, A. ChemMedChem
2009, 4, 1469–1479. (d) Qiao, J. X. J.; Chang, C. H. C.; Cheney, D. L. D.;
Morin, P. E. P.; Wang, G. Z. G.; King, S. R. S.; Wang, T. C. T.; Rendina,
A. R. A.; Luettgen, J. M. J.; Knabb, R. M. R.; Wexler, R. R. R.; Lam, P.
Y. S. P. Bioorg. Med. Chem. Lett. 2007, 17, 4419–4427. (e) El-Latif,
N. A. A.; Abdulla, M. M.; Amr, A. E.-G. E. Acta Pharm. 2008, 58, 43–
59. (f) Brouillette, W. J.; Bajpai, S. N.; Ali, S. M.; Velu, S. E.; Atigadda,
V. R.; Lommer, B. S.; Finley, J. B.; Luo, M.; Air, G. M. Bioorg. Med.
Chem. 2003, 11, 2739–2749.
(2) For select examples of diamines used in materials science, see: (a)
Lee, L. H.; Chen, W. C. Polymer 2005, 46, 2163–2174. (b) Li, X. G.;
Huang, M. R.; Duan, W.; Yang, Y. L. Chem. Rev. 2002, 102, 2925–3030.
(c) Cheng, L.; Jian, X. G.; Mao, S. Z. J. Polym. Sci. 2002, 40, 3489–3496.
(3) For select examples of diamines used in asymmetric synthesis, see:
(a) De Parrodi, C. A.; Juaristi, E. Synlett 2006, 17, 2699–2715. (b)
Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1998, 39, 167–170. (c)
Cimarelli, C.; Fratoni, D.; Palmieri, G. Tetrahedron: Asymmetry 2009,
20, 2234–2239. (d) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008,
130, 17666–17667. (e) Kizirian, J. C. Chem. Rev. 2008, 108, 140–205.
(4) For select examples of medicinally relevant dimine-derived struc-
tures, see: (a) Michalson, E. T. E.; Szmuszkovicz, J. J. Prog. Drug Res.
1989, 33, 135–149. (b) DeMong, D. E.; Williams, R. M. J. Am. Chem.
Soc. 2003, 125, 8561–8565. (c) Rane, D. F.; Girijavallabhan, V. M.;
Ganguly, A. K.; Pike, R. E.; Saksena, A. K.; McPhail, A. T. Tetrahedron
Lett. 1993, 34, 3201–3204. (d) Costello, G. F. G.; Main, B. G. B.; Barlow,
J. J. J.; Carroll, J. A. J.; Shaw, J. S. J. Eur. J. Pharmacol. 1988, 151, 475–
478. (e) Day, T. A. T.; Bennett, J. L. J.; Pax, R. A. R. Parasitol. Today
1992, 8, 342–344.
(5) For synthetic approaches toward 1,2-diamines, see: (a) Lucet, D.;
Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–2627.
(b) Kotti, S. R. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67,
101–114. (c) De Figueiredo, R. Angew. Chem., Int. Ed. 2009, 48, 1190–
~
1193. (d) Savoia, D. Top. Organomet. Chem. 2005, 15, 1–58. (e) Muniz,
K. New J. Chem. 2005, 29, 1371–1385. (f) Westermann, B. Angew.
Chem., Int. Ed. 2003, 42, 151–153. (g) Mortensen, M. S.; O’Doherty,
G. A. Chemtracts: Org. Chem. 2005, 18, 555–561. (h) Du, H.; Yuan, W.;
Zhao, B. J. Am. Chem. Soc. 2007, 129, 11688–11689. (i) Yuan, W.; Du,
H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589–2591. (j) Chong, A. O.;
Oshima, K.; Sharpless, K. J. Am. Chem. Soc. 1977, 99, 3420–3426. (k)
Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269–275. (l) Zhao, B.; Peng,
X.; Zhu, Y.; Ramirez, T. A.; Cornwall, R. G.; Shi, Y. J. Am. Chem. Soc.
ꢀ
~
2011, 133, 20890–20900. (m) Chavez, P.; Kirsch, J.; Streuff, J.; Muniz, K.
J. Org. Chem. 2012, 77, 1922–1930.
r
10.1021/ol302895f
Published on Web 12/10/2012
2012 American Chemical Society

[1,2,3,6]-oxathiadiazinane-2,2-dioxide heterocycles.8 Herein,
we describe the synthesis and unique properties of N-Troc-
derived oxathiadiazinanes as masked 1,2-diamine equiva-
lents. This chemistry offers a general method for vicinal
diamine preparation in a minimal number of steps from
simple alcohol starting materials.
could be easily modified and cleaved to give the desired vic-
diamines. Hydroxylamine-based sulfamate esters appear
to satisfy both of these requirements (Figure 2).10
Figure 2. Access to differentially substituted vicinal diamine
products is facilitated through directed CꢀH amination to form
oxathiadiazinane heterocycles. Tces = 2,2,2-trichloroethoxy-
sulfonyl; Troc = 2,2,2-trichloroethoxycarbonyl.
Figure 1. 1,2-Diamine derivatives as a recurring structural motif
in biologically active, naturally occurring and designed mole-
cules.
Reagents of the general form RNHSO2NH2 in which R
is either a sulfonyl or carbamoyl group are accessible in
multigram quantities from hydroxylamine hydrochloride.
These sulfamate derivatives react with 1° and 2° alcohols
under Mitsunobu conditions to give substrates suitable for
CꢀH amination. The choice of R group influences the
performance of RNHSO2NH2 in the displacement reac-
tion, as evidenced in Table 1. Treatment of cyclohexyl-
methanol with either MbsNHOSO2NH2 or TrocNHOSO2-
NH2 leads efficiently (>85%) to the respective sulfamate
derivatives. By contrast, use of the analogous N-Boc
reagent results in a decreased yield of 1 due to competing
formation of the regioisomeric N-alkylated material (2:1
mixture of N- and N0-products). It appears that a large
differential acidity between the NH protons in these
sulfamate nucleophiles is necessary for optimal perfor-
mance in the Mitsunobu process.
For substrates such as 1, we have found that the effici-
ency of the Rh-catalyzed CꢀH insertion reaction is depen-
dent on the choice of hydroxylamine protecting group
(Table 1). Tertiary and benzylic substrates derived from
MbsNHSO2NH2 can be oxidized with 2 mol % Rh2(esp)2
and PhI(OAc)2 in modest to high yields. These starting
materials show a strong bias toward six-membered ring
formation, as noted with other sulfamate derivatives.10,11
Analogous N-Boc structures perform poorly, generally
giving products in low to modest yields and returning
variable amounts of unreacted starting material. Attempts
tooptimizeCꢀH amination withthe N-Bocsubstrate class
by changing solvent conditions, catalyst, and reaction
temperature have met with limited success.
In considering the potential utility of CꢀH amination
for the preparation of substituted 1,2-diamine products,
our earliest efforts focused on the development of intra-
molecular oxidative cyclization of urea substrates.9 Such
compounds were found to engage in dirhodium-mediated
amination to afford imidazolin-2-one heterocycles. The
stability of these products toward hydrolysis, coupled with
the somewhat restricted substrate range of the CꢀH
amination process, prompted subsequent investigations
to identify alternative nitrogen sources that would (1)
engage in CꢀH amination reactions with functionally rich
starting materials and (2) afford heterocyclic products that
(6) For recent reviews on CꢀH amination, see: (a) Davies, H. M. L.;
Manning, J. R. Nature 2008, 451, 417–424. (b) Dıaz-Requejo, M. M.;
´
ꢀ
Perez, P. J. Chem. Rev. 2008, 108, 3379–3394. (c) Fantauzzi, S.; Caselli,
A.; Gallo, E. Dalton Trans. 2009, 5434–5443. (d) Collet, F.; Dodd, R.;
Dauban, P. Chem. Commun. 2009, 5061–5074. (e) Zalatan, D. N.; Du
Bois, J. Top. Curr. Chem. 2010, 292, 347–378. (f) Li, Z.; Capretto, D.; He,
C. Silver-Catalysed Nitrene Transfer Reactions. In Silver in Organic
Chemistry; Harmata, M., Ed.; Wiley: New York, 2010; pp 167ꢀ182. (g)
Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926–36.
(7) For select reports on CꢀH amination, see: (a) Espino, C. G.;
Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378–
15379. (b) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639–642. (c) Stokes,
B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am.
Chem. Soc. 2007, 129, 7500–7501. (d) Li, Z.; Capretto, D. A.; Rahaman,
R.; He, C. Angew. Chem., Int. Ed. 2007, 46, 5184–5186. (e) Milczek, E.;
Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825–6828. (f)
Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48,
2777–2779. (g) King, E.; Betley, T. Inorg. Chem. 2009, 48, 2361–2363.
€
(h) Norder, A.; Herrmann, P.; Herdtweck, E.; Bach, T. Org. Lett. 2010,
12, 3690–3692. (i) Lu, H.; Tao, J.; Jones, J. E.; Wojtas, L.; Zhang, X. P.
Org. Lett. 2010, 12, 1248–1251. (j) Wiese, S.; Badiei, Y. M.; Gephart,
R. T.; Mossin, S.; Varonka, M. S.; Melzer, M. M.; Meyer, K.; Cundari,
T. R.; Warren, T. H. Angew. Chem., Int. Ed. 2010, 49, 8850–8855. (k)
ꢀ
Lyaskovskyy, V.; Suarez, A. I. O.; Lu, H.; Jiang, H.; Zhang, X. P.; de
N-Troc-protected hydroxylamine sulfamates can be
oxidized efficiently in the presence of a dirhodium catalyst
and PhI(OAc)2 tofurnish oxathiadiazinanesacross a range
of different structural types (Table 2). Oxidative cyclization
Bruin, B. J. Am. Chem. Soc. 2011, 133, 12264–12273. (l) Harvey, M. E.;
Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc. 2011, 133, 17216. (m) Q.
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 133,
2547–2550 and references therein.
(8) We refer to these compounds as oxathiadiazinanes for conve-
nience. We are aware of only one report of such compounds prior to our
studies; see: Arfaei, A.; Smith, S. J. J. Chem. Soc., Perkin Trans. 1 1984,
1791–1794.
(10) Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248–
11249.
(11) Rh2(esp)2 = Rh2(R,R,R0R0-tetramethyl-1,3-benzenedipropionate)2
and is commercially available from Aldrich.
(9) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073–1076.
Org. Lett., Vol. 14, No. 24, 2012
6175

Table 1. Evaluating N-Activating Groups for Both Mitsunobu
Coupling and CꢀH Amination Reactions
Table 2. Oxidative Cyclization of N-Troc Hydroxylamine-
Derived Sulfamate Esters
entrya
R group
yield 1
solvent
conversion 2b
1
2
3
4
Mbs
Boc
Boc
Troc
97
52
ꢀ
PhH
100 (99)
29 (ꢀ)
PhH
iPrOAc
iPrOAc
76 (ꢀ)
88
100 (88)
a Amination reactions were performed with 2 mol % Rh2(esp)2, 1.1
equiv of PhI(OAc)2, and 2.3 equiv of MgO. b Product conversion
estimated by H NMR integration of the unpurified reaction mixture.
1
Values in parentheses represent isolated product yields following chro-
matography on silica gel.
of substrates possessing 3°, benzylic, ethereal, and 2° CꢀH
centers matches or exceeds the performance of the analo-
gous Mbs-derivatives.12 Additionally, the Troc hetero-
cycles may be purified using standard chromatographic
or crystallization techniques and are stable to subsequent
manipulations (vide infra). Mbs-substituted oxathiadia-
zinanes are prone to unusual base-mediated fragmenta-
tion reactions, which can complicate purification, reduce
isolated product yields, and prevent any modification of
the heterocycle except for reductive ring opening.13 N-Troc
oxathiadiazinanes suffer none of these liabilities.
The potential utility of our diamination method is
perhaps best illustrated with the cyclopentyl-derived sulfa-
mate depicted in entry 2 (Table 2). CꢀH amination reac-
tions of carbamates and ureas derived from 2° cyclo-
alkanols generally fail to give even trace product.14 The
cyclopentyl sulfamate, however, affords the desired inser-
tion product as a crystalline solid in 75% yield, a com-
pound that can be readily processed to the corresponding
diamine (see Figure 4). This particular insertion reaction
has been performed on >1 g scale with no dimunition in
yield. Similarly, we have prepared a related diamine deri-
vative from 2-indanol (entry 3). In this example, the analo-
gous Mbs-substituted oxathiadiazinane could not be iso-
lated due to its intrinsic instability.
a Reactions were performed in iPrOAc using 2 mol % Rh2(esp)2, 1.1
equiv of PhI(OAc)2, and 2.3 equiv of MgO. b Isolated yield of product
following chromatography on silica gel, except where noted. c Product
isolated by filtration of the reaction mixture; see Supporting Informa-
tion for details. d Value represents product conversion based on 1H
NMR integration of the unpurified reaction mixture.
The oxidation of unfunctionalized 2° methylene centers
in acyclic substrates is often complicated by poor catalyst
turnover numbers and low isolated product yields. This
point is exemplified with the n-butyl-derived substrate
shown in entry 7. Mechanistic evidence for related sulfa-
mate oxidation reactions suggests that insertion proceeds
through a concerted asynchronous transition state.15 In
principle, judicious placement of a silyl substituent one
carbon removed from this center could impact the overall
efficiency of the amination process by stabilizing charge
polarization in the transition structure. This effect has been
(12) In general, Rh-catalyzed oxidations of Troc-protected sub-
strates are quite efficient. The product oxathiadiazinanes, however,
are typically isolated in slightly lower yields than would be expected
from 1H NMR analysis of the unpurified reaction mixtures, a result that
may stem from problems of solubility of these crystalline materials. In
some cases, isolation of the pure crystalline product can be accomplished
without recourse to chromatography. Details are provided in the
Supporting Information.
(13) (a) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du
Bois, J. J. Am. Chem. Soc. 2009, 131, 4190–4191. (b) Olson, D. E.;
Maruniak, A.; Malhotra, S.; Trost, B. M.; Du Bois, J. Org. Lett. 2011,
13, 3336–3339.
(15) (a) Lin, X.; Zhao, C.; Che, C.; Ke, Z.; Phillips, D. L. Chem.;
Asian J. 2007, 2, 1101–1108. (b) Huard, K.; Lebel, H. Chem.;Eur. J.
2008, 14, 6222–6230. (c) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du
Bois, J. Tetrahedron 2009, 65, 3042–3051.
(14) Espino, C. G.; , Ph.D. Thesis, Stanford University, July 2004.
6176
Org. Lett., Vol. 14, No. 24, 2012

competitive deprotection of the Troc-group, however, can
sometimes interfere with the application of this method.
This problem is completely avoided by utilizing NaI as a
reducing agent (Figure 4). Under these conditions, the
mixture of N-Troc oxathiadiazinane and Iꢀ turns red,
presumably due to the formation of I2. This change in
solution color provides a convenient indicator of reac-
tion progress. The reaction of oxathiadiazinanes with Iꢀ
is one of only few reports demonstrating the use of this
reagent for heteroatom bond reduction.17 As evidence of
the unique reactivity of N-Troc oxathiadiazinanes toward
Iꢀ, other hydroxylamine derivatives, such as uracil sulfa-
mate 3, fail to undergo NꢀO bond reduction when sub-
jected to NaI, even at elevated temperatures. Instead,
hydrolysis of the sulfamoyl group simply results in the
formation of the corresponding hydroxylamine 4 (eq 1).
Figure 3. Troc-protected compounds are readily functionalized
at the sulfamate nitrogen.
documented once prior in carbenoid CꢀH insertion chem-
istry and appears to translate to the Rh-catalyzed oxida-
tion of sulfamate esters, as shown in entry 8.16
Troc-protected hydroxylamine-derived sulfamates are
made available from alcohol starting materials and have
proven to be effective substrates for Rh-catalyzed CꢀH
insertion. Oxathiadiazinane products of varying complex-
ity are formed in high yield, are stable to isolation and
derivatization, and submit to mild reductive cleavage
to afford value-added, differentially substituted diamine
structures. All told, these findings should serve to advance
CꢀH amination as a tool for chemical synthesis.
Figure 4. Mild reductive cleavage of oxathiadiazinanes yields
differentially protected diamines.
Troc-protected oxathiadiazinanes may be easily mod-
ified at the N3 position under standard acylation or
alkylation conditions (Figure 3). These results contrast
rather markedly the chemistry of analogous Mbs-derived
heterocycles, which fragment to liberate MbsNH2 even
under mild base treatment.13 We have ascribed these
differences in reactivity to subtle alterations in ring con-
formation influenced by the different N6 protecting
groups; the mechanism(s) for N-Mbs oxathiadiazinane
cleavage, however, remains opaque. In practice, the avail-
ability of N-Troc oxathiadiazinanes and their favorable
reactivity with electrophilic reagents should expand the
utility of this family of heterocycles for diamine synthesis.
Differentially modified 1,2-diamines can be accessed by
mild NꢀO bond reduction. We have previously shown
that hydrogenolytic NꢀO cleavage of Troc-protected ox-
athiadiazinanes is feasible with H2 and catalytic Pd/C;13a
Acknowledgment. D.E.O. gratefully acknowledges Eli
Lilly for a graduate fellowship. This work has been sup-
ported in part by the National Science Foundation under
the CCI Center for Selective CꢀH Functionalization,
CHE-1205646.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(17) (a) Bowers, A.; Ringold, H. J. J. Am. Chem. Soc. 1958, 80, 3091–
3093. (b) Kohli, J. C.; Arora, S.; Ahluwalia, J.; Badaishak, K. Chem. Ind.
(London) 1982, 14, 491. (c) Milne, J. E.; Storz, T.; Colyer, J. T.; Thiel,
O. R.; Seran, M. D.; Larsen, R. D.; Murry, J. A. J. Org. Chem. 2011, 76,
9519–9524.
(16) (a) Ishii, S.; Zhao, S.; Mehta, G.; Knors, C. J.; Helquist, P. J.
Org. Chem. 2001, 66, 3449–3458. (b) An analogous observation has been
noted in Rh-carbene CꢀH insertion reactions. H. M. L. Davies, personal
communication.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6177