(Cyanomethyl)trialkylphosphonium iodides: Efficient reagents for the intermolecular alkylation of amines with alcohols in solution and on solid phase

Full text of DOI:10.1021/jo001735p

2518
J . Org. Chem. 2001, 66, 2518-2521
Sch em e 1. P r op osed Mech a n ism for a
P h osp h on iu m Sa lt Med ia ted Alk yla tion of Am in es
w ith Alcoh ols.
(Cya n om eth yl)tr ia lk ylp h osp h on iu m
Iod id es: Efficien t Rea gen ts for th e
In ter m olecu la r Alk yla tion of Am in es w ith
Alcoh ols in Solu tion a n d on Solid P h a se
Florencio Zaragoza* and Henrik Stephensen
Novo Nordisk A/ S, Novo Nordisk Park,
DK-2760 Måløv (Denmark)
flo@novonordisk.com
Received December 13, 2000
Sch em e 2. P r op osed Mech a n ism for th e
Alk yla tion of Am in es by Alcoh ols w ith th e Aid of
(Cya n om eth yl)p h osp h on iu m Iod id es 1.
One of the most frequently used procedures for the
preparation of tertiary amines is N-alkylation of second-
ary amines by treatment with alkylating agents (alkyl
halides, sulfonates, oxiranes, etc.) or reductive alkylation
with aldehydes or ketones. Few alkylating agents with
interesting pharmacophoric groups are, however, com-
mercially available, and many of them are toxic. Alde-
hydes are often unstable and cannot be stored for a long
time.
For our parallel synthesis program, we have been
seeking a reagent which would mediate the direct alky-
lation of amines with alcohols.1 Alcohols are usually
stable and easy to handle, can be purchased with a broad
variety of additional functional groups, and are therefore
ideal building blocks for the production of compound
libraries.2 Phosphonium salts A (Scheme 1) appeared to
be promising candidates for such a reaction, which could
proceed as outlined in Scheme 1. Due to the strength of
phosphorus-oxygen bonds, a phosphonium salt A should
selectively react with alcohols, even in the presence of
secondary amines. Because alkoxyphosphonium salts
such as B react faster with anionic nucleophiles than
with neutral nucleophiles, and generally do not react
smoothly with amines,1 salts B are not expected to react
with the amine, but to be converted into C. Anion X-
must be a suitable leaving group, so that intermediate
C is sufficiently reactive to alkylate the amine.
sketched in Scheme 1. Illustrative examples are listed
in Table 1. The reaction required heating and the
presence of a tertiary amine to proceed to completion.6
1
Analysis of the crude products by H NMR and HPLC
only revealed the presence of starting materials and the
desired product, and we assume that the fair yields were
due to losses during recrystallization. Secondary alcohols
could not be used in this reaction. Other suitable solvents
for this reaction, in addition to propionitrile, were aceto-
nitrile and dioxane, but in propionitrile at 90 °C the
reaction was homogeneous in all the cases studied and
proceeded faster than in dioxane (at 90 °C) or than in
refluxing acetonitrile (81 °C). For alkylations in solution,
the trimethylphosphonium iodide 1a (Table 1) proved
particularly advantageous, because the byproduct formed
(Me3PO) is water-soluble and can be easily separated
from the products. For reactions on solid phase (poly-
styrene cross-linked with 1% divinylbenzene), on the
other hand, both 1a and 1b were equally suitable.
Support-bound amines (3i and 3j, Table 1) underwent
the reaction cleanly, and no quaternization of the amines
was observed.7
The phosphonium salt [Ph3P+-N(Me)Ph][I-]3 as well
4
as the phosphorane Ph3P(OCH2CF3)2 has been used
previously to alkylate amines with alcohols, but these
reagents are highly water-sensitive and lead to the
formation of various byproducts (Ph3PO, PhNHMe) which
are difficult to separate from the desired tertiary amines.
Our aim was to find a reagent useful for parallel
synthesis, which should be stable, easy to handle, and
yield crude products of high purity.
A proposed mechanism for this new reaction is shown
in Scheme 2. It has been reported8 that some stabilized
phosphorus ylides react with alcohols to yield symmetric
Resu lts a n d Discu ssion
(5) We also prepared the corresponding (cyanomethyl)phosphonium
triflates, which showed a better solubility but a similar reactivity as
the iodides.
We found that (cyanomethyl)trialkylphosphonium io-
dides 1 (Scheme 25) cleanly underwent the reaction
(6) Kinetic studies, performed by treating an equimolar mixture of
1-(3-chlorophenyl)piperazine and 3-phenyl-1-propanol (each 0.5 mol L-1
in propionitrile) with 1a (1.2 equiv) and DIPEA (1.3 equiv) at various
temperatures and following the progress of the reaction by HPLC-MS,
showed that the reaction at 40 °C proceeded with a half-life of 1.25 h
and required at least 22 h to attain >98% conversion.
(7) The quaternization of amines on cross-linked polystyrene only
proceeds smoothly with strong alkylating agents (benzylic or allylic
halides) and generally requires higher temperatures and longer
reaction times than those used in the current procedure. In solution,
however, quaternization was observed when an excess of alcohol and
phosphonium salt was used.
(1) Zaragoza, F.; Stephensen, H. Tetrahedron Lett. 2000, 41, 1841-
1844.
(2) (a) Zaragoza Do¨rwald, F. Organic Synthesis on Solid Phase;
Wiley-VCH: Weinheim, 2000. (b) Zaragoza, F.; Stephensen, H. Angew.
Chem. 2000, 112, 565-567; Angew. Chem., Int. Ed. 2000, 39, 554-
556.
(3) Tanigawa, Y.; Murahashi, S.; Moritani, I. Tetrahedron Lett. 1975,
471-472. Several attempts by us to use [Ph3P+-N(Me)Ph][I-] for the
alkylation of resin-bound amines with alcohols were unsuccessful.
(4) Kubota, T.; Miyashita, S.; Kitazume, T.; Ishikawa, N. J . Org.
Chem. 1980, 45, 5052-5057. Phosphoranes R3P(OCH2CF3)2 are so
unstable and sensitive to moisture that Kubota et al. were unable to
isolate them.
(8) (a) Grayson, M.; Keough, P. T. J . Am. Chem. Soc. 1960, 82, 3919-
3924. (b) Pappas, J . J .; Gancher, E. J . Org. Chem. 1966, 31, 1287-
1289.
10.1021/jo001735p CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/10/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2519
Ta ble 1. P h osp h on iu m Iod id e Med ia ted Alk yla tion of Secon d a r y Am in es by Alcoh olsa
a
Entries a -h : phosphonium salt 1a (1.2 equiv) and diisopropylethylamine (DIPEA, 1.3 equiv) were added to an equimolar mixture of
the alcohol and the amine (both 1.0 equiv, 0.50 mol L-1) in propionitrile. The mixture was stirred at 90 °C for 2 h. Entries i, j: the
resin-bound amines 3 (1.0 equiv) were treated with a solution of the alcohol 2 (7.2 equiv, 0.56 mol L-1), salt 1b (6.1 equiv), and DIPEA
b
(8.1 equiv) in acetonitrile at 80 °C for 15 h. P ol: 1% cross-linked polystyrene with Wang linker. c Yields of recrystallized products.
d
Yield of trifluoroacetate salt after cleavage from the support.
ethers, presumably via alkoxyphosphonium alkoxides
such as B (Scheme 1, X- ) RO-). (Cyanomethyl)-
phosphonium salts (pKHA 79) can be deprotonated by
diisopropylethylamine (DIPEA) and can then react with
alcohols to yield intermediates 6.10 Thermolysis of the
latter in the presence of DIPEA hydroiodide leads to P-C
bond cleavage and release of acetonitrile, to yield alkoxy-
phosphonium iodides 7, which are known to decompose
smoothly to yield alkyl iodides 8.11 These react with
amines, to yield tertiary amines 4 or quaternary am-
monium salts, if an excess of alcohol and phosphonium
iodide is used.
We conclude that reagents 1 efficiently promote the
direct, intermolecular N-alkylation of amines with alco-
hols. Phosphonium iodides 1 are easy to prepare and to
handle and do not react with air, water, or alcohols at
(9) Zhang, X.; Bordwell, F. G. J . Am. Chem. Soc. 1994, 116, 968-
972.
(10) The isolated (cyanomethylene)phosphoranes 5 have been used
with success for Mitsunobu-type chemistry: Itoˆ, S.; Tsunoda, T. Pure
Appl. Chem. 1999, 71, 1053-1057. Isolated (cyanomethylene)phos-
phoranes 5 do not mediate the intermolecular N-alkylation of amines
with alcohols, because alkoxyphosphonium salts 7 can, in the absence
of other anions, only be formed as alkoxide salts in this case, which
mainly decompose to yield ethers. The intermolecular N-alkylation of
ammonium iodides under conditions of the Mitsunobu reaction has
recently been reported by us.1
(11) Rydon, H. N. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. VI, pp 830-832. The proposed mechanism is substantiated
further by our observation, that under similar reaction conditions as
described herein, (cyanomethyl)tributylphosphonium chloride cleanly
converts primary aliphatic alcohols into the corresponding chlorides.

2520 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
2-(4-Ch lor op h en et h yl)-2,3,4,9-t et r a h yd r o-1H -â-ca r b o-
lin e (4b). Yield: 83%; mp 193-195 °C (MeCN); HPLC-MS m/z
311 [MH+]; 1H NMR (400 MHz, DMSO-d6) δ 2.65-2.73 (m, 2H),
2.75-2.89 (m, 6H), 3.65 (s, 2H), 6.93 (t, J ) 7 Hz, 1H), 7.00 (t,
J ) 7 Hz, 1H), 7.22-7.35 (m, 6H), 10.68 (s, 1H). Anal. Calcd for
C19H19ClN2 (310.83): C, 73.42; H, 6.16; N, 9.01. Found: C, 73.43;
H, 6.37; N, 8.97.
1-(2-Naph th ylm eth yl)-4-ph en ylpiper azin e (4c). Yield: 70%;
mp 158-159 °C (MeCN); HPLC-MS m/z 303 [MH+]; 1H NMR
(400 MHz, DMSO-d6) δ 2.55 (m, 4H), 3.14 (m, 4H), 3.68 (s, 2H),
6.76 (t, J ) 8 Hz, 1H), 6.91 (d, J ) 8 Hz, 2H), 7.19 (t, J ) 8 Hz,
2H), 7.46-7.55 (m, 3H), 7.82 (s, 1H), 7.90 (m, 3H). Anal. Calcd
for C21H22N2 (302.42): C, 83.40; H, 7.33; N, 9.26. Found: C,
83.36; H, 7.48; N, 9.26.
4-(4-P en tylp ip er a zin o)p h en ol (4d ). Yield: 76%; mp 175-
177 °C (aqueous EtOH); HPLC-MS m/z 249 [MH+]; 1H NMR (400
MHz, DMSO-d6) δ 0.87 (t, J ) 7 Hz, 3H), 1.22-1.35 (m, 4H),
1.44 (quint, J ) 7 Hz, 2H), 2.28 (t, J ) 7 Hz, 2H), 2.46 (m, 4H),
2.93 (br s, 4H), 6.63 (d, J ) 8 Hz, 2H), 6.76 (d, J ) 8 Hz, 2H),
8.79 (s, 1H). Anal. Calcd for C15H24N2O (248.37): C, 72.54; H,
9.74; N, 11.28. Found: C, 72.34; H, 10.15; N, 11.27.
1-P h en yl-8-p r op yl-1,3,8-tr ia za sp ir o[4.5]d eca n -4-on e (4e).
Yield: 74%; mp 206-207 °C (AcOEt); HPLC-MS m/z 274 [MH+];
1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J ) 7 Hz, 3H), 1.47 (q,
J ) 7 Hz, 2H), 1.58 (br d, J ) 14 Hz, 2H), 2.30 (m, 2H), 2.50-
2.58 (m, 2H), 2.62-2.80 (m, 4H), 4.56 (s, 2H), 6.73 (t, J ) 7 Hz,
1H), 6.84 (m, 2H), 7.22 (m, 2H), 8.61 (s, 1H). Anal. Calcd for
room temperature. We found these reagents to offer a
convenient alternative to synthetic protocols, in which
an alcohol first is converted into an alkylating agent,
which is then used to alkylate an amine in a second step.
Currently we are exploring the scope of nucleophiles
which can be alkylated with these reagents and will
report our results in due course.
Exp er im en ta l Section
(Cya n om eth yl)tr im eth ylp h osp h on iu m Iod id e (1a ). A
solution of trimethylphosphine in toluene (1 mol L-1, 80 mL, 80
mmol) at 0 °C under nitrogen was diluted with toluene (40 mL)
and tetrahydrofuran (40 mL). Iodoacetonitrile (5.60 mL, 77.5
mmol) was then added dropwise while stirring energetically,
whereby a colorless solid precipitated. When the addition was
finished, the ice-bath was removed and stirring was continued
at room temperature for 40 h. The mixture was filtered, and
the solid was washed with toluene and dried under reduced
pressure. Recrystallization from acetonitrile (50 mL) yielded 14.7
g (78%) of the title compound as colorless crystals: mp 258-
259 °C. 1H NMR (400 MHz, DMSO-d6) δ 2.07 (d, J ) 17 Hz,
9H), 4.06 (d, J ) 17 Hz, 2H). Anal. Calcd for C5H11INP
(243.03): C, 24.71; H, 4.56; N, 5.76. Found: C, 24.81; H, 4.60;
N, 5.68.
Note: If an excess of iodoacetonitrile is used, a colored product
in lower yield may be obtained after recrystallization.
C
16H23N3O (273.38): C, 70.30; H, 8.48; N, 15.37. Found: C,
70.33; H, 8.64; N, 15.38.
(Cya n om et h yl)t r ib u t ylp h osp h on iu m Iod id e (1b ). To a
solution of tributylphosphine (85.7 g, 424 mmol) in toluene (275
mL) at 0 °C under nitrogen was added iodoacetonitrile (71.4 g,
428 mmol) at such a rate that the temperature remained <12
°C, while stirring energically. The mixture was kept at room
temperature for 18 h and was filtered, and the solid was dried
under reduced pressure. This solid was dissolved in hot aceto-
nitrile (75 mL), and then ethyl acetate (1.0 L) was added while
stirring at 78 °C. The mixture was kept at room-temperature
overnight, whereby the product crystallized. Filtration and
drying under reduced pressure yielded 139 g (89%) of the title
compound as colorless needles, mp 105-106 °C. 1H NMR (400
MHz, DMSO-d6) δ 0.93 (t, J ) 7 Hz, 9H), 1.43 (sext, J ) 7 Hz,
6H), 1.50-1.61 (m, 6H), 2.38-2.46 (m, 6H), 4.21 (br d, J ) 17
Hz, 2H). Anal. Calcd for C14H29INP (369.27): C, 45.54; H, 7.92;
N, 3.79. Found: C, 45.73; H, 8.02; N, 3.76.
1-P h en yl-8-(3-p h en ylp r op yl)-1,3,8-tr ia za sp ir o[4.5]d eca n -
4-on e (4f). Yield: 80%; mp 172-173 °C (MeCN); HPLC-MS m/z
1
350 [MH+]; H NMR (400 MHz, DMSO-d6) δ 1.55 (br d, J ) 14
Hz, 2H), 1.75 (quint, J ) 7 Hz, 2H), 2.33 (t, J ) 7 Hz, 2H), 2.46-
2.78 (m, 8H), 4.57 (s, 2H), 6.74 (m, 1H), 6.85 (m, 2H), 7.12-7.30
(m, 7H), 8.62 (s, 1H). Anal. Calcd for C22H27N3O (349.48): C,
75.61; H, 7.79; N, 12.02. Found: C, 75.30; H, 8.04; N, 12.16.
N-[3-(Diben zylam in o)pr opyl]ph th alim ide (4h ). Yield: 68%;
mp 113-115 °C (EtOH); HPLC-MS m/z 385 [MH+]; 1H NMR
(400 MHz, DMSO-d6) δ 1.81 (m, 2H), 2.38 (m, 2H), 3.46-3.57
(m, 6H), 7.13-7.39 (m, 10H), 7.83 (br s, 4H). Anal. Calcd for
C
25H24N2O2 (384.48): C, 78.10; H, 6.29; N, 7.29. Found: C, 77.99;
H, 6.57; N, 7.21.
1-[2-(1-Na p h th yl)eth yl]p ip er a zin e Tr iflu or oa ceta te (4i).
To Wang-resin-bound piperazine12 (1.05 g, 0.71 mmol) were
added phosphonium iodide 1b (1.85 g, 5.01 mmol) and a solution
of 2-(1-naphthyl)ethanol (1.04 g, 6.04 mmol) and DIPEA (1.25
mL, 7.16 mmol) in acetonitrile (15 mL). The mixture was shaken
at 80 °C for 15 h and filtered, and the resin was washed
extensively with N-methylpyrrolidinone (NMP), dichloromethane,
and methanol. Dichloromethane (5 mL) and trifluoroacetic acid
(5 mL) were added, and the mixture was shaken at 20 °C for 45
min. The mixture was filtered, and the filtrate was concentrated
under reduced pressure. The residue was redissolved in ethyl
acetate (4 mL), and upon addition of heptane the title compound
precipitated. A colorless solid (278 mg, 83%) was obtained: mp
191-193 °C; HPLC-MS m/z 241 [MH+]; 1H NMR (400 MHz,
DMSO-d6) δ 3.20-3.55 (m, 12H), 7.45-7.51 (m, 2H), 7.57 (m,
2H), 7.87 (m, 1H), 7.96 (m, 1H), 8.13 (m, 1H), 9.35 (br s, 3H).
Anal. Calcd for C20H22F6N2O4 (468.40): C, 51.29; H, 4.73; N, 5.98.
Found: C, 51.47; H, 4.77; N, 5.93.
Gen er a l P r oced u r e for th e Alk yla tion of Am in es w ith
Alcoh ols. 8-(2-P h en oxyet h yl)-1-p h en yl-1,3,8-t r ia za sp ir o-
[4.5]d eca n -4-on e (4g). The phosphonium iodide 1a (590 mg,
2.43 mmol) was added to a mixture of 2-phenoxyethanol (294
mg, 2.13 mmol; 2g), 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
(468 mg, 2.02 mmol; 3g), DIPEA (0.46 mL, 2.63 mmol), and
propionitrile (4.0 mL), and the mixture was stirred at 90 °C for
2 h. The mixture was allowed to cool to room temperature,
whereby it solidified. A solution of potassium carbonate (2.1 g)
in water (30 mL) was added, and the product was extracted with
dichloromethane (3 × 30 mL). The combined organic layers were
washed with brine (2 × 20 mL), dried with magnesium sulfate,
and concentrated under reduced pressure, to yield 747 mg of a
solid. Recrystallization from ethanol yielded 517 mg (73%) of
the title compound as colorless, microcrystalline solid: mp 219-
1
222 °C; HPLC-MS m/z 352 [MH+]; H NMR (400 MHz, DMSO-
N-(P h en eth yl)p r olin e Tr iflu or oa ceta te (4j). To Wang-
resin-bound N-Fmoc proline (0.73 g, 0.55 mmol) were added
NMP (8.0 mL) and piperidine (2.0 mL), and the mixture was
shaken at room temperature for 25 min. The resin was filtered
and washed with NMP. To the support were added phosphonium
iodide 1b (1.23 g, 3.33 mmol) and a solution of 2-phenylethanol
(0.47 mL, 3.92 mmol) and DIPEA (0.77 mL, 4.41 mmol) in
acetonitrile (7.0 mL). The mixture was shaken at 81 °C for 23 h
and filtered, and the resin was washed extensively with NMP,
dichloromethane, and methanol. Dichloromethane (4.0 mL) and
trifluoroacetic acid (4.0 mL) were added, and the mixture was
shaken at 20 °C for 35 min. Filtration and concentration of the
filtrate yielded an oil, which was redissolved in methanol (1 mL).
d6) δ 1.57 (br d, J ) 14 Hz, 2H), 2.50-2.60 (m, 2H), 2.75 (t, J )
6 Hz, 2H), 2.83 (m, 4H), 4.10 (t, J ) 6 Hz, 2H), 4.57 (s, 2H), 6.75
(t, J ) 7 Hz, 1H), 6.84 (d, J ) 8 Hz, 2H), 6.90-6.99 (m, 3H),
7.20-7.31 (m, 4H), 8.64 (s, 1H). Anal. Calcd for C21H25N3O2
(351.45): C, 71.77; H, 7.17; N, 11.96. Found: C, 71.49; H, 7.36;
N, 11.87.
With the same procedure as used for the preparation of 4g,
the following compounds were prepared:
2-P en t yl-2,3,4,9-t et r a h yd r o-1H -â-ca r b olin e (4a ). Yield:
74%; mp 119-120 °C (MeCN); HPLC-MS m/z 243 [MH+]; 1H
NMR (400 MHz, DMSO-d6) δ 0.89 (t, J ) 7 Hz, 3H), 1.31 (m,
4H), 1.53 (m, 2H), 2.49-2.53 (m, 2H), 2.66 (m, 2H), 2.73 (m, 2H),
3.56 (br s, 2H), 6.93 (t, J ) 7 Hz, 1H), 6.99 (t, J ) 7 Hz, 1H),
7.26 (d, J ) 7 Hz, 1H), 7.34 (d, J ) 7 Hz, 1H), 10.65 (s, 1H).
Anal. Calcd for C16H22N2 (242.37): C, 79.29; H, 9.15; N, 11.56.
Found: C, 79.21; H, 9.19; N, 11.35.
(12) Zaragoza, F.; Petersen, S. V. Tetrahedron 1996, 52, 10823-
10826.

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2521
The product crystallized upon addition of diethyl ether. The title
compound (115 mg, 76%) was obtained as light-brown needles,
mp 176-178 °C. HPLC-MS m/z 220 [MH+]; 1H NMR (400 MHz,
DMSO-d6) δ 1.75-1.87 (m, 1H), 1.94-2.06 (m, 2H), 2.23-2.36
(m, 1H), 2.89-3.00 (m, 2H), 3.03-3.12 (m, 1H), 3.19-3.26 (m,
1H), 3.33-3.41 (m, 1H), 3.56-3.62 (m, 1H), 3.99-4.07 (m, 1H),
7.21-7.38 (m, 5H). Anal. Calcd for C13H17NO2‚0.5(C2HF3O2)
(276.30): C, 60.86; H, 6.38; N, 5.07. Found: C, 60.86; H, 6.53;
N, 4.98.
Ack n ow led gm en t. We thank Vibeke Rode and
Henriette Christensen for HPLC-MS analyses of all
products and Flemming Gundertofte for the elemental
analyses.
J O001735P