A one-pot o-phosphinative passerini/pudovik reaction: Efficient synthesis of highly functionalized α-(phosphinyloxy)amide derivatives

Article abstract of DOI:10.1002/chem.201304618

A one-pot O-phosphinative Passerini/Pudovik reaction has been developed, based on reacting aldehydes, isocyanides, and phosphinic acids followed by the addition of second aldehydes to form the corresponding α-(phosphinyloxy) amide derivatives. This is the first reported instance of a Passerini-type, isocyanide-based multicomponent reaction using a phosphinic acid instead of a carboxylic acid. The nucleophilicity of the phosphinate group allows a subsequent catalytic Pudovik-type reaction, affording the highly functionalized α-(phosphinyloxy)amide derivative in high yield. A wide range of aldehydes and isocyanides are applicable to this reaction.

Full text of DOI:10.1002/chem.201304618

DOI: 10.1002/chem.201304618
Full Paper
&
Organic Synthesis
A One-Pot O-Phosphinative Passerini/Pudovik Reaction: Efficient
Synthesis of Highly Functionalized a-(Phosphinyloxy)amide
Derivatives
Takahiro Soeta,* Syunsuke Matsuzaki, and Yutaka Ukaji*[a]
Abstract: A one-pot O-phosphinative Passerini/Pudovik reac-
tion has been developed, based on reacting aldehydes, iso-
cyanides, and phosphinic acids followed by the addition of
second aldehydes to form the corresponding a-(phosphinyl-
oxy)amide derivatives. This is the first reported instance of
a Passerini-type, isocyanide-based multicomponent reaction
using a phosphinic acid instead of a carboxylic acid. The nu-
cleophilicity of the phosphinate group allows a subsequent
catalytic Pudovik-type reaction, affording the highly func-
tionalized a-(phosphinyloxy)amide derivative in high yield. A
wide range of aldehydes and isocyanides are applicable to
this reaction.
Introduction
the O-arylative Passerini reaction using nitrophenol derivatives,
developed by El Kaim and Grimaud in 2006.[3] Taguchi also re-
ported the direct alkylative Passerini reaction of an aldehyde,
an isocyanide and a free aliphatic alcohol, catalyzed by InIII.[4]
Acetals and ketals are also useful for the reaction of isocya-
nides when catalyzed by Lewis or Brønsted acids, affording a-
alkoxyimidates.[5] As described above, the acyl group in a car-
boxylic acid acts as an electrophile while its OH group works
as a nucleophile to the nitrilium intermediate during the Pass-
erini reaction. Thus, other molecules containing both electro-
philic and nucleophilic groups (Z-OH) could potentially act in
a similar manner to the carboxylic acid during the Passerini re-
action. Based on this hypothesis, we have previously devel-
oped an O-silylative Passerini reaction and the borinic acid cat-
alyzed a-addition of an isocyanide (Scheme 1).[6] We initially ex-
The multicomponent reactions of isocyanides represent con-
vergent processes in which three or more starting materials
are combined to generate a new product in practical, time-
saving, one-pot operations, by applying combinatorial strat-
egies or parallel synthesis. Historically, the reaction of an isocy-
anide with an aldehyde and a carboxylic acid to generate an
a-acyloxy amide was discovered by Passerini in 1921.[1] Subse-
quently, various modifications to this reaction were devel-
oped,[2] although only recently have other species been substi-
tuted for the carboxylic acid. The carboxylic acid is typically
a crucial component of the mixture due to the specific mecha-
nism by which the Passerini reaction progresses. This mecha-
nism has been widely studied and appears to involve activa-
tion of the aldehyde by the carboxylic acid, followed by addi-
tion of the isocyanide and trapping of the resulting nitrilium
intermediate by the carboxylate to afford the final product by
migration of the acyl group onto the oxygen atom derived
from the aldehyde. The carboxylic acid is, therefore, generally
a necessity during the reaction of an isocyanide with an alde-
hyde, or with an imine, as in the Ugi reaction. The requirement
to use a carboxylic acid unfortunately limits the application of
this reaction to the synthesis of a narrow range of molecules.
Only a few examples using other components in place of the
carboxylic acid have been reported to date. One example is
Scheme 1. The O-silylative Passerini reaction and the borinic acid catalyzed
a-addition of an isocyanide.
[a] Dr. T. Soeta, S. Matsuzaki, Prof. Dr. Y. Ukaji
Division of Material Sciences
amined whether phosphinic acid was able to participate in
a three-component coupling reaction with an aldehyde and an
isocyanide to afford the corresponding a-(phosphinyloxy)-
amide [Eq. (1), step 1]. We further investigated the reaction of
the resulting a-(phosphinyloxy)amide with aldehydes to gener-
ate a-hydroxyphosphinate derivatives [Eq. (1), step 2]. It has
been established that a-hydroxyphosphinic acid and its deriva-
Graduate School of Natural Science and Technology
Kanazawa University, Kakuma, Kanazawa
Ishikawa, 920-1192 (Japan)
Fax: (+81)76-264-5742
E-mail: soeta@se.kanazawa-u.ac.jp
ukaji@staff.kanazawa-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304618.
Chem. Eur. J. 2014, 20, 5007 – 5012
5007
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tives, such as the a-hydroxyphosphinates, can function as very
useful enzyme inhibitors.[7] For example, a-hydroxyphosphi-
nate-derived peptides have been applied as inhibitors of
human immunodeficiency virus (HIV) protease[8] and renin,[9] as
well as GABA antagonists[10] and herbicides.[11] The addition of
a phosphite to an aldehyde, known as the Pudovik reaction, is
the most versatile synthetic pathway to the a-hydroxyphosphi-
nates. Herein, we describe the first example of a one-pot phos-
phinative Passerini/Pudovik reaction, consisting of the reaction
between an aldehyde, an isocyanide and a phosphinic acid fol-
lowed by the addition of a second aldehyde to give the corre-
sponding a-hydroxyphosphinate derivative [Eq. (1)].
been used in the Ugi reaction as a protic solvent, produced
a very sluggish reaction from which only 5aa was obtained, in
55% yield, after 24 h (entry 5). Increasing the amount of the
isocyanide or the phosphinic acid to 1.5 equivalents did not
lead to any improvement in yield (entries 6 and 7), which indi-
cated that 1.0 equiv of both the isocyanide and the phosphinic
acid are sufficient to obtain the desired product in high yield
(entry 2). After having established an efficient method for the
O-phosphinative Passerini reaction, we then set out to evaluate
the effectiveness of phosphinic acids bearing other substitu-
ents (entries 8–11). When employing either (4-methoxyphenyl)-
phosphinic acid (3b), (4-tolyl)phosphinic acid (3c), or (4-chloro-
phenyl)phosphinic acid (3d), the product was obtained in
good yields (entries 8–10), while 5aa was the major product
when using (4-nitrophenyl)phosphinic acid (3e) (entry 11).
We also attempted to expand the range of isocyanides and
aldehydes applicable to the present O-phosphinative Passerini
reaction, utilizing phenylphosphinic acid (3a) in all cases, with
the results shown in Table 2. Throughout these trials, the opti-
mal amounts of the aldehydes 1a–e (1.0 equiv) and the isocya-
nides 2a–g (1.0 equiv) were used in the presence of 1.0 equiv
of phenylphosphinic acid (3a). The results demonstrate that
these conditions allow the reaction to proceed when employ-
ing a wide variety of aldehydes and isocyanides, and that most
reactions were complete within 24 h. The reactions of aliphatic
isocyanides (R2 =tOct, cHex, and Bn) with 1a and 3a gave the
products in good to high yields (Table 2, entries 2–4). Aldehyde
1a was consumed within 7 h when tert-octyl isocyanide (2b)
and cyclohexyl isocyanide (2c) were used, generating the
products in 89 and 86% yields, respectively (entries 2 and 3).
In the case of benzyl isocyanide (2d), the desired product
4ada was afforded in 98% yield without any of the hydrolyzed
product 5ad (entry 4). Aromatic isocyanides were also em-
ployed in this reaction (entries 5–7). When phenyl isocyanide
(2e) was used, the corresponding a-hydroxyamide 4aea was
obtained in 67% yield (entry 5). An aromatic isocyanide bear-
ing an electron-donating methoxy group at the para position
also exhibited high reactivity, forming the corresponding prod-
uct in 80% yield (entry 6). In the case of an aromatic isocya-
nide bearing an electron-withdrawing group bromo at the
para position, however, the reaction generated a complex mix-
ture of products (entry 7).
Results and Discussion
Our initial studies used a combination of phenylpropionalde-
hyde (1a), tert-butyl isocyanide (2a) (1.0 equiv), and phenyl-
phosphinic acid (3a) (1.0 equiv) in toluene at room tempera-
ture (Table 1, entry 1). We were pleased to observe that the ex-
pected a-(phosphinyloxy)amide (4aaa) was obtained in 81%
Table 1. Results of the O-phosphinative Passerini reaction under varying
conditions.
Entry Ar
Solvent t [h] Yield of 4 [%] Yield of 5aa [%]
1
2
3
4
Ph (3a)
toluene
CH2Cl2
Et2O
3
3
4
2
24
4
4
5
4
4
81 (4aaa)
96 (4aaa)
90 (4aaa)
62 (4aaa)
–
94 (4aaa)
94 (4aaa)
75 (4aab)
79 (4aac)
86 (4aad)
39 (4aae)
–
–
–
13
55
–
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
4-MeOC6H4 (3b) CH2Cl2
4-MeC6H4 (3c)
4-ClC6H4 (3d)
THF
5
MeOH
CH2Cl2
CH2Cl2
6[a]
7[b]
8
The reactivity of various aldehydes with tert-butyl isocyanide
(2a) was next examined. Aliphatic aldehydes 1b and 1c gave
the products in 84 and 61% yields, respectively (entries 8 and
9). Cinnamaldehyde (1d) and benzaldehyde (1e) both demon-
strated very low reactivities, and their reactions did not pro-
duce any of the desired product (entries 10 and 11).
–
14
14
11
59
9
10
11
CH2Cl2
CH2Cl2
4-O2NC6H4 (3e) CH2Cl2
2
[a] Using 1.5 equiv of 2a. [b] Using 1.5 equiv of 3a.
During the course of this investigation, we anticipated that
the subsequent coupling of a fourth component could be ac-
complished by exploiting the nucleophilic phosphorus atom in
the phosphinate group of 4. Since we had already found that
the a-(phosphinyloxy)amides are relatively unstable during
silica gel column chromatography, the conversion of 4 to more
stable compounds would have an additional practical advant-
age. We focused on the Pudovik-type reaction of aldehydes,
which involves the addition of dialkylphosphites to carbonyl
yield as a mixture of diastereomers after 3 h with little or no
generation of side products under these conditions. This reac-
tion proceeded efficiently in both dichloromethane and diethyl
ether to afford 4aaa in high yields (entries 2 and 3). The use of
the cyclic ether THF as the solvent was less effective, resulting
in the formation of a-hydroxyamide (5aa) in 13% yield, likely
due to the hydrolysis of 4aaa (entry 4). Methanol, which has
Chem. Eur. J. 2014, 20, 5007 – 5012
www.chemeurj.org
5008
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
the reaction was very sluggish
and produced 7Aa only a 23%
yield in the same time frame
(entry 4). Interestingly, when
using organic bases (entries 5
and 6), the reactions were com-
plete within 6 h and afforded
the product in 95 and 96%
yields. Finally, we found that the
use of 20 mol% Et3N afforded
the desired a-hydroxyphosphi-
nate 7Aa in 92% yield as a mix-
ture of four diastereomers
(entry 7).
Table 2. Range of isocyanides and aldehydes applicable to the O-phosphinative Passerini reaction.
Entry
R1
R2
t [h]
Yield of 4 [%]
Yield of 5 [%]
1
2
3
4
5
6
7
8
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
c-Hex (1b)
tBu (1c)
tBu (2a)
4
7
5
5
24
5
24
24
20
24
24
96 (4aaa)
89 (4aba)
86 (4aca)
98 (4ada)
67 (4aea)
80 (4afa)
complex
84 (4baa)
61 (4caa)
n.r.
–
8 (5ab)
13 (5ac)
–
22 (5ae)
10 (5af)
–
9 (5ba)
18 (5ca)
–
t-Oct (2b)
c-Hex (2c)
Bn (2d)
Ph (2e)
4-MeOC6H4 (2 f)
4-BrC6H4 (2g)
tBu (2a)
tBu (2a)
tBu (2a)
Having established an efficient
method for the combined, one-
pot O-phosphinative Passerini/
Pudovik reaction, we next inves-
tigated the scope of this multi-
9
10
11
2-phenylethenyl (1d)
Ph (1e)
tBu (2a)
n.r.
–
compounds to generate a-hydroxyphosphonates and is a pow-
erful and direct means of forming CÀP bonds. To date, a variety
of catalysts have been applied to this reaction, including
component reaction, using a variety of aldehydes (R3CHO) in
conjunction with phenylphosphinic acid (3a) (Table 4). It was
gratifying to find that our reaction system was indeed applica-
ble to a wide range of aldehydes when using 20 mol% Et3N in
CH2Cl2 at room temperature. Both 1-naphthaldehyde (6b) and
2-naphthaldehyde (6c) were found to work well as substrates
cesium
fluoride,[12]
triethylamine,[13]
1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU)[14] and lithium diisopropylamide
(LDA),[15] as well as BF3·OEt2,[16] TMSCl,[17] and trifluoroacetic acid
(TFA).[18] We therefore began by surveying suitable catalysts for
a one-pot phosphinate Passerini/Pudovik reaction aimed at ob-
taining the relatively stable a-hydroxyphosphinate derivatives.
To this end, 1.0 equiv of various additives along with
1.0 equiv of benzaldehyde (6a) were added to the reaction
vessel subsequent to the completion of the phosphinate Pass-
erini reaction of 1a, 2a, and 3a. Using TMSCl or BF3·OEt2 as
the additive, the intermediate species 4A (equivalent to 4aaa)
was consumed after 24 h, and the desired a-hydroxyphosphi-
nate 7Aa (or 7aaaa) was obtained in good yield (Table 3, en-
tries 1 and 2). When using Ti(OiPr)4 or other Lewis acids, how-
ever, the Pudovik reaction did not proceed at all (entry 3). The
effects of basic additives on this one-pot reaction were evalu-
ated next (entries 4–7). When cesium fluoride was employed,
Table 4. Range of aldehydes applicable to the O-phosphinative Passerini/
Pudovik reactions.
Entry
R1
R3
Yield [%]
1
2
3
4
5
6
7
8
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
BnCH2 (1a)
c-Hex (1b)
BnCH2 (1a)
iPr (1 f)
Ph (6a=1e)
92 (7Aa)
87 (7Ab)
87 (7Ac)
86 (7Ad)
90 (7Ae)
85 (7Af)
85 (7Ag)
88 (7Ah)
79 (7Ai)
72 (7Aj)
65 (7Ak)
81 (7Al)
88 (7Am)
n.r.
75 (7Ao)
78 (7Ap)
65 (7Aq)
82 (7baaa)
96 (7aada)
93 (7 fcda)
88 (7 fdaa)
1-naphthyl (6b)
2-naphthyl (6c)
2-MeC6H4 (6d)
2-ClC6H4 (6e)
3-ClC6H4 (6 f)
4-ClC6H4 (6g)
4-BrC6H4 (6h)
4-CF3C6H4 (6i)
4-MeC6H4 (6j)
4-MeOC6H4 (6k)
2-pyridyl (6l)
Table 3. One-pot phosphinate Passerini/Pudovik reactions.
9
10
11
12
13
14
15
16
17
18[a]
19[b]
20[c]
21[d]
2-furyl (6m)
2-phenylethenyl (6n=1d)
2-phenylethynyl (6o)
2-phenylethyl (6p=1a)
c-Hex (6q=1b)
Ph (6a=1e)
Ph (6a=1e)
Ph (6a=1e)
Ph (6a=1e)
Entry
additive
t [h]
Yield [%]
1
2
3
4
5
6
7
TMSCl
BF3·OEt2
Ti(OiPr)4
CsF
DMAP
Et3N
Et3N[a]
24
24
21
6
6
6
79
59
n.r.
23
95
96
92
iPr (1 f)
[a] Reaction time of the second step was 26 h. [b] 3d was used instead of
3a. [c] 2c and 3d were used instead of 2a and 3a, respectively. [d] 2d
was used instead of 2a.
6
[a] 20 Mol% Et3N was used. DMAP=4-dimethylaminopyridine.
Chem. Eur. J. 2014, 20, 5007 – 5012
www.chemeurj.org
5009
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
and the respective products 7Ab and 7Ac were ob-
tained in 87% yield (Table 4, entries 2 and 3). The
ortho-substituted benzaldehydes 6d and 6e were
also applicable to this reaction (entries 4 and 5). We
examined substituted benzaldehydes bearing elec-
tron-withdrawing groups (entries 5–9). Regarding the
substitution pattern of the benzaldehydes, the 2-, 3-,
and 4-chloro substituents were all tolerated, furnish-
ing the corresponding a-hydroxyphosphinate in high
yields (entries 5–7). Similar reactivities were observed
with 4-bromo and 4-(trifluoromethyl)benzaldehydes
(6h and 6i) (entries 8 and 9). The reactions of rela-
tively deactivated 4-methylbenzaldehyde (6j) and 4-
methoxybenzaldehyde (6k) showed lower reactivities
to afford the products in 72 and 65% yields, respec-
tively (entries 10 and 11). The heteroaromatic aldehydes 2-pyri-
dinecarboxaldehyde (6l) and furfural (6m) were also shown to
be applicable to this reaction, without any loss of efficiency in
the process (entries 12 and 13). Although cinnamaldehyde 6n
(=1d) was not effective in this reaction (entry 14), phenylpro-
pargyl aldehyde (6o) was shown to be a reactive substrate
and afforded the product 7Ao in 75% yield (entry 15). Aliphat-
ic aldehydes 6p (equivalent to 1a) and 6q (=1b) were also
useful in this reaction (entries 16 and 17). Finally, when the
combination of 1b, 2a, 3a, and 6a was tested, the corre-
sponding product 7baaa was obtained in 82% yield (entry 18).
The other combination of aldehyde, isocyanide, and phosphin-
ic acid were also useful in this reaction to afford the products
7aada, 7 fcda, and 7 fdaa in high yield (entries 20–22).
To assist in elucidating the reaction mechanism, we conduct-
ed a series of controlled experiments. These trials showed that
the addition reaction of isocyanide 2a to aldehyde 1a in the
absence of phenylphosphinic acid (3a) did not proceed in
CH2Cl2 over a period of 24 h [Eq. (2)]. In addition, when the re-
action of a-hydroxyamide 5aa with phosphinic acid 3a was at-
tempted in CH2Cl2 with reflux, none of the desired product,
4aaa, was obtained and 5aa was instead recovered [Eq. (3)].
This result indicates that the a-(phosphinyloxy)amide cannot
be formed by a dehydration reaction between the a-hydroxy-
amide 5 and the phosphinic acid 3.
Scheme 2. Proposed reaction mechanism.
the nitrilium intermediate A. This intermediate is subsequently
trapped by the phosphinate anion to afford the adduct 4
through migration of the phosphinate group onto the oxygen
atom originating from the aldehyde. Finally, after the deproto-
nation of the phosphinyloxy group by the catalytic base, nu-
cleophilic attack at the second aldehyde proceeds, generating
the corresponding a-(phosphinyloxy)amides (Scheme 2).
Conclusion
In summary, we have developed a one-pot O-phosphinative
Passerini/Pudovik reaction, in which combination of aldehydes,
isocyanides, and a phosphinic acids are first reacted, followed
by the addition of a second aldehydes to give the correspond-
ing highly functionalized a-(phosphinyloxy)amides in high
yields. This reaction is the first reported demonstration of an
isocyanide-based multicomponent reaction using a phosphinic
acid in place of a carboxylic acid. A wide range of aldehydes
and isocyanides are applicable to this reaction. Further studies
on this reaction are in progress in our laboratory.
Experimental Section
General
1H NMR spectra were recorded on a JEOL ECS 400 (400 MHz) NMR
spectrometer. Chemical shifts d are reported in ppm using TMS as
an internal standard. Data are reported as follows: Chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet), coupling constant (J) and integration. 13C NMR spectra
were recorded on JEOL ECS 400 (100 MHz) NMR spectrometer. The
chemical shifts were determined in the d-scale relative to CDCl3
(d=77.0 ppm). 31P NMR spectra were recorded on JEOL ECS 400
(162 MHz) NMR spectrometer. The chemical shifts were determined
in the d-scale relative to H3PO4 (d=0 ppm) as an external standard.
The IR spectra were measured on JASCO FT/IR-230 spectrometers.
The MS spectrum was recorded with JEOL SX-102A mass spectrom-
eter. All of the melting points were measured with YANAGIMOTO
micro melting-point apparatus. Dehydrated solvents were pur-
chased for the reactions and used without further desiccation.
Flash column chromatography was performed by using Cica silica
gel 60N, spherical neutral (37563–84).
Based on these findings, we propose the mechanism for the
present O-phosphinative Passerini reaction shown in Scheme 2.
In this mechanism, the aldehyde is activated by the acidic
proton of the phosphinic acid (pKa =1.75 in H2O)[19] through
coordination with the carbonyl oxygen. Subsequently, nucleo-
philic attack of the isocyanide at the carbonyl group provides
Chem. Eur. J. 2014, 20, 5007 – 5012
www.chemeurj.org
5010
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
Diastereomer 2: H NMR (CDCl3): d=1.37 (s, 9H), 2.00 (m, 1H), 2.17
(m, 1H), 2.58 (m, 2H), 4.66 (m, 1H), 5.15 (d, J=6.9 Hz, 1H), 6.78
(brs, 1H), 7.02 (d, J=6.9 Hz, 2H), 7.19–7.28 (m, 8H), 7.37 (m, 2H),
7.54–7.67 ppm (m, 3H); the OH proton was not observed clearly;
13C NMR (100 MHz, CDCl3): d=28.6, 30.4, 34.9 (d, J=3.8 Hz), 51.5,
73.6 (d, J=177.6 Hz), 75.2 (d, J=8.6 Hz), 126.0, 127.3 (d, J=4.8 Hz),
128.3, 128.4, 128.5, 132.5 (d, J=9.5 Hz), 133.1 (d, J=1.9 Hz), 135.4,
141.0, 168.9 ppm (d, J=2.9 Hz); 31P NMR (162 MHz, CDCl3): d=
39.8 ppm.
General procedure for the O-phosphinative Passerini reac-
tions
Compound 3 (0.5 mmol) was added to a solution of 1 (0.5 mmol)
and 2 (0.5 mmol) in CH2Cl2 (1 mL) and the whole mixture was
stirred at room temperature. After the reaction was completed
(monitored by TLC analysis), the solvent was removed under re-
duced pressure. The residue was purified by silica gel column chro-
matography to give the corresponding products.
Diastereomer 3: 1H NMR (CDCl3): d=1.25 (s, 9H), 1.79 (brs, 1H),
2.25 (m, 2H), 2.69 (m, 2H), 4.56 (m, 1H), 5.16 (d, J=9.6 Hz, 1H),
6.21 (brs, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.24–7.30 (m, 8H), 7.35 (m,
2H), 7.49–7.56 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=28.5,
30.2, 35.0, 51.3, 73.3 (d, J=182.3 Hz), 76.0 (d, J=7.6 Hz), 126.0,
126.9 (d, J=4.8 Hz), 128.3, 128.4, 128.5, 133.0 (d, J=8.6 Hz), 133.2,
136.1, 141.0, 168.4 ppm (d, J=4.8 Hz); 31P NMR (162 MHz, CDCl3):
d=39.1 ppm.
1-(tert-Butylamino)-1-oxo-4-phenylbutan-2-yl
phenylphosphi-
nate (4aaa): Silica gel column chromatography (hexane/ethyl ace-
tate=3:1~1:2) gave 4aaa (182 mg, 95% yield) as a colorless oil.
Diastereomeric ratio was determined to be 6:4 by 31P NMR spec-
troscopy. 1H NMR (CDCl3): d=1.30 (s, 9H), 1.38 (s, 9H), 2.13 (m,
2H), 2.31 (m, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H),
4.62 (m, 1H), 4.74 (m, 1H), 6.39 (brs, 1H), 6.42 (brs, 1H), 7.09 (d,
J=6.9 Hz, 2H), 7.15–7.30 (m, 8H), 7.52–7.58 (m, 4H), 7.67 (d, J=
571 Hz, 1H), 7.66 (m, 2H), 7.74 (d, J=571 Hz, 1H), 7.75–7.81 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=28.4, 28.5, 30.3, 30.6, 34.6
(d, J=3.8 Hz), 34.9 (d, J=3.8 Hz), 51.3, 51.4, 76.2 (d, J=7.6 Hz), 76.5
(d, J=7.6 Hz), 126.1 (d, J=10.5 Hz), 128.3, 128.3 (d, J=5.7 Hz),
128.4 (d, J=5.7 Hz), 129.1 (d, J=13.5 Hz), 129.5 (d, J=19.1 Hz),
130.5 (d, J=12.3 Hz), 133.6, 133.7, 140.5, 167.9 (d, J=2.9 Hz),
168.2 ppm (d, J=2.9 Hz); 31P NMR (162 MHz, CDCl3): d=27.5,
27.8 ppm; IR (neat): n˜ =3430, 2970, 2370, 1680, 1590, 1520, 1460,
1440, 1360, 1230, 1130, 960 cmÀ1; HRMS-FAB (m/z): calcd for
C20H27NO3P: 360.1729 [M++H]; found: 360.1726.
1
Diastereomer 4: H NMR (CDCl3): d=1.38 (s, 9H), 2.07 (m, 1H), 2.21
(m. 1H), 2.63 (t, J=8.2 Hz, 2H), 4.93 (m, 1H), 5.10 (d, J=8.2 Hz,
1H), 5.38 (brs, 1H), 7.00 (brs, 1H), 7.05 (d, J=7.4 Hz, 2H), 7.12–
7.25 (m, 8H), 7.33 (m, 2H), 7.49–7.53 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=28.6, 30.6, 35.4 (d, J=4.8 Hz), 51.7, 73.1 (d,
J=171.1 Hz), 74.3 (d, J=7.6 Hz), 126.1, 127.0 (d, J=5.7 Hz), 127.9,
128.0, 128.0, 128.1, 128.3, 128.4, 132.4 (d, J=9.5 Hz), 132.8, 135.6,
140.8, 170.0 ppm; 31P NMR (162 MHz, CDCl3): d=40.5 ppm.
Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientists
(B) (24750037) and a Grant in-Aid for Scientific Research (B)
(24350022) from the Japan Society for the Promotion of Sci-
ence.
General procedure for the one-pot O-phosphinative Passeri-
ni/Pudovik reactions
Compound 3 (0.5 mmol) was added to a solution of 1 (0.50 mmol)
and 2 (0.5 mmol) in CH2Cl2 (1 mL) and the whole mixture was
stirred at room temperature. After the reaction was completed
(monitored by TLC analysis), the solvent was removed under re-
duced pressure. The residue was diluted by CH2Cl2 (0.1 mL) and
triethylamine (0.01 mmol) and aldehyde (0.5 mmol) were added to
the solution. The whole mixture was stirred at room temperature.
After the reaction had reached completion (monitored by TLC anal-
ysis), water was added and organic layer was separated. The aque-
ous layer was extracted by CHCl3 (5 mL ꢁ3), and the combined or-
ganic layers were washed with brine followed by drying over
Na2SO4. The residue was purified by silica gel column chromatogra-
phy.
Keywords: aldehydes
·
isocyanides
·
multicomponent
reactions · one-pot reactions · Passerini/Pudovik reaction
[1] a) M. Passerini, Gazz. Chem. Ital. 1921, 51, 181–189; b) M. Passerini,
Gazz. Chem. Ital. 1921, 51, 126–129.
[2] For recent enantioselective Passerini-type reactions, see: a) H. Mihara, Y.
Xu, N. E. Shepherd, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009,
131, 8384–8385; b) T. Yue, M.-X. Wang, D.-X. Wang, J. Zhu, Angew.
Chem. 2008, 120, 9596–9599; Angew. Chem. Int. Ed. 2008, 47, 9454–
9457; c) S.-X. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. 2008,
120, 394–397; Angew. Chem. Int. Ed. 2008, 47, 388–391; d) S. E. Den-
mark, Y. Fan, J. Org. Chem. 2005, 70, 9667–9676; e) P. R. Andreana, C. C.
Liu, S. L. Schreiber, Org. Lett. 2004, 6, 4231–4233; f) U. Kusebauch, B.
Beck, K. Messer, E. Herdtweck, A. Dçmling, Org. Lett. 2003, 5, 4021–
4024; g) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2003, 125, 7825–7827.
[3] a) L. El Kaim, M. Gizolme, L. Grimaud, J. Oble, J. Org. Chem. 2007, 72,
4169–4180; b) L. El Kaim, M. Gizolme, L. Grimaud, Org. Lett. 2006, 8,
5021–5023.
[4] a) H. Yanai, T. Sakiyama, T. Oguchi, T. Taguchi, Tetrahedron Lett. 2012, 53,
3161–3164; b) H. Yanai, T. Oguchi, T. Taguchi, J. Org. Chem. 2009, 74,
3927–3929.
[5] a) M. Tobisu, A. Kitajima, S. Yoshioka, I. Hyodo, M. Oshita, N. Chatani, J.
Am. Chem. Soc. 2007, 129, 11431–11437; b) S. Yoshioka, M. Oshita, M.
Tobisu, N. Chatani, Org. Lett. 2005, 7, 3697–3699.
1-(tert-Butylamino)-1-oxo-4-phenylbutan-2-yl
[hydroxy-
(phenyl)methyl](phenyl)phosphinate (7Aa): Silica gel column
chromatography (chloroform/diethyl ether=6:1) gave 7Aa
(208 mg, 92% yield) as a white amorphous solid. The diastereo-
meric mixture was further separated by recycle HPLC (hexane/
AcOEt=2:1) for analysis. Diastereomeric ratio was determined to
be 2:1:1:2 by 31P NMR spectroscopy.
1
Diastereomer 1: H NMR (CDCl3): d=1.24 (s, 9H), 2.18 (m, 2H), 2.70
(m, 2H), 3.64 (brs, 1H), 4.53 (m, 1H), 5.16 (d, J=8.7 Hz, 1H), 6.30
(brs, 1H), 7.19 (m, 2H), 7.24–7.29 (m, 8H), 7.38–7.43 (m, 2H), 7.56
(m, 1H), 7.65 ppm (m, 2H); the OH proton was not observed clear-
ly; 13C NMR (100 MHz, CDCl3): d=28.4, 30.2, 35.2 (d, J=1.9 Hz),
51.2, 73.5 (d, J=184.8 Hz), 76.1 (d, J=7.6 Hz), 125.9, 126.0, 127.2
(d, J=4.8 Hz), 128.3, 128.4, 128.5, 132.5 (d, J=9.5 Hz), 133.1 (d, J=
2.8 Hz), 135.7, 141.1, 168.6 ppm (d, J=3.8 Hz); 31P NMR (162 MHz,
CDCl3): d=38.9 ppm; IR (KBr): n˜3280, 2970, 1670, 1540, 1450, 1370,
1220, 1050 cmÀ1; HRMS-ESI (m/z): calcd for C27H32NO4PNa: 488.1967
[M++Na]; found: 488.1956.
[6] a) T. Soeta, Y. Kojima, Y. Ukaji, K. Inomata, Tetrahedron Lett. 2011, 52,
2557–2559; b) T. Soeta, Y. Kojima, Y. Ukaji, K. Inomata, Org. Lett. 2010,
12, 4341–4343.
[7] For reviews, see: a) Aminophosphonic and Aminophosphinic Acids, (Eds.:
V. P. Kuhkar, H. R. Hudson), John Wiley, Chichester, UK, 2000; b) P. Kafar-
ski, B. Lejczak, Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 301–312;
c) L. Berlicki, P. Kafarski, Curr. Org. Chem. 2005, 9, 1829–1850; d) D. Red-
Chem. Eur. J. 2014, 20, 5007 – 5012
www.chemeurj.org
5011
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
more in Topics in Phosphorus Chemistry (Eds.: E. J. Griffith, M. Grayson),
John Wiley, New York, 1976; Vol. 8, pp. 515–585.
[8] B. Stowasser, K.-H. Budt, L. Jian-Qi, A. Peyman, D. Ruppert, Tetrahedron
Lett. 1992, 33, 6625–6628.
[9] D. V. Patel, K. Rielly-Gauvin, D. E. Ryono, C. A. Free, W. L. Rogers, S. A.
Smith, J. M. DeForrest, R. S. Oehl, E. W. Petrillo, Jr., J. Med. Chem. 1995,
38, 4557–4569.
[12] F. Texier-Boullet, A. Foucaud, Synthesis 1982, 165–166.
[13] R. E. Dolle, T. F. Herpin, Y. C. Shimshock, Tetrahedron Lett. 2001, 42,
1855–1858.
[14] O. Pꢃmies, J.-E. Bꢄckvall, J. Org. Chem. 2003, 68, 4815–4818.
[15] V. J. Blazis, K. J. Koeller, C. D. Spilling, J. Org. Chem. 1995, 60, 931–940.
[16] M. S. Kharasch, R. A. Mosher, I. S. Bengelsdorf, J. Org. Chem. 1960, 25,
1000–1006.
[10] a) W. Froestl, S. J. Mickel, R. G. Hall, G. von Sprecher, D. Strub, P. A. Bau-
mann, F. Brugger, C. Gentsch, J. Jaekel, H.-R. Olpe, G. Rihs, A. Vassout,
P. C. Waldmeier, H. Bittiger, J. Med. Chem. 1995, 38, 3297–3312; b) W.
Froestl, S. J. Mickel, G. von Sprecher, P. J. Diel, R. G. Hall, L. Maier, D.
Strub, V. Melillo, P. A. Baumann, R. Bernasconi, C. Gentsch, K. Hauser, J.
Jaekel, G. Karlsson, K. Klebs, L. Maꢂtre, C. Marescaux, M. F. Pozza, M.
Schmutz, M. W. Steinman, H. van Riezen, A. Vassout, C. Mondadori, H.-R.
Olps, P. C. Waldmeier, H. Bittiger, J. Med. Chem. 1995, 38, 3313–3331.
[11] a) R. E. Rosen, D. G. Weaver, J. W. Cornille, L. A. Spangler, U. S. Patent 5,
500, 405, 1996; b) L. A. Spangler, M. Mikołajczyk, E. L. Burdge, P. Kiełba-
[17] a) A. H. Kategaonkar, R. U. Pokalwar, S. S. Sonar, V. U. Gawali, B. B. Shin-
gate, M. S. Shingare, Eur. J. Med. Chem. 2010, 45, 1128–1132; b) G. A.
Olah, A.-H. Wu, J. Org. Chem. 1991, 56, 902–904.
[18] E. E. Nifant’ev, T. S. Kukhareva, T. N. Popkova, O. V. Davydochkina, Zh.
Obshch. Khim. 1986, 56, 304–309.
[19] L. D. Quin, M. R. Dysart, J. Org. Chem. 1961, 26, 1012–1014.
Received: November 26, 2013
Revised: January 21, 2014
´
´
sinski, H. C. Smith, P. Łyzwa, J. D. Fisher, J. Omelanczuk, J. Agric. Food
Chem. 1999, 47, 318–321.
Published online on March 11, 2014
Chem. Eur. J. 2014, 20, 5007 – 5012
www.chemeurj.org
5012
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim