Synthesis of phosphoramides for the lewis base-catalyzed allylation and aldol addition reactions

Article abstract of DOI:10.1021/jo9820723

Both chiral and achiral phosphoramides of diverse structure were prepared from diamines by the coupling to phosphorus(V) or phosphorus(III) reagents. Several enantiopure 1,2-diphenyl-1,2-ethanediamine analogues have been prepared by the reductive coupling of the corresponding N-silylimine with NbCl₄(THF)₂ and subsequent resolution by the formation of diastereomeric menthyl carbamates. (S,S)-N,N'-Di-(1-naphthyl)-1,2-diphenyl- 1,2-ethanediamine 15 was prepared by the arylation of (S,S)-1,2-diphenyl- 1,2-ethanediamine with naphthyl iodide.

Full text of DOI:10.1021/jo9820723

1958
J . Org. Chem. 1999, 64, 1958-1967
Syn th esis of P h osp h or a m id es for th e Lew is Ba se-Ca ta lyzed
Allyla tion a n d Ald ol Ad d ition Rea ction s
Scott E. Denmark,* Xiping Su, Yutaka Nishigaichi, Diane M. Coe, Ken-Tsung Wong,
Stephen B. D. Winter, and J un Young Choi
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received October 14, 1998
Both chiral and achiral phosphoramides of diverse structure were prepared from diamines by the
coupling to phosphorus(V) or phosphorus(III) reagents. Several enantiopure 1,2-diphenyl-1,2-
ethanediamine analogues have been prepared by the reductive coupling of the corresponding
N-silylimine with NbCl4(THF)2 and subsequent resolution by the formation of diastereomeric
menthyl carbamates. (S,S)-N,N′-Di-(1-naphthyl)-1,2-diphenyl-1,2-ethanediamine 15 was prepared
by the arylation of (S,S)-1,2-diphenyl-1,2-ethanediamine with naphthyl iodide.
Ch a r t 1. P h osp h or a m id es Der ived fr om
Dia m in es
In tr od u ction
Phosphoramides, especially hexamethylphosphoric tri-
amide (HMPA), have found extensive applications in
organic chemistry.1 The strong donor properties and
Lewis basicity of the phosphoramides make them good
ligands for metals and thus modulate the reactivity of
the metal centers.2 The three nitrogen subunits of a
phosphoramide also provide the opportunity for a large
number of structurally diverse analogues and hence a
broad spectrum of properties and shapes can be custom-
ized.3 It is therefore surprising that general methods for
the synthesis of phosphoramides have not been system-
atically developed.4,5
In the course of our survey of Lewis-basic catalysts for
allylation6 and aldol reactions,7 we required a variety of
phosphoramides with broad structural diversity, espe-
cially containing a 1,3,2-diazaphospholidine 2-oxide skel-
eton derived from chiral and achiral 1,2-diamines. Herein
we report on a number of general methods for the
synthesis of such phosphoramides (Chart 1) as well as
the preparation of their chiral 1,2-diamine precursors.
(1) (a) Normant, H. Russ. Chem. Rev. (Engl. Transl.) 1970, 39, 457.
(b) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry;
VCH: Germany, 1988.
(2) (a) Luteri, G. F.; Ford, W. T. J . Org. Chem. 1977, 42, 820. (b)
Gutmann, V. The Donor-Acceptor Approach to Molecular Interactions;
Plenum: New York, 1978. (c) Inanaga, J .; Ishikawa, M.; Yamaguchi,
M. Chem. Lett. 1987, 1485. (d) Romesberg, F. E.; Bernstein, M. P.;
Gilchrist, J . H.; Harrison, A. T.; Fuller, D. J .; Collum, D. B. J . Am.
Chem. Soc. 1993, 115, 3475.
(3) (a) Ishihara, K.; Karumi, Y.; Kondo, S.; Yamamoto, H. J . Org.
Chem. 1998, 63, 5692. (b) Verkade, J . G. Acc. Chem. Res. 1993, 26,
483.
(4) (a) Arcoria, A.; Ballistreri, F. P.; Tomaselli, G. A.; Di Furia, F.;
Modena, G. J . Org. Chem. 1986, 51, 2374. (b) Bortolini, O.; Di Furia,
F.; Modena, G.; Schionato, A. J . Mol. Catal. 1986, 35, 47. (c) Wilson,
S. R.; Price, M. F. Synth. Commun. 1982, 12, 657.
(5) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi,
Y. Tetrahedron 1997, 53, 3513.
(6) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J . Org.
Chem. 1994, 59, 6161.
Resu lts
(7) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J . Am.
Chem. Soc. 1996, 118, 7404. (b) Denmark, S. E.; Wong, K.-T.;
Stavenger, R. A. J . Am. Chem. Soc. 1997, 119, 2333. (c) Denmark, S.
E.; Winter, S. B. D. Synlett 1997, 1087. (d) Denmark, S. E.; Stavenger,
R. A.; Wong, K.-T. J . Org. Chem. 1998, 63, 918. (e) Denmark, S. E.;
Stavenger, R. A.; Wong, K.-T. Tetrahedron 1998, 63, 10389.
The basic strategy for the synthesis of a phosphoramide
is to couple a diamine to a phosphorus reagent. Three
routes were explored within this construct: (1) a diamine
was coupled to a dialkylaminophosphoric dichloride, (2)
10.1021/jo9820723 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/03/1999

Synthesis of Phosphoramides
J . Org. Chem., Vol. 64, No. 6, 1999 1959
Sch em e 2
a diamine was coupled to a dialkylaminophosphorus
dichloride to afford the corresponding phosphorus tria-
mide followed by in-situ oxidation to give the desired
phosphoramide, and (3) PCl3 was combined first with a
hindered diamine and then a secondary amine, followed
by in-situ oxidation. Method 1 is applicable when both
coupling partners are not sterically demanding. Methods
2 and 3 could be used for sterically hindered coupling
partners where method 1 gave less than satisfactory
results.
(S,S)-(12) could be achieved in good yield without detect-
able racemization (Scheme 2).
The diamines used in this study include achiral and
chiral 1,2-diamines, (R,R)-N,N′-dimethyl-1,3-diphenyl-
propane-1,3-diamine and (R)-N,N′-dimethylbinaphthyl-
1,1′-diamine. The preparation of some new, enantiomer-
ically pure 1,2-diamines are also described herein.8
1. P r ep a r a tion of Dia m in es. N,N′-Disubstituted-1,2-
ethanediamines required for the synthesis of phosphora-
mide groups 1-3 were commercially available or made
by the known procedures.9 (R,R)/(S,S)-1,2-Diphenyl-1,2-
ethanediamine (12) used for the preparation of phos-
phoramides 4 and 5 was synthesized and resolved by
literature methods.10,11 As has been reported in previous
accounts, the phosphoramide 4a has proven to be an
effective catalyst for aldol reactions. Therefore, we have
developed an improved procedure for the preparation of
the diamine precursor (S,S)-N,N′-dimethyl-1,2-diphenyl-
1,2-ethanediamine12 (14) from the parent diamine (12),
Scheme 1. We have found that the bis(formamide) 13
(easily prepared by formylation of 12 with acetic formic
anhydride) is superior to the bis(ethyl carbamate)12a in
yield, ease of purification and reproducibility of reduction.
In the presence of sodium tert-butoxide and catalytic
amount of tris(dibenzylideneacetone)dipalladium, enan-
tiomerically pure (S,S)-12 was coupled with 1-naphthyl
iodide to give the desired N,N′-dinaphthyldiamine 15 in
70% yield. Other combinations of catalysts and ligands
gave either no reaction or low yield of the desired
compound. This arylation method provides rapid access
to the enantiopure diamine and should be useful for
synthesis of other types of aryl substituted amines for
asymmetric synthesis.
1.2. Red u ctive Cou p lin g of Im in es. Chiral, nonra-
cemic 1,2-diamines have been used extensively in asym-
metric synthesis.8 Accordingly, the stereoselective syn-
thesis of chiral 1,2-diamines has become an active area
of research.15-17 The reductive coupling of imines to give
1,2-diamines probably represents one of the most versa-
tile methods for the synthesis of symmetrical 1,2-di-
amines because of the readily availability of imines from
aldehydes. Many reducing agents have been employed
in this transformation, including Ti,18,19 Zr,20 Sm,16 Zn,21
Al,22 In,23 and other metals.24 However, usually a mixture
of d,l and meso diastereomers is obtained.25 The most d,l-
selective imine coupling reactions to give 1,2-diphenyl-
1,2-ethanediamine analogues is the coupling of N-si-
lylimines by low valent niobium reagents reported by
Pederson in 1987.26 Thus, application of this method to
imines of aromatic aldehydes with different substitution
patterns provided the desired 1,2-diamines (Table 1).
N-Silylimines 17 were prepared in good yields accord-
ing to literature procedures.18,27 All of the imines 17 were
coupled smoothly to give the desired d,l-1,2-diamines
18a -e in good yields with high diastereoselectivity.
Sch em e 1
1.1. Am in e Ar yla tion Rea ction s. N,N′-Disubstituted
1,2-diphenyl-1,2-ethanediamine used for the synthesis of
phosphoramides 5a -e were prepared either from diphe-
nyl-1,2-ethanediamine itself (5b and 5d ) or by the
coupling of benzylidene aniline.12 (S,S)-N,N′-Diethyl-1,2-
diphenyl-1,2-ethanediamine13 was synthesized by the
reduction of the bis(acetamide) of 1,2-diphenyl-1,2-
ethanediamine. The unknown (S,S)-1,2-diphenyl-N,N′-
dinaphthyl-1,2-ethanediamine (15) was synthesized from
(S,S)-1,2-diphenyl-1,2-ethanediamine (12) by the amine
arylation method developed by Buckwald and Hartwig.14
With judicious choice of reaction conditions, arylation of
(14) (a) Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046.
(b) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 7217.
(c) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 8451.
(15) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi,
L. Tetrahedron Lett. 1998, 39, 3333.
(16) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahe-
dron: Asymmetry 1997, 8, 2381.
(17) Enders, D.; Wiedemann, J . Synthesis 1996, 1443.
(18) Betschart, C.; Schmidt, B.; Seebach, D. Helv. Chim. Acta 1988,
71, 1999.
(8) For recent reviews of the chemistry of chiral 1,2-diamines, see
(a) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161. (b)
Shimizu, M.; Fujisawa, T. J . Synth. Org. J pn. 1998, 56, 672. (c) Lucet,
D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. Engl. 1998, 37,
2580. (d) Kobayashi, S.; Horibe, M.; Saito, Y. Tetrahedron 1994, 50,
9629.
(9) Russell, G. B.; Sutherland, G. J .; Topsom, R. D.; Vaughan, J . J .
Org. Chem. 1962, 27, 4375.
(10) Corey, E. J .; Lee, D.-H.; Sarshar, S. Tetrahedron: Asymmetry
1995, 6, 3.
(11) Pikul, S.; Corey, E. J . Org. Synth. 1991, 71, 22.
(12) (a) Kanemasa, S.; Hayashi, T.; Tanaka, J .; Yamamoto, H.;
Sakurai, T. J . Org. Chem. 1991, 56, 4473. (b) Mangeny, P.; Grosjean,,
F.; Alexakis, A.; Normant, J . F. Tetrahedron Lett. 1988, 29, 2675. For
a new approach to (()-14 see (c) Alexakis, A.; Aujard, I.; Mangeney,
P. Synlett 1998, 875.
(19) Periassamy, M.; Reddy, M. R.; Kanth, J . V. B. Tetrahedron Lett.
1996, 37, 4767.
(20) Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan,
J . C. J . Am. Chem. Soc. 1989, 111, 4486.
(21) Shimizu, M.; Iida, T.; Fujisawa, T. Chem. Lett. 1995, 609.
(22) Beruah, B.; Praiapati, D.; Sandhu, J . S. Tetrahedron Lett. 1995,
36, 6747.
(23) Kalyanam, N.; Venkateswara, R. G. Tetrahedron Lett. 1993,
34, 1647.
(24) (a) Takaki, K.; Tsubaki, Y.; Tanaka, S.; Beppu, F.; Fujiwara,
Y. Chem. Lett. 1990, 203. (b) Imwinkelried, R.; Seebach, D. Helv. Chim.
Acta 1984, 67, 1496. (c) Mehrotra, K. N.; Giri, B. P. Synthesis 1977,
489.
(25) (a) Alexakis, A.; Aujard, I.; Mangeney, P. Synlett 1998, 873.
(26) Roskamp, E. J .; Pedersen, S. F. J . Am. Chem. Soc. 1987, 109,
3152.
(13) Yamashita, J .; Tomiyama, S.; Hashimoto, H.; Kitahara, K.;
Sato, H. Chem. Lett. 1984, 749.
(27) Cainelli, G.; Giacomini, D.; Galletti, P.; Gaiba, A. Synlett 1996,
657.

1960 J . Org. Chem., Vol. 64, No. 6, 1999
Ta ble 1. Red u ctive Cou p lin g of N-Silylim in es
Denmark et al.
Sch em e 3
entry
aryl
17, yield, %a 18, yield, %b dl/mesoc
1
2
3
4
5
4-CF3C6H4 (a )
4-MeOC6H4 (b)
3,5-Me2C6H3 (c)
1-naphthyl (d )
2-naphthyl (e)
88
84
73
76
62
49
45
67
52
48
5/1
>10/1
10/1
>10/1
>10/1
a
b
Yield of isolated and distilled sample. Yield after recrystal-
lization. c Estimated by 1H NMR analysis of the crude product.
Ta ble 2. Resolu tion of Dia m in es 16 a n d Syn th esis of 18
(Scheme 3).29 Thus, HBr hydrolysis of the more polar
diastereomer of the bis(carbamate) 19c led to the known
diamine (S,S)-(-)-18c in 75% yield, while the reduction
of the same carbamate 19c led to the secondary diamine
(-)-20c in 48% yield. The absolute configurations of other
1
diamines 20a ,b,e was deduced by comparison of their H
NMR spectra and relative polarity on TLC of their
corresponding bis(carbamate)s 19a ,b,e to those of 19c.
Thus, all the less polar diastereomers of 19 display a
distinct doublet of triplets at around 4.5 ppm, which was
assigned to the oxygen-bearing methine, and were as-
signed the (1R,2R) configuration at the nitrogen-bearing
stereocenters. All the more polar diastereomers of 19
displayed a broad signal for the oxygen-bearing methine
19,
20,
entry
aryl
yield, %a reductant
conditions
yield, %b
1
2
3
4
4-CF3C6H4 (a )
4-MeOC6H4 (b)
3,5-Me2C6H3 (c)
2-naphthyl (e)
92
69
86
75
BH3•SMe2 PhCH3, 110 °C
LiAlH4
LiAlH4
51
82
48
69
DME, 85 °C
DME, 85 °C
BH3•SMe2 PhCH3, 110 °C
1
in their H NMR spectra.
a
b
Chromatographically homogeneous material. Yield after re-
Diamine 18d was not resolved because the correspond-
ing phosphoramide 6d was not a good catalyst for aldol
reactions. The racemic diamine 18d was converted to the
racemic secondary diamine 20d via its bis(formamide)
19d (Scheme 4).
crystallization.
Fractional crystallization gave the pure diamines 18a -e
in 45-67% yields.
1.3. Resolu tion of 1,2-Dia m in es. Whereas 1,2-diphe-
nyl-1,2-ethanediamine itself is readily resolved by frac-
tional crystallization of the tartrate salt, initial experi-
ments indicated that crystallization conditions for each
diamine 18a -e required extensive optimization.10 To
rapidly access the enantiomerically pure diamines 18a -
e, we employed the chromatographic separation of the
corresponding menthyl carbamate diastereomers formed
by the reaction of the diamine with (-)-menthyl chloro-
formate.28 An additional advantage of the (-)-menthyl
carbamate resolution is that direct reduction of 19 would
provide the desired secondary diamine 20 and return the
enantiopure menthol (Table 2).
Diamines 18a -c,e reacted with (-)-menthyl chloro-
formate in the presence of pyridine to afford bis(carbam-
ate) 19a -c,e in good yields. Reduction of 19b and 19c
with LiAlH4 gave the corresponding secondary diamines
20b and 20c in good yields, but the reduction of 19a and
19e with LiAlH4 met with difficulty, resulting in over-
reduction and other side reactions. A brief survey of
reducing reagents revealed that borane-dimethyl sulfide
was more suitable for these two substrates. Thus, with
excess of borane-dimethyl sulfide the desired diamines
20a and 20e were obtained in 51 and 69% yields,
respectively.
Sch em e 4
1,2-Dicyclohexyl-1,2-ethanediamine (18f) was prepared
by the hydrogenation of (S,S)-1,2-diphenyl-1,2-ethanedi-
amine in 71% yield according to known procedures30 and
was then converted to the secondary diamine 20f in
moderate yields via the bis(carbamate) 19f (Scheme 5).
1.4. Ch ir a l Dia m in es fr om Am in o Acid s. Following
a procedure developed by Mukaiyama and co-workers,31
diamines 24 could be prepared in gram quantities from
Cbz-L-proline 21 in good overall yields (Scheme 6).
2. P r ep a r a tion of P h osp h or a m id es. 2.1. Rea ction
of Dia m in es w ith Am in op h osp h or ic Dich lor id es.
The most direct and commonly used way to prepare
phosphoramides from diamines is to couple the diamines
with a corresponding aminophosphoric dichloride (Table
3).5,32 Although the protocol of fast addition of a diamine
(29) Corey, E. J .; Sarshar, S.; Bordner, J . J . Am. Chem. Soc. 1992,
114, 7938.
(30) Ohkuma, T.; Ooka, H.; Ikanya, T.; Noyori, R. J . Am. Chem. Soc.
1995, 117, 10417.
The absolute configuration of diamine 20c was estab-
lished by correlation to the known diamine (S,S)-(-)-18c
(31) (a) Mukaiyama, T. Tetrahedron 1981, 37, 4111. (b) Asami, M.;
Ohno, H.; Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1978,
51, 1869.
(28) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions; Wiley: New York, 1981.

Synthesis of Phosphoramides
Sch em e 5
J . Org. Chem., Vol. 64, No. 6, 1999 1961
toward nucleophilic displacement.33 Phosphoramides 4d
and 5b were prepared in overall yields of 63-64%, by
the reaction of the corresponding diamines with the
appropriate aminophosphorus dichloride 2634 followed by
oxidation with MCPBA (Scheme 7).35
Sch em e 7
Preparation of phosphoramide 11 required deprotona-
tion with n-butyllithium (Scheme 8), because the diamine
27 is both sterically hindered and electronically deacti-
vated. The desired phosphoramide was obtained in 50%
overall yield after the three-step procedure.
Sch em e 6
Sch em e 8
and an aminophosphoric dichloride to a solution of
triethylamine worked well in a number of cases, the more
reliable protocol is the simultaneous slow addition of a
solution of the diamine and a solution of the correspond-
ing phosphoric dichloride to a refluxing solution of
triethylamine. This method worked well for most of the
diamines in this study, but it failed for sterically more
congested diamines.
With N,N′-dimethyl-1,2-ethanediamine, this method
afforded high yields of the desired phosphoramides 1a ,
2a , and 3a with various aminophosphoric dichlorides 25
(entries 1, 4, and 5). It was also efficient in preparing
most of the phosphoramides 4 and 6 (entries 6-11, 13-
17), although slightly lower yields were observed. The
reaction proceeded well at room temperature for steri-
cally less-demanding diamines (entries 12, 18-20, 23, 24,
30), and elevated temperatures were required for steri-
cally demanding coupling partners (entries 3, 21, 22). A
bulky aminophosphoric dichloride gave a low yield (entry
29).
The synthesis of the lead phosphoramide (S,S)-4a was
further optimized by surveying solvents (CH2Cl2, CHCl3,
(CH2Cl)2), addition rates, and reaction times (2-4 d).
Ultimately the yield of (S,S)-4a could be improved to 61%
after chromatography and recrystallization (compare
entries 6 and 7) by carrying out the preparation in
chloroform at reflux for 48 h.
2.2. Rea ction of Dia m in es w ith Am in op h osp h or u s
Dich lor id e. During the synthesis of 4d and 5b, the
reaction of the diamines with the corresponding amino-
phosphoric dichloride resulted in the recovery of the
starting diamines, presumably due to the low reactivity
of the hindered substrates. To solve this problem, we took
advantage of the fact that phosphorus(III) compounds are
much more reactive than phosphorus(V) compounds
2.3. Rea ction of Dia m in es w ith P h osp h or u s Tr i-
ch lor id e. Hindered phosphoramides can also be pre-
pared through the reaction of a diamine with phosphorus
trichloride followed by reaction with a primary amine and
oxidation with MCPBA.36 Moderate yields of the desired
phosphoramides were obtained over the three steps,
Table 4. For the preparation of phosphoramides with
bulky substituents R or R1 on the nitrogens, this method
gave the best results. For example, the coupling of N,N′-
diphenylethylene-1,2-diamine with diphenylamine gave
72% of the phosphoramide 2b with this method (entry
2).
Discu ssion
P r ep a r a tion of En a n tiom er ica lly P u r e Dia m in es.
The synthesis of (S,S)-1,2-diphenyl-N,N′-dinaphthyl-
ethanediamine (13) provides an example for the rapid
access of enantiomerically pure N-arylamines from readily
available amines such as 1,2-diphenyl-1,2-ethanediamine
or 1,2-cyclohexanediamine. Given the fact that good
yields of the product were obtained in one chemical step
without detectable racemization/epimerization, with the
stringent requirements imposed by the reaction, i.e.,
diarylation with sterically hindered aryl halide, this
method may find broad use in asymmetric synthesis.
The preparation of 1,2-diamines by reductive coupling
of imines has some of the most appealing features of
efficient synthesis; primary among them is that it creates
(33) Holmes, R. R. Chem. Rev. 1996, 96, 927.
(34) Michaelis, A. Liebigs Ann. Chem. 1903, 326, 129.
(35) (a) Petrov, K. A.; Gavrilova, A. I.; Korotkova, V. P. Zh. Obshch.
Khim. 1962, 32, 915. (b) Mikolajczyk, M.; Luczak, J . J . Org. Chem.
1978, 43, 2132. For air oxidation of P (III) to P (V), see (c) Lee, K.;
Wiemer, D. F. J . Org. Chem. 1991, 56, 5556.
(32) Peyronel, J .-F.; Samuel, O.; Fiaud, J .-C. J . Org. Chem. 1987,
52, 5320.
(36) Marre, M. R.; Sanchez, M.; Brazier, J . F.; Wolf, R.; Bellan, J .
Can. J . Chem. 1982, 60, 456.

1962 J . Org. Chem., Vol. 64, No. 6, 1999
Denmark et al.
Ta ble 3. P r ep a r a tion of P h osp h or a m id es fr om Dia m in es a n d Am in op h osp h or ic Dich lor id e 25
diamine
(R1/R2)
entrya
T, °C
time, h
product
R
R1
R2
yield, %b
1
2
Me/H
i-Pr/H
Ph/H
Me/H
Me/H
Me/Ph
Me/Ph
Me/Ph
Me/Ph
Me/Ph
Me/Ph
12
20a
20b
20c
20e
20f
24a
24b
24c
40
40
83
40
40
40
61
40
40
40
40
20
40
40
40
40
40
20
20
20
68
68
20
20
40
40
40
40
40
20
40
40
36
19
15
42
24
48
6
96
42
16
10
96
37
48
48
66
10
3
18
13
10
10
18
24
20
14
21
41
11
20
1a
1b
1c
2a
3a
4a
4a
4b
4c
4e
4f
5a
6a
6b
6c
6e
(CH2)5
(CH2)5
(CH2)5
Ph
see Chart 1
(CH2)5
(CH2)5
Me
Me
i-Pr
Ph
H
H
H
H
99
50
51
87
80
50
61
60
46
63
61
59
41
75
62
52
49
74
93
68
67
67
58
83
59
37
57
27
7
3c
4
5
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
H
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7d
8
9
n-Pr
i-Pr
10
11
12
13
14
15
16
17
18e
19e
20e
21e
22e
23f
24f
25
26
27
28
29
30
31
(CH2)4
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)5
Me
Me
Me
Me
Me
i-Pr
see Chart 1
Me
4-CF3C6H4
4-MeOC6H4
3,5-Me2C6H3
2-naphthyl
cyclohexyl
6f
7a /8a
7b/8b
7c/8c
7d /8d
7e/8e
9a
9b
9c
9d
9e
see Chart 1
see Chart 1
see Chart 1
see Chart 1
see Chart 1
24d
24e
Me/(CH2)4
Me/(CH2)4
Et/(CH2)4
i-Pr/(CH2)4
Bn/(CH2)4
CH2t-Bu/(CH2)4
Me/(CH2)4
Me/(CH2)4
DPPDAg
Me
Me
Et
i-Pr
Bn
CH2t-Bu
Me
Me
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
see Chart 1
9f
9g
9h
10
63
51
Me
a
d
All reactions were carried out in CH2Cl2 unless otherwise noted. b Chromatographically homogeneous material. c ClCH2CH2Cl. CHCl3.
e THF. f EtOAc. N,N′-dimethyl-1,3-diphenylpropane-1,3-diamine.
g
Ta ble 4. P h osp h or a m id es fr om th e Rea ction s of
Dia m in es w ith P Cl3
Sch em e 9
entry
R2
R1
R
product yield, %a
1
2
3
4
5
6
H
H
H
Ph
Ph
1-naphthyl (CH2)5
1d
2b
3b
5c
5d
6d
46
72
50
42
55
38b
tenuated in the coupling of 17a or aliphatic imines.
Similar thermodynamic control has also been observed
in other systems.25,37
Ph
Ph
Ph
Ph
Me, PhCHMe
(CH2)5
1-naphthyl (CH2)5
Syn th esis of P h osp h or a m id es. Nucleophilic substi-
tution at phosphorus is much faster for P(III) compounds
than P(V) compounds.33 Electron-donating groups on
phosphorus also greatly attenuate the ease of nucleophilic
substitution, where the reactivity order for the phospho-
rus reagents is PCl3 > Cl2PNR2 > ClP(NR2)2 g Cl2P(O)-
NR2. Several scenarios can be envisioned to formulate
the synthesis of a phosphoramide from a diamine and a
monoamine: (1) the diamine and the monoamine are
both small, (2) a small diamine but a bulky monoamine,
(3) a hindered diamine but a small monoamine, and (4)
both the diamine and the monoamine are bulky. For the
first scenario the use of less reactive reagents of the type,
Cl2P(O)NR2, is desirable since the coupling reaction is
facile and the less reactive reagents could prevent
1-naphthyl Me
(CH2)5
a
b
Analytically pure sample. Chromatographically homoge-
neous sample.
two stereocenters while making a C-C bond. The origin
of the high selectivity of the reductive coupling by
niobium(IV) reagent is poorly understood. One plausible
explanation is that the coupling step is reversible under
the reaction conditions, and the thermodynamically more
stable d,l-isomer would accumulate in the reaction
mixture with time (Scheme 9). This hypothesis is con-
sistent with the fact that the coupling of the electron-
poor arylimine 17a or aliphatic imines26 was less selective
than that of electron-rich arylimines. Because the radical
intermediate i derived from imine 17a or aliphatic imines
is less stable than that derived from electron-rich aro-
matic imines, the degree of reversibility would be at-
(37) Smith, J . G.; Ho, I. J . Org. Chem. 1972, 37, 653.

Synthesis of Phosphoramides
J . Org. Chem., Vol. 64, No. 6, 1999 1963
1, from triethylamine (2.4 mL, 17.5 mmol, 2.5 equiv), N,N′-
di-(1-methylethyl)-1,2-ethanediamine (1.27 mL, 7.0 mmol), and
piperidinylphosphoric dichloride (1.07 mL, 7.0 mmol, 1.0 equiv)
in CH2Cl2 (150+30+30 mL) was obtained 0.949 g (50%) of 1b
as colorless crystals after chromatography (SiO2, EtOAc,
EtOAc/i-PrOH, 19/1, and then EtOAc/i-PrOH, 9/1 as eluents).
mp 52-53 °C (hexane); bp 145 °C (0.05 mmHg); TLC Rf ) 0.71
(EtOAc/i-PrOH, 9/1); 31P NMR (162 MHz, CDCl3) δ 22.44. Anal.
Calcd for C13H28N3OP (273.36): C, 57.12; H, 10.32; N, 15.37;
P, 11.33. Found: C, 56.82; H, 10.46; N, 15.56; P, 11.21.
1,3-Dip h en yl-2-p ip er id in o-1,3,2-d ia za p h osp h olid in e
2-Oxid e (1c). Following Representative Procedure 1a, from
triethylamine (3.5 mL, 25 mmol, 2.5 equiv) N,N′-diphenyl-1,2-
ethanediamine (2.12 g, 10 mmol), and piperidinylphosphoric
dichloride (1.53 mL, 10 mmol, 1.0 equiv) in dichloroethane (20
mL) was obtained 1.74 g (51%) of 1c as colorless needles after
chromatography (SiO2, CH2Cl2 then CH2Cl2/i-PrOH, 20/1 as
eluents) and recrystallization from benzene/hexane, mp: 169-
171 °C (benzene/hexane); TLC Rf ) 0.83 (EtOAc). 31P NMR
(162 MHz, CDCl3) δ 13.32. Anal. Calcd for C19H24N3OP
(341.39): C, 66.85; H, 7.09; N, 12.31; P, 9.07. Found: C, 66.66;
H, 7.04; N, 12.19; P, 8.88.
complications arising from polymerization. For the type
2 coupling, it is best to use reagents of type Cl2PNR2 as
exemplified by the synthesis of 4d and 5b in this study.
The logic is to use the most reactive phosphorus reagent,
PCl3, to react with the least reactive amine, in this case,
the monoamine. This reasoning also applies to type 3
coupling; thus a hindered diamine is reacted with PCl3
to give intermediates of the type ClP(NR2)2, which was
then reacted with a monoamine. A typical example of this
type is the synthesis of 5d , where an extremely hindered
diamine (S,S)-15 was used and yet a good yield of the
desired phosphoramide was obtained. The most chal-
lenging coupling reaction is the type 4 where both
partners are hindered or difficulty for coupling arises
from other reasons such as the coupling of electronically
deactivated amines. In this case, the coupling of a
diamine with PCl3 and then with a monoamine worked
well in some instances, such as the synthesis of 2b and
3b in this study. Occasionally, the activation of one of
the reaction partners may be needed, such as in the
synthesis of phosphoramide 11 from N,N′-dimethylbi-
naphthyl-1,1′-diamine (27) wherein the deprotonation of
the diamine 27 with n-BuLi and the use of reactive
phosphorus reagent 26b were required. Other conditions
failed to give any detectable product.
1,3-Dim eth yl-2-(d ip h en yla m in o)-1,3,2-d ia za p h osp h oli-
d in e 2-Oxid e (2a ). Following Representative Procedure 1,
from triethylamine (1.74 mL; 12.5 mmol), N,N′-dimethyl-1,2-
ethanediamine (0.53 mL, 5.0 mmol) and diphenylaminophos-
phoric dichloride38 (1.43 g, 5.0 mmol) in CH2Cl2 (150+15+15
mL), was obtained 1.32 g (87%) of 2a as colorless needles after
column chromatography (SiO2, EtOAc, then EtOAc/i-PrOH,
10/1 as eluents) and recrystallization (CH2Cl2/hexane); mp:
115-116 °C (CH2Cl2-hexane); TLC Rf ) 0.61 (EtOAc/i-PrOH,
9/1); 31P NMR (162 MHz, CDCl3) δ 19.39. Anal. Calcd for
Con clu sion
In summary, we have described in detail the prepara-
tion of cyclic phosphoramides of broad structural diver-
sity. Three methods have been examined for the synthe-
sis of these phosphoramides starting with both P(III) and
P(V) reagents. The steric bulk of the coupling amines is
the key factor which affects the choice of coupling
methods. Arylation of readily available enantiomerically
pure primary amines provided a novel route for the
synthesis of enantiomerically pure N-arylamines. Reduc-
tive coupling of N-silylimines and the following resolution
via (-)-menthyl carbamate provided rapid access to
enantiomerically pure symmetrical 1,2-diamines.
C
16H20N3OP (301.33): C, 63.78; H, 6.69; N, 13.95; P, 10.28.
Found: C, 63.73; H, 6.79; N, 14.21; P, 9.97.
(S)-1,3-Dim eth yl-2-[m eth yl(1′-ph en yleth yl)am in o]-1,3,2-
d ia za p h osp h olid in e 2-Oxid e (3a ). Following Representative
Procedure 1, from triethylamine (3.5 mL; 25 mmol, 2.5 equiv),
N,N′-dimethyl-1,2-ethanediamine (1.06 mL; 10 mmol), and (S)-
N-methyl-N-(1-phenylethyl)aminophosphoric dichloride (2.52
g, 10 mmol, 1.0 equiv) in CH2Cl2 (200+25+25 mL) was
obtained 2.14 g (80%) of 3a as colorless crystals after column
chromatography (SiO2, EtOAc/i-PrOH, 10/1, 10/2, then 10/3
as eluents) and distillation (bp 160-165 °C/0.1 mmHg; Kugel-
rohr). An analytical sample was obtained recrystallization from
hexane, mp: 51-52 °C (hexane). [R]22 ) -1.6° (c ) 1.1,
D
CHCl3); TLC Rf ) 0.58 (EtOAc/i-PrOH, 9/1); 31P NMR (162
MHz, CDCl3) δ 27.93. Anal. Calcd for C13H22N3OP: C, 58.41;
H, 8.30; N, 15.72; P, 11.59. Found: C, 58.39; H, 8.38; N, 15.77;
P, 11.37.
Exp er im en ta l Section
Gen er a l Meth od s. See Supporting Information. Rep r e-
sen ta tive P r oced u r e 1. Syn th esis of P h osp h or a m id es
fr om Dia lk yla m in op h osp h or ic Dich lor id e. 1,3-Dim eth yl-
2-p ip er id in o-1,3,2-d ia za p h osp h olid in e 2-Oxid e (1a ). To a
refluxing solution of triethylamine (2.3 mL, 17 mmol, 2.5 equiv)
in 150 mL of CH2Cl2 were simultaneously added solutions of
N,N′-dimethyl-1,2-ethanediamine (0.71 mL, 6.7 mmol) in 30
mL of CH2Cl2 and piperidinylphosphoric dichloride34 (1.02 mL,
6.7 mmol, 1.0 equiv) in 30 mL of CH2Cl2 over 2 h under
nitrogen using a syringe pump. The solution was heated to
reflux for 40 h and then was evaporated under reduced
pressure to provide a colorless residue. The crude product was
purified by column chromatography (SiO2, EtOAc, EtOAc/i-
PrOH, 9/1, and then EtOAc/i-PrOH, 7/3 as eluents) and
Kugelrohr distillation (bp 120-125 °C/(air-bath temperature
(ABT))/0.05 mmHg) to give 1.45 g (99%) of 1a as colorless,
hygroscopic crystals. An analytical sample was prepared by
further recrystallization from hexane, mp 55-56 °C (hexane);
TLC Rf ) 0.20 (EtOAc/i-PrOH, 9/1); 31P NMR (162 MHz,
CDCl3) δ 26.44. Anal. Calcd for C9H20N3OP (217.25): C, 49.76;
H, 9.28; N, 19.34; P, 14.26. Found: C, 49.56; H, 9.22; N, 19.46;
P, 14.34.
(4S,5S)-1,3-Dim et h yl-4,5-d ip h en yl-1-(1-p ip er id in yl)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (4a ). Following Repre-
sentative Procedure 1, from triethylamine (2.34 mL, 16.8
mmol, 2.5 equiv), (S,S)-N,N′-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (12), (1.6 g, 6.66 mmol), and piperidinylphosphoric
dichloride (1.04 mL, 6.69 mmol, 1.0 equiv) in CH2Cl2 (100+
50+50 mL) was obtained 1.228 g (50%) of 4a as white needles
after chromatography (SiO2, EtOAc/i-PrOH, 9/1) and recrys-
tallization from hexane, mp: 110-111 °C (hexane). [R]22
)
D
+18.2° (c ) 1.3, CHCl3); TLC Rf ) 0.42 (EtOAc/i-PrOH, 9/1);
31P NMR (122 MHz, CDCl3) δ 27.35. Anal. Calcd for C21H28N3-
OP (369.45): C, 68.27; H, 7.64; N, 11.37; P, 8.38. Found: C,
68.00; H, 7.68; N, 11.31; P, 8.23.
Following Representative Procedure 1a, from triethylamine
(1.45 mL, 10.4 mmol, 2.5 equiv), diamine 12 (1.0 g, 4.16 mmol,
1.0 equiv), and piperidinephosphoric dichloride (0.70 mL, 4.58
mmol, 1.1 equiv) in CHCl3 (83 mL) was obtained 0.934 g (61%)
of 4a as white needles after chromatography (SiO2, EtOAc/i-
PrOH, 9/1) and recrystallization from hexane. mp 111-112
°C (hexane).
(4S,5S)-1,3-Dim eth yl-4,5-d ip h en yl-2-(d im eth yla m in o)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (4b). Following Repre-
sentative Procedure 1, from triethylamine (0.21 mL, 0.154 g,
A slightly modified procedure (Representative Procedure 1a)
is identical to Representative Procedure 1 except that the
reagents and substrates were mixed together at room tem-
perature and then were heated to reflux for the indicated time.
1,3-Di-(1-m eth yleth yl)-2-(1-piper idin yl)-1,3,2-diazaph os-
p h olid in e 2-Oxid e (1b). Following Representative Procedure
(38) Otto, P. Ber. 1895, 28, 613.

1964 J . Org. Chem., Vol. 64, No. 6, 1999
Denmark et al.
1.53 mmol), (S,S)-N,N′-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (0.146 g, 0.61 mmol), and N,N-dimethylphosphoramic
dichloride (0.073 mL, 0.099 g, 0.61 mmol) in CH2Cl2 (5+1+1
mL), was obtained 0.121 g (60%) of 4b as a white solid after
chromatography (SiO2, EtOAc/i-PrOH 10/1). An analytical
sample was obtained by recrystallization from hexane, mp:
white needles (251 mg, 34%), mp: 115-117 °C (hexane). [R]22
D
) +49.9° (c ) 1.12, CHCl3); TLC Rf ) 0.32 (TBME/MeOH, 20/
1); 31P NMR (162 MHz, CDCl3) δ 27.11. Anal. Calcd for
C
23H32N3O3P (429.50): C, 64.32; H, 7.51; N, 9.78; P, 7.21.
Found: C, 64.18; H, 7.68; N, 9.66; P, 6.96.
(4S,5S)-1,3-Dim eth yl-4,5-bis(3,5-d im eth ylp h en yl)-2-(1-
p ip er id in yl)-1,3,2-d ia za p h osp h olid in e 2-Oxid e (6c). Fol-
lowing Representative Procedure 1a, from triethylamine (185
µL; 1.33 mmol, 2.4 equiv), the diamine 20c (164 mg, 0.55
mmol), and piperidinylphosphoric dichloride (86 µL, 0.56
mmol, 1.02 equiv) in 65 mL of CH2Cl2 was obtained 145 mg
(62%) of 6c as a white foam after column chromatography
(SiO2, TBME/MeOH, 19/1). An analytical sample was obtained
by recrystallization from hexane, mp: 149-150 °C (hexane);
[R]22D ) +7.2° (c ) 1.00, CHCl3); TLC Rf ) 0.47 (TBME/MeOH,
20/1), 31P NMR (162 MHz, CDCl3) δ 27.48. Anal. Calcd for
161-163 °C (hexane); [R]22 ) -5.10° (c ) 1.02, CHCl3); TLC
D
Rf ) 0.23 (EtOAc/i-PrOH, 10/1); 31P NMR (162 MHz, CDCl3)
δ 29.61. Anal. Calcd for C18H24N3OP (329.381): C, 65.64; H,
7.34; N, 12.76; P, 9.40. Found: C, 65.68; H, 7.30; N, 12.65; P,
9.34.
(4S,5S)-1,3-Dim eth yl-4,5-d ip h en yl-2-(d ip r op yla m in o)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (4c). Following Repre-
sentative Procedure 1a, from triethylamine (0.42 mL, 3.0
mmol, 3.0 equiv), (S,S)-N,N′-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (0.248 g, 1.0 mmol), and N,N-dipropylphosphoramic
dichloride (0.218 mL, 1.0 mmol, 1.0 equiv) in CH2Cl2 (20 mL)
was obtained 0.179 g (46%) of 4c as a thick oil after column
chromatography (SiO2, EtOAc/i-PrOH 10/1). 31P NMR (162
MHz, CDCl3) δ 27.74. Anal. Calcd for C22H32N3OP (385.49):
C, 68.55; H, 8.37; N, 10.90. Found: C, 68.52; H, 8.07; N, 10.98.
(4R,5R)-1,3-Dim eth yl-4,5-d ip h en yl-2-(d ip h en yla m in o)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (4e). Following Repre-
sentative Procedure 1, from triethylamine (0.42 mL; 3.0 mmol,
2.3 equiv), (R,R)-N,N′-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (314 mg, 1.31 mmol), and diphenylaminophosphoric
dichloride (450 mg, 1.57 mmol, 1.2 equiv) in CH2Cl2 (30+15+15
mL) was obtained 372 mg (63%) of 4e as an amorphous solid
after chromatography (SiO2, CH2Cl2, CH2Cl2/i-PrOH, 50/1 then
25/1), [R]22D ) +25.7° (c ) 0.65, CHCl3); TLC Rf ) 0.73 (EtOAc);
31P NMR (162 MHz, CDCl3) δ 20.76.
C
25H36N3OP (425.56): C, 70.56; H, 8.53; N, 9.87. Found: C,
70.74; H, 8.63; N, 9.82. HPLC tR (+)-(S,S)-6a , 9.93 min (Daicel
ChiralCel AD, hexane/EtOH, 97/3, 0.5 mL/min.).
(4R,5R)-1,3-Dim eth yl-4,5-bis(2-n a p h th yl)-2-(1-p ip er id i-
n yl)-1,3,2-d ia za p h osp h olid in e 2-Oxid e (6e). Following Rep-
resentative Procedure 1a, from triethylamine (185 µL, 1.32
mmol, 3.5 equiv), the diamine 20e (180 mg, 0.529 mmol), and
piperidinylphosphoramic dichloride (89 µL, 0.582 mmol, 1.1
equiv) in 50 mL of CH2Cl2 was obtained 75 mg (30%) of 6e as
white crystals after column chromatography (SiO2, EtOAc/i-
PrOH, 9/1) and recrystallization (hexane), mp: 205-206 °C
(hexane); [R]22 ) +80.7° (c ) 1.38, CHCl3); TLC Rf ) 0.39
D
(TBME/MeOH 20/1); 31P NMR (202 MHz, CDCl3) δ 27.38. Anal.
Calcd for C29H32N3OP (469.59): C, 74.18; H, 6.87; N, 8.95; P,
6.60. Found: C, 74.12; H, 6.75; N, 8.68; P, 6.72.
(4S,5S)-1,3-Dim et h yl-4,5-d ip h en yl-2-(1-p yr r olid in yl)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (4f). Following Repre-
sentative Procedure 1, from triethylamine (0.55 mL, 3.93
mmol, 2.5 equiv), (S,S)-N,N′-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (0.377 g, 1.57 mmol), and 1-pyrrolidinylphosphoramic
dichloride (0.295 g, 1.57 mmol, 1.0 equiv) in CH2Cl2 (20+8+8
mL) was obtained 0.34 g (61%) of 4f as white crystals after
column chromatography (SiO2, EtOAc/i-PrOH 9/1) and recrys-
tallization (hexane), mp: 105-106 °C (hexane); TLC Rf ) 0.32
(EtOAc/i-PrOH, 10/1). Anal. Calcd for C20H26N3OP (355.42):
C, 67.5; H, 7.37; N, 11.82. Found: C, 67.36; H, 7.13; N, 11.78.
(4S,5S)-4,5-Dip h en yl-2-(1-p ip er id in yl)-1,3,2-d ia za p h os-
p h olid in e 2-Oxid e (5a ). Following Representative Procedure
1, from triethylamine (0.63 mL, 4.5 mmol, 3.0 equiv), (S,S)-
1,2-diphenyl-1,2-ethanediamine (0.318 g, 1.5 mmol), and 1-pi-
peridinylphosphoric dichloride (0.23 mL, 1.5 mmol, 1.0 equiv)
in CH2Cl2 (14+8+8 mL) was obtained 0.301 g (59%) of 5a as
white crystals after column chromatography (SiO2, EtOAc/i-
PrOH 10/1) and recrystallization (CHCl3/hexane). Anal. Calcd
for C19H24N3OP (341,37): C, 66.85; H, 7.09; N, 12.31. Found:
C, 66.52; H, 6.90; N, 12.13.
(4S,5S)-1,3-Dim eth yl-4,5-dicycloh exyl-2-(1-piper idin yl)-
1,3,2-d ia za p h osp h olid in e 2-Oxid e (6f). Following Repre-
sentative Procedure 1a, from triethylamine (305 µL, 2.19
mmol, 2.4 equiv), the diamine 20f (230 mg, 0.911 mmol), and
piperidinylphosphoric dichloride (153 µL, 0.929 mmol, 1.02
equiv) in 100 mL of CH2Cl2 was obtained 172 mg (49%) of 6f
as a white foam after column chromatography (SiO2, EtOAc/
i-PrOH, 19/1), [R]22D ) +1.5° (c ) 2.31, CHCl3); TLC Rf ) 0.52
(EtOAc/i-PrOH 19/1); 31P NMR (162 MHz, CDCl3) δ 27.48.
HRMS (CI) for C21H41N3OP Calcd: 382.2987, Found: 382.2991.
(7aS,3S)- an d (7aS,3R)-3-P iper idin o-1,2,5,6,7,7a-h exah y-
d r o-2-m eth ylp yr r olo[1,2-c][1,3,2]d ia za p h osp h ole 3-Oxid e
(7a a n d 8a ). Following Representative Procedure 1a, from
triethylamine (7.08 mL, 50.8 mmol, 2.1 equiv), the diamine
24a 30 (2.75 g, 24.1 mmol), and piperidinylphosphoric dichloride
(4.0 mL, 25.4 mmol, 1.05 equiv) in 125 mL of THF were
obtained 1.587 g (27%) of 7a and 1.891 g (32%) of 8a as
colorless oils after column chromatography (SiO2, TBME/
MeOH, 9/1) and Kugelrohr distillation.31 Data for 7a: bp:
160-161 °C (ABT, 0.01 mmHg); [R]22 ) +2.7° (c ) 1.43,
D
CHCl3); TLC Rf ) 0.29 (TBME/MeOH, 19/1); 31P NMR (162
MHz, CDCl3) δ 28.22. Anal. Calcd for C11H22N3OP (243.29):
C, 54.31; H, 9.11; N, 17.27. Found: C, 54.49; H, 9.23; N, 17.24.
(4R,5R)-1,3-Dim eth yl-4,5-bis(4-(tr iflu or om eth yl)ph en yl)-
2-(1-p ip er id in yl)-1,3,2-d ia za p h osp h olid in e 2-Oxid e (6a ).
Following Representative Procedure 1a, from triethylamine
(230 µL, 1.64 mmol, 4.5 equiv), 20a (137 mg, 0.364 mmol), and
piperidinylphosphoric dichloride (61 µL, 0.4 mmol, 1.1 equiv)
in 70 mL of CH2Cl2 was obtained 75 mg (41%) of 6a as white
needles after column chromatography (SiO2, TBME/MeOH, 19/
Data for 8a : bp: 195-196 °C (ABT, 0.01 mmHg); [R]22
)
D
-14.2° (c ) 1.28, CHCl3); TLC Rf ) 0.18 (TBME/MeOH, 19/
1); 31P NMR (162 MHz, CDCl3) δ 24.12.
(7aS,3S)- an d (7aS,3R)-3-P iper idin o-1,2,5,6,7,7a-h exah y-
d r o-2-(p h e n ylm e t h yl)p yr r olo[1,2-c][1,3,2]d ia za p h os-
p h ole 3-Oxid e (7b a n d 8b). Following Representative Pro-
cedure 1a, from triethylamine (4.24 mL, 30.5 mmol, 2.1 equiv),
the diamine 24b31 (2.74 g, 14.5 mmol), and piperidinylphos-
phoric dichloride (2.32 mL, 15.2 mmol, 1.05 equiv) in 80 mL
of THF were obtained 7b (1.79 g, 45%) and 8b (1.95 g, 49%)
after column chromatography (SiO2, TBME/MeOH, 19/1, and
then 4/1) and Kugelrohr distillation. Data for 7b: bp: 231 °C
1) and recrystallization, mp: 138-139 °C (hexane). [R]22
)
D
+0.6° (c ) 2.10, CHCl3 (+24.2° at 405 nm)); TLC Rf ) 0.38
(TBME/MeOH, 20/1); 31P NMR (202 MHz, CDCl3) δ 29.54; 19
NMR (470 MHz, CDCl3) δ -64.18, -64.22; HRMS (CI) for
23H27F6N3OP Calcd: 506.1796, Found: 506.1790. Anal. Calcd
F
C
for C23H26F6N3OP (505.45): C, 54.66; H, 5.18; N, 8.31. Found:
C, 54.75; H, 5.22; N, 7.84. HPLC tR (+)-(R,R)-6a, 20.73 min
(Daicel ChiralCel AD, hexane/EtOH, 97/3, 0.5 mL/min).
(4R,5R)-1,3-Dim eth yl-4,5-bis(4-m eth oxyp h en yl)-2-(1-p i-
p er id in yl)-1,3,2-d ia za p h osp h olid in e 2-Oxid e (6b). Fol-
lowing Representative Procedure 1a, from triethylamine (610
µL, 4.35 mmol, 2.5 equiv), the diamine 20b (523 mg, 1.74
mmol), and piperidinylphosphoric dichloride (280 µL, 1.83
mmol, 1.05 equiv) in 160 mL of CH2Cl2 was obtained 560 mg
(75%) of 6b as white foam after column chromatography (SiO2,
EtOAc/i-PrOH, 9/1), which was recrystallized (hexane) to give
(ABT, 0.01 mmHg); [R]22 ) -28.6° (c ) 2.40, CHCl3); TLC Rf
D
) 0.36 (EtOAc/i-PrOH, 19/1). 31P NMR (162 MHz, CDCl3) δ
28.36. Anal. Calcd for C17H26N3OP (319.39): C, 63.93; H, 8.21;
N, 13.16, P, 9.70. Found: C, 64.08; H, 8.23; N, 13.18, P, 9.73.
8b: TLC Rf ) 0.19 (EtOAc/i-PrOH 19/1). 31P NMR (162 MHz,
CDCl3) δ 23.62.
P r ep a r a tion of (-)-(7a S,3S)- a n d (+)-(7a S,3R)-3-P ip -
er id in o-1,2,5,6,7,7a -h exa h yd r o-2-(3,5-d im et h ylp h en yl)-
p yr r olo[1,2-c][1,3,2]-d ia za p h osp h ole 3-Oxid e (7c a n d 8c).

Synthesis of Phosphoramides
J . Org. Chem., Vol. 64, No. 6, 1999 1965
Following Representative Procedure 1a, from triethylamine
(0.94 mL, 6.73 mmol 2.1 equiv), the diamine 24c31 (655 mg,
3.21 mmol), and piperidinylphosphoric dichloride (0.52 mL,
3.37 mmol, 1.05 equiv) in 80 mL of THF were obtained 7c (270
mg, 25%) and 8c (278 mg, 26%) after column chromatography
(SiO2, TBME/MeOH, 19/1) and recrystallization (EtOAc/hex-
was obtained 0.126 g (59%) of 9c as a colorless oil after
chromatography (SiO2, EtOAc/i-PrOH, 10/1) and Kugelrohr
distillation, bp: 185-190 °C (0.5 mmHg); [R]22 ) -94.58 (c
D
) 1.13, CHCl3); TLC Rf ) 0.22 (SiO2, EtOAc/i-PrOH, 10/1);
31P NMR (162 MHz, CDCl3) δ 28.80. Anal. Calcd for C12H26N3-
OP (259.33): C, 55.58; H, 10.11; N, 16.20; P, 11.94. Found:
C, 55.50; H, 10.16; N, 16.15; P, 11.79.
ane). Data for 7c: mp: 136-137 °C (EtOAc/hexane); [R]22
)
D
-29.6° (c ) 1.38, CHCl3); TLC Rf ) 0.43 (TBME/MeOH 20/1);
31P NMR (162 MHz, CDCl3) δ 22.51. Anal. Calcd for C18H28N3-
OP (333.42): C, 64.84; H, 8.46; N, 12.60; P, 9.29. Found: C,
64.73; H, 8.50; N, 12.56; P, 8.89. Data for 8c: mp: 148-149
(3a R,7a R)-1,3-Bis(1′-m et h ylet h yl)oct a h yd r o-2-(d im e-
th yla m in o)-2H-1,3,2-ben zod ia za p h osp h ole 2-Oxid e (9d ).
Following Representative Procedure 1a, from (1R,2R)-N,N′-
bis(1′-methylethyl)-1,2-cyclohexanediamine (0.162 g, 0.82 mmol),
triethylamine (0.285 mL, 2.04 mmol, 2.5 equiv), and dimethyl-
aminophosphoric dichloride (0.097 mL, 0.82 mmol, 1.0 equiv)
in 10 mL of CH2Cl2 was obtained 0.087 g (37%) of 9d as a
white solid after chromtography (SiO2, EtOAc/i-PrOH, 10/1).
Data for 9d : TLC Rf ) 0.36 (SiO2, EtOAc/i-PrOH, 10/1); 31P
NMR (162 MHz, CDCl3) δ 24.42.
°C (EtOAc/hexane); [R]22 ) +68.1° (c ) 1.14, CHCl3); TLC Rf
D
) 0.28 (TBME/MeOH, 20/1); 31P NMR (162 MHz, CDCl3) δ
17.11. Anal. Calcd for C18H28N3OP (333.42): C, 64.84; H, 8.46;
N, 12.60; P, 9.29. Found: C, 64.85; H, 8.36; N, 12.61; P, 9.27.
P r ep a r a tion of (-)-(7a S,3S)- a n d (+)-(7a S,3R)-3-P ip -
er id in o-1,2,5,6,7,7a -h exa h yd r o-2-(2,4,6-tr im eth ylp h en yl)-
p yr r olo[1,2-c][1,3,2]-d ia za p h osp h ole 3-Oxid e (7d a n d 8d ).
Following Representative Procedure 1, from triethylamine
(1.18 mL, 8.45 mmol 2.1 equiv), the diamine 24d 31 (879 mg,
4.03 mmol), and piperidinylphosphoric dichloride (0.65 mL,
4.23 mmol, 1.05 equiv) in 100 mL of THF were obtained 7d
(463 mg, 33%) and 8d (371 mg, 26%) as thick oils after column
chromatography (SiO2, TBME/MeOH, 32/1) and Kugelrohr
distillation. Data for 7d : bp: 175 °C (ABT, 3.8 × 10-5 mmHg);
TLC Rf ) 0.58 (TBME/MeOH 19/1); 31P NMR (162 MHz,
CDCl3) δ 22.20. Data for 8d : bp: 185 °C (ABT, 3.8 × 10-5
mmHg); TLC Rf ) 0.41 (TBME/MeOH, 19/1); 31P NMR (162
MHz, CDCl3) δ 14.27.
(3a R,7a R)-1,3-Bis(p h en ylm eth yl)octa h yd r o-2-(d im eth -
ylam in o)-2H-1,3,2-ben zodiazaph osph ole 2-Oxide (9e). Fol-
lowing Representative Procedure 1a, from triethylamine (0.29
mL, 2.08 mmol, 3.7 equiv), (1R,2R)-N,N′-bis(phenylmethyl)-
1,2-cyclohexanediamine (0.164 g, 0.56 mmol), and dimethyl-
aminophosphoric dichloride (0.066 mL, 0.56 mmol, 1.0 equiv)
in CH2Cl2 (6 mL) was obtained 0.123 g (57%) of 9e as a white
solid after chromatography (SiO2, EtOAc/hexane, 2/1) and
recrystallization (hexane), mp: 135-136 °C (hexane); [R]22
D
) -94.19 (c ) 1.05, CHCl3); TLC Rf ) 0.14 (EtOAc/hexane,
2/1); 31P NMR (162 MHz, CDCl3) δ 30.25. Anal. Calcd for
C22H30N3OP (383.230): C, 68.91; H, 7.89; N, 10.96; P, 8.08.
Found: C, 68.88; H, 7.88; N, 10.95; P, 8.05.
P r ep a r a tion of (+)-(7a S,3S)- a n d (+)-(7a S,3R)-3-P ip -
er id in yl-1,2,5,6,7,7a -h exa h yd r o-2-(1-n a p h t h yl)p yr r olo-
[1,2-c][1,3,2]-d ia za p h osp h ole 3-Oxid e (7e a n d 8e). Follow-
ing Representative Procedure 1a, from triethylamine (3.26 mL,
23.4 mmol 2.1 equiv), the diamine 24e31 (2.56 g, 11.3 mmol),
and piperidinylphosphoric dichloride (1.82 mL, 11.9 mmol, 1.05
equiv) in THF (150 mL) were obtained 7e (1.36 g, 34%) and
8e (1.36 g, 34%) after column chromatography (SiO2, TBME/
MeOH, 19/1) and recrystallization (EtOAc/hexane).5 Data for
7e: mp: 129-131 °C (EtOAc/hexane); [R]22D ) +42.3 (c ) 1.90,
CHCl3); TLC Rf ) 0.39 (TBME/MeOH, 20/1); 31P NMR (162
MHz, CDCl3) δ 22.88. Anal. Calcd for C20H26N3OP (355.42):
C, 67.59; H, 7.37; N, 11.82; P, 8.71. Found: C, 67.37; H, 7.15;
N, 11.57; P, 8.68.
(3a R,7a R)-1,3-Dim et h yloct a h yd r o-2-p ip er id in yl-2H -
1,3,2-ben zod ia za p h osp h ole 2-Oxid e (9a ). Following Rep-
resentative Procedure 1a, from triethylamine (0.50 mL, 3.60
mmol, 2.0 equiv), (1R,2R)-N,N′-dimethyl-1,2-cyclohexanedi-
amine (0.253 g, 1.80 mmol), and piperidinylphosphoric dichlo-
ride (0.364 g, 1.80 mmol, 1.0 equiv) in EtOAc (18 mL) was
obtained 0.282 g (58%) of 9a as white needles after chroma-
tography (SiO2, EtOAc/i-PrOH, 10/1) and recrystallization
(hexane), mp: 111-112 °C (hexane). [R]22D ) -90.8° (c ) 1.15,
CHCl3); TLC Rf ) 0.20 (EtOAc/i-PrOH, 10/1); 31P NMR (162
MHz, CDCl3) δ 29.50. Anal. Calcd for C13H26N3OP (271.34):
C, 57.54; H, 9.66; N, 15.49; P, 11.41. Found: C, 57.49; H, 9.62;
N, 15.40; P, 11.36.
(3a R,7a R)-1,3-Bis(2′,2′-d im et h ylp r op yl)oct a h yd r o-2-
(d im eth yla m in o)-2H-1,3,2-ben zod ia za p h osp h ole 2-Oxid e
(9f). Following Representative Procedure 1, from triethylamine
(0.17 mL, 1.20 mmol, 2.5 equiv), (1R,2R)-N,N′-bis(2′,2′-dim-
ethylpropyl)-1,2-cyclohexanediamine (0.123 g, 0.48 mmol), and
dimethylaminophosphoric dichloride (0.057 mL, 0.48 mmol, 1.0
equiv) in CH2Cl2 (14+1+1 mL) was obtained 45 mg (27%) of
9f as a white solid after chromatography (SiO2, EtOAc/hexane,
1/1). Data for 9f: TLC Rf ) 0.36 (EtOAc/hexane, 1/1); 31P NMR
(162 MHz, CDCl3) δ 35.64.
(3a R,7a R)-1,3-Dim et h yl-2-(b is(1-m et h ylet h yl)a m in o-
2H-1,3,2-octa h yd r oben zod ia za p h osp h ole 2-Oxid e (9g).
Following Representative Procedure 1a, from triethylamine
(0.35 mL, 2.50 mmol, 2.5 equiv), (1R,2R)-N,N′-dimethyl-1,2-
cyclohexanediamine (0.143 g, 1.02 mmol), and bis(1-methyl-
ethyl)aminophosphoric dichloride (0.216 g, 1.00 mmol, 1.0
equiv) in CH2Cl2 (3 mL) was obtained 0.019 g (7%) of 9g as a
white solid after chromatography (SiO2, EtOAc). Data for 9g:
TLC Rf ) 0.17 (EtOAc); 31P NMR (162 MHz, CDCl3) δ 29.81.
(3aR,7aR,1′S)-1,3-Dim eth yloctah ydr o-2-[m eth yl(1′-ph en -
ylet h yl)a m in o]-2H -1,3,2-b en zod ia za p h osp h ole 2-Oxid e
(9h ). Following Representative Procedure 1a, from triethy-
lamine (0.20 mL, 1.43 mmol, 2.5 equiv), (1R,2R)-N,N′-dim-
ethyl-1,2-cyclohexanediamine (0.80 g, 1.80 mmol, 3.2 equiv),
and N-methyl-(1′-phenylethyl)aminophosphoric dichloride (0.143
g, 0.57 mmol, 1.0 equiv) in 6 mL of CH2Cl2 was obtained 0.115
g (63%) of 9h as a white solid after chromatography (SiO2,
EtOAc/i-PrOH, 15/1) and recrystallization (hexane), mp: 107-
(3a R,7a R)-1,3-Dim eth ylocta h yd r o-2-(d im eth yla m in o)-
2H-1,3,2-ben zod ia za p h osp h ole 2-Oxid e (9b). Following
Representative Procedure 1a, from triethylamine (0.84 mL,
0.61 g, 6.04 mmol, 2.01 equiv), (1R,2R)-N,N-dimethyl-1,2-
cyclohexanediamine (0.424 g, 3.00 mmol), and dimethylami-
nophosphoric dichloride (0.36 mL, 3.00 mmol, 1.0 equiv) in 30
mL of EtOAc was obtained 0.578 g (83%) of 9b as a white solid
after chromatography (SiO2, EtOAc/i-PrOH, 10/1) and Kugel-
rohr distillation, bp: 170-175 °C (ABT, 0.3 mmHg); mp: 57-
108 °C (hexane); [R]22 ) -52.96 (c ) 1.06, CHCl3); TLC Rf )
D
0.16 (EtOAc); 31P NMR (162 MHz, CDCl3) δ 31.11. Anal. Calcd
for C17H28N3OP (321.40): C, 63.53; H, 8.78; N, 13.07; P, 9.64.
Found: C, 63.57; H, 8.82; N, 13.04; P, 9.56.
(R,R)-1,3-Dim et h yl-2-(d im et h yla m in o)-4,6-d ip h en yl-
1,3,2-d ia za p h osp h or in a n e 2-Oxid e (10). Following Repre-
sentative Procedure 1, from triethylamine (0.13 mL, 0.93
mmol, 2.5 equiv), (R,R)-N,N′-dimethyl-1,3-diphenyl-1,3-pro-
panediamine (0.094 g, 0.37 mmol), and dimethylaminophos-
phoric dichloride (0.044 mL, 0.37 mmol, 1.0 equiv) in CH2Cl2
(3+1+1 mL) was obtained 0.066 g (51%) of 10 as a white solid
after chromatography (SiO2, EtOAc/i-PrOH, 50/1). An analyti-
cal sample was obtained by recrystallization from hexane,
60 °C (melt). [R]22 ) -88.70 (c ) 1.0, CHCl3); TLC Rf ) 0.22
D
(SiO2, EtOAc/i-PrOH, 10/1); 31P NMR (162 MHz, CDCl3) δ
31.77. Anal. Calcd for C10H22N3OP (231.28): C, 51.93; H, 9.59;
N, 18.17; P, 13.39. Found: C, 51.94; H, 9.62; N, 18.17; P, 13.32.
(3a R,7a R)-1,3-Diet h yloct a h yd r o-2-(d im et h yla m in o)-
2H-1,3,2-ben zod ia za p h osp h ole 2-Oxid e (9c). Following
Representative Procedure 1a, from triethylamine (0.29 mL,
2.08 mmol, 2.5 equiv), (1R,2R)-N,N′-diethyl-1,2-cyclohexanedi-
amine (0.140 g, 0.83 mmol), and dimethylaminophosphoric
dichloride (0.099 mL, 0.83 mmol, 1.0 equiv) in CH2Cl2 (10 mL)
mp: 122-123 °C (hexane); [R]22 ) +16.87 (c ) 1.12, CHCl3);
D
TLC Rf ) 0.16 (EtOAc); 31P NMR (162 MHz, CDCl3) δ 19.00.

1966 J . Org. Chem., Vol. 64, No. 6, 1999
Denmark et al.
Anal. Calcd for C19H26N3OP (343.41): C, 66.45; H, 7.63; N,
12.24; P, 9.02. Found: C, 66.46; H, 7.66; N, 12.23; P, 8.98.
Rep r esen ta tive P r oced u r e 2 for th e Syn th esis of
P h osp h or a m id es fr om Am in op h osp h or u s Dich lor id e.
(4S,5S)-(+)-1,3-Dieth yl-4,5-diph en yl-2-(1-piper idin yl)-1,3,2-
d ia za p h osp h olid in e 2-Oxid e ((S,S)-5b). To a solution of
triethylamine (0.66 mL, 4.73 mmol, 2.2 equiv) in 80 mL of CH2-
Cl2 at reflux was added a solution of (1S,2S)-N,N′-diethyl-1,2-
diphenyl-1,2-ethanediamine (578 mg, 2.15 mmol) in 5 mL of
CH2Cl2 and a solution of piperidinylphosphorus dichloride
(0.33 mL, 2.15 mmol, 1.0 equiv)34 in 5 mL of CH2Cl2 simulta-
neously via a syringe pump in 2 h. After addition the solution
was heated to reflux for an additional 30 min and then was
cooled back to 0 °C. A solution of MCPBA in 10 mL of CH2Cl2
was then added via a syringe, and the solution was stirred at
room temperature overnight. The slightly yellow solution was
poured into a separatory funnel and washed with water (20
mL), saturated aqueous NaHCO3 (2 × 20 mL), and brine (20
mL). The organic layer was dried (Na2SO4) and concentrated
in vacuo to afford a crude product that was purified by column
chromatography (SiO2, CH2Cl2/MeOH, 19/1) to give 549 mg
(64%) of (S,S)-5b as a white solid. Recrystallization from
hexane gave 255 mg (30%) of white prisms, mp: 150-152 °C
(hexane); [R]22D ) +6.2° (c ) 1.20, CHCl3); TLC Rf ) 0.33 (CH2-
Cl2/MeOH, 19/1); 31P NMR: δ 28.12. Anal. Calcd for C23H32N3-
OP (397.50): C, 69.50%; H, 8.11%; N, 10.57%; P, 7.79%.
Found: C, 69.48%; H, 8.08%; N, 10.55%; P, 8.04%.
(4S,5S)-(+)-1,3-Dim eth yl-4,5-d ip h en yl-2-(bis(1-m eth yl-
eth yl)a m in o)-1,3,2-d ia za p h osp h olid in e 2-Oxid e ((S,S)-
4d ). Following Representative Procedure 2, from (S,S)-N,N′-
dimethyl-1,2-diphenyl-1,2-ethanediamine (483 mg, 2.01 mmol),
triethylamine (0.62 mL, 4.42 mmol, 2.2 equiv), and bis(1-
methylethyl)aminophosphoric dichloride39 (0.414 mL, 2.01
mmol, 1.0 equiv) in CH2Cl2 (80+10+10 mL) was obtained 0.549
g (71%) of 4d as a white foam after chromatography (SiO2,
TBME/MeOH, 49/1). TLC Rf ) 0.35 (TBME/MeOH, 19/1). 31P
NMR (202 MHz, CDCl3): δ 28.12. HRMS (CI) for C22H32N3OP
Calcd: 385.2283, Found: 385.2284.
p er id in yl)-1,3,2-d ia za p h osp h olid in e 2-Oxid e (1d ). To a
stirred, cold (-78 °C) solution of PCl3 (0.61 mL, 7.0 mmol, 1.1
equiv) in 10 mL of CH2Cl2 was added a solution of 1,2-bis(1-
naphthylamino)ethane12 (2.0 g, 6.4 mmol) in 10 mL of CH2Cl2
under nitrogen through a dropping funnel. Triethylamine (2.2
mL, 16 mmol, 2.5 equiv) was then added at the same
temperature. The mixture was warmed to room temperature
and stirred for an additional 24 h. After filtration of the
precipitates, the filtrate was condensed under reduced pres-
sure to remove the excess reagents.
The residue was suspended in 13 mL of CH2Cl2, and
piperidine (2.3 mL, 23 mmol, 3.6 equiv) was added with
stirring at room temperature. The mixture was stirred for 20
h and filtered to remove the precipitates, and the filtrate was
concentrated under reduced pressure to remove excess pip-
eridine.
To a solution of the residue in CH2Cl2 (10 mL) was added a
solution of MCPBA (50%, 2.21 g; 6.4 mmol) in CH2Cl2 (10 mL)
dropwise at 0 °C. The mixture was allowed to warm to room
temperature and was stirred for 24 h. Then, saturated aqueous
NaHCO3 was added with stirring. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 twice. The
combined organic extracts were washed with saturated aque-
ous NaHCO3, dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by column chromatography
(SiO2, benzene then benzene/EtOAc, 4/1 as eluents) and
recrystallization (Et2O/hexane) to give slightly tan crystals
(1.29 g; 46%), mp: 170-171 °C (CH2Cl2/hexane); TLC Rf )
0.83 (EtOAc); 31P NMR (162 MHz, CDCl3): δ 16.56. Anal. Calcd
for C27H28N3OP (441.51): C, 73.45; H, 6.39; N, 9.52; P, 7.02.
Found: C, 73.32; H, 6.42; N, 9.61; P, 6.74.
1,3-Dip h en yl-2-(d ip h en yla m in o)-1,3,2-d ia za p h osp h oli-
d in e 2-Oxid e (2b). Following Representative Procedure 3,
from PCl3 (0.5 mL, 5.73 mmol, 1.0 equiv), N,N′-diphenyl-1,2-
ethanediamine (1.10 g, 5.17 mmol), triethylamine (1.8 mL, 13
mmol, 2.5 equiv), diphenylamine (0.875 g, 5.17 mmol, 1.0
equiv), and MCPBA (50%, 1.78 g, 5.17 mmol, 1.0 equiv) was
obtained 1.59 g (72%) of 2b as colorless needles after chroma-
tography (SiO2, hexane/CH2Cl2, 2/1 then hexane/CH2Cl2/i-
PrOH, 2/1/0.03 as eluents) and recrystallization (benzene/
hexane), mp: 210-211 °C (hexane); TLC Rf ) 0.16 (EtOAc);
31P NMR (162 MHz, CDCl3) δ 7.43. Anal. Calcd for C26H24N3-
OP (425.47): C, 73.40; H, 5.69; N, 9.88; P, 7.28. Found: C,
73.48; H, 5.63; N, 9.92; P, 6.98.
(R)-1,3-Dim eth yl-2,3-d ih yd r o-2-p ip er id in yl-d in a p h th o-
[2,1-c:1′2′-e]-1H-[1,3,2]d ia za p h osp h ep in e 2-Oxid e ((R)-11).
A solution of (R)-N,N′-Dimethyl-1,1′-binaphthyl-2,2′-diamine40
((R)-27) (780 mg, 2.5 mmol) in THF (25 mL) was cooled to -72
°C in a dry ice/acetone bath. n-Butyllithium (1.44 M, 3.82 mL,
5.5 mmol) was added dropwise. The resulting orange solution
was allowed to warm to -30 °C before it was cooled back to
-75 °C. 1-Piperidinylphosphoric dichloride (512 mg, 2.75
mmol) in THF (25 mL) was added dropwise over 30 min and
the solution was allowed to slowly warm to room temperature
and stirred overnight. A solution of MCPBA (559 mg, 2.75
mmol) THF (12 mL) was then added dropwise at 0 °C, and
the mixture was stirred at room temperature overnight before
it was transferred to a separatory funnel containing saturated
aqueous NaHCO3 (150 mL) solution. The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (5 ×
35 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 solution (20 mL) and brine (20
mL), dried (Na2SO4) and concentrated under reduced pressure.
The yellow residue was purified by column chromatography
(SiO2, EtOAc/i-PrOH, 32/1 then 19/1) to give 742 mg (67%) of
(R)-11 as a slightly yellow solid. An analytical sample was
obtained by chromatotron separation (SiO2, EtOAc/i-PrOH, 49/
1, 32/1 then 19/1) and crystallization from toluene/hexane to
give white crystals (593 mg, 54%), mp: 276-277 °C (toluene/
(S)-1,3-Dip h en yl-2-[m eth yl(1-ph en yleth yl)a m in o]-1,3,2-
d ia za p h osp h olid in e 2-Oxid e (3b). Following Representative
Procedure 3, from PCl3 (0.95 mL; 11 mmol, 1.1 equiv), N,N′-
1,2-diphenyl-1,2-ethanediamine (2.12 g, 10 mmol), triethyl-
amine (3.5 mL; 25 mmol, 2.5 equiv), (S)-N-methyl-N-(1-
phenylethyl)amine (1.45 mL, 10 mmol, 1.0 equiv), and MCPBA
(50%, 3.45 g; 10 mmol, 1.0 equiv) was obtained 1.96 g (50%)
of 3b as colorless fine needles after chromatography (SiO2,
benzene/CH2Cl2/i-PrOH, 30/20/1) and recrystallization (CH2-
Cl2/hexane). An analytical sample was given by sublimation
at 0.05 mmHg: mp: 204-205 °C (0.05 mmHg). [R]22D ) +1.7°
(c ) 1.10, CHCl3); TLC Rf ) 0.87 (EtOAc); 31P NMR (162 MHz,
CDCl3) δ 15.31. Anal. Calcd for C23H26N3OP (391.45): C, 70.57;
H, 6.69; N, 10.73; P, 7.91. Found: C, 70.35; H, 6.56; N, 10.79;
P, 7.86.
(-)-(4S,5S)-1,3,4,5-Tet r a p h en yl-2-p ip er id in o-1,3,2-d i-
a za p h osp h olid in e 2-Oxid e (5c). Following Representative
Procedure 3, from PCl3 (69 µL, 0.79 mmol, 1.1 equiv), (S,S)-
N,N′,1,2-tetraphenyl-1,2-ethanediamine (261 mg, 0.716 mmol),
triethylamine (0.22 mL, 1.57 mmol, 2.2 equiv), piperidine (0.21
mL, 2.15 mmol, 3.0 equiv), and MCPBA (50%, 250 mg; 0.72
mmol, 1.0 equiv) was obtained 196 mg (55%) of 5c as an
amorphous solid after chromatography (SiO2, CH2Cl2/i-PrOH,
hexane); [R]22 ) -472° (c ) 1.18, CHCl3); TLC Rf ) 0.34
D
(EtOAc/i-PrOH, 19/1); 31P NMR (162 MHz, CDCl3): δ 27.38.
Anal. Calcd for C27H28N3OP (441.52): C, 73.45; H, 6.39; N,
9.52; P, 7.02. Found: C, 73.71; H, 6.42; N, 9.44; P, 6.81.
HPLC: tR (R)-11, 21.21 min (99.76%), tR (S)-11, 14.85 min
(0.24%) (â-GEM-1, hexane/i-PrOH, 65/35, 0.6 mL/min).
Rep r esen ta tive P r oced u r e 3 for th e Syn th esis of
P h osp h or a m id es fr om P Cl3. 1,3-Di(1-n a p h th yl)-2-(1-p i-
20/1), mp: 195-197 °C (hexane); [R]22 ) -194° (c ) 1.01,
D
CHCl3); TLC Rf ) 0.49 (EtOAc); 31P NMR (162 MHz, CDCl3)
δ 17.30. Anal. Calcd for C31H32N3OP (493.59): C, 75.44; H,
6.53; N, 8.51; P, 6.28. Found: C, 75.31; H, 6.30; N, 8.46; P,
6.09.
(-)-(4S,5S)-1,3-Di-(1-n a p h t h yl)-4,5-d ip h en yl-2-p ip er i-
d in o-2H-1,3,2-d ia za p h osp h olid in e 2-Oxid e (5d ). Following
Representative Procedure 3, from PCl3 (100 µL, 1.14 mmol,
(39) King, R. B.; Sundaram, P. M. J . Org. Chem. 1984, 49, 1784.
(40) Miyano, S.; Nawa, M.; Mori, A.; Hashimoto, H. Bull. Chem. Soc.
J pn. 1984, 57, 2171.

Synthesis of Phosphoramides
J . Org. Chem., Vol. 64, No. 6, 1999 1967
1.1 equiv), (S,S)-N,N′-di-(1-naphthyl)-1,2-diphenyl-1,2-ethanedi-
amine (482 mg, 1.04 mmol), triethylamine (363 µL, 3.12 mmol,
3.0 equiv), piperidine (310 µL, 3.12 mmol, 3.0 equiv), and
MCPBA (50%, 431 mg, 1.25 mmol, 1.2 equiv) was obtained
309 mg (50%) of 5d as an off-white foam after column
chromatography (hexane/EtOAc, 3/1 to 1/1), which was re-
crystallized from toluene/hexane to give white amorphous
186 °C (hexane); Rf ) 0.38 (EtOAc/i-PrOH, 9/1); 31P NMR (202
MHz, CDCl3): mixture of rotamers: δ 28.4 (br), 26.4 (br), 25.8
(br). Anal. Calcd for C29H32N3OP (469.57): C, 74.18; H, 6.87;
N, 8.95. Found: C, 74.10; H, 6.75; N, 8.88.
Ack n ow led gm en t. We are grateful to the National
Science foundation for generous financial support (CHE
9500397 and 9803124). X.S. thanks the University of
Illinois for a graduate fellowship. Y. N. thanks the
Ministry of Science and Education of J apan, and J . Y.
C. thanks the Korea Research Foundation (KRF) for
postdoctoral fellowships. D.M.C. thanks the Fulbright
foundation for a travel grant.
powder, mp: 188-190 °C (toluene/hexane); [R]22 ) -356° (c
D
) 1.01, CHCl3); TLC Rf ) 0.33 (hexane/EtOAc, 1/1); 31P NMR
(202 MHz, CDCl3) mixture of rotamers: δ 21.29 (br), 20.25
(br), 14.02 (minor). Anal. Calcd for C39H36N3OP (593.72): C,
78.90; H, 6.11; N, 7.08; P, 5.22. Found: C, 78.86; H, 6.26; N,
6.91; P, 5.18.
(()-1,3-Dim eth yl-4,5-d i-(1-n a p h th yl)-2-p ip er id in o-1,3,2-
d ia za p h osp h olid in e 2-Oxid e (6d ). Following Representative
Procedure 3, from PCl3 (97 µL, 1.11 mmol, 1.02 equiv), (()-
N,N′-dimethyl-1,2-di-(1-naphthyl)-1,2-ethanediamine (370 mg,
1.09 mmol), triethylamine (318 µL, 2.28 mmol, 2.1 equiv),
piperidine (269 µL, 2.72 mmol, 2.5 equiv), and MCPBA (70%,
563 mg, 2.28 mmol, 2.1 equiv) was obtained 196 mg (38%) of
6d as a white solid after column chromatography (EtOAc/i-
PrOH, 19/1 to 9/1) and recrystallization (hexane), mp: 183-
Su p p or tin g In for m a tion Ava ila ble: Characterizations
of the phosphoramides in Chart 1 and the synthesis and
characterizations of their amine precursors. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9820723