Direct synthesis of β-alkyl N-aryl aza Baylis-Hillman adducts via nitroso-ene reaction

Article abstract of DOI:10.1021/jo301266f

A new approach for the direct Fe-catalyzed synthesis of β-alkyl N-aryl aza Baylis-Hillman (ABH) adducts is reported. This approach involves the formation of a C-N bond via a nitroso-ene reaction. This is a simple, fast, and best alternate method to overcome the substrate scope limitations of the ABH reaction, which converts allyl esters and carbonyl compounds to novel ABH adducts. A variety of arylhydroxylamines reacted with esters, aldehydes, ketone, and nitriles to yield the corresponding products in moderate to excellent yields.

Full text of DOI:10.1021/jo301266f

Note
pubs.acs.org/joc
Direct Synthesis of β‑Alkyl N‑Aryl Aza Baylis−Hillman Adducts via
Nitroso-Ene Reaction
Siva Murru, August A. Gallo, and Radhey S. Srivastava*
Department of Chemistry, University of Louisiana at Lafayette, Lafayette, Louisiana 70504, United States
S
* Supporting Information
ABSTRACT: A new approach for the direct Fe-catalyzed synthesis of
β-alkyl N-aryl aza Baylis−Hillman (ABH) adducts is reported. This
approach involves the formation of a C−N bond via a nitroso-ene
reaction. This is a simple, fast, and best alternate method to overcome
the substrate scope limitations of the ABH reaction, which converts
allyl esters and carbonyl compounds to novel ABH adducts. A variety of arylhydroxylamines reacted with esters, aldehydes,
ketone, and nitriles to yield the corresponding products in moderate to excellent yields.
he Aza Baylis−Hillman (ABH) or Aza Morita−Baylis−
Hillman (AMBH) reaction1 is an important carbon−
have been reported so far, the former due to instability7 and the
latter due to poor reactivity of imine functionality. In ABH
reaction, use of aliphatic aldehydes leads to a mixture of β-
amino ester resulting from the attack of the enolate on the
imine and of the corresponding β-hydroxy ester resulting from
a direct attack of the enolate on the aldehyde.8 In light of this,
various research groups have developed multistep approaches
for the synthesis of β-alkyl amino carbonyl compounds via the
traditional Baylis−Hillman reaction and other alternate
methods1a (Scheme 2). The use of ABH reaction/products
always requires the activation of the intermediate alcohol (BH
adduct) function as a bromide, an acetate, a phosphate or as
any other leaving group.9 Another limitation of this method is
that the possibility of obtaining a mixture of products via
nucleophilic substitution (SN2) product and allylic substitution
(SN2′) (Scheme 2).10
T
carbon bond-forming process that affords densely function-
alized β-amino carbonyl compounds, which are widely used for
the synthesis of biologically active compounds, medicinal
reagents, and natural products.2 The N-aryl β-aminoacid
derivatives are key structural elements of many natural
products, drug intermediates, β-peptides, β-lactam antibiotics.3
The N-aryl β-aminoacid derivative, SB-214857, is a potent
GPIIb/IIIa receptor antagonist currently in phase III clinic trials
for the protection of secondary thrombotic events such as heart
attack and stroke.3c,d The classical ABH reaction uses activated
aldimines, α,β-unsaturated carbonyls, and nucleophilic catalysts.
The activated aryl aldimines mainly includes tosylimines,4a
nosylimines,4b SES-imines,4a phosphinoylimines4 of their
corresponding aromatic aldehydes and amides (Scheme 1).
The usefulness of the ABH reaction has encouraged
researchers to employ different alternatives to overcome these
existing limitations. Since there is no report of using aldimines
of their corresponding aliphatic aldehydes and arylamines to
synthesize highly useful β-alkyl N-arylamino ABH adducts, we
envisaged that it would be possible to access the same adducts
via a nitroso-ene reaction11 using arylhydroxylamines and
tiglate esters as substrates (Scheme 3). This method involves a
C−N bond formation, whereas C−C bond formation takes
place in the ABH reaction. We have been working in the field of
iron and copper-catalyzed nitroso-ene reactions using nitro-
soarenes, arylhydroxylamines, and simple olefins as well as
alkynes.12 So far, there is no report on nitroso-ene reactions
using α,β-unsaturated esters. However, to our surprise,
ethyltiglate undergoes a nitroso-ene reaction to yield a β-alkyl
N-arylamino ABH adduct using our previously developed Fe-
catalytic system.12a,b
Scheme 1. Aza Baylis−Hillman Reaction Using Activated
Aryl Aldimines
Enormous efforts have been made to this valuable process in
the past decades;1a nevertheless, the ABH reaction remains to
be restricted in substrate scope, protic (polar) solvents5 and
poor reaction rates.1 Two major limitations of ABH reactions
related to the nature of imine substrates are (i) the nitrogen
counterpart of imine requires activated/protected amine such
as sulfonamides, phosphonamides, etc., and (ii) the aldehyde
counterpart of the imines should always be aromatic, i.e.
benzaldehydes. The activated aromatic aldimines were well
explored for the ABH reaction to prepare N-protected β-amino
carbonyl compounds (Scheme 1). However, neither activated
aliphatic aldimines nor N-aryl aromatic aldimines are suitable
precursors for the ABH reaction, for which very rare examples6
Initially we screened a known set of iron catalysts12a,b,13 such
as Fe(Pc), FeCl2.4H2O, anhydrous FeCl3, Fe(acac),
Received: June 20, 2012
© XXXX American Chemical Society
A
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Note
Scheme 2. Alternate Multistep Process to Prepare β-Alkyl ABH Adducts
Scheme 3. Direct Synthesis of N-Aryl β-Alkyl ABH Adducts
Table 1. β-Alkyl N-Aryl ABH Adducts Formation Using
a
Phenylhydroxylamine
[Fe(azodioxide)3]2+, and copper catalysts12c−f,14a−c [Cu-
(MeCN)4]PF6, CuCl, CuCl2·2H2O, and CuBr·SMe2 for the
synthesis of ABH adduct using phenylhydroxylamine (nitrogen
fragment donor) and ethyltiglate in 1,4-dioxane at a range of
temperatures (up to 100 °C). We have found that FeCl2·4H2O
and [Fe(azodioxide)3]2+ complex12a,b afforded ABH adduct in
75 and 78% yield, respectively, at 40 °C in a relatively very
short time (6 h) unlike the reported methods, which require
longer reaction times, usually 1−3 days.1a Because of easy
availability and low cost, we preferred FeCl2·4H2O catalyst for
the present ABH adduct formation. When a series of α,β-
unsaturated esters (a−d), ketone (e), aldehydes (f, g), and
nitriles (h, i) were subjected to optimized conditions (10 mol %
FeCl2·4H2O, 1,4-dioxane, 40 °C) with phenylhydroxylamine
(1), corresponding N-phenyl β-alkyl ABH adducts (1a−1i)
were produced in good to excellent yields as shown in Table 1.
GC−MS analyses of reaction mixtures indicate that a small
amount (<5%) of aniline and azoxybenzene were detected,
which are due to reduction and condensation of phenyl-
hydroxylamine (1). To minimize the side product formation,
we have used syringe pump to deliver phenylhydroxylamine
solution slowly. The α,β-unsaturated esters having allylic C−H
bonds, ethyltiglate (a), sec-butyltiglate (b), methy-2-methyl-2-
pentenoate (c) reacted well with phenylhydroxylamine (1) and
gave the corresponding ABH adducts (1a, 1b, 1c) in excellent
yields.
Though methyl methacrylate (d) is structurally similar to the
other esters, the reaction gave a moderate yield of adduct 1d
(57%) along with aniline (21%) as a side product. Other
functional groups such as the ketone and aldehydes are well
tolerated under the present reaction conditions. 3-Methyl-3-
penten-2-one (e), 2-methyl-2-pentenal (f), 2-methyl-2-butenal
(g) gave the expected products (1e, 1f, 1g) in good yields,
which are better than previously reported for similar ABH
reaction adducts.15 A relatively lower yield of aldehydes is due
to the possible formation of a condensation product of
PhNHOH with aldehydes. To diminish the condensation
process, reactions of aldehydes (f, g) were carried out at 30 °C.
The reaction of methacrylonitrile (h) was not effective (1h,
<5%) in the present reaction condition, possibly because of the
strong coordination of the nitrile to metal thereby making the
catalyst less active. As we expected, an increase in the reaction
temperature (up to 70 °C) and substrate ratio (PhNHOH/
nitrile: 1/5) improved the yield up to 12% (GC), but the
formation of other side products were also observed in this
reaction. Unsuccessful attempts were made to purify this
product by column chromatography. Surprisingly, when we
replaced the methacrylonitrile (h) with 2-methyl-2-butene
a
All reactions were performed at 40 °C with 1:3 substrate ratio
b
c
(PhNHOH:substrate). Isolated yields. Reactions performed at 30
°C. Reactions performed at 70 °C. GC yield.
d
e
nitrile (i), a very good improvement in the product yield (1i,
42%) was observed at 70 °C. We have carried out an
experiment with phenylhydroxylamine in large scale (5 g) using
ethyltiglate to give ABH adduct (1a) in 62% yield, which
confirms the scalability of the present reaction.
Having established this new approach with various α,β-
unsaturated carbonyls and nitriles using phenylhydroxylamine
(1), we chose to evaluate other substituted arylhydroxylamines
(2, 3, 4) by keeping ethyltiglate (a) constant (Table 2). p-
tolylhydroxylamine (2) reacted very similar to phenylhydroxyl-
amine to give the target product (2a) in 72% yield. This
methodology was successfully applied to other 2-haloaryl
hydroxylamines (3 and 4) and afforded halogenated ABH
adducts (3a and 4a) without any side reaction. The formation
B
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Note
reaction works with a variety of carbonyl derivatives such as
esters, aldehydes, a ketone and nitriles. The present approach is
based on C−N bond formation via a nitroso-ene reaction in
which nitroso compounds are generated in situ from the
corresponding arylhydroxylamines. This is the best alternate
method to Aza Baylis−Hillman reaction to access β-alkyl N-
arylamino ABH adducts. This new strategy is operationally
simple and provides a practical solution to access novel ABH
adducts, and it should allow for the future advances in the field
of aza Baylis−Hillman reactions.
Table 2. β-Alkyl N-Aryl ABH Adducts Formation Using
Ethyltiglate
a
EXPERIMENTAL SECTION
■
General Information. All the reagents were commercial grade and
purified according to the established procedures. Organic extracts were
dried over anhydrous sodium sulfate. Solvents were removed in a
rotary evaporator under reduced pressure. Silica gel (60−120 mesh
size) was used for the column chromatography. Reactions were
monitored by TLC on silica gel 60 F254 (0.25 mm). NMR spectra were
recorded in CDCl3 with tetramethylsilane (TMS) as the internal
1
standard for H NMR (400 MHz) and for 13C NMR (100 MHz).
Mass spectra were recorded by electro spray ionization (ESI) with a
Q-TOF.
a
All reactions were performed at 40 °C with 1:3 substrate ratio
b
General Procedure for the Preparation of β-Alkyl N-Aryl Aza
Baylis−Hillman Adduct (1a). To the solution of FeCl2·4H2O (5 mg,
0.025 mmol), ethyltiglate (80 μL, 0.75 mmol) in dioxane (3 mL) was
added the phenylhydroxylamine (0.25 mmol) solution slowly in
dioxane (4 mL) via syringe pump over 4 h at 40 °C. Reactions were
allowed to continue for two more hours to get complete consumption
of phenylhydroxylamine. After that, the mixture was filtered through
Celite, and the filtrate was concentrated to dryness. The crude product
was purified over a short column of silica gel (hexane/ethylacetate
eluents) to give the corresponding ABH adduct in 75% (41 mg)
isolated yield, which was then directly analyzed by GC−MS, NMR, IR,
and ESI-MS analysis.
Ethyl 2-Methylene-3-(phenylamino)butanoate (1a). 41 mg,
75% yield: Colorless gum; 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H,
J = 7.2 Hz), 1.40 (d, 3H, J = 6.4 Hz), 3.92 (brs, 1H), 4.24 (q, 2H, J =
7.2 Hz), 4.39 (q, 1H, J = 6.4 Hz), 5.75 (s, 1H), 6.17 (s, 1H), 6.53 (d,
2H, J = 6.4 Hz), 6.68 (t, 1H, J = 7.2 Hz), 7.14 (t, 2H, J = 6.4 Hz); 13C
NMR (100 MHz, CDCl3) δ 13.1, 20.9, 49.1, 59.7, 112.4, 116.5, 123.3,
128.1, 141.3, 145.6, 165.5; IR (KBr) 3402, 2975, 2932, 1710, 1619,
1514, 1283, 1182, 1105, 1023, 953, 810 cm−1; HRMS (ESI) calcd for
C13H18NO2 (M + H+), 220.1338, found 220.1336.
(ArNHOH:substrate) unless otherwise mentioned. Isolated yields.
of these halogenated ABH product can undergo further
coupling reactions for the elaboration of more complex
compounds, such as N-heterocycles.16
To confirm the catalyst involvement in the reaction, we
performed two experiments without using catalyst: (i) reaction
of phenylhydroxylamine and ethyltiglate and (ii) reaction of
nitrosobenzene and ethyltiglate. First reaction did not give any
ABH adduct, where as the second reaction gave an N-hydroxy
ABH adduct (1a′, Scheme 4) in lower yield (32%), which is an
Scheme 4. Nitroso-Ene Reaction Pathway to Access β-Alkyl
N-Aryl ABH Adducts
sec-Butyl 2-Methylene-3-(phenylamino)butanoate (1b). 52
mg, 83% yield: Yellow oil; 1H NMR (400 MHz, CDCl3) 0.93 (q, 3H, J
= 7.6 Hz), 1.26 (t, 3H, J = 7.2 Hz), 1.40 (d, 3H, J = 6.8 Hz), 1.58−1.67
(m, 2H), 3.97 (brs, 1H), 4.40 (q, 1H, J = 6.4 Hz), 4.95−4.98 (m, 1H),
5.71 (s, 1H), 6.15 (s, 1H), 6.54 (d, 2H, J = 7.6 Hz), 6.68 (t, 1H, J = 7.2
Hz), 7.13 (t, 2H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 9.7,
19.4, 21.9, 28.8, 50.1, 72.6, 113.4, 117.5, 123.9, 129.1, 142.8, 146.7,
166.2; IR (KBr) 3403, 3020, 2972, 2934, 2878, 1704, 1602, 1505,
1455, 1375, 1282, 1091, 749, 692 cm−1; HRMS (ESI) calcd for
C15H22NO2, 248.1651, found 248.1648.
intermediate in the present method. From these observations,
we concluded that the catalyst is required for the present
reaction. We have already established the mechanism of allylic
amination of unactivated olefins in which metal−nitroso
complexes are found to be the intermediates.12a,b We believe
that the present reaction also follows a similar pathway, which
basically involves three consecutive steps, i.e., oxidation,
nitroso-ene, and reduction as shown in Scheme 4. The
efficiency and high product yields of this method are mainly
due to high reactivity of the esters and carbonyl compounds
when compared to simple allylic substrates.8 This catalytic
process involves both oxidation and reduction steps, thereby
helping to regenerate the catalyst to complete the catalytic
cycle.
Methyl 2-Methylene-3-(phenylamino)pentanoate (1c). 48
1
mg, 88% yield: White solid, Mp. 92−94 °C; H NMR (400 MHz,
CDCl3) δ 0.97 (t, 3H, J = 7.6 Hz), 1.61−1.67 (m, 1H), 1.72−1.85 (m,
1H), 3.76 (s, 3H), 4.17 (t, 1H, J = 6.0 Hz), 5.71 (s, 1H), 6.19 (s, 1H),
6.52 (d, 2H, J = 7.6 Hz), 6.66 (t, 1H, J = 7.2 Hz), 7.12 (t, 2H, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3) δ 11.0, 28.6, 52.0, 56.5, 113.6,
117.6, 125.7, 129.3, 140.8, 147.2, 167.2; IR (KBr) 3395, 2970, 2958,
1700, 1630, 1435, 1309, 1279, 1125, 747, 691 cm−1; HRMS (ESI)
calcd for C13H18NO2, 220.1338, found 220.1332.
Methyl 2-Methylene-3-(phenylamino)propanoate (1d). 27
mg, 57% yield: Brown color Oil; 1H NMR (400 MHz, CDCl3) δ 3.79
(s, 3H), 4.04 (s, 2H), 4.20 (brs, 1H), 5.80 (s, 1H), 6.27 (s, 1H), 6.60
(d, 2H, J = 7.6 Hz), 6.71 (t, 1H, J = 7.2 Hz), 7.17 (t, 2H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3) δ 44.8, 51.9, 113.0, 117.7, 126.0, 129.2,
137.2, 147.4, 166.9.; IR (KBr) 3413, 3052, 3022, 2951, 2848, 1714,
In conclusion, we have described a convenient and efficient
method for the formation of new ABH adducts using
arylhydroxylamines under mild reaction conditions. This
C
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The Journal of Organic Chemistry
Note
1634, 1603, 1506, 1437, 1327, 1263, 1152, 1101, 817, 751, 693 cm−1;
HRMS (ESI) calcd for C11H14NO2, 192.1025, found 192.1019.
3-Methylene-4-(phenylamino)pentan-2-one (1e). 32 mg, 69%
ASSOCIATED CONTENT
■
S
* Supporting Information
General information and copies of 1H, 13C NMR spectra for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
yield: Yellow Gum; H NMR (400 MHz, CDCl3) δ 1.34 (d, 3H, J =
6.8 Hz), 2.37 (s, 3H), 3.93 (brs, 1H), 4.47 (q, 1H, J = 6.4 Hz), 5.97 (s,
1H), 6.05 (s, 1H), 6.47 (d, 2H, J = 8.0 Hz), 6.67 (t, 1H, J = 7.2 Hz),
7.12 (t, 2H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 22.2, 26.7,
48.9, 113.3, 117.5, 125.0, 129.1, 146.6, 150.3, 199.9.; IR (KBr) 3389,
3051, 3020, 2925, 2857, 1663, 1602, 1504, 1389, 1281, 1131, 750, 693
cm−1; HRMS (ESI) calcd for C12H16NO, 190.1232, found 190.1227.
2-Methylene-3-(phenylamino)pentanal (1f). 25 mg, 54% yield:
Colorless gum;1H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J = 8.0
Hz), 1.63 (m, 1H), 1.78 (m, 1H), 3.94 (s, 1H), 4.20 (t, 1H, J = 6.4
Hz), 6.04 (s, 1H), 6.35 (s, 1H), 6.47 (d, 2H, J = 7.2 Hz), 6.66 (t, 1H, J
= 7.2 Hz), 7.11 (t, 2H, J = 8.4 Hz), 9.61 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.9, 28.3, 53.9, 113.5, 117.8, 129.4, 135.4, 147.0, 150.4,
194.6; IR (KBr) 3392, 3022, 2965, 2931, 2873, 1683, 1599, 1504,
1315, 1259, 1031, 751, 693 cm−1; HRMS (ESI) calcd for C12H16NO,
190.1232, found 190.1223.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rss1805@louisiana.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Louisiana Board of Regents for financial
support.
REFERENCES
■
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1
Colorless gum; H NMR (400 MHz, CDCl3) δ 1.40 (d, 3H, J = 6.8
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1H), 6.48 (d, 2H, J = 8.0 Hz), 6.69 (t, 1H, J = 7.6 Hz), 7.13 (t, 2H, J =
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3.6 Hz), 3.80 (d, 1H, J = 4.8 Hz), 4.10 (m, 1H), 5.94 (s, 1H), 5.95 (s,
1H), 6.55 (d, 2H, J = 7.6 Hz), 6.76 (t, 1H, J = 7.6 Hz), 7.18 (t, 2H, J =
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72% yield: Colorless gum; 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H,
J = 7.2 Hz), 1.40 (d, 3H, J = 6.8 Hz), 2.22 (s, 3H), 4.24 (q, 2H, J = 7.2
Hz), 4.36 (q, 1H, J = 6.4 Hz), 5.73 (s, 1H), 6.16 (s, 1H), 6.46 (d, 2H, J
= 7.2 Hz), 6.95 (d, 2H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ
14.4, 20.6, 22.2, 50.7, 60.9, 113.8, 124.5, 126.9, 129.8, 142.6, 144.6,
166.8.; IR (KBr) 3401, 2978, 2893, 1709, 1617, 1519, 1373, 1284,
1182, 1105, 808 cm−1; HRMS (ESI) calcd for C14H19NO2 (M + H+)
234.1494, found 234.1486.
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(e) Murru, S.; Gallo, A. A.; Srivastava, R. S. ACS Catal. 2011, 1, 29.
(f) Murru, S.; Gallo, A. A.; Srivastava, R. S. Eur. J. Org. Chem. 2011, 11,
2035.
Ethyl 3-(2-Bromophenylamino)-2-methylenebutanoate (3a).
1
58 mg, 78% yield: Brownish oil; H NMR (400 MHz, CDCl3) δ 1.33
(t, 3H, J = 6.8 Hz), 1.46 (d, 3H, J = 6.8 Hz), 4.25 (q, 2H, J = 6.8 Hz),
4.47 (t, 1H, J = 6.8 Hz), 4.58 (s, 1H), 5.70 (s, 1H), 6.19 (s, 1H), 6.45
(d, 1H, J = 8.0 Hz), 6.54 (t, 1H, J = 6.8 Hz), 7.10 (t, 1H, J = 7.2 Hz),
7.41 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 14.4, 22.2,
50.0, 61.0, 109.9, 112.7, 118.1, 124.4, 128.5, 132.5, 142.1, 143.5, 166.6;
IR (KBr) 3411, 3068, 2979, 2933, 1713, 1595, 1505, 1459, 1321, 1282,
1128, 1105, 1019, 954, 815, 742 cm−1; HRMS (ESI) calcd for
C13H17BrNO2 (M + H+), 298.0443, 300.0422, found 298.0436,
300.0418.
Ethyl 3-(2-Iodophenylamino)-2-methylenebutanoate (4a).
69 mg, 81% yield: Brownish oil; 1H NMR (400 MHz, CDCl3) δ
1.26 (t, 3H, J = 7.2 Hz), 1.40 (d, 3H, J = 6.0 Hz), 4.20 (q, 2H, J = 7.2
Hz), 4.36 (brs, 2H), 5.62 (s, 1H), 6.12 (s, 1H), 6.30−6.37 (m, 2H),
7.06 (t, 1H, J = 6.8 Hz), 7.58 (d, 1H, J = 8.0 Hz); 13C NMR (100
MHz, CDCl3) δ 13.2, 21.0, 49.1, 59.8, 84.4, 110.8, 117.8, 123.3, 128.3,
138.0, 141.0, 144.6, 165.4; IR (KBr) 3392, 3064, 2970, 2927, 1716,
1589, 1506, 1449, 1270, 1124, 1102, 1005, 742 cm−1; HRMS (ESI)
calcd for C13H17INO2, 346.0304, found 346.0307.
(13) (a) Johannsen, M.; Jorgensen, K. A. J. Org. Chem. 1994, 59, 214.
(b) Singh, S.; Nicholas, K. M. Syn. Commun. 2001, 31, 3087.
D
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(15) (a) Huang, J.-W.; Shi, M. Adv. Synth. Catal. 2003, 345, 953.
(b) Zhao, L.-J.; Song, He, H.; Shi, M.; Toy, P. H. J. Comb. Chem. 2004,
6, 680.
(16) (a) Cao, H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11.
(b) Kim, J. N.; Chung, Y. M.; Im, Y. J. Tetrahedron Lett. 2002, 43,
6209. (c) Chung, Y. M.; Lee, H. J.; Hwang, S. S.; Kim, J. N. Bull.
Korean Chem. Soc. 2001, 22, 799. (d) Kim, J. N.; Kim, H. S.; Gong, J.
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